Chapter 5: Infectious Diseases

Humans live in a world of microbes. Many types of microbes are part of the normal human flora and rarely cause disease. Others have a greater potential for virulence and can cause disease depending on complex interactions between the host and the microbe. A small group of organisms are highly virulent and usually cause disease whenever they infect humans. This chapter on infectious diseases and clinical microbiology focuses on common pathogens and frequently encountered clinical syndromes. Infectious agents include a daunting array of viruses, bacteria, fungi, protozoans, and helminths. Table 5–1 provides information on the basic microbiology and clinical significance of common pathogens. The organisms are grouped based on shared properties because these are often relevant to the diagnostic process.

Because of the large number of potential pathogens, it is not technically possible, practical, or cost-effective to attempt to rule out all of them in each patient who may have an infection. It is, therefore important for the clinician to know what organisms are most likely in a particular patient and whether routine diagnostic tests will detect them or whether specialized tests are needed. Identification of the causative agent is usually important for determining the most appropriate therapy. It can also have infection control or public health implications. The clinical findings are the first major clues in determining the site of infection and identifying a pathogenic organism. For example, a cough is usually indicative of a process in the respiratory tract while pain on urination is a clue to a urinary tract infection (UTI). Radiographic studies can further clarify the type of process and may point to specific categories of organisms.

Often, a single species of microbe can cause multiple syndromes. Conversely, a single syndrome may be caused by multiple organisms. This can lead to a potentially vast array of diagnostic possibilities. In order to determine the diagnosis in a timely and cost-efficient manner, it is essential to take into consideration the clinical setting. For example, the organisms responsible for a community-acquired pneumonia are usually different from those that cause nosocomial pneumonia. If the patient is immunosuppressed, this further enlarges the list of potential organisms. It also matters whether the immunosuppression is due to decreased cell-mediated immunity, for example, due to HIV infection or inhibitors of tumor necrosis factor (TNF), versus neutropenia secondary to chemotherapy because each has its own associated group of opportunistic infections. Other underlying conditions such as diabetes or sickle cell disease, or the presence of prosthetic devices, are associated with specific infections. A history of travel or exposure to arthropod vectors may raise the possibility of additional organisms.

The organization of this chapter reflects the common associations between selected organisms and the site of infection. The discussion of a particular organism in a specific anatomic site in this chapter does not imply that infection by that organism is restricted to that location. Several infectious diseases, such as viral hepatitis (see Chapter 16) and Helicobacter pylori infections (see Chapter 15), are presented elsewhere in this book because these infections are intimately associated with a specific organ or tissue. The organisms and diseases selected for presentation in this chapter were chosen primarily by their incidence, with a preference for common infections. Many lower-incidence infections also have been included because they are often within a differential diagnosis, new information on their diagnosis and treatment is emerging, or they can be overlooked if appropriate tests are not requested. The chapter focuses on infections commonly encountered in the United States, although several travel-associated infections are discussed.

A general clinical approach to the patient with an infectious disease is diagrammed in Figure 5–1.

The laboratory diagnosis of infectious disease utilizes 5 distinct types of tests: direct examination, culture, antigen detection, nucleic acid detection, and serology. Each of these tests has strengths and weaknesses. The types of test(s) that are used in a specific case depend in large part on the organisms that are in the differential diagnosis, as well as the type of specimens that are available. See Chapter 2 for illustrations of these laboratory methods.

Direct Stains

Direct examination involves preparing a smear of the specimen and then using an appropriate staining technique to detect the relevant microorganisms. The Gram stain is rapid and detects most types of bacterial pathogens if they are present in sufficient numbers. It provides a preliminary characterization in terms of the Gram reaction, that is, positive or negative, as well as the morphology (cocci, coccobacilli, or bacilli) and arrangement of the cells (individual cells, pairs, chains, or clusters). It also provides information on the host response, for example, the presence or absence of neutrophils. This stain is routinely performed on most specimen types including respiratory specimens, sterile fluids, tissue biopsies, wounds, and abscesses. It is not routinely performed on stool because of the large numbers of normal flora, urine because similar information is available from the urinalysis, and blood because of the small number of organisms typically found in cases of bacteremia. The analytic sensitivity of the Gram stain is relatively low because the observation of an average of 1 organism per oil immersion field corresponds to a concentration of 10⁵ organisms per milliliter in the specimen. The sensitivity can be increased by concentration of the specimen through centrifugation. Other direct stains include acid-fast stains for mycobacteria and calcofluor white for fungi. Wright stains of peripheral blood are used to detect Plasmodium and Babesia infections. Routine hematoxylin and eosin stains as well as Gram, acid-fast bacteria (AFB), and Gomori methenamine silver (GMS) stains can reveal the presence of microorganisms in paraffin-embedded tissue in the surgical pathology laboratory.

Culture

Isolation of organisms in pure culture continues to be the mainstay of microbiologic diagnosis. In general, culture is very sensitive and specific and remains the “gold standard” for diagnosing many types of infection. Culture provides relatively rapid detection (within usually 1-3 days) of a wide array of organisms that are then available for definitive identification and antimicrobial susceptibility testing. One of the great advantages of culture assays is that microbiology laboratories routinely inoculate a combination of nonselective and selective media that will support the growth of many types of pathogenic bacteria. The person ordering the test does not need to specify which organism or organisms are suspected of causing the infection. A clinician who submits a blood-culture bottle does not have to order a Staphylococcus culture, a Streptococcusculture, a gram-negative rod culture, etc. Nonetheless, it is essential to remember that routine cultures only detect typical bacteria. If other classes of agents, such as mycobacteria, fungi, parasites, or viruses, are in the differential diagnosis, then the clinician must request the appropriate tests. For example, mycobacteria and fungal cultures utilize media designed to inhibit the growth of routine bacteria and they also require prolonged incubation.

Identification of Organisms From Positive Cultures

The majority of bacterial pathogens are routinely identified by the presence of specific combinations of phenotypic traits including production of enzymes, such as catalase, coagulase, oxidase, and urease, ability to ferment or utilize different types of sugars, and additional metabolic reactions. Many of these individual tests have been combined into commercial identification kits. In contrast, slow-growing organisms, such as mycobacteria, and bacteria that are difficult to identify with traditional biochemical methods are now often identified by nucleic acid amplification and sequencing of conserved genes such as 16S ribosomal RNA or RNA polymerase. Yeasts are generally identified with biochemical tests similar to those used for bacteria. Finally, identification of molds is based on colonial and microscopic morphology.

More recently, commercial identification systems have been developed that use matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectroscopy (MS) to generate protein spectra that can be compared with databases to identify bacteria and other microbes. The advantage of MALDI-TOF/MS is that it requires few reagents and can identify organisms in minutes as opposed to the 12- to 24-hour incubations required for most biochemical panels.

Susceptibility Testing

Once an organism has been identified in the clinical microbiology laboratory, the second major task, in most cases, is determining the organism's antibiotic susceptibility profile. Susceptibility tests involve the measurement of the minimum inhibitory concentration (MIC), the lowest concentration of antimicrobial agent that inhibits the growth of the organism. The reference method is the microbroth dilution technique. The MICs are then interpreted as sensitive, intermediate, or resistant according to tables of interpretive breakpoints that are related to therapeutically achievable serum levels for each antibiotic. Other susceptibility methods such as disk diffusion (measuring the diameter of the zone of inhibition surrounding an antibiotic-containing disk) can be correlated with the results of the broth dilution technique.

Susceptibility testing has become increasingly complex due to the widespread dissemination of increasingly resistant pathogens that include methicillin-resistant Staphylococcus aureus (MRSA); vancomycin-resistant enterococci (VRE); and multidrug-resistant strains of Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. These organisms harbor a variety of resistance mechanisms that include altered penicillin-binding proteins, extended-spectrum beta-lactamases, carbapenemases, inducible clindamycin resistance, and multidrug efflux pumps. While molecular methods can be used for rapid detection of specific resistance genes, such as the mecA gene in MRSA and the vanA and vanB genes in VRE, most susceptibility testing depends on phenotypic (MIC-based) methods that require overnight incubation.

