CGD; Fatal granulomatosis of childhood; Chronic granulomatous disease of childhood; Progressive septic granulomatosis ... In chronic granulomatous disease (CGD), immune system cells called ... some types of bacteria and fungi. This disorder leads to long- ...
... Share this: Main Content Area Chronic Granulomatous Disease (CGD) Phagocyte (purple) engulfing Staphylococcus aureus bacteria (yellow). Credit: NIAID CGD is a genetic disorder in which white blood ...
... for This Condition autosomal recessive chronic granulomatous disease CGD granulomatous disease, chronic X-linked chronic granulomatous disease ... Network Patient Support and Advocacy Resources (6 links) CGD Society Immune Deficiency Foundation International Patient Organisation for ...
Chronic granulomatous disease (CGD) is a rare congenital immunodeficiency characterized by recurrent bacterial and fungal infections as well as granuloma formation. The manifestations of this disease can involve single or multiple organ systems. The lungs are the most commonly affected organ; however, lymphatic, hepatic, skeletal, gastrointestinal, genitourinary, head and neck, and central nervous system involvement have also been described. Most patients present with symptoms in their first few years of life. Due to the nonspecific manner in which patients present, the pediatric radiologist may be among the first to recognize the pattern of infection, inflammation, and granuloma formation leading to a diagnosis of CGD. The purpose of this paper is to review the imaging findings of CGD that can manifest throughout the body. (orig.)
Towbin, Alexander J. [Cincinnati Children' s Hospital Medical Center, Department of Radiology, Cincinnati, OH (United States); Chaves, Ian [Advocate Illinois Masonic Medical Center, Department of Internal Medicine, Chicago, IL (United States)
Chronic granulomatous disease (CGD) is a rare congenital immunodeficiency characterized by recurrent bacterial and fungal infections as well as granuloma formation. The manifestations of this disease can involve single or multiple organ systems. The lungs are the most commonly affected organ; however, lymphatic, hepatic, skeletal, gastrointestinal, genitourinary, head and neck, and central nervous system involvement have also been described. Most patients present with symptoms in their first few years of life. Due to the nonspecific manner in which patients present, the pediatric radiologist may be among the first to recognize the pattern of infection, inflammation, and granuloma formation leading to a diagnosis of CGD. The purpose of this paper is to review the imaging findings of CGD that can manifest throughout the body. (orig.)
Frifelt, J J; Schønheyder, Henrik Carl; Valerius, Niels Henrik;
A boy with chronic granulomatous disease (CGD) developed glomerulonephritis at the age of 12 years. The glomerulonephritis progressed to terminal uraemia at age 15 when maintenance haemodialysis was started. The clinical course was complicated by pulmonary aspergillosis and Pseudomonas septicaemia...
Chronic granulomatous disease (CGD) of childhood is a rare entity. The disease is characterized by recurrent infections with granuloma and abscess formation caused by an inherited defective neutrophil leukocyte function. The most common sites of involvements are the lungs, lymph nodes, skin, liver, spleen and bones. Rarely are other organs affected. Two children with CGD are presented. The children were cousins, the older with bone, lung and splenic involvement. The younger had circumferential thickening of the gastric antrum. (orig./GDG)
Jill King; Henriet, Stefanie S. V.; Adilia Warris
Patients with chronic granulomatous disease (CGD) have the highest life-time incidence of invasive aspergillosis and despite the availability of antifungal prophylaxis, infections by Aspergillus species remain the single most common infectious cause of death in CGD. Recent developments in curative treatment options, such as haematopoietic stem cell transplantation, will change the prevalence of infectious complications including invasive aspergillosis in CGD patients. However, invasive asperg...
Chronic granulomatous disease (CGD) is a fatal hereditary disease of childhood characterized by chronic recurrent bacterial infections. Involvement of the genitourinary tract is uncommon. We report a child with CGD with granulomatous cystitis demonstrated by both ultrasound and computed tomography. (orig.)
Full Text Available Patients with chronic granulomatous disease (CGD have the highest life-time incidence of invasive aspergillosis and despite the availability of antifungal prophylaxis, infections by Aspergillus species remain the single most common infectious cause of death in CGD. Recent developments in curative treatment options, such as haematopoietic stem cell transplantation, will change the prevalence of infectious complications including invasive aspergillosis in CGD patients. However, invasive aspergillosis in a previously healthy host is often the first presenting feature of this primary immunodeficiency. Recognizing the characteristic clinical presentation and understanding how to diagnose and treat invasive aspergillosis in CGD is of utmost relevance to improve clinical outcomes. Significant differences exist in fungal epidemiology, clinical signs and symptoms, and the usefulness of non-culture based diagnostic tools between the CGD host and neutropenic patients, reflecting underlying differences in the pathogenesis of invasive aspergillosis shaped by the nicotinamide adenine dinucleotide phosphate (NADPH-oxidase deficiency.
Al-Otaibi, Abdulnasir M; Al-Shahrani, Dayel A; Al-Idrissi, Eman M; Al-Abdely, Hail M
Mucormycosis is a rare opportunistic fungal infection that occurs in certain immunocompromised patients. We present 2 cases of invasive mucormycosis due to Rhizopus spp. in patients with chronic granulomatous disease (CGD) and discuss their clinical presentation, management challenges, and outcomes. PMID:27146621
Marked narrowing of the gastric antrum produced vomiting in a boy with chronic granulomatous disease; the antral stenosis resolved after five months of medical management. A review of the seven previously reported cases indicates that this uncommon lesion may be self-limited and should be given an exhaustive trial of nonsurgical therapy, in view of the high morbidity of surgery in these children. Antibiotics may speed resolution. (orig.)
Chronic Granulomatous Disease (CGD) is a primary immunodeficiency caused by abnormities in the NADPH Oxidase that is involved in the respiratory burst responsible for initiating the killing of microbes ingested by phagocytic cells. The hallmark of CGD is recurrent infection but the inflammatory complications can prove difficult to treat. New insights into the mechanisms responsible for the inflammatory complications have led to new therapies. The treatment of CGD colitis with an anti-tumour necrosis alpha agent has been shown to be successful but associated with significant infectious complications. Haematopoietic stem cell transplants offer the possibility of cure for those with ether a matched or unrelated donor transplant, with results of the latter improving significantly over recent years. Gene Therapy offers the promise of cure without the need for a transplant but better vectors are required. PMID:25264161
Barbara P. Barna
Full Text Available Use of nanomaterials in manufactured consumer products is a rapidly expanding industry and potential toxicities are just beginning to be explored. Combustion-generated multiwall carbon nanotubes (MWCNT or nanoparticles are ubiquitous in non-manufacturing environments and detectable in vapors from diesel fuel, methane, propane, and natural gas. In experimental animal models, carbon nanotubes have been shown to induce granulomas or other inflammatory changes. Evidence suggesting potential involvement of carbon nanomaterials in human granulomatous disease, has been gathered from analyses of dusts generated in the World Trade Center disaster combined with epidemiological data showing a subsequent increase in granulomatous disease of first responders. In this review we will discuss evidence for similarities in the pathophysiology of carbon nanotube-induced pulmonary disease in experimental animals with that of the human granulomatous disease, sarcoidosis.
Reichenbach, J.; Lopatin, U; Mahlaoui, N.; Beovic, B; Siler, U; Zbinden, R.; Seger, R.A.; Galmiche, L; Brousse, N; Kayal, S.; Güngör, T; Blanche, S; Holland, S M
BACKGROUND: Chronic granulomatous disease (CGD) is a rare inherited disease of the phagocyte NADPH oxidase system that causes defective production of toxic oxygen metabolites, impaired bacterial and fungal killing, and recurrent life-threatening infections, mostly by catalase-producing organisms. We report for the first time, to our knowledge, chronic infections with Actinomyces species in 10 patients with CGD. Actinomycosis is a chronic granulomatous condition that commonly manifests as cerv...
Falcone, E Liana; Petts, Jennifer R; Fasano, Mary Beth; Ford, Bradley; Nauseef, William M; Neves, João Farela; Simões, Maria João; Tierce, Millard L; de la Morena, M Teresa; Greenberg, David E; Zerbe, Christa S; Zelazny, Adrian M; Holland, Steven M
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by a defect in production of phagocyte-derived reactive oxygen species, which leads to recurrent infections with a characteristic group of pathogens not previously known to include methylotrophs. Methylotrophs are versatile environmental bacteria that can use single-carbon organic compounds as their sole source of energy; they rarely cause disease in immunocompetent persons. We have identified 12 infections with methylotrophs (5 reported here, 7 previously reported) in patients with CGD. Methylotrophs identified were Granulibacter bethesdensis (9 cases), Acidomonas methanolica (2 cases), and Methylobacterium lusitanum (1 case). Two patients in Europe died; the other 10, from North and Central America, recovered after prolonged courses of antimicrobial drug therapy and, for some, surgery. Methylotrophs are emerging as disease-causing organisms in patients with CGD. For all patients, sequencing of the 16S rRNA gene was required for correct diagnosis. Geographic origin of the methylotroph strain may affect clinical management and prognosis. PMID:26886412
Roos, D; de Boer, M
Patients with chronic granulomatous disease (CGD) suffer from recurrent, life-threatening bacterial and fungal infections of the skin, the airways, the lymph nodes, liver, brain and bones. Frequently found pathogens are Staphylococcus aureus, Aspergillus species, Klebsiella species, Burkholderia cepacia and Salmonella species. CGD is a rare (∼1:250 000 births) disease caused by mutations in any one of the five components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. This enzyme generates superoxide and is essential for intracellular killing of pathogens by phagocytes. Molecular diagnosis of CGD involves measuring NADPH oxidase activity in phagocytes, measuring protein expression of NADPH oxidase components and mutation analysis of genes encoding these components. Residual oxidase activity is important to know for estimation of the clinical course and the chance of survival of the patient. Mutation analysis is mandatory for genetic counselling and prenatal diagnosis. This review summarizes the different assays available for the diagnosis of CGD, the precautions to be taken for correct measurements, the flow diagram to be followed, the assays for confirmation of the diagnosis and the determinations for carrier detection and prenatal diagnosis. PMID:24016250
Pericardial involvement in chronic granulomatous disease (CGD) is very rare. We present two children with known CGD and pericardial effusions in whom no microbial cause for the effusions was found. (orig.)
Macedo, F.; McHugh, K; Goldblatt, D
Pediatr Radiol. 1999 Nov;29(11):820-2. Pericardial effusions in two boys with chronic granulomatous disease. Macedo F, McHugh K, Goldblatt D. SourceDepartment of Radiology, Hospital Geral de Santo Antonio, Porto, Portugal. Abstract Pericardial involvement in chronic granulomatous disease (CGD) is very rare. We present two children with known CGD and pericardial effusions in whom no microbial cause for the effusions was found. PMID: 10552060 [PubMed - indexed for MEDLINE
Ahmad M. Mansour; Al Dairy, Mays; Hamam, Rola; Hidayat, Ahmed A
1-year-old girl was admitted for fever of unknown origin. Funduscopy revealed juxtapapillary retinal inflammatory mass in one eye with a differential diagnosis of sarcoidosis, tuberculosis, retinoblastoma or metastatic disease. Retinal biopsy showed necrotizing granulomatous retinitis. Extensive workup and therapeutic trials failed to confirm the diagnosis of tuberculosis or sarcoidosis. Her 7-month brother and 4-year-old male cousin presented with nystagmus, poor vision, paravascular pigment...
De Ravin, Suk See; Naumann, Nora; Cowen, Edward W.; Friend, Julia; Hilligoss, Dianne; Marquesen, Martha; Balow, James E.; Karyl S. Barron; Turner, Maria L.; Gallin, John I.; Malech, Harry L.
Chronic granulomatous disease (CGD) is characterized by recurrent infections and granuloma formation. In addition, we have observed a number of diverse autoimmune conditions in our CGD population, suggesting that patients with CGD are at an elevated risk for development of autoimmune (AI) disorders. In this report, we describe antiphospholipid syndrome (aPL), recurrent pericardial effusion, juvenile idiopathic arthritis (JIA), IgA nephropathy, cutaneous lupus erythematosus, and autoimmune pul...
Kang, Elizabeth M.; Marciano, Betty E; DeRavin, SukSee; Zarember, Kol; Holland, Steven M.; Malech, Harry L.
Chronic Granulomatous Disease (CGD) still causes significant morbidity and mortality. The difficulty in considering high-risk yet curative treatments, such as allogeneic bone marrow transplantation, lies in the unpredictable courses of both CGD and bone marrow transplantation in different patients. Some CGD patients may have frequent infections and/or suffer from granulomatous or autoimmune disorders necessitating immunosuppressive therapy, but also experience long periods of relative good he...
Leiding, Jennifer W; FREEMAN, ALEXANDRA F.; Marciano, Beatriz E.; Anderson, Victoria L.; Uzel, Gulbu; Malech, Harry L.; DeRavin, SukSee; Wilks, David; Venkatesan, Aradhana M.; Zerbe, Christa S.; Heller, Theo; Holland, Steven M.
Liver abscesses in chronic granulomatous disease (CGD) are typically difficult to treat and often require surgery. We describe 9 X-linked CGD patients with staphylococcal liver abscesses refractory to conventional therapy successfully treated with corticosteroids and antibiotics. Corticosteroids may have a role in treatment of Staphylococcus aureus liver abscesses in CGD.
Shahindokht Bassiri-Jahromi; Aida Doostkam
Objective : Chronic granulomatous disease (CGD) is an inherited disorder of the Nicotinamide adenine dinucleotide phosphate reduced oxidase complex characterized by recurrent bacterial and fungal infections. Disseminated infection by combination of opportunistic agents is being increasingly reported in CGD patients. We presented in the retrospective review of medical records, the etiology, presentation, clinical characteristics the infections detected, predisposing condition and outcome of no...
SARWAR, Ghulam; de Malmanche, Theo; Rassam, Loui; Grainge, Christopher; Williams, Andrew; Arnold, David
We present a case of refractory pneumonia in an adult patient with underlying chronic granulomatous disease (CGD). Her lobectomy tissue grew B urkholderia cepacia and histopathology revealed diffuse severe pneumonic consolidation with suppurative/necrotizing granulomata. An initial attempt to find an underlying immune deficiency was unsuccessful. Following recurrent invasive infections, repeat immunological assessment revealed reduced neutrophil function, demonstrating skewed carrier status (...
Nikolaus Rieber; Andreas Hector; Taco Kuijpers; Dirk Roos; Dominik Hartl
Chronic granulomatous disease (CGD) is the most common inherited disorder of phagocytic functions, caused by genetic defects in the leukocyte nicotinamide dinucleotide phosphate (NADPH) oxidase. Consequently, CGD phagocytes are impaired in destroying phagocytosed microorganisms, rendering the patients susceptible to bacterial and fungal infections. Besides this immunodeficiency, CGD patients suffer from various autoinflammatory symptoms, such as granuloma formation in the skin or urinary trac...
Henriet, S.S.V.; Verweij, P.E.; Holland, S.M.; Warris, A.
Invasive fungal infections are a major threat for chronic granulomatous disease (CGD) patients. The present study provides a comprehensive overview of published invasive fungal infections in the CGD host through an extensive review of epidemiological, clinical, diagnostic and therapeutic data. In ad
Full Text Available Background: Chronic granulomatous disease (CGD is an inherited phagocytes defect, characterized by defects of NADPH-oxidase and inability of bacterial killing, which leads to recurrent life-threatening infections. Respiratory problems, which are the major cause of morbidity in CGD, usually result from recurrent severe infections; however, vigorous inflammatory response could also cause respiratory diseases.Case Presentation: Herein, an 11 year-old patient with CGD is presented who suffered from chronic cough and dyspnea for 7 years. Considering the results of chest X-ray, high-resolution computed tomography, and pulmonary function test, the diagnosis of interstitial lung disease was made.Conclusion: Early recognition of manifestations associated with CGD and appropriate treatment could prevent further complications and reduce morbidity and mortality in this group of patients.
Imanzade, Farid; Sayarri, Aliakbar; Tajik, Pantea
Chronic Granulomatous Disease (CGD) is an inherited primary immunodeficiency disease which increases the body’s susceptibility to infections caused by certain bacteria and fungi. CGD is a rare disease, caused by four genes, one type is 1X linked and the other three are “autosomal recessive”. Although clinical presentation is variable, but characteristic features are recurrent pneumonia, lymphadenitis, hepatic or other abscesses. Gastrointestinal tract symptoms are common in x-linked recessive...
Chronic granulomatous disease (CGD) is a condition of inability to deal with bacterial and fungal infections, due to defective respiratory burst in neutrophils leading to recurrent cutaneous and visceral infections. Usually a disease of childhood, but patients nowadays may survive to adulthood and diagnosis might be difficult if not considered. We describe a 20-year-old female with previously undiagnosed CGD, presenting with recurrent cutaneous and hepatic abscesses. (author)
Van De Veerdonk, Frank L.; Dinarello, Charles A.
Autophagy defects resulting in inflammation appear to be a key feature in the pathogenesis of Crohn colitis. An inflammatory colitis indistinguishable from Crohn disease is described in patients with chronic granulomatous disease (CGD). Patients with CGD have a mutated NADPH complex and are therefore deficient in reactive oxygen species (ROS) production; however, the underlying mechanism for the inflammatory colitis in CGD remained unknown. In a recent study, our group reported that NADPH-dep...
Vining, Mac; Sharma, Nirupma; Guill, Margaret
Chronic granulomatous disease (CGD) is a rare inherited disorder of neutrophil oxidative burst. In patients with CGD, phagocyte destruction of catalase-producing organisms is impaired, resulting in recurrent and potentially fatal infections. Burkholderia cepacia, a catalase-producing organism, is known to infect patients with dysfunctional immune systems. We report a case of a 3-year-old boy with this rare infection that unravelled the diagnosis of CGD. PMID:25103315
Greenberg, David E.; Shoffner, Adam R.; Zelazny, Adrian M.; Fenster, Michael E.; Zarember, Kol A.; Stock, Frida; Ding, Li; Marshall-Batty, Kimberly R.; Wasserman, Richard L.; Welch, David F.; Kanakabandi, Kishore; Sturdevant, Dan E.; Virtaneva, Kimmo; Porcella, Stephen F.; Murray, Patrick R.
Chronic granulomatous disease (CGD) is characterized by frequent infections, most of which are curable. Granulibacter bethesdensis is an emerging pathogen in patients with CGD that causes fever and necrotizing lymphadenitis. However, unlike typical CGD organisms, this organism can cause relapse after clinical quiescence. To better define whether infections were newly acquired or recrudesced, we use comparative bacterial genomic hybridization to characterize 11 isolates obtained from 5 patient...
We review our experience with Gallium scintigraphy in three children with chronic granulomatous disease, an entity characterized by defective neutrophils and recurrent infection. Radiogallium was found to localize in inflammation in these patients. Hematologic disordrs with specific structural of biochemical defects in their polymorphonuclear leukocytes may provide important information as to how these cells contribute to the accumulation of Gallium-67 in inflammation. (orig./MG)
Segal, B H; Veys, P.; Malech, H; Cowan, M J
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency with x-linked or autosomal recessive inheritance involving defects in genes encoding phox proteins which are the subunits of the phagocyte NADPH oxidase. This results in failure to produce superoxide anion and downstream antimicrobial oxidant metabolites and to activate antimicrobial proteases. Affected patients are susceptible to severe, life-threatening bacterial and fungal infections and excessive inflammation character...
Chronic nodular pneumonia is unusual in children. Three children are described who presented with diffuse nodular pulmonary disease and in whom lung biopsy demonstrated Aspergillus infection. One child was known to have chronic granulomatous disease of childhood (CGD) and further investigation demonstrated CGD in the other two patients as well. These cases indicate that Aspergillus infection and CGD should be considered in the differential diagnosis in children who present with chronic diffuse nodular pneumonia. (orig.)
J Merlijn van den Berg
Full Text Available CGD is an immunodeficiency caused by deletions or mutations in genes that encode subunits of the leukocyte NADPH oxidase complex. Normally, assembly of the NADPH oxidase complex in phagosomes of certain phagocytic cells leads to a "respiratory burst", essential for the clearance of phagocytosed micro-organisms. CGD patients lack this mechanism, which leads to life-threatening infections and granuloma formation. However, a clear picture of the clinical course of CGD is hampered by its low prevalence (approximately 1:250,000. Therefore, extensive clinical data from 429 European patients were collected and analyzed. Of these patients 351 were males and 78 were females. X-linked (XL CGD (gp91(phox deficient accounted for 67% of the cases, autosomal recessive (AR inheritance for 33%. AR-CGD was diagnosed later in life, and the mean survival time was significantly better in AR patients (49.6 years than in XL CGD (37.8 years, suggesting a milder disease course in AR patients. The disease manifested itself most frequently in the lungs (66% of patients, skin (53%, lymph nodes (50%, gastrointestinal tract (48% and liver (32%. The most frequently cultured micro-organisms per episode were Staphylococcus aureus (30%, Aspergillus spp. (26%, and Salmonella spp. (16%. Surprisingly, Pseudomonas spp. (2% and Burkholderia cepacia (<1% were found only sporadically. Lesions induced by inoculation with BCG occurred in 8% of the patients. Only 71% of the patients received antibiotic maintenance therapy, and 53% antifungal prophylaxis. 33% were treated with gamma-interferon. 24 patients (6% had received a stem cell transplantation. The most prominent reason of death was pneumonia and pulmonary abscess (18/84 cases, septicemia (16/84 and brain abscess (4/84. These data provide further insight in the clinical course of CGD in Europe and hopefully can help to increase awareness and optimize the treatment of these patients.
Imanzade, Farid; Sayarri, Aliakbar; Tajik, Pantea
Chronic Granulomatous Disease (CGD) is an inherited primary immunodeficiency disease which increases the body's susceptibility to infections caused by certain bacteria and fungi. CGD is a rare disease, caused by four genes, one type is 1X linked and the other three are "autosomal recessive". Although clinical presentation is variable, but characteristic features are recurrent pneumonia, lymphadenitis, hepatic or other abscesses. Gastrointestinal tract symptoms are common in x-linked recessive form of CGD. These include gastric and esophageal obstruction and inflammatory bowel disease. GI involvement including small and large intestines, the findings of luminal narrowing and the presence of granuloma can make it difficult to distinguish from Crohn's disease. On the other hands according to the literature ulcerative colitis is rarely reported in patients with CGD. Our case presented with ulcerative colitis with CGD. PMID:26328046
The contribution of computed tomography (CT), ultrasound (US), and nuclear medicine studies in the evaluation and management of seven patients with chronic granulatous disease was retrospectively reviewed. These modalities proved valuable in detecting sites of infection, particularly in the abdomen. Three patients had liver abscesses, two had suppurative retroperitoneal lymphadenopathy, one had empyema, and one hand a scrotal abscess. Furthermore, CT or US-guided percutaneous aspiration and/or drainage of infected material was successfully performed on three separate occasions in a single patient, obviating the need for surgery. The newer imaging modalities are useful in the prompt diagnosis and in some instances non-operative therapy of complications of chronic granulomatous disease. (orig.)
Ilad Alavi Darazam
Full Text Available Chronic granulomatous disease is an inherited defect in intracellular killing of ingested microorganisms characterized by recurrent life threatening bacterial and fungal infections including invasive aspergillosis in early childhood. We report a disseminated aspergillosis as the representative of adult onset chronic granulomatous disease without previous infection, with dramatic response to combination of antifungal and interferon therapy.
van de Veerdonk, Frank L; Dinarello, Charles A
Autophagy defects resulting in inflammation appear to be a key feature in the pathogenesis of Crohn colitis. An inflammatory colitis indistinguishable from Crohn disease is described in patients with chronic granulomatous disease (CGD). Patients with CGD have a mutated NADPH complex and are therefore deficient in reactive oxygen species (ROS) production; however, the underlying mechanism for the inflammatory colitis in CGD remained unknown. In a recent study, our group reported that NADPH-dependent ROS deficiency results in autophagic dysfunction that subsequently contributes to increased IL1B/interleukin 1β production. Mice deficient in the NADPH-complex component NCF4/p40phox, and CGD patients with a defect in NCF4 display minimal recruitment of LC3 to phagosomes in response to internalized bacteria and fungi. Human monocytes from patients with CGD with defective LC3 recruitment show increased IL1B production after LPS stimulation. Blocking IL1 protects NCF4-deficient mice from experimental colitis; importantly, improved clinical outcome in 2 CGD patients with colitis is also observed with IL1 blockade. Moreover, blocking IL1 restores defective autophagy in CGD mice and cells from patients with CGD. Thus, autophagic dysfunction underlies the pathogenesis of granulomatous colitis in CGD, and blocking IL1 can be used to treat CGD colitis. PMID:24879159
Full Text Available Introduction: Chronic granulomatous disease (CGD is an inherited disorder of phagocyte function . The defect of intracellular killing in phagocytes is the cause of recurrent pyogenic infection of patients . Clinical presentations and infections mostly occur during the first 2 year of life and early diagnosis of disease can prevent or decrease the rates of recurrence of infections and mortality.Case Report: This case report represents a 21 years old man who was admitted and underwent repeated surgery due to pyogenic infections for CGD. The second case was his 20 years old sister who was underwent surgery due to cervical abscess.Conclusion: This case report implies that CGD may rarely go undiagnosed until adulthood, so in adults who develop recurrent pyogenic infection, we should be suspicious to CGD, and Nitroblue tetrazolium test is the convenient method for diagnosis.
Greenberg, David E.; Goldberg, Joanna B.; Stock, Frida; Murray, Patrick R.; Holland, Steven M.; LiPuma, John J.
The epidemiology of Burkholderia infection in persons with chronic granulomatous disease is poorly understood. We used species-specific polymerase chain reaction–based assays and genotyping analyses to identify 32 strains representing 9 Burkholderia species among 50 isolates recovered from 18 patients with chronic granulomatous disease. We found that recurrent pulmonary infection with distinct Burkholderia strains is common in chronic granulomatous disease.
Full Text Available In the last 2 years chronic granulomatous disease (CGD was diagnosed in 5 children in the childrens medical center in Tehran. All of them had been referred because of severe recurrent infections. 4 patients were male, their parents being first cousins. Laboratory tests were normal for chemotaxis, serum complements and T-cells. NBT tests were severely abnormal. 2 patients were tested for cell antigen, the results being negative in both of them. 4 patients, in whom serum immunoglobulins were studied, 2 showed high immunoglobulin levels, one had normal values and one was immune deficient. The treatment consisted in intravenous antibiotics for a long period and surgical intervention where needed. The immunodeficient patient improved by ?-globulin injection.
