Critically Ill Immunosuppressed Host
This chapter emphasizes the important ways in which immunosuppressed patients differ from immunologically normal individuals in terms of infectious complications. The noninfectious complications of immunosuppression are reviewed in Chapter 80.
Host Defense Mechanisms
The microbial complications that any patient develops in the ICU are determined by general, nonspecific barriers; innate immunity; acquired specific immunity; and environmental exposures. Nonspecific barriers include anatomic barriers such as intact skin and mucous membranes; chemical barriers, such as gastric acidity or urine pH; and flushing mechanisms, such as urinary flow or mucociliary transport in the lungs. Organisms that breach these barriers encounter nonspecific and innate host factors termed the acute phase response. Acute phase responses trigger a cascade of acquired specific immune responses including mononuclear phagocytes and antibodies, which also trigger a cascade of effector molecules and nonspecific inflammatory responses.1
Infections result from normal flora that colonize mucosal or cutaneous surfaces or from abnormal flora that are introduced by surface-to-surface contact, inhalation, ingestion, trauma, or medical procedures. Table 53.1 lists organisms that cause disease when specific anatomic defenses are disrupted in individuals with normal microbial flora. Patients with abnormal flora will develop disease that reflects unique, disease-specific characteristics of the host, the abnormal environment, and modifying factors such as drugs. Infections that result from common defects in the inflammatory or immunologic systems are detailed in Table 53.2.
Table 53.1
Normal Flora That Can Cause Disease When Anatomic Barriers Are Disrupted
Compromised Host Defense: Anatomic Disruption | Bacteria | Fungi |
Oral cavity, esophagus | α-Hemolytic streptococci, oral anaerobes | Candida species |
Lower gastrointestinal tract | Enterococci Enteric organisms Anaerobes |
Candida species |
Skin | Gram-positive bacilli Staphylococci, streptococci Corynebacterium, Bacillus species Mycobacterium fortuitum, Mycobacterium chelonei |
Candida species Aspergillus |
Urinary tract | Enterococci Enteric organisms |
Candida species |
Recognition of which host defense mechanisms are disrupted enables the clinician to focus diagnostic, therapeutic, and prophylactic management and optimize patient outcome. For instance, if a patient presents with severe hypoxemia and diffuse pulmonary infiltrates, a health care provider who recognizes a prior splenectomy as the major predisposition to infection would focus the diagnostic evaluation and the empiric therapy on Streptococcus pneumoniae and Haemophilus influenzae.2,3 By contrast, if the patient’s major predisposition to infection was human immunodeficiency virus (HIV) infection with a CD4+ T lymphocyte count below 50 cells/µL, the health care provider would focus on Pneumocystis jiroveci and S. pneumoniae.4,5 However, additional history is also necessary: if the pneumonia occurs during an influenza outbreak, after exposure to a water aerosol (Legionella), or after a seizure (aspiration), the likely cause is plausibly linked to the precipitating event.
Immune competence should ideally be measurable by objective laboratory parameters. In fact, the risk for opportunistic infection in patients with HIV infection can be assessed by clinical laboratories with a high degree of accuracy by measuring the number of circulating CD4+ T lymphocytes. The susceptibility of cancer patients to opportunistic bacterial and Candida infections can be assessed by measuring the number of circulating neutrophils (Fig. 53.1), and treatment algorithms have been established for managing fever in such patients (Figs. 53.2 to 53.4) and Table 53.3).6 The predisposition of patients with certain congenital immunodeficiencies can be assessed by measuring serum immunoglobulin levels.7 Unfortunately, however, for a large number of immunodeficiencies, such as those associated with antilymphocyte monoclonal antibodies or corticosteroids, no objective laboratory measures have been validated as predicting the risk of infection. Moreover, each parameter must be validated for each specific disease entity: for instance, although CD4+ T-cell counts are excellent predictors of opportunistic infection predisposition for patients with HIV/AIDS (acquired immunodeficiency syndrome) (Fig. 53.5), they are not clinically useful for other immunosuppressive disorders.
