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Disorders of Phagocyte Function


Phagocytic leukocytes are an essential component of the innate immune system that has evolved to rapidly respond to the presence of invading bacteria, fungi, and parasites. This first line of host defense also includes natural killer (NK) lymphocytes, complement, and other plasma proteins. As reviewed in Chapter 28, Chapter 49 , phagocytes are responsible for ingesting, killing, and digesting pathogens. Granulocytic phagocytes (neutrophils and eosinophils) circulate in the bloodstream until they sense chemotactic signals from infected tissues, resulting in adhesion to the vascular endothelium and subsequent migration into the site of infection. In contrast, mononuclear phagocytes (macrophages and their circulating precursor, the monocyte) function primarily as resident cells in a variety of tissues such as the lungs, liver, peritoneal cavity, and spleen, where they perform a surveillance role and also interact closely with lymphocytes to promote specific immune responses. Microbial killing is accomplished by two types of mechanisms: (1) de novo synthesis of highly toxic and often unstable derivatives of molecular oxygen by an enzyme known as respiratory burst oxidase and (2) preformed polypeptide “antibiotics” and proteases stored within several types of lysosomal granules that are delivered into phagocytic vacuoles containing the ingested microbes.

This chapter reviews the major congenital and acquired disorders of phagocyte function, which from the clinical standpoint largely involve neutrophils. As would be predicted, these disorders manifest clinically by recurrent bacterial and fungal infections, often with atypical pathogens or unusual presentations. Interestingly, the converse of this is only rarely observed. Most patients with recurrent infections do not have any identifiable abnormality in their phagocytes. There are at least two explanations for the clinical rarity of phagocyte disorders. First, given their critical role in host defense, nature may be quite intolerant of major abnormalities in phagocytes. Before the modern antibiotic era, patients with severe disorders probably did not survive into their childbearing years. Second, there is a remarkable redundancy in the antimicrobial machinery of the phagocytes that permits one system to compensate for a defect in another. For example, the host does not rely on a single chemotactic signal or neutrophil membrane receptor to ensure that phagocytes accumulate at sites of infection. Instead, multiple chemotactic signals and receptors are used. A similar phenomenon is seen in the reactions that kill microbes, as both oxidative and nonoxidative systems are used. It is also important to note that phagocytic leukocytes synthesize and secrete multiple inflammatory mediators, including leukotrienes, chemokines, and other cytokines that amplify and regulate the inflammatory response and initiate cross-talk with adaptive immune cells. Disorders resulting from functional phagocyte defects thus can display not only recurrent, severe bacterial and fungal infections but also aberrant inflammation that is not always related to infection.

This chapter is organized according to the aforementioned cellular functions: disorders of the respiratory burst microbicidal pathway, abnormalities of phagocyte adhesion and chemotaxis, and defects in the structure and function of lysosomal granules. This chapter is not meant to be an encyclopedic review of the numerous papers published on phagocyte abnormalities. It is important to note that many of these reports describe marginal in vitro defects, with little evidence that they are responsible for a clinical problem. Comprehensive reviews offering additional information on phagocyte disorders are available.

Approach to Diagnosis of Phagocyte Function Disorders

Inherited and acquired clinical disorders of phagocyte function result from defects in one or more of the major steps leading to microbial killing—adhesion, chemotaxis, ingestion, degranulation, and production of microbicidal oxidants ( Fig. 51.1 ). Patients with inherited disorders typically present in infancy or childhood with recurrent, unusual, or recalcitrant bacterial and fungal infections, and it is usually not difficult to determine that these are outside the range of normal. The presentation of these different inherited disorders can overlap, so that a specific diagnosis cannot be made on clinical grounds alone. Infections commonly seen include those of skin or mucosa, lung, lymph node, deep tissue abscesses, or childhood periodontitis. These can often have an indolent presentation with only low-grade fevers. Bacterial sepsis is an unusual initial symptom and usually reflects dissemination from an infected site. Inherited defects in phagocyte function are rare and represent only approximately 20% of the primary immunodeficiencies. Thus children with suspected disorders of host defense should also be screened for defects in humoral, cellular, and complement-mediated immunity (see Chapter 50, Chapter 52 ). An approach to evaluating the patient with significant recurrent infections is shown in Fig. 51.2 . Patients in whom a defect is identified should be referred to a center specialized in care of such patients.

Figure 51.1, STEPS IN THE RESPONSE OF CIRCULATION NEUTROPHILS TO INFECTION.

Figure 51.2, EVALUATION OF PATIENTS WITH RECURRENT BACTERIAL OR FUNGAL INFECTIONS.

In clinical practice, although nearly all patients with well-characterized phagocyte abnormalities have recurrent or unusual infections, the majority of individuals with histories of persistent or recurrent infections do not have identifiable phagocyte disorders or other immune defects. In some cases, these reflect another underlying medical condition or nonimmunologic problem related to an anatomic or obstructive defect. This chapter focuses largely on disorders in which a good correlation exists between the clinical condition and an identifiable defect in phagocyte function.

Disorders of the Respiratory Burst Pathway

Reactive oxygen species generated by the phagocyte respiratory burst are critical for microbial killing. The enzyme responsible for the initial reaction in this pathway is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase found in plasma and phagolysosomal membranes. Upon activation by inflammatory stimuli, NADPH oxidase catalyzes the transfer of an electron from NADPH to molecular oxygen, thereby forming superoxide (as the O 2 − ion; Fig. 51.3 , reaction 1). This NADPH oxidase, along with enzymes and reactions that are directly involved in the production or metabolism of O 2 − , constitutes the respiratory burst pathway as depicted in Fig. 51.3 . Superoxide is the precursor to numerous microbicidal oxidants, including hydrogen peroxide and hypochlorous acid. Five clinically significant defects have been identified in the respiratory burst, involving the following enzymes: NADPH oxidase (reaction 1), leukocyte glucose-6-phosphate dehydrogenase (G6PD; reaction 8), myeloperoxidase (MPO; reaction 4), glutathione reductase, and glutathione synthetase (reaction 9). These reactions are involved in the production of O 2 − (reactions 8 and 1) in the conversion of O 2 − and hydrogen peroxide to other toxic derivatives (reaction 4) or in the detoxification of excess hydrogen peroxide needed to protect the phagocyte during the respiratory burst (reactions 7 and 9). Of note, NADPH oxidase (NOX) homologs to the leukocyte NADPH oxidase are present in the gut, vascular cells, and other tissues, which may generate oxidants for local host defense or for regulation of other cellular functions.

Figure 51.3, REACTIONS OF RESPIRATORY BURST PATHWAY.

Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is a genetically heterogeneous group of defects that share in common the failure of neutrophils, monocytes, macrophages, dendritic cells, and eosinophils to undergo a respiratory burst and generate O 2 − due to genetic deficiency of the NADPH oxidase. CGD is relatively rare, having an estimated incidence of between 1 in 200,000 and 1 in 250,000 live births based on data from the United States CGD Registry, although it is still the most common inherited phagocyte disorder of clinical significance (MPO deficiency is more common, but affected patients are rarely symptomatic). The absence of respiratory burst–derived oxidants results in recurrent, often life-threatening bacterial and fungal infections and is also associated with formation of inflammatory granulomas and other manifestations of aberrant inflammation. Dysregulated inflammatory responses, which are not always related to infection, reflect a broad impact of NADPH oxidase–derived reactive oxygen species on cellular pathways involved in innate and adaptive immunity.

CGD was first described in 1957 as a syndrome characterized by severe recurrent infections in boys who also had visceral granulomas containing pigmented histiocytes. The disease was termed fatal granulomatous disease owing to this distinguishing histologic feature and the grim clinical course in most patients. It was not until the late 1960s and early 1970s that the defect in oxygen consumption and O 2 − production was identified and a convenient diagnostic assay, the nitroblue tetrazolium (NBT) test, was developed. In the 1980s a combination of biochemical and molecular genetic approaches led to the identification of four critical subunits of NADPH oxidase and the recognition that mutations in the corresponding genes are responsible for four different genetic subgroups of CGD ( Fig. 51.4 ).

Clinical Approach to Patients with Disorders of Phagocyte Function

Index of Suspicion

Patients with disorders of phagocyte function usually present at a young age with recurrent, deep-seated bacterial and fungal infections. Unlike patients with severe neutropenia caused by bone marrow (BM) failure, these patients usually do not have sepsis. Blood cultures are often negative. The major diagnostic problem faced by the clinician is to determine if the history of infection is unusual enough to warrant consideration of an underlying neutrophil dysfunction defect. The first point to remember is that primary immunodeficiency disorders are rare and primary neutrophil dysfunction syndromes form only a small percentage of all primary immunodeficiency syndromes. The patient is more likely to have recurrent community-acquired Staphylococcus infection than chronic granulomatous disease (CGD).

Specific features that may suggest a phagocytic defect are shown in Fig. 51.2 . Excellent discussions of this problem have been published (see Kyono and Coates and Dinauer, Newburger and Borregaard ). Four aspects of each patient’s infection history should be considered: frequency, severity, location, and responsible pathogen. Patients with unusual features in at least one of these aspects should alert the clinician to a possible underlying phagocyte disorder. When considering frequency, the patient’s age and associated medical conditions must be taken into account. For example, recurrent otitis media in a 2-year-old patient is far less worrisome than a similar history in a 40-year-old patient. The more unusual or severe the infections, the less frequently these have to occur before a phagocyte evaluation is indicated. Infections in unexpected anatomic locations, such as hepatic, pulmonary, and rectal abscesses, may indicate an underlying phagocyte defect. Childhood periodontal disease or gingivitis is normally very uncommon, and in the absence of neutropenic conditions, strongly suggests underlying neutrophil dysfunction. The identification of certain pathogens (e.g., Serratia marcescens , Klebsiella spp., Aspergillus spp., Nocardia spp., Burkholderia cepacia , invasive candidiasis) in children and young adults can provide the strongest indications for pursuing further studies. A history of delayed separation of the umbilical cord is often mentioned as a sign of phagocytic defect. This is fairly common as an isolated finding and is usually of no significance. However, this in conjunction with omphalitis or other pyogenic infections raises the possibility of leukocyte adhesion deficiency (LAD) or chemotactic defects. A child with nystagmus, fair skin, and recurrent staphylococcal infections should be evaluated for Chédiak-Higashi syndrome (CHS). Finally, the family history may provide clues suggesting an inherited disorder.

Evaluation

Performing a good history and physical examination to eliminate common causes of recurrent infection is important before looking for rare syndromes. For example, is the recurrent pneumonia caused by an aspirated foreign body in the bronchus? In general, patients should first be evaluated for lymphocyte or complement defects. A useful algorithm is presented in Fig. 51.2 . Note that testing described in this algorithm is not exhaustive, and patients with truly striking histories of unusual kinds of infections should be referred for unbiased whole-exome sequencing and further evaluation by specialized research laboratories.

Recently, a fifth genetic subgroup due to mutations in a specialized NADPH oxidase subunit was identified, first in a single patient and subsequently in additional families. Another new and uncommon form of CGD results from defects in a protein important for assembling the NADPH oxidase flavocytochrome. Databases for the main four genetic subgroups of CGD have been developed that are accessible through the websites http://structure.bmc.lu.se/idbase/ and http://www.hgmd.cf.ac.uk/ac/index.php . Recent publications on disease manifestations and genotypes in large patient registries are also available and support earlier reports. Interestingly, common hypomorphic variants in NADPH oxidase genes are linked to autoimmune disorders, particularly systemic lupus erythematosus.

Figure 51.4, NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE (NADPH) OXIDASE AND MOLECULAR GENETICS OF CHRONIC GRANULOMATOUS DISEASE.

Molecular Genetics of Chronic Granulomatous Disease

CGD results from mutations in any of the five genes encoding subunits of the NADPH oxidase or a gene encoding a chaperone protein (see Fig. 51.4 ; Table 51.1 ). These genes are expressed primarily in myeloid cells and in B and perhaps T lymphocytes, although here its function is not well understood. The biochemical and genetic analysis of CGD has been instrumental in characterizing this complex enzyme. The oxidase subunits are referred to by their apparent molecular mass (kDa) and have been given the designation phox , for ph agocyte ox idase. A b-type cytochrome known as flavocytochrome b 558 , a membrane-bound heterodimer composed of gp91 phox and p22 phox , is the redox center of the oxidase. In North American, Latin American, and European registries, approximately two-thirds of CGD cases result from defects in the X-linked gene encoding the gp91 phox subunit, which contains both the flavoprotein and heme-binding domains responsible for electron transport. X-linked recessive CGD accounts for a smaller percentage of CGD in areas with higher rates of consanguinity, where autosomal recessive (AR) forms are more frequent. One AR form of CGD is caused by mutations in the gene encoding p22 phox , the smaller subunit of flavocytochrome b 558 , which provides a critical docking site for a regulatory subunit, p47 phox . Defects in EROS, an endoplasmic reticulum protein that facilitates flavocytochrome assembly, are found in a rare new subgroup of AR CGD. Other cases of AR CGD involve genetic defects in p47 phox , p67 phox , or p40 phox , three regulatory proteins associated with each other in the cytosol of unstimulated cells but which rapidly move to the membrane to activate flavocytochrome b 558 and superoxide formation upon cell activation by inflammatory or phagocytic stimuli. The p40 phox subunit plays a selective role in stimulating high-level superoxide production within phagosomes or endosomes via membrane-bound phosphatidylinositol-3-phosphate. Formation of the active NADPH oxidase complex also involves the activation of the small guanosine triphosphate (GTP)-binding protein Rac, which then binds to the plasma membrane and p67 phox . No cases of CGD have been identified resulting from genetic defects in Rac, although a mutation in the blood cell–specific Rac2 isoform was found in an infant with recurrent infections and abnormal neutrophil adhesion, motility, and partial NADPH oxidase defects.

