Chapter 183 Compared with individuals with an intact immune system, infections in immunocompromised patients are more common, progressive, and severe, and they are caused by a wider variety of microorganisms. Immunocompromised persons who present with acute infections may appear deceptively benign initially, their symptoms and signs often mimicking noninfectious complications, only to deteriorate rapidly if they are not aggressively treated. Many interrelated factors cause patients to become immunocompromised and predispose them to the development of infections with potentially pathogenic microorganisms. These include disruption of the body’s protective surfaces, such as skin and mucosal barriers (oral and respiratory mucosa and intestinal and genitourinary surfaces); disorders that directly impair the function of the body’s immune system (e.g., lymphoma, asplenism, and myeloma); drugs and irradiation that suppress or alter immune function; alterations in body substances (hyperglycemia) or solid organ function (kidney and liver failure); and malnutrition, aging, and exposure to antimicrobial agents that inhibit the normal protective resident bacterial flora.1 The body’s defense mechanisms consist of surface barriers, such as skin, enzymes, and mucus, as well as innate (natural) and acquired (adaptive) responses. Innate responses occur to the same extent regardless of how often the body encounters the infectious agent, whereas acquired responses improve on repeated exposure.2 Innate immunity is activated immediately on exposure to an infecting agent, rapidly controlling replication and allowing the requisite 3 to 5 days for the adaptive component to clone sufficient T and B cells to respond more specifically.3–5 The first line of defense against microorganisms consists of physical barriers. These include intact skin, gastrointestinal and respiratory mucosa, cilia, biofilm, gastric acid, antibacterial substances in pancreatic and biliary secretions, antimicrobial peptides and proteins on skin and mucous membranes, and resident microflora.6 In the respiratory tract, mucociliary transport and the cough reflex remove particulate matter and microbes, but this mechanism is impaired with smoking and ineffective cough. Mechanical ventilation or tracheostomy introduces large numbers of microbes that often overwhelm natural clearance.7 The first response to microbial invasion, the initial inflammatory response (formerly called the acute-phase response), acts to promote phagocytosis and microbial killing and to activate the immune system.8 Sentry cells detect pathogens, immediately triggering inflammation. This innate immune response is not dependent on prior exposure to the pathogen. The initial inflammatory response factors, mainly produced in the liver, activate many cell types to synthesize and to release cytokines, chemokines, and “trigger molecules” that kill the invading organism.3 This response delivers humoral and cellular immune components to sites of inflammation and initiates antibody responses. Cytokines, platelet-activating factor, and hormone-like proteins, including interferons, are secreted from various immune cells and play important roles in mediation of this response.9 These cytokines result in migration and adhesion of polymorphonuclear leukocytes and monocytes to sites of bacterial invasion. These cells release granules of substances that mediate vasodilation and increased vascular permeability, leading to edema, warmth, and redness, but also allow both phagocytic cells and humoral components to be concentrated at the site of infection. A family of distinct transmembrane proteins, called Toll-like receptors, are found on many cell types, including macrophages, neutrophils, dendritic cells, mucosal epithelial cells, and endothelial cells. They recognize molecular patterns associated with microorganisms even in the absence of prior exposure, alert the host to the presence of the infectious agent and rapidly initiate a cascade of processes to activate innate immune responses, and help bridge innate and adaptive immune responses.3,6 Antibodies.: Antibodies are produced by B lymphocytes, and each B cell produces a single microbe-specific antibody type. Stimulation by an antigen (or microbe) causes proliferation of this particular B cell so that large quantities of a specific circulating antibody can be produced. Furthermore, B cells are active in presenting antigens to T lymphocytes, which promotes cell-mediated immunity. Immunoglobulins.: IgM is the first immunoglobulin to appear in response to a new antigen. Although it has less affinity at binding antigens than IgG does, IgM provides some recognition of antigens and begins B-cell proliferation