ISSUE 15 | JUNE 2013

IDF MEDICAL ADVISORY COMMITTEE Rebecca Buckley, MD - Chair Duke University School of Medicine, Durham, NC Zuhair Ballas, MD University of Iowa, Iowa City, IA Mark Ballow, MD State University of New York, Buffalo, NY R. Michael Blaese, MD Consulting Medical Director IDF, Towson, MD Clinical Focus Francisco Bonilla, MD, PhD Boston Children’s Hospital, Boston, MA on primary Mary Ellen Conley, MD University of Tennessee, Memphis, TN Charlotte Cunningham-Rundles, MD, PhD Mt. Sinai Medical Center, New York, NY Alexandra Filipovich, MD Cincinnati Children’s Hospital, Cincinnati, OH Thomas Fleisher, MD National Institutes of Health, Bethesda, MD Ramsay Fuleihan, MD Chronic Children’s Memorial Hospital, Chicago, IL Erwin Gelfand, MD National Jewish Medical and Research Center, Denver, CO Granulomatous Vivian Hernandez-Trujillo, MD Miami Children’s Hospital, Miami, FL Steven Holland, MD National Institutes of Health, Bethesda, MD Disease Richard Hong, MD Biomosaics, Burlington, VT Howard Lederman, MD, PhD Johns Hopkins Hospital, Baltimore, MD Harry Malech, MD National Institutes of Health, Bethesda, MD Stephen Miles, MD All Seasons Allergy, Asthma & Immunology, The Woodlands, TX Luigi Notarangelo, MD Boston Children’s Hospital, Boston, MA Hans Ochs, MD Seattle Children’s Hospital, Seattle, WA Jordan Orange, MD, PhD Texas Children’s Hospital, Houston, TX Jennifer Puck, MD University of California, San Francisco, San Francisco, CA AUTHORS John Routes, MD Children’s Hospital of Wisconsin, Milwaukee, WI Jennifer W. Leiding, MD William Shearer, MD, PhD Texas Children’s Hospital, Houston, TX Harry L. Malech, MD E. Richard Stiehm, MD UCLA School of Medicine, Los Angeles, CA Steven M. Holland, MD Kathleen Sullivan, MD, PhD Children’s Hospital of Philadelphia, Philadelphia, PA Troy Torgerson, MD, PhD Seattle Children’s Hospital, Seattle, WA Jerry Winkelstein, MD Baltimore, MD This publication was made possible by an educational grant from

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www.primaryimmune.org Chronic Granulomatous Disease

Authors which lead to CGD 4. The sixth protein, Rac2, is involved in 1 Jennifer W. Leiding, MD control of the cytoskeleton and cell migration, 2 Harry L. Malech, MD as well as activation of the NADPH oxidase 5. Patients have 3 Steven M. Holland, MD some similarities to CGD including recurrent abscesses, poor wound healing, and decreased neutrophil superoxide 1University of South Florida, Department of Pediatrics, production, but unlike CGD, neutrophilia and severe T-cell Division of Allergy, Immunology, and Rheumatology; lymphopenia may be present 5,6 . Laboratories of 2Host Defenses and 3Clinical Infectious Diseases, NIAID, NIH Prior to exposure of , and The authors have no relationships to disclose that could are at rest; the NADPH oxidase is inactive with its subunits represent or be perceived to represent a conflict of residing in different cell compartments. Some are interest. membrane bound (gp91 phox and p22 phox ) and others are in the cytoplasm (p47 phox , p67 phox , and p40 phox ). The Correspondence to: gp91 phox and p22 phox form a single unit called cytochrome Jennifer W. Leiding, MD b558 and require each other for expression within Children’s Research Institute phagocytes, meaning that mutational loss of one results in 140 – 7th Avenue South, Box 9680 the other component also being absent from the cell. After St. Petersburg, Florida 33701 cellular ingestion of and fungi, the components of [email protected] the NADPH oxidase come together on the surface of the phagolysosome and catalyze the transfer of an electron History from cytoplasmic NADPH to molecular oxygen inside the First described in 1957 1,2 and further characterized in phagolysosome thus creating superoxide radicals. The 1959 3, chronic granulomatous disease (CGD), termed fatal metabolites of superoxide, particularly hydrogen peroxide, granulomatous disease of childhood initially, was contribute directly to bacterial killing but also act as characterized by recurrent infections associated with intracellular signals for non-oxidant dependent pathways 4. hypergamma-globulinemia. Over the last six decades, CGD has evolved from an associated with Mutations in all five structural genes that comprise the severe infections with poor prognosis to a disease with NADPH oxidase have been found to cause CGD. effective management and high survival . Mutations in gp91 phox are inherited in an X-linked pattern and account for ~70% of cases. Autosomal recessive Molecular Mechanisms disease is most commonly caused by mutations in p47 phox CGD is primarily a defect in innate immunity caused by occurring in ~25% of cases. The remaining 5% occur due defective phagocyte NADPH oxidase enzyme, resulting in to defects in p6 phox or p22 phox 7,8 . One case of p40 phox the failure of neutrophils and monocytes to produce deficiency has been reported 9 and a second case is superoxide (O 2-.) when stimulated upon encountering known but has not been reported yet in the literature. The bacterial or fungal pathogens, or a variety of soluble incidence of CGD is ~1:200,000 based on 2 large inflammatory stimuli. Within the neutrophil phagosome, retrospective studies in the United States 10 and Europe 11 . superoxide combines with water to produce hydrogen Other countries have rates that are dependent on the peroxide (H 2O2) which provides most of the microbicidal degree of intermarriage and ethnic practices: 1 in 450,000 activity from this oxidative burst. The functional NADPH in Sweden 12 ; 1 in 300,000 in Japan 13 ; 1 in 111,000 in oxidase is comprised of six proteins, mutations in five of Israeli Arabs 14 .

