AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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. CGD 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, as may the Medscape CME course New Directions in the Management of Invasive Fungal Infections in Neonatal and Pediatric Populations.

Pathophysiology

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.

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 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. However, among CGD 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,¹ and the p67phox component. These defects include frame shifts; deletions; and nonsense, missense, splice-region, and regulatory-region mutations.

In contrast, a GT deletion at the beginning of exon 2 accounts for the defective genetic function in almost all patients with p47phox deficiency.² 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.³

Frequency

United States

The exact incidence of 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.⁴

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 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.

Race

CGD affects persons of all races.

Sex

Approximately 90% of patients with CGD are male.

Age

Symptom onset typically occurs at a young age, although the diagnosis has been at an older age in some patients.^{5, 6} 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 CGD.

• Patients with CGD usually present with recurrent bacterial and fungal infections in early childhood. The most common initial manifestations are as follows:
• • 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 CGD emphasize dermatitis as a characteristic and often presenting manifestation of the disease.
• • 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:
• • 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)⁷
• 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 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 CGD 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 following⁸:
• • Pneumonia - Aspergillus, Staphylococcus, Nocardia, and Serratia species and Burkholderia cepacia (formerly Pseudomonas cepacia)⁹
  • 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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Bacterial diseases
Chronic mycoses
Tuberculosis
Histoplasmosis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The nitroblue tetrazolium (NBT) dye test
• • Laboratory diagnosis of CGD is 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 CGD are unable to reduce oxidized NBT to insoluble blue formazan; this principle forms the basis of the standard diagnostic screening test for CGD.
  • This test is best used to identify gene carriers, and it has been used for the prenatal diagnosis of CGD.
• 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 CGD 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 CGD.
  • 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 reaction¹⁰
  • Sequencing
  • Allele-specific restriction enzyme analysis

Procedures

• Skin biopsy is important in correctly diagnosing CGD.

Histologic Findings

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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Modern therapy of CGD includes aggressive and prolonged administration of antibiotics and prednisone.¹¹ 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.¹² Amphotericin B should be added to the therapeutic regimen of CGD 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 CGD.^{13, 14}
• Granulocyte transfusions from granulocyte colony-stimulating factor– and dexamethasone-stimulated donors could be a choice of treatment in CGD patients, especially those with disseminated invasive aspergillosis.¹⁵
• 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.^{16, 17}
• Noninfectious granulomas may resolve spontaneously, and they rarely require systemic corticosteroid therapy unless vital organs are compromised.
• Gene therapy for CGD, due to the disease's monogenic character, may perhaps be possible in the future.^{18, 19, 20, 21}

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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Antibiotics

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

Drug Category: 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.

Drug Category: 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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Skin hygiene is an important element of further outpatient care. 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

• 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.

Complications

• Invasive aspergillosis and candidiasis may occur.
• • Patients with CGD 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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal 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 CGD (see Lab Studies).

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Mar 27, 2008