Clinical Focuson primary immunodeficiencies

ChronicGranulomatousDisease

IDF MEDICAL ADVISORY COMMITTEE

Rebecca Buckley, MD - ChairDuke University School of Medicine, Durham, NC

Zuhair Ballas, MDUniversity of Iowa, Iowa City, IA

Mark Ballow, MDState University of New York, Buffalo, NY

R. Michael Blaese, MDConsulting Medical Director IDF, Towson, MD

Francisco Bonilla, MD, PhDBoston Children’s Hospital, Boston, MA

Mary Ellen Conley, MDUniversity of Tennessee, Memphis, TN

Charlotte Cunningham-Rundles, MD, PhDMt. Sinai Medical Center, New York, NY

Alexandra Filipovich, MDCincinnati Children’s Hospital, Cincinnati, OH

Thomas Fleisher, MDNational Institutes of Health, Bethesda, MD

Ramsay Fuleihan, MDChildren’s Memorial Hospital, Chicago, IL

Erwin Gelfand, MDNational Jewish Medical and Research Center,Denver, CO

Vivian Hernandez-Trujillo, MDMiami Children’s Hospital, Miami, FL

Steven Holland, MDNational Institutes of Health, Bethesda, MD

Richard Hong, MDBiomosaics, Burlington, VT

Howard Lederman, MD, PhDJohns Hopkins Hospital, Baltimore, MD

Harry Malech, MDNational Institutes of Health, Bethesda, MD

Stephen Miles, MDAll Seasons Allergy, Asthma & Immunology,The Woodlands, TX

Luigi Notarangelo, MDBoston Children’s Hospital, Boston, MA

Hans Ochs, MDSeattle Children’s Hospital, Seattle, WA

Jordan Orange, MD, PhDTexas Children’s Hospital, Houston, TX

Jennifer Puck, MDUniversity of California, San Francisco,San Francisco, CA

John Routes, MDChildren’s Hospital of Wisconsin, Milwaukee, WI

William Shearer, MD, PhDTexas Children’s Hospital, Houston, TX

E. Richard Stiehm, MDUCLA School of Medicine, Los Angeles, CA

Kathleen Sullivan, MD, PhDChildren’s Hospital of Philadelphia, Philadelphia, PA

Troy Torgerson, MD, PhDSeattle Children’s Hospital, Seattle, WA

Jerry Winkelstein, MDBaltimore, MD

ISSUE 15 | JUNE 2013

AUTHORS

Jennifer W. Leiding, MD

Harry L. Malech, MD

Steven M. Holland, MD

This publication was made possible by an educational grant from

This book contains general medical information which cannot be applied safely to any individual case.

Medical knowledge and practice can change rapidly. Therefore, this book should not be used as a substitute

for professional medical advice.

Copyright 2013 by Immune Deficiency Foundation, USA.

Readers may redistribute this article to other individuals for non-commercial use, provided that the text,

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Immune Deficiency Foundation: Clinical Focus / 1

Authors1 Jennifer W. Leiding, MD2 Harry L. Malech, MD 3 Steven M. Holland, MD

1University of South Florida, Department of Pediatrics,

Division of Allergy, Immunology, and Rheumatology;

Laboratories of 2Host Defenses and 3Clinical Infectious

Diseases, NIAID, NIH

The authors have no relationships to disclose that could

represent or be perceived to represent a conflict of

interest.

Correspondence to:

Jennifer W. Leiding, MD

Children’s Research Institute

140 – 7th Avenue South, Box 9680

St. Petersburg, Florida 33701

jleiding@health.usf.edu

History First described in 19571,2 and further characterized in

19593, chronic granulomatous disease (CGD), termed fatal

granulomatous disease of childhood initially, was

characterized by recurrent infections associated with

hypergamma-globulinemia. Over the last six decades, CGD

has evolved from an immunodeficiency associated with

severe infections with poor prognosis to a disease with

effective management and high survival.

Molecular MechanismsCGD is primarily a defect in innate immunity caused by

defective phagocyte NADPH oxidase enzyme, resulting in

the failure of neutrophils and monocytes to produce

superoxide (O2-.) when stimulated upon encountering

bacterial or fungal pathogens, or a variety of soluble

inflammatory stimuli. Within the neutrophil phagosome,

superoxide combines with water to produce hydrogen

peroxide (H2O2) which provides most of the microbicidal

activity from this oxidative burst. The functional NADPH

oxidase is comprised of six proteins, mutations in five of

which lead to CGD4. The sixth protein, Rac2, is involved in

control of the neutrophil cytoskeleton and cell migration,

as well as activation of the NADPH oxidase5. Patients have

some similarities to CGD including recurrent abscesses,

poor wound healing, and decreased neutrophil superoxide

production, but unlike CGD, neutrophilia and severe T-cell

lymphopenia may be present5,6.

