CHAPTER 1: APPROACH TO THE PATIENT WITH AN INFECTIOUS DISEASE

APPROACH TO THE PATIENT: Infectious Disease

See also Chap. 18.

As in all of medicine, obtaining a complete and thorough history is paramount in the evaluation of a patient with a possible infectious disease. The history is critical for developing a focused differential diagnosis and for guiding the physical exam and initial diagnostic testing. Although detailing all the elements of a history is beyond the scope of this chapter, specific components relevant to infectious diseases require particular attention. In general, these aspects focus on two areas: (1) an exposure history that may identify microorganisms with which the patient may have come into contact and (2) host-specific factors that may predispose to the development of an infection.

Knowledge about a patient’s previous infections, with the associated microbial susceptibility profiles, is very helpful in determining possible etiologic agents. Specifically, knowing whether a patient has a history of infection with drug-resistant organisms (e.g., methicillin-resistant S. aureus, vancomycin-resistant Enterococcus species, enteric organisms that produce an extended-spectrum β-lactamase or carbapenemase) or may have been exposed to drug-resistant microbes (e.g., during a recent stay in a hospital, nursing home, or long-term acute-care facility) may alter the choice of empirical antibiotics. For example, a patient presenting with sepsis who is known to have a history of invasive infection with a multidrug-resistant isolate of P. aeruginosa should be treated empirically with an antimicrobial regimen that will cover this strain.

Although the social history taken by physicians is often limited to inquiries about a patient’s alcohol and tobacco use, a complete social history can offer a number of clues to the underlying diagnosis. Knowing whether the patient has any high-risk behaviors (e.g., unsafe sexual behaviors, IV drug use), potential hobby-associated exposures (e.g., avid gardening, with possible Sporothrix schenckii exposure), or occupational exposures (e.g., increased risk for M. tuberculosis exposure in funeral service workers) can facilitate diagnosis. The importance of the social history is exemplified by a case in 2009 in which a laboratory researcher died of a Yersinia pestis infection acquired during his work; although this patient had visited both an outpatient clinic and an emergency department, his records at both sites failed to include his occupation—information that potentially could have led quickly to appropriate treatment and infection control measures.

As certain pathogens are associated with specific dietary habits, inquiring about a patient’s diet can provide insight into possible exposures. For example, Shiga toxin–producing strains of Escherichia coli and Toxoplasma gondii are associated with the consumption of raw or undercooked meat; Salmonella typhimurium, Listeria monocytogenes, and Mycobacterium bovis with unpasteurized milk; Leptospira species, parasites, and enteric bacteria with unpurified water; and Vibrio species, norovirus, helminths, and protozoa with raw seafood.

Because animals are often important vectors of infectious diseases, patients should be asked about exposures to any animals, including contact with their own pets, visits to petting zoos, or random encounters (e.g., home rodent infestation). For example, dogs can carry ticks that serve as agents for the transmission of several infectious diseases, including Lyme disease, Rocky Mountain spotted fever, and ehrlichiosis. Cats are associated with Bartonella henselae infection, reptiles with Salmonella infection, rodents with leptospirosis, and rabbits with tularemia (Chap. 40).

Attention should be paid to both international and domestic travel. Fever in a patient who has recently returned from abroad significantly broadens the differential diagnosis (Chap. 6); even a remote history of international travel may reflect patients’ exposure to infections with pathogens such as M. tuberculosis or Strongyloides stercoralis. Similarly, domestic travel may have exposed patients to pathogens that are not normally found in their local environment and therefore may not routinely be considered in the differential diagnosis. For example, a patient who has recently visited California or Martha’s Vineyard may have been exposed to Coccidioides immitis or Francisella tularensis, respectively. Beyond simply identifying locations that a patient may have visited, the physician needs to delve deeper to learn what kinds of activities and behaviors the patient engaged in during travel (e.g., the types of food and sources of water consumed, freshwater swimming, animal exposures) and whether the patient had the necessary immunizations and/or took the necessary prophylactic medications prior to travel; these additional exposures, which the patient may not think to report without specific prompting, are as important as exposures during a patient’s routine daily living.