Antigen Detection

Antigen detection tests do not require the growth of microorganisms. Therefore, they have the potential to provide rapid detection of infectious agents. Immunoassays that detect soluble antigens vary in speed, complexity, sensitivity, and specificity. Usually there is a trade-off between simplicity and sensitivity. Immunochromatographic assays require very few procedural steps and are the basis of many rapid point-of-care tests. These assays are less sensitive than traditional solid-phase enzyme immunoassays (EIAs) that are used for batch testing in the laboratory. Unlike culture-based assays, an immunoassay can only detect the organism that binds to the reagent antibodies; a separate assay must be performed for each organism. Immunoassays generally exhibit good but not perfect specificity. Furthermore, they cannot distinguish viable from nonviable organisms. Direct or indirect fluorescent immunoassays utilize microscopy to identify organisms that bind the reagent antibody. These assays often have high sensitivity and specificity compared with other types of immunoassays, but they require extensive training to insure proper interpretation.

Nucleic Acid Amplification

The introduction of nucleic acid amplification techniques (NAATs) has revolutionized several areas of infectious disease testing including HIV viral load testing, diagnosis of Herpes simplex virus (HSV) encephalitis, and rapid detection of MRSA. They are particularly valuable for detecting difficult-to-grow or slow-growing organisms that may be present in small numbers. NAAT tests have the potential for very high sensitivity and specificity. However, as with antigen tests, they can only be used to diagnose infections caused by organisms that the assay detects. Current technology is not at the stage where it can eliminate the use of traditional culture methods in the routine bacteriology laboratory. Nonetheless, this is a rapidly changing field as illustrated by the widespread adoption of multiplex NAAT assays that can simultaneously detect a panel of common respiratory viruses.

Serology

Serologic tests detect host antibodies that are produced in response to infection with a particular infectious agent. The most important limitation of these assays is that antibody is usually not detectable early in the course of infection. Even if antibody is detected, it may represent a past infection. Serologic diagnosis usually requires demonstration of seroconversion, a 4-fold rise in IgG titer between sequential specimens, or a positive IgM assay. While the latter is usually thought of as a marker of acute infection, IgM can persist for 6 to 12 months. For the reasons outlined above, serologic assays are mainly used to diagnose infections that cannot be detected using more direct methods.

Bacteremia

Description

Normally the blood is sterile. Infection in any of the organs or tissues can result in entry of bacteria into the circulation. Replication of bacteria in the blood can contribute to the signs and symptoms of sepsis (eg, fever, tachycardia, leukocytosis, and hypotension) and may lead to dissemination of the organism to other tissues and organs; however, patients can be septic without having demonstrable bacteria in their blood. Bacteremia is often described as transient, intermittent, or continuous based on the number of positive specimens. Transient bacteremia occurs when small numbers of a commensal organism present on a mucosal surface gain access to the bloodstream. These infections are usually not clinically significant when they occur in an otherwise healthy host. Intermittent bacteremias are usually associated with a sequestered infection somewhere in the organs or tissues (eg, an abscess). Continuous bacteremias are associated with an intravascular focus of infection. Examples include endocarditis or an infected vascular catheter.

Diagnosis

Blood cultures are routinely collected as part of the diagnostic evaluation of patients who present with signs and symptoms of sepsis or disseminated infection. To maximize sensitivity and specificity, it is recommended that 2 to 3 sets of blood cultures be collected per septic episode. Most hospitals use continuous blood culture systems that utilize colorimetric, fluorescent, or manometric methods to defect bacterial growth. Positive bottles are then subcultured to agar plates for further evaluation of the organisms.

To identify intermittent bacteremias, the timing of the blood collection is important to maximize the likelihood of finding organisms while they are in the blood (see the section on sample collection in microbiology in Chapter 2). Ideally, blood from patients with intermittent bacteremias is collected during the hour before a temperature spike, but this is not practical because the febrile episodes are often not predictable. It is common practice for blood to be collected at 30- to 60-minute intervals (if possible) when a febrile patient is suspected of having an intermittent bacteremia. As one might expect, one is much more likely to detect a continuous bacteremia in the first blood culture than to detect an intermittent bacteremia.

A major problem in the interpretation of the blood culture results is incidental contamination of the specimen with the normal bacterial flora from the skin (Table 5–2). The clinical significance of a positive blood culture is dependent on both the number of positive specimens and the type of organism. The isolation of recognized pathogens such as S. aureus, Streptococcus pneumoniae, beta-hemolytic streptococci (Streptococcus pyogenesand Streptococcus agalactiae), enterococci, gram-negative rods (aerobic and anaerobic), or yeast from 1 or more blood cultures is almost always clinically significant (Table 5–3). In contrast, if only 1 of the multiple blood culture specimens is positive for an organism found on the skin (eg, coagulase-negative staphylococci or Corynebacterium spp.), the result is likely to reflect contamination during specimen collection rather than true septicemia. This frequently encountered problem is 1 reason why at least 2 blood samples should be collected for blood cultures. Although skin-derived bacteria are often thought of as nonpathogenic, it is important to remember that they can cause clinically significant infections, particularly in immunosuppressed patients and in patients with intravascular catheters or prosthetic devices. The isolation of the same skin flora organism in 2 separately collected specimens increases the probability that it represents a clinically significant bacteremia.

To avoid the problem of contamination of the blood culture bottles with skin organisms, meticulous preparation of the skin with a bactericidal agent is necessary. The number of blood cultures required for detection of a pathogenic organism is determined by the volume of blood collected per bottle, the timing of the blood collection, the type of organism producing the infection, and previous antibiotic exposure. Three or more blood culture collections may be required to document the presence of certain organisms.

Description

Rickettsia, Ehrlichia, and Anaplasma are obligate intracellular bacteria that cannot be detected in routine bacterial cultures. These organisms are transmitted to humans by ticks; therefore, the risk of acquiring these infections depends on the geographic distribution of the tick vectors and the time of year (see Table 5–4).

Rickettsia rickettsii, the agent of Rocky Mountain spotted fever (RMSF), is mainly transmitted by the dog tick (Dermacentor variabilis) and infects endothelial cells. The resulting vascular injury elicits a widespread vasculitis, consisting of vasodilation with perivascular edema, and at times complicated by thrombosis and hemorrhage. Erythrocytes extravasating into the dermis form nonblanching petechial or purpuric lesions. The characteristic rash is often absent during the early stages of infection, and the infection can progress to a life-threatening encephalitis if not promptly treated.

Ehrlichia chafeensis is transmitted by the lone star tick (Amblyomma americanum) and infects monocytes. Patients present with nonspecific findings including fever, leukopenia, thrombocytopenia, and/or elevations of hepatic enzymes. Similar clinical manifestations are seen with Anaplasma (formerly Ehrlichia) phagocytophilum that is transmitted by deer ticks (Ixodes spp.) and infects granulocytes.

Diagnosis

None of these agents can be cultured on artificial media. RMSF is usually diagnosed retrospectively with serologic tests; however, this should not delay treatment that should be initiated based on clinical findings and potential history of exposure. If the rash is present, organisms can be demonstrated by immunohistochemical staining of a skin biopsy in 70% of cases. Examination of peripheral blood smears in patients with Anaplasma can reveal the presence of organisms within inclusions in neutrophils, but many cases are negative. Ehrlichia infects monocytes but is rarely observed in peripheral blood smears. Polymerase chain reaction (PCR) of blood and/or serologic tests are the best methods for diagnosing Anaplasma and Ehrlichia infections.

Fungemia

Description

Yeast belonging to the genus Candida are a major cause of hospital-acquired bloodstream infections. These organisms are frequently part of the oral and gastrointestinal flora. Treatment with broad-spectrum antibiotics that disrupt the normal bacterial flora, the presence of intravenous catheters, and neutropenia all predispose to the development of candidemia.

Cryptococcus neoformans and Histoplasma capsulatum are important causes of fungemia in patients with markedly depressed cell-mediated immunity (Cryptococcus is further discussed in the section “Chronic Meningitis” and Histoplasma is further discussed in the section “Infections of the Lung and Pleurae”). Although molds such as Aspergillus spp. can cause disseminated infections in immunosuppressed patients, they are rarely detected in the bloodstream.

Diagnosis

Candidemia can usually be detected with routine blood cultures. Specialized techniques (eg, lysis–centrifugation cultures) are usually required to detect H. capsulatum and may enhance the detection of C. neoformans. Immunoassays that detect antigens produced by H. capsulatum and C. neoformans are also used to diagnose disseminated infections caused by these organisms.

Parasitic Infections of the Blood

Overview

Several vector-borne parasites can infect the blood. These include protozoans such as Plasmodium spp. (malaria), Babesia spp., and Trypanosoma spp., and nematodes such as the agents of lymphatic filariasis. Plasmodium infections are an important cause of nonspecific febrile illnesses in returning travelers, and Babesia infections are endemic in the United States; these infections are discussed below. Other blood parasites are uncommon in the United States.

