Acute Infection in the Immunocompromised Host
Jennifer S. Daly
Robert W. Finberg
Advances in the management of neoplastic diseases, transplant immunology, and the therapy of autoimmune diseases have resulted in marked improvements in life expectancy and the quality of patients’ lives. However, patients with autoimmune diseases, neoplasia, or transplants become highly susceptible to infection by virtue of their associated therapies or by the nature of their underlying illness. Infection has been and remains a leading cause of death in patients with leukemia and lymphoma and a major cause of morbidity and mortality in patients with solid tumors or transplants [1,2,3,4]. Rapid progression of fungal, bacterial, and mycobacterial infections occurs in patients given monoclonal antibodies to treat Crohn’s disease and autoimmune diseases such as rheumatoid arthritis [5,6,7,8]. The epidemic of human immunodeficiency virus (HIV)-1 infection has added to the numbers of immunocompromised hosts by virtue of the central event of the virus’s pathogenesis—a progressive, irreversible weakening of cell-mediated immunity unless the patient responds to antiretroviral agents. See Chapter 85.
Traditionally, infection has accounted for up to 75% of deaths in patients with acute leukemia or Hodgkin’s disease [1,9] or in transplant recipients [4,10], but with advances in prophylaxis and management, deaths due to infections have decreased to about 50% while deaths due to graft versus host disease, relapse of malignancy, and multiorgan failure have increased [3,11,12,13]. Once patients require the care of an intensive care unit (ICU), the mortality increases, and the 1-year survival of cancer patients that require mechanical ventilation in the ICU is below 11% in some centers [14] with acute mortality between 44% and 74% [15,16,17]. While intensive efforts are clearly beneficial in stem cell transplant patients requiring ICU care in the pre-engraftment period, patients with graft versus host disease following engraftment have the worst prognosis [14]. Early ICU admission has been advocated based on one small study demonstrating that among patients initially thought to be too sick to benefit from ICU care, many were subsequently admitted to the ICU, and did well [18].
Although a great variety of microorganisms have been noted to cause severe, life-threatening infections in immunocompromised hosts, the clinician can formulate a diagnostic plan and decide on empiric therapy by giving careful consideration to the nature, duration, and severity of the immunosuppression that is causing the patient’s predisposition to infection. Infection can arise as a consequence of derangements in host defenses that result from the primary disease, the medical and surgical treatment of the condition, or a combination of these factors. Additionally, immunocompromised patients are likely to manifest their infections in ways that are characteristically different from those of patients with intact immune responses.
Immune Defects and Associated Organisms and Infections
Underlying disease or treatments affect different aspects of the immune system and, depending on the type of defect, are associated with predisposition to infection with specific classes of organisms or disease syndromes. A level of suspicion of infection with certain organisms depends on the specific immune defect, the duration of immunosuppression, surgical and medical interventions, colonization with nosocomial pathogens, and previous latent or asymptomatic infections that may reactivate after immunosuppression. In general, the most common sites of serious, definable infection in the immunocompromised host are the bloodstream [including infection related to intravenous (IV) access devices], lung, and mucocutaneous surfaces (including oral, gastrointestinal, skin, and perirectal areas). The diverse organisms frequently or uniquely associated with infections in the compromised host are listed in Table 84.1. As a general rule, patients whose underlying disease or treatment leads to a lack of T cells or any abnormality in T cell-macrophage activation will be subject to infections with organisms that live intracellularly such as viruses, fungi, and intracellular bacteria (e.g., Listeria, Legionella, mycobacteria). Patients with profound neutropenia will be subject to infection with aerobic Gram-positive and Gram-negative bacteria that live on the skin and within the gut. Patients lacking antibodies or a spleen will be unusually susceptible to infection with encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis). As for any patient in the ICU, the immunocompromised patient is susceptible to infection with bacteria that are found in ventilators or spread in the ICU. The most common organisms found in patients with bloodstream infections vary by center and whether or not patients are on prophylactic antimicrobials [19]. Escherichia coli and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), continue to be common, followed by coagulase-negative staphylococci, enterococci including vancomycin-resistant enterococci, Pseudomonas aeruginosa, Klebsiella spp, Enterobacter spp, and various streptococci [20,21,22,23]. In patients with neutropenia and documented bacteremia, Gram-positive organisms predominate over Gram-negative bacilli in patients in most centers, and the presence of an intravascular device is associated with having a positive blood culture [24]. Fungal infections increase in frequency with increasing duration of the immunocompromised state and therapy with broad-spectrum antibiotics.
