Pediatrics

Management of Disorders of Neutrophil Function: Chronic Granulomatous Disease

OVERVIEW: What every practitioner needs to know

Are you sure your patient has chronic granulomatous disease? What are the typical findings for this disease?

Chronic granulomatous disease (CGD) is a rare genetic disorder of phagocyte function characterized by recurrent, often life-threatening bacterial and fungal infections. Patients with CGD often present in the first years of life with recurrent purulent bacterial and fungal infections, however, the disease can present even later in adulthood. The clinical presentation of infection is often subtle. Even serious or deep-seated infections in patients with CGD may only cause low grade fever.

A hallmark of CGD is deep-seated recurrent infections that do not respond well or recur after standard antimicrobial treatments. Thus, when what would appear to be a routine case of adenitis or pneumonia recurs after a standard 1 to 2 week course of antibiotic therapy, or when catalase positive organisms such as staphylococcus, serratia, or aspergillus are obtained in a culture, the diagnosis of CGD should be considered. Common sites of infection and the typical organisms that cause infection in patients with CGD are listed in Table 2 and Table 3. Infection with an unusual or opportunistic organism such as B cepacia, S marcesens. C violaceum, Nocardia, or Aspergillus species should prompt consideration of CGD.

Table 2.

Infection sites

Table 3.

Common organisms in CGD

Unlike patients who have severe neutropenia, patients with CGD do not often present with sepsis. When it occurs, bacterial sepsis is often the result of a chronic low-grade infection that may have been overlooked or inadequately treated, allowing the infection to progress into multiple abscesses or multiple organ site involvement. In particular, Burkholderia cepacia that is resistant to the first line of antibiotics used for S aureus and most gram negatives can be a cause of persistent fever or an illness that starts with a low grade fever and then progress to sudden high-grade fever and endotoxic shock.

A major mechanism by which phagocytes kill bacterial and fungal pathogens is through the production of microbicidal oxidants derived from superoxide. Recurrent and serious infections in patients with CGD result from the failure of their phagocytes to effectively kill ingested microbes due to a defect in the production of superoxide by neutrophils, monocytes, macrophages, and eosinophils. Consequently, patients with CGD suffer from severe, chronic recurrent bacterial and fungal infections. Neutrophil chemotaxis and phagocytosis are normal or even slightly increased, and humeral immunity is normal. Thus, individuals with CGD are able to mobilize phagocytes to the site of infection, but microbial killing is impaired. Effective treatment of infections in CGD requires prolonged parenteral antibiotics, often for months.

The disorder was first described in 1957 and the biochemical defect in O2 production was described in the late 1960’s leading to the development of the nitroblue tetrazolium (NBT) test, a convenient screening test for the disorder. The superoxide generating machinery of the neutrophil consists of 91 kD and 22 kD membrane bound proteins and 47 kD and 67 kD cytosolic factors were described in the 1980's and lead to recognition that mutations in the corresponding genes are responsible for four different genetic subgroups of CGD (see Table 1).

Table 1.

CGD sub types

What other disease/condition shares some of these symptoms?

Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, myeloperoxidase deficiency, or defects in the glutathione pathway may have recurrent bacterial infections due to impaired bacterial killing.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The diagnosis of CGD is usually suggested by the unusual clinical histories outlined above or by a family history of CGD. The most common sites of infection and the most common organisms isolated from patients with CGD are listed in Table 2 and Table 3. A positive family history of recurrent infection in young children, particularly males who have died in childhood from infection is suggestive of CGD.

Neutrophil immunodeficiencies comprise less that 15% of all immunodeficiencies. In patients with a history of recurrent infection suggestive of a possible immunodeficiency one should first consider antibody and T-cell deficiencies. However, the nitroblue tetrazolium (NBT) screening test for CGD is so simple, inexpensive, and usually easily available that it is reasonable to include it in the initial evaluation if the patient clinical picture suggests CGD.

The nitroblue tetrazolium (NBT) slide test on fresh blood is the classic diagnostic test. PMN are labeled with NBT, a colorless agent which is converted to blue formazan precipitate in the presence of normal PMN oxidative processes. 100% of the PMN will be positive in normal individuals. None of the PMN from a patient with CGD (either X-linked or recessive) will be blue. Approximately 50% of the PMN from a mother who is a carrier of the X-linked form of CGD will be blue. The test is non-diagnostic for the carrier of recessive forms of CGD.

