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.
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.
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.11–14 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.
Human Immunodeficiency Virus Infection
HIV infection remains a relatively common infection, but acquired immunodeficiency syndrome (AIDS) has become less frequently encountered in ICUs since the advent of highly active antiretroviral therapy. A decline in CD4 counts creates a predisposition to P. jirovecii pneumonia, mycobacterial infection, fungal infection (e.g., cryptococcal meningitis), and viral infection (e.g., CMV infection). Many patients with HIV infection are co-infected with hepatitis C virus, and as a result, liver failure is now a relatively common reason for ICU admission in HIV-infected patients. In some centers, liver transplantation is performed in HIV-infected patients with hepatitis virus–induced liver diseases.15,16
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.
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
History Taking and Review of Prior Records
Major Manifestations of Infection in Immunocompromised Patients
Pulmonary Infection
Infectious microorganisms usually gain access to the respiratory tract through inhalation, although hematogenous spread sometimes may occur. Mechanical defenses remove the bulk of potentially harmful agents from the lungs (Table 137-4). Inhaled particles greater than 10 µm in diameter usually become trapped in the upper airways or are removed by coughing or mucociliary clearance. Most bacteria range from 0.5 to 2 µm in size and are able to reach the terminal airways/alveoli and potentially cause infection. In the alveoli, the alveolar macrophages are the first line of defense. Subsequently an inflammatory response consisting of polymorphonuclear neutrophils is important. Finally, specific T-cell and B-cell immune responses are essential for successful defense against many pathogens.
TABLE 137-4 Host Defenses Against Respiratory Infections and How They Are Affected in Immunocompromised Patients
| Location | Host Defense | Defect |
|---|---|---|
| Upper airway | Filtration | Endotracheal intubation |
| Mucociliary apparatus | CF, cigarette smoking | |
| Cough | Impaired consciousness | |
| Lower airway (nonspecific) | Alveolar macrophages | Immunosuppressive medication, corticosteroids |
| Polymorphonuclear leukocytes | Corticosteroids, malnutrition, chemotherapy, malignancies | |
| Lower airway (specific) | B lymphocytes | Hypogammaglobulinemia, CLL, MM |
| T lymphocytes | AIDS, malignancies, immunosuppressants |
AIDS, acquired immunodeficiency syndrome; CLL, chronic lymphocytic leukemia; CF, cystic fibrosis; MM, multiple myeloma.
As noted earlier, although it may be possible to pinpoint a major immunologic deficiency, most immunocompromised individuals have an assortment of deficiencies in host defense working together. An organ transplant recipient may be intubated, have multiple intravenous lines, be diabetic, and be on corticosteroids and tacrolimus. All these factors contribute to the overall degree of immunity, each paving the way for its peculiar array of susceptibilities to pulmonary infection. In solid-organ transplant recipients, specific causes of pulmonary infection are most frequent at certain times post transplantation (Table 137-5). In a similar manner, specific causes of pulmonary infection are more frequent at different CD4 lymphocyte counts for patients with HIV infection (Table 137-6).
TABLE 137-5 Occurrence of Pulmonary Infection After Solid-Organ Transplantation Stratified by Time from Transplantation
| Time After Transplant (mo) | Organism |
|---|---|
| <1 | Nosocomial bacteria (e.g., MRSA, ESBL-producing Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii) < div class='tao-gold-member'>
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