Annu. Rev. Med. 1998. 49:185-199.

EVALUATION OF THE PATIENT WITH RECURRENT BACTERIAL INFECTIONS¹

Steven M. Holland, MD, and John I. Gallin, MD
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892; e-mail: smh@nih.gov

KEY WORDS: neutrophils, monocytes, chronic granulomatous disease, interferon-

	ABSTRACT
	INTRODUCTION
	PHAGOCYTE IMMUNE DEFECTS: NEUTROPHILS
	PHAGOCYTE ABNORMALITIES: MACROPHAGES
	EPITHELIAL IMMUNITY: DEFENSINS
	COMPLEMENT-MEDIATED IMMUNITY
	ACQUIRED IMMUNE DEFICIENCIES
	FOOTNOTES
	LITERATURE CITED

	ABSTRACT

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Recurrent bacterial infection is a complaint encountered regularly in the course of both adult and pediatric care. Defects of neutrophils and monocytes are most commonly associated with recurrent infection, but abnormalities of immunoglobulins and complement must be considered. Defensins, small antibacterial peptides, have been implicated recently in some of the infectious diathesis of cystic fibrosis. A thorough history and physical examination focused on severity, sequelae, and microbiology of infections can usually determine whether a patient needs further evaluation. The diseases and syndromes most frequently associated with recurrent infection are presented, along with discriminating clinical, pathologic, and microbiologic features.

	INTRODUCTION

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Concern about the immune status of a patient is usually raised on the basis of the frequency, severity, distribution, or infectious agent of one or more episodes that are, or are thought to be, infectious. This chapter focuses primarily on abnormalities of neutrophils and macrophages, since these phagocytes are critical in the control of bacterial infections. However, as shown in Tables 1 and 2, recurrent bacterial infections are also seen in patients with T cell and B cell abnormalities and some as yet undefined immunodeficiencies.

	PHAGOCYTE IMMUNE DEFECTS: NEUTROPHILS

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Symptomatic neutrophil abnormalities include abnormalities of number, adherence and locomotion, granules, and microbicidal activity (Figure 1). The clinical presentations of patients with neutrophil disorders often share the common features of gingivitis and periodontal disease (1). Cutaneous infections with Staphylococcus aureus are recurrent and can be severe. Patients with neutrophil disorders characterized by inadequate inflammation such as neutropenia, leukocyte adhesion deficiency, Chediak-Higashi syndrome, and neutrophil-specific granule deficiency can have infections that extend locally and subcutaneously with little reaction until marked destruction has taken place.

View larger version (65K): [in this window] [in a new window]   Figure 1. Schematic representation of lesioned pathways in the neutrophil. Granule production begins early in neutrophil ontogeny, with primary followed by secondary granule formation. In Chediak-Higashi syndrome, fusion of primary and some secondary granules leads to the accretion of giant lysosomes in the cytoplasm, which are easily demonstrated on routine microscopy. In secondary granule deficiency, secondary granule components and the primary granule component, defensins, are absent. Mutations in CD18 underlie leukocyte adhesion deficiency type 1 (LAD1), leading to reduction or absence of the CD18/Cd11–containing complexes on the leukocyte surface. An abnormality in fucosylation (Fu) appears to underlie leukocyte surface. Adhesion deficiency type 2 (LAD2), in which properly glycosylated CD15s is absent.

Neutropenia
An absolute neutrophil count that falls below 500 cells/µl may carry a serious risk of bacterial and fungal infection (2). The rapidity of the fall in neutrophils, the extent of marrow neutrophil reserve, and the duration of neutropenia are important factors in determining whether a particular episode of neutropenia is of concern. Cyclic neutropenia or cyclic hematopoiesis is a rare disease occurring in autosomal dominant and sporadic forms and is characterized by regular 21-day oscillations in the levels of blood neutrophils, monocytes, eosinophils, lymphocytes, platelets, and reticulocytes (3). The defect in cyclic neutropenia is at the level of the hematopoietic stem cell and is associated with abnormal colony-stimulating factor responses in bone marrow precursor cells. Patients with hereditary forms of cyclic neutropenia usually present in childhood and have recurrent episodes of fever, malaise, mucosal ulcers, and, occasionally, life-threatening infections associated with periods of profound neutropenia (<200/µl) (3). Neutrophil number is recurrently low in cyclic neutropenia but function is normal. The diagnosis is suspected in children or adults with recurrent stomatitis, gingivitis, cutaneous infections, lymphadenopathy, and fever. The diagnosis can only be established after repeated blood counts with differentials at least three times per week for at least six weeks. In congenital agranulocytosis (Kostmann syndrome; 4), neutrophil counts are consistently low from birth and show no periodicity. Both cyclic neutropenia and congenital agranulocytosis can be successfully treated with recombinant granulocyte colony-stimulating factor (5).

