Infections in the Immunocompromised Patient

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137 Infections in the Immunocompromised Patient

Many immunocompromised patients are managed in intensive care units (ICUs) every year, with infection being a leading cause of ICU admission. Common examples of such infections include community-acquired pneumonia, bacteremia, and central nervous system (CNS) infections. The incidence of infections acquired by immunocompromised patients during ICU admissions is also significant.1 Mortality for certain infections in immunocompromised patients exceeds 50%.2 Early diagnosis, initiation of appropriate antimicrobial and supportive therapy, and reduction in immunosuppression where possible can improve outcome significantly.

image Commonly Encountered Immunocompromising Conditions

Immunocompromise can be broadly defined as a state in which the response of the host to a foreign antigen is subnormal. Immunocompromise could be congenital (primary) or acquired. Congenital immunodeficiencies are now much less common than acquired immunodeficiencies. In general, congenital immunodeficiency is observed more frequently in patients in pediatric ICUs than in adult ICUs. Patients with congenital immunodeficiencies usually have repeated infections, especially infections affecting the sinuses and lower respiratory tract. Congenital immunodeficiencies are usually “pure” in that the defects in host response to foreign antigens are usually specific and well defined. For example, Bruton’s X-linked agammaglobulinemia is associated with a defect in the normal maturation process of immunoglobulin-producing B cells. As a result, mature circulating B cells, plasma cells, and serum immunoglobulin are absent. The patient is susceptible to organisms normally dealt with by immunoglobulin, such as Streptococcus pneumoniae and Haemophilus influenzae. Other congenital immunodeficiency syndromes are listed in Table 137-1.

TABLE 137-1 Congenital (Primary) Causes of Immunodeficiency

Condition (Immunodeficiency) Organisms with Increased Tendency to Cause Infection in This Condition
T-lymphocyte Deficiencies
DiGeorge syndrome (thymic aplasia with reduced CD4 and CD3 cells) Viruses (especially HSV and measles), sometimes Pneumocystis jirovecii, fungi, or gram-negative bacteria
Purine nucleoside phosphorylase deficiency (marked T-cell depletion) P. jirovecii and viruses
B-lymphocyte Deficiencies
Bruton’s X-linked agammaglobulinemia (absence of B cells, plasma cells, and antibody) Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, P. jirovecii (after first 4-6 months of life when maternal antibody has been consumed)
Selective IgG subclass deficiencies Variable
Selective IgA deficiency S. pneumoniae, H. influenzae
Hyper-IgM immunodeficiency (elevated IgM but reduced IgG and IgA) S. pneumoniae, H. influenzae, P. jirovecii (rarely)
Mixed T- and B-lymphocyte Deficiencies
Common variable immunodeficiency (leads to various B-cell activation or differentiation defects and gradual deterioration of T-cell number and function) S. pneumoniae, H. influenzae, CMV, VZV, P. jirovecii
Severe combined immunodeficiency (severe reduction in IgG and absence of T cells) P. jirovecii, viruses, Legionella
Wiskott-Aldrich syndrome (decreased T-cell number and function, low IgM, occasionally low IgG) S. pneumoniae, H. influenzae, HSV, P. jirovecii
Ataxia-telangiectasia (decreased T-cell number and function; IgA, IgE, IgG2, and IgG4 deficiency) S. aureus, S. pneumoniae, H. influenzae
Disorders of Complement
C3 deficiency (congenital absence of C3 or consumption of C3 due to deficiency of C3b inactivator) S. pneumoniae, H. influenzae, enteric gram-negative bacilli
Phagocyte Defects
Chronic granulomatous disease (defect in NADPH oxidase in phagocytic cells) S. aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, S. marcescens, P. aeruginosa, Aspergillus
Chédiak-Higashi syndrome (impaired microbicidal activity of phagocytes) S. aureus, H. influenzae, Aspergillus
Kostmann syndrome, Shwachman-Diamond syndrome, cyclic neutropenia (low neutrophil count) S. aureus, enteric gram-negative bacilli, P. aeruginosa

CMV, Cytomegalovirus; HSV, herpes simplex virus; Ig, immunoglobulin; NADPH, nicotinamide adenine dinucleotide phosphate; VZV, varicella-zoster virus.

Most immunocompromised patients managed in adult ICUs have acquired immunocompromise. Although the response of host defenses in the elderly, diabetics, and alcoholics is compromised, this chapter deals primarily with four categories of immunocompromised patients: (1) patients receiving chemotherapy for hematologic malignancies and solid tumors; (2) patients receiving immunosuppressive therapy in the context of solid-organ transplantation; (3) patients receiving corticosteroids, methotrexate, monoclonal antibodies to tumor necrosis factor, and other disease-modifying agents for rheumatoid arthritis, Crohn’s disease, and autoimmune disorders; and (4) patients with human immunodeficiency virus (HIV) infection.

