Approach to the adult with recurrent infections

Approach to the adult with recurrent infections

Author
Mark S Pasternack, MD
Section Editor
E Richard Stiehm, MD
Deputy Editor
Anna M Feldweg, MD



Last literature review version 16.2: May 2008 | This topic last updated: February 15, 2008 (More)


INTRODUCTION — Patients who present with recurrent infections pose a common dilemma to the practicing generalist. The clinician does not want to miss a treatable although uncommon diagnosis, but also does not want to subject patients to the expense and inconvenience of potentially unnecessary laboratory tests.

Several basic themes are valuable in guiding the approach to the management of patients with recurrent infections:

Most congenital immunodeficiency states are rare in adults. Even in a consultative practice, most patients referred for evaluation have no demonstrable host defense defect responsible for recurrent infections. Guidelines to assist the non-immunologist in efficient and appropriate testing for primary immunodeficiencies have been proposed [1] . This evaluation is reviewed separately. (See "Laboratory evaluation of the immune system").

Most congenital immunodeficiencies are diagnosed in infancy or early childhood because of the dramatic resultant phenotypes [2-5] . Typically, infants and children with significant immunodeficiency states require repeated hospitalizations for serious focal infections, and display growth retardation ("failure to thrive") as a result of these repeated illnesses.

In adults, acquired conditions with milder phenotypes (which are relatively straightforward to diagnose) are a much more common cause of recurrent infections than congenital immunodeficiencies.

Anatomic lesions, whether congenital or acquired, are often responsible for recurrent infections.

The initial approach to an adult patient with recurrent infections is discussed here. Non-immunologic disorders that should be considered in the evaluation of recurrent infection at specific anatomic sites will be reviewed. The laboratory tests that are used to evaluate the various components of the immune system are reviewed separately. (See "Laboratory evaluation of the immune system").

OVERVIEW OF IMMUNODEFICIENCY — Immunodeficiency can be broadly classified as either primary (congenital or acquired) or secondary to another underlying condition.

Prevalence of primary immunodeficiency — The prevalence of primary immunodeficiencies in the general population is not precisely known. It has been estimated at 1 in 10,000. However, a 2007 telephone survey of 10,000 randomly-selected households in the United States found that a well-characterized primary immunodeficiency disorder had been diagnosed in approximately 1 in 1200 persons (adults and children combined), suggesting that primary immunodeficiency is significantly more common than previously thought [6] . In addition, the prevalence of the most common immunologic abnormality, selective IgA deficiency, ranges from 1 in 150 (Arabian populations) to 1 in 900 (Brazilian populations) among different ethnic groups, and approximately one third of patients with this disorder experience recurrent infections [7] . Thus, 1 in 10,000 is very probably an underestimation. Defects in antibody production or function and deficiencies in complement proteins are the most common primary immunodeficiencies diagnosed in adulthood [7] .

Secondary immune deficiency — Secondary immunodeficiencies are far more prevalent than primary immune disorders and should be considered in the presence of underlying disease states, medications, or previous surgical procedures:

• Diabetes mellitus
• HIV infection
• Cirrhosis
• Nephrotic syndrome
• Hemoglobinopathy
• Inflammatory bowel disease
• Neurologic disease
• Autoimmune disease
• Splenectomy
• Saphenous vein harvesting
• Malignancy
• Radiation therapy
• Immunosuppressive agents, such as glucocorticoids and others
• Immunomodulatory agents, such as rituximab, etanercept, and others

The causes of secondary immune defects are reviewed elsewhere. (See "Secondary immune deficiency due to malignancy" and see "Secondary immune deficiency due to immunosuppressive drugs and infections other than HIV").