Table 51.1
Classification of Chronic Granulomatous Disease
Component Affected Gene Symbol Gene Locus Inheritance Subtype a NBT Score (% Positive) O 2 − Production (% Normal) Flavocytochrome b Spectrum (% Normal) Defect in Cell-Free NADPH Oxidase Assay Frequency (% of Cases) b
gp91 phox CYBB Xp21.1 X X91° 0 0 0 Membrane 68
X91 − 80−100 (weak) 3−30 Low Membrane 5
X91 − 5−10 5−10 Low Membrane <1
X91 + 0 0 N Membrane 1
p22 phox CYBA 16p24.3 AR A22° 0 0 0 Membrane 4
A22 + 0 0 N Membrane <1
p47 phox NCF1 7q11.23 AR A47° 0 0−1 N Cytosol 17
p67 phox NCF2 1q25.3 AR A67° 0 0 N Cytosol 5
p40 phox NCF4 22q13.1 AR A40 100 <20 (intracellular) N n/a <1
EROS CYBC1 17q25.3 AR — 100 5–20 Low n/a <1
AR , Autosomal recessive inheritance; N , normal; NADPH , nicotinamide adenine dinucleotide phosphate; n/a , not applicable; NBT , nitroblue tetrazolium; X , X-linked inheritance.

a In this nomenclature, the first letter represents the mode of inheritance (X-linked [X] or autosomal recessive [A] ), and the number indicates the phox component that is genetically affected. The superscript symbols indicate whether the level of protein of the affected component is undetectable (°), diminished (−), or normal (+) as measured by immunoblot analysis.

b Combined data from 209 kindreds evaluated at the Scripps Research Institute/Stanford University CGD Clinic and a cooperative European study representing 57 kindreds and 63 patients. (Courtesy Casimir C, Chetty M, Bohler MC, et al. Identification of the defective NADPH-oxidase component in chronic granulomatous disease: a study of 57 European families. Eur J Clin Invest . 1992;22:403; and Curnutte JT. Chronic granulomatous disease: the solving of a clinical riddle at the molecular level. Clin Immunol Immunopathol . 1993;67:S2.) These frequencies remain similar to those in more recent reports from Europe and the United States.

The gene for gp91 phox , termed CYBB , spans approximately 30 kb in the Xp21.1 region of the X chromosome. More than 600 distinct mutations have been identified in the gp91 phox gene in X-linked CGD (MIM306400), which include deletions, frameshifts, splice site, nonsense, and missense mutations that are distributed throughout the gene ( Table 51.2 ). Approximately 10% to 15% of cases of X-linked CGD are caused by new germline mutations. In most X-linked CGD, gp91 phox is completely absent, and there is no measurable flavocytochrome b or superoxide production (the X91° subtype). In about 5% of X-linked cases, gp91 phox can be present in normal levels but be nonfunctional (X91 + ), mutated in such a way that gp91 phox is poorly functional (X91 − ), or expressed in only a small fraction of phagocytes (X91 − ). The first two “variant” forms of X-linked CGD result from coding sequence mutations, and the latter are caused by mutations in the regulatory portion of the gp91 phox gene. Some X-linked CGD patients have large deletions that affect not only CYBB but also portions of or all the flanking gene loci for McLeod hemolytic anemia syndrome (absence of the Kell erythrocyte antigen, Kx), Duchenne

Diagnosis of Chronic Granulomatous Disease

The diagnosis of chronic granulomatous disease (CGD) is easily established by doing a nitroblue tetrazolium (NBT) slide test or flow cytometry of dihydroxyrhodamine (DHR) 123 fluorescence to detect neutrophil nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The NBT slide test is very easy to set up, as is DHR flow cytometry. However, because the probability of getting an abnormal result is very low, there may be confusion in interpretation because of a lack of experience. In the authors’ experience, incorrect positive and negative results have been reported for both assays. Thus, if the index of suspicion is high, consultation should be obtained from a center with extensive experience with the test and with the disorder.

Neutrophil respiratory burst activity is preserved in anticoagulated blood maintained at room temperature for several days; thus DHR testing can be done 1–2 days later after shipping to a commercial laboratory. A normal blood sample should always be shipped with the patient specimen as a control for problems in specimen handling during transport. NBT tests are best performed on the same day the blood sample is obtained.

Nitroblue Tetrazolium Slide Test

  • No NBT reduction (absence of cells with dark blue formazan deposits) in both X-linked and autosomal recessive (AR) forms of CGD (see Fig. 51.5B ).

    Figure 51.5, ANALYSIS OF NEUTROPHIL NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE ACTIVITY FOR THE DIAGNOSIS OF CHRONIC GRANULOMATOUS DISEASE.

  • Usually no reduction in 50% of cells and normal in 50% for X-linked carrier. The percent positive cells can vary if there is unequal X inactivation and may appear normal or like CGD with extreme lyonization (see Fig. 51.5C ).

  • False-positive results can occur (i.e., apparent failure to reduce NBT supporting the diagnosis of CGD) if the neutrophils do not adhere to the slide. This happens with greasy slides or with some cases of leukocyte adhesion deficiency (LAD). Using phorbol myristate acetate to stimulate the cells will avoid this.

Dihydroxyrhodamine Flow Cytometry

  • This approach has replaced the NBT slide test in many laboratories. It has the advantage of assessing large numbers of cells and can give quantitation of the amount of oxidant production.

  • The change in fluorescence channel number with stimulation is the critical number and not the percent positive cells.

  • X-linked CGD patients will not respond at all and show no increase in fluorescence with stimulation (see Fig. 51.5F ).

  • X-linked carriers will show approximately 50% of the cells that respond with a normal increase in fluorescence, and the other half will have no response. Degrees of unequal X inactivation are much more accurately quantified by this assay (see Fig. 51.5G ).

  • AR patients, particularly those with absent p47 phox , have some response to stimulation and show a small increase in fluorescence (see Fig. 51.5H ). This level of oxidant production is usually not visible on the NBT test.

  • AR carriers have a good response, but the histogram may be broader than normal and may even appear bimodal with a weakly fluorescent peak and a strongly fluorescent peak. This is not distinguishable on the NBT slide test.