Table 53.3
Modification of Standard Empiric Therapy in Patients with Neutropenia
Clinical Event | Possible Modifications of Standard Empiric Therapy |
Breakthrough bacteremia | For gram-positive isolate (e.g., Staphylococcus aureus): Add vancomycin or daptomycin or linezolid until susceptibility pattern of isolate is known. For gram-negative isolate: Add two new agents likely to have activity until susceptibility pattern of pathogen is known. |
Cellulitis or catheter-associated infection | Add vancomycin or daptomycin. |
Severe necrotizing mucositis or gingivitis | Add specific antianaerobic agent (e.g., metronidazole, meropenem, imipenem, piperacillin-tazobactam) plus agent with activity against streptococci; consider acyclovir. |
Ulcerative mucositis or gingivitis | Add acyclovir and anaerobic coverage. |
Esophagitis | Add fluconazole or caspofungin; consider adding acyclovir. |
Pneumonitis, diffuse or interstitial | Add trimethoprim-sulfamethoxazole and azithromycin or levofloxacin or moxifloxacin (plus broad-spectrum antibiotics if the patient is granulocytopenic). |
Perianal tenderness | Include anaerobic agents such as metronidazole, imipenem, meropenem, or piperacillin-tazobactam. |
Abdominal involvement | Add antianaerobic agent (e.g., metronidazole, meropenem, imipenem, piperacillin-tazobactam). |
Clinical series that document the frequency, the timing, and the causative organisms associated with infectious complications are extremely valuable for managing specific populations of immunosuppressed patients. Timelines that depict the time periods of vulnerability following stem cell transplantation (Figs. 53.6 and 53.7) and solid organ transplants (Fig. 53.8) are very useful for clinicians in terms of guiding diagnostic evaluations and for guiding empiric therapy. However, a specific microbial diagnosis should be established for each syndrome that presents in an immunosuppressed patient because the range of possible pathogens is quite broad, and the timelines and laboratory parameters cannot take into account all of the individual patient variables that influence the infectious complications that develop. Although it is useful to narrow the list of likely pathogens by analyzing risk factors, identifying the true causative agents allows therapy to be focused, avoiding unnecessary toxicity and allowing specific therapy to be optimized for efficacy and safety.
General Approach to Management
1. Life-threatening complications often present with subtle symptoms and signs that can easily be overlooked.
2. Fever is not invariably present when patients are infected.
3. Patients are predisposed to deteriorate precipitously.
4. Diagnostic evaluation needs to be prompt and definitive.
5. Infections may be community acquired, nosocomial, or latent, emphasizing the need for a thorough history of the patient’s prior infections and exposures in order to assure the proper diagnostic tests and the optimal empiric therapeutic regimens.
6. Not all infections are related to the underlying disease or immunosuppression.
7. Empiric therapy should be started promptly.
Intensivists are more and more aware of the importance for all patients of “time to antibiotics,” that is, the importance of starting antibiotics sooner rather than later, and including a drug that is active against the pathogen that is ultimately shown to be the causative organism.8,9
8. Empiric therapy should be broad spectrum.
9. Antibiotic therapy should be narrowed when the causative organism is known, and monotherapy is usually adequate.
The development of potent β-lactam and quinolone drugs in the 1980s and 1990s provided single agents that appear to be as effective as combination therapy for the treatment of gram-negative bacillary infections.10–15
10. Foreign bodies and infectious foci should be assessed promptly for drainage or removal.
11. Consideration should be given to reducing the level of immunosuppression.
There is no proven survival benefit to interventions meant to augment or improve the immune or inflammatory response such as granulocyte colony-stimulating factor, neutrophil transfusions, or cytokines. It is plausible to reduce immunosuppression by reducing the dose of corticosteroid or other immunosuppressive agent if that is clinically feasible. Some institutions administer granulocyte infusions or colony-stimulating factors for patients with established infections. There is no documentation that such interventions improve survival, and deleterious effects, especially from granulocyte transfusions, can be life-threatening.16,17