Non-infectious characteristics of patients with immunodeficiency — A fundamental function of the immune system is to distinguish "self" from "non-self." This capacity is critical not only to defend against invading microorganisms, but also to the prevention of autoimmune disease and detection and destruction of malignant cells. Therefore, in addition to infections, many immune disorders are associated with autoimmune disease and a higher risk of malignancies. The clinician's threshold for initiating an evaluation of the immune system should be lower in a patient with disorders in one or more of these categories of disease.

Several other health problems are more common in patients with immunodeficiency, such as poor wound healing, premature loss of adult teeth, chronic diarrhea, and unexplained bronchiectasis [7] .

Infectious disease — Patients with immunodeficiency disorders usually display one or more of the following characteristics with respect to infectious disease [7] :

• An increased frequency of infections
• Infections of unusual severity
• Prolonged infections
• Infections with unusual organisms
• Uncommon complications following infections


CLINICAL EVALUATION — The evaluation of an adult with recurrent infections begins with a complete history and thorough physical examination.

A detailed family history is important. Illnesses or childhood deaths in relatives may suggest an X-linked or autosomal recessive process. Multiple family members with autoimmune diseases or malignancies should also raise the suspicion of a familial immune disorder. Consanguinity increases the likelihood that a rare condition could be expressed.

Whenever possible, culture information should be obtained to document the organism responsible for current or past infections. The etiology and subsequent approach varies according to the type and pattern of infections present.

PATTERNS OF INFECTION — Patients with immunodeficiency typically experience stereotypic patterns of recurrent infection, which provide clues regarding which limb of the immune system is affected (show table 1). The laboratory evaluation of each of these components of the immune system is reviewed separately. (See "Laboratory evaluation of the immune system").

Typical patterns of infection include the following:

Defects in immunoglobulins and/or complement proteins — Recurrent sinopulmonary infections, chronic gastrointestinal infections, bacteremia, and/or meningitis are associated with defects in immunoglobulins and/or complement proteins [5,8,9] . Common pathogens include the encapsulated bacteria Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis, as well as Giardia and Campylobacter. (See "Primary humoral immune deficiencies: An overview" and see "Inherited and acquired disorders of the complement system").

Granulocyte (neutrophil) defects — Recurrent invasive skin infections, especially focal abscesses requiring incision and drainage, are associated with granulocyte (neutrophil) defects [3,10-12] . Characteristic organisms include Staphylococcus aureus, gram-negative bacteria, Aspergillus, and Nocardia [7] . (See "Primary disorders of phagocytic function: An overview").

Defects in cell mediated immunity — Progressive infections with ordinarily "benign" viruses, opportunistic intracellular pathogens, or fungi suggest defective cell-mediated immunity, particularly defects of T cells. Typical microorganisms include cytomegalovirus, herpes viruses, mycobacteria, and fungi (Candida, Cryptococcus, and Pneumocystis) [7] . NK cell defects also present with severe and fulminant herpes virus infections, although these conditions are rare [13,14] . (See "Combined immune deficiencies" and see "NK cell deficiency syndromes: Clinical manifestations and diagnosis").

However, some syndromes of recurrent infection do not fit into one of these simple patterns. As examples:

Leukocyte adhesion molecule deficiency (eg, LFA-1 deficiency) results in both lymphocyte and phagocyte dysfunction. As a result, both bacterial infections and life-threatening viral infections may recur early in life [15] . (See "Primary disorders of phagocytic function: An overview" and see "Leukocyte adhesion deficiency").

Deficiency of mannose-binding lectin, a complement-like protein that confers innate immunity to a variety of pathogens, has been described in adults as well as in children, and is associated with skin abscesses, cryptosporidiosis, pneumonia, and meningococcal sepsis [16] . (See "Inherited and acquired disorders of the complement system", section on Inherited mannose-binding lectin pathway deficiencies).

Hyperimmunoglobulin E syndrome (Job's syndrome), should be suspected in the presence of eczema, mucocutaneous candidiasis, recurrent cutaneous and respiratory tract bacterial infections, and marked elevation of serum IgE [17,18] . (See "Hyperimmunoglobulin E syndrome").