Adult onset of cyclic neutropenia is associated with clonal or polyclonal proliferation of large granular lymphocytes. The adult form of cyclic neutropenia is less regular in its periodicity but has clinical features similar to the hereditary forms. In these cases, peripheral blood shows abnormal levels of lymphocytes expressing CD8 and CD57 surface markers (6). Successful treatment of the lymphocyte proliferation with cyclosporine, chemotherapy, or steroids has been reported.

Neutropenia is not always associated with an increased susceptibility to infection. In some chronic neutropenias there may be adequate marrow reserve of granulocytes to respond to infections when necessary and no need for specific therapy to increase the neutrophil count (7). Bone marrow granulocyte reserve and the marginated pool of granulocytes can be assessed by injection of low-dose intravenous endotoxin. Endotoxin challenge should produce stereotyped increases in body temperture, white blood cell count, and cytokine profile (8). One patient hyporesponsive to endotoxin and interleukin-1 (IL-1) had recurrent life-threatening bacterial infections with minimal systemic response. Her defect appears to be in the post-binding–signal transduction pathways for endotoxin and IL-1 and may prove informative for cellular events in endotoxin activation (8).

Neutrophil Granule Defects
Chediak-Higashi syndrome is a rare autosomal recessive disorder characterized by recurrent bacterial infections, partial oculo-cutaneous albinism, photophobia, nystagmus, and peripheral neuropathy. Many patients die in childhood from infection. About half of the patients who survive into adolescence develop an aggressive lympho-proliferative phase with diffuse organ infiltration and death. Several patients have lived into adulthood, at which time an aggressive, severe, debilitating peripheral neuropathy is a common feature (9). Low intelligence has been noted in some series. Pathologically, giant lysosomal granules are found in neutrophils, lymphocytes, melanocytes, hair, Schwann cells, the central nervous system, and other granule-containing cells (9). In neutrophils the granules are formed mainly by fusion of azurophilic or primary granules to each other and to a lesser extent with specific or secondary granules (10). The diagnosis of Chediak-Higashi syndrome is easily made by inspection of the peripheral smear for giant lysosomes or microscopic examination of hair for characteristic melanin clumps. The gene has recently been identified as lysosomal transport protein (Lyst), a gene located on chromosome 1q43 (11). To date, the function of Lyst is not clear.

Neutrophil-specific granule deficiency is a rare disorder characterized by recurrent infections in which neutrophil-specific granules, eosinophil specific granule proteins, and the primary granule component defensins are absent (12, 13). Myeloperoxidase deficiency is a common disorder in which the enzyme for conversion of neutrophil hydrogen peroxide to bleach is absent but is not associated per se with increased susceptibility to infections, probably because of up-regulated superoxide production (14).

Leukocyte Adhesion Deficiencies
Leukocyte adhesion to endothelium, other leukocytes, bacteria, and complement is mediated by the integrins, heterodimeric surface molecules stored in the secondary granules of neutrophils that are displayed on the cell surface with cellular activation. Leukocyte adhesion deficiency type 1 is a rare autosomal recessive disorder involving the common beta chain, CD18, of integrins (15). Deficiency of CD18 leads to lack of the three CD18-containing complexes: CD18/CD11a (LFA-1) binds to other leukocytes and endothelium (ICAM-1 and ICAM-2) and mediates tight adhesion; CD18/CD11b [Mac-1, Mo-1, or complement receptor 3 (CR3)] binds to endothelium (ICAM-1) and the inactivated form of the third component of complement (C3bi) and facilitates complement mediated phagocytosis; and CD18/CD11c (p150,95 or CR4), whose target and function are not yet clear (15). Clinical abnormalities confirm the basic defect. Absence of LFA-1 makes for inability to bind tightly to and traverse activated endothelium to infected areas. The inability to bind tightly leads to reduction in the marginated pool of neutrophils, chronic leukocytosis, and poor neutrophil penetration to sites of bacterial invasion. Absence of Mac-1 (CR3) leads to inability to perform complement-mediated phagocytosis, although antibody-mediated phagocytosis remains intact.

