Primary Immunodeficiency and Other Diseases With Immune Dysregulation


Primary immunodeficiency states are not uncommon disorders which can affect the innate or adaptive arms of the immune system. All of these diseases have the potential for adverse pulmonary manifestations, including infections and noninfectious complications. In this chapter, we review the major diseases of the innate and adaptive immune system with a focus on their effects on the lung. Included are descriptions of the disorders, laboratory and diagnostic findings, associated cellular and biochemical effects, genetic abnormalities and inheritance, infectious or noninfectious pulmonary manifestations, and management approaches.


primary immunodeficiency, chronic granulomatous disease, common variable immunodeficiency, B-cell immunodeficiencies, severe combined immunodeficiency, ataxia telangiectasia, hyper-IgE syndrome, deficiencies of innate immunity


Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) of childhood was first described by Berendes and colleagues and by Landing and Shirkey as a distinct clinical entity of unknown cause. This disease is characterized by recurrent infections, usually with low-grade pathogens, formation of abscesses and suppurative granulomas, and normal humoral and cellular immunity. The usual onset of symptoms is early in life (most in the first 2 years of life). The disease is generally chronic, and unless diagnosed and treated, the outcome is commonly death from overwhelming infection.

After the original patients, similar cases were reported using various names. CGD is now the generally accepted term for this syndrome. In 1967 Quie and colleagues defined the basic step in pathophysiology as an inability of phagocytic cells to kill ingested bacteria; and Baehner and Nathan reported that CGD neutrophils did not undergo the phagocytosis-associated “respiratory burst” of oxygen consumption and hydrogen peroxide (H 2 O 2 ) production that characterizes phagocytic cells.

Although all of the cases initially documented were in males, later reports described females, suggesting the possibility of autosomal-recessive variants. In the 1970s, progress was made in elucidating the nature of the basic biochemical defect, decreased oxidase activity, a process by which oxygen (O 2 ) is reduced to superoxide anion (O 2 ) using nicotinamide adenine dinucleotide phosphate (NADPH) as the electron source. In 1978 Segal and Jones reported the association of a b-type cytochrome and the NADPH oxidase, as well as its deficiency in CGD. Continued studies firmly defined the relationship between X-linked CGD and deficiency of cytochrome b 558 . In the late 1980s, the gene that is abnormal in X-linked CGD was cloned and subsequently shown to produce the heavy-chain component of the cytochrome b 558 heterodimer (gp91phox). Subsequently, the light chain (p22phox) was described and found to be the basis for the autosomal-recessive form of cytochrome b–deficient CGD.

In the late 1980s and early 1990s, the molecular basis for other forms of autosomal-recessive CGD was defined. Cytosolic components, p47phox and p67phox, were identified, linked to distinct variants of CGD, and sequenced, and their genes were cloned. Deficiency of p40phox has been more recently described.

Thus, 84 years after Metchnikoff first posited that phagocytosis is essential in fighting infection (in 1883), studies in patients with CGD demonstrated for the first time clearly that a defect in phagocyte function is a major breach in host defense against severe infections. Since 1967, the biochemistry of the oxidase enzyme system has been elucidated, the major components defined, and the molecular basis for the most common variants of CGD described. Taking advantage of this syndrome as an “experiment of nature” has greatly expanded our knowledge of the role of the phagocyte in host defense.

Clinical Features

The hallmark of this disease is the occurrence of purulent inflammation due to catalase-positive, low-grade pyogenic bacteria. This syndrome should be considered in any individual with recurrent catalase-positive bacterial or fungal infections. Table 63.1 summarizes the relative frequencies of the most common clinical findings in patients with CGD in the earliest reported cases, before the general use of prophylactic antimicrobial therapy. A more recent analysis of infections in 368 patients enrolled in a registry for CGD shows a general decline in most types of infection, with the notable exception of pneumonia ( Table 63.2 ).

Table 63.1

Clinical Findings in the 168 Earliest Reported Patients With Chronic Granulomatous Disease

Finding Percentage of Patients Involved
Marked lymphadenopathy 82
Pneumonitis 80
Dermatitis 71
Hepatosplenomegaly 68
Onset by age 1 year 65
Suppuration of nodes 62
Splenomegaly 57
Hepatic-perihepatic abscesses 41
Osteomyelitis 32
Onset with dermatitis 25
Onset with lymphadenitis 23
Facial periorificial dermatitis 21
Persistent diarrhea 20
Septicemia or meningitis 17
Perianal abscess 17
Conjunctivitis 16
Death from pneumonitis 15
Persistent rhinitis 15
Ulcerative stomatitis 15

Modified from Johnston RB Jr, Newman SL. Chronic granulomatous disease. Pediatr Clin North Am . 1977;24:365.

Table 63.2

Most Common Infections in 368 Patients Enrolled in a Registry for Chronic Granulomatous Disease

Infection Percentage of Patients
Pneumonia 79
Abscess (any) 68
Subcutaneous 42
Liver 27
Lung 16
Perirectal 15
Brain 3
Suppurative adenitis 53
Osteomyelitis 25
Bacteremia/fungemia 18
Cellulitis or impetigo 10

Data from Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine . 2000;79:155.