Full Text Available Chronic granulomatous disease (CGD is the most common inherited disorder of phagocytic functions, caused by genetic defects in the leukocyte nicotinamide dinucleotide phosphate (NADPH oxidase. Consequently, CGD phagocytes are impaired in destroying phagocytosed microorganisms, rendering the patients susceptible to bacterial and fungal infections. Besides this immunodeficiency, CGD patients suffer from various autoinflammatory symptoms, such as granuloma formation in the skin or urinary tract and Crohn-like colitis. Owing to improved antimicrobial treatment strategies, the majority of CGD patients reaches adulthood, yet the autoinflammatory manifestations become more prominent by lack of causative treatment options. The underlying pathomechanisms driving hyperinflammatory reactions in CGD are poorly understood, but recent studies implicate reduced neutrophil apoptosis and efferocytosis, dysbalanced innate immune receptors, altered T-cell surface redox levels, induction of Th17 cells, the enzyme indolamine-2,3-dioxygenase (IDO, impaired Nrf2 activity, and inflammasome activation. Here we discuss immunological mechanisms of hyperinflammation and their potential therapeutic implications in CGD.
Ramesh, Manish; Resnick, Elena; Hui, Yiqun; Maglione, Paul J; Mehta, Harshna; Kattan, Jacob; Bouvier, Nicole M; LaBombardi, Vincent; Victor, Tanya R; Chaturvedi, Sudha; Cunningham-Rundles, Charlotte
Chronic Granulomatous Disease (CGD), caused by genetic defects in components of the phagocyte NADPH oxidase pathway, leads to recurrent life-threatening bacterial and invasive fungal infections. While a number of unique pathogens have been associated with this disease, the causative organisms may be difficult to identify. Here, we present a 24 year old male with known X-linked CGD who concurrently developed a cervical abscess and an abscess in the subcutaneous tissues of the right hip, both of which were surgically drained. Cultures failed to identify any organisms. He was treated empirically with ertapenem but the hip abscess recurred at the original site and in contiguous dependent areas in the posterior thigh and knee. A filamentous organism was observed microscopically, initially considered a contaminant, but on culture yielded a mold growth, identified as Phellinus tropicalis (synonym: Inonotus tropicalis) based on phenotypic and molecular methods. This is the third case report of human infection with P. tropicalis, all in subjects with CGD. The patient was treated with voriconazole with resolution of his symptoms. PMID:24310980
Salvator, Hélène; Mahlaoui, Nizar; Catherinot, Emilie; Rivaud, Elisabeth; Pilmis, Benoit; Borie, Raphael; Crestani, Bruno; Tcherakian, Colas; Suarez, Felipe; Dunogue, Bertrand; Gougerot-Pocidalo, Marie-Anne; Hurtado-Nedelec, Margarita; Dreyfus, Jean-François; Durieu, Isabelle; Fouyssac, Fanny; Hermine, Olivier; Lortholary, Olivier; Fischer, Alain; Couderc, Louis-Jean
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by failure of superoxide production in phagocytic cells. The disease is characterised by recurrent infections and inflammatory events, frequently affecting the lungs. Improvement of life expectancy now allows most patients to reach adulthood. We aimed to describe the pattern of pulmonary manifestations occurring during adulthood in CGD patients. This was a retrospective study of the French national cohort of adult patients (≥16 years old) with CGD. Medical data were obtained for 67 adult patients. Pulmonary manifestations affected two-thirds of adult patients. Their incidence was significantly higher than in childhood (mean annual rate 0.22 versus 0.07, p=0.01). Infectious risk persisted despite anti-infectious prophylaxis. Invasive fungal infections were frequent (0.11 per year per patient) and asymptomatic in 37% of the cases. They often required lung biopsy for diagnosis (10 out of 30). Noninfectious respiratory events concerned 28% of adult patients, frequently associated with a concomitant fungal infection (40%). They were more frequent in patients with the X-linked form of CGD. Immune-modulator therapies were required in most cases (70%). Respiratory manifestations are major complications of CGD in adulthood. Noninfectious pulmonary manifestations are as deleterious as infectious pneumonia. A specific respiratory monitoring is necessary. PMID:25614174
Deffert, Christine; Cachat, Julien; Krause, Karl-Heinz
Infection of humans with Mycobacterium tuberculosis remains frequent and may still lead to death. After primary infection, the immune system is often able to control M. tuberculosis infection over a prolonged latency period, but a decrease in immune function (from HIV to immunosenescence) leads to active disease. Available vaccines against tuberculosis are restricted to BCG, a live vaccine with an attenuated strain of M. bovis. Immunodeficiency may not only be associated with an increased risk of tuberculosis, but also with local or disseminated BCG infection. Genetic deficiency in the reactive oxygen species (ROS)-producing phagocyte NADPH oxidase NOX2 is called chronic granulomatous disease (CGD). CGD is among the most common primary immune deficiencies. Here we review our knowledge on the importance of NOX2-derived ROS in mycobacterial infection. A literature review suggests that human CGD patient frequently have an increased susceptibility to BCG and to M. tuberculosis. In vitro studies and experiments with CGD mice are incomplete and yielded - at least in part - contradictory results. Thus, although observations in human CGD patients leave little doubt about the role of NOX2 in the control of mycobacteria, further studies will be necessary to unequivocally define and understand the role of ROS. PMID:24916152
Two brothers with chronic granulomatous disease of childhood are presented with circumferential gastric antral thickening demonstrated on sonography. Barium studies and sonography correlated well in one brother. The antral changes can resolve quickly without antibiotic therapy. (orig.)
Pulmonary Aspergillus infection in patients with chronic granulomatous disease tends to involve the chest wall and consequently carries a high mortality rate. We report the findings of computed tomography (CT) and magnetic resonance imaging (MRI) in three such cases. We suggest that CT and MRI have a complementary role in evaluating chest wall invasion by pulmonary Aspergillus infection in chronic granulomatous disease. (orig./GDG)
Smith, D. M.; Walsh, C E; DeChatelet, L R; Waite, M.
The effect of the calcium ionophore A23187 on the release and metabolism of [3H]arachidonic acid was examined in normal polymorphonuclear leukocytes and those obtained from patients with chronic granulomatous disease. The ionophore A23187 which stimulates oxidative metabolism in normal polymorphonuclear leukocytes was ineffective in increasing oxidative metabolism (chemiluminescence) in polymorphonuclear leukocytes from patients with chronic granulomatous disease. However, the ionophore A2318...
Chronic granulomatous disease(CGD) is a group of genetic disorders characterized by recurrent pyogenic infections of the respiratory tract, skin, and soft tissue. The aim of this study is to describe the radiological findings of CGD. We retrospectively analyzed radiological findings of 11 patients of CGD, which were diagnosed by nitroblue tetrazolium test. We analyzed the pattern of pneumonia on chest radiograph in all infants. Three cases of chest CT and one case of digital subtraction angiography were performed. According to infant's symptom, abdominal ultrasonography(n = 8), abdominal CT(n = 5), simple bone radiography(n = 2), and brain CT (n = 1) were performed. Repeated infiltration(100%), mass-like consolidation(73%), hilar or mediastinal lymph node largement(64%), scattered nodules(55%), cavity formation(27%), and pleural effusion(27%) were found on the chest radiographs(n = 11) and CT(n = 3). On the abdominal imagings(n = 8), there were hepatosplenomegaly(n = 6), calcification in the liver(n = 2) and kidney(n = 1), hepatic granuloma(n = 1) and renal abscess(n = 1). Two patients had osteomyelitis. There were findings of meningitis on brain CT(n 1). We believe that the combinations of these radiological findings may suggest the diagnosis of CGD in patients with history of reccurent infection
Yavuz Köker m
Full Text Available Mutations in any of four known NADPH-oxidase components lead to CGD. X-linked CGD (X-CGD is caused by defects in CYBB, the gene that encodes gp91-phox. Autosomal recessive (AR CGD is caused by defects in the genes for p47 phox, p22-phox or p67-phox. The aim of this study was to screen the molecular defect in the fetus of an X-CGD carrier mother and postnatal confirmation of the results. In a family whose first-born child died from X-CGD, fetal DNA was obtained from an ongoing pregnancy by chorionic villus sampling (CVS. Direct sequencing was used to detect the previously identified CYBB gene mutation. The NADPH oxidase activity in the neutrophils from the carrier mother and from the newborn was analyzed by the DHR assay. Our studies predicted that the fetus in question was not affected by chronic granulomatous disease, which was demonstrated to be correct at birth. For prenatal screening in a pregnant X-CGD carrier, direct sequencing is a good method for detecting the mutation in the fetal DNA. Postnatal confirmation of results with the DHR assay is more practical than mutation screening to show whether the newborn have normal NADPH oxidase activity or does not.
Sarwar, Ghulam; de Malmanche, Theo; Rassam, Loui; Grainge, Christopher; Williams, Andrew; Arnold, David
We present a case of refractory pneumonia in an adult patient with underlying chronic granulomatous disease (CGD). Her lobectomy tissue grew B urkholderia cepacia and histopathology revealed diffuse severe pneumonic consolidation with suppurative/necrotizing granulomata. An initial attempt to find an underlying immune deficiency was unsuccessful. Following recurrent invasive infections, repeat immunological assessment revealed reduced neutrophil function, demonstrating skewed carrier status (lyonization) for X-linked CGD (only 3% normal cells). A pathogenic mutation in the CYBB gene was found on sequencing. CYBB gene encodes the gp91phox, a catalytic subunit of nicotinamide adenine dinucleotide phosphate-oxidase that produces reactive oxygen species in phagocytes. Lyonization increases with age, explaining the delayed clinical CGD. CGD is a rare neutrophil disorder that usually presents in early life with recurrent infections due to bacteria and fungi primarily involving lungs and skin. It is secondary to a defective NADPH oxidase system needed to kill intracellular organisms and activate the formation of neutrophil extracellular traps. PMID:26090111
Chiriaco, Maria; Salfa, Irene; Di Matteo, Gigliola; Rossi, Paolo; Finocchi, Andrea
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by defects in the genes encoding any of the NADPH oxidase components responsible for the respiratory burst of phagocytic leukocytes. CGD is a genetically heterogeneous disease with an X-linked recessive (XR-CGD) form caused by mutations in the CYBB gene encoding the gp91(phox) protein, and an autosomal recessive (AR-CGD) form caused by mutations in the CYBA, NCF1, NCF2, or NCF4 genes encoding p22(phox) , p47(phox) , p67(phox) , and p40(phox) , respectively. Patients suffering from this disease are susceptible to severe life-threatening bacterial and fungal infections and excessive inflammation characterized by granuloma formation in any organ, for instance, the gastrointestinal and genitourinary tract. An early diagnosis of and the prompt treatment for these conditions are crucial for an optimal outcome of affected patients. To prevent infections, CGD patients should receive lifelong antibiotics and antifungal prophylaxis. These two measures, as well as newer more effective antimicrobials, have significantly modified the natural history of CGD, resulting in a remarkable change in overall survival, which is now around 90%, reaching well into adulthood. At present, hematopoietic stem cell transplantation (HSCT) is the only definitive treatment that can cure CGD and reverse organ dysfunction. Timing, donor selection, and conditioning regimens remain the key points of this therapy. In recent years, gene therapy (GT) for XR-CGD has been proposed as an alternative to HSCT for CGD patients without a matched donor. After the failure of the first trials performed with retroviral vectors, some groups have proposed the use of regulated SIN-lentiviral vectors targeting gp91(phox) expression in myeloid cells to increase the safety and efficacy of the GT protocols. PMID:26680691
Milman, Nils; Byg, Keld-Erik
Blau syndrome is a rare hereditary granulomatous disease presenting in patients of young age with exanthema, granulomatous arthritis and uveitis. Genetic analysis has shown an autosomal dominant inheritance and a number of specific mutations on chromosome 16q in codon 334, of which the most predominant are R334W and R334Q. Blau syndrome exists in Caucasian, Asian and Afro-American families, and de novo mutations have been reported. The estimated minimum incidence in Denmark is 0.05 per 100,000 person-years. Blau syndrome has pathological, clinical and therapeutic features in common with sarcoidosis but rarely involves the lungs or other parenchymatous organs. Discrimination between Blau syndrome and early-onset sarcoidosis should rely on chromosome analysis. PMID:17069723
Full Text Available Objective : Chronic granulomatous disease (CGD is an inherited disorder of the Nicotinamide adenine dinucleotide phosphate reduced oxidase complex characterized by recurrent bacterial and fungal infections. Disseminated infection by combination of opportunistic agents is being increasingly reported in CGD patients. We presented in the retrospective review of medical records, the etiology, presentation, clinical characteristics the infections detected, predisposing condition and outcome of nocardiosis and actinomycosis involved in a group of pediatric patients diagnosed with CGD. Materials and Methods: The clinical presentation of CGD-related infections was reviewed retrospectively from the medical records of all 12 patients with CGD. We studied respectively 12 patients between 2001 and 2008, and we analyzed two pediatric patients with CGD who acquired Nocardia and Actinomyces infections, and their clinical and microbiological characteristics were described. The material for investigations was collected from scrapings, crusts, pus from subcutaneous abscesses or exudation from sinus tracts, surgical debridement, and biopsy specimens. The microbiological diagnosis was determined by biochemical tests, histology, microscopy, and culture of clinical samples. Results: The medical records of 12 diagnosed CGD patients with suspected nocardiosis or actinomycosis were reviewed. One patient was diagnosed with actinomycosis and one patient with nocardiosis. Patients consisted of seven males and five females with ranging ages of 3 to 18 years. Nocardiosis and actinomycosis isolated in the two patients were confirmed by histology and culture methods. Neutrophil oxidative burst were absent (NBT=0 in both patients. The most common manifestations of CGD due to fungal infections, actinomycosis, and nocardiosis were osteomyelitis (42.8%, pulmonary infections (28.6%, lymphadenopathy (14.3%, and skin involvement (14.3% during their illness. Conclusion: Nocardiosis
Shin, Kyung-Sue; Lee, Mu Suk
Chronic granulomatous disease (CGD) is a rare inherited disorder caused by defective nicotinamide adenine dinucleotide phosphate oxidase enzyme and characterized by recurrent bacterial and fungal infections. Although liver abscess is a common manifestation of CGD, its management in CGD patients is not well-defined. In addition, the generalized guidelines for treating liver abscesses do not necessarily apply to CGD patients. Corticosteroids are commonly used to control granulomatous complicati...
Ezekowitz, R A; Orkin, S H; Newburger, P E
We examined the potential of interferon gamma (IFN-gamma) to ameliorate the physiologic defect of chronic granulomatous disease (CGD) by studying its effects on CGD phagocyte superoxide generation, NADPH oxidase kinetics, cytochrome b559 content, and expression of X-CGD (the gene for the X-linked disease). Granulocytes and macrophages from three patients in two kindreds with "variant" X-linked CGD (i.e., with very low, but detectable, baseline superoxide-generating activity) responded to IFN-...
Pao, Maryland; Wiggs, Edythe A; Anastacio, Melissa M; Hyun, Jenny; DeCarlo, Ellen S; Miller, Judi T; Anderson, Victoria L; Malech, Harry L; Gallin, John I; Holland, Steven M
Chronic granulomatous disease is an inherited immunodeficiency in which phagocytes fail to generate superoxide and its metabolites, resulting in severe recurrent infections and frequent hospitalizations. Chronic illness and frequent hospitalizations can affect growth and development as well as social and educational opportunities. Since no data have been reported on cognitive functioning in patients with this illness, the authors sought to examine cognitive function in a group of patients with chronic granulomatous disease. A retrospective chart review of 26 patients seen and followed at the National Institutes of Health who had received cognitive testing at the request of parent or staff was performed. Demographic information including medical, psychiatric, and developmental histories was gathered. Six patients (23%) were found to have an IQ of 70 or below, indicative of cognitive deficits, and all of those patients had defects in the membrane-linked cytochrome b558. The prevalence of cognitive deficits in this selected population of chronic granulomatous disease patients was high. The determination of the true distribution of cognitive functioning in the general chronic granulomatous disease population is important, since cognitive deficits have implications for educational planning and potential therapies such as transplantation and gene therapy in children. PMID:15123849
Full Text Available Chronic Granulomatous Disease (CGD is a rare primary immunodeficiency disease. Although the most affected patients are diagnosed in childhood, there are several reports of the disease presenting in adult patients. Here we present a 40 years old man who was admitted in hospital due to respiratory symptoms and ground glass pattern in high resolution computed tomography of lung. Open lung biopsy revealed lymphocytic bronchiolitis. Because of past medical history of granulomatous lesion in lung and recurrent abscesses of skin and soft tissue, NBT test was conducted which its result revealed that the disorder was compatible with CGD and then it was confirmed by fluorescent cytometry.
Falcone, E. Liana; Hanses, Stephan; Stock, Frida; Holland, Steven M.; Zelazny, Adrian M.; Uzel, Gulbu
Streptococcus intermedius caused a liver abscess in a patient with chronic granulomatous disease (CGD). In contrast to typical staphylococcal abscesses in CGD, this abscess was liquid, easily drained, and resolved without surgery or steroids. This case and literature review provide insight into this organism’s pathogenesis, including in CGD.
Fernandez-Boyanapalli, Ruby; Frasch, S. Courtney; Riches, David W.H.; Vandivier, R. William; Henson, Peter M.; Bratton, Donna L.
Absence of a functional nicotinamide adenine dinucleotide phosphate (NADPH) oxidase predisposes chronic granulomatous disease (CGD) patients to infection, and also to unexplained, exaggerated inflammation. The impaired recognition and removal (efferocytosis) of apoptotic neutrophils by CGD macrophages may contribute to this effect. We hypothesized that peroxisome proliferator-activated receptor γ (PPARγ) activation during CGD inflammation is deficient, leading to altered macrophage programmin...
Matharu, Kabir; Zarember, Kol A.; Marciano, Beatriz E.; Kuhns, Douglas B; Spalding, Christine; Garofalo, Mary; DiMaggio, Thomas; Estwick, Tyra; Huang, Chiung-yu; Fink, Danielle; Priel, Debra L.; Fleisher, Thomas A.; Holland, Steven M.; Malech, Harry L.; Gallin, John I.
Chronic Granulomatous Disease (CGD) is an inherited defect in superoxide production leading to life-threatening infections, granulomas, and, possibly, abnormal immunoglobulin concentrations. We investigated whether factors controlling antibody production, such as B-cell activating factor (BAFF), were altered in CGD. CGD subjects had significantly increased mean (2.3-fold, p
Hipolito, E.; Faria, E.; Alves, A.; de Hoog, G.S.; Anjos, J.; Goncalves, T.; Morais, P.V.; Estevao, H.
In the present report, we describe the first case of a phaeohyphomycotic brain abscess in a 5-year-old boy with chronic granulomatous disease (CGD) admitted to hospital with seizures. A computed tomography (CT) scan revealed a cerebral abscess and the microbiology study showed a dark, melanin-pigmen
Gompels, M M; Bethune, C A; Jackson, G; Spickett, G P
A patient with chronic granulomatous disease who was being treated with steroids was diagnosed with a soft tissue Scedosporium apiospermum infection. Despite extensive treatment with antifungals progression to involve solid tissue (bone) occurred. Treatment required an HLA matched bone marrow transplant, which led to complete clearance of the fungal infection, although the patient subsequently died.
Fattahi, Fatemeh; Badalzadeh, Mohsen; Sedighipour, Leyla; Movahedi, Masoud; Fazlollahi, Mohammad Reza; Mansouri, Seyed Davood; Khotaei, Ghamar Taj; Bemanian, Mohammad Hassan; Behmanesh, Fatemeh; Hamidieh, Amir Ali; Bazargan, Nasrin; Mamishi, Setareh; Zandieh, Fariborz; Chavoshzadeh, Zahra; Mohammadzadeh, Iraj; Mahdaviani, Seyed Alireza; Tabatabaei, Seyed Ahmad; Kalantari, Najmeddin; Tajik, Shaghayegh; Maddah, Marzieh; Pourpak, Zahra; Moin, Mostafa
Chronic granulomatous disease (CGD) is a rare immunodeficiency due to a genetic defect in one of the NADPH-oxidase components. We studied CGD inheritance forms (autosomal recessive (AR) or X-linked (XL)) and AR-CGD subtypes in Iran. Clinical and functional investigations were conducted in 93 Iranian
Leiding, Jennifer W; Marciano, Beatriz E.; Zerbe, Christa S.; DeRavin, Suk See; Malech, Harry L.; Holland, Steven M.
Chronic granulomatous disease is a rare immunodeficiency due to defects in the phagocyte NADPH oxidase. The X-linked form (gp91phox deficiency) accounts for about 70 % of cases; autosomal recessive p47phox deficiency accounts for about 25 % of cases. We identified a 10 % incidence of diabetes in p47phox deficient CGD, but none in X-linked CGD. Renal and cardiovascular diseases were also higher in p47phox deficiency. p47phox deficient CGD has noninfectious morbidities distinct from those in X-...
Lewis, Colleen J.; Cobb, Brian A
Chronic granulomatous disease (CGD) is a primary immunodeficiency defined by mutations in the NADPH oxidase complex leading to reduced superoxide production, increased susceptibility to infection, chronic inflammation, and recurring abscess and granuloma formation. Here, we found that CGD mice were hyperresponsive to abscess-inducing T-cell-dependent carbohydrate antigens (glycoantigens) due to a ten-fold increase in NO production within APCs, which is known to be necessary for glycoantigen p...
Chronic granulomatous disease (CGD) is a rare disorder of phagocytes, predisposes patients to bacterial and fungal infections. The main purpose of this study was to determine the clinical, radiological, pathologicial features, outcome and response to treatment of children with CGD. Thirteen patients with CGD, who had been referred to National Research Institute of Tuberculosis and Lung Disease (NRITLD), were reviewed during a 6 year period (1999-2005). There were 10 (76%) male and 3(24%) fema...
Ramírez-Uribe, Nideshda; Hernández-Martínez, Claudia; López-Hernández, Gerardo; Pérez-García, Martín; Ramírez-Sánchez, Emmanuel; Espinosa-Padilla, Sara Elva; Yamazaki-Nakashimada, Marco; Olaya-Vargas, Alberto; Blancas-Galicia, Lizbeth
The incidence of chronic granulomatous disease in international reports is 1:250,000; however, in Mexico it is unknown. At the National Institute of Pediatrics of Mexico a project for facilitating the diagnosis of the disease was implemented by us in 2009. From the start of such project up to date 68 cases have been studied; 80% of those are X-linked forms (LX) and moreover, it has become noticeable the diagnosis at a younger age. The new challenge we are facing its to provide a successful treatment to those patients diagnosed with chronic granulomatous disease (CGD). We are reporting the case of a one-month old newborn patient diagnosed with CGD-LX that was successfully transplanted in Mexico. PMID:26943834
Full Text Available Abstract Background Invasive Aspergillus infections are frequently seen in immunocompromised patients but arthritis is a rare complication of Aspergillus infections in the absence of immune suppressive therapy, trauma or surgical intervention. Case presentation A 17 years old male patient with arthritis and patellar osteomyelitis of the left knee whose further investigations revealed chronic granulomatous disease as the underlying disease is followed. Aspergillus fumigatus was isolated from the synovial fluid and the tissue samples cultures. He was treated with Amphotericin B deoxicolate 0.7 mg/kg/day. Also surgical debridement was performed our patient. Amphotericin B nephrotoxicity developed and the therapy switched to itraconazole 400 mg/day. Itraconazole therapy were discontinued at the 6th month. He can perform all the activities of daily living including. Conclusion We think that, chronic granulomatous disease should be investigated in patients who have aspergillar arthritis and osteomyelitis.
O'Gorman, M R; Corrochano, V
Chronic granulomatous disease (CGD) is characterized by defective killing of intracellular microorganisms due to mutations in one of the four known components of the NADPH oxidase system. This system is responsible for the generation of superoxide and related antimicrobial oxidants. Diagnosis of CGD requires the demonstration of an abnormal oxidase system in the leukocytes of affected patients. Recently, several flow cytometry-based procedures which measure various reactive oxygen intermediat...
Chronic granulomatous disease (CGD) is caused by a congenital defect in phagocyte reduced nicotinamide dinucleotide phosphate (NADPH) oxidase production of superoxide and related species. It is characterized by recurrent life-threatening bacterial and fungal infections and tissue granuloma formation. We have created a mouse model of CGD by targeted disruption of p47phox, one of the genes in which mutations cause human CGD. Identical to the case in human CGD, leukocytes from p47phox-/- mice pr...
Meissner, F; Seger, R.A.; Moshous, D.; Fischer, A; Reichenbach, J.; Zychlinsky, A
Chronic granulomatous disease (CGD) is an inherited disorder characterized by recurrent infections and deregulated inflammatory responses. CGD is caused by mutations in subunits of the NADPH oxidase, an enzyme that generates reactive oxygen species in phagocytes. To elucidate the contribution of the proinflammatory protease caspase-1 to aberrant inflammatory reactions in CGD, we analyzed cells isolated from patients with defects in the phagocyte oxidase subunits p22phox, p47phox or gp91phox. ...
Saito, Sachiko; Oda, Arata; Kasai, Masashi; Minami, Kisei; Nagumo, Haruo; Shiohara, Masaaki; Ogiso, Yoshifumi; Kawakami, Yoshiyuki
Chronic granulomatous disease (CGD) often presents with infectious illness, such as repeating bacterial and fungal infections, due to the inability to generate superoxide, which would destroy certain infectious pathogens, and is usually diagnosed in childhood. We describe a CGD case diagnosed in neonatal period, who initially presented with invasive aspergillosis. Neonatal invasive pulmonary aspergillosis is very rare and, to the best of our knowledge, this might be the youngest case in Japan. PMID:24674387
Newburger, P E; Kruskall, M S; Rappeport, J M; Robinson, S H; Chovaniec, M E; Cohen, H J
Chronic granulomatous disease (CGD), an often fatal syndrome of recurrent infections results from the inability of patients' peripheral blood phagocytic leukocytes to generate superoxide despite otherwise normal phagocytic functions such as ingestion and degranulation. Circulating granulocytes and monocytes are the progeny of bone marrow progenitor cells, colony-forming units in culture. We compared the function of cells grown in two different in vitro cuture systems from the bone marrow of a...
