Chronic Granulomatous Disease

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Practice Essentials

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. Patients with CGD are at increased risk of life-threatening infections with catalase-positive bacteria and fungi and inflammatory complications such as CGD colitis. The implementation of routine antimicrobial prophylaxis and the advent of azole antifungals has considerably improved overall survival. 

Background

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. This enzyme generates superoxide and is essential for intracellular killing of pathogens by phagocytes.

CGD is a primary immunodeficiency that affects phagocytes of the innate immune system and leads to recurrent or persistent intracellular bacterial and fungal infections and to granuloma formation. 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. The clinical picture can be quite variable, with some infants having several of these complications and others appearing to be far less ill.[1] Cutaneous disease occurs in 60-70% of patients. Rasamsonia has been identified as an emerging pathogen in this population.[2]

Also see Pediatric Chronic Granulomatous Disease.

Pathophysiology

Chronic granulomatous disease (CGD) is a genetically heterogeneous immunodeficiency disorder resulting from the inability of phagocytes to kill microbes they have ingested. This impairment in killing is caused by any of several defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, which generates the microbicidal respiratory burst. In CGD, phagocytes ingest bacteria normally, but they cannot kill them.[3]

Patients with CGD are susceptible to severe and recurrent infections due to catalase-positive organisms and organisms resistant to nonoxidative killing. Catalase-negative bacteria, such as streptococci and pneumococci that have the capacity to generate hydrogen peroxide, are killed as they usually are. The intracellular survival of ingested bacteria leads to the development of granulomata in the lymph nodes, skin, lungs, liver, gastrointestinal tract, and/or bones.

CGD is usually inherited in an X-linked recessive fashion. Most patients (approximately 80%) are males, who have hemizygous mutations on the X-linked gene coding for gp91phox. The gene responsible for this form of the disease has been mapped to the p21.1 region of the X chromosome.[4] However, among chronic granulomatous disease subtypes, the autosomal recessive (AR) forms may be associated with milder disease. The extent to which environmental and secondary genetic factors influence phenotypic expression of disease is unknown. A wide variety of molecular defects have been described in the genes for the gp91phox component, the p22phox component,[5] and the p67phox component. These defects include frame shifts; deletions; and nonsense, missense, splice-region, and regulatory-region mutations.[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.[9] Another protein, p40phox, has been implicated in the regulation of the NADPH oxidase, but no individual with a mutation in the protein has been found to date. A new variant of CGD has been described; this form is caused by an inhibitory mutation in Rac2, which regulates activity of the neutrophil respiratory burst and actin assembly.[10]

Etiology

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. This renders the patients susceptible to severe, recurrent bacterial and fungal infections. The intracellular survival of ingested bacteria leads to the development of granulomata in the lymph nodes, skin, lungs, liver, gastrointestinal tract, and/or bones.

Leukocytes ingest bacteria but do not kill them because of a defect in the production of the superoxide anion.

Most infections in CGD are caused by Staphylococcus aureus. Infections are also caused by unusual opportunistic organisms such as Chromobacterium violaceum; Serratia marcescens; and Nocardia, Legionella, and atypical Mycobacteria species.

BCG vaccination may cause CGD.

Fungal infections in CGD patients have been reported to account for approximately 20% of infections. The most common fungal infections in these patients are caused by Aspergillus species. The spectrum of infection caused by Aspergillus species varies from flulike pneumonia to life-threatening invasive aspergillosis. The most common form of aspergillosis in chronic granulomatous disease patients is Aspergillus pneumonia, which can be accompanied by dissemination to the ribs, chest wall, and soft tissues. Infections with Aspergillus species, particularly of the lungs or bones, are difficult to eradicate.

The most common infecting organisms, on the basis of the type and site of infection, include the following[11] :

Epidemiology

Frequency

United States

The exact incidence of chronic granulomatous disease (CGD) is unknown. CGD affects approximately 1 infant per 200,000-250,000 live births.

International

The prevalence of CGD varies among the populations investigated, with studies reporting variations from 1 case per 1 million individuals to 1 case per 160,000 individuals.[13, 14]

Race

Chronic granulomatous disease affects persons of all races.