Of the 368 registry patients, 76% had the X-linked recessive form of CGD. The mean age at diagnosis in the registry patients was 3.0 years with the X-linked form and 7.8 years with an autosomal-recessive form. These ages are much higher than they should be for the sake of the patient. In rare instances, the initial diagnosis has been made in adulthood. Reviews have suggested that autosomal-recessive variants generally have clinically milder diseases.

Although any organ may be involved with infections, two patterns have been evident in CGD populations across the world. Tables 63.1 and 63.2 exemplify data from the United States. First, the inability of phagocytic cells to effect microbicidal activity at the interface between the host and the environment leads to infections such as pneumonitis, infectious dermatitis, and perianal abscesses. With the involvement of the mononuclear phagocyte system, deep-seated infections result in purulent lymphadenitis, hepatomegaly, splenomegaly, and hepatic and perihepatic abscesses. At all sites of infection, microbes may be sequestered and protected from intracellular killing mechanisms and antibiotics. Unable to destroy the microbes, the phagocytes die and release the organisms. Further microbial proliferation and leukocyte accumulation lead to the abscesses and granulomas that characterize the disorder. Septicemia may also occur because of the inability of phagocytes to localize microbial invasion.

Purulent rhinitis and otitis are common clinical features of this disease. With adequate antibiotic therapy, rhinitis clears slowly, only to recur within a few days after the treatment is discontinued. The oropharynx and gastrointestinal tract are frequently infected, with ulcerative stomatitis, gingivitis, esophagitis, rectal abscesses, perianal abscesses, and fissures being common. Urinary tract infections and glomerulonephritis, renal abscesses, and cystitis have all been reported. Gonadal infections are rare but have been described. Osteomyelitis is common; the most frequent sites include metacarpals, metatarsals, spine, and ribs.

Lymphadenitis, a characteristic clinical feature, occurs in the majority of patients during the course of the disease. It is typically chronic, suppurative, and granulomatous and very often requires surgical drainage. Cervical, axillary, and inguinal nodes are usually involved, but hilar and mesenteric lymph nodes are also commonly enlarged.

Skin lesions include impetiginous eruptions that progress slowly to suppuration. The healing process can be slow, resulting in granulomatous nodules that persist for months. These lesions may be found in any part of the body, the face and neck being the most frequent sites. Sweet’s syndrome (acute febrile neutrophilic dermatosis) has been associated with CGD. Furunculosis and subcutaneous abscesses may be chronic problems. Eczematoid dermatitis can be seen early in the diagnosis.

Carriers of X-linked CGD can have discoid lupus, aphthous ulcers, and systemic lupuslike symptoms. If X-linked inactivation is skewed so that less than 10% of neutrophils express the normal NADPH oxidase, carrier females can have clinical CGD. The progressive skewing of the X chromosome that occurs with age can result in adult-onset CGD in these carriers.

While the major problems of patients with CGD are related to infections, these individuals can also be afflicted with a number of conditions reflecting a vigorous inflammatory response without a clear infectious cause. Pyloric stenosis, with associated decrease in gastric emptying, is common, and sterile granulomas can be found in the pyloric antrum. Similar lesions in the small and large bowel may be associated with persistent abdominal pain, diarrhea, malabsorption, or obstruction. Some of the gut lesions have been described as eosinophilic gastroenteritis, gastrointestinal dysmotility, or inflammatory bowel disease. Granulomas in the urinary bladder can result in obstructive uropathy. Pericarditis and pleuritis have been noted. Chorioretinitis was detected in 9 of 30 boys with X-linked CGD and in 3 of 15 related carriers in one clinic. The single patient reported with p40phox deficiency had a partial deficiency in the respiratory burst, no severe infections, but severe and chronic granulomatous colitis. Patients with CGD can also have a typical autoimmune disease, including systemic and discoid lupus, idiopathic thrombocytopenic purpura, juvenile rheumatoid arthritis, IgA nephropathy, or antiphospholipid syndrome. It seems likely that there is a common mechanism for this spectrum of inflammatory conditions, perhaps related to the fact that CGD neutrophils do not undergo normal cell death by apoptosis, are not cleared efficiently by macrophages, and therefore release toxic constituents into the tissues. Whatever the mechanism, the response of pyloric and bladder granulomas to steroids is well documented.

Pulmonary Complications

Patient surveys, as exemplified in Tables 63.1 and 63.2 , show that pneumonia continues to be one of the most common types of infection, occurring in about 80% of patients with CGD. Pulmonary disease has also become a major cause of mortality in this disease. The overall pulmonary infection rate and incidence of fungal infections are increased in adults compared to children. The onset of lower respiratory tract infection may be heralded by the usual clinical presentation of fever, cough, tachypnea, pleuritic pain, and abnormal auscultatory findings. However, in some patients, particularly those with a fungal infection, few if any signs or symptoms have been noted in the presence of marked infiltration on radiography. Chronic granulomatous infiltrations, bronchiolitis obliterans, pulmonary fibrosis, bronchiectasis, interstitial lung disease (ILD), and sarcoidosis have been noted in both pediatric and adult patients.