Immune Deficiency Foundation : Clinical Focus / 1 FIGURE 1A - DHR Patterns of DHR assay in different types of CGD (MFI = Mean Fluorescence Index on X-axis)

FIGURE 1B - DHR Typical two peak DHR pattern in following PMA activation of neutrophils from a female carrier of X-linked CGD

2 / Immune Deficiency Foundation: Clinical Focus Diagnosis X-linked female carriers; one normal superoxide producing The diagnosis of CGD relies on direct measurement of population and one abnormal non-superoxide producing superoxide production. The nitroblue tetrazolium (NBT) population 19 . A DHR assay should be requested for the dye test is the oldest and most recognized diagnostic test mother of a male patient with CGD as this can provide for CGD, but it relies on light microscopy to provide a confirmation that the patient has X-linked CGD. If the mostly qualitative determination of NADPH oxidase mother’s neutrophil DHR pattern shows only a single activity. The NBT test is typically performed on a normal oxidase peak, this may mean the patient has AR microscope slide which is read manually to distinguish CGD, but this is only presumptive, because approximately reducing (blue-black insoluble formazan precipitate) from 10% of X-linked CGD patients have new mutations in non-reducing (unstained) cells 15 . Because the NBT is which case the mother will not have an X-linked CGD semi-quantitative, it can miss mild genetic forms of CGD carrier genotype or phenotype. Infections are uncommon associated with residual oxidase activity, and has been in female carriers unless there is significant skewing of X- largely abandoned and replaced by the dihydrorho- inactivation such that normal neutrophils are <10%. damine (DHR) assay, which is available from most major However, discoid lupus, photosensitivity rashes, and commercial laboratories. The DHR test uses flow aphthous ulcers are common in female carriers 20 . cytometry to measure the production of hydrogen peroxide in the presence of peroxidase. Oxidation of non- Clinical Manifestations fluorescent dihydrorhodamine 123 results in production of The majority of patients with CGD present before age 5, highly fluorescent rhodamine 123 in stimulated but later presentations, including well into adulthood, have neutrophils 16 . The presence of myeloperoxidase is also become more common with the routine use of potent oral necessary for neutrophils to generate superoxide; antibiotics and reduction in environmental exposures myeloperoxidase deficiency can therefore lead to (e.g., Salmonella, BCG) in the industrial world. Infections abnormal DHR assay results 17 . The DHR is preferable of the skin, lungs, lymph nodes, and liver represent the because of its ability to distinguish many X-linked patients most commonly involved sites. The overwhelming majority from the p47 phox deficient autosomal recessive form of of infections in CGD in North America result from five CGD, its sensitivity to very low numbers of functional organisms: Staphylococcus aureus, Burkholderia cepacia neutrophils, its ability to measure residual superoxide complex, Serratia marcescens, Nocardia species and production, its capacity to accurately identify X-linked Aspergillus species 10 . Salmonella, bacille-Calmette Guerin carriers, and its ease of use. Figure 1A shows the typical (BCG), and tuberculosis are important causes of DHR assay patterns (top to bottom) with neutrophils from in other parts of the world 11 . In the setting of antibiotic a healthy subject, a typical null oxidase function X-linked prophylaxis, staphylococci are primarily confined to the CGD patient, a partial oxidase activity function X-linked liver and lymph nodes. Infection with Burkholderia species CGD patient, and a typical p47 phox deficient AR CGD causes pneumonia and rarely sepsis 21 . Nocardia species patient. The p40 phox deficient form of CGD has a DHR are a common cause of pneumonia but can also cause pattern similar to p47 phox , while the p22 phox and p67 phox osteomyelitis and brain abscesses 22 . Outside of CGD, CGD patterns can demonstrate null or partial function. Nocardia infections only occur in the setting of high dose The DHR assay makes it possible to assess the amount of corticosteroids. Chromobacterium violaceum 23 and residual oxidase activity in a patient’s neutrophils by Francisella philomiragia 24 are uncommon causes of observing the mean fluorescence index (MFI) of the infection and are virtually pathognomonic of CGD; both peak 18 . When obtaining a DHR test from a commercial are found in brackish water and can cause sepsis in CGD. laboratory on a patient who has or is suspected of having CGD, it is essential to request that the commercial lab Fungal infections in CGD are a leading cause of mortality send the histograms and peak MFI information in addition and are often indolent in their presentation 25,26 . They are to their interpretation of the result. As shown in Figure 1B , typically acquired through inhalation of fungal elements two populations of phagocytes are seen with the DHR in leading to pneumonia (Figure 2) that can spread locally to