CONSIDERATIONS BY SITE OF INFECTION — Adult patients will sometimes present with recurrent infections of one type. In this setting, there are specific non-immunologic conditions which should be considered before an immune evaluation is undertaken.

Skin infections

Cellulitis — Cellulitis is likely to recur in the setting of lymphatic stasis (lymphedema) and/or breaches in the skin barrier (eg, dermatophyte infections or trauma).

Lymphedema can be classified as familial and congenital (Milroy's disease) or sporadic (congenital or acquired [lymphedema precox]) [19-21] . It may complicate vascular insufficiency, trauma to an extremity, particularly if there is retained foreign material, or may develop following irradiation or surgery (inguinal or axillary lymph node dissection, saphenous vein harvesting) [22,23] .

A previous episode of cellulitis itself can lead to lymphatic scarring and impaired lymphatic drainage, thereby promoting the development of recurrent cellulitis. (See "Lymphedema", see "Recurrent cellulitis after saphenous venectomy for coronary artery bypass graft surgery",and see "Cellulitis syndromes unique to women").

Dermatophyte infections can predispose patients to recurrent cellulitis, especially when tinea pedis develops after saphenous venectomy [24] . The dermatophyte infection provides a portal of entry for bacteria, most often streptococci or staphylococci, and predisposes to the development of cellulitis. Infections in these patients are often reduced in frequency by treatment of dermatophyte infections and other primary dermatologic conditions, meticulous podiatric care, and consideration of antibiotic prophylaxis. (See "Recurrent cellulitis after saphenous venectomy for coronary artery bypass graft surgery", section on Chronic suppressive therapy).

Abscess — Recurrent abscess formation in the same anatomic location often arises from a local defect, such as a congenital branchial cleft cyst, pilonidal cyst, hidradenitis suppurativa, or a retained foreign body. In these situations, recurrent infection is limited to the neck, axilla, groin, or site of previous trauma, and there is no need to suspect a generalized susceptibility to infection.

Crohn's disease may rarely lead to inguinal abscesses complicating enteric fistula and intraabdominal abscess formation. Inflammatory bowel disease occasionally co-exists with antibody deficiencies [25] . (See "Clinical manifestations; diagnosis and natural history of Crohn's disease in adults").

Multiple or recurrent abscesses in a variety of locations may be the result of autoinoculation in the setting of drug abuse ("skin-popping") or Munchausen syndrome [26,27] . (See "Factitious disorder and Munchausen syndrome").

Most patients who experience recurrent cutaneous abscesses respond to treatment of chronic nasal colonization with staphylococci using nasal mupirocin [28] and topical disinfection using pHisohex or chlorhexidine. In refractory cases, combined intranasal, topical and systemic decontamination has been effective at reducing S. aureus colonization and recurrent abscess formation [29] .

Initial immunologic evaluation — Immunologic evaluation would be appropriate in patients with recurrent cellulitis affecting different sites, who do not have lymphatic or venous abnormalities or associated dermatologic conditions that could predispose to infection. Neutropenia should be excluded as a risk factor by routine differential white blood cell count. Cyclic neutropenia presenting in adulthood is extremely unusual. (See "Cyclic neutropenia").

In patients with recurrent cutaneous abscesses affecting different sites, neutropenia should be excluded. A variety of functional defects in phagocytes should also be considered:

Milder phenotypes of chronic granulomatous disease (CGD) have been associated with the autosomal recessive form of the disease (deficiencies of the cytochrome-associated proteins p67phox or p47phox) and some cases of classic X-linked CGD (gp91-phox deficiency) [30] . (See "Primary disorders of phagocytic function: An overview").

Myeloperoxidase deficiency is a common genetic defect but is frequently clinically silent [11,31] . Some patients have increased susceptibility to invasive candidal infection. (See "Myeloperoxidase deficiency and other enzymatic WBC defects causing immunodeficiency").