  • Falsely negative results not supporting the diagnosis of CGD have been reported in specimens that have been run a few days after phlebotomy.

  • Falsely abnormal results suggesting CGD can be seen in patients with myeloperoxidase (MPO) deficiency because MPO is required to generate strong DHR fluorescence.

Genetic Analysis

  • Genetic analysis for X-linked and AR CGD is clinically available and should be performed on at least the proband in each kindred.

Those with fewer than 5% oxidase-positive cells have full-blown CGD.

muscular dystrophy, and X-linked retinitis pigmentosa. Rare missense point mutations in CYBB lead to markedly impaired flavocytochrome b expression and activity in macrophages, with much less effects in neutrophils. Affected patients were susceptible to mycobacterial infections but did not have other bacterial and fungal infections characteristic of CGD, highlighting the importance of macrophages for controlling mycobacteria.

Table 51.2
Summary of Mutations in the CYBB Gene Encoding gp91 pbox in 261 Kindreds With X-linked Chronic Granulomatous Disease
Data from Roos D, Curnutte J, Hossle JP, et al. X-CGDbase: a database of X-CGD-causing mutations. Immunol Today. 1996;17:517.
Type of Mutation Number of Kindreds Frequency (%) Phenotype
Deletions 63 24.2 X91°
Insertions 27 10.3 X91°
Splice-site mutations 42 16.1 X91°
Missense mutations 59 22.6 X91°, X91 − , X91 +
Nonsense mutations 70 26.8 X91°

AR CGD involving p22 phox (MIM 233690) occurs in approximately 5% of CGD patients and usually involves the complete absence of cytochrome b (A22°), encoded by CYBA . Mutations in A22 CGD are heterogeneous and range from large interstitial gene deletions to point mutations associated with missense, frameshift, or RNA splicing defects. Because the full expression of flavocytochrome b in the membrane requires the production of both subunits, a primary deficiency of either component leads to a secondary loss of the other. Thus neither subunit can be detected on immunoblot analysis in either X91° or A22° CGD. A patient with A22 + CGD has been described with a missense mutation disrupting the binding site for p47 phox .

AR patients with p47 phox -deficient CGD (MIM 233700) account for approximately one-fourth of cases in the United States and Europe, but only approximately 7% of cases in Japan. The p47 phox subunit is encoded by the NCF1 gene. A limited number of mutations have been identified in NCF1 . Virtually all patients are either homozygotes or compound heterozygotes for a mutant allele with a GT deletion at the beginning of exon 2 that predicts a premature stop codon following the amino acid residue and results in absence of the p47 phox protein. The high frequency of the p47 phox GT deletion mutation appears to reflect the existence of at least one closely linked highly conserved p47 phox pseudogene(s) that contains this GT deletion. This close physical proximity leads to recombination events between the wild-type gene and pseudogene(s).

A heterogeneous group of mutations in the p67 phox gene, NCF2 , are responsible for A67 CGD, a rare AR form of CGD (MIM233710) accounting for approximately 5% of cases overall. Almost all mutations identified to date in A67 CGD lead to absent expression of the p67 phox protein. However, one A67 + patient has been reported in which a nonfunctional form of p67 phox with an amino acid deletion is expressed but is unable to translocate to the membrane or bind to Rac.

Two additional forms of AR CGD, both with partial loss of oxidase activity, have been described. Affected patients have a different phenotype than “classic” CGD, with more inflammatory manifestations, including granulomatous gastrointestinal disease and lupus-like skin lesions and few if any severe deep-seated infections. Following an initial report in a boy with mutations in NCF4 , which encodes p40 phox , other patients with defects in NCF4 (MIM613960) were identified in another dozen families. Although NADPH oxidase activity on the plasma membrane is typically normal in p40 phox -deficient CGD, intracellular oxidant production is markedly impaired. Another uncommon form of AR CGD results from AR mutations in CYBC1 (MIM 618935), which encodes the endoplasmic reticulum-resident protein EROS (essential for reactive oxygen species [ROS]) that helps mediate assembly of the flavocytochrome b 558 heterodimer. Most patients were from Iceland and homozygous for the same founder mutation. CYBC1 defects seem to affect flavocytochrome b 558 expression in monocytes and macrophages much more substantially than in neutrophils. Although several patients with CYBC1 defects developed mycobacterial disease, invasive bacterial and opportunistic fungal infections have not been reported.

Even though more than 90% of patients with CGD have respiratory burst defects that result in undetectable levels of O 2 − production, there is a surprising heterogeneity in the clinical manifestations of the disease. At one end of the spectrum are patients who begin to have severe bacterial and fungal infections during infancy and who rarely have more than 4 to 12 months between such serious infections. At the other end of the spectrum are patients who are well for many years and then unexpectedly develop a serious infection typical of CGD, such as a staphylococcal hepatic abscess or Aspergillus pneumonia. After their first major infection, some of these patients may be relatively healthy again for another 3 to 10 years before the next severe infection occurs. As a group, patients with X-linked CGD, A22 CGD, and A67 CGD seem to have a more severe clinical course compared with patients with A47 CGD, who have a small amount of detectable oxidant production even in the complete absence of this subunit ( Fig. 51.5G ). Individuals with partial respiratory burst activity but less than 10% of normal (most X91 − patients; see Table 51.1 ) also tend to have disease of intermediate severity. Polymorphisms in oxygen-independent antimicrobial systems or other components regulating the innate immune response are also likely to play an important role in modifying disease severity. Specific polymorphisms in the MPO, mannose-binding lectin, and FcγRIIa genes are associated with a higher risk for granulomatous or autoimmune or rheumatologic complications. Finally, as already mentioned, in contrast to “classic” CGD, the clinical spectrum of disease in patients with mutations involving p40 phox or CYBC1 resemble an atypical form of CGD, with inflammatory manifestations much more prominent than infections. Because of this heterogeneity, the diagnosis of CGD should be entertained, not only in young children with recurrent severe infections but also in adolescents and young adults who experience exceptionally severe or unusual infections or granulomatous intestinal inflammation.

Clinical Manifestations

In approximately two-thirds of patients, the first symptoms of CGD appear during the first year of life, with the onset of recurrent, purulent bacterial, and fungal infections. Table 51.3 summarizes the types of infections and infecting organisms most frequently encountered in CGD. The most common types of infections are those that involve sites in contact with the outside world, which is consistent with the role of neutrophils as a first line of defense against infection. Staphylococcus aureus , enteric gram-negatives, Serratia marcescens , Burkholderia cepacia , Nocardia spp., and Aspergillus spp. represent the most frequently encountered pathogens in North American patients, but Burkholderia and Nocardia spp. are less frequently seen in Europe. S. aureus is the most frequently isolated organism overall. CGD patients have increased risk from Mycobacterium tuberculosis in endemic areas and can develop severe local or systemic disease with Bacille Calmette Guérin (BCG), an attenuated strain of Mycobacterium bovis , following BCG vaccination. The most common causes of death have been pneumonia or sepsis caused by B. cepacia and Aspergillus spp., although use of newer azole antifungals has markedly improved the outcome of the latter in recent years.