Sex

Approximately 80% of patients with CGD are male, because the main cause of the disease is a mutation in an X-chromosome–linked gene. However, defects in autosomal genes may also underlie the disease and cause CGD in both males and females.[1]

Age

Symptom onset typically occurs at a young age, although the diagnosis has been at an older age in some patients.[15, 16, 17] Typically, patients with CGD have recurrent pyogenic infections that start in the first year of life. Occasionally, the onset may be delayed until the patient is aged 10-20 years.

Prognosis

The long-term survival of patients who develop symptoms after the end of the first year of life is significantly better than that of patients whose illness starts in infancy. Survival rates are variable but improving; approximately 50% of patients survive to age 30-40 years. Infections are less common in adults than in children, but the propensity for severe life-threatening bacterial infections persists throughout life.

Fungal infections remain a major determinant of survival in chronic granulomatous disease (CGD). Morbidity secondary to infection or granulomatous complications remains significant for many patients, particularly those with the X-linked form. X-linked patients generally have more severe disease, and this is generally in those with lower residual superoxide production. Survival in CGD has increased over the years, but infections are still major causes of morbidity and mortality.[18] Currently, the annual mortality rate is 1.5% per year for persons with autosomal recessive CGD and 5% for those with X-linked CGD.

Since the advent of prophylactic antibiotics, antifungals, and interferon-gamma (INF-gamma), the prognosis for patients with CGD has improved. Patients living to their 30s and 40s is now common.

Patients with CGD and modest residual production of reactive oxygen intermediates (ROIs) have significantly less severe illness and a greater likelihood of long-term survival than patients with little residual ROI production. The production of residual ROI is predicted by the specific NADPH oxidase mutation, regardless of the specific gene affected, and is a predictor of survival in patients with CGD.[19]

Patient Education

Good hygiene of the skin is an important element of treatment because the skin is a common portal of entry in serious infections. To prevent infections, chronic granulomatous disease (CGD) patients should receive lifelong antibiotics and antifungal prophylaxis.

History

Chronic granulomatous disease (CGD) becomes apparent during the first 2 years of life in most patients, but the onset is occasionally delayed into the second decade of life. The earliest manifestations often involve the skin. Recurrent pyodermas are common, and they often appear as perianal, axillary, or scalp abscesses.

Systemic findings include osteomyelitis, pulmonary abscesses and granulomas, spleen and/or liver abscesses, and hepatosplenomegaly. Pyrexia may be noted. Diarrhea may occur.

Physical Examination

Short stature is a prominent clinical feature in children and adults with chronic granulomatous disease (CGD). Patients with CGD usually present with recurrent bacterial and fungal infections in early childhood. The most common initial manifestations are as follows[20] :

Patients may have inflammatory and presumably noninfectious conditions such as granulomatous colitis and obstructive granulomas.

The earliest reports of CGD emphasize dermatitis as a characteristic and often presenting manifestation of the disease.[22, 23] The dermatitis was described as an eczematoid, seborrheic, or infectious eczematoid dermatitis that predominantly involved the eyelids and periorbital skin, nares, perioral skin, and ears. The skin lesions frequently became pustular. Similar eruptions were described on the scalp, neck, axillae, inguinal folds, retroauricular folds, and interdigital web spaces. Generalized maculopapular, pustular, and papulopustular eruptions of the newborn were also reported.

Cutaneous manifestations other than dermatitis can be present. Neonatal pustulosis is commonly the first sign of the disease. Recurrent pyodermas are common, and they appear as perianal or axillary abscesses. Eczema of the scalp and lesions of the periorbital, nasal, and postauricular regions are typical, and it is often complicated by infection with staphylococci or other bacteria. Minor abrasions frequently lead to furunculosis and subcutaneous abscesses. Abscesses characteristically heal slowly and leave prominent scars. Skin manifestations in older patients include healed scars of old lesions in the cervical or inguinal areas or scars secondary to multiple surgical procedures performed to drain abscesses.

Associated chronic blepharoconjunctivitis and serosanguineous nasal discharge is often described.

