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

image Major Manifestations of Infection in Immunocompromised Patients

The organism causing infection in an individual immunocompromised patient sometimes can be inferred by the specific host defect in immunologic defense or the specific clinical manifestation. In most circumstances, the differential diagnosis is too broad, however, for definitive clinical diagnosis.

Pulmonary Infection

Pneumonia is a significant cause of morbidity and mortality in immunocompromised patients. In contrast to the normal host, the impaired responsiveness of the immune system means that the disease presents in unusual ways, which may lead to challenges in establishing a diagnosis.

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

1-6

>6

CMV, cytomegalovirus; ESBL, extended-spectrum β-lactamase; HSV, herpes simplex virus; MRSA, methicillin-resistant Staphylococcus aureus; RSV, respiratory syncytial virus; VZV, varicella-zoster virus.

* These organisms should be considered when immune-suppression is still substantial.

These organisms are less likely in patients on prophylactic cotrimoxazole.

These viruses are less likely in patients on prophylactic ganciclovir or valganciclovir.

A normal chest radiograph does not rule out pulmonary infection in immunocompromised patients. Additionally, although some diseases have suggestive radiologic findings (e.g., apical cavitations in tuberculosis), most radiographic findings have to be interpreted in the light of all other data available. Frequently, computed tomography (CT) is required (e.g., evaluation of pulmonary nodules). Pulmonary nodules have a broad differential diagnosis in immunocompromised patients, including infections due to fungi (especially Cryptococcus neoformans, Coccidioides immitis, and Aspergillus fumigatus), Nocardia, mycobacteria, Rhodococcus equi, and Bartonella. Additionally, carcinomas and posttransplant lymphoproliferative disorders may present with pulmonary nodules. The differential diagnosis of cavitary lesions includes mycobacteria, invasive pulmonary aspergillosis, legionellosis, and infection with R. equi. As noted earlier, the broad differential diagnosis of pulmonary infection in immunocompromised patients mandates early and aggressive diagnostic strategies such as bronchoscopy with bronchoalveolar lavage sent for a comprehensive battery of microbiologic investigations.

Central Nervous System Infections

Most infectious agents reach the CNS via hematogenous dissemination from an extraneural site. Exceptions include retrograde propagation of infected thrombi within emissary veins, spread along olfactory nerves, and spread from a contiguous focus of infection. The blood-brain barrier presents a natural and efficient barrier to hematogenous infection. The function of the blood-brain barrier in immunocompromised patients has not been well studied. It is well known, however, that when CNS infection is established, immune defenses (even in immunologically competent hosts) are inadequate to control the infection. Local opsonization is deficient within the brain. In animal models of bacterial brain abscess, corticosteroid administration led to a reduction in macrophage and glial response, with an increased number of viable bacteria in the abscess.25

Bacterial meningitis due to N. meningitidis is relatively uncommon in immunocompromised patients, except if they have undergone splenectomy. In contrast, pneumococcal meningitis seems to occur with increased frequency in patients who have undergone stem cell transplantation2628 and in patients with HIV infection.29,30 Meningitis due to Listeria monocytogenes is classically associated with immunocompromise, reflecting the need for adequate T-cell function and IFN-γ production to kill this intercellular pathogen.31 In addition to meningitis, Listeria infection may be associated with brain abscess, particularly that occurring in the brainstem.32,33 Enteric bacteria (e.g., Escherichia coli) are rare causes of bacterial meningitis in immunocompromised patients. A classic association exists, however, between meningitis with such organisms and disseminated infection with Strongyloides stercoralis.34,35 In the presence of immunosuppression (e.g., large doses of corticosteroids), Strongyloides can migrate from the gastrointestinal (GI) tract to the CNS, carrying enteric bacterial flora into the CNS. Mortality is high without prompt recognition and treatment. Nocardia and mycobacteria must also be considered in the differential diagnosis of CNS infections in immunocompromised patients; diagnostic samples should be sent for inoculation onto appropriate media for isolation of these organisms.3638