before the subsequent development of IgG.10 IgM is detectable earlier in serum than IgG and serves as a marker for a patient’s early response to acute infection. Secretory IgA is the predominant immunoglobulin present in gastrointestinal fluids, nasal and oral secretions, tears, and other mucous fluids. IgA inhibits cell adherence of viral, bacterial, and protozoan pathogens and therefore prevents invasion by organisms through the respiratory or gastrointestinal tract.10 Complement.: The complement cascade, consisting of a complex interaction of 30 proteins, is another crucial component of humoral response. Complement is important in producing inflammation and leukocytosis and in recruiting leukocytes to sites of infection by production of chemoattractants. Complement also neutralizes viruses, enhances opsonization of bacteria, and produces bacterial cell wall and membrane lysis. Individuals with inherited complement deficiencies are predisposed to frequent and recurrent infections with S. pneumoniae, H. influenzae, and especially Neisseria meningitidis and Neisseria gonorrhoeae.11 The risk of meningococcal infection is increased several thousand-fold and most often develops in people deficient in C3 and in late complement components (C5-C8). Paradoxically, the disease is usually milder with complement deficiency, and mortality is likewise reduced fivefold to tenfold.12 This suggests that the host response may be, in part, responsible for the severity of disease in normal individuals and is attenuated in complement deficiency. People with meningococcemia should be tested for inherited complement deficiencies because they may benefit from immunization. Acquired deficiencies of complement function may develop in people with rheumatologic diseases, especially systemic lupus erythematosus (SLE). Approximately 40% of patients with SLE have an inhibitor of C5a-derived chemotaxis in their serum that results in enhanced susceptibility to infection.13 Only 5% of lymphocytes are in circulating blood. Most mature and are active in the marrow, thymus, spleen, and lymph nodes. The last two sites expose T cells to circulating antigen from invading microbes.6 Specialized antigen-presenting cells in the lymphoid system sequester antigen and antigen-antibody complexes and present them to T cells. This process involves internalization and processing of the antigen, followed by formation of peptides that bind to a cell surface molecule called the major histocompatibility complex (MHC). Only with this specific presentation can a T lymphocyte become activated against a particular antigen. Two major types of T lymphocytes are CD4 (helper cell) and CD8 (suppressor cell), corresponding to type II and type I of MHC, respectively. CD4 lymphocytes provide help for other cells in the immune system, including enhanced B-cell antibody production and production of cytokines. CD8 lymphocytes are generally cytotoxic and mediate the eradication of virally infected target cells and certain tumors. A decline in the number of CD4 cells, with predominance of CD8 cells, is responsible for the increased susceptibility to infection in patients with acquired immunodeficiency syndrome (AIDS).6 Despite the cytotoxicity of CD8 cells, immunity is reduced without adequate numbers of CD4 cells. Patients with defects in CMI are at increased risk for disseminated infection with intracellular bacteria, such as Mycobacterium tuberculosis, Listeria monocytogenes, and Salmonella species. The DNA viral infections, such as cytomegalovirus, herpes simplex, and varicella-zoster, also affect these patients more severely, as do fungal infections with Candida, Cryptococcus, Mucor, Aspergillus, and Pneumocystis. Finally, some protozoa are pathogenic without intact CMI, as infections with Toxoplasma gondii demonstrate.14,15 Some infections are seen only below a certain CD4 cell count. Pneumocystis pneumonia is seen almost exclusively in patients with counts below 200 cells/mL (2 × 105 cells/L), whereas almost all patients with toxoplasmosis or cryptococcal meningitis have counts below 100 cells/mL (1 × 105 cells/L). NK cells, closely related to lymphocytes but neither B nor T cells, are important in the innate immune response and are found in high concentrations in blood and spleen.3,6 NK cells recognize infected cells and respond by directly killing these cells, and they secrete cytokines that activate macrophages to destroy phagocytosed microbes. These cells are important in defense against intracellular microbes, particularly viruses and intracellular bacteria such as L. monocytogenes. Two other types of granulocytes, eosinophils and basophils, are less involved in the ingestion of organisms.16 Eosinophils