Intraoral ulcerations are described in many patients. These ulcerations resemble aphthous stomatitis, chronic gingivitis, perioral ulcers, scalp folliculitis, chronic suppurative paronychia, or seborrheic dermatitis. Recurrent ulcerative stomatitis is present at some time in almost all patients with CGD.

Systemic findings are pronounced and include the following:

Mothers of affected boys with the most commonly involved gene often have Jessner lymphocytic infiltrate or discoid lupus erythematosus. In rare instances, systemic lupus erythematosus is reported.

Complications

Invasive aspergillosis and candidiasis may occur in patients with chronic granulomatous disease (CGD). Patients with chronic granulomatous disease can be sensitized to Aspergillus species. Allergic bronchopulmonary aspergillosis can develop.

Gastrointestinal complications include the following:

Rheumatologic disorders include the following:

Other complications include the following:

Laboratory Studies

The nitroblue tetrazolium (NBT) dye test

Laboratory diagnosis of chronic granulomatous disease (CGD) can be made using the NBT test, stimulated with substances such as phorbol myristate acetate or Escherichia coli lipopolysaccharide, which promote an oxidative response in 90-100% of normal neutrophils.

Neutrophils in patients with chronic granulomatous disease are unable to reduce oxidized NBT to insoluble blue formazan; this principle forms the basis of the standard diagnostic screening test for chronic granulomatous disease.

This test is best used to identify gene carriers, and it has been used for the prenatal diagnosis of chronic granulomatous disease.

Flow cytometric reduction of dihydrorhodamine

This test can also be used to diagnose chronic granulomatous disease. The principles are the same as for the NBT dye test, but a different dye is used. Additionally, X-linked carrier status can also be detected.

Complete blood cell counts

Peripheral blood leukocytosis (>8.5 X 103/µL) is a characteristic finding that reflects increased numbers of circulating neutrophils. Most patients are anemic (hemoglobin < 12.5 g%), usually with a microcytic hypochromic picture.

Microbiologic studies

Culture and sensitivity studies may be helpful. Bacteria isolated from lesions in patients with chronic granulomatous disease are usually catalase positive.

Quantitative immunoglobulin tests

Levels of the three major classes of immunoglobulins, immunoglobulin G, immunoglobulin M, and immunoglobulin A, are increased. Immunoglobulin E levels are increased or in the reference range.

Imaging Studies

Radiography and CT imaging

Pulmonary disease is prominent, with recurrent pneumonia, empyema, and lung abscess formation.

Discrete areas of persistent consolidation may be observed on radiographs and are often called encapsulating pneumonia. This sign is highly distinctive of chronic granulomatous disease. Less specific reticulonodular shadowing and hilar lymphadenopathy are also commonly observed.

Other Tests

Other diagnostic tests include the following:

Molecular diagnostics may include the following:

Procedures

Skin biopsy is important in correctly diagnosing chronic granulomatous disease.

Histologic Findings

Chronic granulomatous disease (CGD) is histologically characterized by a mixed suppurative and granulomatous inflammation. A typical feature of visceral granulomas is the presence of golden-brown–pigmented histiocytes. Histochemical stains show that this material is composed of unsaturated fatty acids, phospholipids, and glycoproteins.

Periodic acid-Schiff (PAS) staining demonstrates the presence of carbohydrates, particularly polysaccharides such as mucoproteins. These substances stain reddish purple with the PAS reaction.

Electron microscopic findings suggest that the pigment represents lipofuscin bodies and appears to be derived from lysosomes. Granulomas consist of neutrophils and macrophages that contain yellow inclusions with areas of necrosis.

Aspergillus species is shown below.



View Image

Scanning electron micrograph of Aspergillus species.

Medical Care

Early diagnosis and treatment can significantly improve the prognosis.[27] Modern therapy for chronic granulomatous disease (CGD) includes aggressive and prolonged administration of antibiotics and prednisone.[28] Treatment for inflammatory and autoimmune complications in patients with CGD is problematic because most agents are immune suppressive and immunity is already impaired in patients with CGD. Many patients respond well to corticosteroids, but they might require prolonged courses.