Prior to exposure of infections, neutrophils and monocytes

are at rest; the NADPH oxidase is inactive with its subunits

residing in different cell compartments. Some are

membrane bound (gp91phox and p22phox) and others are

in the cytoplasm (p47phox, p67phox, and p40phox). The

gp91phox and p22phox form a single unit called cytochrome

b558 and require each other for expression within

phagocytes, meaning that mutational loss of one results in

the other component also being absent from the cell. After

cellular ingestion of bacteria and fungi, the components of

the NADPH oxidase come together on the surface of the

phagolysosome and catalyze the transfer of an electron

from cytoplasmic NADPH to molecular oxygen inside the

phagolysosome thus creating superoxide radicals. The

metabolites of superoxide, particularly hydrogen peroxide,

contribute directly to bacterial killing but also act as

intracellular signals for non-oxidant dependent pathways4.

Mutations in all five structural genes that comprise the

NADPH oxidase have been found to cause CGD.

Mutations in gp91phox are inherited in an X-linked pattern

and account for ~70% of cases. Autosomal recessive

disease is most commonly caused by mutations in p47phox

occurring in ~25% of cases. The remaining 5% occur due

to defects in p6phox or p22phox7,8. One case of p40phox

deficiency has been reported9 and a second case is

known but has not been reported yet in the literature. The

incidence of CGD is ~1:200,000 based on 2 large

retrospective studies in the United States10 and Europe11.

Other countries have rates that are dependent on the

degree of intermarriage and ethnic practices: 1 in 450,000

in Sweden12; 1 in 300,000 in Japan13; 1 in 111,000 in

Israeli Arabs14.

Chronic Granulomatous Disease

2 / Immune Deficiency Foundation: Clinical Focus

FIGURE 1A - DHRPatterns of DHR assay in different types of CGD (MFI = Mean Fluorescence Index on X-axis)

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

Immune Deficiency Foundation: Clinical Focus / 3

DiagnosisThe diagnosis of CGD relies on direct measurement of

superoxide production. The nitroblue tetrazolium (NBT)

dye test is the oldest and most recognized diagnostic test

for CGD, but it relies on light microscopy to provide a

mostly qualitative determination of NADPH oxidase

activity. The NBT test is typically performed on a

microscope slide which is read manually to distinguish

reducing (blue-black insoluble formazan precipitate) from

non-reducing (unstained) cells15. Because the NBT is

semi-quantitative, it can miss mild genetic forms of CGD

associated with residual oxidase activity, and has been

largely abandoned and replaced by the dihydrorho-

damine (DHR) assay, which is available from most major

commercial laboratories. The DHR test uses flow

cytometry to measure the production of hydrogen peroxide

in the presence of peroxidase. Oxidation of non-

fluorescent dihydrorhodamine 123 results in production of

highly fluorescent rhodamine 123 in stimulated

neutrophils16. The presence of myeloperoxidase is also

necessary for neutrophils to generate superoxide;

myeloperoxidase deficiency can therefore lead to

abnormal DHR assay results17. The DHR is preferable

because of its ability to distinguish many X-linked patients

from the p47phox deficient autosomal recessive form of

CGD, its sensitivity to very low numbers of functional

neutrophils, its ability to measure residual superoxide

production, its capacity to accurately identify X-linked

carriers, and its ease of use. Figure 1A shows the typical

DHR assay patterns (top to bottom) with neutrophils from

a healthy subject, a typical null oxidase function X-linked

CGD patient, a partial oxidase activity function X-linked

CGD patient, and a typical p47phox deficient AR CGD

patient. The p40phox deficient form of CGD has a DHR

pattern similar to p47phox, while the p22phox and p67phox

CGD patterns can demonstrate null or partial function.