Fungal infection of the CNS may cause meningitis or space-occupying lesions. Cryptococcal meningitis is associated with advanced HIV infection (CD4 lymphocyte count < 100/mm3) but also can occur in transplanted patients.39 The presentation is usually subacute, although dangerous elevations in intracranial pressure sometimes are observed. Space-occupying lesions in the brain may occur with disseminated mold infections. These infections usually arise in the lung, but dissemination to the brain is part of multiorgan spread. Mortality is extremely high. Any of the pathogenic molds40,41 such as Aspergillus,2 zygomycetes,42,43 Scedosporium,44 or Fusarium45 can undergo dissemination to the brain. The dimorphic fungi (e.g., Histoplasma, Coccidioides) also may disseminate from the lung, causing infection of the CNS. Zygomycetes also may be associated with frequently fatal infection arising within the nose or sinuses (rhinocerebral mucormycosis).42,43

The most common protozoal pathogen to affect the CNS is Toxoplasma gondii. The classic association is between T. gondii infection and advanced HIV infection, although cases have been reported associated with other forms of immunocompromise.4648 Amebic encephalitis has been reported occasionally in conjunction with advanced HIV infection or organ transplantation.49

A variety of viruses can cause CNS infections in immunocompromised patients. Perhaps as a result of the widespread use of antiherpesvirus prophylaxis in many immunocompromised populations, herpes simplex virus (HSV) encephalitis is rare.50 Some of the newer herpesviruses, such as human herpesvirus-6 (HHV-6), have been associated with neurologic infection in transplant recipients.5153 Lack of diagnostic capabilities for these viruses may partially explain their apparent infrequency. CMV meningoencephalitis is well described in patients with advanced HIV infection54 and occasionally has been reported in transplant recipients.55 Disseminated infection with varicella-zoster virus (VZV) in immunocompromised patients also may result in CNS infection. West Nile virus may be acquired from transplanted organs or blood transfusions and is associated with a significant meningoencephalitis in transplant recipients.56,57 Table 137-7 summarizes agents capable of causing CNS infections in an immunocompromised host.

TABLE 137-7 Central Nervous System Infections in the Immunocompromised Host

Etiologic Agent Special Considerations
Meningitis
Streptococcus pneumoniae Especially in HIV-infected individuals
Listeria monocytogenes Predilection for brainstem
Enteric bacteria Associated with disseminated Strongyloides infection
Cryptococcus neoformans Rapid diagnosis by cryptococcal antigen or India ink stain
Mycobacterium tuberculosis Consider PCR for rapid diagnosis
Meningoencephalitis
HSV Rare in immunocompromised patients
HHV-6 May be associated with lack of CSF pleocytosis
VZV Skin lesions yield diagnosis
West Nile virus Transmitted via transplanted organ or blood
Space-Occupying Lesions
Nocardia Pulmonary lesions usually also present
Toxoplasma gondii Especially in HIV-infected individuals
Fungi Pulmonary lesions usually also present

CSF, cerebrospinal fluid; HHV-6, human herpesvirus-6; HIV, human immunodeficiency virus; HSV, herpes simplex virus; PCR, polymerase chain reaction; VZV, varicella-zoster virus.

The wide variety of organisms that could be responsible for CNS infection presents a need for a broadly based diagnostic workup before empirical therapy is begun. If cerebrospinal fluid (CSF) is collected, it should be sent for Gram stain and Ziehl-Neelsen stain for rapid diagnosis of bacterial and mycobacterial infections. PCR can be applied to the diagnosis of most viral infections such as HSV, CMV, and VZV. Cryptococcal antigens can be detected rapidly in CSF, enabling a rapid diagnosis of this form of meningitis, but for patients with space-occupying lesions of the brain, collection of CSF may not be possible. Aspiration may be performed in some circumstances. Before invasive diagnostic testing of the brain is performed, however, the patient’s skin is examined for lesions (such as may occur with cryptococcosis or nocardiosis), and the lungs are carefully reviewed by CT. Because most CNS lesions arise from infection in other parts of the body, a diagnosis may often be made more easily by microbiological sampling of these body sites.