Malaria

Description

Malaria is one of the largest causes of mortality and morbidity in the world. Individuals who travel to areas where malaria is endemic and develop fever within weeks of return should be suspected of suffering from malaria.

There are 4 species of Plasmodium that cause most cases of human malaria. These parasites are transmitted by Anopheles mosquitoes that are widely distributed throughout Africa, Asia, and Latin America. The most dangerous of the 4 species is Plasmodium falciparum. This organism can achieve very high levels of parasitemia and adheres to capillary endothelium, and this can lead to severe organ damage. P. falciparum infection may be fatal within days. P. vivax and P. ovale are morphologically similar and generally cause less severe infection, but unlike P. falciparum, they can establish persistent infection and cause relapses several months after the initial infection. P. malariae is the least virulent species and can cause low-level infection that may cause few symptoms, but it can persist for years. P. knowlesi, which infects monkeys, can also cause human infections.

Diagnosis

Currently, the diagnosis of malaria and the identification of each of the 4 species of Plasmodium responsible for malaria are based on the microscopic examination of stained erythrocytes in thick and thin blood films. These organisms have maturation cycles involving a variety of specific structures in the RBC, including ring trophozoites, growing trophozoites, mature schizonts, and gametocytes. The stippling of the RBCs with different dot patterns is also important in differentiating between the 4 species. Thus, the size and shape of the various malarial forms, their alteration of RBC morphology, and the stippling pattern in the RBCs provide the identification of the particular type of malaria. Quantitation of the level of parasitemia is also important. Marked parasitemia is a poor prognostic sign for P. falciparum infection. However, ill patients may have relatively low levels of parasitemia due to trapping of organisms in capillaries. PCR is starting to be used for the diagnosis of malaria and is particularly useful when low levels of parasitemia make it difficult to identify individual species. A rapid immunodiagnostic test for malaria may also be useful in settings where microscopy is not immediately available. Table 5–5 summarizes the relevant laboratory information for the diagnosis of malaria.

Babesiosis

Description

Babesia species are protozoa that, like Plasmodium species, infect erythrocytes. They are delivered to the infected host by the same tick (Ixodes) that transmits the agent of Lyme disease and human granulocytic anaplasmosis. Babesiosis mimics malaria in that it causes hemolysis, fever, anorexia, and hemoglobinuria. In the United States, B. microti is responsible for most cases of human babesiosis. In Europe, B. bovis and B. bigeminahave been implicated as agents of human disease. Babesiosis occurs mainly in the Northeast and upper Midwest in the United States. It affects patients of all ages, but most cases occur during the sixth and seventh decades of life. The infection from Babesia tends to be self-limited. In most cases, it lasts from weeks to months, following an incubation period of 1 to 6 weeks. Mild symptoms, including malaise, fever, and headache, characterize the disease in normal hosts, but asplenic patients often develop severe infections with high levels of parasitemia.

Diagnosis

The laboratory diagnosis rests upon the identification of the Babesia organisms inside erythrocytes in stained thick and thin peripheral blood smears. There are a number of morphologic features that differentiate Babesia from Plasmodium. Despite its relative shortcomings, serologic testing for B. microti can be performed as noted in Table 5–6. The level of parasitemia with Babesia does not always correlate with the severity of symptoms.

Viral Infections of the Blood

Overview

Many viruses such as varicella zoster virus (VZV), measles, enteroviruses, and arboviruses (such as West Nile virus) exhibit a viremic phase. These viruses also exhibit organ-specific manifestations and are discussed in other sections of this chapter. Cytomegalovirus (CMV), Epstein–Barr virus (EBV), and parvovirus B19 are discussed below because they are common viruses that can have a direct effect on the blood.

Infectious Mononucleosis/Epstein–Barr Virus

Description

Most cases of mononucleosis are caused by EBV, a member of the herpesvirus family that infects B lymphocytes and causes them to proliferate. This in turn stimulates the proliferation of cytotoxic T cells that control the active infection but do not eradicate the latent state. Infection with EBV is extremely common, and most individuals have asymptomatic infections. Patients with infectious mononucleosis typically present with fever, sore throat, and enlarged cervical lymph nodes.

In addition to mononucleosis, EBV is associated with 2 types of human tumor (Burkitt lymphoma and nasopharyngeal carcinoma) and is responsible for lymphoproliferative disorders in patients with severe immunosuppression following organ transplantation or AIDS. It also causes oral hairy leukoplakia in HIV-infected patients.

Diagnosis

Large atypical lymphocytes (cytotoxic T cells) are usually present in peripheral blood smears of patients with infectious mononucleosis caused by EBV, but they are also found in many other infections. The diagnosis of EBV-associated infectious mononucleosis is usually confirmed by a positive serum heterophile antibody test that detects the presence of antibodies that agglutinate horse or cow erythrocytes. The heterophile test is often negative in young children or in patients with atypical presentations; EBV-specific serologic tests are especially important in establishing the diagnosis in these situations. Quantitation of EBV DNA in peripheral blood is important in the diagnosis and management of EBV-associated lymphoproliferative disease in solid organ and bone marrow transplant recipients.

The use of laboratory tests in the diagnosis of infectious mononucleosis is shown in Table 5–7.

Cytomegalovirus

Description

CMV causes several clinical syndromes. It infects leukocytes, where it remains latent in immunocompetent individuals but readily reactivates in immunosuppressed individuals. CMV is a leading cause of opportunistic infections in transplant recipients and AIDS patients. In transplant recipients, it often presents as a nonspecific febrile illness, but it can also cause more invasive infections including esophagitis, hepatitis, colitis, pneumonitis, and retinitis, particularly in severely immunocompromised patients. CMV is also the most common congenital viral infection. It affects approximately 40,000 infants born each year in the United States. Hematogenous spread appears to be responsible for transmission of the virus to the fetus. Most congenital infections occur when the mother has a primary CMV infection during the pregnancy. Neonates can also acquire the infection from maternal breast milk. Approximately 10% of infants congenitally infected with CMV are symptomatic at birth. Common sites of involvement are liver, spleen, lungs, and central nervous system (CNS). Because specific antiviral therapy is available for treatment of these infants, rapid detection of CMV infection is necessary. Although most congenitally infected infants are asymptomatic at birth, approximately 10% to 15% of these will develop later problems such as hearing loss and other neurologic problems. In children and young adults, primary CMV infection can cause a mononucleosis-like illness.

Diagnosis

The detection of CMV in blood and tissues generally correlates with active disease, whereas detection of CMV in urine is not necessarily diagnostic of active CMV disease, even in immunocompromised patients. Quantitative PCR assays of CMV DNA in blood correlate with the likelihood of severe infection. Congenital CMV infection is established when CMV is isolated from the urine of neonates less than 3 weeks of age. CMV isolation from respiratory secretions of bone marrow transplant recipients is likely to be clinically significant because interstitial pneumonia is a complication of bone marrow transplantation. In AIDS patients, shedding of CMV in respiratory secretions does not always correlate with active infection. CMV serology is used to determine whether donors and/or recipients are latently infected with CMV. This has important implications for preventing subsequent infections. Diagnostic testing for CMV is summarized in Table 5–8.

Parvovirus B19

Description

Parvovirus B19 is a small single-stranded DNA virus that is transmitted by respiratory droplets. It is a common cause of infection in children in whom it causes a distinctive rash known as fifth disease. In adults, it often causes a significant arthropathy. An unusual feature of this virus is that it replicates in erythroid precursor cells and causes a temporary cessation of RBC production until the virus is cleared by the immune system. In normal hosts this has little, if any, consequence, but in patients who have a chronic hemolytic anemia such as sickle cell disease or hereditary spherocytosis, the parvovirus B19 infection causes a transient aplastic crisis in which there is a profound drop in the hematocrit. Parvovirus B19 can cause a chronic anemia in immunocompromised patients who are unable to clear the virus. Intrauterine infection of the fetus can also cause a severe anemia that leads to congestive failure and hydrops fetalis.

Diagnosis

Acute parvovirus infection can be confirmed by demonstration of IgM antibodies or detection of viral DNA by PCR. During a transient aplastic crisis, the reticulocyte count decreases to <0.1% even as the hematocrit is declining.