Sulfasalazine and azathioprine are useful steroid-sparing agents. Tumor necrosis factor-α (TNF-α) inhibitors such as infliximab are effective anti-inflammatory agents but might significantly increase the risk of severe and even fatal infections. The risk of infection needs to be weighed carefully against the risks of uncontrolled mucosal inflammation or surgery that might be further complicated by persistent inflammation, abscesses, and fistulae formation at surgical sites. If TNF-α inhibitors are used, augmented prophylaxis and enhanced vigilance regarding exposures are mandatory.

Methotrexate and hydroxychloroquine (Plaquenil) can be effective in those with arthritides or lupuslike problems.

Conventional treatment consists of lifelong anti-infectious prophylaxis with antibiotics such as trimethoprim-sulfamethoxazole (TMP-SMZ), antimycotics such as itraconazole, and/or interferon (INF)–gamma.

Long-term antibiotic therapy may be helpful. All infections should be treated with broad-spectrum systemic antibiotics. Aggressive treatment should be initiated at the first signs of infection. Every episode of fever must be treated promptly by an aggressive use of drugs able to cross the phagocyte cell membrane and accumulate within the phagocytic cells. Initial empirical therapy should include at least two antibiotics against gram-positive and gram-negative bacteria. In case of failure to respond within 48 hours, empirical changes in antibiotic coverage may be needed before definitive pathogen identification, including the administration of an antifungal drug, if not administered from the beginning. Treatment should be continued for weeks or months, even when there is significant improvement in the inflammatory index and the patient’s clinical condition in order to eradicate the infection completely.[23]

If a fungal invasive infection is identified or strongly suspected, intravenous voriconazole is recommended as initial treatment. Voriconazole serum concentrations present great variability, and drug monitoring is recommended to document bioavailability and efficient blood levels. Severe photosensitivity leading to squamous cell carcinoma and melanoma has been reported with long-term voriconazole treatment. Therefore, voriconazole should be used carefully for durations longer than 6-9 months, particularly among patients with risk factors for skin cancer. In patients requiring prolonged voriconazole, diligent skin examinations, avoidance of excess sunlight, and liberal use of ultraviolet protectants are advisable.[23] When infections are refractory to voriconazole or when there is intolerance, intravenous liposomal amphotericin B and caspofungin have been shown effective. Posaconazole, an orally well-tolerated broad-spectrum triazole antifungal agent, has proven efficacy as prevention of and salvage therapy for invasive fungal infection. When the fungal cause is uncertain, combined antifungal therapy can be considered. The most common combinations are voriconazole and caspofungin combination or caspofungin and liposomal amphotericin B. Amphotericin B should be added to the therapeutic regimen of CGD patients with established invasive aspergillosis. Aspergillus and other fungal infections of the lung typically require prolonged treatment (3-6 mo).[29]

In case of multidrug refractoriness, life-threatening infections (eg, aspergillosis), hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning represents a valid curative option.[30]

Alternatively, a combination of sequential granulocyte transfusions (GTs), leading to a transitory beneficial effect on preexisting infections, and HSCT have been proposed.[23]

Gene editing is being studied.[31]

INF-gamma therapy subcutaneously appears to be a promising way of improving neutrophil and monocyte function and may prove to be of particular value in the prevention or treatment of deep fungal infections. INF-gamma is now recommended as life-long therapy for infection prophylaxis in persons with CGD.[32, 33]

HSCT may be considered as an early treatment option for CGD. Since the beginning of the 21st century, there have been many reports on HSCT in patients with CGD and the encouraging results obtained with regard to survival rate, engraftment, and graft versus host disease (GVHD). In particular, it is notable that HSCT can cure CGD and reverse organ dysfunction. There is continuing controversy about indications and optimum timing of HSCT in CGD. Patients with absent NADPH oxidase activity and poor prognosis have been recommended for early HSCT. Present HSCT indication criteria in children are as follows: (1) one or more life-threatening infection, (2) noncompliance with antimicrobial prophylaxis, or (3) steroid-dependent autoinflammation. Indication criteria in adolescents and young adults are more difficult to apply because organ dysfunction is frequent and transplant-related mortality after HSCT has been high.[23, 34]

Bone marrow transplantation (BMT), as a last resort, can be undertaken. This treatment has been partially successful. Transplantations with other than perfectly matched donors are presently discouraged.[35, 36]

Recurrent impetigo, frequently in the perinasal area and caused by S aureus, usually requires prolonged courses of oral and topical antibiotics to clear.