The range of microbial agents causing pulmonary infections is shown in Table 63.3 . Since the 1970s, the use of daily antimicrobial therapy in CGD has reduced the rate of infections due to Staphylococcus aureus and enteric bacteria, but Aspergillus species has become a particularly troublesome offender. Fungal infection of the lung can present as discreet nodular, miliary, or pan-lobular involvement. Fungi now cause a large percentage of infections in CGD; these typically cause less fever and can be hard to diagnose in early stages. Fungal lung involvement may spread to the pleura and adjacent bone and soft tissues of the chest wall. Although Aspergillus accounts for most of the fungal agents (>80%), other agents such as Acremonium striatum, Candida albicans, Pneumocystis carinii, and Paecilomyces species may also be isolated from infected lungs. Aspergillus pneumonia, with or without dissemination, was the leading cause of death in the 368 registry patients (23 of 65 total deaths). Nocardia, atypical mycobacteria, and the bacillus Calmette-Guérin vaccine strain of mycobacteria can also cause pulmonary disease.

Table 63.3

Most Common Infecting Organisms in the 368 Patients in the Chronic Granulomatous Registry

Type of Infection Organism Percentage of Patients a
Pneumonia Aspergillus species 33
Staphylococcus species 9
Burkholderia cepacia 7
Nocardia species 6
Serratia species 4
Abscess—subcutaneous, liver, and/or perirectal Staphylococcus species 26
Serratia species 3
Aspergillus species 3
Abscess—lung Aspergillus species 4
Abscess—brain Aspergillus species 2
Suppurative adenitis Staphylococcus species 14
Serratia species 5
Osteomyelitis Serratia species 7
Aspergillus species 5
Bacteremia/fungemia Salmonella species 3
Burkholderia cepacia 2
Candida species 2

Data from Winkelstein JA, Merino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine . 2000;79:155.

a Percentage of the 368 patients who had this organism isolated at least once from the infection shown.

Pulmonary lesions on x-ray include extensive infiltration of the lung parenchyma and prominent hilar adenopathy ( Fig. 63.1 ). Bronchopneumonia, lobar pneumonia, extensive reticulonodular infiltration, pleural effusion, pleural thickening, pulmonary abscess, and atelectasis (especially of the right middle lobe) have been described.

Fig. 63.1

A chest roentgenogram from a patient with chronic granulomatous disease, showing extensive bilateral lung involvement. This patient died of the overwhelming infection.

In spite of extensive antibiotic treatment, the various expressions of CGD pulmonary disease often regress slowly over a period of weeks to months, or they can progress to involve an entire lobe. An unusual manifestation of pulmonary involvement observed in these patients is so-called encapsulated pneumonia. This pneumonia is characteristically seen on roentgenography as a homogeneous, discrete, relatively round lesion; it may occur singly or in groups of two to three infiltrates ( Fig. 63.2 ). The size and contour of the lesions may change over days or weeks or remain unchanged. Histologically, they take the form of caseating granulomas ( Fig. 63.3 ). A homogeneous “shot-gun” distribution of small granulomatous lesions can occur, which gives the radiographic appearance of miliary tuberculosis. Discoid atelectasis, thickening of the bronchi, air bronchograms, “honeycombing,” loss of lobar volume, and bronchiectasis associated with hemoptysis are occasionally observed.

Fig. 63.2

(A) Encapsulated pneumonia in a patient with chronic granulomatous disease. A computed tomography (CT) scan with nodular lesion in left upper lobe. (B) PA chest Roentgenogram for comparison at same time as A does not demonstrate lesion. (C) Progression of lesion on CT scan. (D) Lesion resolving in response to appropriate antifungal therapy.

(Images courtesy of Thomas Hay, MD.)

Fig. 63.3

Typical granuloma of lung tissue removed from the patient in Fig. 63.2 .

(Image courtesy of Kelli Capocelli, MD.)

Laboratory Findings and Diagnosis

Except for abnormalities of phagocyte function, clinical laboratory findings reflect acute or chronic infection and inflammation. Leukocytosis with neutrophilia, elevated erythrocyte sedimentation rate and C-reactive protein, and the anemia of chronic inflammation are common. The anemia is usually not due to a deficiency of iron stores but to a decrease in iron release from the mononuclear phagocyte system and diminished utilization by the marrow. It typically does not respond to iron administration but improves with resolution of infection. Evidence of hemolytic anemia with acanthocytosis suggests absence of the K x antigen on red blood cells, a trait encoded close to the gp91phox gene on the X chromosome.