The DHR assay makes it possible to assess the amount of

residual oxidase activity in a patient’s neutrophils by

observing the mean fluorescence index (MFI) of the

peak18. When obtaining a DHR test from a commercial

laboratory on a patient who has or is suspected of having

CGD, it is essential to request that the commercial lab

send the histograms and peak MFI information in addition

to their interpretation of the result. As shown in Figure 1B,

two populations of phagocytes are seen with the DHR in

X-linked female carriers; one normal superoxide producing

population and one abnormal non-superoxide producing

population19. A DHR assay should be requested for the

mother of a male patient with CGD as this can provide

confirmation that the patient has X-linked CGD. If the

mother’s neutrophil DHR pattern shows only a single

normal oxidase peak, this may mean the patient has AR

CGD, but this is only presumptive, because approximately

10% of X-linked CGD patients have new mutations in

which case the mother will not have an X-linked CGD

carrier genotype or phenotype. Infections are uncommon

in female carriers unless there is significant skewing of X-

inactivation such that normal neutrophils are <10%.

However, discoid lupus, photosensitivity rashes, and

aphthous ulcers are common in female carriers20.

Clinical ManifestationsThe majority of patients with CGD present before age 5,

but later presentations, including well into adulthood, have

become more common with the routine use of potent oral

antibiotics and reduction in environmental exposures

(e.g., Salmonella, BCG) in the industrial world. Infections

of the skin, lungs, lymph nodes, and liver represent the

most commonly involved sites. The overwhelming majority

of infections in CGD in North America result from five

organisms: Staphylococcus aureus, Burkholderia cepacia

complex, Serratia marcescens, Nocardia species and

Aspergillus species10. Salmonella, bacille-Calmette Guerin

(BCG), and tuberculosis are important causes of infection

in other parts of the world11. In the setting of antibiotic

prophylaxis, staphylococci are primarily confined to the

liver and lymph nodes. Infection with Burkholderia species

causes pneumonia and rarely sepsis21. Nocardia species

are a common cause of pneumonia but can also cause

osteomyelitis and brain abscesses22. Outside of CGD,

Nocardia infections only occur in the setting of high dose

corticosteroids. Chromobacterium violaceum23 and

Francisella philomiragia24 are uncommon causes of

infection and are virtually pathognomonic of CGD; both

are found in brackish water and can cause sepsis in CGD.

Fungal infections in CGD are a leading cause of mortality

and are often indolent in their presentation25,26. They are

typically acquired through inhalation of fungal elements

leading to pneumonia (Figure 2) that can spread locally to

4 / Immune Deficiency Foundation: Clinical Focus

FIGURE 3A - Liver abscess in CGDTypical multicentric CT pattern of liver abscesses in CGD

FIGURE 3B - Liver abscess in CGDTypical solid granulomatous pattern of CGD liver abscessas seen in a surgical specimen

FIGURE 2A - Fungal PneumoniaChest CT of an X-linked CGD patient with Aspergilluspneumonia

FIGURE 2B - Fungal PneumoniaLung biopsy fungal stain from an X-linked CGD patient withAspergillus

Immune Deficiency Foundation: Clinical Focus / 5

the ribs or metastatically. Insidious symptoms such as

failure to thrive, cough, fever, and chest pain may be the

first presenting symptoms. Aspergillus species are the

most common fungal infections in CGD, but other unusual

fungi also occur, including Paecilomyces species25,26.

Interestingly, the endemic dimorphic molds Histoplasma,

Coccidioides, and Blastomyces do not cause

infection in CGD27.

Formation of granulomata and dysregulated inflammation

in the genitourinary and gastrointestinal tracts in CGD

contribute significantly to morbidity. Bladder granulomata

cause ureteral obstruction which are usually sterile, but

urinary tract infections can be seen28, as well as

pseudotumors of the bladder and eosinophilic cystitis29.

Intrinsic kidney disease and chronic renal failure following

use of nephrotoxic agents is more common in patients

with p47phox deficiency30. Gastric outlet obstruction, with

a similar presentation to that seen in pyloric stenosis, can

be a first manifestation of disease. Esophageal, jejunal,

ileal, cecal, rectal, and perirectal granulomata similar to

those seen in Crohn’s disease have also been described.

Symptomatic inflammatory bowel disease affects

approximately 50% of CGD patients and can also be a

presenting finding. Other symptoms of CGD-related colitis

include abdominal pain, diarrhea, strictures, and fistulae.

Colitis can be an important cause of growth retardation.