Noninfectious granulomas may resolve spontaneously, and they rarely require systemic corticosteroid therapy unless vital organs are compromised.

Gene therapy for CGD

Gene therapy for hematopoietic cells (GT-HSC) represents an attractive alternative to HSCT as therapy for CGD patients without a matched donor. The observation that XR-CGD carriers in whom 10% or greater of normal neutrophils were healthy suggested that a minor functional correction of neutrophils would be sufficient to restore a normal phenotype in GT-HSC–treated patients. Nevertheless, GT-CGD is difficult to perform because corrected HSCs do not have a selective growth advantage compared with deficient cells, and, at the same time, a large number of cells needs to be corrected to ensure a good restoration of neutrophil activity. Thus, myeloablative conditioning is necessary to ensure an efficient engraftment of progenitor cells.[23, 37, 38, 39, 40]

Surgical Care

In addition to systemic antifungal treatment, surgical debridement or excision of consolidated infection is advised when possible,[23] including surgical drainage of abscesses and resection (when possible) of granulomas.

Consultations

Gastrointestinal manifestations include perineal abscesses; fistulae; and, characteristically, obstructive lesions associated with granulomatous infiltration; thus consultation with a surgeon may be necessary.

An internist consultation may be necessary because pyrexia should be carefully investigated to reveal the site of the causative infection and the responsible microorganism. Pulmonary disease (eg, recurrent pneumonia, empyema, lung abscess formation) should be treated.

Prevention

Chronic granulomatous disease (CGD) in adults may be more common than previously assumed. Because timely treatment, infection prophylaxis, and genetic counseling for affected families are possible, CGD should be excluded in any patient with unexplained infections or granulomas. Patients with the disease should be counseled about prophylaxis for bacterial and fungal disease and avoidance of unnecessary exposure to mold and nonchlorinated water. Prophylactic therapy is based on daily doses of trimethoprim/sulfamethoxazole and itraconazole.

Long-Term Monitoring

Skin hygiene is an important element of further outpatient care for chronic granulomatous disease (CGD). The skin should be washed twice daily with a disinfectant soap. The fingernails should be cut short. The patient should be monitored for the results of antibacterial and antifungal prophylaxis.

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Continuous antifungal therapy is effective in preventing infection by Aspergillus species.[41]

Trimethoprim and sulfamethoxazole (Bactrim, Septra)

Clinical Context:  Trimethoprim and sulfamethoxazole (TMP-SMZ) is current standard therapy. It inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid. The antibacterial activity of TMP-SMZ includes common urinary tract pathogens, except Pseudomonas aeruginosa.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Itraconazole (Sporanox)

Clinical Context:  Continuous antifungal therapy is effective in preventing infection by Aspergillus species. Itraconazole is a synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.

Class Summary

These agents exert a fungicidal effect by altering the permeability of the fungal cell membrane. Their mechanism of action may also involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Interferon gamma - 1b (Actimmune)

Clinical Context:  Interferon (INF)–gamma 1b reduces the frequency and severity of serious infections associated with chronic granulomatous disease (CGD). Interferons are synthesized by eukaryotic cells in response to viruses and a variety of natural and synthetic stimuli. INF-gamma possesses antiviral, immunomodulatory, and antiproliferative activity. INF-gamma has potent phagocyte-activating effects not seen with other interferon preparations, including generation of toxic oxygen metabolites within phagocytes capable of mediating intracellular killing of microorganisms.

Class Summary

These agents regulate the immune system by a variety of mechanisms including enhancing activity of macrophages and cytotoxic actions of T lymphocytes.