Screening evaluations of various aspects of immune function are usually normal, including complement, cellular immunity, and antibody production in response to immunization in spite of recent data that the NADPH oxidase may modulate MCH class II antigen presentation by b-cells. Polyclonal hypergammaglobulinemia is common. A deficiency of microbicidal activity against catalase-positive bacteria (e.g., staphylococci and Escherichia coli ) and a diminished or absent respiratory burst by neutrophils and monocytes are the essential functional and biochemical findings of CGD.

Patients with CGD have a predisposition to infections with a broad variety of bacteria and fungi (see Table 63.3 ). The most common organisms are S. aureus, Serratia species and other gram negative organisms, and Aspergillus, but unusual and rare pathogenic organisms may cause disease in patients with CGD. Recent studies have focused on Burkholderia cepacia as a significant pathogen, particularly in the lung. Infection by this organism was the second leading cause of death in patients in the CGD registry. Its propensity to infect patients with either CGD or cystic fibrosis is not understood.

Microbial agents associated with pulmonary infections are the same as those that cause infections in other parts of the body. Fungal pneumonitis is frequent, especially due to Aspergillus. Other pulmonary pathogens include Nocardia species, P. carinii, Actinomyces, and mycobacteria. Mycobacterial disease is relatively common in patients with CGD in countries where tuberculosis is endemic, BCG vaccine is mandatory, or both. Infections due to pneumococci, streptococci, and Haemophilus species are no more common in children with CGD than in normal children, presumably because these catalase-negative organisms cannot protect against their own H 2 O 2 production within the phagocytic vacuole.

Tissue from infected sites shows granulomas like those typically seen with intracellular parasites such as mycobacteria. Granulomas in CGD patients include mononuclear phagocytes that can contain a tan or yellow pigmented material. Granulomas in the presence of the pathogens noted above strongly suggest the diagnosis of CGD.

Simple screening tests for CGD are currently available. The histochemical nitroblue tetrazolium (NBT) test remains a reliable screening measure. Stimulation of microbicidal activity and the respiratory burst results in the reduction of O 2 to ; NBT dye is reduced by the extra electron in and converted from a yellow, water-soluble dye to a purple, insoluble substance. In normal individuals, 95% or more of phagocytic cells reduce NBT; the phagocytes from patients with the common variants of CGD do not reduce NBT. Carriers of X-linked CGD exhibit two populations of cells, normal and NBT-negative.

Fluorescence-based screening assays using flow cytometry avoid the subjective element of the NBT test. Dihydrorhodamine-123 can be readily preloaded into neutrophils or monocytes, and it interacts with oxygen metabolites produced during the respiratory burst to generate products with increased fluorescence. Patients’ phagocytes do not shift fluorescence after stimulation. X-linked carriers have two populations. Additionally, some CGD variants, e.g., p47phox deficiency and milder variants of X-linked CGD, have very low oxidase activity in all cells, and this activity can be detected with this technique. This assay is more quantitative than the NBT test since it measures oxidase activity of the entire phagocyte population and can quantify partial reduction in the respiratory burst.

A positive screening test should be confirmed with one or more quantitative tests. Bactericidal assays with E. coli or S. aureus may be diagnostic. Quantitative assays of O 2 consumption, O 2 production, or generation of H 2 O 2 can be helpful Finally, an analysis of the various oxidase components will define the molecular variant of CGD. Cytochrome b 558 can be quantitated spectroscopically, and the individual oxidase components can be analyzed by Western blot. Several cell-free systems that can reproduce the assembly and activation of the oxidase in intact cells with the use of plasma membrane and cytosol from neutrophils may be helpful in defining the molecular variants of CGD. Identification of the genetic mutation responsible for the protein defect may be helpful for genetic counseling, prenatal studies, and judging prognosis, and a recent review presents a flow diagram for evaluation.

Prenatal diagnosis may be achieved with screening tests on fetal neutrophils obtained by percutaneous umbilical blood sampling. The diagnosis for some CGD variants can be made from chorionic villus or amniocyte samples using restriction fragment length polymorphism or gene analysis without the risk of fetal blood sampling.

NADPH Oxidase

The oxidase enzyme resides in the plasma membrane of stimulated cells, and through the oxidation of NADPH catalyzes the reduction of O 2 to , the first step in production of antimicrobial oxygen metabolites. Phagocyte oxidase (phox) activity results from the interaction of several components that form an enzyme complex. In resting cells, these components reside in different compartments. With stimulation of the cell, they assemble in the plasma membrane to express oxidase activity ( Fig. 63.4 ).

Fig. 63.4

Schematic diagram of the NADPH oxidase enzyme system, its components, and its activation. In resting neutrophils, membrane components (gp91phox and p22phox) reside in plasma membrane and specific granules. With stimulation, degranulation of specific granules expands the amount of cytochrome b558 in plasma membrane and translocation of cytosolic components (rac2, p47phox, p67phox, and p40phox) and p29 peroxiredoxin 6 (Prdx6) to the plasma membrane results in assembly of an active oxidase enzyme system that uses electrons from NADPH to reduce O 2 to form O 2 .