Description

The clinical features of infectious endocarditis, a microbial infection of the valvular or nonvalvular endothelium of the heart, depend on the type of organism, location, and type of valve. Acute infective endocarditis can present with temperatures ≥103°F, shaking chills, rapid worsening of valve function, and a variety of septic embolic complications. Subacute bacterial endocarditis is characterized by a low-grade or absent fever (as a result of infection by low-virulence organisms), and a variety of nonspecific signs and symptoms such as anorexia, weight loss, and malaise. Acute bacterial endocarditis typically occurs on native heart valves. It is most often caused by virulent organisms such as S. aureus, beta-hemolytic streptococci, and less commonly by S. lugdunensis, enterococci, and S. pneumoniae. Subacute bacterial endocarditis is usually caused by viridans group streptococci, enterococci, and fastidious gram-negative rods from the oral cavity. Several difficult-to-grow organisms are associated with “culture-negative” endocarditis. Prosthetic valve endocarditis is often caused by coagulase-negative staphylococci but can also be caused by S. aureus, other skin flora, enteric gram-negative rods, and fungi.

There are a number of risk factors for endocarditis, particularly in the acute form. These include diabetes, alcoholism, intravenous drug use, malignancy, infections in other sites, and immunosuppression. Anatomic defects also predispose patients to the development of infectious endocarditis. Such defects include mitral valve prolapse, congenital or rheumatic heart disease, and calcific aortic stenosis. The worst prognosis among patients with valvular disease is associated with those who have aortic valve involvement. The mitral valve, however, is the most frequently involved. Most individuals with endocarditis are between 45 and 60 years of age.

Diagnosis

The clinical and laboratory features of acute and subacute bacterial endocarditis are different (Table 5–9). It should be noted, however, that patients can present with a syndrome of intermediate severity between acute and subacute endocarditis, usually as a result of infection by organisms of intermediate virulence, such as Enterococcus species, Haemophilus species, and the Streptococcus bovis group. Laboratory confirmation of infective endocarditis usually involves isolation of the same organism from multiple blood cultures. Organisms are more likely to be isolated from blood cultures in patients who have acute bacterial endocarditis because they have a high-grade persistent bacteremia. If 3 sets of blood cultures are obtained, the blood cultures are positive in more than 99% of patients who have not received antibiotics. At least 2 sets of blood cultures should be obtained by separate venipunctures at presentation. The erythrocyte sedimentation rate is a nonspecific test that is almost always elevated in cases of endocarditis, but it is useful for monitoring the response to therapy. It is not uncommon to obtain negative blood cultures in patients who meet the clinical and echocardiographic criteria for infectious endocarditis. Many of these “culture-negative” cases are due to prior antibiotic therapy. In the past, the “HACEK” group of fastidious oral gram-negative rods was linked to culture-negative endocarditis, but these organisms are readily detected by modern blood culture systems. More recently, interest has focused on Coxiella burnetii, Bartonella spp., Tropheryma whipplei, and Brucella spp. as potential causes of “culture-negative” endocarditis. These agents can be detected by a combination of serologic and molecular methods.

Overview

Many organisms can produce an infection within the CNS. The major sites of infection are the meninges and brain parenchyma. Most organisms gain access to the CNS by hematogenous spread or by direct extension from an adjacent site. Bacterial infections can cause acute meningitis or may lead to formation of a brain abscess. Viral infections can present as meningitis or encephalitis, but often both sites are involved and the infection is more appropriately described as meningoencephalitis. Both fungi and mycobacteria can cause chronic meningitis while several parasites can cause intracerebral mass lesions. Each of these syndromes is often associated with specific organisms, information that can be used to guide the diagnostic workup. Rational test ordering based on clinical presentation is particularly important in patients with CNS infections since diagnostic specimens are difficult to obtain and are often present in limited quantities. Table 5–10 provides information on organisms that are frequently described causes of meningitis and/or encephalitis.

Acute Bacterial Meningitis

Description

Bacterial meningitis may present as a progressive illness over several days, or as a fulminant process that develops within hours. There is no single clinical sign that is pathognomonic of meningitis. Adolescents and adults typically present with combinations of fever, headache, nuchal rigidity, and other meningeal signs, and a decreased level of consciousness that can range from lethargy to coma; however, these findings are not present in all patients. Neonates and infants often present with nonspecific signs such as irritability, while nausea and vomiting are frequent complaints in children. Confusion, often without fever, is a common presenting sign in the elderly.

In most cases, the bacteria responsible for meningitis are acquired through the upper respiratory tract and then invade the blood. From the blood, they can then seed the meninges. There are a variety of factors that increase the risk for development of meningitis. These include splenectomy, sickle cell disease, cerebrospinal fluid leak, fistula or shunt, recent neurosurgical procedure, and infection contiguous to the CNS.

The organisms responsible for acute bacterial meningitis are highly dependent on the age of the patient and the clinical setting. S. agalactiae (group B Streptococcus [GBS]), E. coli, or Listeria monocytogenes are responsible for most cases of neonatal and infant meningitis. S. pneumoniae and N. meningitidis are responsible for most cases of community-acquired bacterial meningitis in children and adults (widespread vaccination for Haemophilus influenzae type b has nearly eliminated this previous childhood scourge). Elderly patients are at increased risk of infection with L. monocytogenes and aerobic gram-negative rods. In contrast, staphylococci and gram-negative rods are major causes of CNS shunt infections and postneurosurgery nosocomial infections. Knowledge of these patterns is important when deciding on empiric antibiotic therapy.

Diagnosis

Examination and culture of CSF is essential. There is usually a markedly elevated WBC count with a preponderance of neutrophils, elevated protein, and decreased glucose (relative to the blood level). Gram stain of CSF reveals the causative organism in 70% to 90% of cases of pneumococcal and meningococcal meningitis. The percentage is generally lower for other bacteria. Bacterial culture is essential in all cases because it has the greatest sensitivity and specificity. Patients who have rapidly progressive or severe disease frequently receive a dose of antibiotics before a CSF specimen can be collected. Although this may cause a false-negative culture, it should have little or no effect on the cell count and differential, protein, glucose, and Gram stain. Immunoassays that detect S. pneumoniae and N. meningitidis capsular antigens in CSF are useful in these patients with partially treated meningitis, but they are not more sensitive than a Gram stain.

Acute Viral Meningitis

Description

Viral meningitis (often described as aseptic meningitis due to the absence of bacteria) presents with fever, headache, and meningeal signs. There may be a mildly decreased level of consciousness. At least 75% of these infections are caused by members of the enterovirus family that includes the coxsackieviruses and echoviruses. Arboviruses (arthropod-borne viruses), HSV-2, HIV, and many other viruses can also cause this syndrome. Both enterovirus and arbovirus infections exhibit seasonal variation; most cases occur in the summer and early fall. Viral meningitis is usually a self-limited illness with a generally good prognosis. This is fortunate since there are currently no clinically useful antiviral drugs that are active against the enteroviruses and arboviruses. The clinical diagnosis of viral meningitis is often not clear-cut because there can be parenchymal involvement leading to varying degrees of encephalitis (see below). In addition, several other conditions can cause a similar clinical syndrome. These include partially treated bacterial meningitis, neoplastic diseases that have spread to the meninges, and immune-mediated diseases. It is important to identify these conditions because each of them is treatable and requires specific therapy.

Acute bacterial meningitis must be differentiated from viral and fungal meningitis. There is a significant difference in the CSF findings between viral and bacterial meningitis (Table 5–11).

Diagnosis

CSF analysis usually reveals an elevated WBC count with a preponderance of mononuclear cells, elevated protein, and a normal glucose. Identification of the causative agent is best achieved through the use of specific nucleic acid amplification tests or immunoassays; routine viral culture has a relatively poor yield in most cases. Many clinical or reference laboratories offer RT-PCR assays for enteroviruses, HSV, and West Nile virus. Immunoassays for detection of IgM and IgG are used to detect other viruses. Bacterial culture and cytopathology examination may be indicated if the diagnosis is unclear.

Chronic Meningitis

Description

Patients suffering from chronic meningitis usually present with a variety of signs including low-grade fever, headache, lethargy, confusion, nausea, vomiting, and stiff neck that develop over a period of 1 to 4 weeks. Fungi and mycobacteria are responsible for many cases of chronic meningitis. The encapsulated yeast, C. neoformans, is 1 of the most common causes, particularly in patients with depressed cell-mediated immunity due to HIV infection or immunosuppressive therapy. C. neoformans is acquired by inhalation that usually causes an asymptomatic pulmonary infection. These organisms then spread to the CNS by the hematogenous route. C. gattii, previously classified as a subspecies of C. neoformans, often causes meningitis in patients who are not infected with HIV. Coccidioides immitis and C. posadasii, dimorphic fungi that are prevalent in the southwestern United States, are also acquired by inhalation and have a predilection for infecting the meninges and CNS. Immunosuppressed patients who harbor Mycobacterium tuberculosis are at increased risk of CNS tuberculosis (TB). Neoplastic and immune-mediated diseases can also cause chronic meningeal symptoms; it is important to distinguish between these conditions and infection.