Table 51.3
Infections in Chronic Granulomatous Disease
Infections Infections (%) Infecting Organisms
Pneumonia 70−80 Aspergillus , Staphylococcus , Burkholderia cepacia , Pseudomonas , Nocardia , Mycobacterium (including atypical), Serratia , Candida , Klebsiella , Paecilomyces
Lymphadenitis 50−60 Staphylococcus , Serratia , Klebsiella , B. cepacia, Candida , Nocardia, Mycobacteria
Cutaneous infections/impetigo 50−60
Hepatic or perihepatic abscesses 20−30 Staphylococcus , Serratia , Streptococcus viridans , Nocardia , Aspergillus
Osteomyelitis 20−30 Serratia , Aspergillus , Paecilomyces , Staphylococcus , B. cepacia , Pseudomonas , Nocardia
Perirectal abscesses or fistulae 15−30 Enteric gram-negative organisms, Staphylococcus
Septicemia 10−20 B. cepacia , Pseudomonas , Salmonella , Staphylococcus , Serratia , Klebsiella
Urinary tract infections or pyelonephritis 5−15 Enteric gram-negative organisms
Brain abscesses <5 Aspergillus , Staphylococcus
Meningitis <5 Candida lusitaniae , Haemophilus influenzae , B. cepacia
The relative frequencies of different types of infections in chronic granulomatous disease are estimated from data pooled from mainly several large series of patients in the United States, Europe, and Japan: (1) Mouy R, Fischer A, Vilmer E, et al. Incidence, severity, and prevention of infections in chronic granulomatous disease. J Pediatr. 1989;114:555; (2) Bemiller LS, Roberts DH, Starko KM, et al. Safety and effectiveness of long-term interferon gamma therapy in patients with chronic granulomatous disease. Blood Cells Mol Dis. 1995;21:239.; (3) Forrest CB, Forehand JR, Axtell RA, et al. Clinical features and current management of chronic granulomatous disease. Hematol Oncol Clin North Am. 1988;2:253; (4) Hitzig WH, Seger RA. Chronic granulomatous disease, a heterogeneous syndrome. Hum Genet. 1983;64:207; (5) Tauber AI, Borregaard N, Simons E, et al. Chronic granulomatous disease: a syndrome of phagocyte oxidase deficiencies. Medicine (Baltimore). 1986;62:286; (6) Cohen MS, Isturiz RE, Malech HL, et al. Fungal infection in chronic granulomatous disease. The importance of the phagocyte in defense against fungi. Am J Med. 1981;71:59; (7) Hayakawa H, Kobayashi N, Yata J. Chronic granulomatous disease in Japan: a summary of the clinical features of 84 registered patients. Acta Paediatr Jpn. 1985;27:501; and (8) Johnston RB, Newman SL. Chronic granulomatous disease. Pediatr Clin North Am. 1977;24:365. These series encompass approximately 550 patients with chronic granulomatous disease (CGD) after accounting for overlap between reports. Unpublished data from the United States CGD Registry encompassing 368 patients was also used to estimate the relative frequencies of infections and the responsible organisms. The infecting organisms are arranged in approximate order of frequency for each type of infection. Note: B. cepacia was previously classified as Pseudomonas cepacia.

Most CGD pathogens share the property of being catalase negative, and as such inadvertently “lend” H 2 O 2 secreted from the pathogen to the peroxide-starved CGD phagocyte, which in turn uses it (after being converted to hypochlorous acid [HOCl] by MPO; see Fig. 51.3 ) to kill the microbe. It also appears that at least some of the CGD pathogens are resistant to the nonoxidative killing mechanisms of the phagocyte. It is somewhat surprising how often one fails to identify the infecting organism in CGD—perhaps greater than half the time despite aggressive culturing. In this situation, one treats empirically with the antibiotic that should work and if it fails, one then aggressively pursues more invasive diagnostic procedures looking for one (or more) of the less commonly seen microbes such as Nocardia spp., Candida spp., mycobacteria, and a host of other bacteria and fungi (see Table 51.3 ). Other unusual organisms that cause infection in CGD include other members of the Burkholderia family, including Burkholderia cenocepacia , Burkholderia gladioli , and Burkholderia mallei (the causative agent in melioidosis, a septic illness common in East Asia), and Chromobacterium violaceum , found in brackish fresh water and which can cause a febrile illness with bacteremia in CGD. A previously unknown gram-negative bacteria, Granulobacter bethesdensis , was identified in a CGD patient with recurrent fevers associated with chronic necrotizing deep lymphatic infection. This organism is a member of the Acetobacteraceae family, which has previously not been linked to invasive human disease.

Pneumonia is the most common type of infection seen in CGD with S. aureus , Aspergillus spp., B. cepacia , and enteric gram-negative organisms as the major pathogens. It is noteworthy that B. cepacia has emerged as a particularly lethal organism in CGD. This organism often is not covered with the first line of antibiotics used for S. aureus and most gram-negative organisms and can quietly proliferate (with persistent fevers) to the point of quick, explosive collapse caused by endotoxic shock. Intravenous trimethoprim-sulfamethoxazole (TMP-SMX) has been most effective in treating patients if given before widespread dissemination of the infection. Proven or suspected Aspergillus infections were previously treated with amphotericin B therapy, but azole antifungal agents are now typically used.

Lymphadenitis is the second most common infection and is usually caused by gram-negative organisms, S. aureus , or S. marcescens . Incision and drainage should not be delayed if the lesion fails to respond to parenteral antibiotics. Cutaneous abscesses should be similarly managed. Recurrent perinatal impetigo is almost a signature infection in CGD and often requires months of therapy (mostly oral antibiotics) to clear. Hepatic (and perihepatic) abscesses are also common in CGD and are usually, but not always, caused by S. aureus . Lesions often require drainage (needle or surgical) to permit efficient healing to occur. Bone infections, most commonly caused by Serratia spp. or Aspergillus spp., are particularly problematic in CGD and arise from either hematogenous or contiguous spread (as often is the case with Aspergillus infections in the lung invading the ribs, vertebral bodies, or the diaphragm). Perirectal abscesses are difficult to treat, even with months of therapy, and can lead to fistula formations.