The main catalytic component of the oxidase is the cytochrome b 558 . In resting cells, 10%–20% of total cellular cytochrome b 558 appears to be located in plasma membrane, and 80%–90% is in the membranes of specific granules. This protein is a heterodimer composed of α (p22phox) and β (gp91phox) subunits. Cytochrome b 558 binds NADPH; its flavin binding site and a heme moiety are critical to shuttling electrons between NADPH and O 2 . With stimulation, specific granule membranes fuse with plasma membrane, increasing the amount of cytochrome b 558 associated with the plasma membrane. The cytosolic oxidase components translocate to the plasma membrane and specific granules, providing an active oxidase complex that is increased in the plasma membrane. A low molecular weight G protein, Rap1a, is associated with cytochrome b 558 and may be important in assembly and activation of the oxidase complex.

The cytosolic oxidase components include p47phox, p67phox, and p40phox. A cytosolic low molecular weight guanosine triphosphate (GTP)–binding protein, p21 rac 2, is also involved, and there may be other proteins that control GTP binding to the rac 2 protein. These latter elements link with receptors on the plasma membrane and help transmit and/or amplify biochemical signals (e.g., from opsonized microbes) that regulate assembly and activation of the oxidase.

p47phox and p67phox appear to exist as a complex in cytosol of resting cells. Interactions between this complex, plasma membrane, and the cytoskeletal elements are critical for activation of the oxidase. Precise details of the relevant domains for interactions of phox proteins, changes which occur during cell activation, and the relationship with signaling pathways has been under intense investigation in recent years and is summarized in a recent review. The gene for p40phox (NCF4) has been cloned, and p40phox was identified as binding strongly to p67phox. More recent work suggests that p40phox function within the NADPH oxidase complex depends on its binding to phosphatidylinositol 3-phosphate. An additional protein closely associated with p67phox has been described. This 29-kd protein (termed p29) is categorized as a peroxiredoxin by its sequence and activity. Peroxiredoxins are a class of peroxidases that oxidize H 2 O 2 with sulfur groups on cysteine residues. Neutrophil p29 peroxiredoxin enhances production in subcellular systems of oxidase activity and in intact cells and translocates to plasma membrane after stimulation of the respiratory burst. The p29 peroxiredoxin stabilizes and enhances the activity of the oxidase enzyme system.

Molecular Defects and Inheritance

Genetic testing documenting a patient/family mutation is currently available through commercial or research laboratories. In addition to confirming the correct classification of the patient and his/her prognosis, the specific defect will be important if more aggressive management strategies such as gene therapy and/or hematopoietic stem cell transplantation are considered. With the discovery of the various oxidase components over the past 15 years, the molecular basis of CGD has come into focus. Most patients express genetic or molecular abnormalities in one of the four major components of the oxidase: gp91phox, p22phox, p47phox, or p67phox ( Table 63.4 ). One patient has been reported with a mutation in rac 2, but no patients have been described with an abnormality of rap-1. p40phox, encoded by the NCF4 gene on chromosome 22 (22a13.1), is reported to be diminished in individuals with p67phox deficiency, and a single patient has been described with an autosomal recessive deficiency in this component, deficiency of the phagocytosis-stimulated respiratory burst, and granulomatous colitis.

Table 63.4

Molecular and Genetic Classification of Chronic Granulomatous Disease

Affected Component a Chromosome Location Gene a Inheritance a Subtype Class a NBT/DHR (% Positive)/O 2 Production Cytochrome b 558 Spectrum Western Blot Analysis b Frequency
gp91phox Xp21.1 CYBB XL X91° 0/0 0 Absent gp91phox
Markedly decreased or absent p22phox
X91 80%–100%/3%–30% (weak) 3%–30% Decreased gp91 and p22phox
X91 5%–10%/5%–10% 5%–10% Decreased gp91 and p22phox
X91 + 0/0 100% Normal gp91 and p22phox
p22phox 16p24 CYBA AR A22° 0/0 0 Absent p22 and gp91phox 5%–6%
A22 + 0/0 100% Normal p22 and gp91phox
p47phox 7q11.23 NCF-1 AR A47° 0/0%–1% 100% Absent p47phox 20%
p67phox 1q25 NCF-2 AR A67° 0/1%–1% 100% Absent p67phox 5%–6%

Activity measurements may be made in the cell-free system of activation. In this system, activity is defined by both cytosol (and associated components) and membrane. Deficiencies in gp91phox and p22phox exhibit diminished or absent membrane contribution and deficiencies of p47phox and p67phox exhibit diminished or absent cytosol contribution.

Data from Roos D, Kuhns DB, Roesler J, et al. Hematologically important mutations: X-linked chronic granulomatous disease (third update). Blood Cells Mol Dis . 2010;45:246; and Roos D, Kuhns DB, Maddalena A, et al. Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (second update). Blood Cells Mol Dis . 2010;44:29.

a Oxidase components expressed as gp91phox, p22phox, p47phox, p67phox, and their genes as CYBB, CYBA, NCF-1, and NCF-2, respectively. Subtypes represented by letter designating type of inheritance. The superscripts designate detection of protein in patient samples. A, Autosomal; AR, autosomal-recessive inheritance; X, X-linked; XL, X-linked inheritance; O, absent, −, diminished, +, present.

b For Western blot analysis, abnormalities in specific phox proteins are noted. Other components not described are normal with this technique.

