Perspective

Immunocompromised patients frequently visit emergency departments (EDs) for evaluation and treatment of various conditions. Infectious complications are common, and they are a diagnostic priority because clinical presentations are often subtle and atypical. This chapter covers infections in patients with malignant disease, in patients receiving immunosuppressive and corticosteroid therapy, in patients who have undergone solid organ or bone marrow transplantation, and in diabetic patients. Human immunodeficiency virus infection is discussed in Chapter 175.

Epidemiology

Fever associated with neutropenia is often a presenting sign of infection in patients receiving chemotherapy for cancer. Patients with severe neutropenia (absolute neutrophil count < 100 cells/mm³) or prolonged neutropenia (>7 days’ duration) are at higher risk of bacteremia.¹

Pathophysiology

Patients with malignant diseases are predisposed to infections from various organisms, including bacterial, fungal, and viral pathogens. Patients with malignant disease are more prone to infections because of impairment of normal host defenses (e.g., neutropenia associated with acute leukemia), complications associated with tumor growth and spread (e.g., bronchial obstruction from bronchogenic carcinoma that results in pneumonia), the use of chemotherapeutic agents and corticosteroids, a history of splenectomy, and infections associated with intravascular catheters or other implanted devices.²

Neutropenia is a significant risk factor for infections in patients with malignant disease, and it can be a result of the condition itself (e.g., acute leukemia) or a consequence of the myelosuppressive effects of agents used in disease management. The 2010 guidelines of the Infectious Disease Society of America (IDSA) for the use of antimicrobial agents in neutropenic patients with cancer defined neutropenia as an absolute neutrophil count of less than 500 cells/mm³ or an absolute neutrophil count expected to decrease to less than 500 cells/mm³ during the next 48 hours.¹ The frequency and severity of infection are inversely proportional to the neutrophil count, and susceptibility to infection increases when the neutrophil count falls to less than 1000 cells/mm³.³ In addition, vulnerability to infection increases with longer periods of neutropenia. The same guidelines also defined fever, in the absence of obvious environmental causes, as a single oral temperature measurement of 38.3° C (101° F) or higher or a temperature of 38.0° C (100.4° F) or higher for at least 1 hour.¹

In addition to the neutrophils, other components of cell-mediated immunity, such as lymphocytes, monocytes, or macrophages, may also become deficient or defective in certain types of cancers (e.g., lymphoma, leukemia, Hodgkin disease). Many organisms may be responsible for infections in patients with these types of cancers that impair cell-mediated immunity² (Box 173.1). These patients most often undergo an extensive work-up to establish the etiologic agent of infection. Special attention also needs to be paid to patients who have undergone splenectomy. These patients are at a higher risk of developing fulminant infection by Streptococcus pneumoniae, Haemophilus influenzae, or Neisseria meningitidis.

Approximately 60% of bacterial infections are the result of gram-positive cocci, and 35% are caused by gram-negative bacilli.² Bacteremia complicates approximately 20% of the infections. The most common causes of bacteremia in febrile neutropenic patients are listed in Box 173.2.^1,4 Anaerobes are uncommon culprits of infection in neutropenic patients, except in the presence of clinical features of oral mucositis or perirectal or intraabdominal infections.^2,5

Fungal infections most commonly involve Candida and Aspergillus species and are typically encountered in patients with prolonged neutropenia, or they manifest as secondary infections in patients who have received broad-spectrum antibiotics. Fungal infections can cause fever following recovery from chemotherapy-induced neutropenia. Candidal infections commonly manifest with thrush and esophagitis, and less frequently as acute disseminated candidiasis. Aspergillus infections usually manifest with sinus and pulmonary infections. This organism infects catheter sites and the gastrointestinal tract, and it causes thrombosis and infarction of blood vessels. Both Candida and Aspergillus are difficult to grow on blood cultures. Identification of these fungi requires multiple blood cultures, as well as other diagnostic tests (e.g., nasal endoscopy, biopsy of lesions).

Presenting Signs and Symptoms

Neutropenic patients may have fever as their only presenting feature of infection, without other specific clinical manifestations of infection. Cellulitis, pustulation, or lymphadenopathy may be diminished. A pulmonary infiltrate may be absent on initial radiographs. Meningitis and urinary tract infection may cause minimal pleocytosis and pyuria, respectively. Pain at any site should heighten the suspicion of occult infection despite the absence of typical physical signs of infection.

Medical Decision Making

The initial evaluation often includes broad diagnostic testing, including serum chemistry studies, complete blood cell count, liver and renal function tests, urinalysis, blood and urine cultures, and radiographic evaluations (e.g., plain chest radiographs). Blood cultures should be drawn before the initiation of antimicrobial therapy. When a catheter-related infection is suspected, blood cultures should be simultaneously drawn through the central venous catheter and the peripheral vein.⁶ Urine cultures are especially indicated if the patient has signs and symptoms of urinary tract infection, if a urinary catheter is present, or if the urinalysis results are abnormal. A chest radiograph is indicated if the patient has any respiratory abnormalities or chest discomfort. A negative chest radiograph does not rule out the presence of a pulmonary infection in a neutropenic patient. In this population of patients, multiple studies have shown that high-resolution computed tomography (CT) scanning of the chest is a better diagnostic test than plain chest radiographs for the early detection of pneumonia.^7–9 Unless clinically indicated, routine lumbar puncture and cerebrospinal fluid examination are not recommended.⁴

Treatment

Empiric antibiotic therapy should be administered promptly to all neutropenic febrile patients and to afebrile neutropenic patients who have signs and symptoms consistent with infection. Box 173.3 depicts recommended initial antimicrobial therapy for the management of febrile neutropenic patients.^1,4,5 The 2010 IDSA guidelines¹ advocated that high-risk patients should receive intravenous antimicrobial monotherapy with any one of these agents: piperacillin-tazobactam, cefepime, ceftazidime, meropenem, or imipenem. Other antimicrobials such as vancomycin or metronidazole can be added in the presence of specific clinical situations (see Box 173.3).

When a catheter-related infection is suspected, empiric intravenous antibiotic therapy with vancomycin should be initiated⁶ (see Box 173.3). Peripheral venous catheters should be removed if the patient shows signs of infection at the site (e.g., drainage of pus, erythema) or evidence of septic shock with no other source of infection. Prompt removal of the catheter is warranted when intravascular catheterization is complicated by septic thrombophlebitis.⁶ The diagnosis can be made by ultrasonography with color Doppler imaging. Emergency physicians (EPs) should involve the oncologist and the infectious disease specialists in the decision-making process when considering removal of a central line.

Antiviral agents should not be initiated empirically as initial therapy in the ED for all patients with neutropenic fever. However, the presence of lesions resulting from herpes simplex virus or varicella-zoster virus warrants the initiation of antiviral agents (e.g., acyclovir, valacyclovir), even if these pathogens are not suspected as the cause of fever.¹