Specific granule deficiency can be congenital or acquired [32] . Specific granules are thought to play a role in the evolution of the inflammatory response.

(See "Normal neutrophil development and kinetics").

Chediak-Higashi syndrome, a rare autosomal recessive condition, is associated with a more generalized defect in cells possessing granules, and is generally diagnosed in childhood in the setting of partial albinism, thrombocytopenia, neurologic disease, and recurrent infections. (See "Primary disorders of phagocytic function: An overview").

Respiratory tract infections

Sinusitis — Recurrent respiratory infections are extremely common and most patients do not have an underlying immune defect. Recurrent sinusitis in isolation is rarely associated with an immunodeficiency state, and more likely reflects inadequate antibiotic therapy (either spectrum of antimicrobial activity or duration of treatment) and/or underlying allergic rhinitis or anatomic abnormalities.

In contrast, adult patients with recurrent or chronic sinus infections in combination with lower respiratory tract infections or otitis media may have a defect in antibody production or function, such as common variable immunodeficiency, IgG subclass deficiencies, or selective antibody deficiency with polysaccharide non-response [33-36] . A quantitative or qualitative granulocyte disorder or a deficiency of complement proteins are other possible explanations. (See "Clinical manifestations and epidemiology of common variable immunodeficiency", see "Clinical manifestations, diagnosis, and treatment of IgG subclass deficiency", see "Selective antibody deficiency with normal immunoglobulins (polysaccharide non-responses)", and see "Primary disorders of phagocytic function: An overview").

Pharyngitis — Recurrent streptococcal pharyngitis usually reflects inadequacy of therapy to eradicate pharyngeal carriage of group A beta-hemolytic streptococci. Molecular analyses of symptomatic patients show persistence of individual isolates, rather than serial infection by independent strains. Symptomatic patients often benefit from the use of a beta-lactamase resistant agent. (See "Treatment and prevention of streptococcal tonsillopharyngitis", section on Penicillin tolerance and section on Increases in penicillin treatment failures).

Pneumonia — Patients with recurrent pneumonia limited to a particular anatomic region (eg, right middle lobe) generally have a local anatomic abnormality. This may be extrinsic to the trachea and bronchi (eg, bronchial compression by mediastinal adenopathy, neoplasm, or vascular anomaly) or intrinsic to the bronchus or alveoli (eg, retained foreign body, bronchiectasis, bronchomalacia, bronchial stenosis, tracheobronchial fistula, bronchial sequestration or cyst) [37,38] . Patients with tracheal disorders such as tracheomegaly [39] or tracheomalacia may have recurrent infections in a limited or more generalized pattern. (See "Airway foreign bodies in adults").

Recurrent aspiration due to seizures, ethanol or other drug use, dysphagia, reflux, Zenker's diverticulum, or achalasia can cause recurrent pneumonitis restricted to the lung bases and posterior segments. In such cases, a barium swallow or other appropriate gastroenterologic studies should be considered. In contrast, patients with sequential infections involving different regions of the lung are more likely to have an underlying systemic process. Examples include:

A prominent pulmonary defect - These include cystic fibrosis and immotile cilia syndrome [40-44] . It is important to screen adults with suggestive symptoms for cystic fibrosis, as this may present in adulthood and de novo mutations may be responsible for illness despite a negative family history. (See "Clinical manifestations and diagnosis of cystic fibrosis" and see "Primary ciliary dyskinesia (immotile-cilia syndrome)")

Noninfectious processes, particularly pulmonary vasculitis, may mimic recurrent infectious pneumonitis. Flexible fiberoptic bronchoscopy and transbronchial biopsy can be extremely valuable in establishing a diagnosis in these challenging patients.
A secondary immunodeficiency, including HIV infection, hemoglobinopathy, multiple myeloma, or chronic lymphocytic leukemia [45,46] . HIV testing, hemoglobin electrophoresis, and serum and urine electrophoresis for multiple myeloma may be indicated. (See "Secondary immune deficiency due to malignancy" and see "Secondary immune deficiency due to immunosuppressive drugs and infections other than HIV").