The most common molecular defects in CGD are related to gp91phox and account for about 70% of all cases of this syndrome. Located on the short arm of the X chromosome (Xp21.1), defects in the gp91phox gene are inherited as X-linked recessive. In the most common variety, mutations in the gene result in the lack of gp91phox protein due to mRNA or protein instability. NADPH oxidase activity is totally absent, no cytochrome b 558 is seen spectrophotometrically, and no gp91phox is detected on Western blot. A defect in the membrane contribution to oxidase activity is documented with analysis in cell-free systems. Cytosol and its components are normal. Deletions, insertions, rare duplications and splice site, missense, and nonsense mutations have all been described and reviewed in detail.

Other variants of gp91phox deficiency have been described. Some mutations have resulted in partial loss of protein expression and diminished oxidase activity in proportion to the decrease in protein content. In some, a truncated protein is expressed. Defects are found in exons, introns, intron/exon junctions, and promoters. A few cases have been described with normal gp91phox protein expression but nearly complete absence of oxidase activity. Additional variants have been reported with the inability to interact with NADPH or with p47phox and p67phox or to bind flavin adenine dinucleotide (FAD). Severity of disease in these less common genetic variants correlates with the level of cytochrome b expression and superoxide production.

Patients who lack both the respiratory burst and cytochrome b 558 and exhibit an autosomal-recessive mode of inheritance have a deficiency in p22phox, the gene for which is found on chromosome 16 (16q24). These patients account for 5%–6% of all cases. In the usual form, the deficiency in membrane contribution of oxidase activity is accompanied by absence of the cytochrome b 558 spectrum and both gp91phox and p22phox by Western blot. Analysis of cytosolic components is normal. Although fewer genetic analyses have been completed, deletion, insertion, missense, nonsense, and splice site mutations have been described. In one variant, a homozygous missense mutation affects the area of interaction between p22phox and p47phox, resulting in a normal cytochrome b 558 that cannot form an oxidase complex.

Patients who exhibit an autosomal-recessive mode of inheritance but whose neutrophils contain normal amounts of cytochrome b 558 may have a deficiency of either p47phox or p67phox. The gene for p47phox falls on chromosome 7 (7q11.23), and that for p67phox on chromosome 1 (1q25). Defects in these genes account for approximately 20% and 5%–6% of CGD cases, respectively. Absent or nearly absent oxidase in whole cells is coupled with deficient cytosol contribution in the cell-free system and deficiency of the protein on Western blot. There appears to be much less heterogeneity in genetic mutations causing deficiency of p47phox than of p67phox. Patients studied to date are either homozygous for a GT dinucleotide (ΔGT) deletion at the start of exon 2 of the NCF-1 gene or are compound heterozygotes with a GT deletion on one allele and a point mutation on the second allele. The reason for the homogeneity is that most normal individuals have p47phox pseudogenes, each of which colocalize with the functional gene at 7q11.23. Recombination events between the functional and pseudogenes lead to incorporation of ΔGT into the NCF-1 gene. In addition to heterozygous GT changes, missense and splice junction changes have been described. In many patients studied, normal amounts of mRNA and complete absence of p47phox are found in neutrophils, suggesting translation of an unstable protein.

Relatively few molecular defects have been characterized in patients with p67phox deficiency. As with p47phox deficiency, mRNA for p67phox is usually present, but in most cases no protein is detected. Nonsense, missense, homozygous point, splice site, insertion, and deletion mutations have been documented, as well as one duplication, suggesting a heterogeneity of genetic abnormalities for p67phox.

A patient with rac 2 deficiency presented with severe, recurrent perirectal abscesses and pyoderma, omphalitis, and poor wound healing. His neutrophils exhibited a unique pattern of functional abnormalities, including markedly diminished random and directed migration, decreased ingestion and bactericidal activity, and absent degranulation of azurophilic granules. Expression of CD11b and degranulation of specific granules were normal. Production of in response to N-formyl-methionyl-leucyl-phenylalanine and platelet-activating factor was absent, to opsonized zymosan was decreased, but to phorbol myristate acetate was normal. Rac 2 was 30% of control, and all other oxidase components were normal. A mutation in one nucleotide of codon 57 for one rac 2 allele resulted in a substitution of asparagine for aspartic acid. Although both the wild-type and mutant alleles were expressed, the mutant protein had a defect in the GTP binding site, could only bind guanosine diphosphate, and had a dominant-negative effect on the wild-type rac 2 as well as other low molecular weight GTPases. Because of this, the oxidase as well as other neutrophil functions were affected. The patient was cured by a bone marrow transplant from his human leukocyte antigen (HLA)–identical sibling.