Hematologic Malignancies and Solid Tumors

Prolonged neutropenia from chemotherapy has a significant risk of bacterial and fungal infection. Classically, gram-negative organisms such as Pseudomonas aeruginosa and fungal organisms such as Aspergillus species have been associated with severe neutropenia. It has long been known that the severity and duration of neutropenia influence the risk of infection.3 It also has been well established that aggressive chemotherapy and radiotherapy for Hodgkin’s disease coupled with splenectomy significantly impairs humoral defense against encapsulated organisms such as S. pneumoniae, H. influenzae, and Neisseria meningitidis.4 Transplantation is associated with a risk of graft-versus-host disease (GVHD). Prophylaxis and treatment for GVHD may involve use of drugs such as cyclosporine or tacrolimus plus corticosteroids. Cyclosporine and tacrolimus inhibit calcineurin, an enzyme important in the lymphocyte activation cascade. Corticosteroids also affect lymphocyte function and depress functions of activated macrophages. As a result, patients receiving therapy for GVHD may be prone to fungal, viral, and mycobacterial infections.

Solid-Organ Transplantation

Solid-organ transplant recipients are uniquely susceptible to infection.5 They undergo significant surgery, breaching the defenses provided by the skin. They remain in ICUs for prolonged periods, requiring intravenous access and mechanical ventilation—here, cutaneous and pulmonary barriers to infection are breached. Finally, solid-organ transplant recipients receive immunosuppressive therapy to prevent graft rejection. Commonly used immunosuppressive medications are listed in Table 137-2. Immunosuppressive regimens are in a constant state of flux—more recent trends have been toward aggressive “pretreatment” immediately before transplantation, coupled with decreased immunosuppression in the posttransplant period.6

TABLE 137-2 Immunosuppressive Drugs Used in Solid-Organ Transplantation and Their Mechanisms of Activity

Immunosuppressive Mode of Action
Corticosteroids Negative regulation of cytokine gene expression
Azathioprine Inhibits DNA and RNA synthesis; inhibits T- and B-cell function
Cyclosporine Calcineurin inhibitor; inhibits cytokine expression
Tacrolimus Calcineurin inhibitor; inhibits cytokine expression
Sirolimus (rapamycin) Prevents translation of mRNAs encoding cell cycle regulators
Mycophenolate mofetil Blocks purine biosynthesis; inhibits T- and B-cell proliferation
Polyclonal antilymphocyte Lymphocyte depletion antibodies (e.g., Atgam, Thymoglobulin)
Muromonab-CD3 (OKT3) Anti-CD3 monoclonal antibody
Alemtuzumab (Campath) Anti-CD52 monoclonal antibody
Daclizumab, basiliximab Anti-CD25 monoclonal antibody

In the early posttransplant period, transplant recipients are susceptible to nosocomially acquired bacterial infections such as pneumonia, catheter-related bloodstream infection associated with general ICU care, and wound and intraabdominal infections associated with surgical procedures. Opportunistic infections may be acquired from the organ graft; cytomegalovirus (CMV) is the most pertinent example,7 but a wide variety of infections (e.g., rabies, histoplasmosis, tuberculosis, West Nile virus) have been acquired from grafts. Solid-organ transplant recipients, by virtue of their iatrogenic immunosuppression, also are susceptible to reactivation of latent infection (e.g., CMV infection, tuberculosis, histoplasmosis) or to infections acquired through the hospital environment (e.g., aspergillosis, legionellosis, tuberculosis).

Rheumatoid Arthritis and Autoimmune Disorders

Therapy for rheumatoid arthritis and other autoimmune disorders may be with simple analgesics or nonsteroidal antiinflammatory drugs (NSAIDs). Drugs with the potential to cause significant immunocompromise are also frequently used. Classically, therapy has been with corticosteroids or disease-modifying antirheumatic drugs such as azathioprine, cyclosporine, penicillamine, gold salts, hydroxychloroquine, leflunomide, methotrexate, or sulfasalazine. The effects of corticosteroids, azathioprine, and cyclosporine on host defenses have been noted previously (see Table 137-2). Methotrexate reversibly inhibits dihydrofolate reductase and interferes with DNA synthesis, repair, and cellular replication. In addition to its use in rheumatoid arthritis, it also can be used as an antineoplastic agent. Methotrexate can cause significant neutropenia. Low-dose methotrexate is generally less likely to increase infection risk in patients with rheumatoid arthritis.8,9

A variety of anticytokine agents have become available for rheumatoid arthritis (Table 137-3). Use of these drugs also has been reported in treatment of Behçet’s disease, Crohn’s disease, GVHD, hairy cell leukemia, psoriasis, pyoderma gangrenosum, sarcoidosis, and ulcerative colitis. Considerable attention has been paid to the possibility of tuberculosis developing after treatment with such agents.10 The risk is sufficiently high that it is recommended that tuberculin skin testing or interferon gamma (IFN-γ) release assays be performed to detect latent tuberculosis before the initiation of anticytokine agents. Invasive infections with Histoplasma, Candida, Pneumocystis jirovecii, Aspergillus, Cryptococcus, Nocardia, Salmonella, Listeria, Brucella, Bartonella, nontuberculous mycobacteria, Leishmania, and Toxoplasma have also been reported associated with the use of these medications.1114 As is the case with transplant-associated immunocompromise, these infections may be reactivation of latent infection or new acquisition of organisms through environmental exposure.