Immune Deficiency Foundation: Clinical Focus / 3 FIGURE 2A - Fungal Pneumonia FIGURE 2B - Fungal Pneumonia Chest CT of an X-linked CGD patient with Aspergillus Lung biopsy fungal stain from an X-linked CGD patient with pneumonia Aspergillus

FIGURE 3A - Liver abscess in CGD FIGURE 3B - Liver abscess in CGD Typical multicentric CT pattern of liver abscesses in CGD Typical solid granulomatous pattern of CGD liver abscess as seen in a surgical specimen

4 / Immune Deficiency Foundation: Clinical Focus the ribs or metastatically. Insidious symptoms such as granulomata and CGD-related colitis but can have long- failure to thrive, cough, fever, and chest pain may be the term complications including growth retardation, first presenting symptoms. Aspergillus species are the osteoporosis, and increased risk of infection. Prednisone most common fungal infections in CGD, but other unusual 1mg/kg/day is initiated for treatment of proven colitis fungi also occur, including Paecilomyces species 25,26 . typically for 1-2 weeks followed by a slow taper of 0.1- Interestingly, the endemic dimorphic molds Histoplasma, 0.25mg/kg/day over 1-2 months 31 . Metronidazole, salicylic Coccidioides, and Blastomyces do not cause acid derivatives, 6-mercaptopurine, and mesalamine are infection in CGD 27 . also useful in treatment of CGD colitis 27 . TNF-alpha inhibitors should be avoided in CGD as they lead to Formation of granulomata and dysregulated increased frequency of CGD related infections and death, in the genitourinary and gastrointestinal tracts in CGD even though they successfully treat CGD-related colitis 32 . contribute significantly to morbidity. Bladder granulomata cause ureteral obstruction which are usually sterile, but Liver abscesses occur in about one third of CGD patients, 28 urinary tract infections can be seen , as well as regardless of genotype, typically due to Staphylococcus 29 pseudotumors of the bladder and eosinophilic cystitis . aureus. They are typically dense, caseous, and difficult to Intrinsic kidney disease and chronic renal failure following drain (Figure 3), previously requiring surgery in most use of nephrotoxic agents is more common in patients cases 33 . More recently, corticosteroids in combination with phox 30 with p47 deficiency . Gastric outlet obstruction, with antimicrobials have been demonstrated to be effective in a similar presentation to that seen in pyloric stenosis, can treating staphylococcal liver abscesses without surgery 34 . be a first manifestation of disease. Esophageal, jejunal, Liver enzyme elevation, persistent elevations in alkaline ileal, cecal, rectal, and perirectal granulomata similar to phosphatase, and drug-induced hepatitis are associated those seen in Crohn’s disease have also been described. with high rates of portal venopathy, splenomegaly, and Symptomatic inflammatory bowel disease affects nodular regenerative hyperplasia. Portal hypertension and approximately 50% of CGD patients and can also be a thrombocytopenia are both important risk factors for presenting finding. Other symptoms of CGD-related colitis mortality in CGD 35 . include abdominal pain, diarrhea, strictures, and fistulae. Colitis can be an important cause of growth retardation. Hyperinflammation is common in CGD especially in Corticosteroids are the mainstay of treatment for response to infectious agents. Fungi elicit an exuberant