Anatomic Barriers
The skin and mucosal surfaces serve a primary role in the defense of the host against invasion by endogenous and exogenous microorganisms. Mucous membrane ulceration in the mouth and gastrointestinal tract can occur spontaneously in patients with acute leukemia, although this complication more commonly arises after chemotherapy. In patients with solid tumors, disruption of mucocutaneous barriers can result from invasion, obstruction, or perforation by the malignancy. Iatrogenic disruption of the normal skin and mucosal barriers results from medical and surgical support interventions common to the ICU, including intravascular and urinary catheters [25]
(see Chapter 81 on catheter infections). Organisms that most frequently cause infection of intravascular catheters include coagulase-negative staphylococci, S. aureus, enterococci, Corynebacterium spp (including C. jeikeium), and Candida spp [1,25,26]. Percutaneously inserted central catheters (PICC) are associated with an increased risk of both infection and thrombosis [27]. The risk of these infections can be reduced, although not eliminated, through the use of permanent, subcutaneously tunneled catheters (e.g., Hickman, Broviac, Groshong, or Portacath systems) [28]. Genitourinary tract infections are associated with disruption of the urinary tract integrity, as occurs with urinary catheter drainage, pelvic tumors, or radiation with resultant ureteral obstruction, or after renal transplant.
(see Chapter 81 on catheter infections). Organisms that most frequently cause infection of intravascular catheters include coagulase-negative staphylococci, S. aureus, enterococci, Corynebacterium spp (including C. jeikeium), and Candida spp [1,25,26]. Percutaneously inserted central catheters (PICC) are associated with an increased risk of both infection and thrombosis [27]. The risk of these infections can be reduced, although not eliminated, through the use of permanent, subcutaneously tunneled catheters (e.g., Hickman, Broviac, Groshong, or Portacath systems) [28]. Genitourinary tract infections are associated with disruption of the urinary tract integrity, as occurs with urinary catheter drainage, pelvic tumors, or radiation with resultant ureteral obstruction, or after renal transplant.
Table 84.1 Organisms Commonly or Uniquely Associated with Acute Infection in the Immunocompromised Host | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The gastrointestinal tract is a source of occult bacteremia or fungemia, as chemotherapy and neutropenia cause breakdown in normal mucosal defenses of the gut, facilitating entry of bacteria or yeast into the bloodstream. Clinically apparent intestinal problems seen in neutropenic patients include typhlitis, anorectal cellulitis/fasciitis/abscess, necrotizing colitis, and Clostridium difficile-associated colitis caused by chemotherapy or antibiotics [29]. Typhlitis, an inflammatory disease of the cecum, may lead to toxic megacolon and perforation and requires a high index of suspicion and prompt diagnosis. Unusually severe and prolonged viral gastroenteritis caused by cytomegalovirus (CMV), adenovirus, rotavirus, and Coxsackie virus has been observed in marrow transplant recipients [30,31,32]. Herpes simplex virus (HSV) should be suspected as a possible cause for any lesion of mucous membranes in an immunocompromised host, and may also cause fatal hepatitis [33]. Adenovirus may cause hepatitis, pneumonitis, or hemorrhagic cystitis [32], and BK and JC viruses may cause persistent fever and renal insufficiency [34,35]. Necrotizing gingivostomatitis caused by oral anaerobes as well as severe periodontal infection may also complicate neutropenia.
Defective Phagocytosis
Neutrophils and macrophages provide defense against infection by bacteria and many fungi. Patients with leukemia, particularly an acute type of leukemia, commonly have a reduction in their absolute number of circulating neutrophils; qualitative defects of neutrophil function have also been described in these patients. Aplastic anemia, as well as extensive bone marrow involvement caused by lymphoma or metastatic solid tumors, may result in neutropenia. By far the most common cause of neutropenia, however, is cytotoxic chemotherapy. Patients whose neutrophils are reduced in number by malignancy or chemotherapy are at risk for development of spontaneous bacteremia. The risk becomes significant at absolute neutrophil counts that are persistently below 500 per mm3 (or below 1,000 per mm3 and falling) and increases dramatically at counts below 100 per mm3 [32,36].