TABLE 137-3 Commonly Used Anticytokines for Management of Rheumatoid Arthritis

Drug Mechanism of Action FDA-Approved Indications
Adalimumab (Humira) Recombinant, fully human anti-TNF monoclonal antibody

Anakinra (Kineret) Recombinant human interleukin-1 receptor antagonist

Etanercept (Enbrel) TNF receptor p75 Fc fusion protein Infliximab (Remicade) Chimeric monoclonal antibody to TNF Tocilizumab (Actemra) IL-6 receptor–inhibiting monoclonal antibody

FDA, U.S. Food and Drug Administration; IL-6, interleukin 6; TNF, tumor necrosis factor.

image General Diagnostic Approach to Immunocompromised Patients with Severe Infections

Immunocompromised patients are a heterogeneous group. The infections commonly encountered by a patient with neutropenia as a consequence of chemotherapy may be different from infections observed in a patient with rheumatoid arthritis who is receiving infliximab. Even within a particular category, different renal transplantation recipients, for example, may have a different degree of immunocompromise and a different susceptibility to infection. In solid-organ transplant recipients, the “net state of immunosuppression” (i.e., the cumulative burden of immunosuppression with a special weighting toward recent T-cell ablative therapy) influences the risk of infection. A renal transplant recipient who is receiving tacrolimus monotherapy twice per week would be less susceptible to opportunistic infection than a patient with recent acute cellular rejection treated with OKT3 or alemtuzumab. There have been more recent attempts to quantify immune function in solid-organ transplant recipients,17 although it has not yet been definitively proved that such tests predict infection risk. In contrast, with HIV infection, CD4 lymphocyte count and HIV RNA quantification (“viral load”) predict risk of infection.18 Patients with CD4 counts greater than 500 are unlikely to be infected with an opportunistic pathogen. Patients with CD4 counts of 200 to 500 may be infected with organisms such as Mycobacterium tuberculosis, but they are unlikely to be infected with opportunistic pathogens such as CMV or Mycobacterium avium complex. Patients with CD4 counts less than 200 have an increased risk of a wide variety of opportunistic infections.

Specific environmental exposures may be potentially important for immunocompromised patients. A travel history to the deserts of the southwestern United States and northern Mexico may increase the likelihood that an immunocompromised patient has coccidioidomycosis.19 Histoplasmosis is endemic in the Ohio River valley.20 Alternatively, there may be environmental risks within the ICU. Outbreaks of invasive pulmonary aspergillosis have been linked to construction activity within the hospital. Outbreaks of legionellosis may be waterborne.21 It is possible that many fungal and bacterial infections may also be waterborne.22,23 Tuberculosis transmission has been well described in ICUs caring for transplant recipients or HIV-infected patients.24 The net state of immunosuppression must be considered in the context of recent environmental exposures.

Although elements of history taking and physical examination may narrow the differential diagnosis of the causative agent of infection in immunocompromised patients, some of the “rules” applied to diagnosis in immunocompetent patients do not apply. Caution must be exercised in use of the diagnostic principle that follows Occam’s razor: “entities are not to be multiplied without necessity.” In an immunocompetent patient, given all the patient’s symptoms, signs, and noninvasive laboratory test results, one unifying diagnosis usually explains all. In contrast, immunocompromised patients may have more than one infection at any given time. A neutropenic patient may have bacterial pneumonia and invasive pulmonary aspergillosis simultaneously, whereas an immunocompromised patient with HIV infection may have P. jirovecii pneumonia and pulmonary infiltrates due to human herpesvirus-8 (HHV-8) infection (Kaposi sarcoma).

The potential for multiple diagnoses underscores the need for early invasive testing in immunocompromised patients with severe infection. Patients with unexplained severe community-acquired pneumonia may be best managed by early bronchoalveolar lavage performed before antimicrobial therapy has commenced. Bronchoalveolar lavage could be sent for Gram stain, Ziehl-Neelsen stain, modified acid-fast stain, calcofluor stain, direct fluorescent antibody tests, polymerase chain reaction (PCR), and cytologic analysis to enable rapid diagnosis of infection with bacteria, mycobacteria, Nocardia, fungi, Legionella, CMV, community-acquired respiratory viruses, and P. jirovecii. The bronchoalveolar lavage should be inoculated onto solid media, and molecular diagnostic testing should be used as appropriate. An outline of the diagnostic approach in immunocompromised patients is given in Box 137-1.

Box 137-1

Diagnostic Approach for Severe Infections in Immunocompromised Patients

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