Because many opportunistic infections (e.g., with Pneumocystis jirovecii, Aspergillus species, or JC virus) affect only immunocompromised patients, it is of vital importance to determine the immune status of the patient. Defects in the immune system may be due to an underlying disease (e.g., malignancy, HIV infection, malnutrition), a medication (e.g., chemotherapy, glucocorticoids, monoclonal antibodies to components of the immune system), a treatment modality (e.g., total body irradiation, splenectomy), or a primary immunodeficiency. The type of infection for which the patient is at increased risk varies with the specific type of immune defect. In concert with determining whether a patient is immunocompromised for any reason, the physician should review the immunization record to ensure that the patient is adequately protected against vaccine-preventable diseases (Chap. 5).

Similar to the history, a thorough physical examination is crucial in evaluating patients with an infectious disease. Some elements of the physical exam (e.g., skin, lymphatics) that are often performed in a cursory manner as a result of the ever-increasing pace of medical practice may help identify the underlying diagnosis. Moreover, serial exams are critical since new findings may appear as the illness progresses. A description of all the elements of a physical exam is beyond the scope of this chapter, but the following components have particular relevance to infectious diseases.

Given that elevations in temperature are often a hallmark of infection, paying close attention to the temperature may be of value in diagnosing an infectious disease. The idea that 37°C (98.6°F) is the normal human body temperature dates back to the nineteenth century and was initially based on axillary measurements. Rectal temperatures more accurately reflect the core body temperature and are 0.4°C (0.7°F) and 0.8°C (1.4°F) higher than oral and axillary temperatures, respectively. Although the definition of fever varies greatly throughout the medical literature, the most common definition, which is based on studies defining fever of unknown origin (Chap. 13), uses a temperature ≥38.3°C (101°F). Although fever is very commonly associated with infection, it is also documented in many other diseases (Chap. 11). For every 1°C (1.8°F) increase in core temperature, the heart rate typically rises by 15–20 beats/min. Table 1-1 lists infections that are associated with relative bradycardia (Faget’s sign), where patients have a lower heart rate than might be expected for a given body temperature. Although this pulse-temperature dissociation is not highly sensitive or specific for establishing a diagnosis, it is potentially useful in low-resource settings given its ready availability and simplicity.

There are ∼600 lymph nodes throughout the body, and infections are an important cause of lymphadenopathy. A physical examination should include evaluation of lymph nodes in multiple regions (e.g., popliteal, inguinal, epitrochlear, axillary, multiple cervical regions), with notation of the location, size (normal, <1 cm), presence or absence of tenderness, and consistency (soft, firm, or shotty) and of whether the nodes are matted (i.e., connected and moving together). Of note, palpable epitrochlear nodes are always pathologic. Of patients presenting with lymphadenopathy, 75% have localized findings, and the remaining 25% have generalized lymphadenopathy (i.e., that involving more than one anatomic region). Localized lymphadenopathy in the head and neck region is found in 55% of patients, inguinal lymphadenopathy in 14%, and axillary lymphadenopathy in 5%. Determining whether the patient has generalized versus localized lymphadenopathy can help narrow the differential diagnosis, as various infections present differently.

The fact that many infections have cutaneous manifestations gives the skin examination particular importance in the evaluation of patients (Chaps. 12, 14, and 26). It is important to perform a complete skin exam, with attention to both front and back. Specific rashes are often extremely helpful in narrowing the differential diagnosis of an infection (Chaps. 12 and 14). In numerous anecdotal instances, patients in the intensive care unit have had “fever of unknown origin” that was actually due to unrecognized pressure ulcers. Moreover, close examination of the distal extremities for splinter hemorrhages, Janeway lesions, or Osler’s nodes may yield evidence of endocarditis or other causes of septic emboli.

As previously mentioned, many infections are caused by members of the indigenous microbiota. These infections typically occur when these microbes escape their normal habitat and enter a new one. Thus, maintenance of epithelial barriers is one of the most important mechanisms in protection against infection. However, hospitalization of patients is often associated with breaches of these barriers—e.g., due to placement of IV lines, surgical drains, or tubes (such as endotracheal tubes and Foley catheters) that allow microorganisms to localize in sites to which they normally would not have access (Chap. 17). Accordingly, knowing what lines, tubes, and drains are in place is helpful in ascertaining what body sites might be infected.