Baehner, R. L.; Kunkel, L M; Monaco, A P; Haines, J. L.; Conneally, P M; Palmer, C.; Heerema, N; Orkin, S H
Chronic granulomatous disease (CGD) is a disorder of phagocytes that is usually inherited as an X chromosome-linked trait. Previous family studies suggested that the CGD locus resides on the distal short arm (Xp22-Xpter). Using cloned, polymorphic DNA probes we have performed a linkage analysis within CGD families that suggests a more proximal location (Xp21). In addition, the CGD locus is proximal to the Duchenne muscular dystrophy locus and lies within a broad region of Xp in which recombin...
Garcia-de-Eulate, R. (Reyes); Hussain, N.; Heller, T.; Kleiner, D.; Malech, H; Holland, S.; Choyke, P L
We describe the spectrum of radiologic appearances of hepatic abscesses in patients with chronic granulomatous disease (CGD), a hereditary immunodeficiency presenting in childhood that occurs at a rate of 1 in 200,000-250,000 live births and predisposes patients to infection with catalase-positive organisms. CONCLUSION: Hepatic abscesses in patients with CGD show an atypical radiologic appearance compared with sporadic hepatic abscesses, ...
Gallin, John I.; Zarember, Kol
Chronic Granulomatous Disease (CGD) is a rare disorder caused by mutations in the NADPH oxidase. The CGD phenotype includes granuloma formation and susceptibility to infection with microorganisms including Aspergillus. The immune adjuvant interferon-γ and the antifungal agent itraconazole have reduced the incidence of infections in CGD. Studies using CGD phagocytes have shown that reactive oxygen species (ROS), products of the NAPDH oxidase, are critical for killing Aspergillus hyphae. But de...
Jürgens, Birgit; Fuchs, Dietmar; Reichenbach, Janine; Heitger, Andreas
Chronic granulomatous disease (CGD) is characterized by a disability to produce reactive oxygen intermediates (ROI) caused by a defect of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. A hyperinflammatory response to immune activation has been reported to contribute to the pathology of CGD. The tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) is considered critical for regulating immune responses and suppression of inflammation. IDO is generally believe...
Mohammadpour, Masoud; MAMISHI, Setareh; Oaji, Mahsa; POURPAK, Zahra; Parvaneh, Nima
Background Chronic granulomatous disease (CGD) is an immunodeficiency affecting phagocytic leukocytes. Defective respiratory burst mechanism renders the affected patients to be susceptible to catalase positive microorganisms. With the great successes in antibacterial prophylaxis and therapy, fungal infections are a persistent problem. Invasive aspergillosis is the most important cause of mortality in CGD. Case Presentation We describe a nine year-old boy with CGD who presented with aspergillu...
Yaman, Aytaç; Kuloğlu, Zarife; Doğu, Figen; İkincioğulları, Aydan; Ensari, Arzu; Çiftçi, Ergin; Kansu, Aydan
Chronic granulomatous disease (CGD) is an autosomal recessive or X-linked disorder caused by NADPH oxidase deficiency leading to an impaired ability of reactive superoxide anion and metabolite formation and recurring severe bacterial and fungal infections, with a high mortality rate. Diarrhea, colitis, ileus, perirectal abscess formation and anal fissures are reported gastrointestinal findings in these patients. We report a case of intractable colitis associated with CGD in a young girl. PMID:26690604
Matsuura, Ryoji; Kobayashi, Masao; Usui, Tomofusa
The activation of NADPH oxidase on the plasma membranes of polymorphonuclear leukocytes (PMNL) follows the change of membrane potential. It is thought that the activation of NADPH oxidase is disturbed in the PMNL of patients with chronic granulomatous disease (CGD). The change of membrane potential was examined in the PMNL of normal subjects and patients with CGD, with a lipophilic probe, di-O-C5(3). There was a disturbance in phorbol myristate acetate (PMA) and formyl-methionyl-leucyl-phenyl...
The median age at the time of study was 14.5 years old (1-56 years. The median onset age of symptoms was 5 months (1 month – 13.75 years, and that of diagnostic age was 5 years (2 months- 54.1 years, with a diagnostic delay of 33 months, on average. Seven patients were presented with acute diarrhea, 3 with oral candidiasis, and 2 with liver abscesses as the first chief complaints. Twenty-four cases (42.1% had been complicated by gastrointestinal manifestations during their course of the disease. Of those, 12 cases (21.1% had diarrhea, 7 (12.3% oral candidiasis, 5 (8.8% hepatitis, 4 (7.0% hepatic abscess, and 2 cases (3.5% gastric outlet obstruction. Also, failure to thrive was detected in 6 patients (10.5%. Four patients died (7%. CGD should be excluded in any patient with gastrointestinal manifestations especially chronic diarrhea, hepatic abscess, and gastric outlet obstruction.
Jakobsen, Marianne Antonius; Pedersen, Svend Stenvang; Barington, Torben
AIMS: Chronic granulomatous disease (CGD) is a rare inherited disorder caused by mutations in the subunits of the NADPH oxidase complex, leaving phagocytes unable to produce superoxide and thereby unable to kill invading microorganisms. A subgroup of CGD patients (approximately 20%) is reported to...... dinucleotide repeat was set up and used to identify a novel mutation in exon 7 of NCF-1 in a patient with autosomal recessive CGD, explaining the disease by changing a UGG codon to a premature UGA STOP codon. CONCLUSION: The method is generally applicable for the detection of NCF-1 mutations in patients with...... suspected CGD....
Higgins Bernard; Gilmour Kimberley; Aldridge Catherine; Mclean-Tooke Andrew PC; Hudson Mark; Spickett Gavin P
Abstract Background Chronic granulomatous disease (CGD) is an inherited disorder of phagocytic cells caused by an inability to generate active microbicidal oxygen species required kill certain types of fungi and bacteria. This leads to recurrent life-threatening bacterial and fungal infections with tissue granuloma formation. Case presentation We describe a case of X-linked Chronic granulomatous disease (CGD) diagnosed in an 18-year-old male. He initially presented with granulomatous disease ...
Gutierrez, Maria J.; McSherry, George D.; Ishmael, Faoud T.; Horwitz, Alexandra A.; Gustavo Nino
Chronic granulomatous disease (CGD) is characterized by inherited immune defects resulting from mutations in the NADPH oxidase complex genes. The X-linked type of CGD is caused by defects in the CYBB gene that encodes gp91-phox, a fundamental component of the NADPH oxidase complex. This mutation originates the most common and severe form of CGD, which typically has absence of NADPH oxidase function and aggressive multisystemic infections. We present the case of a 9-year-old child with a rare ...
Arai, Takashi; Oh-ishi, Tsutomu; Yamamoto, Hideaki; Nunoi, Hiroyuki; Kamizono, Junji; Uehara, Masahiko; Kubota, Takeo; Sakurai, Takuya; Kizaki, Takako; Ohno, Hideki
Mutations in genes for any of the six subunits of NADPH oxidase cause chronic granulomatous disease (CGD), but almost 2/3 of CGD cases are caused by mutations in the X-linked CYBB gene, also known as NAD (P) H oxidase 2. Approximately 260 patients with CGD have been reported in Japan, of whom 92 were shown to have mutations of the CYBB gene and 16 to have chromosomal deletions. However, there has been very little detailed analysis of the range of the deletion or close understanding of the dis...
Intan Hakimah Ismail
Full Text Available The awareness of primary immunodeficiency (PID in Malaysia is still not forthcoming. Certain practical issues such as lack of clinical immunologists and specialized laboratory diagnostic facilities remain to be addressed. However, great efforts taken by passionate clinicians and scientists in the immunology networking have ascertained some prevalence. Despite the limitation, all suspected cases of PID are being properly investigated and competently managed. In this case report we highlighted the obstacles we faced in managing PID patients, particularly preparing for bone marrow transplant. This is the first transplanted case of chronic granulomatous disease in Malaysia, which emphasizes the importance of collaborative work to ensure further morbidities or mortalities are prevented.
Ismail, Intan Hakimah; Jamli, Faizah Mohamed; Othman, Ida Shahnaz; Noh, Lokman Mohd; Abdul Latiff, Amir Hamzah
The awareness of primary immunodeficiency (PID) in Malaysia is still not forthcoming. Certain practical issues such as lack of clinical immunologists and specialized laboratory diagnostic facilities remain to be addressed. However, great efforts taken by passionate clinicians and scientists in the immunology networking have ascertained some prevalence. Despite the limitation, all suspected cases of PID are being properly investigated and competently managed. In this case report we highlighted the obstacles we faced in managing PID patients, particularly preparing for bone marrow transplant. This is the first transplanted case of chronic granulomatous disease in Malaysia, which emphasizes the importance of collaborative work to ensure further morbidities or mortalities are prevented. PMID:27417247
Full Text Available Francisella philomiragia is a rare and opportunistic pathogen capable of producing invasive infection in patients with compromised neutrophil function and in patients that have survived a near-drowning. A case of F philomiragia adenitis and lung nodules, refractory to cephalosporin therapy, is reported in a 10-year-old boy with chronic granulomatous disease following a facial abrasion from a saltwater crab. To the authors' knowledge, this is the first Canadian clinical isolate to be reported. Genus and species identification was confirmed via 16S ribosomal RNA sequence analysis. A literature review revealed three groups at risk of F philomiragia infection: young patients with chronic granulomatous disease; adults with hematogenous malignancy; and near-drowning patients. Pneumonia, fever without an apparent source and sepsis are the main clinical presentations. Invasive procedures may be required to isolate this organism and ensure appropriate antimicrobial therapy. Limited awareness of F philomiragia has led to delayed identification, patient death and misidentification as Francisella tularensis - a biosafety level three pathogen and potential bioterrorism agent.
Uzzan, Mathieu; Ko, Huaibin M; Mehandru, Saurabh; Cunningham-Rundles, Charlotte
Common variable immune deficiency (CVID) and chronic granulomatous disease (CGD) are two of the well-characterized primary immune deficiencies with distinct pathologic defects. While CVID is predominantly a disorder of the adaptive immune system, in CGD, innate immunity is impaired. In both syndromes, the clinical manifestations include an increased susceptibility to infections and a number of non-infectious, inflammatory conditions including systemic autoimmunity, as well as organ-specific pathology. Among the organ-associated disorders, gastrointestinal (GI) manifestations are one of the most intractable. As such, non-infectious inflammatory disorders of the GI tract are clinically challenging as they have protean manifestations, often resembling inflammatory bowel disease (IBD) or celiac disease, are notoriously difficult to treat, and hence are associated with significant morbidity and mortality. Therefore, assessing the pathogenesis and defining appropriate therapeutic approaches for GI disease in patients with CVID and CGD is imperative. PMID:26951230
Full Text Available Chronic granulomatous disease (CGD is a primary immune deficiency disorder of the phagocytes. In this disorder, phagocytic cells (polymorphonuclear leukocytes and monocytes cannot produce active oxygen metabolites, and therefore, cannot destroy the ingested intracellular bacteria. Clinically, patients with CGD usually have recurrent bacterial and fungal infections causing abscess and granuloma formation in the skin, lymph nodes and visceral organs.In this report, we present a boy from Libya with a rare autosomal recessive trait of CGD (defect of p22-phox who has chronic lung disease following multiple severe pneumonia attacks. The case we present suffered from bloody diarrhea since the third month of his life. He also had recurrent episodes of fever, and later, developed persistent cervical lymphadenitis and failure to gain weight. CGD is a very rare condition worldwide. It is also not recognized here in Libya, and usually not in the list of differential diagnosis for chronic pulmonary infections. We advise that pediatricians and general practitioners who treat chronic cases of lung diseases (with or without chronic diarrhea should consider primary immunodeficiency disorders in the hope that early diagnosis and treatment may prevent chronic complications especially of the respiratory tract. Furthermore, we state that, to the best of our knowledge, this is the first documented case of CGD from Libya.
Kepenekli, Eda; Soysal, Ahmet; Kuzdan, Canan; Ermerak, Nezih Onur; Yüksel, Mustafa; Bakır, Mustafa
Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Among primary immunodefiencies, chronic granulomatous disease (CGD) has the highest prevalence of invasive fungal diseases. Voriconazole is recommended for the primary treatment of invasive aspergillosis in most patients. In patients whose aspergillosis is refractory to voriconazole, therapeutic options include changing class of antifungal, for example using an amphotericin B formulation, an...
Chronic granulomatous disease (CGD) is a rare inherited condition rendering neutrophils incapable of killing invading pathogens. This condition is due to the failure of a multicomponent microbicidal oxidase that normally yields a low-midpoint-potential b cytochrome (cytochrome b245). Although defects in the X chromosome-linked cytochrome account for the majority of CGD patients, as many as 30% of CGD cases are due to an autosomal recessive disease. Of these, >90% have been shown to be defective in the synthesis of a 47-kDa cytosolic component of the oxidase. The authors demonstrate here in three unrelated cases of autosomal recessive CGD that the identical underlying molecular lesion is a dinucleotide deletion at a GTGT tandem repeat, corresponding to the acceptor site of the first intron - exon junction. Slippage of the DNA duplex at this site may contribute to the high frequency of defects in this gene
Shin, Kyung-Sue; Lee, Mu Suk
Chronic granulomatous disease (CGD) is a rare inherited disorder caused by defective nicotinamide adenine dinucleotide phosphate oxidase enzyme and characterized by recurrent bacterial and fungal infections. Although liver abscess is a common manifestation of CGD, its management in CGD patients is not well-defined. In addition, the generalized guidelines for treating liver abscesses do not necessarily apply to CGD patients. Corticosteroids are commonly used to control granulomatous complications, such as inflammatory gastrointestinal and genitourinary lesions, in patients with CGD, Corticosteroids have also been used in combination with antimicrobials to treat refractory infections in patients with CGD. Because corticosteroids are capable of suppressing symptomatic inflammation, all potential infections must be adequately controlled prior to corticosteroid initiation. We report 3 typical CGD cases with liver abscesses refractory to conventional treatments that were successfully treated with the concomitant use of corticosteroid and antimicrobials. It remains unclear whether corticosteroid therapy is required for liver abscesses in CGD refractory to conventional treatments. However, based on our observations, use of corticosteroids in combination with optimal antimicrobials should be considered for refractory liver abscesses in CGD. PMID:27186231
Katz, P.; Simone, C B; Henkart, P A; Fauci, A S
The present study characterized the antibody-dependent cellular cytoxicity (ADCC) of leukocyte effector cells (neutrophils, lymphocytes, and monocytes) from normal subjects and from chronic granulomatous disease (CGD) patients. CGD phagocytic cells (neutrophils and monocytes) had depressed ADCC activity against antibody-coated human erythrocyte (HRBC) targets in suspension cultures indicative of abnormal intracellular postphagocytic killing. However, when phagocytosis was prevented by using a...
G. Isman-Nelkenbaum; B. Wolach; R. Gavrieli; D. Roos; E. Sprecher; E. Bash; A. Gat; H. Sprecher; R. Ben-Ami; T. Zeeli
Chronic granulomatous disease (CGD) is a rare congenital immunodeficiency that affects 1 : 250 000 of the population, which is characterized by recurrent bacterial and fungal infections and by granuloma formation. We investigated a 61-year-old man presented with a 20-year history of a relapsing skin
Full Text Available In chronic granulomatous disease (CGD patients, esophageal stricture is a rare complication and the treatment of choice is still controversial. There are few reports of successful therapy with antibiotics, corticosteroids, multiple balloon dilatations or their combination.We report a 3-three-year-old Iranian boy with recurrent esophageal obstruction due to CGD. The patient transiently responded to dilatation in one occasion and at another time to short term steroid therapy. We observed an excellent response when long term and high dose of corticosteroid was administered. It showed that a long term and high dose steroid therapy is more effective than a short term in a patient with CGD and esophageal stricture.
Takeuchi, Yasuo; Takeuchi, Emiko; Ishida, Takashi; Onodera, Masafumi; Nakauchi, Hiromitsu; Otsu, Makoto
Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by defective microbial killing in phagocytes. Long-term prognosis for CGD patients is generally poor, highlighting the need to develop minimally toxic, curative therapeutic approaches. We here describe the establishment of a mouse model in which X-linked CGD can be cured by allogeneic bone marrow transplantation. Using a combination of non-myeloablative-dose total body irradiation and a single injection of anti-CD40 ligand monoclonal antibody, transplantation of whole bone marrow cells achieved long-lasting mixed chimerism in X-linked CGD mice in a haploidentical transplantation setting. Stable mixed chimerism was maintained for up to 1 year even at a low range (CGD models. These results warrant future development of a simplified allogeneic hematopoietic cell transplantation regimen that would benefit CGD patients by allowing the use of haploidentical donor grafts without serious concerns of severe treatment-related toxicity. PMID:25921405
Shigemura, T; Nakazawa, Y; Amano, Y; Sudo, A; Watanabe, M; Kobayashi, M; Kobayashi, N; Koike, K; Agematsu, K; Nishimura, K
Chronic granulomatous disease (CGD), a primary immunodeficiency caused by impaired phagocyte killing of intracellular pathogens, is characterized by recurrent, life-threatening, bacterial and fungal infections. As a result of improvements in microbiologic culture and identification techniques, a number of unique filamentous fungi have been reported as significant pathogens in patients with CGD. We report a case of subcutaneous basidiomycete Phellinus mori infection in a patient with CGD. To the best of our knowledge, this is the first reported case of human infection by this fungus. The causative fungus was identified on the basis of its morphological characteristics and nucleotide sequence on the internal transcribed spacer region of the ribosomal RNA gene. This is the fifth case report of filamentous basidiomycetes infecting a patient with CGD; all of these cases have been caused by Phellinus species. We highlight the importance of recognizing filamentous basidiomycetes Phellinus species as possible agents of non-Aspergillus fungal infections in patients with CGD. PMID:25600930
Watkins Casey E
Full Text Available Abstract Chronic Granulomatous Disease (CGD, a disorder of the NADPH oxidase system, results in phagocyte functional defects and subsequent infections with bacterial and fungal pathogens (such as Aspergillus species and Candida albicans. Deletions and missense, frameshift, or nonsense mutations in the gp91phox gene (also termed CYBB, located in the Xp21.1 region of the X chromosome, are associated with the most common form of CGD. When larger X-chromosomal deletions occur, including the XK gene deletion, a so-called "Contiguous Gene Deletion Syndrome" may result. The contiguous gene deletion syndrome is known to associate the Kell phenotype/McLeod syndrome with diseases such as X-linked chronic granulomatous disease, Duchenne muscular dystrophy, and X-linked retinitis pigmentosa. These patients are often complicated and management requires special attention to the various facets of the syndrome.
Full Text Available Chronic granulomatous disease (CGD is a rare disorder of phagocytes, predisposes patients to bacterial and fungal infections. The main purpose of this study was to determine the clinical, radiological, pathologicial features, outcome and response to treatment of children with CGD. Thirteen patients with CGD, who had been referred to National Research Institute of Tuberculosis and Lung Disease (NRITLD, were reviewed during a 6 year period (1999-2005. There were 10 (76% male and 3(24% female cases. The median age of the patients was 9 years (1 month-12 years.Family history of CGD was reported by 7 patients. The median diagnostic age was 8 years, with a diagnostic delay of 4.5 years. The most common manifestations of CGD were pulmonary infections and skin involvement, followed by generalized lymphadenopathy. The most common radiological findings were multiple lymphadenopathy in mediastinal region and fibrotic changes in lung fields. Two patients died of pulmonary infections. Based on the results of this research, immunologic evaluations especially evaluation for CGD is highly recommended in children suffering from recurrent pulmonary infections, cutaneous or hepatic abscesses, or infections caused by uncommon pathogens. Early diagnosis and prophylactic treatment both, prevent further development of the lesions, irreversible complications and decreasing mortality and morbidity rates in children suffering from CGD.
Chu, Jessica; Song, Helen H.; Zarember, Kol A.; Mills, Teresa A.; Gallin, John I.
Granulibacter bethesdensis is a Gram-negative pathogen in patients with Chronic Granulomatous Disease (CGD), a deficiency in the phagocyte NADPH oxidase. Repeated isolation of genetically identical strains from the same patient over years, and prolonged waxing and waning seropositivity in some subjects, raises the possibility of long-term persistence. G. bethesdensis resists killing by serum, CGD polymorphonuclear leukocytes (PMN), and antimicrobial peptides, indicating resistance to non-oxid...
Merling, Randall K; Sweeney, Colin L; Chu, Jessica; Bodansky, Aaron; Choi, Uimook; Priel, Debra Long; Kuhns, Douglas B; WANG, HONGMEI; Vasilevsky, Sam; De Ravin, Suk See; Winkler, Thomas; Dunbar, Cynthia E; Zou, Jizhong; Zarember, Kol A.; Gallin, John I.
There are five genetic forms of chronic granulomatous disease (CGD), resulting from mutations in any of five subunits of phagocyte oxidase, an enzyme complex in neutrophils, monocytes, and macrophages that produces microbicidal reactive oxygen species. We generated induced pluripotent stem cells (iPSCs) from peripheral blood CD34+ hematopoietic stem cells of patients with each of five CGD genotypes. We used zinc finger nuclease (ZFN) targeting the AAVS1 safe harbor site together with CGD geno...
Van De Veerdonk, Frank L.; Smeekens, Sanne P.; Joosten, Leo A. B.; Kullberg, Bart Jan; Dinarello, Charles A.; van der Meer, Jos W.M.; Netea, Mihai G.
Humans with chronic granulomatous diseases (CGDs) due to mutations in p47-phox have defective NADPH activity and thus cannot generate NADPH-dependent reactive oxygen species (ROS). The role of ROS in inflammation is controversial; some in vitro studies suggest that ROS are crucial for secretion of IL-1β via inflammasome activation, whereas mice defective for ROS and patients with CGD have a proinflammatory phenotype. In this study, we evaluated activation of the IL-1β inflammasome in cells fr...
Agudelo-Flórez P.; López J.A.; Redher J.; Carneiro-Sampaio M.M.S.; Costa-Carvalho B.T.; Grumach A.S.; Condino-Neto A.
Chronic granulomatous disease (CGD) is an inherited disorder of the innate immune system characterized by a defective oxidative burst of phagocytes and subsequent impairment of their microbicidal activity. Mutations in one of the NADPH-oxidase components affect gene expression or function of this system, leading to the phenotype of CGD. Defects in gp91-phox lead to X-linked CGD, responsible for approximately 70% of CGD cases. Investigation of the highly heterogeneous genotype of CGD patients ...
Jakobsen, M A; Katzenstein, Terese Lea; Valerius, Niels Henrik; Roos, D; Fisker, N; Mogensen, T H; Jensen, P Ø; Barington, T
Chronic granulomatous disease (CGD) is a rare inherited disorder of the innate immune system caused by a defect in NADPH oxidase, leaving the granulocytes unable to kill invading microorganisms. CGD is caused by mutation in one of the five components gp91phox, p22phox, p47phox, p67phox and p40phox......, encoded by the X-linked CYBB gene and the autosomal CYBA, NCF1, NCF2 and NCF4 genes respectively. We have collected samples from all Danish patients with known CGD followed in the clinic or newly diagnosed during a 5-year period, a cohort of 27 patients, and characterized them genetically. The cohort...... includes 10 male patients with X-linked CGD and one female with extremely lyonized expression of a defective CYBB allele. Six patients had mutation in CYBA. Seven of 10 patients with a defect in NCF1 were homozygous for the common GT deletion, one was compound heterozygous for the GT deletion and a splice...
Al-Zadjali, S; Al-Tamemi, S; Elnour, I; AlKindi, S; Lapoumeroulie, C; Al-Maamari, S; Pathare, A; Dennison, D; Krishnamoorthy, R
Chronic granulomatous disease (CGD), a rare inherited disorder of the innate immune system, results from mutations in any one of the five genes encoding the subunits of the nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase enzyme, and is characterized by recurrent life-threatening bacterial and fungal infections. Molecular analysis of 14 Omani CGD patients from 10 families, diagnosed to have CGD on clinical (recurrent infections) and biochemical grounds (positive for both the nitroblue tetrazolium (NBT) test and the dihydrorhodamine (DHR-1,2,3 assay), revealed that only one patient had X-linked CGD, with a large deletion involving both the gp91-phox gene (CYBB) and the McLeod gene (XK). The remaining 13 patients were all homozygotes from a previously described c.579G>A (p.Trp193X) mutation in the NCF1 gene on chromosome 7, responsible for autosomal recessive CGD (AR-CGD). Although X-linked CGD is the most common type of CGD disorder in most population groups, AR-CGD is the most prevalent type in Oman. PMID:24446915
Maria J. Gutierrez
Full Text Available Chronic granulomatous disease (CGD is characterized by inherited immune defects resulting from mutations in the NADPH oxidase complex genes. The X-linked type of CGD is caused by defects in the CYBB gene that encodes gp91-phox, a fundamental component of the NADPH oxidase complex. This mutation originates the most common and severe form of CGD, which typically has absence of NADPH oxidase function and aggressive multisystemic infections. We present the case of a 9-year-old child with a rare CYBB mutation that preserves some NADPH oxidase activity, resulting in an atypical mild form of X-linked CGD with isolated lung involvement. Although the clinical picture and partially preserved oxidase function suggested an autosomal recessive form of CGD, genetic testing demonstrated a mutation in the exon 3 of CYBB gene (c.252 G>A, p.Ala84Ala, an uncommon X-linked CGD variant that affects splicing. Atypical presentation and diagnostic difficulties are discussed. This case highlights that the diagnosis of mild forms of X-linked CGD caused by rare CYBB mutations and partially preserved NADPH function should be considered early in the evaluation of atypical and recurrent lung infections.
