All patients with IgA deficiency are at increased risk for allergies and autoimmune diseases. Chronic Granulomatous Disease is the most commonly encountered immunodeficiency involving the phagocyte, and is characterized by repeated infections with bacterial and fungal pathogens, as well as the formation of granulomas in tissue. [QxMD MEDLINE Link]. Occasionally, the onset may be delayed until the patient is aged 10-20 years. The main defect in chronic granulomatous disease (CGD) is a failure of neutrophils, monocytes, macrophages, and eosinophils to mount a respiratory burst and, therefore, to generate superoxide anions and other reactive oxygen species derived from superoxide, such as hydrogen peroxide. reported a mortality rate of 5% per year for X-linked CGD and 2% per year for autosomal recessive CGD [2]. Because of the risk of infection, OPV also should not be given to persons in close contact with these patients.14 In addition, most patients with primary immunodeficiencies should not receive measles, bacille Calmette-Gurin, and varicella vaccines. [2]. Patients with CGD are at increased risk of life-threatening infections with catalase-positive bacteria and fungi and inflammatory complications such as CGD colitis. Clinical outcome in children with chronic granulomatous disease managed conservatively or with hematopoietic stem cell transplantation. et al. As in the UK survey, there was no association between neutrophil oxidative capacity and symptomatic autoimmunity. Unable to load your collection due to an error, Unable to load your delegates due to an error. Female carriers with skin abscesses and chronic diarrhea were found to have a significantly lower neutrophil respiratory oxidative burst than unaffected carriers. [6, 7, 8], In contrast, a GT deletion at the beginning of exon 2 accounts for the defective genetic function in almost all patients with p47phox deficiency. J Infect. Further study specifically aimed to address late effects and durability of immune reconstitution are needed. Successful HLA haploidentical hematopoietic SCT in chronic granulomatous disease. Preprint. The urological manifestations of chronic granulomatous disease. David F Butler, MD Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic Both patients ultimately went on to develop myelodysplastic syndrome (MDS); one patient died at 27months post-gene therapy from septic shock, and the other patient went on to receive a MUD HCT at 45months [85]. 1982:543-571. Rasamsonia has been identified as an emerging pathogen in this population. Recurrent Granulibacter bethesdensis infections and chronic granulomatous disease. Affected patients often present early in life with failure to thrive and disseminated infection.7 DiGeorge syndrome is one of the most recognized disorders in this category, and severe combined immunodeficiency is the most severe. 2005 Jan. 116(1-2):72-82. This review aims to summarize the clinical phenotype of CGD, including infectious and inflammatory manifestations, and to update the current data on conventional management, HCT, and gene therapy. The prophylactic use of IFN- remains variable. eCollection 2021 Sep. Bylund J, Campsall PA, Ma RC, Conway BA, Speert DP. As such, CGD should be considered in all patients who present with early onset inflammatory bowel disease. However, many CGD patients have unique mutations, and these approaches would require engineering unique systems for each individual patient. The NADPH oxidase complex is comprised of both membrane-bound and cytosolic proteins that function in concert upon phagocyte activation to produce reactive oxygen species (ROS) essential for the normal killing of bacteria and fungi [1]. 2015 May. Marks DJ, Miyagi K, Rahman FZ, et al. For example, in patients with chronic granulomatous disease, prophylactic therapy with trimethoprim-sulfamethoxazole (Bactrim, Septra) reduces the incidence of severe infections by 50 percent.4 Similarly, treatment for complement deficiencies is directed at preventing infection, and consists of antibiotic prophylaxis and immunizations for encapsulated bacteria (e.g., heptovalent pneumococcal vaccine, Haemophilus b conjugate vaccine, meningococcal polysaccharide vaccine).14, Other treatments for primary immunodeficiencies include enzyme replacement in patients with adenosine deaminase deficiency (a subtype of severe combined immunodeficiency) and cytokine therapy in patients with chronic granulomatous disease.8. Barese CN, Podest M, Litvak E, et al. [QxMD MEDLINE Link]. Low-dose total-body irradiation and alemtuzumab-based reduced-intensity conditioning regimen results in durable engraftment and correction of clinical disease among children with chronic granulomatous disease. This website also contains material copyrighted by 3rd parties. About 10% of patients also had autoimmune complications. Stein S, Ott MG, Schultze-Strasser S, et al. Reduced-intensity conditioning and HLA-matched hematopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study. Segal BH, Barnhart LA, Anderson VL, et al. The National Institute of Child Health and Human Development recently initiated an educational program to raise awareness of primary immunodeficiencies. In response to the high incidence of MDS seen with the -retroviral vectors and concerns related to stem cell toxicity mentioned above, codon-optimized self-inactivating (SIN) lentiviral vectors have been developed whereby transgene expression is limited to the myeloid lineage. 