What is chronic granulomatous disease (CGD)?How common is chronic granulomatous disease (CGD)?What is the pathophysiology of chronic granulomatous disease (CGD)?What causes chronic granulomatous disease (CGD)?What is the US prevalence of chronic granulomatous disease (CGD)?What is the global prevalence of chronic granulomatous disease (CGD)?What are the racial predilections of chronic granulomatous disease (CGD)?What are the sexual predilections of chronic granulomatous disease (CGD)?Which age groups have the highest prevalence of chronic granulomatous disease (CGD)?What is the prognosis of chronic granulomatous disease (CGD)?What is included in patient education about chronic granulomatous disease (CGD)?Which clinical history findings are characteristic of chronic granulomatous disease (CGD)?Which physical findings are characteristic of chronic granulomatous disease (CGD)?What are the possible complications of chronic granulomatous disease (CGD)?What are the differential diagnoses for Chronic Granulomatous Disease?How is chronic granulomatous disease (CGD)diagnosed?What is the role of flow cytometry in the diagnosis of chronic granulomatous disease (CGD)?What is the role of CBC counts in the workup of chronic granulomatous disease (CGD)?What is the role of culture and sensitivity studies in the workup of chronic granulomatous disease (CGD)?What is the role of immunologic testing in the workup of chronic granulomatous disease (CGD)?What is the role of imaging studies in the workup of chronic granulomatous disease (CGD)?Which tests are used to diagnose chronic granulomatous disease (CGD)?What is the role of molecular testing in the diagnosis of chronic granulomatous disease (CGD)?What is the role of skin biopsy in the diagnosis of chronic granulomatous disease (CGD)?Which histologic findings are characteristic of chronic granulomatous disease (CGD)?How is chronic granulomatous disease (CGD) treated?What is the role of gene therapy in the treatment of chronic granulomatous disease (CGD)?What is the role of surgery in the treatment of chronic granulomatous disease (CGD)?Which specialist consultations are beneficial to patients with chronic granulomatous disease (CGD)?What is the role of prophylactic therapy in the treatment of chronic granulomatous disease (CGD)?What is included in the long-term monitoring of chronic granulomatous disease (CGD)?What is the role of medications in the treatment of chronic granulomatous disease (CGD)?Which medications in the drug class Biologic response modifiers are used in the treatment of Chronic Granulomatous Disease?Which medications in the drug class Antifungal agents are used in the treatment of Chronic Granulomatous Disease?Which medications in the drug class Antibiotics are used in the treatment of Chronic Granulomatous Disease?

Author

Roman J Nowicki, MD, PhD, Professor and Chairman, Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, University Clinical Centre, Poland

Disclosure: Nothing to disclose.

Specialty Editors

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

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Jacek C Szepietowski, MD, PhD, Professor, Vice-Head, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University; Director of the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Poland

Disclosure: Received consulting fee from Orfagen for consulting; Received consulting fee from Maruho for consulting; Received consulting fee from Astellas for consulting; Received consulting fee from Abbott for consulting; Received consulting fee from Leo Pharma for consulting; Received consulting fee from Biogenoma for consulting; Received honoraria from Janssen for speaking and teaching; Received honoraria from Medac for speaking and teaching; Received consulting fee from Dignity Sciences for consulting; .