The NBT slide test is very good for diagnosing the disease state and very reliable if done in a laboratory that runs the test reasonably frequently and the results are interpreted by a clinician who has experience with CGD. False positives can occur if a fresh sample is not used for the test, if the sample is not properly handled, or if the cells do not adhere adequately to the slide, causing them to not reduce the NBT. Such false positives can occur when the study is handled as a “send-out” test or when an NBT extraction variation of the NBT test is used.

The NBT slide test is very good for carrier testing for X-linked CGD in most cases. However, extreme Lyonization can occur in an individual carrier, resulting in a high percent of NBT positive cells. In these cases it may not be possible to accurately determine the carrier state.

The diagnosis can also be made by flow cytometry of PMNs using dihydroprhodamine123 (DHR). DHR is converted to rhodamine by the PMN oxidase system. This assay is particularity good for carrier detection in X-linked carriers with extreme Lyonization because it can evaluate a large number of cells and more clearly delineate the differences been normal and a carrier who has a very high positive cell percentage. However, it also can give erroneous results. If the sample is old or with certain recessive mutations, there can be baseline shift yielding false negative results.

DNA diagnostic methods are now commercially available for all of the common X-linked and recessive mutations (see Table 1). We recommend that DNA diagnostics be done in all kindreds, as it can be useful for prenatal diagnosis.

Carriers are usually asymptomatic. Carriers of X-linked CGD who have less than 10% to 15% NBT positive cells should be followed carefully, as they may develop clinically significant and chronic infections similar to CGD patients. About 25% of X-linked carriers will develop discoid lupus, which is easily managed.

If you are able to confirm the patient has chronic granulomatous disease, what treatment should be initiated?

Infection Prophylaxis:

All patients with CGD should be on daily trimethoprim-sulfamethoxazole (6 mg/kg/day of trimethoprim) as anti-bacterial prophylaxis. In the sulfa allergic CGD patient one can use dicloxacillin (25 to 50 mg/kg/day).

Prophylactic itraconazole should be given to minimize fungal infections. Doses of 200 mg daily if 13 years of age or older or if weighing at least 50 kg, or 100 mg daily if less than 13 years of age or weighing less than 50 kg are generally recommended.

Recombinant human gamma-interferon (rIFN-g) is also given three times per week in a dose of 0.05 mg/m2 or 0.0015 mg/kg if the patient's body surface area is < 0.5 m2.

Management of suspected infection:

Potentially serious infections in patients with CGD commonly present with only low-grade fever and localizing symptoms may be minimal. Thus all febrile illnesses must be considered possibly serious infections in these patients and promptly investigated. Any suspicious symptoms should not be ignored but always appropriately evaluated with a complete history and a careful physical exam, paying special attention to the sinuses, lungs, lymph nodes, skin and perirectal areas. Especially in young children where nonspecific viral syndromes are common, it can be very challenging to avoid needless hospitalizations and invasive diagnostic procedures yet be certain not to miss more serious, potentially fatal infections.

After a thorough history and exam one should obtain a CBC and sedimentation rate (ESR), blood cultures, urine analysis and cultures of any suspicious lesions or sites of possible infection.

A chest radiograph (x-ray) should also be obtained. Although non-specific, the ESR can be particularity helpful. If it is normal, it is less likely there is a serious deep-seated infection. If the exam and CXR are negative and the ESR is not significantly elevated (<20), a follow up clinical exam and ESR in a few days is a reasonable approach. By contrast, if the ESR is significantly elevated, an exhaustive search for the site of infection should be undertaken. This often requires a CAT scan with contrast of sinuses, chest (if the chest x-ray is negative), abdomen, and pelvis.

Children with CGD, like normal children, get common childhood infections. If the chest x-ray is negative and there are no other concerning factors, they can be treated with standard approaches. However, they need to be followed very carefully clinically. We would repeat a CBC and ESR in 3-4 days and institute a full workup if they are not improving rapidly at the same rate expected for a normal child. This approach can only be entertained if there is excellent follow-up and compliance by the family and if providers familiar with management of CGD are available to monitor.