Laboratory and radiologic testing has advanced greatly over the past few decades and has become an important component in the evaluation of patients. The dramatic increase in the number of serologic diagnostics, antigen tests, and molecular diagnostics available to the physician has, in fact, revolutionized medical care. However, all of these tests should be viewed as adjuncts to the history and physical examination—not a replacement for them. The selection of initial tests should be based directly on the patient’s history and physical exam findings. Moreover, diagnostic testing should generally be limited to those conditions that are reasonably likely and treatable, important in terms of public health considerations, and/or capable of providing a definitive diagnosis that will consequently limit other testing.

Elevations in the WBC count are often associated with infection, though many viral infections are associated with leukopenia. It is important to assess the WBC differential, given that different classes of microbes are associated with various leukocyte types. For example, bacteria are associated with an increase in polymorphonuclear neutrophils, often with elevated levels of earlier developmental forms such as bands; viruses are associated with an increase in lymphocytes; and certain parasites are associated with an increase in eosinophils. Table 1-2 lists the major infectious causes of eosinophilia.

The erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP) level are indirect and direct measures of the acute-phase response, respectively, that can be used to assess a patient’s general level of inflammation. Moreover, these markers can be followed serially over time to monitor disease progress/resolution. It is noteworthy that the ESR changes relatively slowly, and its measurement more often than weekly usually is not useful; in contrast, CRP concentrations change rapidly, and daily measurements can be useful in the appropriate context. Although these markers are sensitive indicators of inflammation, neither is very specific. An extremely elevated ESR (>100 mm/h) has a 90% predictive value for a serious underlying disease (Table 1-3). Work is ongoing to identify other potentially useful inflammatory markers (e.g., procalcitonin, serum amyloid A protein); however, their clinical utility requires further validation.

Assessment of CSF is critical for patients with suspected meningitis or encephalitis. An opening pressure should always be recorded, and fluid should routinely be sent for cell counts, Gram’s stain and culture, and determination of glucose and protein levels. A CSF Gram’s stain typically requires >10⁵ bacteria/mL for reliable positivity; its specificity approaches 100%. Table 1-4 lists the typical CSF profiles for various infections. In general, CSF with a lymphocytic pleocytosis and a low glucose concentration suggests either infection (e.g., with Listeria, M. tuberculosis, or a fungus) or a noninfectious disorder (e.g, neoplastic meningitis, sarcoidosis). Bacterial antigen testing of CSF (e.g., latex agglutination tests for Haemophilus influenzae type b, group B Streptococcus, S. pneumoniae, and Neisseria meningitidis) is not recommended as a screening assay, given that these tests are no more sensitive than Gram’s stain; however, these assays can be helpful in presumptively identifying organisms seen on Gram’s stain. In contrast, other antigen tests (e.g., for Cryptococcus) and some CSF serologic testing (e.g., for Treponema pallidum, Coccidioides) are highly sensitive and are useful for select patients. In addition, polymerase chain reaction (PCR) analysis of CSF is increasingly being used for the diagnosis of bacterial (e.g., N. meningitidis, S. pneumoniae, mycobacteria) and viral (e.g., herpes simplex virus, enterovirus) infections; while these molecular tests permit rapid diagnosis with a high degree of sensitivity and specificity, they often do not allow determination of antimicrobial resistance profiles.

The mainstays of infectious disease diagnosis include the culture of infected tissue (e.g., surgical specimens) or fluid (e.g., blood, urine, sputum, purulence from a wound). Samples can be sent for culture of bacteria (aerobic or anaerobic), fungi, or viruses. Ideally, specimens are collected before the administration of antimicrobial therapy; in instances where this order of events is not clinically feasible, microscopic examination of the specimen (e.g., Gram-stained or potassium hydroxide [KOH]–treated preparations) is particularly important. Culture of the organism(s) allows identification of the etiologic agent, determination of the antimicrobial susceptibility profile, and—when there is concern about an outbreak—isolate typing. While cultures are extremely useful in the evaluation of patients, determining whether culture results are clinically meaningful or represent contamination (e.g., a non-aureus, non-lugdunensis staphylococcal species growing in a blood culture) can sometimes be challenging and requires an understanding of the patient’s immune status, exposure history, and microbiota. In some cases, serial cultures to demonstrate clearance of the organism may be helpful.