Diagnosis

The diagnosis of chronic meningitis requires evaluation of the CSF. Typically there are an increased number of mononuclear cells, mildly elevated protein, and normal glucose (except in TB). Immunoassays for C. neoformans capsular polysaccharide can be performed in less than an hour, have a very high sensitivity and specificity, and are superior to visual examination of India ink preparations (the antigen test does not distinguish between C. neoformans and C. gattii). Fungal culture should also be performed. If the patient is at increased risk of disseminated TB (ie, purified protein derivative [PPD]-positive or a history of pulmonary TB), then the CSF should be tested for mycobacteria. AFB smears are quite insensitive. PCR of CSF can provide early confirmation of M. tuberculosis infection in many cases. However, culture should still be performed to obtain an isolate for susceptibility testing.

Encephalitis

Description

Viral encephalitis is an infection of the brain parenchyma that can produce permanent neurologic damage or death in persons of all ages. A higher incidence of viral encephalitis is found in young children, the elderly, and persons with impaired immunity. For some viruses, there is a seasonal variation for infection. Most of the viruses that produce encephalitis enter the CNS via the hematogenous route. In its mildest form, viral encephalitis can present with fever and headache, and in its most severe form as an acute fulminating disorder with seizures and death. Prominent clinical findings include altered level of consciousness, altered mental status, headache, seizures, and other signs of neurologic dysfunction. The most important cause of sporadic encephalitis is HSV-1 that often causes permanent neurologic damage or death. Fortunately, there is effective antiviral therapy for HSV encephalitis that can prevent most of these complications if given early in the infection. Arboviruses transmitted by mosquitoes are responsible for periodic epidemics of encephalitis. A dramatic example of this phenomenon was the appearance of West Nile virus in the eastern United States in the summer of 1999 and its subsequent spread across the country during the next 4 years. Arboviral encephalitis is usually a self-limited infection. Most patients recover, but a significant number have persistent neurologic symptoms. Amebas such as Naegleria should also be considered in the differential diagnosis of encephalitis since they require specific therapy.

Diagnosis

The diagnosis of viral encephalitis includes evaluation of CSF. In patients with viral encephalitis, there is a predominantly lymphocytic pleocytosis, with a slight to moderate elevation of CSF protein, and no change in glucose content from normal. However, there are variations, depending on the virus that produces the encephalitis. Some of the agents can produce CSF findings that mimic those of bacterial meningitis (eg, pleocytosis with an increased number of neutrophils), particularly during the early stages of infection. The diagnosis of HSV encephalitis should be confirmed with a PCR assay of CSF that detects HSV DNA. This test is very sensitive and specific. Because of the severity of HSV infections and the availability of effective treatment, it should be performed on any patient with suspected encephalitis. Viral culture of CSF is insensitive and should not be routinely performed. Encephalitis caused by other viruses is often diagnosed by detection of viral nucleic acid or virus-specific IgM and IgG in serum or CSF.

Table 5–10 presents the laboratory evaluation for meningitis and encephalitis by disease and/or organism. Organisms not listed in the table also may cause CNS infections. Chapter 2 provides descriptions of many of the tests mentioned in the table.

Brain Abscess

Description

A brain abscess is a focal lesion and therefore presents differently from meningitis and encephalitis. The most common clinical presentation is persistent, worsening headache. More than half of patients will have focal neurologic deficits, but only half have fever. Bacterial abscesses can result from hematogenous dissemination or extension from an adjacent site. The most common organisms are viridans group streptococci, Haemophilus spp., and anaerobic gram-negative rods. If the patient is immunosuppressed, then the abscess could be caused by Aspergillus and other fungi, Nocardia spp. and Mycobacterium spp., and Toxoplasma gondii. Neurocysticercosis, a mass lesion that results from infection with the pork tapeworm Taenia solium, often presents as new-onset seizures in an adult.

Diagnosis

Unlike other CNS infections, examination of CSF is unlikely to yield useful information and even performing a lumbar puncture may be contraindicated. The initial diagnosis is usually based on CT and MRI findings. Identification of the causative agent is important for guiding therapy. This usually requires stereotactic biopsy of the abscess to obtain material for microscopic examination and culture. Serologic assays performed on serum may be helpful in the diagnosis of Toxoplasma infections and neurocysticercosis.

Description

Osteomyelitis is an infection of the bone characterized by progressive, inflammatory destruction of the bone tissue. It can be classified by the route of infection (hematogenous, contiguous spread, direct traumatic, or surgical inoculation), the site of infection, the type of patient, or duration of infection (acute or chronic). Hematogenous osteomyelitis is most common in prepubertal children, where it usually involves the long bones, and older adults where it usually involves the vertebrae. Less common sites of osteomyelitis include the sternoclavicular and sacroiliac joints, and symphysis pubis. Children with acute osteomyelitis appear ill with fever, chills, localized pain, and leukocytosis. In contrast, adults with vertebral osteomyelitis often have a subacute course with slowly worsening back pain and little or no fever or leukocytosis. Hematogenous osteomyelitis is usually caused by a single organism. S. aureus accounts for half of cases. Other frequently encountered organisms are streptococci and enterobacteriaceae in neonates, gram-negative rods in the elderly, Salmonella spp. in patients with sickle cell disease, P. aeruginosa in intravenous drug users, and Candida spp. in patients with intravascular catheters. TB and brucellosis can cause vertebral osteomyelitis in patients who have been exposed to these organisms.

Osteomyelitis caused by a contiguous focus of infection often results from an injury associated with an open fracture or following surgery for reconstruction of bone. It is also common in patients with poorly controlled diabetes mellitus due to peripheral neuropathy and vascular insufficiency. This form of osteomyelitis is found almost exclusively in the foot and starts insidiously in areas of traumatized skin. The infection of the skin may be easily overlooked as the organism makes its way to the bones in the toes, metatarsal heads, and tarsal bones. Unlike hematogenous osteomyelitis, these contiguous focus infections are usually polymicrobial involving combinations of staphylococci, streptococci, enterococci, and gram-negative rods. Additional classes of organisms may be present in the wound if the injury site was contaminated with soil. With between 500,000 and 1,000,000 hip replacements per year worldwide, infections associated with prosthetic joints are also common (see the section “Infections of the Joints”).

Diagnosis

Imaging techniques can be used to detect osteomyelitis in the early phase and reveal the extent of damage to bones and joints. Definitive diagnosis requires biopsy and culture of the infected tissue in most cases. This permits an accurate identification of the organisms responsible for the osteomyelitis. In some situations, the organisms suspected of causing osteomyelitis may be identified from the culture of synovial fluid, blood, or biopsy of contiguous lesions. Microbiologic culture of blood or contiguous tissue does not definitively identify the organism in the bone, but it may provide a strong indication of the organisms responsible for the osteomyelitis.

Table 5–12 lists the organisms most likely to cause osteomyelitis and identifies the populations at risk for infection by the named organisms.

Description

Acute pain and swelling in the joint can be produced by infectious agents, crystals of monosodium urate or other compounds, and a variety of less common causes. Because some organisms can destroy cartilage in a matter of days, the diagnosis of infectious arthritis must be made quickly. Organisms can seed the joint through the hematogenous route (via intravenous drug abuse, indwelling catheters, endocarditis), through direct inoculation from intra-articular injections or arthroscopy, or from a contiguous site of infection, especially the bones and bursae. Septic arthritis can resemble a variety of noninfectious processes, but an acutely inflamed joint should be considered septic until proved otherwise. Septic arthritis is most often monoarticular with polyarticular involvement in less than 20% of the cases.

Diagnosis

The mainstays of the laboratory investigation for a joint infection are synovial fluid Gram stain and culture to identify infecting organisms, and polarized microscopy of the synovial fluid to identify crystals in crystal-induced arthritis. It should be noted, however, that crystal-induced and infectious arthritis can coexist. Synovial fluid WBC counts consistent with infection are ≥50,000/μL, with more than 90% as neutrophils. Table 5–13 summarizes the organisms associated with joint infection and the relevant clinical features for each infection.