If a site of infection is found that can be easily sampled for culture, this should be done immediately. Serology for aspergillus and tuberculosis should be obtained.

Very often it is not possible to identify a specific organism and it becomes necessary to treat empirically with broad spectrum antibiotics that are effective against the most common pathogens in CGD. Empirically one would start treatment with parenteral anti-staph and anti-gram negative antibiotics and follow daily or every-other-day ESRs. If there is steady decrease in the ESR over 2 to 5 days on this therapy one can assume the patient has a bacterial infection and it is responsive to the chosen antibiotics.

Antibiotics should be continued for at least a few weeks past the time the ESR has normalized and all radiographic evidence of infection has resolved. This may take weeks or months. Once there has been substantial improvement, a change to oral antibiotics can be considered. However, the ESR and clinical exam must be followed closely to make sure the infection does not recur or resistance is developing. If there is not clear evidence of response to antibacterial treatment within a few days to a week or if there is evidence of worsening, anti-aspergillus treatment should be initiated, empirically. Again, there should be a change in ESR within a week or two if the patient is responding to the anti-fungal treatment.

If the patient is toxic appearing or has significant pneumonia with respiratory compromise, a sequential approach to antimicrobials may not be advisable. Combined antibacterial and anti-fungal therapy may be needed from the outset. In addition, if the patient is toxic, antibiotic coverage for Burkholderia cenocepacia and other organisms in the Burkholderia family should be added.

Serial change in the ESR can be very helpful to determine if there is a response to the antimicrobial regimen that has been selected. Usually, there is a change in the ESR within several days if the organism is sensitive, though complete response can take a very long time.

Judicious use of systemic steroids can be very helpful in pulmonary infections. Bronchial swelling can be significant and lead to obstruct airways, particularly in very young children. Improvement in respiratory status can be quite rapid after initiating steroids due to improved air exchange and clearance of secretions.

If the patient continues to be febrile in spite of what seems to be broad microbial coverage, or develops hematologic cytopenias, one must consider the possibility of secondary macrophage activation syndrome / hemophagocytic lymphohistiocytosis.

Routine monitoring / health maintenance:

Routine health monitoring of height, weight, blood pressure and physical exam at least twice a year is advisable. Weight loss and growth failure are not part of the basic defect and when found usually indicate underlying pathology such as chronic infection or malabsorption. A focused history of gastrointestinal symptoms is important as dysphagia and gastric outlet obstruction as well as a Crohn’s-like syndrome can be due to gastrointestinal granulomas.

Patients with CGD should receive all routine recommended immunizations including pneumococcal, meningococcal, and regular influenza vaccines.

In the absence of symptoms, we recommend monitoring a CBC and ESR three to four times a year to establish a patient's baseline for reference during future evaluation of suspected infectious illnesses.

Similarly, a patient who has had pneumonia and recovered back to baseline may need a chest computed tomography (CT) scan for comparison during future illnesses, especially if there is chronic scarring. Routine or annual CT exams, however, are not recommended.

Renal ultrasound every year or two is non-invasive and can help detect ureteral obstruction by granulomas which have been reported as a cause of insidious renal failure in patients with CGD.

Curative therapy:

Chronic granulomatous disease can be cured by bone marrow transplantation. Other than donor availability, the major obstacle to the transplantation is pre-existing infection. While CGD patients can be maintained in good health when monitored by experienced providers, even in the best of hands, life-threatening and irreversible infectious complications can occur.

Given the extreme rarity of this disorder and the few number of centers with significant experience in management, it is our opinion that all patients with identical donors should undergo bone marrow transplantation. It is critical that all of their existing infections be completely eradicated prior to attempting transplant. The transplant should also be carried out at a center with physicians who are familiar with chronic granulomatous disease management. If a suitable well matched unrelated donor is available, then matched unrelated donor transplantation should be seriously considered.

Research on gene therapy for CGD is underway and a few patients have been treated under experimental protocols.

Genetic counseling:

Families should receive genetic counseling. We recommend this be done by physicians who have experience managing CGD, or by general genetic counselors who are experienced with the clinical course of this disorder and its management.

New patients should be offered specific gene testing and mutation analysis.

Prenatal diagnosis is possible and pre-implantation selection is also possible for this disorder.

What are the possible outcomes of this disease?