Morillo-Gutierrez, Beatriz; Beier, Rita; Rao, Kanchan; Burroughs, Lauri; Schulz, Ansgar; Ewins, Anna-Maria; Gibson, Brenda; Sedlacek, Petr; Krol, Ladislav; Strahm, Brigitte; Zaidman, Irina; Kalwak, Krzysztof; Talano, Julie-An; Woolfrey, Ann; Fraser, Chris; Meyts, Isabelle; Müller, Ingo; Wachowiak, Jacek; Bernardo, Maria Ester; Veys, Paul; Sykora, Karl-Walter; Gennery, Andrew R; Slatter, Mary
Chronic granulomatous disease (CGD) can be cured by allogeneic hemopoietic stem cell transplantation (HSCT). Complications include graft failure, graft-versus-host disease (GVHD), infection, and transplant-related mortality; therefore, reduced-intensity conditioning regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of treosulfan-based conditioning in HSCT for pediatric patients with CGD. The following data were collected: risk features pre-HSCT, additional conditioning agents, donor type and stem cell source, toxicity, engraftment, GVHD, chimerism, viral reactivation, post-HSCT complications, length of follow-up, and outcome. Seventy patients (median age, 107 months; interquartile range [IQR], 46-232 months) from 16 centers worldwide were transplanted between 2006 and 2015. Ninety-one percent had high-risk features. Fifty-seven HLA-matched donors, 12 HLA-mismatched donors, and 1 CD3(+)TCR αβ/CD19 depleted parental haploidentical transplants were performed. No major toxicity was reported. Median times to neutrophil and platelet engraftment were 17 (IQR, 15-35) and 16 (IQR, 13-50) days. At a median follow-up of 34 months (IQR, 13-102 months), the overall survival was 91.4%, and event-free survival was 81.4%. The cumulative incidence of acute grade III-IV GVHD was 12%. Nine patients developed chronic GVHD. When split cell chimerism was available, 95% or more myeloid donor chimerism was documented in 80% of surviving patients. Secondary graft failure occurred in 12% of patients. Treosulfan-containing conditioning regimens can be used safely in HSCT for children with CGD and high-risk clinical features, achieving excellent survival with high myeloid chimerism. Further studies are needed to compare with other regimens and evaluate the long-term outcome, particularly on fertility. PMID:27216217
Full Text Available Abstract Background Chronic granulomatous disease (CGD is an inherited disorder of phagocytic cells caused by an inability to generate active microbicidal oxygen species required kill certain types of fungi and bacteria. This leads to recurrent life-threatening bacterial and fungal infections with tissue granuloma formation. Case presentation We describe a case of X-linked Chronic granulomatous disease (CGD diagnosed in an 18-year-old male. He initially presented with granulomatous disease mimicking sarcoidosis and was treated with corticosteroids. He subsequently developed Burkholderia cepacia complex pneumonia and further investigation confirmed a diagnosis of CGD. Conclusion Milder phenotypes of CGD are now being recognised. CGD should be considered in patients of any age with granulomatous diseases, especially if there is a history of recurrent or atypical infection.
Full Text Available Chronic granulomatous disease (CGD is a rare inherited disease of the phagocyte NADPH oxidase system causing defective production of toxic oxygen metabolites, impaired bacterial and fungal killing, and recurrent life-threatening infections. We identified a novel gram-negative rod in excised lymph nodes from a patient with CGD. Gram-negative rods grew on charcoal-yeast extract, but conventional tests could not identify it. The best 50 matches of the 16S rRNA (using BLAST were all members of the family Acetobacteraceae, with the closest match being Gluconobacter sacchari. Patient serum showed specific band recognition in whole lysate immunoblot. We used mouse models of CGD to determine whether this organism was a genuine CGD pathogen. Intraperitoneal injection of gp91(phox (-/- (X-linked and p47 (phox -/- (autosomal recessive mice with this bacterium led to larger burdens of organism recovered from knockout compared with wild-type mice. Knockout mouse lymph nodes had histopathology that was similar to that seen in our patient. We recovered organisms with 16S rRNA sequence identical to the patient's original isolate from the infected mice. We identified a novel gram-negative rod from a patient with CGD. To confirm its pathogenicity, we demonstrated specific immune reaction by high titer antibody, showed that it was able to cause similar disease when introduced into CGD, but not wild-type mice, and we recovered the same organism from pathologic lesions in these mice. Therefore, we have fulfilled Koch's postulates for a new pathogen. This is the first reported case of invasive human disease caused by any of the Acetobacteraceae. Polyphasic taxonomic analysis shows this organism to be a new genus and species for which we propose the name Granulobacter bethesdensis.
David E Greenberg
Full Text Available Chronic granulomatous disease (CGD is a rare inherited disease of the phagocyte NADPH oxidase system causing defective production of toxic oxygen metabolites, impaired bacterial and fungal killing, and recurrent life-threatening infections. We identified a novel gram-negative rod in excised lymph nodes from a patient with CGD. Gram-negative rods grew on charcoal-yeast extract, but conventional tests could not identify it. The best 50 matches of the 16S rRNA (using BLAST were all members of the family Acetobacteraceae, with the closest match being Gluconobacter sacchari. Patient serum showed specific band recognition in whole lysate immunoblot. We used mouse models of CGD to determine whether this organism was a genuine CGD pathogen. Intraperitoneal injection of gp91(phox -/- (X-linked and p47 (phox -/- (autosomal recessive mice with this bacterium led to larger burdens of organism recovered from knockout compared with wild-type mice. Knockout mouse lymph nodes had histopathology that was similar to that seen in our patient. We recovered organisms with 16S rRNA sequence identical to the patient's original isolate from the infected mice. We identified a novel gram-negative rod from a patient with CGD. To confirm its pathogenicity, we demonstrated specific immune reaction by high titer antibody, showed that it was able to cause similar disease when introduced into CGD, but not wild-type mice, and we recovered the same organism from pathologic lesions in these mice. Therefore, we have fulfilled Koch's postulates for a new pathogen. This is the first reported case of invasive human disease caused by any of the Acetobacteraceae. Polyphasic taxonomic analysis shows this organism to be a new genus and species for which we propose the name Granulobacter bethesdensis.
Kepenekli, Eda; Soysal, Ahmet; Kuzdan, Canan; Ermerak, Nezih Onur; Yüksel, Mustafa; Bakır, Mustafa
Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Among primary immunodefiencies, chronic granulomatous disease (CGD) has the highest prevalence of invasive fungal diseases. Voriconazole is recommended for the primary treatment of invasive aspergillosis in most patients. In patients whose aspergillosis is refractory to voriconazole, therapeutic options include changing class of antifungal, for example using an amphotericin B formulation, an echinocandin, combination therapy, or further use of azoles. Posaconazole is a triazole derivative which is effective in Aspergillosis prophylaxis and treatment. Rarely, surgical therapy may be needed in some patients. Lesions those are contiguous with the great vessels or the pericardium, single cavitary lesion that cause hemoptysis, lesions invading the chest wall, aspergillosis that involves the skin and the bone are the indications for surgical therapy.Chronic granulomatous disease (CGD) is an inherited immundeficiency caused by defects in the phagocyte nicotinamide adenine dinucleotidephosphate (NADPH) oxidase complex which is mainstay of killing microorganisms. CGD is characterized by recurrent life-threatening bacterial and fungal infections and by abnormally exuberant inflammatory responses leading to granuloma formation, such as granulomatous enteritis, genitourinary obstruction, and wound dehiscence. The diagnosis is made by neutrophil function testing and the genotyping.Herein, we present a case with CGD who had invasive pulmonary aspergillosis refractory to voriconazole and liposomal amphotericine B combination therapy that was controlled with posaconazole treatment and pulmonary surgery. PMID:24401677
Full Text Available Mutations in genes for any of the six subunits of NADPH oxidase cause chronic granulomatous disease (CGD, but almost 2/3 of CGD cases are caused by mutations in the X-linked CYBB gene, also known as NAD (P H oxidase 2. Approximately 260 patients with CGD have been reported in Japan, of whom 92 were shown to have mutations of the CYBB gene and 16 to have chromosomal deletions. However, there has been very little detailed analysis of the range of the deletion or close understanding of the disease based on this. We therefore analyzed genomic rearrangements in X-linked CGD using array comparative genomic hybridization analysis, revealing the extent and the types of the deletion genes. The subjects were five Japanese X-linked CGD patients estimated to have large base deletions of 1 kb or more in the CYBB gene (four male patients, one female patient and the mothers of four of those patients. The five Japanese patients were found to range from a patient exhibiting deletions only of the CYBB gene to a female patient exhibiting an extensive DNA deletion and the DMD and CGD phenotype manifested. Of the other three patients, two exhibited CYBB, XK, and DYNLT3 gene deletions. The remaining patient exhibited both a deletion encompassing DNA subsequent to the CYBB region following intron 2 and the DYNLT3 gene and a complex copy number variation involving the insertion of an inverted duplication of a region from the centromere side of DYNLT3 into the deleted region.
Ko, Sun Hi; Rhim, Jung Woo; Shin, Kyung Sue; Hahn, Youn Soo; Lee, So Young; Kim, Joong Gon
Chronic granulomatous disease (CGD) is a rare hereditary disorder that is characterized by a greatly increased susceptibility to life-threatening bacterial and fungal infections. CGD is caused by mutations in any one of the genes encoding subunits of phagocyte NADPH oxidase. X-linked CGD, more than half of all CGD cases, is caused by mutations in CYBB gene encoding gp91-phox subunit. We identified the mutations in the CYBB gene of 29 Korean patients with X-linked CGD from 26 unrelated families. Twenty-three mutations were identified: five splice site mutations (c.45 + 1G > C, c.141 + 5G > A, c.897 + 2T > C c.1461 + 1G > T, c.1586 + 2T > A), four frameshift mutations (c.27dupG, [c.737A > C; c.742delA], c.742dupA, c.1636 del C), seven non-sense mutations (c217C > T, c.469C > T, c.676C > T, c.868C > T, c.1222G > T, c.1272G > A, c.1281T > A), five missense mutations (c.164 C > A, c.422T > C, c.665 A > G, c.1012C > T, c.1461G > T) and two gross deletions. Eight out of 23 mutations identified in this study are novel mutations: two splice mutations(c.897 + 2T > C, c.1586 + 2T > A), two frame shift mutations ([c.737A > C; c.742delA], c.1636 del C), two nonsense mutations (c.1222G > T, c.1281T > A), one missense mutation (c.1461G > T), one gross deletion (c.1667_1629 del.). Our results confirmed that mutations of CYBB gene in the X-CGD are very heterogeneous and not show the peculiarity of the ethnic group. PMID:24999735
Delibalta, Güler; Seringeç, Murat; Öncül, Oral
BCG (Bacillus Calmette-Guérin) vaccine is a widely used vaccine with the recommendation of World Health Organization to protect children against miliary tuberculosis (TB) and TB meningitis. Severe side effects related to this vaccine mostly manifest in the presence of underlying immunosuppressive disease. In this report, an infant case with unknown chronic granulomatous disease (CGD) who developed disseminated BCG infection after administration of BCG vaccine, was presented. High fever, left axillary lymphadenopathy and hepatosplenomegaly have developed in a 3-month 28-day female infant, without a known health problem, following BCG vaccination. The acid-fast bacilli (ARB) was isolated from the material of excised lymph node cultivated in Löwenstein-Jensen medium, and the isolate was identified as Mycobacterium bovis. Mycobacterium tuberculosis complex DNA was detected in the axillary lymph node sample by polymerase chain reaction. Anti-tuberculous treatment included 20 mg/kg of rifampicin+10 mg/kg of isoniazid+15 mg/kg of ethambutol+30 mg/kg of streptomycin was started. The patient was then further evaluated for immunodeficiency and on the basis of the results of dihydroamine and LAD (lymphocyte adhesion defect) tests, diagnosed as autosomal recessive CGD. Based on the anamnesis, there was no known immunodeficiency history both in the case during neonatal period and her family members. Interferon-gamma therapy, which is recommended for the patients with CGD living in endemic areas, was initiated. Our patient's fever dropped at the 15th day of anti-tuberculosis treatment, and she was discharged on the 35th day and continued to receive treatment at home. The patient was followed up at outpatient clinic and had no additional complaints; her hepatosplenomegaly was back to normal at the third month. As a result, since BCG vaccine is contraindicated in CGD carriers, newborns with a family history of CGD should be immunologically examined and BCG vaccine should be
Akagi, Kazuko; Kawai, Toshinao; Watanabe, Nobuyuki; Yokoyama, Midori; Arai, Katsuhiro; Harayama, Shizuko; Oana, Shinji; Onodera, Masafumi
Although macrophage activation syndrome (MAS) develops in some patients with chronic granulomatous disease (CGD), all of the reported cases have been associated with pathogenic microbial infections. We report a 2-year-old boy with CGD-associated colitis who suffered from MAS without any clinical signs of a microbial infection. He was treated with 1 course of methylprednisolone pulse therapy and the clinical symptoms improved; however, the colitis was difficult to control even with immunosuppressive drugs, and he eventually required hematopoietic stem cell transplantation 1 year after the onset of MAS. It is likely that MAS develops in patients with CGD colitis independent of microbial infections. PMID:23652865
Moir, Susan; De Ravin, Suk See; Santich, Brian H.; Kim, Jin Young; Posada, Jacqueline G.; Ho, Jason; Buckner, Clarisa M.; Wang, Wei; Kardava, Lela; Garofalo, Mary; Marciano, Beatriz E.; Manischewitz, Jody; King, Lisa R.; Khurana, Surender; Chun, Tae-Wook
CD27+ memory B cells are reduced in the blood of patients with chronic granulomatous disease (CGD) for reasons and consequences that remain unclear. Here we confirm not only decreased CD27+ but also IgG+ B cells in the blood of CGD patients compared with healthy donors (HDs). However, among IgG+ B cells, the ratio of CD27− to CD27+ was significantly higher in CGD patients compared with HDs. Similar to conventional memory B cells, CD27−IgG+ B cells of CGD patients expressed activation markers ...
Full Text Available Chronic granulomatous disease is an infrequent primary immunodeficiency characterized by defective intracellular killing of ingested microorganisms thereby making patients highly susceptible to recurrent lite threatening bacterial and fungal infections. In this study, we review the medical course of an 8 yr old girl with AR-CGD. She suffered from recurrent dermal and deep abscesses, retractable salmonellosis, disseminated BCGosis, recurrent aspergillus infection presenting as mandibular osteomyelitis and pulmonary involvement with invasion to rib and vertebral bodies. Despite of longterm IV amphotricin B, itraconazole and IFN-y administration, and surgical interventions (drainage and resection, she died in spite of long term antibiotic anti fungal prophylaxis and interferon-gamma administrations, invasive aspergillosis resistant to current conventional therapies is the cause of 1/2 to 1/3 of CGD deaths.
Saul Oswaldo Lugo Reyes
Full Text Available Chronic granulomatous disease (CGD is a primary immunodeficiency characterized by increased susceptibility to bacteria and fungi since early in life, caused by mutations in any of the five genes coding for protein subunits in NADPH oxidase. X-linked variant CGD can be missed during routine evaluation or present later in life due to hypomorphic mutations and a residual superoxide production. The case of a 10-month-old boy who died of pneumonia is reported. The isolation of Burkholderia cepacia from his lung, together with a marginally low nitroblue tetrazolium reduction assay (NBT, made us suspect and pursue the molecular diagnosis of CGD. A postmortem genetic analysis finally demonstrated CGD caused by a hypomorphic missense mutation with normal gp91phox expression. In a patient being investigated for unusually severe or recurrent infection, a high index of suspicion of immunodeficiency must be maintained.
Song, Sang-Mi; Park, Mi-Ran; Kim, Do-Soo; Kim, Jihyun; Kim, Yae-Jean; Ki, Chang-Seok; Ahn, Kangmo
Chronic granulomatous disease (CGD) is a rare immunodeficiency disease, which is characterized by the lack of a functional nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. The disease presents leukocytosis, anemia, hypergammaglobulinemia, and granuloma formation of the skin, lung, or lymph nodes. The mutation of the CYBB gene encoding gp91phox, located on chromosome Xp21.1 is one of the causes of CGD. We report a patient with X-linked CGD who carried a novel mutation...
Flynn, Rowan; Grundmann, Alexander; Renz, Peter; Hänseler, Walther; James, William S; Cowley, Sally A; Moore, Michael D
Chronic granulomatous disease (CGD) is a rare genetic disease characterized by severe and persistent childhood infections. It is caused by the lack of an antipathogen oxidative burst, normally performed by phagocytic cells to contain and clear bacterial and fungal growth. Restoration of immune function can be achieved with heterologous bone marrow transplantation; however, autologous bone marrow transplantation would be a preferable option. Thus, a method is required to recapitulate the function of the diseased gene within the patient's own cells. Gene therapy approaches for CGD have employed randomly integrating viruses with concomitant issues of insertional mutagenesis, inaccurate gene dosage, and gene silencing. Here, we explore the potential of the recently described clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 site-specific nuclease system to encourage repair of the endogenous gene by enhancing the levels of homologous recombination. Using induced pluripotent stem cells derived from a CGD patient containing a single intronic mutation in the CYBB gene, we show that footprintless gene editing is a viable option to correct disease mutations. Gene correction results in restoration of oxidative burst function in iPS-derived phagocytes by reintroduction of a previously skipped exon in the cytochrome b-245 heavy chain (CYBB) protein. This study provides proof-of-principle for a gene therapy approach to CGD treatment using CRISPR-Cas9. PMID:26101162
De Ravin, Suk See; Reik, Andreas; Liu, Pei-Qi; Li, Linhong; Wu, Xiaolin; Su, Ling; Raley, Castle; Theobald, Narda; Choi, Uimook; Song, Alexander H; Chan, Andy; Pearl, Jocelynn R; Paschon, David E; Lee, Janet; Newcombe, Hannah; Koontz, Sherry; Sweeney, Colin; Shivak, David A; Zarember, Kol A; Peshwa, Madhusudan V; Gregory, Philip D; Urnov, Fyodor D; Malech, Harry L
Gene therapy with genetically modified human CD34(+) hematopoietic stem and progenitor cells (HSPCs) may be safer using targeted integration (TI) of transgenes into a genomic 'safe harbor' site rather than random viral integration. We demonstrate that temporally optimized delivery of zinc finger nuclease mRNA via electroporation and adeno-associated virus (AAV) 6 delivery of donor constructs in human HSPCs approaches clinically relevant levels of TI into the AAVS1 safe harbor locus. Up to 58% Venus(+) HSPCs with 6-16% human cell marking were observed following engraftment into mice. In HSPCs from patients with X-linked chronic granulomatous disease (X-CGD), caused by mutations in the gp91phox subunit of the NADPH oxidase, TI of a gp91phox transgene into AAVS1 resulted in ∼15% gp91phox expression and increased NADPH oxidase activity in ex vivo-derived neutrophils. In mice transplanted with corrected HSPCs, 4-11% of human cells in the bone marrow expressed gp91phox. This method for TI into AAVS1 may be broadly applicable to correction of other monogenic diseases. PMID:26950749
Reichenbach, Janine; Van de Velde, Hilde; De Rycke, Martine; Staessen, Cathérine; Platteau, Peter; Baetens, Patricia; Güngör, Tayfun; Ozsahin, Hulya; Scherer, Franziska; Siler, Ulrich; Seger, Reinhard A; Liebaers, Inge
Allogeneic hematopoietic stem cell transplantation from an human leukocyte antigen (HLA)-identical donor is currently the only proven curative treatment for chronic granulomatous disease. Hematopoietic stem cell transplantation with alternative donors is associated with higher morbidity and mortality. Therefore, we performed in vitro fertilization and preimplantation HLA matching combined with female sexing for hematopoietic stem cell transplantation in chronic granulomatous disease. Ethical and psychological issues were considered carefully. We used in vitro fertilization with X-enriched spermatozoa followed by preimplantation genetic diagnosis to identify female HLA-genoidentical embryos in a family in need of a suitable donor for their boy affected with severe X-linked chronic granulomatous disease. Two preimplantation genetic diagnosis cycles were performed in the family. In the second cycle, 2 HLA-genoidentical female embryos were transferred and a singleton pregnancy was obtained, resulting in the birth of an unaffected girl at term. Because of insufficient cell numbers in the cord-blood source, conventional hematopoietic stem cell transplantation had to be performed at 12 months of age of the donor and 5 years of age of the recipient and resulted in complete stable donor chimerism and immunologic reconstitution up to 25 months post-hematopoietic stem cell transplantation. Hematopoietic stem cell transplantation after in vitro fertilization and combined female sexing and HLA matching offers a new and relatively rapid therapeutic option for patients with X-linked primary immunodeficiency such as chronic granulomatous disease who need hematopoietic stem cell transplantation but lack an HLA-genoidentical donor. PMID:18762514
Fernandez-Boyanapalli, Ruby; McPhillips, Kathleen A.; Frasch, S. Courtney; Janssen, William J.; Dinauer, Mary C.; Riches, David W.H.; Henson, Peter M.; Byrne, Aideen; Bratton, Donna L.
Immunodeficiency in chronic granulomatous disease (CGD) is well characterized. Less understood are exaggerated sterile inflammation and autoimmunity associated with CGD. Impaired recognition and clearance of apoptotic cells resulting in their disintegration may contribute to CGD inflammation. We hypothesized that priming of macrophages (Mϕs) with IFN-γ would enhance impaired engulfment of apoptotic cells in CGD. Diverse Mϕ populations from CGD (gp91phox−/−) and wild-type mice, as well as huma...
Greenberg, David E.; Sturdevant, Daniel E.; Marshall-Batty, Kimberly R.; Chu, Jessica; Pettinato, Anthony M.; Virtaneva, Kimmo; Lane, John; Geller, Bruce L.; Porcella, Stephen F.; Gallin, John I.; Holland, Steven M.; Zarember, Kol A.
Polymorphonuclear leukocytes (PMN) from patients with chronic granulomatous disease (CGD) fail to produce microbicidal concentrations of reactive oxygen species (ROS) due to mutations in NOX2. Patients with CGD suffer from severe, life-threatening infections and inflammatory complications. Granulibacter bethesdensis is an emerging Gram-negative pathogen in CGD that resists killing by PMN of CGD patients (CGD PMN) and inhibits PMN apoptosis through unknown mechanisms. Microarray analysis was u...
Morgenstern, David E.; Gifford, Mary A.C.; Li, Ling Lin; Doerschuk, Claire M.; Dinauer, Mary C.
Mice with X-linked chronic granulomatous disease (CGD) generated by targeted disruption of the gp91 phox subunit of the NADPH–oxidase complex (X-CGD mice) were examined for their response to respiratory challenge with Aspergillus fumigatus. This opportunistic fungal pathogen causes infection in CGD patients due to the deficient generation of neutrophil respiratory burst oxidants important for damaging A. fumigatus hyphae. Alveolar macrophages from X-CGD mice were found to kill A. fumigatus co...
Zou, Jizhong; Sweeney, Colin L; Chou, Bin-Kuan; Choi, Uimook; Pan, Jason; WANG, HONGMEI; Dowey, Sarah N.; Cheng, Linzhao; Malech, Harry L.
We have developed induced pluripotent stem cells (iPSCs) from a patient with X-linked chronic granulomatous disease (X-CGD), a defect of neutrophil microbicidal reactive oxygen species (ROS) generation resulting from gp91phox deficiency. We demonstrated that mature neutrophils differentiated from X-CGD iPSCs lack ROS production, reproducing the pathognomonic CGD cellular phenotype. Targeted gene transfer into iPSCs, with subsequent selection and full characterization to ensure no off-target c...
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder characterized by a greatly increased susceptibility to severe fungal and bacterial infections caused by defects in NADPH oxidase of phagocytic cells. We aimed to investigate immunophenotype alterations of naïve and memory B cells and B1a cells in peripheral whole blood from Iranian patients with CGD. Flow cytometric analysis was performed on peripheral blood samples from 31 CGD patients and 23 healthy controls (HC...
Chang, Y.C.; Segal, B.H.; Holland, S M; Miller, G.F.; Kwon-Chung, K. J.
Chronic granulomatous disease (CGD) is a rare genetic disorder in which phagocytes fail to produce superoxide because of defects in one of several components of the NADPH oxidase complex. As a result, patients develop recurrent life-threatening bacterial and fungal infections. The organisms to which CGD patients are most susceptible produce catalase, regarded as an important factor for microbial pathogenicity in CGD. To test the role of pathogen-derived catalase in CGD directly, we have gener...
Roesler, J.; Hockertz, S; Vogt, B.; Lohmann-Matthes, M L
Granulocytes and monocytes/macrophages from patients suffering from chronic granulomatous disease (CGD) are ineffective in killing specific kinds of phagocytized bacteria, e.g., Staphylococcus aureus, due to decreased or lacking ability to produce reactive oxygen intermediates. Commonly used antibiotics like flucloxacillin are of limited therapeutic value, because the staphylococci are protected against their action in the interior of phagocytes. However, encapsulation of flucloxacillin into ...
