Approach to Fever and Suspected Infection in the Immunocompromised Host

General Concepts

The innate immune system serves as the first line of host defense ( Table 260-1 ). Components of the innate immune system ( Chapter 35 ) include natural physical and chemical barriers, phagocytic cells, and germline-encoded signaling systems that recognize molecular components unique to microbes that are invariant because they are essential for survival of the microbe. These signaling systems rapidly (minutes to hours) distinguish “nonself” from “self,” thereby leading to the activation of protective phagocytic cells, proteolytic enzyme cascades, antimicrobial peptides, and other products. The innate immune system also primes the adaptive immune system, which is distinguished by the ability to create pathogen-specific responses and immunologic memory over several days. Like the innate immune system, the adaptive immune system is composed of both cellular and soluble factors ( Chapter 35 ).

The risk for infection depends on the specific type of defect in host defenses. For example, impaired macrophage function as a consequence of tumor necrosis factor (TNF)–directed therapy is a predisposing risk for infection due to intracellular pathogens such as Mycobacterium tuberculosis ( Chapter 299 ) and Histoplasma capsulatum ( Chapter 308 ), whereas splenectomy and functional asplenism ( Chapter 154 ) predispose to sepsis due to encapsulated bacteria, including pneumococcus ( Chapter 268 ) and meningococcus ( Chapter 274 ). Detailed understanding of the nature of compromised host defense mechanisms and how the defect influences susceptibility to potential viral, bacterial, fungal, or parasitic pathogens can guide appropriate diagnostic evaluations, therapies, and prevention strategies (through vaccination, antimicrobial prophylaxis, pre-emptive monitoring, and lifestyle changes).

Determining whether an immunocompromised individual has a clinically significant infectious disease can be challenging. Several factors make it more difficult to identify infectious disease in individuals with compromised immune defenses. Potential causes of infection are diverse and range from typical, community-acquired pathogens to less common, opportunistic pathogens. Signs of inflammation, including fever, pain, and erythema, may be reduced. Laboratory markers of infection, such as changes in the white blood cell count and hepatic transaminase levels, may be subtle or difficult to interpret owing to the influence of baseline noninfectious processes (e.g., medications, organ dysfunction). Radiographic findings may also be blunted. Accordingly, infection may be advanced at the time of presentation. Furthermore, multiple infections or processes may occur simultaneously. Diagnosis can be challenging because serologic testing may not be useful. However, recent advances in the development and adoption of molecular diagnostic assays have proved especially useful tools in immunocompromised patients. Finally, numerous noninfectious causes of fever, including neoplastic disease, collagen vascular disease, allograft rejection, graft-versus-host disease, and medications (e.g., antibiotic-induced fever, cytokine release syndromes following monoclonal antibody therapies) may cause febrile illnesses that are indistinguishable from infectious processes. Consequently, significant and expedited efforts should be made to establish the cause of fevers in a compromised host. Invasive procedures, such as imaging-guided biopsy, endoscopic procedures, and surgery, may be required to establish a diagnosis.

Approach to the Patient

Broadly speaking, the factors that predispose immunocompromised patients to infection can be divided into two categories: intrinsic host factors as a consequence of illness and factors associated with medical treatment. Intrinsic host factors include underlying immunodeficiencies, medical comorbidities, past infections, metabolic derangements, and poor nutritional status. For patients with cancer, mechanical obstruction from tumors can predispose to organ dysfunction, infection, and the formation of abscesses. Tumors of the head and neck, respiratory tract, gastrointestinal tract, and female genitourinary tract predispose to infections in and adjacent to those anatomic spaces. Patients with chronic progressive organ dysfunction and failure are predisposed to infection as a consequence of their illness. Structural lung problems, such as cavitary lung disease, increase the risk for colonization and superinfection by Aspergillus ( Chapter 311 ) and nontuberculous mycobacteria ( Chapter 300 ). Progressive respiratory failure predisposes persons to pneumonia due to community-associated, health care–associated, and opportunistic pathogens ( Chapter 85 ). Progressive liver failure predisposes to fungal infections, including cryptococcosis ( Chapter 309 ). Immunodeficiency as a direct consequence of acquired immune system disorders, such as hematologic malignancies or bone marrow infiltration by metastasis of solid tumors, adds another layer of risk of infection.

Medical treatment is the other major consideration that influences the risk for infection. Radiation therapy and cytotoxic chemotherapy of malignant disease directly or indirectly target cells of the immune system, thereby leading to significant risk for infection. Physical and natural barriers, such as skin, mucosal membranes, uroepithelium, and ciliated respiratory epithelium, may be injured or impaired as a consequence of disease or treatment. Surgery and medical devices, such as central venous catheters, indwelling urinary catheters, and circulatory support devices, among others, predispose to infections from a range of nosocomial pathogens, including Staphylococcus aureus , coagulase-negative staphylococci, enterococci, enteric gram-negative bacteria, Pseudomonas aeruginosa , other multidrug-resistant gram-negative bacteria, and Candida . Bleeding and fluid collections, such as urinomas and bilomas, may become seeded and infected after surgery. Repeated surgery is a risk for both organ transplant recipients and patients with solid tumors. Patients with primary or metastatic lung cancer are susceptible to recurrent pneumonia. Patients with head and neck cancer and brain cancer are predisposed to aspiration pneumonitis and pneumonia. The use of immunosuppressive medications following allogeneic stem cell or organ transplantation is a significant risk factor. The consequences of prior infections, empirical antibiotics, and treatment of infections lead to unbalanced changes in the composition of the gastrointestinal microbiome (termed dysbiosis ) that may reduce barriers to colonization with drug-resistant pathogens and increase the risk of chemical infection.

The approach to the immunosuppressed patient requires detailed information about the nature of the immunodeficiency and known related risks. Specific immune defects in host responses are associated with specific underlying conditions and medical interactions ( Table 260-2 ).

Fever in the Compromised Host

The onset of fever in an immunocompromised patient can be an ominous development. Depending on the nature and magnitude of the impaired host defenses, including comorbid conditions, a febrile response can indicate the onset of a life-threatening systemic infection. A diagnostic approach should be derived by careful consideration of the patient’s signs and symptoms of infection, exact form(s) of immunocompromise, and whether the patient is at heightened risk for reactivation of latent infection. Because infection can progress rapidly, particularly in patients with absolute neutropenia (see later), empirical antimicrobial therapy is often indicated even before an infection is definitively identified.

In the setting of disease-associated or chemotherapy-induced neutropenia, fever is typically an important and often the only clinical indication of infection. Some patients with neutropenia and serious infection, especially patients who are elderly, may be afebrile or even hypothermic on presentation. The risk for bacterial infection increases proportionally with the decline in neutrophil count, especially with prolonged durations of significant neutropenia ( Chapter 153 ). Infection rates increase with neutrophil levels below 1000 cells/μL and progressively increase as counts decline to less than 100 cells/μL. The duration of significant neutropenia is also an important determinant of the type of infection most likely to occur, with the risk for bacterial and fungal infections increasing with each successive week in which leukocyte counts are less than 500 cells/μL.