Deficiency of glucose-6-phosphate dehydrogenase (G6PD) in leukocytes, which occurs in a small number of patients with erythrocytes deficient in this enzyme, has been considered a variant of CGD. Patients whose neutrophils contain less than 5% of normal activity suffer from recurrent, sometimes fatal, infections. Their neutrophils do not exhibit a respiratory burst and exhibit a microbicidal defect against catalase-positive organisms. Deficiency of NADPH as the efficient electron donor to the oxidase may explain this disorder.


The key to the successful management of CGD remains early diagnosis, prophylactic antimicrobial therapy, and rapid and vigorous treatment of infections. This approach begins with prophylactic daily doses of trimethoprim-sulfamethoxazole (4–5 mg/kg trimethoprim, 20–25 mg/kg sulfamethoxazole, once or divided into two doses daily), which has reduced the incidence of severe bacterial infections by 70%. Ciprofloxacin may be used as an alternative. Interferon (IFN)-γ given at a dose of 1.5 µg/kg (surface area <0.5 m 2 ) or 50 µg/m 2 (surface area ≥0.5 m 2 ) three times weekly by subcutaneous injection also reduces the incidence and severity of infections. Administration before bedtime along with acetaminophen reduces fever and myalgias. Daily itraconazole at 100–200 mg/day (4–5 mg/kg in two doses) taken with food has been advocated as fungal prophylaxis. Care should be taken to avoid environmental conditions that present a high risk for exposure to Nocardia and fungi, especially Aspergillus (e.g., garden mulch, construction sites, leaves, and marijuana).

When infections develop, aggressive attempts should be made to obtain culture and antibiotic sensitivity of organisms from localized areas. Surgical drainage, including drainage of pulmonary abscesses or empyema, is also critical to treatment, since antibiotics required to resolve infection do not penetrate well into abscesses. The infected site should be aggressively débrided with prolonged drainage to prevent loculation and sequestration of infected areas.

In patients with fever and elevated C-reactive protein and sedimentation rate but no definite locus for an infection, an empiric trial of parenteral antibiotics may be necessary. During the initiation of this therapy, definition of the infected area should be sought with routine radiographs, computed tomography, magnetic resonance imaging studies, or radionucleotide scans.

Identification of the infected site may provide clues to initial antibiotic coverage. For example, the vast majority of liver abscesses are caused by staphylococci (see Table 63.3 ), and vancomycin and levofloxacin might be used initially. Burkholderia cepacia is found in a higher incidence in the lung and Serratia in soft tissue and bones. For these infections, increasing the trimethoprim-sulfamethoxazole to a full therapeutic dose and adding a cephalosporin, meropenem, or levofloxacin should be considered until antibiotic sensitivities are available. Antibiotic coverage should be reorganized later in response to antibiotic sensitivities of recovered organisms. Initial parenteral treatment and oral antimicrobials for weeks or months may be required to resolve the infection.

If fungus is suspected or defined, vigorous antifungal therapy should be instituted. Although amphotericin has been advocated in the past, other agents may be required, such as itraconazole, voriconazole (6 mg/kg every 12 hours on day 1, then 4 mg/kg every 12 hours), or posaconazole (200 mg 3 times daily; currently approved only for children over 12 years old and adults). Prednisone may be considered for miliary involvement. Although not proved efficacious, daily granulocyte transfusions (at least 10 10 granulocytes per transfusion) have been used as a supplement to aggressive surgical and antibiotic therapy, but these can cause alloimmunization, which could hamper later bone marrow transplantation.

Some patients with CGD inherit, as a closely associated X-linked allele, a deficiency in the K x antigen affecting both erythrocytes and leukocytes. This results in the lack of Kell antigens on the surface of the red cells, which can be associated with a chronic hemolytic anemia. Transfusion of these patients can result in true isoimmunization for Kell antigens and the risk of immediate or delayed transfusion reactions.

Inflammatory conditions or obstructive lesions of the gastrointestinal tract (seen in up to 50% of the patients) or genitourinary tract (in up to 70% of the patients) usually respond to treatment with steroids. The response may be prompt, but relapses are common.

Hematopoietic Cell Transplantation and Gene Therapy

Hematopoietic cell transplantation has been attempted with mixed results. Long-term engraftment and reversal of the defect has been documented. Sources of stem cells include bone marrow, mobilized peripheral blood, and umbilical cord blood. Although unrelated donors have been used, the majority of successful transplants have been completed with HLA-identical siblings. In a series from the United Kingdom, transplantation led to resolution of colitis and catch-up growth in children with growth failure. The best predictors of success have been absence of overt preexisting infection at the time of transplantation and transplantation at a relatively early age, before numerous infections and end-organ damage have occurred. A comparison of outcome for children with CGD treated with conservative medical management, compared to those treated with stem cell transplantation, documented fewer infections and better growth after transplantation. However survival was 90% for both transplanted and nontransplanted groups.