Gastrointestinal Infections

Severe GI infections in immunocompromised patients may occasionally warrant ICU admission because of dehydration or visceral perforation. As with respiratory and CNS infections, the differential diagnosis is usually broad, and a precise diagnosis rarely can be made based on clinical suspicion only. Immunocompromised patients have an increased predisposition to GI infections, depending on the type and degree of immunocompromise and exposure to certain pathogens.

The most commonly involved organisms in the etiology of infective esophagitis or gastritis are Candida, CMV, and HSV, although a variety of other organisms (e.g., mycobacteria, zygomycetes) occasionally are implicated. Candidal esophagitis is a common opportunistic infection in patients with AIDS. Rates of about 13.3 events of candidal esophagitis per 100 person-years occur in HIV-infected patients with CD4 counts less than 300/mm3.58 A study of renal transplant patients in the United States showed that esophageal candidiasis is the most common fungal infection in these patients, making up 22% of all fungal infections.59 Other predisposing factors for severe esophageal candidiasis include broad-spectrum antibiotic therapy, steroid therapy, cancer chemotherapy, diabetes mellitus, cutaneous burns, radiotherapy, and hematologic stem cell transplant. Although Candida albicans is the most frequently diagnosed organism, there is an increase of other species, including Candida krusei and Candida glabrata—this is notable because of the increase in resistance to fluconazole in these species. Finally, as noted previously, patients with immunocompromise may have a combination of pathogens causing infection at any one time. Upper GI endoscopy with biopsy is the gold standard for making the diagnosis.

Diarrhea is a common problem in immunocompromised patients with multifactorial etiologies. It may lead to diagnosis of immunosuppression in a previously undiagnosed patient when an opportunistic pathogen is found and appropriately investigated. Severe complications such as malabsorption leading to malnutrition, dehydration, and wasting can occur. Occasionally, intestinal perforation may result from GI infection. In an immunosuppressed patient, it is important to differentiate diarrhea due to opportunistic infections from diarrhea due to neoplasms, GVHD, drugs, and other therapeutic agents. GVHD accounts for more diarrhea in blood and bone marrow transplant patients than infective organisms.60 In these patients, organisms that cause mild self-limiting disease in the normal host may cause severe and life-threatening infections.60

Prolonged use of multiple antibiotics in high doses predisposes patients to colonization with Clostridium difficile and development of pseudomembranous colitis. Antibiotic prophylaxis to prevent P. jirovecii pneumonia or spontaneous bacterial peritonitis has been associated with C. difficile. In addition to the classic antibiotic risk factors of clindamycin or cephalosporin use, fluoroquinolones may predispose to epidemic strains of C. difficile (BI/NAP1/027 strain).61 Enteric bacterial pathogens such as Salmonella occur at increased frequency in immunocompromised patients, especially HIV-infected individuals. In some regions of Africa, nontyphoidal Salmonella infections are among the most common causes of bacteremia.62 Severe Salmonella infections may be associated with intestinal perforation. Shigella, Campylobacter jejuni, E. coli (enterotoxigenic, enteroadherent, and enteroaggregative), and Yersinia species are other bacterial causes of diarrhea, although less commonly associated with bacteremia.

Protozoal infections are seen more commonly in HIV-infected patients than other immunocompromised groups. At CD4 counts less than 200 cells/mm3, patients with HIV infection may present with unusual protozoa (e.g., Cryptosporidium and Microsporidium). Occasionally these pathogens are also seen in transplant recipients.63,64 Such pathogens are not detected on routine microscopic examination for ova, cysts, and parasites. Special stains and microbiological techniques are needed. Routine examination usually detects Giardia lamblia, Entamoeba histolytica, and other more common pathogenic protozoa.