mediate the destruction of certain parasitic helminths through release of toxic proteins. Normally only 3% of total granulocytes, this cell type can reach 20% during times of high parasite load. Basophils (rare in circulation) and their tissue counterparts, mast cells, have high affinity for IgE. On exposure to antigens, they release granules with histamine, prostaglandins, and leukotrienes, which affect the allergic-inflammatory response with increased vascular permeability, bronchospasm, and vasodilation.2 Neutrophils constitute 90% of circulating granulocytes and spend only 6 to 8 hours of their average 4-day life in circulation (the remainder in tissues). Effective antibacterial activity depends on the ability of neutrophils to travel to sites of infection, a process known as chemotaxis. The locomotion of neutrophils along vascular endothelium is facilitated by adherence to cell surface proteins whose production is enhanced in the initial inflammatory response.16 In addition to phagocytosis, macrophages (located in the spleen, alveoli, liver, and lymph nodes) modulate the immune response by presenting antigens to lymphocytes and releasing cytokines and complement components. Activation of macrophages to ingest bacteria depends on interaction with interferon-γ, a cytokine manufactured by T cells.6 Thus the once clear demarcation between cellular and humoral immunity is breaking down as more is understood about the interdependent immune system. Patients with cancer frequently have multiple immune defects, such as neutropenia and impaired function of T and B cells, induced by cancer chemotherapy or by the disease process itself, which predisposes them to infection. Other factors leading to infection are defects in physical barriers (skin and mucous membranes), including cytotoxic effects of chemotherapy on cells lining the gastrointestinal tract. In addition, splenic dysfunction or splenectomy, use of long-term intravascular catheters, frequent use of complex invasive diagnostic and therapeutic procedures, toxic effects of radiation therapy, and frequent colonization with antimicrobial-resistant pathogens are predisposing factors. Cancer treatments (e.g., allogeneic bone marrow and autologous stem cell transplantation, platelet transfusion, granulocyte colony-stimulating factor, and implanted central venous catheters) increase survival during episodes of profound immunosuppression, allowing patients to receive more intense cytotoxic cancer chemotherapy regimens. This results in long survival of patients with neoplastic diseases that were formerly rapidly fatal. Despite many advances in supportive care, infections continue to result in serious morbidity and mortality. Furthermore, increasing resistance to antimicrobials is occurring among common pathogens along with the emergence of new opportunistic pathogens. Infection is much more common in patients with acute leukemia and lymphoma (75% of patients) and multiple myeloma (50% of patients) than in those with solid tumors.17 Factors predisposing to infection in immunocompromised patients are listed in Box 183-1. Principles of Disease.: Neutropenia is defined as a neutrophil count of less than 500 cells/mL (5 × 105 cells/L), including band forms, or less than 1000 cells/mL (1 × 106 cells/L) and expected to fall to less than 500 cells/mL.18,19 It usually results from cytotoxic chemotherapy or radiation therapy or the disease process, especially in hematologic malignant neoplasms. In addition, cancer chemotherapeutic agents and radiation therapy can cause functional defects in granulocytes. The risk of febrile neutropenia and mortality is higher in the first one or two cycles of multicycle cytotoxic chemotherapy regimens.20 The incidence and severity of infection in cancer patients with neutropenia are inversely proportional to the absolute neutrophil count and directly proportional to the duration of neutropenia. Although the incidence begins to rise as the neutrophil count falls below 500 cells/mL (5 × 105 cells/L), most severe infections and almost all bacteremias occur when the neutrophil count is less than 100 cells/mL.21 Fever in the neutropenic patient is defined as a single temperature of 38.3° C (101° F) or higher or a temperature of 38.0° C (100.4° F) or higher during 1 or 2 hours.19 In neutropenic patients, the temperature should be measured orally or tympanically, not rectally. Although fever can be suppressed or lessened by immunosuppressive agents such as corticosteroids and nonsteroidal anti-inflammatory drugs, most cancer patients with infection manifest fever despite the use of these agents.22 Also, although it is uncommon, immunocompromised patients can have serious local or systemic