Gungor, T; Engel-Bicik, I; Eich, G.; Willi, U; Nadal, D; Hossle, J; Seger, R.; Steinert, H
AIMS—To compare whole body positron emission tomography (PET) using fluorine-18-fluoro-2-deoxy-D-glucose (FDG) with computed tomography (CT) in detecting active infective foci in children with chronic granulomatous disease. METHODS—We performed 22 whole body FDG PET studies in seven children with X linked (n = 6) or autosomal recessive (n = 1) CGD. All had clinical signs of infection and/or were evaluated prior to bone marrow transplantation (BMT). Nineteen PET studies...
de Boer, Martin; Tzur, Shay; van Leeuwen, Karin; Dencher, Paula C D; Skorecki, Karl; Wolach, Baruch; Gavrieli, Ronit; Nasidze, Ivane; Stoneking, Mark; Tanck, Michael W T; Roos, Dirk
Chronic granulomatous disease (CGD) is a rare congenital immune deficiency caused by mutations in any of the five genes encoding NADPH oxidase subunits. One of these genes is NCF1, encoding the p47(phox) protein. A group of 39 patients, 14 of whom are of Kavkazi Jewish descent, was investigated for a founder effect for the mutation c.579G>A (p.Trp193Ter) in NCF1. We analyzed various genetic markers in the NCF1 region, including two single nucleotide polymorphisms (SNPs) in NCF1 and two short tandem repeats (STRs) located near NCF1. Most patients were homozygous for the c.579G>A mutation, but three patients were hemizygotes, with a deletion of NCF1 on the other allele, and three patients were compound heterozygotes with another mutation in NCF1. All Kavkazi Jewish patients had a c.295G_c.345T SNP combination in NCF1 and shared a common number of repeats in STR3. In addition, 90% of the Kavkazi Jewish patients shared a common number of repeats in STR1. This uniformity indicates that the c.579G>A mutation in NCF1 was introduced some 1200-2300 years ago in the Kavkazi Jewish population. Variation amongst the other investigated populations from the Middle East indicates that this mutation exists in these non-Kavkazi populations already for more than 5000 years. PMID:26460255
Merling, Randall K; Sweeney, Colin L; Chu, Jessica; Bodansky, Aaron; Choi, Uimook; Priel, Debra Long; Kuhns, Douglas B; Wang, Hongmei; Vasilevsky, Sam; De Ravin, Suk See; Winkler, Thomas; Dunbar, Cynthia E; Zou, Jizhong; Zarember, Kol A; Gallin, John I; Holland, Steven M; Malech, Harry L
There are five genetic forms of chronic granulomatous disease (CGD), resulting from mutations in any of five subunits of phagocyte oxidase, an enzyme complex in neutrophils, monocytes, and macrophages that produces microbicidal reactive oxygen species. We generated induced pluripotent stem cells (iPSCs) from peripheral blood CD34(+) hematopoietic stem cells of patients with each of five CGD genotypes. We used zinc finger nuclease (ZFN) targeting the AAVS1 safe harbor site together with CGD genotype-specific minigene plasmids with flanking AAVS1 sequence to target correction of iPSC representing each form of CGD. We achieved targeted insertion with constitutive expression of desired oxidase subunit in 70-80% of selected iPSC clones. Neutrophils and macrophages differentiated from corrected CGD iPSCs demonstrated restored oxidase activity and antimicrobial function against CGD bacterial pathogens Staphylococcus aureus and Granulibacter bethesdensis. Using a standard platform that combines iPSC generation from peripheral blood CD34(+) cells and ZFN mediated AAVS1 safe harbor minigene targeting, we demonstrate efficient generation of genetically corrected iPSCs using an identical approach for all five genetic forms of CGD. This safe harbor minigene targeting platform is broadly applicable to a wide range of inherited single gene metabolic disorders. PMID:25288370
Vilaiphan, Prapaporn; Chatchatee, Pantipa; Ngamphaiboon, Jarungchit; Tongkobpetch, Siraprapa; Suphapeetiporn, Kanya; Shotelersuk, Vorasuk
X-linked chronic granulomatous disease (X-CGD) is an immunodeficiency disorder characterized by defective intracellular killing of microorganisms due to the neutrophils' inability to generate superoxide ions. Although it is always caused by mutations in the CYBB gene, clinical and molecular characteristics vary in different ethnic backgrounds. Two unrelated Thai boys presented with severe persistent pulmonary infections at the age of two months. Their abnormal dihydrorhodamine (DHR) flow cytometry assays supported the diagnosis of X-CGD. Mutation analysis was performed by polymerase chain reaction (PCR) amplification and sequencing of the entire coding regions of CYBB. Mutations identified were confirmed by restriction enzyme analyses. PCR-sequencing of the entire coding regions of CYBB identified nonsense mutations, 271C>T (R91X) in exon 4 and 456T>A (Y152X) in exon 5, in probands of each family. Both of the patients' mothers were found to be carriers. This observation supports that CYBB is the gene responsible for X-CGD across different populations and nonsense mutations are associated with severe phenotypes. PMID:18402298
Dreyer, Anne-Kathrin; Hoffmann, Dirk; Lachmann, Nico; Ackermann, Mania; Steinemann, Doris; Timm, Barbara; Siler, Ulrich; Reichenbach, Janine; Grez, Manuel; Moritz, Thomas; Schambach, Axel; Cathomen, Toni
X-linked chronic granulomatous disease (X-CGD) is an inherited disorder of the immune system. It is characterized by a defect in the production of reactive oxygen species (ROS) in phagocytic cells due to mutations in the NOX2 locus, which encodes gp91phox. Because the success of retroviral gene therapy for X-CGD has been hampered by insertional activation of proto-oncogenes, targeting the insertion of a gp91phox transgene into potential safe harbor sites, such as AAVS1, may represent a valid alternative. To conceptually evaluate this strategy, we generated X-CGD patient-derived induced pluripotent stem cells (iPSCs), which recapitulate the cellular disease phenotype upon granulocytic differentiation. We examined AAVS1-specific zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) for their efficacy to target the insertion of a myelo-specific gp91phox cassette to AAVS1. Probably due to their lower cytotoxicity, TALENs were more efficient than ZFNs in generating correctly targeted iPSC colonies, but all corrected iPSC clones showed no signs of mutations at the top-ten predicted off-target sites of both nucleases. Upon differentiation of the corrected X-CGD iPSCs, gp91phox mRNA levels were highly up-regulated and the derived granulocytes exhibited restored ROS production that induced neutrophil extracellular trap (NET) formation. In conclusion, we demonstrate that TALEN-mediated integration of a myelo-specific gp91phox transgene into AAVS1 of patient-derived iPSCs represents a safe and efficient way to generate autologous, functionally corrected granulocytes. PMID:26295532
Song, Sang-Mi; Park, Mi-Ran; Kim, Do-Soo; Kim, Jihyun; Kim, Yae-Jean; Ki, Chang-Seok; Ahn, Kangmo
Chronic granulomatous disease (CGD) is a rare immunodeficiency disease, which is characterized by the lack of a functional nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. The disease presents leukocytosis, anemia, hypergammaglobulinemia, and granuloma formation of the skin, lung, or lymph nodes. The mutation of the CYBB gene encoding gp91phox, located on chromosome Xp21.1 is one of the causes of CGD. We report a patient with X-linked CGD who carried a novel mutation, a c.1133A>G (paAsp378Gly) missense mutation, in the CYBB gene. PMID:24991462
Full Text Available Chronic granulomatous disease (CGD is an inherited disorder of the innate immune system characterized by a defective oxidative burst of phagocytes and subsequent impairment of their microbicidal activity. Mutations in one of the NADPH-oxidase components affect gene expression or function of this system, leading to the phenotype of CGD. Defects in gp91-phox lead to X-linked CGD, responsible for approximately 70% of CGD cases. Investigation of the highly heterogeneous genotype of CGD patients includes mutation analysis, Northern blot or Western blot assays according to the particular case. The aim of the present study was to use reverse transcription (RT-PCR for the analysis of molecular defects responsible for X-linked CGD in eight Brazilian patients and to assess its potential for broader application to molecular screening in CGD. Total RNA was prepared from Epstein B virus-transformed B-lymphocytes and reverse transcribed using random hexamers. The resulting cDNA was PCR-amplified by specific and overlapping pairs of primers designed to amplify three regions of the gp91-phox gene: exons 1-5, 3-9, and 7-13. This strategy detected defective gp91-phox expression in seven patients. The RT-PCR results matched clinical history, biochemical data (nitroblue tetrazolium or superoxide release assay and available mutation analysis in four cases. In three additional cases, RT-PCR results matched clinical history and biochemical data. In another case, RT-PCR was normal despite a clinical history compatible with CGD and defective respiratory burst. We conclude that this new application of RT-PCR analysis - a simple, economical and rapid method - was appropriate for screening molecular defects in 7 of 8 X-linked CGD patients.
de Luca, Antonella; Smeekens, Sanne P; Casagrande, Andrea; Iannitti, Rossana; Conway, Kara L; Gresnigt, Mark S; Begun, Jakob; Plantinga, Theo S; Joosten, Leo A B; van der Meer, Jos W M; Chamilos, Georgios; Netea, Mihai G; Xavier, Ramnik J; Dinarello, Charles A; Romani, Luigina; van de Veerdonk, Frank L
Patients with chronic granulomatous disease (CGD) have a mutated NADPH complex resulting in defective production of reactive oxygen species; these patients can develop severe colitis and are highly susceptible to invasive fungal infection. In NADPH oxidase-deficient mice, autophagy is defective but inflammasome activation is present despite lack of reactive oxygen species production. However, whether these processes are mutually regulated in CGD and whether defective autophagy is clinically relevant in patients with CGD is unknown. Here, we demonstrate that macrophages from CGD mice and blood monocytes from CGD patients display minimal recruitment of microtubule-associated protein 1 light chain 3 (LC3) to phagosomes. This defect in autophagy results in increased IL-1β release. Blocking IL-1 with the receptor antagonist (anakinra) decreases neutrophil recruitment and T helper 17 responses and protects CGD mice from colitis and also from invasive aspergillosis. In addition to decreased inflammasome activation, anakinra restored autophagy in CGD mice in vivo, with increased Aspergillus-induced LC3 recruitment and increased expression of autophagy genes. Anakinra also increased Aspergillus-induced LC3 recruitment from 23% to 51% (P CGD patients. The clinical relevance of these findings was assessed by treating CGD patients who had severe colitis with IL-1 receptor blockade using anakinra. Anakinra treatment resulted in a rapid and sustained improvement in colitis. Thus, inflammation in CGD is due to IL-1-dependent mechanisms, such as decreased autophagy and increased inflammasome activation, which are linked pathological conditions in CGD that can be restored by IL-1 receptor blockade. PMID:24550444
We report the case of a boy with chronic septic granulomatosis (CSG) who presented with a marked gastric antrum narrowing which was evaluated by MRI after oral intake of magnetic contrast particles, and after gadolinium i.v. administration. In particular, a mammillated aspect of the gastric wall in the antral region was seen. Follow-up by MRI clearly showed the gradual resolution of hyperemic wall thickness, after medical management. The antral stenosis resolved after 3 months. Magnetic resonance imaging provides detailed evaluation of gastric wall inflammation in course of CSG. (orig.)
Kaufmann, Kerstin B; Chiriaco, Maria; Siler, Ulrich; Finocchi, Andrea; Reichenbach, Janine; Stein, Stefan; Grez, Manuel
Several Phase I/II clinical trials aiming at the correction of X-linked CGD by gene transfer into hematopoietic stem cells (HSCs) have demonstrated the therapeutic potential of gene modified autologous HSCs for the treatment of CGD. Resolution of therapy-resistant bacterial and fungal infections in liver, lung and spinal canal of CGD patients were clearly documented in all trials. However, clinical benefits were not sustained over time due to the failure of gene transduced cells to engraft long-term. Moreover, severe adverse effects were observed in some of the treated patients due to insertional mutagenesis leading to the activation of growth promoting genes and to myeloid malignancy. These setbacks fostered the development of novel safety and efficacy improved vectors that have already entered or are about to enter the clinics. Meanwhile, ongoing research is constantly refining the CGD disease phenotype, including the definition of factors that may explain the unique engraftment phenotype observed in CGD gene therapy trials. This review provides a condensed overview on the current knowledge of the molecular pathomechanisms and clinical manifestations of CGD and summarizes the lessons learned from clinical gene therapy trials, the preclinical progress in vector design and the future perspectives for the gene therapy of CGD. PMID:25245086
Kim, Young Mee; Park, Ji Eun; Kim, Jin Young; Lim, Hee Kyung; Nam, Jae Kook; Cho, Moonjae; Shin, Kyung-Sue
Chronic granulomatous disease (CGD) is a rare hereditary disorder characterized by recurrent life-threatening bacterial and fungal infections. The underlying defect in CGD is an inability of phagocytes to produce reactive oxygen species as a result of defects in NADPH oxidase. Considering that CGD generally affects about 3-4 in 1,000,000 individuals, it is surprising that the prevalence of CGD on Jeju Island is 20.7 in 1,000,000 individuals. We performed genetic analysis on 12 patients from 1...
Boer, M.; Klein, A; Hossle, J P; Seger, R.; Corbeel, L; Weening, R S; Roos, D.
Chronic granulomatous disease (CGD) is characterized by the failure of activated phagocytes to generate superoxide. Defects in at least four different genes lead to CGD. Patients with the X-linked form of CGD have mutations in the gene for the beta-subunit of cytochrome b558 (gp91-phox). Patients with a rare autosomal recessive form of CGD have mutations in the gene for the alpha-subunit of this cytochrome (p22-phox). Usually, this leads to the absence of cytochrome b558 in the phagocytes (A2...
Zhen, L.; KING, A.A.; Xiao, Y.; Chanock, S. J.; Orkin, S H; Dinauer, M.C.
The X chromosome-linked chronic granulomatous disease (X-CGD) locus, which encodes the gp91phox subunit of the phagocyte respiratory-burst oxidase cytochrome b, was disrupted by homologous recombination in the PLB-985 human myeloid cell line to develop an in vitro model of X-CGD. Superoxide formation was absent in targeted cells after differentiation to granulocytes but was rescued by stable transfection and expression of wild-type gp91phox cDNA. The targeted cell line should be useful in exp...
Purpose. To present the unusual case of chronic granulomatous disease (CGD) manifestating as pulmonal aspergillosis in female enzygotic twins during the neonatal period. To demonstrate and to discuss the complex diagnosis and the diagnostic value of FDG-PET in monitoring the spread and activity of the disease. Patients. Plain chest X-ray and CT of the lung showed multiple, mostly round lesions in one of the former preterm twins at the age of 8 weeks. The girl with known ASD II was then suffering from dyspnoea and recurrent pulmonary infections. Because of the imaging findings invasive pulmonary aspergillosis due to an underlying immunodeficiency was suspected. Results. Aspergillosis was confirmed histologically and microbiologically by specimens taken from an open lung biopsy. Because of coexisting granulocytic dysfunction the diagnosis of CGD was made. This diagnosis was equally confirmed by noninvasive methods in the asymptomatic sister. FDG-PET did not show any evidence of extrapulmonary spread of disease. Conclusion. CGD can present as isolated pulmonal aspergillosis even in the neonatal period when an immunodeficiency is discussed. In enzygotic twins screening of the asymptomatic twin is mandatory. FDG-PET is a useful tool in screening for spread of the disease and in evaluating disease activity. (orig.)
Shahin Shamsian Bibi
Full Text Available Immunodeficiency and autoimmune disease may occur concomitantly in the same individual. Some of the immunodeficiency syndromes, especially humoral defects are associated with autoimmune disorders. Hematological manifestations such as thrombocytopenia and hemolytic anemia are the most common presentations. Persistent antigen stimulation due to an inherent defect in the ability of the immune system to eradicate pathogens is the primary cause leading to autoimmunity in patients with primary immunodeficiency states.We describe a 10 year old Iranian girl with chronic granulomatous disease -the autosomal recessive type with mutation of NCF1 gene P47- associated with selective IgA deficiency, refractory immune thrombocytopenia that showed an excellent response to Rituximab (Anti-CD20 monoclonal antibody.Patients with primary immunodeficiencies may have variable autoimmune manifestations. So for early detection and appropriate treatment, autoimmune diseases should always be suspected in such patients.
Lin, Chao-Jen; Wang, Shih-Chung; Ku, Cheng-Lung; Kao, Jun-Kai; Chen, Ming; Liu, Chin-San
A 19-month-old boy with chronic granulomatous disease (CGD) received umbilical cord blood transplantation (UCBT) from an unrelated donor after experiencing a life-threatening disseminated Bacillus Calmette-Guérin infection. After busulfan and cyclophosphamide conditioning, we performed a 5/6-matched UCBT. Engraftment and mixed chimerism was 100% in peripheral blood, and 100% of his neutrophils had normal oxidative burst activity on day 17. The patient is now 3 years old, free from infection, and growing well. To our knowledge, this is the second case of CGD treated with UCBT in Taiwan. His successful outcome illustrates that UCBT in a patient with CGD should be considered early if a human leukocyte antigen-matched donor is not available or the patient has just recovered from a severe infection. PMID:23680261
Full Text Available Two brothers in their fifties presented with a medical history of suspected fungal allergy, allergic bronchopulmonary aspergillosis, alveolitis, and invasive aspergillosis and pulmonary fistula, respectively. Eventually, after a delay of 50 years, chronic granulomatous disease (CGD was diagnosed in the index patient. We found a new splice mutation in the NCF2 (p67-phox gene, c.1000 + 2T → G, that led to several splice products one of which lacked exons 11 and 12. This deletion was in frame and allowed for remarkable residual NADPH oxidase activity as determined by transduction experiments using a retroviral vector. We conclude that p67-phox which lacks the 34 amino acids encoded by the two exons can still exert considerable functional activity. This activity can partially explain the long-term survival of the patients without adequate diagnosis and treatment, but could not prevent progressing lung damage.
Nwawka, O Kenechi; Nadgir, Rohini; Fujita, Akifumi; Sakai, Osamu
Granulomatous diseases have a varied etiology that includes autoimmune, infectious, idiopathic, and hereditary causes. The unifying factor in these diseases is the formation of granulomas, which histologically are mononuclear inflammatory cells or macrophages surrounded by lymphocytes. Granulomatous diseases often have systemic manifestations that affect organs throughout the body. Granulomatous diseases with head and neck manifestations include granulomatosis with polyangiitis, Churg-Strauss syndrome, Behçet disease, chronic granulomatous disease, and sarcoidosis. Infectious causes include tuberculosis, cat-scratch disease, syphilis, leprosy, actinomycosis, rhinoscleroma, and fungal infections. In the head and neck, granulomatous disease may affect the orbits, sinonasal cavities, salivary glands, aerodigestive tract, temporal bone, or skull base. Imaging findings include sinonasal opacification, ocular and other soft-tissue masses, osseous erosion, airway narrowing, lymphadenopathy, and salivary gland infiltration. Vascular involvement may also be evident, with displacement, narrowing, or occlusion of arteries and veins. Some radiologic findings of granulomatous processes have a considerable overlap with findings of malignancy, and a radiologic differential diagnosis inclusive of both is critical to avoid incorrect clinical treatment. Without the benefit of a prior clinical diagnosis, laboratory findings, or suggestive clinical signs and symptoms, granulomatous diseases may be difficult to differentiate radiologically. Although individual granulomatous diseases may have overlapping findings at imaging, certain radiologic findings should prompt the inclusion of granulomatous diseases in the differential diagnosis, thus facilitating appropriate clinical management. PMID:25208278
Ben Abdallah Chabchoub, R; Turki, H; Mahfoudh, A
The association of chronic granulomatosis disease (CGD) with autoimmune diseases such as lupus has been described but remains rare. K… is a boy born of a consanguineous marriage. In the family history, two brothers had died at a young age. He had been followed up since the age of 6 months for CGD. At 11 years of age, he developed malar rash, cheilitis, oral ulceration, and photosensitivity. Systemic lupus erythematosus (SLE) was confirmed by the presence of high levels of antinuclear antibodies. This observation demonstrates that with the clinical association of recurrent infections and skin lesions the diagnosis of CGD with SLE must be considered. PMID:25445129
Pulmonary aspergillosis as first manifestation of chronic granulomatous disease in enzygotic twins-use of FDG-PET in diagnosing spread of disease; Pulmonale Aspergillose als Erstmanifestation einer septischen Granulomatose (chronic granulomatous disease, CGD) bei eineiigen weiblichen Zwillingsfruehgeborenen und Ausbreitungsdiagnostik mittels FDG-PET
Theobald, I.; Fischbach, R.; Heindel, W. [Muenster Univ. (Germany). Radiologische Klinik und Poliklinik; Huelskamp, G.; Frosch, M.; Roth, J. [Klinik und Poliklinik fuer Kinderheilkunde und Allgemeine Kinderheilkunde des UKM, Muenster (Germany); Franzius, C. [Klinik und Poliklinik fuer Nuklearmedizin des UKM, Muenster (Germany)
Purpose. To present the unusual case of chronic granulomatous disease (CGD) manifestating as pulmonal aspergillosis in female enzygotic twins during the neonatal period. To demonstrate and to discuss the complex diagnosis and the diagnostic value of FDG-PET in monitoring the spread and activity of the disease. Patients. Plain chest X-ray and CT of the lung showed multiple, mostly round lesions in one of the former preterm twins at the age of 8 weeks. The girl with known ASD II was then suffering from dyspnoea and recurrent pulmonary infections. Because of the imaging findings invasive pulmonary aspergillosis due to an underlying immunodeficiency was suspected. Results. Aspergillosis was confirmed histologically and microbiologically by specimens taken from an open lung biopsy. Because of coexisting granulocytic dysfunction the diagnosis of CGD was made. This diagnosis was equally confirmed by noninvasive methods in the asymptomatic sister. FDG-PET did not show any evidence of extrapulmonary spread of disease. Conclusion. CGD can present as isolated pulmonal aspergillosis even in the neonatal period when an immunodeficiency is discussed. In enzygotic twins screening of the asymptomatic twin is mandatory. FDG-PET is a useful tool in screening for spread of the disease and in evaluating disease activity. (orig.) [German] Ziel. Im Rahmen einer Fallbeschreibung wird eine aussergewoehnlich fruehe Erstmanifestation einer septischen Granulomatose (chronic granulomatous disease ''CGD'') als invasive pulmonale Aspergillose in der Neonatalzeit bei eineiigen weiblichen Zwillingen vorgestellt. Zusaetzlich wird auf die komplexe Diagnostik unter besonderem Hinweis des Stellenwerts der FDG-PET zur Ausbreitungsdiagnostik und Aktivitaetsbeurteilung eingegangen. Patienten. Bei dem 8 Wochen alten ehemaligen Fruehgeborenen zeigten Roentgenthoraxbild und CT der Lunge multiple, meist rundliche Lungeninfiltrate. Bei bekanntem ASD lagen Dyspnoe und rezidivierende
Laugsch, Magdalena; Rostovskaya, Maria; Velychko, Sergiy; Richter, Cornelia; Zimmer, Ariane; Klink, Barbara; Schröck, Evelin; Haase, Michael; Neumann, Katrin; Thieme, Sebastian; Roesler, Joachim; Brenner, Sebastian; Anastassiadis, Konstantinos
Chronic granulomatous disease (CGD) is an inherited immunodeficiency, caused by the inability of neutrophils to produce functional NADPH oxidase required for fighting microbial infections. The X-linked form of CGD (X-CGD), which is due to mutations in the CYBB (gp91phox) gene, a component of NADPH oxidase, accounts for about two-thirds of CGD cases. We derived induced pluripotent stem cells (iPSCs) from X-CGD patient keratinocytes using a Flp recombinase excisable lentiviral reprogramming vector. For restoring gp91phox function, we applied two strategies: transposon-mediated bacterial artificial chromosome (BAC) transgenesis and gene targeting using vectors with a fixed 5' homology arm (HA) of 8 kb and 3'HA varying in size from 30 to 80 kb. High efficiency of homologous recombination (up to 22%) was observed with increased size of the 3'HA. Both, BAC transgenesis and gene targeting resulted in functional restoration of the gp91phox measured by an oxidase activity assay in X-CGD iPSCs differentiated into the myeloid lineage. In conclusion, we delivered an important milestone towards the use of genetically corrected autologous cells for the treatment of X-CGD and monogenic diseases in general. PMID:26316390
Malur, Anagha; Barna, Barbara P; Patel, Janki; McPeek, Matthew; Wingard, Christopher J; Dobbs, Larry; Thomassen, Mary Jane
Recent studies suggest additive effects of environmental pollutants and microbial antigens on respiratory disease. We established a granuloma model in which instilled multiwall carbon nanotubes (MWCNT) elicit granulomatous pathology. We hypothesized that mycobacterial antigen ESAT-6, a T cell activator associated with tuberculosis and sarcoidosis, might alter pathology. Wild-type C57Bl/6 mice received MWCNT with or without ESAT-6 peptide. Controls received vehicle (surfactant-PBS) or ESAT-6 alone. Mice were evaluated 60 days later for granulomas, fibrosis, and bronchoalveolar lavage (BAL) cell expression of inflammatory mediators (CCL2, MMP-12, and Osteopontin). Results indicated increased granulomas, fibrosis, and inflammatory mediators in mice receiving the combination of MWCNT+ESAT-6 compared to MWCNT or vehicle alone. ESAT-6 alone showed no significant effect on these pathological endpoints. However, CD3 (+) lymphocyte infiltration of lung tissue increased with MWCNT+ESAT-6 versus MWCNT alone. Findings suggest that concurrent exposure to microbial antigen and MWCNT exacerbates chronic pulmonary disease. PMID:27019768
The respiratory burst oxidase of phagocytes and B lymphocytes is a multicomponent enzyme that catalyzes the one-electron reduction of oxygen by NADPH. It is responsible for the O2-production that occurs when these cells are exposed to phorbol 12-myristate 13-acetate or physiologic stimuli, such as phagocytosis in phagocytes or cross- linking of surface immunoglobulin in B lymphocytes. The activity of this enzyme is greatly diminished or absent in patients with chronic granulomatous disease (C...