Chronic inflammation with granuloma formation is a distinctive hallmark of CGD and contributes to some of its more problematic complications. In some cases, this results from imperfectly controlled infections in which stalemates develop between the pathogen and the patient’s leukocytes. These lesions become granulomas as the host uses lymphocytes and activated macrophages to assist in containing the pathogens. However, this complication is not always clearly linked to persistent infection and, in these cases, is speculated to involve a dysregulated inflammatory response. Inflammatory complications in CGD are thought to reflect the importance of oxidants generated from the NADPH oxidase to downregulate the inflammatory response through redox-mediated effects, promote efficient degradation of debris, or both. In the absence of oxidant production, excessive production of cytokines and delayed neutrophil apoptosis and clearance at inflammatory sites appear to contribute as underlying mechanisms. Subtle defects in the absence of NADPH oxidase in memory B or T cells may also play a role.

As a result of persistent inflammatory stimulation, CGD patients can have a variety of chronic complications ( Table 51.4 ). Lymphadenopathy, hepatosplenomegaly, eczematoid dermatitis, and anemia of chronic disease (hemoglobin levels usually 8 to 10 g/dL) are common manifestations of this process and are most prominent in the first 5 to 10 years of life in those with CGD. Throughout the body, granuloma formation can lead to dysfunction and obstruction in the esophagus, urinary bladder, and kidneys. In the stomach, the gastric antral narrowing can be severe enough in infants and children to resemble pyloric stenosis. Inflammatory involvement of the gastrointestinal tract can be seen in many CGD patients. A chronic ileocolitis resembling Crohn disease occurs in up to 30% of patients and can range from mild diarrhea to a debilitating syndrome of bloody diarrhea and malabsorption that can necessitate a colectomy. Interestingly, antigliadin antibodies suggesting Crohn disease are positive in more than 50% of CGD patients. Inflammatory lung disease with interstitial and/or micronodular infiltrates, often seen better on computed tomography (CT) scan rather than regular X-ray, can develop in many older patients and lead to reduced diffusion capacity and progressive hypoxia. Other types of chronic inflammation include gingivitis, chorioretinitis, destructive white matter lesions in the brain, and glomerulonephritis. Discoid lupus has been reported in 10% to 20% of patients, and occasional patients may develop systemic lupus erythematosus, sarcoidosis, or rheumatoid arthritis. The underlying mechanisms are poorly defined, although recent studies suggest that these manifestations may be partly related to subtle defects in the absence of NADPH oxidase in memory B or T cells. Finally, infections in CGD due to fungi, bacteria (especially B. cepacia ), or Leishmania in endemic areas can trigger the macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) in CGD.

Table 51.4
Chronic Conditions Associated With Chronic Granulomatous Disease a
Condition Relative Frequency (%)
Lymphadenopathy 98
Hypergammaglobulinemia 60−90
Hepatomegaly 50−90
Splenomegaly 60−80
Anemia of chronic disease Common
Underweight 70
Chronic diarrhea 20−60
Short stature 50
Gingivitis 50
Dermatitis 35
Hydronephrosis 10−25
Granulomatous ileocolitis 10−15
Gastric antral narrowing 10−15
Ulcerative stomatitis 5−15
Granulomatous cystitis 5−10 b
Chronic lung disease 10–50 c
Esophagitis <10 b
Granulomatous cystitis <10
Chorioretinitis <10
Glomerulonephritis <10
Discoid lupus erythematosus <10

a The relative frequencies of chronic conditions associated with chronic granulomatous disease (CGD) were estimated from the series of reports listed in Table 50.3 .

b The incidence is estimated from the 50 cases of CGD followed at Scripps Research Institute and Stanford University (unpublished data).

c Chronic lung disease can be especially problematic in adults with CGD; see Campos LC, Di Colo G, Dattani V, et al. Long-term outcomes for adults with chronic granulomatous disease in the United Kingdom. J Allergy Clin Immunol . 2021;147:1104 and Dunogué B, Pilmis B, Mahlaoui N, et al. Chronic granulomatous disease in patients reaching adulthood: a nationwide study in France. Clin Infect Disease . 2017;64, 767.

Carriers of CGD, whether the X-linked form or any one of the AR forms, are usually asymptomatic, with two important exceptions. First, approximately one-fourth of X-linked carriers are at risk of developing mild to moderately severe discoid lupus erythematosus characterized by discoid skin lesions and photosensitivity. The onset is usually in the second decade of life. The disease does not progress to systemic lupus nor does one find serologic evidence of even subclinical disease. Those with severe discoid lupus can be treated with hydroxychloroquine. Recurrent stomatitis, significant gingivitis, or both have also been noted in as many as half of X-CGD carriers. A few also have arthralgias, polyarthritis, and Raynaud phenomenon. The second important complication of the X-linked CGD carrier state is serious infection in women who have an unusually high degree of inactivation of the normal X chromosome in their myeloid cells. If the circulating neutrophil population is skewed to the point that fewer than 10% to 15% of the cells function, then the carrier has an increased risk of bacterial infections that in some cases have been severe.

Diagnosis

The diagnosis of CGD is usually suggested by the unusual clinical histories outlined earlier or by a family history of CGD. The NBT slide test on fresh blood is the classic diagnostic test. A typical result is shown in Fig. 51.5 . Fig. 51.5A shows the normal positive staining of a group of seven neutrophils and one monocyte. Fig. 51.5B shows the complete absence of NBT staining in a patient with X91° CGD, the classic X-linked form of the disease. Fig. 51.5C shows the mixed population of NBT-positive and NBT-negative cells observed in that patient’s mother, reflecting random X chromosome inactivation. Because nearly 100% of the normal cells in this test are positive, the carrier state in X-linked CGD can be detected when as few as 5% of the cells are NBT-negative. This test also permits detection of diffuse populations of weakly positive cells such as those seen in X91 − CGD, which are characterized by a partial deficiency of flavocytochrome b . Because X-linked CGD can arise by new mutations in the maternal germline, one does not always see NBT-negative cells in the mother. Flow cytometric assays of oxidase activity, such as those based on the conversion of dihydroxyrhodamine (DHR) 123 to rhodamine 123, can also provide both quantitative measurements of oxidant generation and the cell-by-cell distribution of activity (see Fig. 51.5D–G ). The DHR 123 assay for oxidase activity is now available in many referral centers and reference laboratories. In addition to X91 − CGD neutrophils, weak staining in the NBT test or a small but measurable level of DHR fluorescence can be seen in A47° cells (see Fig. 51.5H ) because of a small amount of residual oxidant production. Regardless of diagnostic assay used, it is important to have these tests performed on appropriately handled blood samples and by experienced laboratories to avoid inconclusive or false-normal results.