infections without fever. This is manifested by unexplained tachypnea or tachycardia, mental status changes, metabolic acidosis, increased volume requirements, rapid changes in serum glucose or sodium concentration, or acute abdominal pain. Because the onset of life-threatening infections can be rapid in cancer patients with severe neutropenia or a history of splenectomy, urgent evaluation and initiation of antimicrobial therapy are essential. A prospective multicenter observational study of febrile neutropenic cancer patients in EDs in France found that critically ill patients were poorly recognized and undertreated, low-risk patients were overtreated, and compliance with established guidelines was low.23 The most common sites of infection in neutropenic patients are the lung (25%); mouth and pharynx (25%); gastrointestinal tract (15%); skin, soft tissue, and intravascular catheters (15%); perineum and anorectal area (10%); urinary tract (5%); and nose and sinuses (5%).24 Pneumonia and anorectal infection are more likely to be associated with bacteremia. Bacteremia may occur without an obvious source despite intensive investigation. Historically, the most important bacteria are three gram-negative bacilli—Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa—and four gram-positive cocci—Staphylococcus epidermidis, viridans group streptococci, Enterococcus species, and S. aureus. Many centers that treat large numbers of cancer patients note a decrease in these gram-negative bacilli and an increase in infections caused by others, such as Enterobacter, Citrobacter, and Serratia species, which are capable of rapidly developing resistance to cephalosporins and extended-spectrum penicillins. Anaerobes are uncommon but may be important in certain mixed infections (e.g., mouth, abdominal, and perianal). During the past 25 years, infection with gram-positive organisms (e.g., coagulase-negative staphylococci, S. aureus, viridans streptococci, and Enterococcus species) has increased, and this is now the leading cause of bacterial infection (50-70% at some centers) in febrile neutropenic cancer patients in the United States, Canada, and western Europe. Gram-negative organisms still predominate in developing countries.25,26 With the exception of viridans streptococci, most of these gram-positive organisms do not produce immediately life-threatening infections compared with the rapid lethality of many gram-negative infections. Life-threatening bloodstream infections caused by viridans streptococci (especially Streptococcus mitis) are common in many cancer centers and often respond poorly to penicillins and cephalosporins. Risk factors for serious viridans streptococcal infections include aggressive cytoreduction therapy for acute leukemia or allogeneic bone marrow transplantation (especially after high-dose cytosine arabinoside treatment), profound neutropenia, and severe oral mucositis. Other factors include prophylactic use of trimethoprim-sulfamethoxazole or fluoroquinolones, use of antacids or H2 receptor antagonists, and childhood.27,28 Aspergillus and Candida species are the most common fungi producing infection in cancer patients with fever and neutropenia.24,29,30 Infection is most likely to develop in neutropenic patients treated with broad-spectrum antimicrobials and in those whose fever persists for more than 7 days. Aspergillus species usually produce necrotizing infections in the lung or sinuses. Pulmonary aspergillosis often is manifested with pleuritic pain, hemoptysis, and localized wheezing. The chest radiograph demonstrates pleural effusion or focal infiltrates. Computed tomography (CT) is more sensitive in detection of pulmonary infiltrates compatible with aspergillosis, and it may demonstrate a distinct halo of low attenuation surrounding a pulmonary infiltrate. This pattern is highly suggestive of invasive aspergillosis, although mucormycosis and other disorders may mimic the halo. Invasive aspergillosis originating in the paranasal sinuses may extend to the surrounding bone and brain. Often, an initial red-purple lesion on the nasal turbinate or palate turns pale and then black as vascular invasion produces infarction of the mucosa and bone. The black eschar on the nose or palate is easily misdiagnosed as dried blood. Patients presenting with head or facial pain or swelling, or proptosis, should be rapidly evaluated for invasive aspergillosis and mucormycosis. Candida species produce infections of the skin, oral cavity, and esophagus as well as fungemia. The sudden onset of generalized rash consisting of pink-purple, nontender subcutaneous nodules is characteristic of candidemia. Clinical Features.: Certain clinical findings are characteristic