Mohsenzadegan, Monireh; Fattahi, Fahimeh; Fattahi, Fatemeh; Mirshafiey, Abbas; Fazlollahi, Mohammad Reza; Naderi Beni, Fariba; Movahedi, Masoud; Pourpak, Zahra
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder characterized by a greatly increased susceptibility to severe fungal and bacterial infections caused by defects in NADPH oxidase of phagocytic cells. We aimed to investigate immunophenotype alterations of naïve and memory B cells and B1a cells in peripheral whole blood from Iranian patients with CGD. Flow cytometric analysis was performed on peripheral blood samples from 31 CGD patients and 23 healthy controls (HC) to study naïve (IgD+/CD27-), memory (CD27+) B and B1a (CD5+) cells. Soluble CD27 (sCD27) and immunoglobulins were also measured by ELISA and the nephelometric method, respectively. We found significantly higher levels of naïve B cells and B1a cells but lower levels of memory B cells in CGD patients compared to HC.. There was no significant difference in soluble CD27 (sCD27) alteration between CGD patients and HC. Our findings suggested a role for NADPH oxidase in process of B cell differentiation and impairing conversion of naïve B cells to memory B cells and altered B1a cells in CGD patients. Increased susceptibility of CGD patients to opportunistic infections and autoimmune disorders could be partly explained by the altered phenotype of B lymphocytes in these patients. PMID:24659119
Ben-Farhat, Khaoula; Ben-Mustapha, Imen; Ben-Ali, Meriem; Rouault, Karen; Hamami, Saber; Mekki, Najla; Ben-Chehida, Amel; Larguèche, Beya; Fitouri, Zohra; Abdelmoula, Selim; Khemiri, Monia; Guediche, Mohamed-Neji; Boukthir, Samir; Barsaoui, Sihem; Chemli, Jalel; Barbouche, Mohamed-Ridha
Chronic granulomatous disease (CGD) is the prototypic functional neutrophil disorder caused by genetic defects in one of the five genes encoding the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase subunits of phagocytes. Mutations causing the most prevalent form of CGD in western populations are located in the X-linked-CYBB gene. The four remaining autosomal recessive (AR) forms collectively account for one-third of CGD cases. We investigated the clinical and molecular features of eleven patients with CGD from 6 consanguineous families, originating from contiguous regions in the west of Tunisia. The patients' clinical phenotype is characterized by a high incidence of mycobacterial infections. Five out of the eleven patients died despite treatment arguing in favor of a severe clinical form of CGD. These findings correlated with the absence of functional p67phox protein as well as the absence of residual reactive oxygen intermediates (ROI) production. Genetic analysis showed the presence, in all patients, of a unique mutation (c.257 + 2T > C) in NCF2 gene predicted to affect RNA splicing. Segregating analysis using nine polymorphic markers overlapping the NCF2 gene revealed a common haplotype spanning 4.1 Mb. The founder event responsible for this mutation was estimated to have arisen approximately 175 years ago. These findings will facilitate the implementation of preventive approaches through genetic counseling in affected consanguineous families. PMID:27220316
Full Text Available Chronic granulomatous disease (CGD is a rare primary immunodeficiency disorder characterized by a greatly increased susceptibility to severe fungal and bacterial infections caused by defects in NADPH oxidase of phagocytic cells. We aimed to investigate immunophenotype alterations of naïve and memory B cells and B1a cells in peripheral whole blood from Iranian patients with CGD. Flow cytometric analysis was performed on peripheral blood samples from 31 CGD patients and 23 healthy controls (HC to study naïve (IgD+/CD27-, memory (CD27+ B and B1a (CD5+ cells. Soluble CD27 (sCD27 and immunoglobulins were also measured by ELISA and the nephelometric method, respectively. We found significantly higher levels of naïve B cells and B1a cells but lower levels of memory B cells in CGD patients compared to HC.. There was no significant difference in soluble CD27 (sCD27 alteration between CGD patients and HC. Our findings suggested a role for NADPH oxidase in process of B cell differentiation and impairing conversion of naïve B cells to memory B cells and altered B1a cells in CGD patients. Increased susceptibility of CGD patients to opportunistic infections and autoimmune disorders could be partly explained by the altered phenotype of B lymphocytes in these patients.
Wolach, Baruch; Scharf, Yitshak; Gavrieli, Ronit; de Boer, Martin; Roos, Dirk
Most patients with chronic granulomatous disease (CGD) have mutations in the X-linked CYBB gene that encodes gp91phox, a component of the phagocyte NADPH oxidase. The resulting X-linked form of CGD is usually manifested in boys. Rarely, X-CGD is encountered in female carriers with extreme expression of the mutated gene. Here, we report on a woman with a novel mutation in CYBB (CCG[90-92]-->GGT), predicting Tyr30Arg31-->stop, Val in gp91phox, who presented with clinical symptoms at the age of 66. The mutation was present in heterozygous form in genomic DNA from her leukocytes but was fully expressed in mRNA from these cells, indicating that in her leukocytes the X chromosome carrying the nonmutated CYBB allele had been inactivated. Indeed, only 0.4% to 2% of her neutrophils showed NADPH oxidase activity. This extreme skewing of her X-chromosome inactivation was not found in her cheek mucosal cells and is thus not due to a general defect in gene methylation on one X chromosome. Moreover, the CYBB mutation was not present in the DNA from her cheek cells and was barely detectable in the DNA from her memory T lymphocytes. Thus, this patient shows a somatic mosaic for the CYBB mutation, which probably originated during her lifetime in her bone marrow. PMID:15308575
Uzel, Gulbu; Orange, Jordan S.; Poliak, Nina; Marciano, Beatriz E.; Heller, Theo; Holland, Steven M.
Background. Chronic granulomatous disease (CGD) is a genetic disorder of the phagocyte NADPH oxidase, which predisposes patients to infections and inflammatory complications, including severe colitis. Management of CGD colitis is a challenge because standard immunosuppressive therapy increases the risk of infection in already immunocompromised hosts.
Greenberg, David E; Sturdevant, Daniel E; Marshall-Batty, Kimberly R; Chu, Jessica; Pettinato, Anthony M; Virtaneva, Kimmo; Lane, John; Geller, Bruce L; Porcella, Stephen F; Gallin, John I; Holland, Steven M; Zarember, Kol A
Polymorphonuclear leukocytes (PMN) from patients with chronic granulomatous disease (CGD) fail to produce microbicidal concentrations of reactive oxygen species (ROS) due to mutations in NOX2. Patients with CGD suffer from severe, life-threatening infections and inflammatory complications. Granulibacter bethesdensis is an emerging Gram-negative pathogen in CGD that resists killing by PMN of CGD patients (CGD PMN) and inhibits PMN apoptosis through unknown mechanisms. Microarray analysis was used to study mRNA expression in PMN from healthy subjects (normal PMN) and CGD PMN during incubation with G. bethesdensis and, simultaneously, in G. bethesdensis with normal and CGD PMN. We detected upregulation of antiapoptotic genes (e.g., XIAP and GADD45B) and downregulation of proapoptotic genes (e.g., CASP8 and APAF1) in infected PMN. Transcript and protein levels of inflammation- and immunity-related genes were also altered. Upon interaction with PMN, G. bethesdensis altered the expression of ROS resistance genes in the presence of normal but not CGD PMN. Levels of bacterial stress response genes, including the ClpB gene, increased during phagocytosis by both normal and CGD PMN demonstrating responses to oxygen-independent PMN antimicrobial systems. Antisense knockdown demonstrated that ClpB is dispensable for extracellular growth but is essential for bacterial resistance to both normal and CGD PMN. Metabolic adaptation of Granulibacter growth in PMN included the upregulation of pyruvate dehydrogenase. Pharmacological inhibition of pyruvate dehydrogenase by triphenylbismuthdichloride was lethal to Granulibacter. This study expands knowledge of microbial pathogenesis of Granulibacter in cells from permissive (CGD) and nonpermissive (normal) hosts and identifies potentially druggable microbial factors, such as pyruvate dehydrogenase and ClpB, to help combat this antibiotic-resistant pathogen. PMID:26283340
Full Text Available Chronic granulomatous disease (CGD, a rare inherited primary immunodeficiency disorder, is caused by mutation in any one of the genes encoding components of nicotinamide adenine dinucleotide phosphate (NADPH-oxidase enzyme. NCF2 gene (encoding P67-phox component is one of them and its mutation is less common to cause CGD (around 5-6%. Here, we assessed mutation analysis of NCF2 in 4 CGD patients with p67-phox defect in Iran.These patients showed classical CGD symptoms. NCF2 sequence analyses revealed two different homozygous mutations including a nonsense mutation in exon 4, c.304C>T (Arg102X in one case and a CA deletion in exon 13 (Leu346fsX380 in one brother and sister;the latter is a new mutation which has not been reported in previous studies.In another patient in whom the attempts to amplify exon 2 individually from genomic DNA were unsuccessful, PCR amplification of exon 2 revealed no band of this exon on agarose gel. A PCR amplification mix of exon 2 and exon 7, with an internal control, confirmed the lack of exon 2 in this patient. Although a gross deletion in other exons of NCF2 has been previously reported, a large deletion encompassing exon 2 has been not reported yet. This abstract was also presented in ESID 2012, Florence, Italy.
Relationship of protein phosphorylation to the activation of the respiratory burst in human neutrophils. Defects in the phosphorylation of a group of closely related 48-kDa proteins in two forms of chronic granulomatous disease
When 32P-labeled human neutrophils were activated by exposure to phorbol myristate acetate, three 48-kDa proteins (designated pp48/6.8, pp48/7.3, and pp48/7.8, from their isoelectric points) were found to have become labeled. With maximal stimulation, labeling was complete by 30 s. With lesser degrees of stimulation, the extent of labeling at 2 min correlated with rates of production by the phorbol-treated cells. Increased labeling of these 48-kDa proteins was also seen in cells exposed to f-Met-Leu-Phe. In phorbol-treated neutrophils from patients with X-linked cytochrome b558-negative chronic granulomatous disease, pp48/7.8 was labeled in a normal fashion, but pp48/6.8 and pp48/7.3 failed to take up 32P. In cells from patients with autosomal recessive cytochrome b558-positive chronic granulomatous disease, however, none of the three proteins took up 32P in response to phorbol. The three proteins appear to be very closely related, as indicated by the findings that phosphoserine was the only phosphoamino acid found in any of the three, and all three yielded identical one-dimensional phosphopeptide maps after digestion with either chymotrypsin or staphylococcal proteinase V8. These results reconcile earlier observations on protein phosphorylation in chronic granulomatous disease and provide further evidence for a relationship between the phosphorylation of this group of 48-kDa proteins and the activation of the respiratory burst oxidase
Relationship of protein phosphorylation to the activation of the respiratory burst in human neutrophils. Defects in the phosphorylation of a group of closely related 48-kDa proteins in two forms of chronic granulomatous disease
Okamura, N.; Curnutte, J.T.; Roberts, R.L.; Babior, B.M.
When 32P-labeled human neutrophils were activated by exposure to phorbol myristate acetate, three 48-kDa proteins (designated pp48/6.8, pp48/7.3, and pp48/7.8, from their isoelectric points) were found to have become labeled. With maximal stimulation, labeling was complete by 30 s. With lesser degrees of stimulation, the extent of labeling at 2 min correlated with rates of production by the phorbol-treated cells. Increased labeling of these 48-kDa proteins was also seen in cells exposed to f-Met-Leu-Phe. In phorbol-treated neutrophils from patients with X-linked cytochrome b558-negative chronic granulomatous disease, pp48/7.8 was labeled in a normal fashion, but pp48/6.8 and pp48/7.3 failed to take up 32P. In cells from patients with autosomal recessive cytochrome b558-positive chronic granulomatous disease, however, none of the three proteins took up 32P in response to phorbol. The three proteins appear to be very closely related, as indicated by the findings that phosphoserine was the only phosphoamino acid found in any of the three, and all three yielded identical one-dimensional phosphopeptide maps after digestion with either chymotrypsin or staphylococcal proteinase V8. These results reconcile earlier observations on protein phosphorylation in chronic granulomatous disease and provide further evidence for a relationship between the phosphorylation of this group of 48-kDa proteins and the activation of the respiratory burst oxidase.
Andrés Augusto Arias Sierra
Full Text Available Reactive oxygen species (ROS production by phagocytes is an important mechanism to kill invading microorganisms. Neutrophils from individuals with chronic granulomatous disease (CGD do not produce ROS, thereby rendering these individuals more susceptible to infection. CGD results from mutations in the genes encoding essential subunits of respiratory burst NADPH oxidase, the enzyme complex necessary for the production of these reactive molecules. The absence of phagocyte ROS results in recurrent fungal and bacterial infections and inflammatory granulomas, associated with significant morbidity and mortality. Currently, the curative treatment is the allogenic bone marrow transplant (BMT; nevertheless, this therapy has some disadvantages including the HLA incompatibility, the immunosupression due to the myeloablative conditions necessary for the transplant and the high risk to develop graft vs. host disease. As an alternative to BMT the ex vivo gene therapy in hematopoietic stem cells has been intensely studied. Although this option could be the most appropriate treatment, it can give rise to other kinds of adverse effects. The genetic features of CGD have made it a very attractive candidate to be cured with gene therapy. This review summarizes and discusses the current advances about gene therapy and its application to CGD. El sistema NADPH oxidasa de las células fagocíticas es un complejo enzimático encargado de producir anión superóxido durante la respuesta contra los microorganismos. Mutaciones en los genes que codifican para las proteínas de este sistema son responsables de la Enfermedad Granulomatosa Crónica (EGC que es una inmunodeficiencia primaria caracterizada por la presencia de infecciones recurrentes debidas a un grupo específico de microorganismos, principalmente oportunistas. Actualmente el tratamiento para la mayoría de los pacientes con EGC está dirigido a la prevención o al control de los procesos infecciosos, pero no a
Zelazny, Adrian M.; Ding, Li; Elloumi, Houda Z.; Brinster, Lauren R; Benedetti, Fran; Czapiga, Meggan; Ulrich, Ricky L.; Ballentine, Samuel J.; Goldberg, Joanna B.; Sampaio, Elizabeth P.; Holland, Steven M.
Chronic granulomatous disease (CGD) patients are susceptible to life-threatening infections by the Burkholderia cepacia complex. We used leukocytes from CGD and healthy donors and compared cell association, invasion, and cytokine induction by Burkholderia multivorans strains. A CGD isolate, CGD1, showed higher cell association than that of an environmental isolate, Env1, which correlated with cell entry. All B. multivorans strains associated significantly more with cells from CGD patients tha...
Gurleyik, Gunay; Aktekin, Ali; Aker, Fugen; Karagulle, Hikmet; Saglamc, Abdullah
Purpose Idiopathic granulomatous lobular mastitis (IGLM) is a rare chronic inflammatory disease of the breast with obscure etiology that mimics invasive carcinoma both clinically and radiologically. The treatment of IGLM remains controversial. The aim of proper management is to use a combination of medical and surgical treatment of this benign condition to achieve a good cosmetic result and low recurrence rate. Methods A retrospective analysis of 19 patients with IGLM is performed based on th...
Full Text Available Purpose. This study aimed to investigate the autoimmune basis of idiopathic granulomatous mastitis (IGM by determining the anti-nuclear antibody (ANA and extractable nuclear antigen (ENA levels of patients diagnosed with IGM. Material and Methods. Twenty-six IGM patients were evaluated. Serum samples were analyzed for autoantibodies by indirect immunofluorescence (IIF using a substrate kit that induced fluorescein-conjugated goat antibodies to human immunoglobulin G (IgG. IIF patterns were read at serum dilutions of 1 : 40 and 1 : 100 for ANA positivity. Using the immunoblot technique, the sera of patients were assayed at dilutions of 1 : 40 and 1 : 100 for human autoantibodies of the IgG class to 15 lines of highly purified ENAs. Results. In the IIF studies for ANA, positivity was identified for four different patterns in the 1 : 40 diluted preparations, for three different patients in the 1 : 100 diluted preparations and only one pattern was identified at the 1 : 320 dilution. In the ENA studies, positivity was identified for four different pattern in the 1 : 40 dilution, and only one pattern was identified at the 1 : 100 dilution. Conclusion. This study was not able to support the eventual existence of an autoimmune basis for IGM.
Luís Roberto C. M. Bonilha
Full Text Available OBJETIVO: Relatar caso ilustrativo de doença granulomatosa crônica cujo diagnóstico ocorreu durante o aparecimento do primeiro episódio infeccioso, colaborando com a iniciativa do Brazilian Group for Immunodeficiency para a sensibilização do pediatra geral em relação ao diagnóstico precoce das imunodeficiências primárias, o que está associado a melhor qualidade de vida e maior sobrevida desses indivíduos. DESCRIÇÃO DE CASO: Paciente do sexo masculino, 39 dias de vida, admitido em pronto-socorro pediátrico por febre alta há cinco dias e irritabilidade. No dia seguinte, observou-se abscesso cervical, isolando-se Staphylococcus aureus comunitário. Durante a internação, ocorreram outros abscessos superficiais e em cadeias ganglionares profundas, além de resposta lenta aos antimicrobianos. Solicitou-se investigação para imunodeficiências, que confirmou a hipótese de doença granulomatosa crônica por quantificação dos ânions superóxido e teste de redução do nitrobluetetrazolio. Paciente foi encaminhado a serviço especializado, no qual identificou-se doador de medula óssea compatível, realizando-se o transplante seis meses após o diagnóstico. Quatro meses após o transplante, ocorreu normalização do burst oxidativo, indicando sucesso. COMENTÁRIOS: O paciente mostrou apresentação típica da doença, o que permitiu seu diagnóstico por pediatras gerais já na primeira infecção, tendo como consequência o acompanhamento por especialistas em imunodeficiências primárias, a introdução da profilaxia antimicrobiana e a procura bem sucedida de doador de medula HLA-compatível.OBJECTIVE: To report a case of chronic granulomatous disease diagnosed during the first infectious episode in order to collaborate with the Brazilian Group for Immunodeficiency, in sensitizing the general pediatrician that the early diagnosis of primary immunodeficiency results in better quality of life and longer life expectancy for the
Ten cases of acquired antibody deficiency syndrome with chronic granulomatous infection were diagnosed in our hospital during the past 10 years. We were able to perform a retrospective analysis of the initial and follow-up chest radiographs in 8 of these patients. The following pathological findings could be demonstrated: 1. increased bronchovascular markings in the basal lung fields, 2. reticular densities in the middle and basal lung fields, 3. confluent nodular densities of varying size in the periphery of the basal and middle fields, 4. pulmonary infiltrates in the middle and lower lobes, 5. hilar node enlargement of moderate extent. Findings 2, 3 and 5 completely disappeared under steroid therapy whereas 1 showed only partial recovery. If both the radiologic and serologic findings are considered, it is possible to differentiate this disease from sarcoidosis. (orig.)
Madden, Jesse L; Schober, Michelle E; Meyers, Rebecka L.; Bratton, Susan L.; Holland, Steven M.; Hill, Harry R; Rollins, Michael D
A 9-year-old boy presented with pneumonia, bilateral pulmonary lesions, and fulminant respiratory failure requiring support with extracorporeal membrane oxygenation (ECMO). Open lung biopsy and subsequent bronchoscopy identified Nocardia cyriacigeorgica and Burkholderia cepacia pneumonia. Chronic granulomatous disease (CGD) was diagnosed by an abnormal neutrophil oxidative burst assay. An aggressive diagnostic and therapeutic strategy, which included ECMO, allowed for patient survival and ret...
van den Berg, J Merlijn; van Koppen, Elsbeth; Ahlin, Anders;
CGD is an immunodeficiency caused by deletions or mutations in genes that encode subunits of the leukocyte NADPH oxidase complex. Normally, assembly of the NADPH oxidase complex in phagosomes of certain phagocytic cells leads to a "respiratory burst", essential for the clearance of phagocytosed m...... the clinical course of CGD in Europe and hopefully can help to increase awareness and optimize the treatment of these patients....
Chronic inflammation is a result of long lasting of acute inflammation, if not treated or resolved, this condition is a cause of many inflammatory and autoimmune diseases. Aegiceras corniculatum a mangrove plant has been using for many years for the treatment of many inflammatory and autoimmune diseases like atherosclerosis, rheumatoid arthritis, asthma and is well known as a folklore medicine constituting various novel chemical constituents. Methodology: Methanol and ethyl acetate extracts derived from A. corniculatum were evaluated against chronic inflammation by using cotton pellet induced granuloma and Adjuvant induced arthritis models in rats. Vascular permeability and leukocyte migration were studied in the presence of extracts. Results: In cotton pellet granuloma, both the methanol and ethanol extracts were found to highly effective in reducing granulomatous tissue formation in a dose dependent manner. These extracts also suppressed the paw thickness induced by using adjuvant in rat arthritis model, at maximum oral dose of 50 mg/kg methanol extract inhibited swelling in paw by 67%, whereas ethyl acetate extract caused 75% of inhibition in paw swelling at 200 mg/kg. Additionally, ethyl acetate extract has shown inhibition in leukocytes migration (63% at 50 mg/kg) against LTB4 and carrageenan. However, methanol extract failed to produce inhibitory effect against cell infiltration induced by LTB4. Interestingly, methanol and ethyl acetate extract has shown remarkable reduction in the acetic acid induced vascular permeability. Conclusion: A. corniculatum extracts has shown remarkable effect as an anti-arthritic and anti-inflammatory agent to combat with chronic inflammatory diseases, this study provides significant justification for its folklore medical use against rheumatism interfering with inflammatory and cellular immune responses. (author)
Rae, William; Doffinger, Rainer; Shelton, Fenella; Sproson, Eleanor; Ismail-Koch, Hasnaa; Lund, Valerie J.; Harries, Philip G.; Eren, Efrem
Background: Chronic granulomatous invasive fungal rhinosinusitis (CGIFRS) is a rare disease. The underlying immune responses that drive the development of CGIFRS, as opposed to successful pathogen clearance and controlled inflammation, are not currently known. Objective: To characterize the immune responses associated with CGIFRS. Methods: In addition to a battery of basic investigations, more in-depth immunologic testing involves ex vivo whole-blood stimulation with the polyclonal T-cell mitogen phytohemagglutinin and fungal antigens with interleukin (IL) 12, was undertaken to investigate cell-mediated immune responses associated with CGIFRS. Results: Ex vivo whole-blood stimulation with the polyclonal T-cell mitogen phytohemagglutinin and fungal antigens with IL-12 identified reduced interferon gamma and increased IL-17A levels within the supernatant, which indicated increased in vivo T-helper (Th)17 responses and impaired Th1 responses compared with healthy controls. Conclusion: These findings suggest that the development of CGIFRS may be associated with an abnormally exaggerated host Th17 response, which caused failure to clear the fungal pathogen with refractory fungal infection of mucosal membranes, resulting in chronic tissue inflammation.
Liomara Andressa do Amaral Kwirant
Full Text Available A 4-year-old Criollo stallion was presented at the equine clinic of veterinary hospital of the Federal University of Santa Maria, RS, with a 30-day history of progressive weight loss, anemia and swelling of the forelimbs and face. Physical examination revealed that the swelling was firm and had a bone-like consistency, also radiographs showed extensive periosteal proliferation on the forelimb long bones that suggested hypertrophic osteopathy (Marie´s disease. Physical examinations identified no respiratory findings. However, during ultrasound examination, superficial lung disease was identified. The animal was treated with antibiotics and nonsteroidal anti-inflammatory drugs for 12 days. Due to a complete lack of response to this treatment, the horse was euthanized. At necropsy several granulomatous lesions were identified in the thorax, abdomen and testicular tunics. Bony proliferation was evident on many bones of the appendicular skeleton and face. Based on these findings the diagnosis of hypertrophic osteopathy associated with sarcoidosis was established. It is important to perform a thorough clinical examination and include hypertrophic osteopathy in the differential diagnosis of diseases that are accompanied by swelling of the face and limbs as edema from various causes, fibrous osteodystrophy, for example. Key words: Pulmonary. Periosteal. Sarcoidosis. Pathology
Nasr, Samih H; Shanafelt, Tait D; Hanson, Curtis A; Fidler, Mary E; Cornell, Lynn D; Sethi, Sanjeev; Chaffee, Kari G; Morris, Joseph; Leung, Nelson
Granulomatous interstitial nephritis (GIN) is an uncommon pathologic lesion encountered in 0.5% to 5.9% of renal biopsies. Drugs, sarcoidosis, and infections are responsible for most cases of GIN. Malignancy is not an established cause of GIN. Here, we report a series of 5 patients with GIN secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients were mostly elderly white males with an established history of CLL/SLL who presented with severe renal impairment (median peak serum creatinine, 7.3 mg/dL), leukocyturia, and mild proteinuria. One had nephromegaly. In 2 patients, the development and relapse of renal insufficiency closely paralleled the level of lymphocytosis. Kidney biopsy in all patients showed GIN concomitant with CLL/SLL leukemic interstitial infiltration. Granulomas were nonnecrotizing and epithelioid and were associated with giant cells. One biopsy showed granulomatous arteritis. One patient had a granulomatous reaction in lymph nodes and skin. Steroids with/without CLL/SLL-directed chemotherapy led to partial improvement of kidney function in all patients except 1 who had advanced cortical scarring on biopsy. In conclusion, we report an association between CLL/SLL and GIN. Patients typically present with severe renal failure due to both GIN and leukemic interstitial infiltration, which tends to respond to steroids with/without CLL/SLL-directed chemotherapy. The pathogenesis of GIN in this clinical setting is unknown but may represent a local hypersensitivity reaction to the CLL/SLL tumor cells. PMID:25795422
Molecular characterization in patients with chronic granulomatous disease due to p47phox deficiency Caracterización molecular en pacientes con enfermedad granulomatosa crónica por deficiencia en p47 phox
Diana García de Olarte
Full Text Available NADPH oxidase system is an enzymatic electron transport complex localized in the membrane of phagocytic cells. Several proteins belong to this system: A flavocytochrome b558, formed by a b chain (gp91.phox and an a chain (p22.phox and, at least, 3 cytosolic proteins (p47.phox, p67.phox and p40 phox. Genetic alteration in any of these proteins causes the syndrome of Chronic Granulomatous Disease (CGD. Characterization of mutations in patients with CGD has been fundamental to elucidate the structure and function of NADPH oxidase system ComponentS. Several findings make p47.phoX an interesting model to study the molecular mechanism involved in regulating the expreSSion and bioChemical function ofthis system. So far, in patients with p47.phoX defect a deletion of dinucleotide GT has been foUnd at the beginning of exon 2; most of them are homocygotic for this deletion which is probably due to recombinant events between normal p47.phoX gen and a recently described pseudogen. Any mutation found when diagnosing non.homocygotic patients (gDNA or cDNA may represent a pseudogen change. Therefore, for precise identification of the genetic defect it is necessary to separate the normal gen from the pseudogen and to analyze individual sequences. Non.homocygotic patients posibly have a second mutation in the wild type allele different fron GT deletion. On the other hand, through site. oriented mutagenesis it is posible to modify some of the aminoacids or domains of p47.phoX, which may be essential for its function and relationship with CGD. With this method010gy it is possible to introduce changes in a gen whoSe sequence is thoroughly known and which is amplified; mutants So generated can give information concerning the structure and function of the analyzed genes, observing their effect on function. In this way the importance of a structural change on the function of a protein can be determined. El sistema NAOPH oxidasa es un complejo enzimático transportador
... airways disease; Chronic obstructive lung disease; Chronic bronchitis; Emphysema; Bronchitis - chronic ... a protein called alpha-1 antitrypsin can develop emphysema. Other risk factors for COPD are: Exposure to ...
Full Text Available Murine models of human genetic disorders provide a valuable tool for investigating the scope for application of induced pluripotent stem cells (iPSC. Here we present a proof-of-concept study to demonstrate generation of iPSC from a mouse model of X-linked chronic granulomatous disease (X-CGD, and their successful differentiation into haematopoietic progenitors of the myeloid lineage. We further demonstrate that additive gene transfer using lentiviral vectors encoding gp91(phox is capable of restoring NADPH-oxidase activity in mature neutrophils derived from X-CGD iPSC. In the longer term, correction of iPSC from human patients with CGD has therapeutic potential not only through generation of transplantable haematopoietic stem cells, but also through production of large numbers of autologous functional neutrophils.