Corticosteroids are the mainstay of treatment for

granulomata and CGD-related colitis but can have long-

term complications including growth retardation,

osteoporosis, and increased risk of infection. Prednisone

1mg/kg/day is initiated for treatment of proven colitis

typically for 1-2 weeks followed by a slow taper of 0.1-

0.25mg/kg/day over 1-2 months31. Metronidazole, salicylic

acid derivatives, 6-mercaptopurine, and mesalamine are

also useful in treatment of CGD colitis27. TNF-alpha

inhibitors should be avoided in CGD as they lead to

increased frequency of CGD related infections and death,

even though they successfully treat CGD-related colitis32.

Liver abscesses occur in about one third of CGD patients,

regardless of genotype, typically due to Staphylococcus

aureus. They are typically dense, caseous, and difficult to

drain (Figure 3), previously requiring surgery in most

cases33. More recently, corticosteroids in combination with

antimicrobials have been demonstrated to be effective in

treating staphylococcal liver abscesses without surgery 34.

Liver enzyme elevation, persistent elevations in alkaline

phosphatase, and drug-induced hepatitis are associated

with high rates of portal venopathy, splenomegaly, and

nodular regenerative hyperplasia. Portal hypertension and

thrombocytopenia are both important risk factors for

mortality in CGD35.

Hyperinflammation is common in CGD especially in

response to infectious agents. Fungi elicit an exuberant

Gene Protein Inheritance Patten Proportion of CGD*

CYBA p22phox AR 6%

NCF1 p47phox AR 20%

NCF2 p67phox AR 6%

NCF4 p40phox AR 1 individual

CYBB gp91phox XL 70%

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

TABLE 1Summary of Molecular Defects in CGD

6 / Immune Deficiency Foundation: Clinical Focus

TABLE 2Infections in CGD: Common Pathogens and Sites of Involvement

Pathogen PresentationBacterial Infections

Staphylococcus aureus

Soft tissue infectionsLymphadenitisLiver abscessOsteomyelitisPneumoniaSepsis

Burkholderia speciesPneumoniaSepsis

Serratia marcescens

More common: OsteomyelitisSoft tissue infectionsLess common:PneumoniaSepsis

Nocardia speciesPneumoniaOsteomyelitisBrain abscess

Granulibacter bethesdensisNecrotizing lymphadenitisSepsis

Chromobacterium violaceum Sepsis

Francisella philomiragia Sepsis

Fungal Infections

Aspergillus species

PneumoniaOsteomyelitisBrain abscessLymphadenitis

Paecilomyces speciesPneumoniaSoft tissue infectionsOsteomyelitis

Other moldsGeosmitha argillacea Cephalosporum speciesChaetomium strumariumPhialophora richardsiaeScedosporium apiospermumExophiala speciesCladosporium speciesZygomycete speciesAcremonium speciesNeosartorya udagawae

PneumoniaSoft tissue infection

Yeast Infections

CandidaSepsisSoft tissue infectionLiver abscess

Trichosporon Arthrographis kalrae

Pneumonia Soft tissue infection

Immune Deficiency Foundation: Clinical Focus / 7

inflammatory response regardless of whether the organism

is alive or dead36. “Mulch pneumonitis” is a syndrome

caused by inhalation of aerosolized decayed organic

matter, such as hay or dead leaves, leading to acute

fulminant pneumonitis similar to that seen in

hypersensitivity pneumonitis37. Because of the risk of

pneumonitis, activities that expose CGD patients to

decayed organic matter such as mulching, gardening, leaf

raking, and house demolition should be avoided.

Heightened inflammation has also been described in

chronic colitis31, granulomatous cystitis29, pulmonary

infections with Nocardia38, and staphylococcal liver

abscesses34,39. In each of these cases, directed treatment

of the heightened inflammatory response in addition to

proper anti-microbials is extremely helpful for

clinical resolution.

Many other non-infectious manifestations affect patients

with CGD. Growth delay is common and failure to thrive

can be a presenting symptom as well as compounded by

colitis. Growth may improve in late adolescence and many

affected adults attain normal predicted weight and

height31. Oral manifestations include gingivitis, aphthous

ulcers, and gingival hypertrophy. Characteristically poor

wound healing at sites of surgical incisions leads to wound

dehiscence; other cutaneous manifestations include

photosensitivity, granulomatous lesions, and vasculitis.

Diabetes and renal and cardiovascular disease occur more

commonly in patients with p47phox deficient CGD30.