Overview

Many different organisms can produce infections of the skin and soft tissue. Clinical manifestations and severity vary widely and include aggressive, fast-moving infections such as necrotizing fasciitis, abscesses that require incision and drainage, chronic superficial fungal infections, and rashes that can be caused by local or systemic viral infections. A brief description of infections associated with particular organisms is provided in Table 5–14. The diagnostic information to identify infecting organisms is also included in the table. Lyme disease and Bartonella infections are discussed in Tables 5–15 and 5–16. A number of other infectious diseases, such as syphilis and herpes simplex infections, also have skin manifestations and are more fully described elsewhere in this chapter.

Abscesses, infected wounds, and cellulitis are common acute infections of the skin. The most common organisms are S. aureus, beta-hemolytic streptococci (groups A and B), other streptococci and staphylococci, and several gram-negative rods. Certain underlying conditions, such as diabetes and peripheral vascular disease, predispose to polymicrobial infections involving gram-positive cocci and gram-negative rods.

Cat/dog and human bite wounds are commonly infected with the above organisms, but they are also associated with specific organisms (Pasteurella multocida and Eikenella corrodens, respectively).

Necrotizing fasciitis (usually caused by S. pyogenes) and clostridial myonecrosis (also known as gas gangrene) are uncommon, but they are life-threatening infections that require prompt surgical and medical intervention. Traumatic gas gangrene is usually caused by contamination of wounds by Clostridium perfringens (an anaerobic spore-forming gram-positive rod). Spontaneous gas gangrene is usually caused by C. septicum, often in patients with underlying gastrointestinal malignancies or neutropenia.

Description

The causative agent of Lyme disease is Borrelia burgdorferi, which is spread by the bite of a tick of the genus Ixodes. Lyme disease is the most common vector-borne infection in North America and in Europe. It tends to go unnoticed by many patients because the associated influenza-like symptoms are not specific for the disease. Within days to weeks of infection, a distinctive skin rash, known as erythema migrans, appears. It is important to treat the patient at the time that this rash appears to prevent subsequent potential neurologic, cardiac, or musculoskeletal complications.

Diagnosis

Unlike many infections, this laboratory diagnosis is rarely based on culture of B. burgdorferi. This is because there are few organisms in clinical specimens, and these organisms require specialized media for growth with prolonged incubation. Therefore, the diagnosis rests upon a characteristic clinical picture supported by positive serologic tests consistent with the infection. In patients who present with erythema migrans, the diagnosis is straightforward. However, for many patients with less specific symptoms and equivocal serologic test results, it is difficult to make a definitive diagnosis. Serologic testing for Lyme disease is a 2-step process involving a screening enzyme-linked immunoassay (ELISA), followed by a confirmatory immunoblot (see Chapter 2 for a description of these assays). There are several important issues regarding the serologic assays to detect Lyme disease:

• The serologic tests are not entirely specific for Lyme disease.

• Serum samples collected in the early stage of the disease may contain no antibodies to the organism because there is little or no antibody production in many patients until 3 to 4 weeks after the onset of the illness.

• The immune response is variable, and treatment with antibiotics can reduce the magnitude of the response.

Cross-reactivity between the antigens from B. burgdorferi and antigens from other organisms may occur. For example, false-positive serologic reactions for Lyme disease have been reported in patients with RMSF, leptospirosis, and syphilis. False-positive reactions can also occur in some patients with autoimmune diseases.

PCR-based assays for detection of B. burgdorferi DNA may be useful for testing joint fluid or CSF. Only properly validated assays should be used since in a low-prevalence population (ie, patients with nonspecific symptoms and no history of a tick bite) the positive predictive value can be very low. A summary of the different assays currently available for diagnosis of Lyme disease is provided in Table 5–15.

Descriptions

Several organisms of the genus Bartonella were found to be associated with human disease in the 1990s when they were identified as the etiologic agents in cat-scratch disease and bacillary angiomatosis. Most cases of cat-scratch disease are caused by B. henselae (other Bartonella spp. and Afipia felis may account for a small percentage of these cases). Initially a papule or pustule forms at the site of the scratch, but most individuals seek medical attention several weeks later because of the development of a regional lymphadenopathy (mainly in the neck or upper extremity). In most cases, it resolves spontaneously, although in rare cases severe complications can occur, including encephalitis, conjunctivitis, and neuroretinitis. Bacillary angiomatosis is a disorder in which there are distinctive and potentially lethal vascular proliferative responses in the skin, the bones, and other organs. Bacillary angiomatosis is most commonly diagnosed in individuals infected with HIV.

Diagnosis

A further description of cat-scratch disease and bacillary angiomatosis and recommendations for their diagnosis are included in Table 5–16. Serologic tests and PCR-based tests may be useful to support the histopathologic findings from lymph node biopsies in cat-scratch disease and from skin biopsies in bacillary angiomatosis. Bartonella spp. are difficult to culture.

Fungal infections of the skin can be characterized as superficial, cutaneous, and subcutaneous. Infections caused by fungi such as Malassezia spp. are limited to the superficial layers of the skin and can result in patchy alteration of pigmentation. The more invasive cutaneous infections caused by dermatophytes and subcutaneous infections are discussed in the following sections.

Descriptions

The dermatomycoses (also known as ringworm) are skin infections caused by dermatophytes. These organisms are closely related fungi that invade keratinous tissues such as skin, hair, and the fur of animals. The dermatophytes are classified into 3 genera, Epidermophyton, Microsporum, and Trichophyton. Dermatophyte infections are named according to the anatomic location (in Latin) for the body site, following the word “tinea.” For example, tinea pedis is a dermatophyte infection of the foot. The diagnosis of a dermatophyte infection is made by microscopic examination of a scraping of the lesion and by culturing the specimen on selective agar that inhibits the growth of commensal bacteria and other fungi. When organisms are successfully grown in culture, they are identified to the species level by colony and microscopic morphology.

Sporotrichosis is a chronic infection characterized by nodular lesions in cutaneous and subcutaneous tissues and adjacent lymphatics. This infection is caused by Sporothrix schenckii, a dimorphic fungus that is typically introduced by traumatic implantation into the skin (eg, during gardening). Sporotrichosis commonly displays a lymphocutaneous pattern as it tracks up the lymphatic system in the hand and arm. Rare manifestations include pulmonary and disseminated infections. Histologic examination of a specimen will often reveal granulomatous inflammation, but organisms are rarely seen. Therefore, diagnosis usually depends on culturing the specimen to permit microbiologic isolation of the S. schenckii organisms.

Mycetoma is a chronic infectious disease that involves cutaneous and subcutaneous tissues, fascia, and bone, and remains localized. It is characterized by draining sinuses, with aggregates of the etiologic agent in the pus draining from the sinuses. The fungi that produce the mycetomata are associated with woody plants and soil. The organisms are usually introduced by traumatic inoculation into the skin. A tumor-like deforming disease can develop during subsequent years if untreated. Dozens of fungal organisms have been documented as causes of mycetoma. In the United States, the most common agent is Pseudoallescheria boydii. The asexual form of this organism is known as Scedosporium apiospermum. Other fungi predominate in tropical and subtropical areas. The fungal elements are most often found in the center of a suppurative and granulomatous lesion that develops in a deep site and extends out to the skin for drainage. Draining sinuses appear in essentially all patients within 1 year of the initial trauma. Identification of the causative agent is made by fungal smear and culture of the material draining from the sinus tracts. Clinically similar infections are caused by filamentous gram-positive bacteria in the genus Nocardia. It is important to identify the infecting agent because the therapy for fungi is very different from that used for bacteria.

Chromomycosis is a subcutaneous infection by organisms originating in the soil, with only rare cases of dissemination. It is most often seen in tropical or subtropical environments and is rare in the United States. The lesions typically appear on the lower extremities. They are pink, scaly papules that expand to form a superficial nodule, and their presence suggests the diagnosis. Examination of the lesions microscopically in potassium hydroxide (KOH) or calcofluor white preparations can be diagnostic. Without therapy, which is usually surgical, the scaly papules grow to form nodules with a verrucous and friable surface.

Diagnosis

A further description of the infections and the tests used to identify the associated organisms are included in Table 5–17.

Overview

Viral infections can cause a variety of macular, papular, or vesicular rashes. Many of these typically occur in the pediatric age range and may be associated with systemic signs and symptoms. enteroviruses and parvovirus B19 are discussed in other sections.

Description

Primary infection with VZV causes chickenpox, a vesicular rash that occurs predominantly on the trunk, scalp, and face. This disease is usually self-limited, with the symptoms resolving after 7 days. Varicella can also produce pneumonia, with pulmonary symptoms manifested approximately 4 days after the varicella rash. After primary infection, the virus enters the latent phase and remains in sensory ganglia. On reactivation, which occurs in a minority of adults, it produces herpes zoster, a vesicular rash that occurs along a dermatome distribution. The incidence of varicella has been declining since the introduction of a live virus vaccine.