TABLE 1 Summary of Molecular Defects in CGD

Gene Protein Inheritance Patten Proportion of CGD* CYBA p22 phox AR 6%

NCF1 p47 phox AR 20%

NCF2 p67 phox AR 6%

NCF4 p40 phox AR 1 individual

CYBB gp91 phox XL 70%

*These rates apply to North America and Europe but do not apply to regions in which high rates of intermarriage lead to higher rates of recessive diseases.

Immune Deficiency Foundation: Clinical Focus / 5 TABLE 2 Infections in CGD: Common Pathogens and Sites of Involvement

Pathogen Presentation Bacterial Infections Soft tissue infections Lymphadenitis Liver abscess Staphylococcus aureus Osteomyelitis Pneumonia Sepsis Pneumonia Burkholderia species Sepsis More common: Osteomyelitis Soft tissue infections Serratia marcescens Less common: Pneumonia Sepsis Pneumonia Nocardia species Osteomyelitis Brain abscess Necrotizing lymphadenitis Granulibacter bethesdensis Sepsis Chromobacterium violaceum Sepsis Francisella philomiragia Sepsis

Fungal Infections Pneumonia Osteomyelitis Aspergillus species Brain abscess Lymphadenitis Pneumonia Paecilomyces species Soft tissue infections Osteomyelitis

Other molds Geosmitha argillacea Cephalosporum species Chaetomium strumarium Phialophora richardsiae Pneumonia Scedosporium apiospermum Soft tissue infection Exophiala species Cladosporium species Zygomycete species Acremonium species Neosartorya udagawae

Yeast Infections Sepsis Candida Soft tissue infection Liver abscess

Trichosporon Pneumonia Arthrographis kalrae Soft tissue infection

6 / Immune Deficiency Foundation: Clinical Focus inflammatory response regardless of whether the organism Diabetes and renal and cardiovascular disease occur more is alive or dead 36 . “Mulch pneumonitis” is a syndrome commonly in patients with p47 phox deficient CGD 30 . caused by inhalation of aerosolized decayed organic matter, such as hay or dead leaves, leading to acute Discoid lupus erythematosus occurs in CGD but is more fulminant pneumonitis similar to that seen in common in X-linked female carriers 10,20,40 . Other hypersensitivity pneumonitis 37 . Because of the risk of autoimmune diseases reported in CGD include idiopathic pneumonitis, activities that expose CGD patients to thrombocytopenic purpura, juvenile idiopathic arthritis, decayed organic matter such as mulching, gardening, leaf autoimmune pulmonary disease, celiac disease with co- raking, and house demolition should be avoided. existing pulmonary hemosiderosis, myasthenia gravis, IgA Heightened inflammation has also been described in nephropathy, antiphospholipid syndrome, and recurrent chronic colitis 31 , granulomatous cystitis 29 , pulmonary pericardial effusion 10,40 . Autoimmune disease is likely a infections with Nocardia 38 , and staphylococcal liver co-morbid condition and not entirely a result of abscesses 34,39 . In each of these cases, directed treatment hyperinflammation associated with CGD. Diagnosis relies of the heightened inflammatory response in addition to on specific symptoms without an identifiable infectious proper anti-microbials is extremely helpful for cause, presence of serologic markers, and response to clinical resolution. immunosuppression. Autoimmune disease associated with CGD responds surprisingly well to immunosuppression Many other non-infectious manifestations affect patients such as corticosteroids 40 . with CGD. Growth delay is common and failure to thrive can be a presenting symptom as well as compounded by Treatment colitis. Growth may improve in late adolescence and many affected adults attain normal predicted weight and Effective management of CGD relies on lifelong height 31 . Oral manifestations include gingivitis, aphthous antibacterial and antifungal propylaxis and interferon ulcers, and gingival hypertrophy. Characteristically poor (IFN) . Prophylactic trimethoprim/sulfamethoxazole at a wound healing at sites of surgical incisions leads to wound dose oγf 5mg/kg/day divided twice daily reduces the dehiscence; other cutaneous manifestations include frequency of major infections from one episode every year photosensitivity, granulomatous lesions, and vasculitis. to one every 3.5 years 41 . Prophylactic itraconazole at