T.W. Kuijpers; H. IJspeert; E.M.M. van Leeuwen; M.H. Jansen; M.D. Hazenberg; K.C. Weijer; R.A.W. van Lier; M. van der Burg
A girl presented during childhood with a single course of extensive chickenpox and moderate albeit recurrent pneumonia in the presence of idiopathic CD4(+) T lymphocytopenia (ICL). Her clinical condition remained stable over the past 10 years without infections, any granulomatous disease, or autoimm
T.W. Kuijpers (Taco W.); H. IJspeert (Hanna); E.M.M. van Leeuwen (Ester); M.H. Jansen (Machiel H.); M.D. Hazenberg (Mette D.); K. Weijer (Kees); R.A.W. Van Lier (Rene A. W.); M. van der Burg (Mirjam)
textabstractA girl presented during childhood with a single course of extensive chickenpox and moderate albeit recurrent pneumonia in the presence of idiopathic CD4+T lymphocytopenia (ICL). Her clinical condition remained stable over the past 10 years without infections, any granulomatous disease, o
... Content Marketing Share this: Main Content Area "Chronic Lyme Disease" What is "chronic Lyme disease?" Lyme disease is an infection caused by ... J Med 357:1422-30, 2008). How is Lyme disease treated? For early Lyme disease, a short ...
Assimakopoulos Stelios F
Full Text Available Abstract Introduction Lymphadenopathy is found in about 65% of patients with adult-onset Still’s disease and is histologically characterized by an intense, paracortical immunoblastic hyperplasia. Adult-onset Still’s disease has not been previously described as an etiology of suppurative necrotizing granulomatous lymphadenitis. Case presentation We describe a 27-year-old Greek man who manifested prolonged fever, abdominal pain, increased inflammatory markers, episodic skin rash and mesenteric lymphadenopathy histologically characterized by necrotizing granulomatous adenitis with central suppuration. Disease flares were characterized by systemic inflammatory response syndrome with immediate clinico-laboratory response to corticosteroids but the patient required prolonged administration of methylprednisolone at a dose of above 12mg/day for disease control. After an extensive diagnostic work-up, which ruled out any infectious, malignant, rheumatic or autoinflammatory disease the patient was diagnosed as having adult-onset Still’s disease. The patient is currently treated with 4mg of methylprednisolone, 100mg of anakinra daily and methotrexate 7.5mg for two consecutive days per week and exerts full disease remission for six months. Conclusion To the best of our knowledge this is the first report of suppurative necrotizing granulomatous lymphadenitis attributed to adult-onset Still’s disease. This case indicates that the finding of a suppurative necrotizing granulomatous lymphadenitis should not deter the consideration of adult-onset Still’s disease as a potential diagnosis in a compatible clinical context; however, the exclusion of other diagnoses is a prerequisite.
Approximately 10% of patients with common variable immune deficiency have systemic granulomatous disease with associated interstitial lung disease. From a population of patients with CVID attending a large tertiary referral clinic for primary immunodeficiency diseases we selected a cohort who had a restrictive defect or impaired gas transfer on pulmonary function testing and/or histologically proven granulomatous disease. HRCT scans of the thorax were reviewed retrospectively in 18 patients by two radiologists. Thirteen patients had diffuse reticulation, which varied from fine to coarse with features of fibrosis. Nodules were found in eight patients. In seven, these were associated with reticulation and in one they were an isolated finding. Bronchiectasis was found as the only abnormality in three and in addition to diffuse reticulation or nodules in another three patients. Greater appreciation of the spectrum of the radiological abnormalities in CVID patients with interstitial lung disease is important. Deteriorating lung function in patients with granulomatous CVID may be secondary to interstitial lung disease rather than bronchiectasis, and treatment should be tailored accordingly
Park, J.E.S. [Royal Free and Hampstead NHS Trust, Pond Street, London NW3 2QG (United Kingdom); Beal, I. [Royal Free and Hampstead NHS Trust, Pond Street, London NW3 2QG (United Kingdom); Dilworth, J.P. [Royal Free and Hampstead NHS Trust, Pond Street, London NW3 2QG (United Kingdom); Tormey, V. [Royal Free and Hampstead NHS Trust, Pond Street, London NW3 2QG (United Kingdom); Haddock, J. [Royal Free and Hampstead NHS Trust, Pond Street, London NW3 2QG (United Kingdom)]. E-mail: email@example.com
Approximately 10% of patients with common variable immune deficiency have systemic granulomatous disease with associated interstitial lung disease. From a population of patients with CVID attending a large tertiary referral clinic for primary immunodeficiency diseases we selected a cohort who had a restrictive defect or impaired gas transfer on pulmonary function testing and/or histologically proven granulomatous disease. HRCT scans of the thorax were reviewed retrospectively in 18 patients by two radiologists. Thirteen patients had diffuse reticulation, which varied from fine to coarse with features of fibrosis. Nodules were found in eight patients. In seven, these were associated with reticulation and in one they were an isolated finding. Bronchiectasis was found as the only abnormality in three and in addition to diffuse reticulation or nodules in another three patients. Greater appreciation of the spectrum of the radiological abnormalities in CVID patients with interstitial lung disease is important. Deteriorating lung function in patients with granulomatous CVID may be secondary to interstitial lung disease rather than bronchiectasis, and treatment should be tailored accordingly.
Kuijpers, Taco W.; IJspeert, Hanna; Leeuwen, Ester; Jansen, Machiel H.; Mette D Hazenberg; Weijer, Kees; Van Lier, Rene A. W.; van der Burg, Mirjam
textabstractA girl presented during childhood with a single course of extensive chickenpox and moderate albeit recurrent pneumonia in the presence of idiopathic CD4+T lymphocytopenia (ICL). Her clinical condition remained stable over the past 10 years without infections, any granulomatous disease, or autoimmunity. Immunophenotyping demonstrated strongly reduced naive T and B cells with intact proliferative capacity. Antibody reactivity on in vivo immunizations was normal. T-cell receptor-Vβ r...
Silva Aloísio S. Felipe da
Full Text Available Some kinds of interstitial pneumonia present a histopathological pattern dominated by sarcoid - necrotizing or non-necrotizing - granulomas, which can be divided into two main groups: infectious and non-infectious. The infectious causes include tuberculosis, histoplasmosis, fungi in general, paracoccidioidomycosis, ascaridiasis, echinococcosis and dirophilariosis. The non-infectious causes include histiocytosis-X, hipersensitivity pneumonia, vasculitis, lymphomas, sarcoidosis, and pneumoconioses such as silicosis and berylliosis. The purpose of this review is to provide a practical guideline to enable general pathologists to make the differential diagnosis of granulomatous pulmonary diseases. For this purpose, anatomical-clinical-radiological correlations will be presented and targeted to each diagnosis discussed. Whenever a granulomatous inflammatory process is in progress, the search for infective agents by direct observation, by culture, and by histochemical methods should be mandatory. The histological aspects of infectious granulomas to be analyzed should include their random histo-anatomical location, the type of inflammatory reaction, and necrosis. A panel of complementary reactions (immunohistochemistry and PCR should identify the infectious agent and, whenever their results and the culture are negative, the possibility of non-infectious granulomatous diseases has to be evaluated. In such cases, the histo-anatomical distribution (bronchocentric, lymphangitic, angiocentric, random, the qualitative characteristics of the lesions (type of necrosis and inflammatory reaction, and the correlation with the X-ray findings will help the diagnosis.
Liomara Andressa do Amaral Kwirant; Flavio Desessards De La Côrte; Karin Erica Brass; Cláudio Severo Lombardo de Barros; Ricardo Barbosa Lucena; Maria Elisa Trost; Rafael Costa Ebling; Mariana Cocco
A 4-year-old Criollo stallion was presented at the equine clinic of veterinary hospital of the Federal University of Santa Maria, RS, with a 30-day history of progressive weight loss, anemia and swelling of the forelimbs and face. Physical examination revealed that the swelling was firm and had a bone-like consistency, also radiographs showed extensive periosteal proliferation on the forelimb long bones that suggested hypertrophic osteopathy (Marie´s disease). Physical examinations identified...
Seo, Hee Ri Na; Na, Kuk Young; Yim, Hyun Ee; Kim, Tae Hee; Kang, Doo Kyoung; Oh, Ki Keun; Kang, Seok Yun; An, Young-Sil; Chun, Mison; Kim, Woojae; Park, Rae Woong; Jung, Yong Sik; Kim, Ku Sang
Purpose Idiopathic granulomatous mastitis (IGM) is a rare chronic inflammatory disease of unknown etiology. The diagnosis of IGM requires that other granulomatous lesions in the breast be excluded. Tuberculous mastitis (TM) is also an uncommon disease that is often difficult to differentiate from IGM. The purpose of this study is to develop a new algorithm for the differential diagnosis and treatment of IGM and TM. Methods Medical records of 68 patients (58 with IGM and 10 with TM) between Ju...
Newman, L. S.; Lloyd, J.; Daniloff, E.
With the advent of in vitro immunologic testing, we can now detect exposed individuals who are sensitized to beryllium and those who have chronic beryllium disease (CBD) with lung pathology and impairment. Earlier detection and more accurate diagnostic tools raise new questions about the natural history of sensitization and granulomatous disease. Preliminary data suggest that early detection identifies people who are sensitized to beryllium and that these individuals are at risk for progressi...
Haftel Hilary M
Full Text Available Abstract Background Sulfasalazine is a widely used anti-inflammatory agent in the treatment of inflammatory bowel disease and several rheumatological disorders. Although as many as 20% of treated patients may experience reversible, dose-dependent side effects, less frequent but potentially severe, systemic reactions have also been reported. Case Presentation A severe systemic reaction to sulfasalazine developed in a 21-year old female with rheumatoid arthritis characterized by eosinophilia, granulomatous enteritis and myelotoxicity, cholestatic hepatitis, and seizures. The clinical course and management of this patient are presented as well as a review of the incidence and outcome of severe systemic reactions to sulfasalazine. Conclusions Granulomatous myelotoxicity and enteritis developed in a 21 year old female within 3 weeks of initiating sulfasalazine for rheumatoid arthritis. Following a short course of corticosteroids, the patient had resolution of her cholestatic hepatitis, rash, eosinophilia, and gastrointestinal symptoms with no residual manifestations at 7 months follow-up. Although severe reactions to sulfasalazine are rare and unpredictable, practicing physicians should be aware of unusual clinical presentations of toxicity when prescribing sulfasalazine.
Pathria, Mohini; Urbine, Daniel; Zumberg, Marc Stuart; Guarderas, Juan
A 61-year-old woman presented with longstanding cough and progressive dyspnoea. She underwent an extensive evaluation and was diagnosed with common variable immunodeficiency (CVID) with granulomatous lymphocytic interstitial lung disease (GLILD). She was initially treated with subcutaneous immunoglobulin therapy, having declined intravenous immunoglobulin (IVIG) therapy. She also declined treatment with oral glucocorticoids. Over several months, she became increasingly symptomatic and developed increased pulmonary infiltrates, pleural effusions, mediastinal adenopathy, splenomegaly, pancytopenia and ascites. An interdisciplinary team composed of an immunologist, pulmonologist and haematologist deliberated over a therapeutic management approach. The patient received a recently reported immunotherapy regimen with azathioprine and rituximab. The therapy led to rapid improvement of her constitutional and respiratory symptoms, with clinical and radiographic improvement in her interstitial lung disease, lymphadenopathy, pleural effusions and ascites. This case report reviews the literature surrounding the diagnosis and management of GLILD. PMID:27335365
Rončević Nevenka; Stojadinović Aleksandra; Odri Irena
Introduction. The prevalence of chronic diseases in adolescence is constantly increasing, especially in the last two decades. Adolescence is a period of important changes: body growth and development, sexual development, development of cognitive abilities, change in family relations and between peers, formation of personal identity and personal system of values, making decisions on future occupation etc. Chronic diseases in adolescence. Chronic disorders affect all development issues and repr...
Mutations in any of four known NADPH-oxidase components lead to CGD. X-linked CGD (X-CGD) is caused by defects in CYBB, the gene that encodes gp91-phox. Autosomal recessive (AR) CGD is caused by defects in the genes for p47 phox, p22-phox or p67-phox. The aim of this study was to screen the molecular defect in the fetus of an X-CGD carrier mother and postnatal confirmation of the results. In a family whose first-born child died from X-CGD, fetal DNA was obtained from an ongoing pregnancy by c...
M.Y. Köker; A. Metin; T.T. Özgür; M. de Boer; D. Roos
Mutations in any of four known NADPH-oxidase components lead to CGD. X-linked CGD (X-CGD) is caused by defects in CYBB, the gene that encodes gp91-phox. Autosomal recessive (AR) CGD is caused by defects in the genes for p47 phox, p22-phox or p67-phox. The aim of this study was to screen the molecula
Full Text Available Introduction. The prevalence of chronic diseases in adolescence is constantly increasing, especially in the last two decades. Adolescence is a period of important changes: body growth and development, sexual development, development of cognitive abilities, change in family relations and between peers, formation of personal identity and personal system of values, making decisions on future occupation etc. Chronic diseases in adolescence. Chronic disorders affect all development issues and represent an additional burden for adolescents. The interaction between chronic disorders and various development issues is complex and two-way: the disease may affect development, and development may affect the disease. Developmental, psychosocial and family factors are of great importance in the treatment of adolescents with chronic disorders. Chronic disorders affect all aspects of adolescent life, including relations with peers, school, nutrition, learning, traveling, entertainment, choice of occupation, plans for the future. Physicians should keep in mind that chronic diseases and their treatment represent only one aspect of person's life. Adolescents with chronic diseases have other needs as well, personal priorities, social roles and they expect these needs to be recognized and respected. Adolescent health care should be adjusted to the life style of adolescents.
The global prevalence of physiologically defined chronic obstructive pulmonary disease (COPD) in adults aged >40 yr is approximately 9-10 per cent. Recently, the Indian Study on Epidemiology of Asthma, Respiratory Symptoms and Chronic Bronchitis in Adults had shown that the overall prevalence of chronic bronchitis in adults >35 yr is 3.49 per cent. The development of COPD is multifactorial and the risk factors of COPD include genetic and environmental factors. Pathological changes in COPD are...
Anemia of inflammation; AOCD; ACD ... Anemia is a lower-than-normal number of red blood cells in the blood. Some conditions can lead to anemia of chronic disease include: Autoimmune disorders , such as ...
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Full Text Available Background. Granulomatous myocarditis is one of the mysterious diseases: it occurs extremely rare, clinical signs and symptoms are often absent, it manifested suddenly, unexpectedly by symptoms of acute heart failure, cardiogenic shock or ventricular arrhythmia, usually finished fatally for a short period of time. The etiology and pathogenesis of this disease are unknown. Objective. The purpose of the investigation is to show the clinical course and pathological features of granulomatous myocarditis and its clinical-morphological correlations. Methods. The clinical course and anamnesis of the case were retrospectively analyzed. The data of the postmortem examination was examined in details. Results. We presented a case of idiopathic granulomatous myocarditis with fulminant onset and fatal outcome in 54-year-old man. The disease began suddenly with signs of cardiogenic shock, which was regarded as the debut of myocardial infarction. Despite the intensive care, open chest cardiac massage and artificial circulation patient died soon. Autopsy revealed extensive granulomatous myocarditis with involvement of all parts of the heart, interstitial sclerosis and left ventricle hypertrophy. Antemortal clinical signs of the disease were not observed. Conclusion. Sudden unexpected debut with hyperacute progression and rapid death in previously completely health middle-aged man are typical characteristics of this disease. Multiple foci of substitutive myocardial sclerosis are results of healed granulomas and evidences of chronic course of the disease. It remains unclear why preexisting granulomas had never manifested in the past. Extension and degree of myocardium injury does not coincide with fulminant course of the disease. The cause of the myocarditis as well as the factor which provoked exacerbation of the disease remained uncertain. Citation: Hritsyna IV. [The case of fulminant granulomatous myocarditis]. Morphologia. 2014;8(1:35-9. Ukrainian.
Straub, Rainer H.; Schradin, Carsten
It has been recognized that during chronic inflammatory systemic diseases (CIDs) maladaptations of the immune, nervous, endocrine and reproductive system occur. Maladaptation leads to disease sequelae in CIDs. The ultimate reason of disease sequelae in CIDs remained unclear because clinicians do not consider bodily energy trade-offs and evolutionary medicine. We review the evolution of physiological supersystems, fitness consequences of genes involved in CIDs during different life-history sta...
Barnes, Peter J; Burney, Peter G J; Silverman, Edwin K; Celli, Bartolome R; Vestbo, Jørgen; Wedzicha, Jadwiga A; Wouters, Emiel F M
Chronic obstructive pulmonary disease (COPD) is a common disease with high global morbidity and mortality. COPD is characterized by poorly reversible airway obstruction, which is confirmed by spirometry, and includes obstruction of the small airways (chronic obstructive bronchiolitis) and emphysema, which lead to air trapping and shortness of breath in response to physical exertion. The most common risk factor for the development of COPD is cigarette smoking, but other environmental factors, such as exposure to indoor air pollutants - especially in developing countries - might influence COPD risk. Not all smokers develop COPD and the reasons for disease susceptibility in these individuals have not been fully elucidated. Although the mechanisms underlying COPD remain poorly understood, the disease is associated with chronic inflammation that is usually corticosteroid resistant. In addition, COPD involves accelerated ageing of the lungs and an abnormal repair mechanism that might be driven by oxidative stress. Acute exacerbations, which are mainly triggered by viral or bacterial infections, are important as they are linked to a poor prognosis. The mainstay of the management of stable disease is the use of inhaled long-acting bronchodilators, whereas corticosteroids are beneficial primarily in patients who have coexisting features of asthma, such as eosinophilic inflammation and more reversibility of airway obstruction. Apart from smoking cessation, no treatments reduce disease progression. More research is needed to better understand disease mechanisms and to develop new treatments that reduce disease activity and progression. PMID:27189863
Kuijpers, Taco W; Ijspeert, Hanna; van Leeuwen, Ester M M; Jansen, Machiel H; Hazenberg, Mette D; Weijer, Kees C; van Lier, Rene A W; van der Burg, Mirjam
A girl presented during childhood with a single course of extensive chickenpox and moderate albeit recurrent pneumonia in the presence of idiopathic CD4+ T lymphocytopenia (ICL). Her clinical condition remained stable over the past 10 years without infections, any granulomatous disease, or autoimmunity. Immunophenotyping demonstrated strongly reduced naive T and B cells with intact proliferative capacity. Antibody reactivity on in vivo immunizations was normal. T-cell receptor-Vβ repertoire was polyclonal with a very low content of T-cell receptor excision circles (TRECs). Kappa-deleting recombination excision circles (KRECs) were also abnormal in the B cells. Both reflect extensive in vivo proliferation. Patient-derived CD34+ hematopoietic stem cells could not repopulate RAG2(-/-)IL2Rγc(-/-) mice, indicating the lymphoid origin of the defect. We identified 2 novel missense mutations in RAG1 (p.Arg474Cys and p.Leu506Phe) resulting in reduced RAG activity. This report gives the first genetic clue for ICL and extends the clinical spectrum of RAG mutations from severe immune defects to an almost normal condition. PMID:21502542
SHI Xiu-yan; MA Dong-lai; FANG Kai
A case of cutaneous Rosai-Dorfman disease (CRDD) presenting as a granulomatous rosacea-like rashs was reported. A 45-year-old Chinese woman presented with a 1-month history of a widespread nonpruiginous papulonodular eruption.The rash had begun on her face and rapidly progressed to involve the neck and extremities. She was otherwise healthy,with no history of fever, malaise, or weight loss. Physical examination revealed multiple symmetrically distributed discrete and coalescing red plaques, papules and nodules scattered over the face, neck and extremities. No appreciable lymphadenopathy or hepatosplenomegaly was noted. There was no mucosal involvement. The biopsy specimen obtained from the face demonstrated the epidermis was normal, while the superficial dermis contained sheets of histiocytes with abundant, focally foamy cytoplasm. The histiocytes were surrounded by a patchy lymphocytic and plasma cell infiltrate. There was no significant histiocytic atypia. Some of these histiocytes engulfed, without destroying,lymphocytes and neutrophils (emperipolesis). Immunohistochemical staining revealed that the histiocytes were strongly positive for S100 protein, weakly positive for CD68, and negative for CD1a. A diagnosis of CRDD was made. Oral prednisone therapy was initiated at a dosage of 30 mg/d for 3 weeks and then tapered over the ensuing 2 weeks. After 5weeks of treatment, the lesions had markedly improved.
V K Vijayan
Full Text Available The global prevalence of physiologically defined chronic obstructive pulmonary disease (COPD in adults aged >40 yr is approximately 9-10 per cent. Recently, the Indian Study on Epidemiology of Asthma, Respiratory Symptoms and Chronic Bronchitis in Adults had shown that the overall prevalence of chronic bronchitis in adults >35 yr is 3.49 per cent. The development of COPD is multifactorial and the risk factors of COPD include genetic and environmental factors. Pathological changes in COPD are observed in central airways, small airways and alveolar space. The proposed pathogenesis of COPD includes proteinase-antiproteinase hypothesis, immunological mechanisms, oxidant-antioxidant balance, systemic inflammation, apoptosis and ineffective repair. Airflow limitation in COPD is defined as a postbronchodilator FEV1 (forced expiratory volume in 1 sec to FVC (forced vital capacity ratio <0.70. COPD is characterized by an accelerated decline in FEV1. Co morbidities associated with COPD are cardiovascular disorders (coronary artery disease and chronic heart failure, hypertension, metabolic diseases (diabetes mellitus, metabolic syndrome and obesity, bone disease (osteoporosis and osteopenia, stroke, lung cancer, cachexia, skeletal muscle weakness, anaemia, depression and cognitive decline. The assessment of COPD is required to determine the severity of the disease, its impact on the health status and the risk of future events (e.g., exacerbations, hospital admissions or death and this is essential to guide therapy. COPD is treated with inhaled bronchodilators, inhaled corticosteroids, oral theophylline and oral phosphodiesterase-4 inhibitor. Non pharmacological treatment of COPD includes smoking cessation, pulmonary rehabilitation and nutritional support. Lung volume reduction surgery and lung transplantation are advised in selected severe patients. Global strategy for the diagnosis, management and prevention of Chronic Obstructive Pulmonary Disease
Understanding Task Force Recommendations Screening for Chronic Kidney Disease The U.S. Preventive Services Task Force (Task Force) has issued a final recommendation on Screening for Chronic Kidney Disease (CKD) . This recommendation ...
The etiology of chronic diseases of the ankle joint comprises a wide spectrum including chronic inflammatory processes and chronic degenerative, tumorous and neuropathic processes, as well as some specific syndromes based on chronic changes of the ankle joint. Of the inflammatory processes, chronic juvenile arthritis (JVC) is the most common disease. However, also Reiter disease, psoriasis or chronic monoarthritid diseases such as gout, as well as granulomatous diseases (tuberculosis, sarcoidosis) and fungal infections, may affect the ankle joint in a chronic course. Chronic degenerative changes are usually secondary due to abnormal positioning of the joint constituents or repetitive trauma. Neuropathic changes, as frequently seen in the course of diabetes, present with massive osseous destruction and malposition of the articular constituents. Chronic osseous as well as cartilaginous and synovial changes are seen in hemoplici patients. Chronic traumatic changes are represented by pigmented villonodular synovitis (PVNS), and chondromatosis, both with a predilection for the ankle joint. Due to the possibilities of magnetic resonance imaging (MRI), diagnosis of chronic ankle changes includes chronic ligamentous, tendinous and soft tissue changes. With the use MRI, specific syndromes can be defined which particularly affect the ankle joint in a chronic way, such as the os trigonum syndrome, the anterolateral impingement syndrome and the sinus tarsi syndrome. Nevertheless, plain film radiographs are still the basic element of any investigation. MRI, however, can be potentially used as a second investigation, saving an unnecessary cascade of investigations with ultrasound and CT. The latter investigations are used only with very specific indications, for instance CT for subtle bone structures and sonography for a limited investigation of tendons or evaluation of fluid. Particularly due to the possibilities of MRI and the development of special gradient-echo imaging or
Full Text Available A 21-year-old female presented with erythematous, painful, crusted plaques on her right arm and left thigh of 4 month's duration. There was no history of preceding trauma or constitutional symptoms. Response to oral antibioticas was poor. Clinical differential diagnoses of pyoderma gangrenosum (PG and granulomatous skin diseases such as deep fungal infection, lupus vulgaris and sarcoidosis were considered. Histopathology revealed features of granulomatous variant of PG. The patient was initially treated with dapsone and topical clobetasone propionate but she developed dapsone induced hepatitis and anemia warranting stoppage of the drug. She recovered completely from these side effects and was subsequently treated successfully with intralesional triamcinolone injections.
Full Text Available A 21-year-old female presented with erythematous, painful, crusted plaques on her right arm and left thigh of 4 month's duration. There was no history of preceding trauma or constitutional symptoms. Response to oral antibioticas was poor. Clinical differential diagnoses of pyoderma gangrenosum (PG and granulomatous skin diseases such as deep fungal infection, lupus vulgaris and sarcoidosis were considered. Histopathology revealed features of granulomatous variant of PG. The patient was initially treated with dapsone and topical clobetasone propionate but she developed dapsone induced hepatitis and anemia warranting stoppage of the drug. She recovered completely from these side effects and was subsequently treated successfully with intralesional triamcinolone injections.
Trifunović Gordana; Plavec Goran; Tomić Ilija; Popović Lidija; Stefanović Dušan
Allergic granulomatous angiitis (AGA) - Churg-Strauss syndrome, is a rare autoimmune disease characterized by three distinct clinical phases prodromal, eosinophilic, and vasculitic, and most of respiratory symptoms and signs begin in the first two phases of the disease. Two female patients of different age, who fulfilled the diagnostic criteria for AGA, and were in different phases and with the different duration of the disease are presented. The first patient (24 years of age) was admitted t...