Invasive and disseminated fungal infections also may be a consequence of neutropenia and become more common after the neutropenic patient has received broad-spectrum antibiotic therapy [32,37]. Candida and Aspergillus spp are the most common fungal pathogens observed in neutropenic hosts, but unusual genera such as Fusarium, Trichosporon, Scedosporium (Pseudallescheria), and Cunninghamella have been described with increasing frequency [38,39]
Altered Humoral Immunity
B-cell lymphocytic function and antibody production may be impaired in untreated patients with chronic lymphocytic leukemia, multiple myeloma, and lymphoma. Acquired deficits in antibody production may also be encountered in otherwise healthy patients (e.g., immunoglobulin A deficiency, common variable immunodeficiency). Hypogammaglobulinemia or impaired antibody response predisposes patients to infections attributable to encapsulated bacteria such as S. pneumoniae, H. influenzae, and N. meningitidis; moreover, these infections are likely to be sudden, severe, and associated with fulminant bacteremia [32]. Infections caused by enteric Gram-negative bacilli and P. aeruginosa also may be seen in previously untreated patients with defective humoral immunity secondary to B-cell malignancies.
Impaired Cell-Mediated Immunity
T cell-mediated immunity includes cytotoxic (killer) T cells, activated macrophages, and antibody-dependent cellular cytotoxicity. These critical components of immunity are impaired in patients with Hodgkin’s disease [40] and other lymphomas and in those taking antirejection drugs (e.g., cyclosporine, mycophenolate mofetil, tacrolimus, sirolimus, and antilymphocyte antibodies), antibodies against tumor necrosis factor-α, or corticosteroids [4,6,8,41]. Patients infected with HIV-1 experience a progressive and devastating loss of T cell-mediated immunity. This virus selectively infects and lyses CD4+ lymphocytes that play a central role in governing humeral and cellular immune responses. Defects in cell-mediated immunity are commonly associated with primary or reactivation of infection by herpes viruses (varicella-zoster virus, CMV, HSV), protozoa (Toxoplasma gondii and Cryptosporidium spp), fungi (Pneumocystis jiroveci, Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, and Candida spp), helminths (Strongyloides stercoralis), mycobacteria (M. tuberculosis, M. avium-intracellulare, M. kansasii, M. chelonae), and other intracellular bacteria (Listeria monocytogenes, Salmonella, and Legionella spp) [4,40,42].
Immunosuppressive Medications
Cytotoxic chemotherapy, corticosteroids, anticytokine antibodies, and other immunosuppressive therapeutic regimens can alter host defenses in several ways. Immunosuppressive effects depend on the class of drug, dose and duration of therapy, and timing relative to other therapeutic modalities (e.g., radiation, which may contribute to neutropenia). Several new inhibitors of cytokines and cytokine activation (including anti-TNF and anti-IL-1 antibodies) used to treat autoimmune disorders have resulted in the reactivation of latent tuberculosis and histoplasmosis as well as invasive aspergillosis [6,43,44]. Physicians need to be aware of the fact that patients on such agents have a risk of reactivation of intracellular organisms.
Antimicrobial Therapy
Antibiotic therapy is highly effective in the management of documented infections and febrile episodes in the compromised host. These agents are double-edged swords, however, and promote a shift toward increasing frequency of infections caused by progressively more resistant organisms, including P. aeruginosa, Enterobacter spp, expanded spectrum β-lactamase producing Klebsiella spp, multiply resistant enterococci, methicillin-resistant S. aureus, and fluconazole-resistant Candida spp. Unusual, intrinsically resistant bacteria (e.g., Capnocytophaga and Corynebacterium spp) and fungi (e.g., Scedosporium and Fusarium spp) are being seen with increasing frequency in oncology centers.
Splenectomy
Splenectomy, which results in the loss of the reticuloendothelial capacity to clear organisms from the bloodstream, predisposes patients to fulminant, overwhelming bacteremia caused by encapsulated bacteria (S. pneumoniae, H. influenzae, and N. meningitidis) as well as S. aureus. Although the syndrome of overwhelming postsplenectomy infection is most common in patients whose splenectomy was for malignancy or reticuloendothelial disease, overwhelming postsplenectomy infection can occur in any splenectomized patient regardless of underlying disease or interval since surgery (see Chapter 3). Accordingly, fever higher than 38°C in the splenectomized patient warrants immediate investigation and empiric therapy for possible bacteremia or focal bacterial infection. Consideration of ICU admission and presumptive antibiotic therapy is appropriate if the patient appears systemically toxic. A third-generation cephalosporin (e.g., ceftriaxone or cefotaxime) is reasonable empiric therapy, although if skin or skin structure infection is present, vancomycin should be added because of the increasing likelihood of community-acquired methicillin-resistant S. aureus.