Many of the centers transplanting CGD patients have used a myeloablative preparative regimen. While engraftment has occurred in a high percentage of patients, the presence of concurrent infection has presented a significant risk for severe complications, and death has been common. The National Institutes of Health published its experience using a nonmyeloablative preparative regimen with T cell–depleted peripheral blood stem cells from HLA-identical siblings. After a median follow-up of 17 months, 8 of 10 patients had sufficient neutrophils to provide normal host defense and resolution of granulomatous lesions. Another center used marrow from matched unrelated donors; 7 of 9 patients were alive and well 20–79 months after transplantation. Restrictive lung disease was resolved in two of these individuals.

A prospective study from 16 centers in 10 countries worldwide was recently published. Patients with CGD received hematologic stem cell transplantation (HSCT) from matched related or matched, unrelated donors after a reduced intensity conditioning regimen, administration of unmanipulated bone marrow, or peripheral blood stem cells. Fifty-six patients were enrolled of whom 75% were judged to be high risk because of infections or inflammatory complications. With a median follow-up of 21 months, overall survival was 93% and event free survival 89%. Two-year probability of survival was 96% and event free survival 91%.

With results of reduced conditioning regimens, some have suggested that stem cell transplantation should be the preferred choice performed early if a suitable donor is available. However, conventional medical management by many groups does not include IFN-gamma in addition to prophylactic antibiotics and antifungals. A single center U.S. study of 27 patients with CGD was presented of whom which 24 were compliant on the medical management with IFN-gamma, Bactrim, and an azole antifungal. One was lost to follow-up and 23 were alive after 3276 patient months of follow-up with an infection rate of 0.62/patient year. No controlled comparison of medical management with HSCT is available. Although CGD can be cured by successful hematopoietic cell transplantation, the possibility of infections, graft failure and rejection, and graft-versus-host disease remain major impediments, and the risks and benefits must be weighed carefully with each individual patient. Patient selection and timing of bone marrow transplantation are timely areas for developing research.

Since CGD arises from gene defects in a finite group of proteins expressed in myeloid cells, transfer of a normally functioning gene into the pluripotent stem cell would, theoretically, constitute definitive treatment. The groundwork for this approach was laid with experiments in which Epstein-Barr virus–transformed B-lymphocyte or myelomonoblastic cell lines from CGD patients with various molecular defects were transfected with complementary DNA (cDNA) for the missing oxidase component. Partial correction of protein expression and oxidase activity was obtained. Reconstitution in vivo, however, would require transfection of normal genes into pluripotent stem cells. To this end, CD34 + peripheral blood hematopoietic progenitor cells were transduced with cDNA for p47phox, p22phox, or gp91phox. Murine models of CGD have also provided useful information for successful application of human gene therapy trials.

Malech and coworkers developed a model process for CGD gene therapy and employed it in a clinical trial of five patients with p47phox-deficient CGD. CD34 + progenitor cells were mobilized by granulocyte colony-stimulating factor infusion, harvested by apheresis, purified, then expanded ex vivo in the presence of growth factors. These expanded CD34 + cells were transfected with cDNA for normal p47phox in a retroviral vector. The patients received 0.1 to 4.7 × 10 6 transfected cells/kg. After 3–5 weeks, low levels of blood neutrophils with normal ability to oxidize dihydrorhodamine were detected; but these cells declined to undetectable numbers over 3–6 months. Although the numbers of normal cells were too small to reconstitute the defect and the effect was not long-lasting, the general principles of this approach were demonstrated.

This experience was extended by Ott and colleagues. After nonmyeloablative marrow conditioning with bulsufan, two young adults with X-linked CGD were treated with autologous CD34 + stem cells that had been transfected with a retrovirus vector expressing gp91phox. Substantial gene transfer occurred in both individuals, and life-threatening infections resolved within the first few months. However, the level of gene-positive neutrophils subsequently rose as a result of oligoclonal outgrowth of cells in which the vector had inserted at the site of a proto-oncogene. Bone marrow exam showed myelodysplasia with monosomy 7 in both men; one died of sepsis, and the other received an allogeneic hematopoietic stem-cell transplantation.

Based on the clearance of severe infections achieved in the otherwise failed trial of Ott et al., Kang, Malech, and colleagues treated 3 adult X-linked CGD patients suffering severe, unresolving infections with a different retroviral vector encoding gp91phox after busulfan marrow conditioning. The three patients had 26%, 5%, and 4% oxidase-normal neutrophils initially, but these normal cells declined over time. One of the patients with a sustained level of 1.1% normal cells cleared treatment-intractable liver abscesses and has been free of infection for 3 years; a second patient with 0.03% sustained normal-cell levels resolved his Aspergillus lung infection that had extended to ribs and vertebrae. The patient with no detectable normal cells by 4 weeks died of his Paecilomyces lung infection. With improvements in viral vector profiles, stem cell culturing techniques, new sources of stem cells including induced pleuripotent stem cells, and site-specific gene editing platforms, the field of gene therapy continues to progress. Although gene therapy has not yet cured a patient, with CGD the field clearly holds out hope for the future.

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Jul 3, 2019 | Posted by in RESPIRATORY | Comments Off on Primary Immunodeficiency and Other Diseases With Immune Dysregulation
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