12. The effectiveness and safety of antimicrobial therapy should be monitored regularly.
13. Noninfectious syndromes can masquerade as infections and can be life-threatening.
Management of Specific Patient Populations
Cancer Patients with Neutropenia
General Principles
Cytotoxic therapy–induced neutropenia is a major predisposition to infection.6 Neutrophil counts below 1000 cells/µL (the total absolute number of polymorphonuclear neutrophils plus bands) increase susceptibility to infection in a linear fashion (i.e., the lower the neutrophil count, the greater the degree of susceptibility)18 (see Fig. 53.1). Although most research studies use 500 cells/µL as an arbitrary definition of neutropenia, intensivists must recognize that susceptibility increases as the neutrophil count declines below 500 to 1000 cells/µL. A patient with a neutrophil count of 100 cells/µL is much more vulnerable to infection than a patient with 500 or 1000 cells/µL, and a patient with zero neutrophils is at much higher risk for fulminant infection than a patient with 50 or 100 cells/µL. The trajectory of the neutrophil count is also important: a patient with a neutrophil count of 1500 cells/µL whose counts are dropping precipitously should best be treated like a patient with absolute neutropenia. Similarly, a patient with 500 neutrophils/µL whose counts are rising quickly is not nearly as vulnerable to a poor outcome as a patient with a count of 500 neutrophils/µL that is stable.
Patients with neutropenia are generally divided into high-risk and low-risk patients based on their likelihood of developing severe infectious complications. Markers for high risk include neutropenia for more than 7 days’ duration and neutrophil count less than 100 cells/µL, as well as obvious signs of a life-threatening process such as hypotension, obtundation, pneumonia, or severe abdominal pain. As Figures 53.2 to 53.4 outline, this risk assessment is used in designating empiric regimens.
In the 1960s and 1970s, aerobic gram-negative bacilli such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa predominated as pathogens in neutropenic patients. In the 1990s the spectrum of causative pathogens in neutropenic patients shifted from a predominance of gram-negative bacilli to a majority of gram-positive cocci including streptococci, staphylococci (including oxacillin-resistant Staphylococcus aureus), and enterococci (including vancomycin-resistant enterococci).10,12–15,19–21 Candida species have also become more frequent as pathogens, especially as patients are on broad-spectrum antibacterials and have long-term venous access devices in place.
More recently, highly resistant gram-negative bacilli have become major threats for nosocomial transmission. Clinicians must consider the possibility that a patient may be colonized and then infected with a Stenotrophomonas, a Burkholderia, or a carbapenemase-producing gram-negative Enterobacteriaceae such as a Klebsiella, an Enterobacter, or an E. coli that has developed mechanisms that evade currently marketed drugs.22–26
The management of febrile, neutropenic fever is reviewed in a guideline that is widely used to direct care in North America.6 Figures 53.2 to 53.4 summarize important aspects of management. Table 53.3 also provides a summary of useful management information. Table 53.4 outlines common prevention strategies that will modify the spectrum of causative pathogens. Box 53.1 summarizes the organisms that most often cause disease in neutropenic patients.
Table 53.4
Prevention of Infectious Complications in Compromised Patients
Method/Agent to Prevent Acquisition of, Suppress, or Eliminate Microbial Flora | Description/Example |
Isolation | Total protective isolation with high-efficiency particulate air filters and absorbable or nonabsorbable antibiotics for bone marrow transplant recipient |
Prophylactic antibacterial drugs | |
Ciprofloxacin | Reduce bacterial infections in neutropenic patients |
Trimethoprim-sulfamethoxazole | Suppress flora in patients with chronic bronchitis |
Penicillin | Reduce frequency of streptococcal infections after splenectomy or in rheumatic valvular disease or graft-versus-host disease |
Clarithromycin | Prevention of Mycobacterium avium complex infection in patients with advanced HIV disease |
Isoniazid | Prevention of tuberculosis in PPD-positive individuals |
Nonabsorbable broad-spectrum agents (i.e., aminoglycoside, plus bacitracin) | Gut decontamination for neutropenic patients |
Prophylactic antiviral drugs | |
Oral acyclovir or valganciclovir, or IV ganciclovir | Reduce frequency of CMV disease after transplantation |
Rimantadine, oseltamivir | Prevent influenza |
Prophylactic antifungal drugs | |
Fluconazole | Prevent recurrent candidiasis |
Liposomal amphotericin B or voriconazole or caspofungin | Prevent Candida or mold infections |
Trimethoprim-sulfamethoxazole | Prevent Pneumocystis pneumonia |
Prophylactic antiprotozoal/anthelmintic drugs | |
Albendazole or ivermectin | Prevent disseminated strongyloidiasis in high-risk patients |