Cellular components of bronchoalveolar lavage (BAL) fluid were studied in 26 sarcoid patients, 8 patients with farmer's lung, 10 healthy controls and 10 control patients. The investigations by Ga scintigraphy or transbronchial lung biopsy (TBLB) and measurement of serum angiotensin converting enzyme (SACE) activity were also carried out in 21 sarcoid patients and 8 patients with farmer's lung. 1) Percentage of foamy cells in alveolar ma crophage fraction, percentage of lymphocytes and number of mast cells were increased significantly in BLA fluid from patients with farmer's lung as compared with that from sarcoid patients. Analysis of cellular component of BAL flu id is useful for differential diagnosis of these diseases. 2) Granulomatous lung lesions were frequently observed in specimens obtained by TBLB from patients with sarcoidosis and farmer's lung who showed abnormal Ga uptake in lung. In contrast, there was no significant difference in percentage of lymphocytes in BAL fluid between patients whose pulmonary Ga uptake was positive and those in whom pulmonary Ga uptake was negative. To investigate the mechanism of pulmonary Ga accumulation in granulomatous lung disease, BAL was performed in 2 sarcoid patients and 3 patients with farmer's lung at 48 to 72 hrs after Ga injection. The radioactivity in cell fractions was evaluated at 96 hrs after Ga injection. Most of the radioactivity was found in macrophages, with little in lymphocytes. Pulmonary Ga uptake in patients with sarcoidosis and farmer' s lung reflects granuloma formation or accumulation of activated macrophages in lung, but not the intensity of T-cell alveolitis. 3) Some relationship among SACE, granulomatous lung lesions in specimens obtained by TBLB and abnormal Ga accumulation in lung or hilar lymphnodes in sarcoid patients was observed, suggesting that SACE might reflect the degree of granuloma formation in sarcoidosis. (J.P.N.)
Hruska, Keith A.; Mathew, Suresh; Lund, Richard; Qiu, Ping; Pratt, Raymond
Observational studies have determined hyperphosphatemia to be a cardiovascular risk factor in chronic kidney disease. Mechanistic studies have elucidated that hyperphosphatemia is a direct stimulus to vascular calcification, which is one cause of morbid cardiovascular events contributing to the excess mortality of chronic kidney disease. This review describes the pathobiology of hyperphosphatemia that develops as a consequence of positive phosphate balance in chronic kidney disease and the me...
... from our online catalog. Alternate Language URL Español Chronic Kidney Disease and Medicines: What You Need to Know Page ... What you need to know Because you have chronic kidney disease, you should take steps to protect your kidneys. ...
Meola, Mario; Samoni, Sara; Petrucci, Ilaria
Chronic tubulointerstitial diseases are a common final pathway toward chronic renal failure regardless the primary damage (glomerular, vascular or directly the tubulointerstitium). Chronic tubulointerstitial nephritis (CTN) is characterized by interstitial scarring, fibrosis and tubule atrophy, resulting in progressive chronic kidney disease. Most frequent causes of CTN are drugs, heavy metals, obstructive uropathy, nephrolithiasis, reflux disease, immunologic diseases, neoplasia, ischemia, metabolic diseases, genetics and miscellaneous. At ultrasound (US), kidneys' morphological aspect is similar in all forms of chronic interstitial nephropathy and only chronic pyelonephritis with or without reflux shows distinguishing characteristics. In interstitial nephropathy, kidneys' profiles are finely irregular and corticomedullary differentiation is altered because of a diffused hyperechogenicity. The only indirect sign of chronic interstitial damage can be derived from the value of intrarenal resistive indexes that hardly overcome 0.75. US is mandatory in clinical chronic pyelonephritis work-up because it provides information on kidney's diameter and on growth nomogram in children. Renal profiles can be more or less altered depending on the number of cortical scars and the presence of pseudonodular areas of segmental compensatory hypertrophy. In the early stages, US diagnosis of renal tuberculosis is difficult because parenchymal lesions are non-specific. US sensitivity in the diagnosis of hydronephrosis is very high, close to 100% and, finally, US is the first choice imaging technique in the diagnosis of urinary lithiasis. PMID:27169608
... American > Chronic Liver Disease Chronic Liver Disease and African Americans Among African Americans, chronic liver disease is a ... white women. At a glance – Cancer Rates for African Americans (2008-2012) Cancer Incidence Rates per 100,000 – ...
Verhaak, P.F.M.; Heijmans, M.J.W.M.; Peters, L.; Rijken, M.
The aim of this study was to achieve a better understanding of the relationship between chronic medical illness and mental distress. Therefore, the association between chronic medical illness and mental distress was analysed, taking into account the modifying effects of generic disease characteristi
Marco Silva; Sara Gomes; Armando Peixoto; Paulo Torres-Ramalho; Hélder Cardoso; Rosa Azevedo; Carla Cunha; Guilherme Macedo
Protein-calorie malnutrition is a transversal condition to all stages of chronic liver disease. Early recognition of micro or macronutrient deficiencies is essential, because the use of nutritional supplements reduces the risk of complications. The diet of patients with chronic liver disease is based on a standard diet with supplements addition as necessary. Restrictions may be harmful and should be individualized. Treatment management should aim to maintain an adequate protein and caloric...
Omland, Oyvind; Würtz, Else Toft; Aasen, Tor Brøvig;
Occupational-attributable chronic obstructive pulmonary disease (COPD) presents a substantial health challenge. Focusing on spirometric criteria for airflow obstruction, this review of occupational COPD includes both population-wide and industry-specific exposures.......Occupational-attributable chronic obstructive pulmonary disease (COPD) presents a substantial health challenge. Focusing on spirometric criteria for airflow obstruction, this review of occupational COPD includes both population-wide and industry-specific exposures....
Full Text Available BACKGROUND: Granulomatous lobular mastitis (GLM is an inflammatory disease of the breast, which can mimic breast cancer in clinical and radiological findings. We conducted the present study in order to determine the diagnostic and other important aspects of this disease. METHODS: In this study, we reviewed the records of 38 patients with granulomatous lobular mastitis in order to describe the clinical, imaging, laboratory, pathologic, and treatment aspects of this disease. RESULTS: All of the patients’ ages were in the range of 22-62 years (mean age: 42 years. All of them had children, history of oral contraceptive pill (OCP usage, antibiotic therapy and mammoplasty. In physical examination, dimpling, edema, inflammation, ulcer, abscess, and firm mass were detected. Size of masses was in the range of 2 × 2 to 8 × 6 cm and their location, in most cases, was in the superior lateral quadrant or central region. In Ultrasonography, a hypoechoic fibroglandular mass and collection, and in pathologic findings, granulomatous reaction was reported. These patients were treated by antibiotics, corticosteroids, and surgery. CONCLUSIONS: GLM is a chronic inflammatory lesion of the breast which can mimic breast cancer. A history of child bearing, lactation, and OCP drug usage have suspicious roles in the formation of GLM. The most common clinical sign in these patients is a painful mass in the breast. We uncovered that clinical and radiological findings are not specific and sufficient for diagnosis of GLM. Therefore, for better diagnosis of this disease, usage of core, incisional, or excisional biopsy are recommended.
Full Text Available Hepatic granulomas are reported in 2-15% of all liver biopsies that are attributable to various causes. Owing to the diverse prognostic and therapeutic implications, a detailed workup of all liver biopsies with granulomatous lesions is mandatory. The cause of the disease may remain obscure in up to 50% cases of "idiopathic granulomatous hepatitis" (IGH. This disease runs a chronic relapsing course. Hepatocellular dysfunction may be an early predominant manifestation unlike that in the available literature. Timely recognition and diagnosis of IGH is imperative as the disease responds well to immunosuppressants that can prevent permanent liver damage. We report a case of a young boy with IGH who was successfully treated with immunosuppressive therapy.
... Disease Organizations . (PDF, 345 KB) Alternate Language URL Anemia in Chronic Kidney Disease Page Content On this ... Nutrition Points to Remember Clinical Trials What is anemia? Anemia is a condition in which the body ...
“Chronic Lyme disease” is a confusing term that has been used to describe very different patient populations. Studies have shown that most patients diagnosed with “chronic Lyme disease” either have no objective evidence of previous or current infection with B. burgdorferi or are patients that should be classified as having post-Lyme disease syndrome, which is defined as continuing or relapsing non-specific symptoms (such as fatigue, musculoskeletal pain, and cognitive complaints) in a patient...
Verhaak, P.F.M.; Heijmans, M.J.W.M.; L. Peters; Rijken, M.
The aim of this study was to achieve a better understanding of the relationship between chronic medical illness and mental distress. Therefore, the association between chronic medical illness and mental distress was analysed, taking into account the modifying effects of generic disease characteristics (concerning course, control and possible stressful consequences), physical quality of life indicators and social and relationship problems. Panel data from the Dutch national Panel of Patients w...
Going, J J; Anderson, T. J.; Wilkinson, S; Chetty, U.
The clinical and pathological features of nine cases of granulomatous mastitis were compared with those of 10 cases of duct ectasia/periductal mastitis (DE/PM), all of which were associated with active granulomatous inflammation. Granulomatous mastitis affects a younger age group, and although there is some overlap with DE/PM, it has distinctive pathological features, particularly a lobule centred distribution, for which the term "granulomatous lobular mastitis" is recommended. There is a str...
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... Many foods contain extra iron (liver, beef, pork, chicken, lima and kidney beans, iron-fortified cereals). Talk to your provider or dietitian about which foods with iron you can eat because of your kidney disease.
Guarino, M; Loperto, I; Camera, S; Cossiga, V; Di Somma, C; Colao, A; Caporaso, N; Morisco, F
Osteoporosis is a complication of chronic liver disease, with impact on morbidity, quality of life, and survival. The progress of medicine and the new therapies stretched the disease's natural history and improved the survival of patients with liver disease. So, it is fundamental to make better the quality of life and to prevent complications. Metabolic bone disorders are common complications of chronic liver disease (CLD). Patients with CLD have an increased risk of bone fractures, with significant impact on morbidity, quality of life, and even on survival. Bone diseases, including osteomalacia, osteoporosis, and osteopenia, are frequently observed in many types of liver disease. The pathogenesis of damage and the mechanisms of bone loss are different in relation to the specific liver disease. The relevance of these conditions induced many authors to create a new nosographic entity known as "hepatic osteodystrophy", although this term is rarely used anymore and it is now commonly referred to as osteopenia or osteoporosis associated with chronic liver disease. This review is based on the personal experiences of the authors and upon research done of the available literature on this subject matter. The authors searched the PubMed database for publications containing the term "liver disease" in combination with "bone disease", "hepatic osteodistrophy", "osteoporosis", "osteopenia", "osteomalacia", and "fractures". They selected publications from the past 10 years but did not exclude older seminal publications, especially for colestatic liver diseases. This review of literature shows that osteoporosis crosses all CLD. It is important to underline that the progress of medicine and the new therapies stretched the disease's natural history and improved the survival of patients with CLD. It is fundamental to make better the quality of life and it is mandatory to prevent complications and in particular the osteoporotic ones, especially fractures. PMID:26846777
... an immune response or “allergy” to beryllium metal, ceramic or alloy, termed beryllium sensitization (BeS). Beryllium sensitization occurs after ... Mroz MM, Newman LS. Beryllium disease screening in ceramics industry: Blood test ... at a metal, alloy and oxide production plant. Occup Environ Med 1997; ...
Alexandre Hassler Príncipe de Oliveira
Full Text Available Relatamos caso de paciente do sexo feminino, brasileira, 23 anos, residente na Alemanha, que cursou com quadro de conjuntivite granulomatosa bilateral crônica, sem acometimento ganglionar, não responsiva a tratamento tópico. A pesquisa laboratorial confirmou diagnóstico de conjuntivite por Bartonella henselae. O caso demonstra que a ausência de acometimento ganglionar não exclui o diagnóstico de doença da arranhadura do gato.We report a case of a 23-year-old female patient, Brazilian, resident of Germany, who presented with a bilateral chronic granulomatous conjunctivitis, without lymphoadenopathy and irresponsive to topical treatment. Laboratorial work-up confirmed Bartonella henselae as the etiologic agent. The case shows that the absence of lymphoadenopathy does not exclude the diagnosis of cat-scratch disease.
S.W.I. Reeder (Suzan)
textabstractIn chapter 1 we provide a general introduction of this thesis. Chronic venous disease (CVD) is a common medical condition that affects 2-64% of the worldwide population and leads to leg ulcers in 1% of the Western population. Venous leg ulceration (VLU) has an unfavorable prognosis with
Full Text Available Non-alcoholic fatty liver disease (NAFLD is the most common cause of chronic liver disease in developed countries and it is now considered a risk factor for cardiovascular disease. Evidence linking NAFLD to the development and progression of chronic kidney disease (CKD is emerging as a popular area of scientific interest. The rise in simultaneous liver-kidney transplantation as well as the significant cost associated with the presence of chronic kidney disease in the NAFLD population make this entity a worthwhile target for screening and therapeutic intervention. While several cross-sectional and case control studies have been published to substantiate these theories, very little data exists on the underlying cause of NAFLD and CKD. In this review, we will discuss the most recent publications on the diagnosis of NAFLD as well new evidence regarding the pathophysiology of NAFLD and CKD as an inflammatory disorder. These mechanisms include the role of obesity, the renin-angiotensin system, and dysregulation of fructose metabolism and lipogenesis in the development of both disorders. Further investigation of these pathways may lead to novel therapies that aim to target the NAFLD and CKD. However, more prospective studies that include information on both renal and liver histology will be necessary in order to understand the relationship between these diseases.
Full Text Available Allergic granulomatous angiitis (AGA - Churg-Strauss syndrome, is a rare autoimmune disease characterized by three distinct clinical phases prodromal, eosinophilic, and vasculitic, and most of respiratory symptoms and signs begin in the first two phases of the disease. Two female patients of different age, who fulfilled the diagnostic criteria for AGA, and were in different phases and with the different duration of the disease are presented. The first patient (24 years of age was admitted to the hospital due to aggravation of asthma, heart failure, and polyneuropathy. The second one (45 years of age was also hospitalized due to the worsening of asthma polyneuropathy, and fever. Both were treated continuously with glucocorticoids. The older patient also received a total of six pulse doses of cyclophosphamide. Satisfactory response to such a treatment was achieved in both cases.
Stem Cell Transplantation; Bone Marrow Transplantation; Peripheral Blood Stem Cell Transplantation; Allogeneic Transplantation,; Genetic Diseases; Thalassemia; Pediatrics; Diamond-Blackfan Anemia; Combined Immune Deficiency; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; X-linked Lymphoproliferative Disease; Metabolic Diseases
Camilo Guarín Patarroyo
Full Text Available Granulomatous epiescleritis nodular disease in canines is a very unusual presentation that affects or external fibrous tunic of the eyeball and conjunctiva, which was an increase similar to a unilateral or bilateral tumor. Suspected immune-mediated disease due to lack of identification of an etiologic agent and the response to treatment with immunosuppressive drugs (Couto, 1992. The ideal therapy is the application of steroids via intralesional, topical or systemic, or other immunosuppressants such as cyclosporine and azathioprine; it is still advisable to apply antibiotic is the ideal combination of tetracycline and neomycin (Gilger & Whitley, 1999. The diagnostic method of episcleritis is made by histopathology, which is evident in changes similar to chronic granulomatous inflammation. Are claiming a racial bias in Alsatian, Shepherd Collie Shetland Shepherd, Coker Spaniel, Rottweiler and Labrador Retriever (Gough & Thomas, 2004. The following case is a report of a nodular epiescleritis affecting the cornea, sclera, and the corneoscleral limbus, which describes the diagnosis, signology and treatment.
Brusasco, Vito; Martinez, Fernando
COPD is characterized by airflow limitation that is not fully reversible. The morphological basis for airflow obstruction results from a varying combination of obstructive changes in peripheral conducting airways and destructive changes in respiratory bronchioles, alveolar ducts, and alveoli. A reduction of vascularity within the alveolar septa has been reported in emphysema. Typical physiological changes reflect these structural abnormalities. Spirometry documents airflow obstruction when the FEV1/FVC ratio is reduced below the lower limit of normality, although in early disease stages FEV1 and airway conductance are not affected. Current guidelines recommend testing for bronchoreversibility at least once and the postbronchodilator FEV1/FVC be used for COPD diagnosis; the nature of bronchodilator response remains controversial, however. One major functional consequence of altered lung mechanics is lung hyperinflation. FRC may increase as a result of static or dynamic mechanisms, or both. The link between dynamic lung hyperinflation and expiratory flow limitation during tidal breathing has been demonstrated. Hyperinflation may increase the load on inspiratory muscles, with resulting length adaptation of diaphragm. Reduction of exercise tolerance is frequently noted, with compelling evidence that breathlessness and altered lung mechanics play a major role. Lung function measurements have been traditionally used as prognostic indices and to monitor disease progression; FEV1 has been most widely used. An increase in FVC is also considered as proof of bronchodilatation. Decades of work has provided insight into the histological, functional, and biological features of COPD. This has provided a clearer understanding of important pathobiological processes and has provided additional therapeutic options. PMID:24692133
Møller, Søren; Henriksen, Jens Henrik
and neurohumoral dysregulation found in cirrhosis. Recent studies have shown that the ET system is highly activated in most cirrhotic patients. Circulating ET-1 and ET-3 levels have a positive relation to the severity of the disease and fluid retention, with the highest values recorded in patients...... venous hypertension. In addition, marked associations with disturbance of systemic haemodynamics and with abnormal distribution of blood volume have been reported. Although the pathophysiological importance of the ET system in chronic liver disease is not completely understood, similarities to other......This review describes recent progress in the accumulation of knowledge about the endothelins (ETs), a family of vasoactive 21-amino acid polypeptides, in chronic liver disease. Particular prominence is given to the dynamics of ET-1 and ET-3 and their possible relation to the disturbed circulation...
Kohlicek, J; Svec, V
A group of patients between 35 and 65 years old with chronic prostatitis were examined for the presence of Becherew's disease. In this connection the New York and Roman criterions for morbus Bechterew were applied. There were found one ankyosing spondylarthritis, one ankylosis of the sacroiliac joint, and 11 times a tentative sacroileitis were stated. Altogether the proved and tentative findings were only 3.68 per cent of all examinations. In our countries the morbus Bechterew is found in 0,21 per cent of the normal population. So the protion of the Bechterew's disease in patients with chronic prostatitis is indeed a little higher than average, but not so frequent as often pretended in recent times. After a second series 58 patients being treated because of Bechterew's disease of different stages and different terms were examined for the possibility of a simultaneously elapsing chronic prostatitis. A chronic prostatitis was found in 38 per cent of these patients which correspondents to the incidence published in literature for the medium-age manhood. Nobody of the test persons had complaints on the part of the urologenital tract. PMID:602457
Caramori, Gaetano; Papadopoulos, Nikos; Contoli, Marco; Marku, Brunilda; Forini, Giacomo; Pauletti, Alessia; Johnston, Sebastian L; Papi, Alberto
There are increasing data to support the "hygiene" and "microbiota" hypotheses of a protective role of infections in modulating the risk of subsequent development of asthma. There is less evidence that respiratory infections can actually cause the development of asthma. There is some evidence that rhinovirus respiratory infections are associated with the development of asthma, particularly in childhood, whereas these infections in later life seem to have a weaker association with the development of asthma. The role of bacterial infections in chronic asthma remains unclear. This article reviews the available evidence indicating that asthma may be considered as a chronic infectious disease. PMID:22929096
Objective was to discuss the clinical and radiological features and treatment approaches in 14 patients diagnosed with idiopathic granulomatous mastitis (GM). We retrospectively evaluated the clinical features, radiological findings and treatment approaches in 14 patients with idiopathic GM in the General Surgery Department, Gulhane School of Medicine, Ankara, Turkey between April 2000 and June 2006. The mean age of the patients was 34.5 years (range 27-41 years). The complaints at admission were a mass in the breast in 7 (50%) patients, an abscess and a mass in 6 (42.8%) and a skin fisculain one (7.2%). Granulomatous mastitis was unilateral in all subjects (on the right in 5 patients and on the left in 9). All of the patients underwent ultrasonographic evaluation. Mammography was performed in 8 and magnetic resonance imaging in 5 patients. Seven patients (50%) were suspected to have breast carcinoma according radiological findings. We performed the large excision in 11, incisional biopsy plus abscess drainage in one, and incisional biopsy plus abscess drainage plus medical treatment (prednisolone, methotrexate) in 2 patients. Due to the development of abscess after 9 months, drainage and large excision were performed in one patient who received medical treatment. Idiopathic GM is a disease that generally affects young women of reproductive age and may be mistaken for breast carcinoma in clinical and radiological evaluations. The gold standard for the diagnosis is histopathologic evaluation. (author)
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Rowley, Jessica E; Johnson, Jill R
Pericytes are mesenchymal cells embedded within the abluminal surface of the endothelium of microvessels such as capillaries, pre-capillary arterioles, post-capillary and collecting venules, where they maintain microvascular homeostasis and participate in angiogenesis. In addition to their roles in supporting the vasculature and facilitating leukocyte extravasation, pericytes have been recently investigated as a subpopulation of mesenchymal stem cells (MSCs) due to their capacity to differentiate into numerous cell types including the classic MSC triad, i.e. osteocytes, chondrocytes and adipocytes. Other studies in models of fibrotic inflammatory disease of the lung have demonstrated a vital role of pericytes in myofibroblast activation, collagen deposition and microvascular remodelling, which are hallmark features of chronic lung diseases such as asthma, chronic obstructive pulmonary disorder, pulmonary fibrosis and pulmonary hypertension. Further studies into the mechanisms of the pericyte-to-myofibroblast transition and migration to fibrotic foci will hopefully clarify the role of these cells in chronic lung disease and confirm the importance of pericytes in human fibrotic pulmonary disease. PMID:25034005
Møller, S; Henriksen, Jens Henrik Sahl
This review describes recent progress in the accumulation of knowledge about the endothelins (ETs), a family of vasoactive 21-amino acid polypeptides, in chronic liver disease. Particular prominence is given to the dynamics of ET-1 and ET-3 and their possible relation to the disturbed circulation...... with functional renal failure. Studies on liver biopsies have revealed synthesis of ET-1 in hepatic endothelial and other cells, and recent investigations have identified the hepatosplanchnic system as a major source of ET-1 and ET-3 spillover into the circulation, with a direct relation to portal...... venous hypertension. In addition, marked associations with disturbance of systemic haemodynamics and with abnormal distribution of blood volume have been reported. Although the pathophysiological importance of the ET system in chronic liver disease is not completely understood, similarities to other...
Madhusudhana Rao, A; Anand, Usha; Anand, C. V.
Numerous lines of evidence implicate a role of myeloperoxidase (MPO) in the pathogenesis of cardiovascular disease (CVD). It is a well accepted fact that patients with chronic kidney disease (CKD) are at an increased risk for CVD. MPO is a pro-oxidant enzyme which could be involved in the increased susceptibility of these patients to CVD. Hence, the levels of plasma MPO was determined in healthy controls as well as in patients with CKD [stratified with the level of their kidney failure as CKD...
Metformin has traditionally been regarded as contraindicated in chronic kidney disease (CKD), though guidelines in recent years have been relaxed to permit therapy if the glomerular filtration rate (GFR) is > 30 mL/min. The main problem is the perceived risk of lactic acidosis (LA). Epidemiological...... reduction, including weight loss, which are beneficial to patients. The risk of death and cardiovascular disease is reduced by about a third in non-CKD patients. Since metformin intoxication undoubtedly causes LA, and metformin is renally excreted, inappropriate dosage of metformin will increase the risk of...
Full Text Available Despite significant decreases in morbidity and mortality of cardiovascular diseases (CVD and cancers, morbidity and cost associated with chronic obstructive pulmonary disease (COPD continue to be increasing. Failure to improve disease outcomes has been related to the paucity of interventions improving survival. Insidious onset and slow progression halter research successes in developing disease-modifying therapies. In part, the difficulty in finding new therapies is because of the extreme heterogeneity within recognized COPD phenotypes. Novel biomarkers are necessary to help understand the natural history and pathogenesis of the different COPD subtypes. A more accurate phenotyping and the ability to assess the therapeutic response to new interventions and pharmaceutical agents may improve the statistical power of longitudinal clinical studies. In this study, we will review known candidate biomarkers for COPD, proposed pathways of pathogenesis, and future directions in the field.
Burton, Graham J; Fowden, Abigail L; Thornburg, Kent L
Epidemiological evidence links an individual's susceptibility to chronic disease in adult life to events during their intrauterine phase of development. Biologically this should not be unexpected, for organ systems are at their most plastic when progenitor cells are proliferating and differentiating. Influences operating at this time can permanently affect their structure and functional capacity, and the activity of enzyme systems and endocrine axes. It is now appreciated that such effects lay the foundations for a diverse array of diseases that become manifest many years later, often in response to secondary environmental stressors. Fetal development is underpinned by the placenta, the organ that forms the interface between the fetus and its mother. All nutrients and oxygen reaching the fetus must pass through this organ. The placenta also has major endocrine functions, orchestrating maternal adaptations to pregnancy and mobilizing resources for fetal use. In addition, it acts as a selective barrier, creating a protective milieu by minimizing exposure of the fetus to maternal hormones, such as glucocorticoids, xenobiotics, pathogens, and parasites. The placenta shows a remarkable capacity to adapt to adverse environmental cues and lessen their impact on the fetus. However, if placental function is impaired, or its capacity to adapt is exceeded, then fetal development may be compromised. Here, we explore the complex relationships between the placental phenotype and developmental programming of chronic disease in the offspring. Ensuring optimal placentation offers a new approach to the prevention of disorders such as cardiovascular disease, diabetes, and obesity, which are reaching epidemic proportions. PMID:27604528
Benson, John R; Dumitru, Dorin
Idiopathic granulomatous mastitis (IGM) is a rare chronic inflammatory condition of the breast which although benign can mimic carcinoma. Establishing a diagnosis can be challenging and requires a high index of suspicion with exclusion of infective and autoimmune breast diseases. IGM is characterized histologically by noncaseating granulomas which are of a lobulo-centric pattern and often associated with microabscess formation. Management of confirmed cases remains controversial with proponents of initial surgical or medical therapies - each has its associated problems which can be worse than the original symptoms of IGM. However, many patients require more than one modality of treatment to completely resolve IGM lesions and careful judgment is necessary to ensure optimal type and sequencing of treatments. PMID:27067146