Primary immunodeficiency should be suspected in adults with recurrent infections of the lung in association with other infections, such as sinusitis, otitis media, or bronchitis. A defect in antibody production or function, such as common variable immunodeficiency, IgG subclass deficiencies, or selective antibody deficiency with polysaccharide non-response should be considered [33-36] . A quantitative or qualitative granulocyte disorder is also possible. (See "Clinical manifestations and epidemiology of common variable immunodeficiency", see "Clinical manifestations, diagnosis, and treatment of IgG subclass deficiency", see "Selective antibody deficiency with normal immunoglobulins (polysaccharide non-responses)", and see "Primary disorders of phagocytic function: An overview").

Initial immunologic evaluation — Initial evaluation includes IgG, IgA, and IgM levels and screening test for chronic granulomatous disease. (See "Primary humoral immune deficiencies: An overview" and see "Primary disorders of phagocytic function: An overview").

Urinary tract infections — Local anatomic considerations increase the risk of recurrent urinary tract infections. However, recurrent urinary tract infections are also a common problem in sexually active women without any identifiable predisposing condition. Isolated recurrent urinary tract infections, in the absence of infections in other organ systems, is not a typical presentation of immunodeficiency.

Anatomic abnormalities resulting in obstruction, stasis, or reflux of urinary flow all predispose toward recurrent urinary infections. (See "Bacterial adherence and other virulence factors for urinary tract infection").

Recurrent urinary tract infections are a common problem in sexually active women in the absence of an identifiable structural abnormality. Sexual activity may cause local irritation of the urethral meatus and lead to cystitis ("honeymoon cystitis"). Women with frequent recurrences often benefit from prevention strategies, including antibiotic prophylaxis that is given after intercourse. (See "Recurrent urinary tract infection in women", section on Prevention strategies).

Older men can develop recurrent urinary tract infections with increasing frequency, largely due to obstructive and/or neurogenic abnormalities. Neurogenic abnormalities leading to hypotonic bladder result in urine stasis and an increased risk of infection. In about one-half of men with recurrent urinary tract infections, the prostate is the source of infection. (See "Acute and chronic bacterial prostatitis" section of Chronic bacterial prostatitis).

Intraluminal (indwelling bladder catheter, calculi, neoplasms), intramural (ureteral stenosis, urethral strictures, prostatic obstruction) and extramural lesions (paravesical inflammatory mass, neoplasm, or fibrosis) all may predispose to recurrent urinary infection. (See "Urinary tract infection associated with indwelling bladder catheters").

Meningitis — Recurrences can occur with bacterial, viral, and noninfectious causes of meningitis.

Mollaret's meningitis — Mollaret's meningitis is a form of benign recurrent aseptic meningitis that is usually due to HSV infection. Genital lesions are usually absent at the time of presentation (See "Aseptic meningitis in adults", section on Recurrent (Mollaret's) meningitis).

Noninfectious meningitis — Noninfectious meningitides that can recur include Behcet's syndrome, chemical meningitis, neoplastic meningitis, Vogt-Koyanagi-Harada syndrome, and the hypersensitivity meningitis syndromes occasionally triggered by sulfonamides, azathioprine, and nonsteroidal antiinflammatory drugs [47-50] .

Bacterial meningitis — The epidemiology of recurrent bacterial meningitis was evaluated in a review of 493 episodes in 445 adults seen at a single center in Boston from 1962 to 1988 [51] . Among 275 patients with community-acquired meningitis, 17 (6.2 percent) had more than one episode of community-acquired disease and 10 had 3 or more episodes.