References

  1. Roos D, de Boer M. Molecular diagnosis of chronic granulomatous disease. Clin Exp Immunol. 2014. 175(2):139-49. [View Abstract]
  2. Babiker A, Gupta N, Gibas CFC, Wiederhold NP, Sanders C, Mele J, et al. Rasamsonia sp: An emerging infection amongst chronic granulomatous disease patients. A case of disseminated infection by a putatively novel Rasamsonia argillacea species complex involving the heart. Med Mycol Case Rep. 2019 Jun. 24:54-57. [View Abstract]
  3. Segal BH, Romani L, Puccetti P. Chronic granulomatous disease. Cell Mol Life Sci. 2009 Feb. 66(4):553-8. [View Abstract]
  4. Hauck F, Heine S, Beier R, Wieczorek K, Müller D, Hahn G. Chronic granulomatous disease (CGD) mimicking neoplasms: a suspected mediastinal teratoma unmasking as thymic granulomas due to X-linked CGD, and 2 related cases. J Pediatr Hematol Oncol. 2008 Dec. 30(12):877-80. [View Abstract]
  5. Rae J, Noack D, Heyworth PG, Ellis BA, Curnutte JT, Cross AR. Molecular analysis of 9 new families with chronic granulomatous disease caused by mutations in CYBA, the gene encoding p22(phox). Blood. 2000 Aug 1. 96(3):1106-12. [View Abstract]
  6. Jurkowska M, Bernatowska E, Bal J. Genetic and biochemical background of chronic granulomatous disease. Arch Immunol Ther Exp (Warsz). 2004 Mar-Apr. 52(2):113-20. [View Abstract]
  7. Jurkowska M, Kurenko-Deptuch M, Bal J, Roos D. The search for a genetic defect in Polish patients with chronic granulomatous disease. Arch Immunol Ther Exp (Warsz). 2004 Nov-Dec. 52(6):441-6. [View Abstract]
  8. Stasia MJ, Bordigoni P, Floret D, et al. Characterization of six novel mutations in the CYBB gene leading to different sub-types of X-linked chronic granulomatous disease. Hum Genet. 2005 Jan. 116(1-2):72-82. [View Abstract]
  9. Noack D, Rae J, Cross AR, et al. Autosomal recessive chronic granulomatous disease caused by defects in NCF-1, the gene encoding the phagocyte p47-phox: mutations not arising in the NCF-1 pseudogenes. Blood. 2001 Jan 1. 97(1):305-11. [View Abstract]
  10. Segal BH, Leto TL, Gallin JI, Malech HL, Holland SM. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore). May 2000. 79(3):170-200.
  11. Johnston RB Jr. Clinical aspects of chronic granulomatous disease. Curr Opin Hematol. 2001 Jan. 8(1):17-22. [View Abstract]
  12. Bylund J, Campsall PA, Ma RC, Conway BA, Speert DP. Burkholderia cenocepacia induces neutrophil necrosis in chronic granulomatous disease. J Immunol. 2005 Mar 15. 174(6):3562-9. [View Abstract]
  13. Arnold DE, Heimall JR. A Review of Chronic Granulomatous Disease. Adv Ther. 2017 Dec. 34 (12):2543-2557. [View Abstract]
  14. Oh HB, Park JS, Lee W, Yoo SJ, Yang JH, Oh SY. Molecular analysis of X-linked chronic granulomatous disease in five unrelated Korean patients. J Korean Med Sci. 2004 Apr. 19(2):218-22. [View Abstract]
  15. Lun A, Roesler J, Renz H. Unusual late onset of X-linked chronic granulomatous disease in an adult woman after unsuspicious childhood. Clin Chem. 2002 May. 48(5):780-1. [View Abstract]
  16. Wolach B, Scharf Y, Gavrieli R, de Boer M, Roos D. Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB. Blood. 2005 Jan 1. 105(1):61-6. [View Abstract]
  17. Fijolek J, Wiatr E, Gawryluk D, Bestry I, Bernatowska E, Jablonski W. [Chronic granulomatous disease recognised in 42-years-old patient]. Pneumonol Alergol Pol. 2008. 76(1):58-65. [View Abstract]
  18. Marciano BE, Spalding C, Fitzgerald A, Mann D, Brown T, Osgood S, et al. Common severe infections in chronic granulomatous disease. Clin Infect Dis. 2015. 60(8):1176-83. [View Abstract]
  19. Kuhns DB, Alvord WG, Heller T, et al. Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med. 2010 Dec 30. 363(27):2600-10. [View Abstract]
  20. Carnide EG, Jacob CA, Castro AM, Pastorino AC. Clinical and laboratory aspects of chronic granulomatous disease in description of eighteen patients. Pediatr Allergy Immunol. 2005 Feb. 16(1):5-9. [View Abstract]