Genetic testing is useful to solidify the diagnosis and for genetic counseling and is commercially available for the five genetic subgroups involving NADPH oxidase subunits (see Table 51.1 ). The analysis of mutations in NCF1 can require specialized polymerase chain reaction (PCR) testing due to the presence of adjacent pseudogenes. Laboratories specializing in neutrophil biochemistry can also perform immunoblot analysis of neutrophil extracts, flavocytochrome b spectroscopy, or functional analysis of membrane and cytosol fractions in the cell-free oxidase assay.

Testing for the McLeod red cell phenotype should be done in patients diagnosed with X-linked CGD who harbor large CYBB deletions that potentially involve the locus encoding the Kell erythrocyte antigen. Loss of Kell causes a mild hemolytic anemia. More importantly, there can be serious problems with development of hemolytic antibodies if these patients are transfused with Kell-positive blood.

Prognosis and Treatment

The cornerstones of therapy in CGD are currently (1) prevention and early treatment of infections, (2) aggressive use of parenteral antibiotics for most infections, (3) use of prophylactic TMP-SMX (5 mg/kg/day of trimethoprim) or dicloxacillin (25 to 50 mg/kg/day) for sulfa-allergic patients, (4) prophylactic itraconazole (200 mg/day if 13 years of age or older or if weighing at least 50 kg, or 100 mg daily if younger than 13 years of age or weighing less than 50 kg), and (5) use of prophylactic recombinant human interferon-γ (rIFN-γ; 0.05 mg/m 2 or 0.0015 mg/kg if less than 0.5 m 2 three times per week). Using these guidelines, the prognosis for patients with CGD has improved dramatically since the disorder was first described in the 1950s, when almost all patients died in childhood. In a large study based on data collected by a CGD registry in the United States in the 1990s, the overall mortality rate was estimated to be 5% per year for X-CGD and 2% per year for AR CGD, and a more recent single-institutional study of 76 patients reported an overall mortality rate of 1.5% per year.

There is a general consensus that a large majority of newly diagnosed children should survive well into their adult years with aggressive and careful management. While survival is improved, many of these adults continue to have significant complications due to chronic inflammation. The quality of their survival is further affected by the paucity of providers with sufficient experience in the management of this very rare disorder. As already noted, patients with deficiency of p47 phox have a tendency for milder disease compared with those with flavocytochrome-negative CGD. On the other hand, some patients (usually X-linked) prove to have more frequent serious infections or inflammatory complications (or both), likely because of the effects of modifier genes; these patients may warrant more aggressive treatment such as bone marrow transplantation (BMT; see later).

Several approaches can be used to prevent infections. Patients with CGD should receive all their routine immunizations on schedule (including live virus vaccines), with influenza vaccine administered each year as well. Cuts and skin abrasions should be cleansed promptly with soap and water and a topical antiseptic applied (2% hydrogen peroxide, Betadine ointment, or both). Frequent brushing, flossing, use of antibacterial mouthwash, and professional cleaning of teeth can help prevent gingivitis. Constipation should be avoided because it can lead to rectal or anal fissures and abscesses. Early anal infections can be treated with soaking in soapy water (with or without betadine). The frequency of pulmonary infections can be reduced by not using commercially available bedside humidifiers; avoiding smoking (cigarettes and marijuana); and refraining from handling decaying plant materials (e.g., hay, mulch, rotting sawdust), which often contain numerous Aspergillus spp. Avoidance of construction sites, especially demolition of old buildings that may harbor fungi, is recommended. There have been clear outbreaks of Aspergillus pneumonias in immunosuppressed children visiting hospitals undergoing renovation.

There is clear evidence that chronic prophylactic TMP-SMX can decrease the number of bacterial infections in CGD patients by more than half without a concomitant increased risk of fungal infection. In addition, itraconazole is an effective agent for prophylaxis for fungal infections in CGD. Liver function tests should be monitored in patients receiving itraconazole.

Prophylactic rIFN-γ has been another mainstay of current management of CGD. The clinical benefit of rIFN-γ is probably related to generally enhanced phagocyte function and killing by nonoxidative mechanisms because its use is not accompanied by any measurable improvement in NADPH oxidase activity in the vast majority of CGD patients. In the original multicenter trial, patients were randomized in a double-blind fashion to receive either placebo or rIFN-γ (0.05 mg/m 2 three times per week). As summarized in Table 51.5 , there was a substantial decrease in the number of serious infections in the rIFN-γ arm. Side effects were observed in some of the patients but typically were restricted to mild fever and flu-like symptoms. Additional adverse reactions, including any increased incidence of chronic inflammatory complications, have not been noted with more prolonged courses of prophylactic rIFN-γ (more than 10 years), and the patients continued to have a substantial benefit, with fivefold fewer serious infections compared with the placebo group in the phase III study in Table 51.5 . This group of patients averaged one serious infection per patient every 4 to 5 years. However, rIFN-γ is used less frequently in Europe because nonrandomized trial data did not suggest much benefit. The use in a cohort followed at the National Institutes of Health was recently reported to be only 36% of patients because of either lack of access or because of side effects (fever, myalgia); the availability of more potent antifungals and oral antibiotics may be a mitigating factor for reducing serious infectious complications in the absence of prophylactic rIFN-γ.

Table 51.5
Efficacy of Interferon-γ in Preventing Serious Infections in Chronic Granulomatous Disease
Variable Clinical Study
Phase III Placebo a Phase III IFN-γ a Phase IV (US) IFN-γ b Phase IV (Europe) IFN-γ c Phase IV IFN-γ d
Patients ( n ) 65 63 30 28 76
Average duration of therapy on study (years) 0 0.83 1.03 2.4 4.3
Patient-years in study 50.9 52.1 31.10 67.2 328
Serious infections per patient-year 1.1 0.38 0.13 0.4 0.30
Number of hospital days per patient-year 28.2 8.6 2.2 15.0 Not reported
IFN , Interferon.

a Results from The International Chronic Granulomatous Disease Cooperative Study Group: A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. N Engl J Med . 1991;324:509.

b Results from Weening RS, Leitz GJ, Seger RA. Recombinant human interferon-gamma in patients with chronic granulomatous disease—European follow up study. Eur J Pediatr . 154:295, 1995.

c Results from Bemiller LS, Roberts DH, Starko KM, et al. Safety and effectiveness of long-term interferon gamma therapy in patients with chronic granulomatous disease. Blood Cells Mol Dis . 21:239, 1995.

d Results from Marciano BE, Wesley R, De Carlo ES, et al. Long-term interferon-gamma therapy for patients with chronic granulomatous disease. Clin Infect Dis . 39:692, 2004.