Recurrent bacterial meningitis can result from a breach in the cranial vault. Defects in the cribriform plate, sphenoid or other sinuses, or temporal bone may be congenital or acquired (posttraumatic or postneurosurgical, especially in the setting of cerebrospinal fluid [CSF] rhinorrhea or other CSF leak). Recurrent meningitis also occurs with the use of indwelling medical devices (eg, Ommaya reservoirs, ventricular shunts) placed into the central nervous system. (See "Infections of central nervous system shunts and other devices").
A bony cranial defect can usually be detected by high resolution CT scanning [52] . Lumbar puncture and instillation of fluorescein or radionuclides for localizing a CSF leak are rarely necessary [52] .

Abnormalities in both complement and opsonizing antibodies have also been associated with recurrent bacterial meningitis:

Deficiency of one or more of the terminal complement components (C7, C8, C9) has been associated with recurrent N. meningitidis meningitis [53-56] . Low complement levels may be due to either congenital complement deficiency or acquired diseases such as systemic lupus erythematosus. (See "Inherited and acquired disorders of the complement system").

Immunoglobulin deficiency disorders or impaired reticuloendothelial function resulting from splenectomy or hemoglobinopathy are associated with an increased risk of bacteremia, and therefore meningitis, due to encapsulated pathogens. Recurrent enteroviral (aseptic) meningitis has been associated with agammaglobulinemia [57] . (See "Primary humoral immune deficiencies: An overview" and see "Clinical features and management of sepsis in the asplenic patient").

Initial immunologic evaluation — In patients with recurrent meningitis and in those recovering from an initial episode of meningococcal meningitis, screening complement testing with C3, C4, and CH50 should be performed; if abnormal, further testing of the terminal complement components (C6 through C9) is warranted. In addition, levels of IgG, IgA, and IgM should be measured.

Brain abscess — Anatomic factors are almost always responsible for the development of parenchymal brain abscesses. Although most brain abscesses result from direct extension from adjacent foci of infection such as sinusitis or mastoiditis, a variety of remote abnormalities may be important in selected patients.

As an example, shunting of venous blood to the systemic circulation may occur through intracardiac right-to-left or bidirectional shunts, anomalous pulmonary arteries, or extracardiac vascular malformations (eg, Rendu-Osler-Weber syndrome). In addition, extracranial infections that can seed the systemic arterial supply, such as lung abscesses and rarely subacute infective endocarditis, may predispose patients to the development of brain abscess.

Bacteremia and sepsis — Patients with deficiency or dysfunction of mannose binding lectin, a component of the innate immune system that is involved in complement activation, may be at higher risk for bacteremia and sepsis [58,59] . Deficiency of C3 has also been associated with bacteremia due to encapsulated pathogens such as Streptococcus pneumoniae and Hemophilus influenzae [8] . (See "Inherited and acquired disorders of the complement system", section on Inherited mannose-binding lectin pathway deficiencies).

SUMMARY — The vast majority of adults presenting with recurrent infections, especially localized to one organ system, have an anatomic abnormality or other condition (such as allergic rhinitis or asthma with recurrent respiratory infections) that predisposes to infections, rather than a congenital or acquired immune defect. (See "Introduction" above).

When an immune defect is suspected in an adult, secondary causes of immunodeficiency are more common than primary immunodeficiencies. Patients with primary immunodeficiency may also have autoimmune disease and suffer higher rates of malignancies. (See "Overview of immunodeficiency" above).

Patients with immunodeficiencies may experience more frequent infections, unusually severe infections, protracted infections, infections with unusual organisms, or uncommon complications of infections. (See "Infectious disease" above).
Patterns of infections can provide clues about which limb of the immune system is defective (show table 1). (See "Patterns of infection" above).

Adult patients may present with recurrent infections of one type, such as recurrent cellulitis or recurrent urinary tract infections. Each type of infection should prompt consideration of specific predisposing conditions, most of which are non-immunologic. (See "Considerations by site of infection" above).