Patients with CGD suffer from severe, chronic recurrent bacterial andfungal infections. Neutrophil chemotaxis and phagocytosis are normal oreven slightly increased, and humeral immunity is normal. Thus,individuals with CGD are able to mobilize phagocytes to the site ofinfection, but microbial killing is impaired. Effective treatment ofinfections in CGD requires prolonged parenteral antibiotics, often formonths.

What causes this disease and how frequent is it?

CGD is a rare genetic disorder of phagocyte function. It has an estimated incidence of between 1/200,000 and 1/250,000 livebirths and is characterized by recurrent, often life-threatening bacterial and fungal infections.

How do these pathogens/genes/exposures cause the disease?

Neutrophil motility and phagocytosisare normal but bacteriocidal ability is severely reduced. Thiscombination of factors leads to the formation of inflammatory granulomasand exuberant inflammatory reactions that contribute to the morbidityof the disorder.

What complications might you expect from the disease or treatment of the disease?

Chronic infection, inflammation with granuloma formation is common in patients with CGD. While CGD neutrophils are not able to kill bacteria, chemotaxis and phagocytosis are normal if not slightly enhanced. Thus, a significant inflammatory reaction seems to occur even with minimal invasion by organism. Not infrequently, the inflammatory reaction itself results in significant complications. For example, infants and young children can have significant respiratory compromise from bronchial swelling and judicious use of steroids can be life saving.

The most common organisms that are isolated from patients with CGD are listed in Table 3. While one must assume that infection is at the basis of all symptoms, it is often impossible to identify a specific organism. Thus, when a pathogen cannot be identified despite aggressive attempts to isolate bacterial and fungal organisms from sites of infection, the patient must be treated empirically with antimicrobial agents effective against the most likely pathogens.

When properly managed, many CGD patients show no clinical evidence of inflammation most of the time. One should not assume that an elevated ESR or chronic organomegaly (e.g., lymphadenopathy or hepatomegaly) is “normal” for these patients. These findings usually indicate that there is significant pathology ongoing and it is important to make a definitive diagnosis and treat accordingly. Chronic inflammatory findings usually occur when an infection has gone undetected and has become deep seated or has been inadequately treated.

Inflammation itself causes a number of chronic complications in patients with CGD including lymphadenopathy, hepatosplenomegaly, eczematoid dermatitis and anemia of chronic disease (hemoglobin levels usually 8-10 gm/dl) are common. However, if infections are managed aggressively, these complications can be reduced or eliminated. Chronic inflammation in patients with CGD can result in secondary macrophage activation syndrome or hemophagocytic lymphohistiocytosis which can also be associated with recurrent fever.

Inflammatory involvement of the gastrointestinal tract including gastric antral narrowing in infants and young children can be severe enough to cause significant obstruction and may be present in up to a third of patients. A Crohn’s disease-like picture can be the presentation of CGD including positive anti-gliadin antibodies in up to 70% of patients.

Inadequately treated chronic pulmonary or hepatic infections can lead to organ failure due to the effects of chronic low-grade inflammation.

In general, the frequency of infections tends to decrease in later childhood (around 8 to 10 years of age) as the patient's other immune systems mature. However, the underlying PMN defect does not improve. While there are many patients who have survived into their fifth decade of life, median survival for patients with CGD is shortened.

How can CGD be prevented?

Families should receive genetic counseling. We recommend thisbe done by physicians who have experience managing CGD, or by generalgenetic counselors who are experienced with the clinical course of thisdisorder and its management.

New patients should be offered specific gene testing and mutation analysis.

Prenatal diagnosis is possible and pre-implantation selection is also possible for this disorder.

What is the evidence?

Dinauer, MC, Coates, TD, Hoffman, R, Benz, EJ, Shattil, SJ, Furie, B, Silberstein, McGlave, Helsop. "Disorders of phagocyte function and number". Hematology: Basic Principles and Practice. 2009. pp. 687.

(This is an exhaustive review of the topic with treatment recommendations. The next edition will be out in 2013 and will have more summary information regarding management and diagnosis.)

Kyono, W, Coates, TD. "A practical approach to neutrophil disorders.Pediatr". Clinc. North Am.. vol. 49. 2002. pp. 929-971.

(This is a review aimed at general physicians and focuses on practical approaches.)

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