One of the most frequent errors in the management of CGD patients is the failure to treat potentially serious infections promptly and aggressively with appropriate parenteral antibiotics. Even the best antibiotics can be rendered ineffective if given too late in the course of an infection in CGD. Therefore early intervention is advisable. Although many of the minor infections and low-grade fevers in CGD patients can be managed on an outpatient basis, episodes of consistently high fever over a 24-hour period or clearly established infections (e.g., pneumonia or lymphadenitis) should be treated with parenteral antibiotics that cover, at least initially, S. aureus and enteric gram-negative organisms. Reasonable attempts to define the source of the infection and the responsible microbe should also begin promptly. The use of PCR to supplement culture-based methods to detect microbial pathogens may be very helpful. A few organisms can cause a large inflammatory response, so often an organism cannot be found and empiric treatment must be administered without specific identification of an organism. Monitoring markers of inflammation such as the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) can be very useful, both as a clue to the presence of a significant infection as well as following the patient’s response to therapy. If the patient fails to respond, then more aggressive diagnostic procedures should be instituted (CT, bone, and gallium scans; open biopsies if indicated) and empirical changes in the antibiotics used to broaden coverage to Pseudomonas cepacia . If fungus is identified or strongly suspected, amphotericin B has been the drug of choice in the past, but newer azole antifungal agents such as voriconazole are supplanting its use.

Even with appropriate antibiotics, certain types of infections respond slowly and may require many months of therapy. This point about duration of treatment is critical. Especially deep tissue infections such as pneumonia require continued treatment until they are clear radiographically, and the sedimentation rate has normalized. This can take many months of intensive treatment. Otherwise, the infection will recur and long-term complications such as emphysema develop. In this sense, treatment of infection in CGD is very different than the normal population. Surgical drainage or resection can sometimes play a key role in accelerating healing of certain types of infection such as lymphadenitis, osteomyelitis, and abscesses of visceral organs such as the liver or lung. Corticosteroids in combination with high-dose antibiotics can help to avoid surgical intervention for liver abscesses. Finally, granulocyte transfusions may be of benefit in the treatment of stubborn or life-threatening infections.

Recurrent fever in CGD always raises the possibility of infection in these patients; however, the MAS-HLH spectrum of disorders should be considered, especially if the patient has splenomegaly, leukopenia, or thrombocytopenia. If significant MAS/HLH is suspected, IFN-γ should be stopped. As in inflammatory disorders such as rheumatoid arthritis, secondary MAS-HLH has been reported in CGD, often in association with bacterial or fungal infection, and is probably often overlooked (see Chapter 53 ). Specific treatment may be indicated, especially if the patient has significant cytopenias or evidence of hepatic dysfunction.

Inflammatory complications of CGD can occur at all ages but can be an increased burden in adults. These can be challenging to treat in CGD because use of agents to suppress the inflammatory response can increase the risk of fungal or bacterial infections. Judicious use of corticosteroids can be indicated, including in cases of severe asthma, esophageal strictures, gastric antral narrowing, granulomatous cystitis, inflammatory bowel disease, or certain cases of pneumonia. Clear evidence shows that corticosteroids are beneficial in these clinical settings because the steroids induce rapid regression of obstructive symptoms at low oral doses (e.g., 1 mg/kg/day of prednisone). Steroids can be lifesaving in young children with airway obstruction because of inflammation. Because of the exaggerated inflammatory reaction seen in CGD, there can be significant swelling in the airway and compression by pulmonary nodes that can block air movement and impede drainage. In these cases, the physician and patient should be aware of the risks of the additional immunosuppression caused by corticosteroids, particularly for fungal infection. Corticosteroids have also emerged as important component of treating Staphylococcal liver abscesses in combination with antibiotics, with improved outcomes and often avoidance of invasive procedures for abscess drainage. In colitis, steroid-sparing agents such as sulfasalazine and azathioprine for colitis can be helpful. Biologic agents such as TNF-α inhibitors or those blocking IL-1 are also occasionally used in patients with difficult-to-manage inflammatory disease, but with caution due to the increased risk of infection. The chronic lung disease that can develop in older patients with CGD can be difficult to treat and may be an indication for stem cell transplantation.

Rare patients with X91° CGD have genomic deletions that span the gp91 phox gene and the Xk gene, which encodes a membrane protein necessary for expression of the Kell genes. Absence of the Xk gene product results in the McLeod syndrome, in which red blood cells have weak Kell antigens and variable acanthocytosis along with nerve and muscle disorders related to its expression in nonerythroid tissues. Transfusion of patients with McLeod syndrome poses a serious problem because they can develop alloantibodies of wide specificity that can preclude any further transfusions except with Kell-negative blood products. McLeod-matched blood is extremely rare, and patients with this syndrome should have their own blood frozen in case it is needed. Note that use of maternal blood does not solve the problem because only 50% of the mother’s blood will match. Because of the difficulty in finding blood, transfusion with non-McLeod blood is likely to occur. Although management is difficult and use of steroids is necessary, the hemolytic anemia can be managed successfully.

Allogeneic hematopoietic stem cell transplant (HSCT) can be used to treat CGD, including using matched unrelated donors. Because of risks associated with this procedure, HSCT was previously considered only for patients who have a fully human leukocyte antigen (HLA)-matched sibling and frequent and severe infections or refractory gastrointestinal disease despite aggressive medical management. However, reduced-intensity conditioning regimens for allogeneic transplantation with sibling or nonsibling donors have now been successfully used for HSCT in CGD and has a high curative rate with low mortality. Which patients with CGD should undergo transplantation is an individualized decision, particularly for those with residual NADPH oxidase activity, for adults, or when well-matched donor marrow is not available. The best results are in young patients without preexisting complications. Because it is currently not possible to predict which patients will develop significant inflammatory complications such as gastrointestinal or lung disease later in life, transplantation in the first decade of life should be strongly considered for any patient with a fully HLA-matched healthy sibling or fully matched high-resolution HLA-typed unrelated donor, regardless of infection history. The indications for transplant in adults should be carefully assessed in consultation with an experienced HSCT center, although results in recent years have been encouraging. While the resolution of gastrointestinal disease in CGD following transplant has been appreciated for some time, the problematic inflammatory lung disease with progressive dyspnea that can develop in older CGD patients also appears to be reversible to a remarkable degree with successful HSCT.

Finally, gene therapies aimed at correcting the defective gene in bone marrow (BM) stem cells hold promise for the future if obstacles can be solved to achieve effective and safe gene delivery and their transplantation (see Chapter 104 ). Observations on female carriers of X-linked CGD with skewed X-inactivation and preclinical studies in murine CGD models suggest that complete correction of NADPH oxidase activity in 10% of circulating neutrophils will lead to clinically relevant improvements in host defense, although inflammatory complications may still be problematic if only partial correction is achieved.

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