CMV can cause significant colitis in all immunocompromised populations. CMV colitis may occur in the absence of systemic evidence of infection (i.e., PCR on peripheral blood may be negative65,66). Intestinal biopsy may be required to make the diagnosis. CMV intestinal infection may present with diarrhea but may have more profound presentations such as intestinal perforation.67,68

Finally, mycobacterial infections such as tuberculosis occasionally can be associated with colitis.69 M. avium complex can be grown readily from the feces of patients with HIV infection and CD4 counts of less than 50/mm3, but it is not always the cause of diarrhea in such patients.

image Therapeutic Difficulties in Immunocompromised Patients

Empirical Therapy

The choice of empirical antimicrobial therapy is often difficult in immunocompromised patients because of the broad differential diagnosis involved. As emphasized earlier, management of infection in an immunocompromised patient can be simplified by narrowing the differential diagnosis by thorough history taking, review of prior medical records, and careful physical examination. Aggressive early diagnostic maneuvers before beginning empirical antimicrobial therapy can enable a definitive diagnosis to be made. Failure to collect specimens before beginning empirical therapy can lead to prolonged, expensive, and unnecessary therapy.

Empirical antibiotic therapy in suspected bacterial infections should be tailored to the individual patient to maximize the chance that the therapy is microbiologically adequate. There is a clear link between microbiologically adequate empirical therapy and successful outcome from infections in the ICU.70 In settings such as severe pneumonia in the immunocompromised patient, empirical regimens comprising vancomycin, ciprofloxacin, meropenem, amphotericin (or voriconazole), ganciclovir, and trimethoprim/sulfamethoxazole may be necessary to cover potentially lethal infection with methicillin-resistant Staphylococcus aureus, P. aeruginosa, Legionella, fungi, CMV, and P. jirovecii. There is no established role for combination empirical therapy with antifungal agents. The decision to start empirical mycobacterial therapy is never an easy one. In general, we only advise it when there is a risk factor for tuberculosis. Empirical therapy for disseminated Strongyloides infection may have a place in immunocompromised patients coming from an endemic area and with the classic presentation of disseminated infection.

Immunocompromised patients presenting with acute meningitis should receive treatment that covers S. pneumoniae and L. monocytogenes. The combination of vancomycin, ampicillin, and ceftriaxone may be necessary (vancomycin and ceftriaxone for multidrug-resistant S. pneumoniae and ampicillin for Listeria). The combination of amphotericin and 5-flucytosine is recommended empirically for meningitis in which antigen testing or India ink stain of CSF reveals encapsulated fungi consistent with C. neoformans. Immunocompromised patients with space-occupying lesions of the brain can be treated empirically with an antifungal drug (amphotericin or voriconazole) if suspicion of disseminated fungal infection is high, although nocardiosis, toxoplasmosis, or mycobacterial infection would not be covered without specific therapy.

For immunocompromised patients with severe diarrhea requiring ICU admission, empirical treatment with metronidazole or oral vancomycin (for C. difficile) and ganciclovir (for CMV) may be given after fecal samples have been collected. Colonic biopsy may be necessary if it can be safely performed. For immunocompromised patients with intestinal perforation, antibiotic coverage against gut flora (i.e., treatment of peritonitis) plus treatment of the most likely causes of perforation (e.g., ganciclovir for CMV) may be chosen.