Discoid lupus erythematosus occurs in CGD but is more

common in X-linked female carriers10,20,40. Other

autoimmune diseases reported in CGD include idiopathic

thrombocytopenic purpura, juvenile idiopathic arthritis,

autoimmune pulmonary disease, celiac disease with co-

existing pulmonary hemosiderosis, myasthenia gravis, IgA

nephropathy, antiphospholipid syndrome, and recurrent

pericardial effusion10,40. Autoimmune disease is likely a

co-morbid condition and not entirely a result of

hyperinflammation associated with CGD. Diagnosis relies

on specific symptoms without an identifiable infectious

cause, presence of serologic markers, and response to

immunosuppression. Autoimmune disease associated with

CGD responds surprisingly well to immunosuppression

such as corticosteroids40.

Treatment

Effective management of CGD relies on lifelong

antibacterial and antifungal propylaxis and interferon

(IFN) γ. Prophylactic trimethoprim/sulfamethoxazole at a

dose of 5mg/kg/day divided twice daily reduces the

frequency of major infections from one episode every year

to one every 3.5 years41. Prophylactic itraconazole at

TABLE 3Recommended Prophylaxis for CGD Patients

Drug Dose

Antibacterial* Trimethoprim-sulfamethoxazole5mg/kg/day up to 320mg in 2divided doses

Antifungal Itraconazole100mg/day <13y or <50kg200mg/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, orfluoroquinolones.

8 / Immune Deficiency Foundation: Clinical Focus

doses of 100mg daily for patients <13 years or weighing

<50kg and 200mg daily for patients >13 years or weighing

>50kg is effective at reducing the frequency of fungal

infections42. In a large international multicenter

randomized placebo-controlled trial, IFNγ was effective at

reducing the number and severity of infections by 70%

regardless of inheritance pattern, sex, or use of

prophylactic antibiotics43. Dosing of IFNγ is 50mcg/m2

subcutaneously three times per week. Close follow-up of

patients with CGD is recommended. Practitioners should

have a high suspicion and always be in search of new

infections. Evaluation should include tests looking for

evidence of infection such as C-reactive protein or

erythrocyte sedimentation rate, sensitive but non-specific

markers of inflammation27. Anemia may be due to chronic

disease or iron deficiency. Iron deficiency anemia and

hypoalbuminemia often accompany CGD-related colitis31.

Imaging is exquisitely helpful for diagnosis and following

the treatment of infections. Children with CGD should

receive routine vaccinations as recommended by the

American Academy of Pediatrics including live virus

vaccines. Patients with CGD do not have any defect in

immunity to viruses, so they are able to receive live virus

vaccines without adverse effect. Many countries in Europe

and Asia vaccinate children with the tuberculosis live

bacterial vaccine, BCG, but this is not recommended

practice in the U.S. Children with CGD should never

receive the BCG live bacterial vaccine as it can result in a

severe life-threatening systemic BCG infection.

Allogeneic hematopoietic stem cell transplant (HSCT) is

the only known cure for CGD; both myeloablative and non-

myeloablative regimens have been successful44-47. Non-

myeloablative transplants have reduced the risk of

regimen-related toxicity and allow for transplantation in the

setting of active infection44,45,47. CGD is an attractive

target for gene therapy since it results from a single gene

defect and complete protection does not require full

correction of superoxide production, as shown by many

healthy X-linked carriers. Gene therapy protocols using

lentivectors will start soon in the U.S. and Europe.

Although HSCT is an attractive option for cure of patients

with CGD, the overwhelming majority of CGD patients

survive without HSCT, albeit with co-morbidities. Survival

in CGD has improved greatly over the last several decades

and is approximately 90% at 10 years18,48,49. Residual

NADPH oxidase activity correlates well with survival in

CGD. This can be determined directly by DHR or a

specific cytochrome reduction assay, and both tests

correlate quite well with specific mutations. Patient’s with

autosomal recessive CGD typically have higher levels of

residual oxidase activity than patients with X-linked CGD

and therefore, have higher overall survival rates. In general

for X-linked CGD, mutations that abolish protein

expression or that occur in the intracellular FAD or

NADPH binding domains are severe and are associated

with worse overall outcomes, whereas patients with protein

positive mutations in the extracellular domains tend to

have a better outcome. Therefore, the specific X-linked

mutation can be used to predict superoxide production

and overall risk of mortality, providing information that can

help decide about HSCT18.

Over the last 60 years, CGD has taught many lessons in

basic science, infection susceptibility, and the role of

inflammation in immune responses. It has evolved from a

disease characterized as a deficiency of the immune

system with no cure to one of dysregulation with multiple

therapeutic avenues available and a far better outlook for

the CGD patient.

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