eMedicine Specialties > Dermatology > Pediatric Diseases

Chronic Granulomatous Disease

Roman Janusz Nowicki, MD, PhD, Associate Professor, Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Poland

Updated: May 29, 2009

Introduction

Background

Chronic granulomatous disease (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. Chronic granulomatous disease is a syndrome that typically manifests as pneumonia, infectious dermatitis, and recurrent or severe subcutaneous abscess formation. In addition to increased susceptibility to infections, patients have a higher prevalence of mucosal inflammatory disorders such as colitis, enteritis, and gastric outlet obstruction. Cutaneous disease occurs in 60-70% of patients.

eMedicine's Pediatrics article Chronic Granulomatous Disease may be of interest.

Pathophysiology

Chronic granulomatous disease 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 chronic granulomatous disease, phagocytes ingest bacteria normally, but they cannot kill them.¹

Patients with chronic granulomatous disease 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.

Chronic granulomatous disease is usually inherited in an X-linked recessive fashion. Most patients (approximately 90%) 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.² 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,³ and the p67phox component. These defects include frame shifts; deletions; and nonsense, missense, splice-region, and regulatory-region mutations.^4,5,6

In contrast, a GT deletion at the beginning of exon 2 accounts for the defective genetic function in almost all patients with p47phox deficiency.⁷ 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 chronic granulomatous disease has been described; this form is caused by an inhibitory mutation in Rac2, which regulates activity of the neutrophil respiratory burst and actin assembly.⁸

Frequency

United States

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

International

The prevalence of chronic granulomatous disease varies among the populations investigated, with studies reporting variations from 1 case per 1 million individuals to 1 case per 160,000 individuals.^9,10

Mortality/Morbidity

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.

• Morbidity secondary to infection or granulomatous complications remains significant for many patients, particularly those with the X-linked form. Currently, the annual mortality rate is 1.5% per year for persons with autosomal recessive chronic granulomatous disease and 5% for those with X-linked chronic granulomatous disease.
• Since the advent of prophylactic antibiotics, antifungals, and interferon-gamma (INF-gamma), the prognosis for patients with chronic granulomatous disease has improved. Patients living to their 30s and 40s is now common.

Race

Chronic granulomatous disease affects persons of all races.

Sex

Approximately 90% of patients with chronic granulomatous disease are male.

Age

Symptom onset typically occurs at a young age, although the diagnosis has been at an older age in some patients.^11,12,13 Typically, patients with chronic granulomatous disease 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.

Clinical

History

The disease 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

Short stature is a prominent clinical feature in children and adults with chronic granulomatous disease.

• Patients with chronic granulomatous disease usually present with recurrent bacterial and fungal infections in early childhood. The most common initial manifestations are as follows¹⁴ :
  • Pneumonias
  • Otitis
  • Adenitis
  • Skin infections
  • Septicemia
  • Diarrhea
  • Spleen and/or liver abscesses
  • Gingival abscesses
  • Suppurative lymphadenitis
• Patients may have inflammatory and presumably noninfectious conditions such as granulomatous colitis and obstructive granulomas.
• The earliest reports of chronic granulomatous disease emphasize dermatitis as a characteristic and often presenting manifestation of the disease.^15,16
  • 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 chronic granulomatous disease.
• Systemic findings are pronounced and include the following:
  • Hepatosplenomegaly
  • Osteomyelitis (particularly that caused by Aspergillus species)
  • Recurrent pneumonia with lung abscesses and granulomas (Pneumonia occurs in almost all affected children and may lead to abscess formation, cavitation, and empyema.)
  • Gastrointestinal manifestations (eg, malabsorption, perianal abscesses and fistulae, oral ulceration, characteristic obstructive lesions associated with granulomatous infiltration)¹⁷
• 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.

Causes

The main defect in chronic granulomatous disease 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 chronic granulomatous disease 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 chronic granulomatous disease.
• Fungal infections in chronic granulomatous disease 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 following¹⁸ :
  • Pneumonia -Aspergillus, Staphylococcus, Nocardia, and Serratia species and Burkholderia cepacia (formerly Pseudomonas cepacia)¹⁹
  • Subcutaneous, liver, or perirectal abscess -Staphylococcus, Serratia, and Aspergillus species
  • Lung abscess -Aspergillus species
  • Brain abscess -Aspergillus species
  • Suppurative adenitis -Staphylococcus and Serratia species
  • Osteomyelitis -Serratia and Aspergillus species
  • Bacteremia and/or fungemia -Salmonella and Candida species and B cepacia

Differential Diagnoses

Other Problems to Be Considered

Bacterial diseases
Chronic mycoses 
Tuberculosis
Histoplasmosis

Workup

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 3 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

• X-ray 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:
  • Chemiluminescence testing to detect the degree of light generated by activated phagocytic cells
  • Direct measurements of oxygen consumption
  • Direct measurements of superoxide anion production
• Molecular diagnostics
  • Polymerase chain reaction²⁰
  • Sequencing
  • Allele-specific restriction enzyme analysis

Procedures

• Skin biopsy is important in correctly diagnosing chronic granulomatous disease.

Histologic Findings

Chronic granulomatous disease 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.