Leukocyte adhesion deficiency type 1 falls into two broad categories: severe (<0.5% of normal protein expression) and moderate (2.5–10% of normal protein expression), depending on the degree of CD18/CD11 deficiency (16). The severe deficiency is manifested by delayed umbilical stump separation, umbilical stump infection, persistent leukocytosis in the absence of active infection (15,000/µl), and severe, destructive periodontitis with associated loss of teeth and alveolar bone. Recurrent infections of the skin, upper and lower airway, bowel, perirectal area, and septicemia are common and usually due to S. aureus or gram-negative rods, most notably Pseudomonas sp. Infections tend to be necrotizing and may progress to ulceration, with almost complete absence of neutrophil invasion on histopathology. Patients with the moderate phenotype tend to be diagnosed later in life and, less commonly, have life- threatening infections. Leukocytosis is still the rule, as is delayed wound healing and periodontal disease. Patients with the moderate form of the disease are less ill and tend to live past childhood, but deaths from infection have been reported in young adults (16). The diagnosis is made by fluorescent-activated cell sorting, which shows reduction or absence of CD18 and the co-expressed molecules CD11a, CD11b, and CD11c.

The ability of neutrophils to "roll" along the endothelium is mediated by selectins, surface glycoproteins on the endothelium, and sialyl-Lewis^x (CD15S), a surface glycoprotein on neutrophils (15). Leukocyte adhesion deficiency type 2 occurs in the absence of properly processed CD15s, leading to neutrophilia; recurrent pulmonary, periodontal, and cutaneous infections; and abnormal chemotaxis. The patients reported also had mental retardation, short stature, distinctive facies, and the Bombay (hh) blood phenotype (17). The underlying defect is apparently autosomal recessive and appears to be in fucose metabolism (17).

Chronic Granulomatous Disease of Childhood
Chronic granulomatous disease (CGD) of childhood is a group of disorders of phagocytic cell oxidative metabolism characterized by recurrent life-threatening infections with bacteria and fungi and dysregulated granuloma formation (18). CGD is caused by defects in the NADPH oxidase, which is responsible for the generation of superoxide and its metabolites—hydrogen peroxide and bleach. The estimated frequency is 1 in about 250,000 but may be higher. CGD is clinically variable, ranging in presentation from infancy to adulthood, with most patients diagnosed in childhood (18). Pulmonary, cutaneous, lymphatic, and hepatic infections are common, as are osteomyelitis, perianal fistulae and abscess, and gingivitis (19). The microbiology of chronic granulomatous disease is relatively specific: Organisms frequently encountered include S. aureus, Burkholderia cepacia, Serratia marsescens, Nocardia sp., Aspergillus sp., and other catalase-producing microbes. Exuberant inflammation and granulomata occur, leading to involvement or obstruction of the gastrointestinal and genitourinary tracts (20). Esophageal, gastric, jejunal, ileal, cecal, rectal, and perirectal involvement with granulomata, often mimicking Crohn's disease, have been described (21).

There are four genetic types of CGD, the most common being X-linked (60% of cases) and the others autosomal recessive (18). Diagnosis of CGD is made by assays of superoxide or hydrogen peroxide production, such as nitroblue tetrazolium reduction, chemiluminescence, or dihydrorhodamine oxidation (22). Treatment of CGD hinges on aggressive, prolonged therapy for infections, followed by lifelong treatment with trimethoprim/sulfamethoxazole and interferon- (IFN) (23). With the use of prophylactic antibiotics and IFN, survival in CGD has been dramatically prolonged. Gene therapy for CGD is effective in a mouse model and is being developed for use in humans (24).