Diagnosis

Chickenpox and herpes zoster are diagnosed clinically in most cases because of the characteristic presentation of the diseases. Laboratory tests for the VZV virus, although they represent the gold standard for diagnosis, are typically unnecessary. Cutaneous lesions may be evaluated for the presence of VZV by direct immunofluorescence. Serologic testing is often important to determine whether an individual has ever been infected with VZV. Assays for VZV infection are summarized in Table 5–18.

Description

Rubeola and rubella infections are often confused because of the similarity in their names and similar clinical manifestations. Measles (or rubeola) is a highly contagious childhood disease characterized primarily by fever and a rash. The primary portal of entry for the rubeola virus is the upper respiratory tract. Approximately 14 days after exposure to the rubeola virus, a characteristic measles rash appears, and within 1 to 2 additional days there is a measurable amount of antibody to rubeola virus in the bloodstream. The leading cause of death in patients with measles is secondary bacterial pneumonia. Rubella, also known as German measles, is most often a mild illness in children and young adults. It is widely recognized as a dangerous infection in early pregnancy when an infection of the fetus can cause congenital abnormalities. Rubella is characterized by a rash and an enlargement of lymph nodes. Like the rubeola virus, the portal of entry of rubella virus is most often the respiratory tract. The availability of vaccines against measles and rubella has greatly decreased the incidence of these infections in the United States.

Diagnosis

The laboratory diagnosis of measles or rubella can be important for epidemiologic surveillance purposes and to limit its transmission to susceptible individuals. The laboratory diagnosis is usually based on detecting virus-specific IgM in serum or isolation of the virus from urine or respiratory specimens.

Within 24 to 48 hours of the development of a rash, antibodies to rubella become detectable. Primary infection stimulates production of antibodies that confer lifelong immunity. It is for this reason that the presence of antibodies to rubella is desirable before initiating pregnancy. The antibodies can be demonstrated in a serologic test that indicates exposure to the rubella virus. Serologic testing is an important component of the evaluation of a pregnant woman with the clinical signs and symptoms of rubella. Table 5–19 summarizes the laboratory evaluation for rubeola and rubella.

Description and Diagnosis

Infectious agents play a prominent role in many diseases of the eye. Table 5–20 describes the infections of the eye according to anatomic site of infection within the eye. Many organisms that produce eye infections are described in detail in other sections of this chapter. The microbiologic isolation and tests for identification of the organisms listed in Table 5–20 as causative for disease are presented in other sections of this chapter.

Description and Diagnosis

Table 5–21 describes the infections of the pharynx, larynx, mouth, ear, orbit, and sinuses. Because there are such a large number of organisms that produce these infections, a brief description of the infections and their associated organisms is presented in Table 5–21. For similar reasons, the diagnostic studies useful in identifying the disease and its causative organisms are also provided in the table.

Overview

Many categories of organisms can cause pneumonia and other types of pulmonary infections. It is very important to consider the clinical setting when evaluating and managing a patient with pneumonia because the types of organisms that are responsible depend on whether or not specific risk factors are present.

Community-acquired pneumonia is commonly caused by S. pneumoniae, Mycoplasma pneumoniae, respiratory viruses, H. influenzae, and Legionella spp. In contrast, hospital-associated and ventilator infections are likely to be caused by multidrug-resistant organisms including K. pneumoniae, P. aeruginosa, Acinetobacter baumanii complex, and MRSA. P. aeruginosa, Burkholderia cepacia, and MRSA are also important causes of lung infections in patients with cystic fibrosis. In recent years there has been an increase in the number of Bordetella pertussis infections that has been attributed to waning immunity following the introduction of acellular pertussis vaccines.

Travel and/or exposure history can be an important clue in patients with persistent pulmonary signs and symptoms, as they may have TB or dimorphic fungal infections (described below). Patients with depressed cell-mediated immunity (eg, transplant recipients or HIV infection) are at increased risk of Pneumocystis and CMV infections. Patients who have prolonged neutropenia from chemotherapy, for example, are at increased risk of invasive infections caused by Aspergillus spp. and other fungi.

Table 5–22 describes the infections of the lung and pleurae. The many different lung infections are grouped into bacterial, fungal, parasitic, and viral diseases. There are 2 major challenges in the laboratory diagnosis of pulmonary infections. First, it can be difficult to obtain respiratory specimens that are not contaminated with oropharyngeal flora. This is particularly true of expectorated sputum. It is 1 of the reasons why this type of specimen is routinely screened microscopically for the presence of squamous epithelial cells to determine whether it is a true lower respiratory specimen. The other problem is that there is no single test that detects all of the potential respiratory pathogens. While routine Gram stain and sputum culture readily detects S. pneumoniae, common gram-negative rods, and S. aureus, separate cultures and/or test methods are required to detect Legionella, mycobacteria, fungi, respiratory viruses, CMV, and Pneumocystis. These are discussed in more detail in the following sections.

Description

TB is a major cause of morbidity and mortality around the world and remains a major challenge for public health officials. Approximately one third of the world's population is estimated to be infected with the causative agent, M. tuberculosis. This slow-growing AFB continues to be an important concern in industrialized countries because of the development of drug-resistant strains and a growing population of immunosuppressed patients who are at increased risk of TB. Although it can infect a variety of organs, M. tuberculosis primarily causes pulmonary disease. It is usually acquired by inhalation of infectious aerosolized droplets. The majority of primary infections are asymptomatic; however, the organisms are not completely eliminated. This leads to a quiescent phase known as latent tuberculosis infection (LTBI). Otherwise healthy individuals with LTBI have an approximately 10% lifetime risk of developing secondary or reactivation pulmonary TB. Prophylaxis of asymptomatic-infected individuals reduces the risk of subsequent reactivation TB.

Clinical features of active pulmonary TB include fever, night sweats, weight loss, productive cough, and hemoptysis in later stages of the disease. Radiographic studies often show cavitary lung lesions, usually in the lung apices. It is important to realize that immunosuppressed patients who develop active TB often have atypical clinical presentations and can have nonspecific radiographic changes. Before the epidemic of HIV infection in the United States, approximately 85% of newly diagnosed infections with TB were limited to the lung, with 15% involving nonpulmonary sites or both pulmonary and nonpulmonary sites. With advanced HIV infection, less than half the cases are limited to pulmonary involvement. Extrapulmonary TB commonly involves the lymph nodes, pleura, genitourinary tract, bones and joints, meninges, peritoneum, and pericardium.

Early identification of patients with active pulmonary TB is crucial for preventing transmission of this serious infection to other patients and health care workers. Treatment of active TB caused by sensitive strains requires combination therapy for 6 months. Multidrug-resistant and extremely resistant M. tuberculosis (MDR-TB and XDR-TB, respectively) are more difficult to treat and have a poorer outcome.

Diagnosis

There are 2 categories of laboratory tests for TB: those that detect latent infection and those that detect active disease. Skin testing with PPD detects previous exposure to M. tuberculosis. A delayed-type hypersensitivity response to the M. tuberculosis antigens (mediated by T cells) leads to induration at the site of injection. One problem with the PPD test is that individuals who have been vaccinated with bacille Calmette–Guerin (BCG) can also have a positive reaction. BCG is derived from M. bovis, a member of the M. tuberculosis complex, and is widely used outside the United States. Recent advances in immunology and genomics have led to the development of alternatives to the PPD test, such as interferon-gamma release assays (IGRAs). Peripheral blood or purified mononuclear cells are incubated with antigenic peptides that are unique to M. tuberculosis (ie, they are not present in BCG) and then an immunoassay is performed to measure production of interferon-gamma. The IGRAs are at least as sensitive as the PPD and are more specific since BCG vaccination does not produce a false-positive result.

The diagnosis of secondary TB depends on detection of M. tuberculosis in clinical samples. This testing is particularly important since the PPD and IGRAs can be negative in patients with active TB. Acid-fast staining of sputum specimens (using either a fuchsin [red] stain or a fluorescent stain) enables visualization of the mycobacteria in ~70% of cases of pulmonary TB. Detection of mycobacteria in sputum using an AFB stain provides only presumptive evidence of pulmonary TB in the presence of characteristic radiologic findings. The presence of M. tuberculosis must be confirmed by culturing the organism in liquid and/or solid media or by using NAATs. Modern automated liquid culture systems routinely detect growth of M. tuberculosis in 1 to 2 weeks versus 4 to 6 weeks with traditional culture on solid media. These systems also make it possible to perform rapid susceptibility testing in liquid culture for first-line antituberculous drugs. The NAATs make possible same-day confirmation of smear-positive specimens, which contain relatively large numbers of organisms. Culture remains the gold standard for detecting M. tuberculosis in smear-negative specimens.