Diagnostic Approach to Fever
In the evaluation of acutely ill, immunocompromised patients with fever in the ICU, a meticulous and thorough history and physical examination must be performed initially and repeated daily. Particular attention should be directed to sites of high risk, such as the oropharynx, anorectal region, lungs, skin, optic fundi, and vascular catheter sites [32,45]. Patients with focal abnormalities such as solid tumors, organ transplants, or recent surgery need to have these specific sites investigated with special care. Patients with neutropenia and infection exhibit fewer and less striking physical findings of infection (e.g., local warmth, swelling, adenopathy, exudate, or fluctuance) than are ordinarily encountered in immunocompetent individuals (see Chapter 76).
Initial laboratory studies that should be performed in the evaluation of the acutely ill, febrile, compromised host include (a) cultures of blood; (b) cultures of urine if symptoms or abnormal urinalysis; (c) routine sputum culture if the patient has symptoms or signs of pulmonary disease; (d) swab, aspiration, or biopsy of suspect skin, mucous membrane, or other lesions for smears, cultures, and pathologic examination; (e) semiquantitative culture of IV catheters in place when fever develops, if possible (if the cannula is a critical lifeline or a subcutaneously tunneled device that shows no local signs of infection, removal can be deferred pending results of routine blood cultures); (f) chest radiography; and (g) serum chemistries (i.e., electrolytes, liver chemistries, creatinine), in part to detect possible visceral involvement or multiorgan failure caused by disseminated infection and also to serve as baselines for monitoring possible adverse reactions to subsequent antimicrobial therapy.
Patients with defects in cell-mediated immunity (e.g., HIV-1 infection, lymphoma, transplant recipients) often harbor organisms that are best diagnosed by histological examination (e.g., Pneumocystis jiroveci, T. gondii) or special culture techniques (e.g., mycobacteria, viruses). In instances in which such organisms are high in the differential diagnosis, initial evaluation often entails immediate biopsy of the pathologic process. Localizing symptoms and signs may indicate the need for other studies, such as computed tomography (CT), magnetic resonance imaging (MRI), or nuclear medicine scans [e.g., gallium-67 scan to detect P. jiroveci pneumonia (PCP)]. Tachypnea warrants arterial blood gas studies because progressive hypoxemia in the absence of radiographic findings can be an early indicator of pulmonary infection, especially PCP, and may indicate a need for bronchoscopy. Depending on the nature of the abnormality and the state of immunosuppression, consider lung biopsy and/or quantitative culture of washings or protected brushings obtained through the bronchoscope if patient presents with pulmonary symptoms and a new finding on chest X-ray [46,47].
Approach to Specific Infectious Disease Presentations
Acute Fever without Obvious Source: Neutropenia
In patients with fever and neutropenia, shock may be an early complication of bacteremia. Consequently, even though the wide use of antibiotic prophylaxis during episodes of neutropenia has decreased the incidence of documented infection in febrile neutropenic patients to only 20% to 30% [48,49], multiple randomized trials and consensus guidelines support the initiation of empiric broad-spectrum antibiotic therapy for all patients with fever greater than 38°C and absolute neutrophil counts less than 500 per μL (or less than 1,000 per μL and falling) [36,37,45,50]. The immediate institution of such therapy in these patients (even in the absence of documentation of bacterial infection) dramatically reduces morbidity and mortality. The most rapidly fatal infectious agents that are documented to cause acute fever in the critically ill neutropenic cancer patient are enteric Gram-negative bacilli (e.g., E. coli, Klebsiella spp, Proteus spp), P. aeruginosa, and S. aureus [36,37]. In the patient without an obvious site of infection, initial empiric antibiotic therapy should be directed against these pathogens (Table 84.2). Such therapy should take into consideration idiosyncrasies of the antimicrobial susceptibility patterns of organisms in the institutions where the patient has resided in the months before infection and recent antibiotic use in a particular patient.
Related posts:
Full access? Get Clinical Tree