Hyper Immunoglobulin E-Recurrent Infection Syndrome (Job's Syndrome)
Hyper immunoglobulin (Ig) E is a rare disorder characterized by recurrent infections, typically of the lower respiratory system and skin, eczema, extremely elevated levels of IgE, and eosinophilia. The majority of patients have facial abnormalities, including ocular hypertelorism; a prominent, protruding, triangular mandible; and a broad somewhat bulbous nose (25). Failure of deciduous teeth to fall out is common. Most patients develop moderate to severe kyphoscoliosis. Other bony abnormalities include frequent osteoporosis, fractures, relatively short stature, craniosynostosis, and macrocephaly (26). Hyper IgE occurs sporadically in all racial and ethnic groups and, in some cases, appears to be transmitted as an autosomal dominant trait (27).

Patients usually present within the first days to months of life with severe eczema, mucocutaneous candidiasis, and cutaneous, sinus, or pulmonary infections predominantly with S. aureus or Haemophilus influenzae. Otitis media and externa are common, as are intertriginous infections and breast abscesses. Infections occur less frequently in bone and joints, and rarely in liver, kidneys, and the gastrointestinal tract; documented sepsis is rare. Deep-tissue infections may extend from paronychia or apical abscesses. Recurrent cold abscesses of the skin are commonly due to staphylococci. Substantial infection typically elicits only modest reaction and is often unassociated with a sense of illness on the part of the patient. Pathogens include S. aureus, H. influenzae, Pseudomonas aeruginosa, Streptococcus pneumoniae, group A streptococci, Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, and Aspergillus sp. Pulmonary infections lead to local destruction: bronchiectasis and pneumatocoele formation, with subsequent accumulation of secretions and mucus, which becomes the site of future infection. Colonization of these cavities with Aspergillus leads to severe local irritation and potentially fatal hemoptysis. Patients may have years of relatively low disease activity, but on average infections that required therapy, such as incision and drainage or oral antibiotics, occurred every 3.6 months, while those requiring intravenous antibiotics or surgery occurred about once per year (25).

Marked elevations of IgE (2000 IU/ml), with levels of more than 50,000 IU/ml, are reported (28), with high specific IgE binding to S. aureus and C. albicans (29). Chronic leukopenia with borderline neutropenia has been observed, but leukocyte counts are typically normal with mild to moderate eosinophilia (25). There is no correlation between IgE level and degree of eosinophilia or clinical disease activity. Diagnosis is still largely clinical, and the major factor in the differential diagnosis is atopic eczema, in which one can also see very high IgE levels. Prophylactic anti-staphylococcal antibiotics have been advocated and are used extensively, but no controlled trials show benefit.

	PHAGOCYTE ABNORMALITIES: MACROPHAGES

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Patients with recurrent and severe mycobacterial infections who are not HIV infected have demonstrated defects in macrophage proteins and functions. These abnormalities involve the pathways for the generation and utilization of IFN, the T cell cytokine necessary for mycobacterial killing (30). Infected macrophages produce IL-12, which acts on T and NK cells, leading to T cell production of IL-2 and T and NK cell production of IFN. IFN feeds back onto the infected macrophage through its cognate receptor, leading to up-regulation of tumor necrosis factor production, enhanced killing of intracellular parasites, and further upregulation of IL-12 production.

IL-12 has been shown to be abnormally regulated leading to low IFN production in a family with severe, refractory Mycobacterium avium complex infection (31). Three males in two generations presented between 4 and 44 years of age with cutaneous or bacteremic disease with M. avium complex infection refractory to conventional antimycobacterials. In vitro proliferative potential to mitogens was normal, whereas in vitro IFN production was significantly depressed. The patients responded well to treatment with IFN (32). Diagnosis was established by in vitro stimulation of cells for proliferation and cytokine production, showing intact proliferation but low IFN production and low IL-12 production in response to bacterial antigens.