  21. Sarwar G, de Malmanche T, Rassam L, Grainge C, Williams A, Arnold D. Chronic granulomatous disease presenting as refractory pneumonia in late adulthood. Respirol Case Rep. 2015. 3(2):54-6. [View Abstract]
  22. Chowdhury MM, Anstey A, Matthews CN. The dermatosis of chronic granulomatous disease. Clin Exp Dermatol. 2000 May. 25(3):190-4. [View Abstract]
  23. Chiriaco M, Salfa I, Di Matteo G, Rossi P, Finocchi A. Chronic granulomatous disease: Clinical, molecular, and therapeutic aspects. Pediatr Allergy Immunol. 2016 May. 27 (3):242-53. [View Abstract]
  24. Marciano BE, Rosenzweig SD, Kleiner DE, et al. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics. 2004 Aug. 114(2):462-8. [View Abstract]
  25. Agudelo-Florez P, Lopez JA, Redher J, et al. The use of reverse transcription-PCR for the diagnosis of X-linked chronic granulomatous disease. Braz J Med Biol Res. 2004 May. 37(5):625-34. [View Abstract]
  26. Kuhns DB. Diagnostic Testing for Chronic Granulomatous Disease. Methods Mol Biol. 2019. 1982:543-571. [View Abstract]
  27. Agarwal S. Chronic Granulomatous Disease. J Clin Diagn Res. 2015 May. 9 (5):SD01-2. [View Abstract]
  28. Yamazaki-Nakashimada MA, Stiehm ER, Pietropaolo-Cienfuegos D, Hernandez-Bautista V, Espinosa-Rosales F. Corticosteroid therapy for refractory infections in chronic granulomatous disease: case reports and review of the literature. Ann Allergy Asthma Immunol. 2006 Aug. 97(2):257-61. [View Abstract]
  29. Gallin JI, Alling DW, Malech HL, et al. Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med. 2003 Jun 12. 348(24):2416-22. [View Abstract]
  30. Tang XF, Lu W, Jing YF, Huang YZ, Wu NH, Luan Z. [A clinical study of haploid hematopoietic stem cells combined with third-party umbilical cord blood transplantation in the treatment of chronic granulomatous disease]. Zhongguo Dang Dai Er Ke Za Zhi. 2019 Jun. 21 (6):552-557. [View Abstract]
  31. Sweeney CL, Merling RK, De Ravin SS, Choi U, Malech HL. Gene Editing in Chronic Granulomatous Disease. Methods Mol Biol. 2019. 1982:623-665. [View Abstract]
  32. Marciano BE, Wesley R, De Carlo ES, et al. Long-term interferon-gamma therapy for patients with chronic granulomatous disease. Clin Infect Dis. 2004 Sep 1. 39(5):692-9. [View Abstract]
  33. Wang J, Mayer L, Cunningham-Rundles C. Use of GM-CSF in the treatment of colitis associated with chronic granulomatous disease. J Allergy Clin Immunol. 2005 May. 115(5):1092-4. [View Abstract]
  34. Martinez CA, Shah S, Shearer WT, Rosenblatt HM, Paul ME, Chinen J, et al. Excellent survival after sibling or unrelated donor stem cell transplantation for chronic granulomatous disease. J Allergy Clin Immunol. 2012 Jan. 129(1):176-83. [View Abstract]
  35. Horwitz ME, Barrett AJ, Brown MR, et al. Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft. N Engl J Med. 2001 Mar 22. 344(12):881-8. [View Abstract]
  36. Seger RA, Gungor T, Belohradsky BH, et al. Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000. Blood. 2002 Dec 15. 100(13):4344-50. [View Abstract]
  37. Grez M, Becker S, Saulnier S, et al. Gene therapy of chronic granulomatous disease. Bone Marrow Transplant. 2000 May. 25 Suppl 2:S99-104. [View Abstract]
  38. Kume A, Dinauer MC. Gene therapy for chronic granulomatous disease. J Lab Clin Med. 2000 Feb. 135(2):122-8. [View Abstract]
  39. Malech HL, Choi U, Brenner S. Progress toward effective gene therapy for chronic granulomatous disease. Jpn J Infect Dis. 2004 Oct. 57(5):S27-8. [View Abstract]
  40. Seger RA. Modern management of chronic granulomatous disease. Br J Haematol. 2008 Feb. 140(3):255-66. [View Abstract]
  41. Ballard E, Zoll J, Melchers WJG, Brown AJP, Warris A, Verweij PE. Raw genome sequence data for 13 isogenic Aspergillus fumigatus strains isolated over a 2 year period from a patient with chronic granulomatous disease. Data Brief. 2019 Aug. 25:104021. [View Abstract]

Scanning electron micrograph of Aspergillus species.

Scanning electron micrograph of Aspergillus species.