of specific pathogens (Table 183-1). Noninfectious causes of fever also need to be considered, such as drug toxicity, drug allergy, transfusion reactions, and pulmonary emboli.17 Fever is frequently the only sign of infection because these patients are unable to mount a full inflammatory response at a site of infection.24 Usual symptoms and signs of infection may not be present, especially when the neutrophil count is less than 100 cells/mL (1 × 105 cells/L). When pneumonia develops, purulent sputum may be absent, and the initial chest radiograph may not show an infiltrate. Pyuria may be absent in the presence of urinary tract infection. Areas of cellulitis may have diminished or absent induration and redness and no purulent drainage. Tenderness may be the only finding in perineal and anal infections. The neutropenic patient with a documented infectious cause of fever may be difficult to distinguish from the patient with fever not caused by infection. The performance of a procedure before the onset of fever, presence of chills, “toxic appearance,” and lack of localized findings do not help determine whether the patient is bacteremic.31 Only 20% of febrile neutropenic patients have a clinical focus of infection identified at presentation, and only 30% of patients have positive blood cultures. Table 183-1 Diagnostic Strategies.: The evaluation of the cancer patient with fever and neutropenia should include a meticulous search for subtle symptoms and signs of inflammation at common sites: oral cavity and pharynx, lower esophagus, lung, skin, perineum including anus, bone marrow aspiration sites, vascular catheter sites, and tissue around the nails.21 In nearly two thirds of patients, the initial evaluation does not identify a focus of infection.22 Two sets of blood culture specimens should be obtained. If the patient has a central venous catheter, culture specimens of blood should be obtained from each lumen of a multilumen catheter and from at least one peripheral site.19 Specimens for culture should also be obtained from any site of inflammation, including inflamed or draining catheter exit sites. Patients with severe mucositis should have herpes simplex cultures performed if they are not receiving antiherpes prophylaxis, and they should have a smear for Candida pseudohyphae. Complete blood count, electrolyte values, transaminase levels, blood urea nitrogen concentration, and creatinine concentration should be determined to plan management and to monitor the occurrence of drug toxicity. A chest radiograph should be obtained in patients with respiratory symptoms and signs.19 If the chest radiograph is normal or inconclusive but there is still suspicion for pneumonia, high-resolution CT or thin-section multislice CT scanning of the chest without contrast enhancement should be obtained because pneumonia is often detected by chest CT in febrile neutropenic patients with normal findings on the chest radiograph.32 CT evaluation of the sinuses should be performed if facial pain or swelling is present. In patients with abdominal pain and tenderness, CT scanning of the abdomen is useful for diagnosis of neutropenic enterocolitis (“typhlitis”), a necrotizing infection of the bowel wall that usually affects the cecum. This is more commonly seen in acute leukemia and is not generally treated surgically. Ultrasonography over a subcutaneous tunneled catheter track and its vein of insertion may reveal the presence of an abscess or infected thrombus.33
The Immunocompromised Patient
Perspective
Principles of Disease
Non–Microbe-Specific Immunity
Initial Inflammatory Response and Innate Immunity
Adaptive (Microbe-Specific) Immunity
Cell-Mediated Immunity
Granulocytic Phagocytes
Specific Immunocompromised States
Cancer
Neutropenia
CHARACTERISTIC CLINICAL FINDINGS
SUSPECT PATHOGENS
Ulcerative lesions in the mouth
Viridans streptococci, herpes simplex, Candida, anaerobes
Necrotizing skin lesions
Pseudomonas aeruginosa, Aeromonas hydrophila, Aspergillus, Mucor
Nontender subcutaneous nodules
Nocardia, Cryptococcus
Nontender pink skin papules
Candida
Black eschar of nose or palate
Aspergillus, Mucor
Generalized macular red rash
Viridans streptococci
Right lower quadrant abdominal pain, tenderness, distention, bloody diarrhea
Typhlitis (neutropenic enterocolitis) caused by Pseudomonas aeruginosa, Escherichia coli, Clostridium septicum
Perineal pain and tenderness without inflammation or abscess
Gram-negative bacilli, anaerobes
Redness or pain at vascular catheter sites
Coagulase-negative staphylococci, Corynebacterium, Bacillus species
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The Immunocompromised Patient
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