Additional evidence for the central role of IFN in the control of mycobacterial infections was provided by the recognition of IFN receptor 1 (IFNR1)–deficient patients. Patients with IFNR1 deficiency presented before age 5 with disseminated nontuberculous mycobacterial infections, adenopathy, and organomegaly. This disease is caused by disabling mutations in the IFNR1 gene (33, 34). Survival has been poor despite aggressive therapy, indicating the critical role of IFN in the control of mycobacteria even in the presence of antimycobacterials. The diagnosis is established by flow cytometry of peripheral blood showing absence or profound reduction of the IFNR1 on mononuclear cell surfaces, and functional studies demonstrating absent IFNR1 signaling.

Patients with IL-12 production defects and IFNR1 deficiency are the first examples of discrete human hereditable abnormalities in susceptibility to mycobacterial infections. Patients with CD4+ T- lymphocytopenia associated with mycobacterial infections have been identified and may have discrete but as yet uncharacterized abnormalities of macrophage or lymphocyte immunity (32, 35).

	EPITHELIAL IMMUNITY: DEFENSINS

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Defensins are small (~10 kD), abundant cationic proteins that exert a profound antibacterial activity (36). They are produced by a variety of cell types, such as neutrophils, in which they comprise up to 1% of the total protein, and epithelial cells. In species other than humans, these types of proteins have been found in many other tissues as well, including the trachea, cornea, and vagina. Defensins are most active against gram-negative rods, such as Pseudomonas aeruginosa. Explant cultures of bronchial epithelium have shown that there is a human bronchial epithelial defensin, hBD-1 (37). In the abnormally high salt concentration found in bronchial fluid in cystic fibrosis (cystic fibrosis, 125 nM NaCl; normal, 75 nM NaCl), hBD-1 antibacterial activity is markedly inhibited. Therefore, the increased frequency and susceptibility to P. aeruginosa infections in cystic fibrosis appears at least in part due to hypertonic inhibition of local defensins (37). Other infections in cystic fibrosis, such as B. cepacia and S. aureus, are relatively defensin resistant, indicating that other host defense abnormalities must be present in cystic fibrosis as well.

	COMPLEMENT-MEDIATED IMMUNITY

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The complement system is divided into two main branches: classical or antibody dependent, and alternative or antibody independent. Both systems converge at the third complement component, C3, and use the same pathway and components from that point onward, leading to assembly of the membrane attack complex (C5-C9) and ultimately to cell lysis (38). Bacteremia and meningitis are common in all the complement deficiencies (38). Pneumonia is common in the early classical pathway (C1, C4, C2) and alternative pathway (factors I, H, properdin, C3) defects. The late component defects (C5-C9) are associated with recurrent Neisseria sp. bacteremia and meningitis. The meningococcal bacteremias associated with late-component defects occur at a much later age (average 17 years) than do meningococcal bacteremia in the normal population. Although these patients also have much higher rates of relapse and reinfection than the normal population, their mortality from the infection is lower than normal. Patients with deficiencies of the early components of complement, C1- 4, tend to have considerably higher rates of collagen-vascular diseases, such as systemic and discoid lupus erythematosus, than either the normal population or patients with late-component defects.

The diagnosis of a complement deficiency is established by the CH50 assay, which examines the integrity of the classical pathway of the complement system. Direct determinations of immunologically reactive protein, including members of the alternative pathway, can be performed using enzyme-linked immunosorbent assays or diffusion assays.

	ACQUIRED IMMUNE DEFICIENCIES

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Specific infecting organisms may point to acquired abnormalities in host defense (Table 3). Iron overload and chelation therapy with desferroximine provide a hospitable environment for certain bacteria, notably Yersinia enterocolitica, which is often bacteremic (39, 40). Liver disease from alcoholic cirrhosis or other causes is associated with a predisposition to septicemic infections with such organisms as Aeromonas hydrophila and Vibrio vulnificus (41). Splenectomy, especially post-traumatic, predisposes to overwhelming infection with encapsulated organisms such as Streptococcus pneumoniae and Capnocytophaga canimorsus (DF-2), and parasites such as Babesia microti and malaria (42). Severe thermal injury is associated with selective degranulation of neutrophil-specific granules, decreased chemotaxis, and profound susceptibility to infections (43).

	FOOTNOTES

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¹ The US Government has the right to retain a nonexclusive, royalty-free license in and to any copyright covering this paper.

Annu. Rev. Med. 1998. 49:185-199

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