Numerous pathogen-specific tests (e.g., serology, antigen testing, PCR testing) are commercially available, and many hospitals now offer some of these tests in-house to facilitate rapid turnaround that ultimately enhances patient care. The reader is directed to relevant chapters on the pathogens of interest for specific details. Some of these tests (e.g., universal PCRs) identify organisms that currently are not cultivable and have unclear relationships to disease, thereby complicating diagnosis. As these tests become more commonplace and the work of the Human Microbiome Project progresses, the relevance of some of these previously unrecognized bacteria to human health will likely become more apparent.

Imaging provides an important adjunct to the physical examination, allowing evaluation for lymphadenopathy in regions that are not externally accessible (e.g., mediastinum, intraabdominal sites), assessment of internal organs for evidence of infection, and facilitation of image-guided percutaneous sampling of deep spaces. The choice of imaging modality (e.g., CT, MRI, ultrasound, nuclear medicine, use of contrast) is best made in consultation with a radiologist to ensure that the results will address the physician’s specific concerns.

Physicians often must balance the need for empirical antibiotic treatment with the patient’s clinical condition. When clinically feasible, it is best to obtain relevant samples (e.g., blood, CSF, tissue, purulent exudate) for culture prior to the administration of antibiotics, as antibiotic treatment often makes subsequent diagnosis more difficult. Although a general maxim for antibiotic treatment is to use a regimen with as narrow a spectrum as possible (Chap. 41), empirical regimens are necessarily somewhat broad, given that a specific diagnosis has not yet been made. Table 1-5 lists empirical antibiotic treatment regimens for commonly encountered infectious presentations. These regimens should be narrowed as appropriate once a specific diagnosis is made. In addition to antibiotics, there is sometimes a role for adjunctive therapies, such as intravenous immunoglobulin G (IVIG) pooled from healthy adults or hyperimmune globulin prepared from the blood of individuals with high titers of specific antibodies to select pathogens (e.g., cytomegalovirus, hepatitis B virus, rabies virus, vaccinia virus, Clostridium tetani, varicella-zoster virus, Clostridium botulinum toxin). Although the data suggesting efficacy are limited, IVIG is often used for patients with suspected staphylococcal or streptococcal toxic shock syndrome.

When evaluating a patient with a suspected infectious disease, the physician must consider what infection control methods are necessary to prevent transmission of any possible infection to other people. In 2007, the U.S. Centers for Disease Control and Prevention published guidelines for isolation precautions that are available for download at www.cdc.gov/hicpac/2007IP/2007isolationPrecautions.html. Persons exposed to certain pathogens (e.g., N. meningitidis, HIV, Bacillus anthracis) should receive postexposure prophylaxis to prevent disease acquisition. (See relevant chapters for details on specific pathogens.)

At times, primary physicians need assistance with patient management, from a diagnostic and/or therapeutic perspective. Multiple studies have demonstrated that an infectious disease consult is associated with positive outcomes for patients with various diseases. For example, in a prospective cohort study of patients with S. aureus bacteremia, infectious disease consultation was independently associated with a 56% reduction in 28-day mortality. In addition, infectious disease specialists provide other services (e.g., infection control, antimicrobial stewardship, management of outpatient antibiotic therapy, occupational exposure programs) that have been shown to benefit patients. Whenever such assistance would be advantageous to a patient with a possible infection, the primary physician should opt for an infectious disease consult. Specific situations that might prompt a consult include (1) difficult-to-diagnose patients with presumed infections, (2) patients who are not responding to treatment as expected, (3) patients with a complicated medical history (e.g., organ transplant recipients, patients immunosuppressed due to autoimmune or inflammatory conditions), and (4) patients with “exotic” diseases (i.e., diseases that are not typically seen within the region).