52(2):113-20. However, results to date have not been encouraging. GI symptoms are generally non-specific and include abdominal pain, noninfectious diarrhea, oral aphthae, nausea and vomiting, and failure to thrive [3638]. CGD is caused by defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which constitutes the phagocyte oxidase . Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in any of the five subunits of the NADPH oxidase complex responsible for the respiratory burst in phagocytic leukocytes. [1] Cutaneous disease occurs in 60-70% of patients. 2019. Chiriaco M, Salfa I, Di Matteo G, Rossi P, Finocchi A. [. However, cell engraftment progressively decreased with time in all patients, and several patients developed MDS. Chronic Granulomatous Disease (CGD) is caused by genetic defects in the phagocyte NADPH oxidase leading to potentially severe infections with catalase positive micro-organisms. Genetic, biochemical, and clinical features of chronic granulomatous disease. This site needs JavaScript to work properly. Mucormycosis in chronic granulomatous disease: association with iatrogenic immunosuppression. 2017 Dec. 34 (12):2543-2557. Aspergillus infection is the most common cause of death in patients with phagocytic primary immunodeficiency disorders.4, Complement disorders account for only 2 percent of all primary immunodeficiency disorders.6 They result from the disruption of one of the proteins involved in the classic or nonclassic activation pathways of the complement response.15 Defects in the classic pathway account for the more common type of complement deficiency, and patients often have a high number of autoimmunity disorders, including lupus-like syndromes. Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School Primary immunodeficiencies generally are considered to be relatively uncommon. Inflammatory complications are a significant contributor to morbidity in CGD, and they are often refractory to standard therapies. Adv Ther. [QxMD MEDLINE Link]. Chiriaco et al. Symptom onset may be at any time, but most affected patients develop GI involvement in the first decade of life [37]. Infections should be treated early and aggressively, and initial antibiotic therapy should provide strong coverage for both S. aureus and Gram-negative bacteria, including B. cepacia (e.g., combination of vancomycin/clindamycin/oxacillin and ceftazidime/carbapenem depending on local resistance patterns). Invasive mold infections in chronic granulomatous disease: a 25-year retrospective survey. Roman J Nowicki, MD, PhD is a member of the following medical societies: American Academy of Dermatology, European Academy of Allergy and Clinical Immunology, European Academy of Dermatology and Venereology, International Society for Human and Animal Mycology, International Society of Dermatology, Polish Dermatological Society, Polish Society of AllergologyDisclosure: Nothing to disclose. In approximately two thirds of patients, the first symptoms of CGD appear during the first year of life in the form of infections, dermatitis (sometimes seen at birth), gastrointestinal complications (obstruction or intermittent bloody diarrhea due to colitis), and a failure to thrive. Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000. Clin Immunol. [QxMD MEDLINE Link]. Lublin M, Bartlett DL, Danforth DN, et al. [QxMD MEDLINE Link]. Genitourinary tract manifestations are common and include bladder granulomata, ureteral obstruction, and urinary tract infections, especially in patients with gp91phox and p22phox deficiency [43]. Paecilomyces lilacinus infection in a child with chronic granulomatous disease. Of note, macrophage activation syndrome has also been reported in CGD patients and is a potentially life-threatening inflammatory complication [46, 47]. Approximately 15% of peripheral blood neutrophils were found to express gp91phox within the first 5months after transplantation, and both patients experienced clinical benefit with resolution of bacterial and fungal infections. Phellinus tropicalis abscesses in a patient with chronic granulomatous disease. Childrens Hospital of Philadelphia, Wood Center, Rm 3301, 3401 Civic Center Blvd, Philadelphia, PA 19104 USA. [QxMD MEDLINE Link]. Clinical, functional, and genetic characterization of chronic granulomatous disease in 89 Turkish patients. Patients with X-linked CGD had two times the rate of inflammatory complications compared to patients with autosomal recessive CGD. As such, we currently use MAC in all patients with CGD at our institution. 