Pathogen-Directed Therapy

The importance of appropriate specimen collection is that empirical therapy can be streamlined (de-escalated) if cultures or other diagnostic tests are positive. With immunocompromised patients, antimicrobial therapy often is complicated by drug interactions or adverse reactions. Transplant recipients taking calcineurin inhibitors (e.g., cyclosporine or tacrolimus) or HIV-infected patients taking protease inhibitors are most at risk because these drugs may be metabolized by the cytochrome P450 system.71,72 Significant interactions may occur between rifampin, macrolide antibiotics, azole antifungal drugs, and the calcineurin inhibitors.72 Aggressive treatment of infections in immunocompromised hosts (e.g., with amphotericin, pentamidine, or foscarnet) may be associated with renal dysfunction, compounding the nephrotoxic effects of the calcineurin inhibitors. Antimicrobial agents such as linezolid or ganciclovir frequently cause neutropenia, potentially adding further host defense defects.

image Conclusion

Infection is likely to be one of the most significant problems an immunocompromised patient faces. These patients may present with severe infection or acquire infection while critically ill for other reasons. Prevention of infection in the ICU is of primary importance. Pneumonia can be readily prevented by many strategies. Ventilator-associated pneumonia may be prevented by a bundle of interventions.73 Aspiration of subglottic secretions and selective digestive tract decontamination, while supported by some trials, are still controversial. Opportunistic pneumonia with P. jirovecii can be prevented by use of prophylaxis with trimethoprim/sulfamethoxazole, dapsone, or nebulized pentamidine. Environmental exposure to Legionella and Aspergillus spp. can be prevented by ensuring water purification techniques (e.g., copper-silver ionization) and by preventing exposure of patients to construction activity. Infections due to pathogens transmitted human to human, such as M. tuberculosis, can be prevented by isolation precautions.

Many extrapulmonary infections can also be prevented. CMV infection can be prevented by universal prophylaxis with ganciclovir, valganciclovir, valacyclovir, or a preemptive approach using serial PCR of peripheral blood.74,75 A similar preemptive approach may be useful in preventing aspergillosis by monitoring peripheral blood for the galactomannan antigen, although this remains controversial.76,77 C. difficile infection is difficult to prevent because there is a clear need for antibiotic therapy for immunocompromised patients with infection. The increasing incidence, severity, and high rate of recurrence of C. difficile infection has become a significant problem.78 A recent randomized controlled study demonstrated that the addition of monoclonal antibodies against C. difficile toxins to antibiotic agents significantly reduced the recurrence of C. difficile infection, even among patients with the epidemic BI/NAP1/027 strain.79 Finally, attention to classic infection control practices such as appropriate immunizations,8082 hand hygiene, and contact isolation is paramount in immunocompromised patients.

Annotated References

Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007;357:2601-2614.

This review article is suitable to comprehensively understand management of infections associated with solid-organ transplantation. It describes clinical problems related to the use of solid-organ transplants, potential drug interactions with medications commonly used in the ICU, and controversies surrounding the use of antiretroviral therapy in the ICU.

Huang L, Quartin A, Jones D, Havlir DV. Intensive care of patients with HIV infection. N Engl J Med. 2006;355:173-181.

Antiretroviral therapy has changed the long-term prognosis and clinical spectrum of diseases in patients with HIV infection who are admitted to the ICU.

Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor-α neutralizing agent. N Engl J Med. 2001;345:1098-1104.

Although patients with rheumatoid arthritis may become immunocompromised by way of therapy with corticosteroids or methotrexate, the development of anticytokine agents for this condition has opened the way for a new range of opportunistic infections in this patient population. This study showed that tuberculosis occurs with increased frequency in patients receiving infliximab.

Kotton CN, Kumar D, Caliendo AM, et al. International consensus guidelines on the management of CMV in solid organ transplantation. Transplantation. 2010;89:779-795.

CMV is one of the most common infections after solid-organ transplantation, resulting in significant morbidity and mortality. However, management of CMV varies considerably among transplant centers. This evidence and expert opinion-based guidelines include topics on diagnostics, immunology, prevention, treatment, resistance, and pediatrics.

Kowalski R, Post D, Schneider MC, et al. Immune cell function testing: an adjunct to therapeutic drug monitoring in transplant patient management. Clin Transplant. 2003;17:77-88.

The degree of immunocompromise and the subsequent risk of infection in transplant recipients have been difficult to quantify. This study examined the utility of an in vitro immune cell function assay as a means of quantifying global immune response in transplant recipients.

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