TABLE 3 Recommended Prophylaxis for CGD Patients

Drug Dose 5mg/kg/day up to 320mg in 2 Antibacterial* Trimethoprim-sulfamethoxazole divided doses 100mg/day <13y or <50kg Antifungal Itraconazole 200mg/day >13y or >50kg

Immunomodulatory Interferon gamma 50mcg/m2 SQ three times per week

*Alternatives to TMP-SMX for patients allergic to sulfonamides: trimethoprim as a single agent, dicloxacillin, cephalosporins, or fluoroquinolones.

Immune Deficiency Foundation: Clinical Focus / 7 doses of 100mg daily for patients <13 years or weighing setting of active infection 44,45,47 . CGD is an attractive <50kg and 200mg daily for patients >13 years or weighing target for gene therapy since it results from a single gene >50kg is effective at reducing the frequency of fungal defect and complete protection does not require full infections 42 . In a large international multicenter correction of superoxide production, as shown by many randomized placebo-controlled trial, IFN was effective at healthy X-linked carriers. Gene therapy protocols using reducing the number and severity of infeγctions by 70% lentivectors will start soon in the U.S. and Europe. regardless of inheritance pattern, sex, or use of Although HSCT is an attractive option for cure of patients prophylactic antibiotics 43 . Dosing of IFN is 50mcg/m2 with CGD, the overwhelming majority of CGD patients subcutaneously three times per week. Cγlose follow-up of survive without HSCT, albeit with co-morbidities. Survival patients with CGD is recommended. Practitioners should in CGD has improved greatly over the last several decades have a high suspicion and always be in search of new and is approximately 90% at 10 years 18,48,49 . Residual infections. Evaluation should include tests looking for NADPH oxidase activity correlates well with survival in evidence of infection such as C-reactive protein or CGD. This can be determined directly by DHR or a erythrocyte sedimentation rate, sensitive but non-specific specific cytochrome reduction assay, and both tests markers of inflammation 27 . Anemia may be due to chronic correlate quite well with specific mutations. Patient’s with disease or iron deficiency. Iron deficiency anemia and autosomal recessive CGD typically have higher levels of hypoalbuminemia often accompany CGD-related colitis 31 . residual oxidase activity than patients with X-linked CGD Imaging is exquisitely helpful for diagnosis and following and therefore, have higher overall survival rates. In general the treatment of infections. Children with CGD should for X-linked CGD, mutations that abolish protein receive routine vaccinations as recommended by the expression or that occur in the intracellular FAD or American Academy of Pediatrics including live virus NADPH binding domains are severe and are associated vaccines. Patients with CGD do not have any defect in with worse overall outcomes, whereas patients with protein immunity to viruses, so they are able to receive live virus positive mutations in the extracellular domains tend to vaccines without adverse effect. Many countries in Europe have a better outcome. Therefore, the specific X-linked and Asia vaccinate children with the tuberculosis live mutation can be used to predict superoxide production bacterial vaccine, BCG, but this is not recommended and overall risk of mortality, providing information that can practice in the U.S. Children with CGD should never help decide about HSCT 18 . receive the BCG live bacterial vaccine as it can result in a severe life-threatening systemic BCG infection. Over the last 60 years, CGD has taught many lessons in basic science, infection susceptibility, and the role of Allogeneic hematopoietic stem cell transplant (HSCT) is inflammation in immune responses. It has evolved from a the only known cure for CGD; both myeloablative and non- disease characterized as a deficiency of the immune myeloablative regimens have been successful 44-47 . Non- system with no cure to one of dysregulation with multiple myeloablative transplants have reduced the risk of therapeutic avenues available and a far better outlook for regimen-related toxicity and allow for transplantation in the the CGD patient.

8 / Immune Deficiency Foundation: Clinical Focus References

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