Treatment

Medical Care

Modern therapy of chronic granulomatous disease (CGD) includes aggressive and prolonged administration of antibiotics and prednisone.²¹ Antibiotics should be chosen carefully, and therapy should be vigorous. Conventional treatment consists of lifelong anti-infectious prophylaxis with antibiotics such as trimethoprim-sulfamethoxazole (TMP-SMZ), antimycotics such as itraconazole, and/or 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. Antibiotics should be carefully chosen, and therapy should be vigorous. Currently, standard therapy is continuous antibiotic treatment with TMP-SMZ.  
  • Continuous antifungal therapy with itraconazole is effective in preventing infection by Aspergillus species.²² Amphotericin B should be added to the therapeutic regimen of chronic granulomatous disease patients with established invasive aspergillosis.
  • 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 chronic granulomatous disease.^23,24
• Granulocyte transfusions from granulocyte colony-stimulating factor– and dexamethasone-stimulated donors could be a choice of treatment in chronic granulomatous disease patients, especially those with disseminated invasive aspergillosis.²⁵
• Bone marrow transplantation, as a last resort, can be undertaken. This treatment has been partially successful. Transplantations with other than perfectly matched donors are presently discouraged.^26,27
• Noninfectious granulomas may resolve spontaneously, and they rarely require systemic corticosteroid therapy unless vital organs are compromised.
• Gene therapy for chronic granulomatous disease, due to the disease's monogenic character, may perhaps be possible in the future.^28,29,30,31

Surgical Care

Surgical drainage of abscesses and resection (when possible) of granulomas.

Consultations

• Surgeon: Gastrointestinal manifestations include perineal abscesses; fistulae; and, characteristically, obstructive lesions associated with granulomatous infiltration.
• Internist: 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.

Medication

Antibiotics

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

Trimethoprim and sulfamethoxazole (Bactrim, Septra)

Current standard therapy. Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Antibacterial activity of TMP-SMZ includes common urinary tract pathogens, except Pseudomonas aeruginosa.

Dosing

Adult

160 mg TMP/800 mg SMZ PO q12h continuous treatment

Pediatric

<2 months: Do not administer
>2 months: Not established

Interactions

May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenic purpura in elderly patients; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine

Contraindications

Documented hypersensitivity; megaloblastic anemia due to folate deficiency; G-6-PD deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Discontinue at first appearance of skin rash or signs of adverse reaction; obtain CBC counts frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, administer leucovorin 5-15 mg/d); caution in folate deficiency (eg, elderly patients, patients who drink excessive amounts of alcohol, those who receive anticonvulsant therapy, those with malabsorption syndrome); hemolysis may occur in G-6-PD deficiency; patients with AIDS may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation

Antifungal agents

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.

Itraconazole (Sporanox)

Continuous antifungal therapy is effective in preventing infection by Aspergillus species. 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.

Dosing

Adult

200 mg PO qd; not to exceed 400 mg/d; increase in 100-mg increments if no improvement (administer >200 mg/d in divided doses)

Pediatric

Not established

Interactions

Antacids may reduce absorption of itraconazole; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations with high doses; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce levels (phenytoin metabolism may be altered)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic insufficiency

Biologic response modifiers

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

Interferon gamma - 1b (Actimmune)

Reduces frequency and severity of serious infections associated with chronic granulomatous disease. Interferons are synthesized by eukaryotic cells in response to viruses and a variety of natural and synthetic stimuli. 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.

Dosing

Adult

50 mcg/m²/dose SC 3 times/wk

Pediatric

BSA <0.5 m²: 1.5 mcg/kg/dose SC 3 times/wk
BSA >0.5 m²: 50 mcg/m²/dose SC 3 times/wk

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use caution in patients receiving potentially myelosuppressive drugs

Follow-up

Further Outpatient Care

• 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.

Deterrence/Prevention

• Chronic granulomatous disease in adults may be more common than previously assumed.
• Because timely treatment, infection prophylaxis, and genetic counseling for affected families are possible, chronic granulomatous disease should be excluded in any patient with unexplained infections or granulomas.

Complications

• Invasive aspergillosis and candidiasis may occur.
  • Patients with chronic granulomatous disease can be sensitized to Aspergillus species.
  • Allergic bronchopulmonary aspergillosis can develop.
• Gastrointestinal complications include the following:
  • Enteritis and/or colitis
  • Crohn disease
  • Gastric outlet obstruction
  • Chronic gastrointestinal inflammation
• Rheumatologic disorders include the following:
  • Discoid lupus erythematosus
  • Systemic lupus erythematosus
  • Raynaud syndrome
  • Nodular vasculitis
  • Juvenile rheumatoid arthritis
  • Immune-mediated thrombocytopenia
• Other complications include the following:
  • Chorioretinitis
  • Obstruction of the urinary tract
  • Severe aphthous stomatitis
  • Granulomatous cheilitis

Prognosis

• The long-term survival of patients in whom symptoms appear after they are aged 1 year 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.

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.

Miscellaneous

Medicolegal Pitfalls

• Failure to make the diagnosis is a pitfall because the granulomas can occlude vital structures, especially those in the gastrointestinal and genitourinary systems.
• Recurrent infections in the lungs, visceral lymph nodes, liver, and bones may lead to morbidity and mortality.

Special Concerns

• The NBT test has been used for the prenatal diagnosis of chronic granulomatous disease (see Lab Studies).

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Keywords

chronic granulomatous disease, CGD, fatal granulomatosis of childhood, immunodeficiency disorders, X-linked recessive disorder, gp91phox, p22phox, p67phox, Xp21.1, Rac2, impaired phagocytic function, defective cytochrome b function, oxidase absence, oxidase malfunction

Contributor Information and Disclosures

Author

Roman Janusz Nowicki, MD, PhD, Associate Professor, Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Poland
Roman Janusz Nowicki, MD, PhD is a member of the following medical societies: American Academy of Dermatology, European Academy of Dermatology and Venereology, and International Society for Human and Animal Mycology
Disclosure: Nothing to disclose.

Medical Editor

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: Stiefel Salary Employment; Orfagen Consulting fee Consulting; Maruho Consulting fee Consulting; Astellas Consulting fee Consulting

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology
Disclosure: elsevier Royalty Other; american college of physicians Honoraria Other

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