Augmentation of host defenses | |
Immunization | Pneumococcal and Haemophilus vaccine for patients before splenectomy |
Immune serum globulin | Augment levels in deficient patients (e.g., common variable immunodeficiency) |
Fresh frozen plasma | Augment complement levels in deficient patients |
Neutrophil transfusions | Augment inflammatory response in neutropenic patients or patients with chronic functional neutrophil disorders |
Lymphocyte or other mononuclear cell transfusions | Experimental therapies for tumors, various immunodeficiencies |
Bone marrow or stem cell transplantion | Reconstitute patients with congenital immunodeficiencies or certain acquired cytopenias |
Bone marrow human stem cell stimulation | G-CSF or GM-CSF to increase neutrophil or mononuclear cell quantity and function |
Gene therapy | Replace genes to allow normal function |
As noted earlier, the initial regimen should not be parsimonious in terms of spectrum. Because this population of patients is susceptible to a wide variety of bacterial and fungal pathogens, a very wide broad-spectrum regimen should be used. There are many potential regimens, each of which must be tailored to the local experience with the patient population and the hospital, specific patient factors such as evidence of prior colonization or recent antimicrobial therapy, and clinical manifestations suggesting infection. Popular regimens would include (1) meropenem or cefepime or piperacillin-tazobactam for broad-spectrum antibacterial activity plus (2) vancomycin or daptomycin for staphylococcal infections27,28 plus (3) ciprofloxacin or moxifloxacin or aztreonam for broader gram-negative bacillus coverage. Many experienced clinicians would add an echinocandin for anti-Candida activity given the frequency of intravascular catheter-associated infections due to Candida species.29–33 Intensivists need to work closely with their infectious disease consultants, microbiology laboratories, and referring teams to develop regimens that are optimal for their hospital environment, for the patient population involved, and for the specific, unique patient who is being managed.
As noted previously, there is no documented reason, even in this population, to use combination therapy to treat a specific pathogen in most situations, although combination therapy is needed for the empiric approach for the duration of neutropenia (Box 53.2). In rare situations, if the causative organism is not susceptible to agents with well-documented efficacy, combination therapy may be an appropriate strategy out of desperation. As an example, for treating enteric carbapenemase-producing organisms, a combination of tigecycline plus colistin plus an aminoglycoside might be desirable given the high minimum inhibitory concentrations for all antibiotics for these organisms and the dreadful clinical results with any therapeutic intervention.34–38
If a neutropenic patient is started on antibacterial therapy without fungal therapy, and defervescence has not occurred by days 3 to 5, an antifungal agent should be added (Figs. 53.3 and 53.4). The choice of antifungal agent depends on the patient population and the patient’s specific history. In the current era many patients have been receiving short- or long-term prophylaxis with fluconazole, voriconazole, or posaconazole. Although in general clinicians could add fluconazole, an echinocandin (e.g., caspofungin or micafungin or anidulofungin) or liposomal amphotericin B can also be used. An echinocandin is often a preferred choice if the patient has been on long-term azole prophylaxis and if a mold infection is not suspected.39–42
As patients receive chemoprophylaxis with quinolones or azoles during periods of intense neutropenia or immunosuppression, breakthrough pathogens are more and more likely to be resistant to the prophylactic agents.40,42 Thus empiric regimens must be chosen with keen attention to the drugs that patients have received in the recent past, as well as pathogens they have previously been colonized or infected with.
Diagnostic Approach
Some of these approaches, despite their promising initial reports, are not yet clinically practical because of their level of sensitivity, specificity, or the cost or expertise required to perform them adequately. For instance, the PCR test for Pneumocystis is so sensitive that there is no clear separation of patients who are colonized with Pneumocystis (and whose pulmonary dysfunction is due to another process), and the serum β-glucan antigen detection system is so nonspecific that some clinicians are not confidant that the test provides useful information.43–45 Similarly, the PCR test for respiratory syncytial virus (RSV) or influenza or parainfluenza is so sensitive that immunosuppressed patients may shed small quantities of virus for many weeks after acute infection, confusing the diagnosis of the new pulmonary processes that occur after the acute viral infection is over, and at a time when another process is causing fever or pulmonary manifestations. Thus, these new tests must be interpreted with caution.