2008 Feb. 140(3):255-66. Sharma M, Dhaliwal M, Tyagi R, Goyal T, Sharma S, Rawat A. Pathogens. Chronic granulomatous disease: Clinical, molecular, and therapeutic aspects. Gene therapy of chronic granulomatous disease. The implementation of routine antimicrobial prophylaxis and the advent of azole antifungals has considerably improved overall survival. Chronic granulomatous disease (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. Liver manifestations are often progressive, and, notably, the development of thrombocytopenia secondary to splenic sequestration is a strong predictor of mortality [42]. Khandelwal P, Bleesing JJ, Davies SM, Marsh RA. Chronic granulomatous disease as a risk factor for autoimmune disease. Finally, targeted genome editing approaches using zinc-finger nucleases (ZFN), transcription activator-like effector nucleases, or the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system have been proposed to allow gene correction in situ such that gene expression remains under the control of the genes own cell-specific promoters. Chronic granulomatous disease (CGD) is a genetic disorder in which white blood cells called phagocytes are unable to kill certain types of bacteria and fungi. Thus, defects in either cell type have the potential to affect both cellular and humoral immunity to varying degrees. Genetic and biochemical background of chronic granulomatous disease. Nevertheless, gene editing approaches remain limited by low efficiency and hematopoietic stem cell toxicity through the process of transfection, expansion, and selection. 2023 Apr 20;14:1134852. doi: 10.3389/fimmu.2023.1134852. Treatment strength dosing of trimethoprim-sulfamethoxazole to cover ceftazidime-resistant B. cepacia and Nocardia should also be considered as part of the initial empiric therapy. For infections refractory to voriconazole, liposomal amphotericin B, caspofungin, posaconazole, or some combination thereof may be considered. X-linked carriers of chronic granulomatous disease: Illness, lyonization and stability. Corrected HSCs do not have a selective growth advantage compared to NADPH oxidase-deficient cells, contrary to what is seen with some other primary immunodeficiencies. . This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. J Allergy Clin Immunol. Marciano BE, Rosenzweig SD, Kleiner DE, et al. Siler U, Paruzynski A, Holtgreve-Grez H, et al. The Israeli experience with 84 patients. Diagnostic and treatment options for severe IBD in Female X-CGD carriers with non-random X-inactivation. Dual-regulated lentiviral vector for gene therapy of X-linked chronic granulomatosis. catalase-positive species (S. aureus, E. coli, Aspergillus, and Candida) can neutralize own peroxide with catalase CGD patients are susceptible especially to catalase-positive species can ingest bacteria, but can't kill it persistent survival of bacteria leads to granulomas in body IL-1R blockade using Anakinra resulted in rapid and sustained improvement of colitis in two patients with CGD [63]. and transmitted securely. A case of disseminated infection by a putatively novel Rasamsonia argillacea species complex involving the heart. doi: 10.1371/journal.pone.0005234. Patients with CGD should receive all routine childhood immunizations except for the BCG vaccine. The intracellular survival of ingested bacteria leads to the development of granulomata in the lymph nodes, skin, lungs, liver, gastrointestinal tract, and/or bones. Mulch pneumonitis deserves special mention, as it is exclusive to CGD and is associated with a high rate of mortality if not identified early. This is of particular concern as many CGD patients may be treated early in life, leading to early exposure to the toxicities of conditioning agents. Conti F, Lugo-Reyes SO, Blancas Galicia L, et al. [11] : The exact incidence of chronic granulomatous disease (CGD) is unknown. -, Winkelstein JA, Marino MC, Johnston RB, et al. Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic Granulomatous Disease: an Italian multicenter study. 2005 May. In most instances, a normal CBC eliminates the diagnosis of T-cell defects or combined B-cell and T-cell defects. Chronic granulomatous disease: the European experience. GI tract manifestations are common, with a reported incidence ranging from 33% to 60% of patients with CGD [36, 37]. Pneumonol Alergol Pol. Oh HB, Park JS, Lee W, Yoo SJ, Yang JH, Oh SY. 558. [1]. Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000. Primary Immunodeficiencies Linked to Early-Onset GI Cancers. Unfortunately, patient 2 had no detectable corrected neutrophils at 4weeks, and he died at 6months post-gene therapy from a pre-existing fungal infection. Women with less that 20% normal neutrophil oxidative capacity had increased infections, and less than 10% was highly associated with severe infection. Marciano BE, Spalding C, Fitzgerald A, Mann D, Brown T, Osgood S, et al. Molecular analysis of X-linked chronic granulomatous disease in five unrelated Korean patients. Sweeney CL, Merling RK, De Ravin SS, Choi U, Malech HL. In contrast to patients with common variable immunodeficiency, patients with IgA deficiency have a normal IgG response to vaccinations. Most cases of CGD are diagnosed in children; however, it may rarely go undiagnosed until adulthood in individuals with unexplained infections and granulomatous inflammation. Patients with CGD are at increased risk of life-threatening infections with catalase-positive bacteria and fungi and inflammatory complications such as CGD colitis. Patients with CGD are at increased risk of life-threatening infections with catalase-positive bacteria and fungi and inflammatory complications such as CGD colitis. Arch Immunol Ther Exp (Warsz). Furthermore, full engraftment is likely unnecessary for CGD, as data from healthy female carriers of X-linked CGD indicate that as low as 1020% functional neutrophils is adequate to protect against severe infection [53, 54]. Cole et al. Early recognition and diagnosis can alter the course of primary immunodeficiencies significantly and have a positive effect on patient outcome. Chronic granulomatous disease (CGD) is a genetically heterogeneous condition characterized by recurrent, life-threatening bacterial and fungal infections and granuloma formation. Importantly, 42 of the 56 patients were considered high risk due to active infection and/or autoinflammation. Vinh DC, Freeman AF, Shea YR, et al. Retroviral gene therapy for X-linked chronic granulomatous disease: results from phase I/II trial. [QxMD MEDLINE Link]. 2005 Mar 15. Read more about this advance. Seger RA. Chronic granulomatous disease affects persons of all races. CGD affects approximately 1 infant per 200,000-250,000 live births. It also aims to identify questions that remain with regard to optimal management of patients with CGD, particularly with respect to HCT. The current evidence suggests that myeloablative conditioning results is more durable myeloid engraftment but with increased toxicity and high rates of graft-versus-host disease. As with all HCT recipients, there is concern regarding the potential for development of late effects and durability of immune reconstitution in CGD patients following HCT. 2009;4(4):e5234. A patient information handout on the warning signs of primary immunodeficiency, adapted with permission from a list of warning signs prepared by The Jeffrey Modell Foundation, is provided on page 2011. [QxMD MEDLINE Link]. Surgical intervention is often necessary, and patients generally require prolonged treatment courses. 21 (6):552-557. In a survey of more than 2,700 patients conducted by the Immune Deficiency Foundation,3 48 percent of affected patients were male, and 52 percent were female. 2001 Jan. 8(1):17-22. The diagnosis of chronic granulomatous disease should be considered in any patient with recurrent infections with catalase-positive organisms; infections with unusual organisms such as Serratia marcescens, A nidulans, or B cepacia; or infections in sites normally considered to be rare in children, such as a Staphylococcus aureus infection in a . Horwitz ME, Barrett AJ, Brown MR, et al. This is why patients with G6PD deficiency are susceptible to oxidizing drugs (e.g., dapsone, primaquine) and hemolytic anemia, because their NADPH production is less efficient, so they can't neutralize H2O2 and other oxidizing agents as readily, leaving their RBC membranes more prone to lysis. 2004 May. 27 (3):242-53. At our institution, the decision for IFN- prophylaxis is made on a case-by-case basis, and is particularly encouraged for patients experiencing increased infections. In CGD, phagocytes ingest bacteria normally, but they cannot kill them. https://profreg.medscape.com/px/getpracticeprofile.do?method=getProfessionalProfile&urlCache=aHR0cHM6Ly9lbWVkaWNpbmUubWVkc2NhcGUuY29tL2FydGljbGUvMTExNjAyMi1vdmVydmlldw==, Subcutaneous, liver, or perirectal abscess -, Osteomyelitis - Can arise from hematogenous spread of organisms (, Other frequently encountered catalase-positive microbial agents -. Successful combination of sequential gene therapy and rescue allo-HSCT in two children with X-CGDimportance of timing. Pulmonary manifestations may include granulomatous lung disease and interstitial pulmonary fibrosis [36, 38]. Steroid-sparing agents used with varying degrees of success include salicylic acid derivatives, antimetabolites such as azathioprine, and 6-mercaptopurine. The probability of finding an unaffected MSD in most populations is less than 25%. Mutations in any of the five structural subunits of the NADPH oxidase complex result in defective ROS production and the syndrome of CGD. Trimethoprim-sulfamethoxazole has been shown to reduce the incidence of bacterial infections from 15.8 to 6.9 infections per 100 patient-months in patients with X-linked CGD and from 7.1 to 2.4 per 100 patient-months in patients with autosomal recessive CGD [53].