Table 5–23 includes the clinical and laboratory information relevant to the diagnosis of pulmonary and extrapulmonary TB.

Other nontuberculous mycobacteria, including slow-growing organisms such as M. avium complex and M. kansasii, and rapid growers, such as M. abscessus, can cause chronic pulmonary disease in both normal and immunocompromised hosts.

Description

Legionella pneumophila is a fastidious, slow-growing gram-negative rod. Legionella species are widespread in the environment and are a cause of community-acquired pneumonia. They are usually found in surface or potable water and are associated with moist environments. Approximately 10,000 to 15,000 cases of Legionella pneumonia occur each year in the United States. Most cases occur sporadically, but outbreaks have been associated with aerosolized transmission from cooling towers, evaporative condensers, potable hot water lines, showers, respiratory therapy equipment, decorative fountains, and whirlpool spas. Outbreaks in health care facilities are especially worrisome because of the large population of patients with compromised immunity or impaired pulmonary function who are at increased risk of severe Legionella infections.

Legionella infections can present as subclinical infections, pneumonia, and extrapulmonary infections including endocarditis. Patients with Legionella pneumonia can present with a broad spectrum of symptoms, ranging from mild cough to widespread pulmonary infiltrates and multisystem failure. Patients with Legionella pneumonia may also experience hemoptysis, diarrhea, and a change in mental status.

Diagnosis

The diagnosis of legionellosis can be easily missed because the organisms are not detected on routine Gram stain (Legionella stains very poorly) and growth of the organism in culture requires special types of agar. A sputum Gram stain showing mostly neutrophils, without associated bacteria, should raise suspicion of Legionnaires disease or other atypical pneumonia. L. pneumophila serogroup 1 infections, which account for most community-acquired legionellosis, can be readily diagnosed using rapid immunoassays that detect a Legionella antigen that is excreted in urine. These tests detect 80% to 90% of cases and have good specificity. Another advantage is that they remain positive for several weeks, even after the patient has been started on antibiotics. Bacterial culture is the gold standard for the diagnosis of Legionella infection. Cultures from sputum, bronchoalveolar lavage (BAL), and/or lung tissue may require 4 to 5 days of growth for isolation of Legionella colonies. The sensitivity for organism detection is greater with a BAL specimen than with an expectorated sputum specimen. Isolation of Legionella from specimens requires the use of a charcoal-based bacteriologic medium, with the addition of antibiotics if the specimens are from nonsterile sites. The isolation and identification of Legionella, in association with pneumonia, is diagnostic for Legionella pneumonia. Direct fluorescent antibody tests of respiratory specimens are no longer recommended because they are relatively insensitive, and the specificity is greatly dependent on the experience of the individual performing the test. PCR testing and serology also may be useful in diagnosis of Legionella infections.

Table 5–24 summarizes the laboratory tests relevant to diagnosis of the Legionella infections.

Description

Nocardia spp. are aerobic gram-positive actinomycetes that are found worldwide in soil and decaying organic matter. Nocardiosis is chiefly an opportunistic infection, particularly in patients with impaired cell-mediated immunity such as hematopoietic malignancies, HIV/AIDS, those receiving immunosuppressive therapy, and transplant recipients. Pulmonary nocardiosis is the most common presentation. It can exhibit the full spectrum of acute or chronic pulmonary infection, including pneumonia and abscess formation. Other clinical manifestations include anorexia, productive cough, pleurisy, dyspnea, hemoptysis, and weight loss.

Primary Nocardia infection in the lung, skin, or soft tissue may erode into blood vessels and spread hematogenously to a variety of different organs. Nocardia have a well-recognized predilection for invasion into the CNS.

Diagnosis

Detection of the organism can be accomplished by microscopic examination of specimens combined with culture. Gram staining may reveal filamentous gram-positive rods with or without branching. They are also partially acid-fast; that is, they are positive on a modified acid-fast stain (which uses a less stringent decolorizer) but are negative on a regular acid-fast stain. Nocardia spp. are slowly growing organisms and may be difficult to recover. Traditionally they were identified based on biochemical reactions. More recently introduced DNA-based methods reveal that many of organisms that would previously have been identified as Nocardia asteroides are separate species with distinct antibiotic susceptibility profiles.

The laboratory information for diagnosis of nocardiosis in different anatomic sites is provided in Table 5–25.

Description

Pneumocystis spp. are single-cell organisms that were originally described as protozoans, but phylogenetic analysis indicates that they are more appropriately classified with the fungi. These organisms are a well-recognized cause of pulmonary infection in patients with profoundly impaired cell-mediated immunity. These infections were originally attributed to P. carinii (which is found in rats), but it is now known that human infections are caused by the morphologically similar P. jirovecii. From the beginning of the HIV epidemic in the early 1980s until 1993, P. jirovecii was the indicator infection for more than 20,000 newly diagnosed cases of AIDS in the United States reported to the Centers for Disease Control and Prevention. It has become much less common since the introduction of highly active antiretroviral therapy. In a small number of cases, Pneumocystis can also cause extrapulmonary infections.

Pneumocystis spp. cannot be cultured in vitro. Laboratory diagnosis depends on identification of the organism in stained preparations of clinical specimens, most often induced sputum or BAL fluid. These are concentrated onto a slide by cytocentrifugation. Other specimens include transbronchial or open lung biopsies. The Pneumocystis life cycle includes trophozoite and cyst stages. The most sensitive method for detecting these forms is staining the preparation with fluorescently labeled monoclonal antibodies. Other frequently used stains are GMS (stains cyst walls) and Giemsa (stains trophozoites and intracystic stages). PCR analysis of respiratory specimens may be useful in the diagnosis of Pneumocystis, but it is not widely available.

Table 5–26 summarizes the laboratory information that supports a diagnosis of P. jirovecii infection.

Description

The dimorphic fungi grow as filamentous molds in the environment but transform into yeast (or related forms) in infected tissue. The most important members of this group are H. capsulatum and Coccidioides spp. These organisms are usually acquired by inhalation, but they can disseminate and cause life-threatening systemic infections.

H. capsulatum is endemic along the Mississippi and Ohio River Valleys, as well as in parts of Central America and the Caribbean region. Most infections are asymptomatic or subclinical; however, inhalation of large quantities of spores or hyphal fragments can cause symptomatic lung infection that requires antifungal therapy. As with TB, primary infection with H. capsulatum is contained by the cell-mediated immune response. However, the organism may not be eradicated. H. capsulatum infection in patients with underlying lung disease can lead to chronic progressive pulmonary histoplasmosis that must be treated to prevent further lung damage. Patients who have depressed cell-mediated immunity (due to underlying disease or immunosuppressive therapy) are at a risk of developing disseminated histoplasmosis. This form of the disease may present with nonspecific findings such as fever, weight loss, and hepatosplenomegaly, and it is fatal if untreated. Patients who harbor H. capsulatum and receive drugs that inhibit TNF or its receptor are also at a high risk of developing disseminated infection.

Coccidioides spp. are endemic in the southwestern United States (C. immitis in the central valley of California and C. posadasii in Arizona). The life cycle of Coccidioides is similar to H. capsulatum except that it forms spherules in infected tissue. Immunosuppressed patients and certain ethnic groups are at increased risk of disseminated coccidioidomycosis and CNS infections.

Immunosuppressed patients are susceptible to a variety of other fungal lung infections, including Aspergillus spp. and other septate molds, nonseptate molds such as Mucor and Rhizopus, and the encapsulated yeast C. neoformans.

Diagnosis

Diagnostic tests for H. capsulatum include fungal culture, immunoassays that detect a fungal cell wall antigen, and serology. Culture is the gold standard, but fungal growth is usually not detected for 1 to 2 weeks. Serology is useful for patients with chronic pulmonary histoplasmosis, but it is relatively insensitive for diagnosis of disseminated histoplasmosis. The antigen test performed on serum or urine is particularly useful for diagnosing disseminated disease. Coccidioidomycosis is diagnosed by serology and/or culture depending on the clinical presentation. The diagnosis of dimorphic fungal infections can also be confirmed by demonstration of characteristic structures in biopsy specimens. Currently the diagnosis of other fungal lung infections relies on culturing respiratory secretions and/or histopathologic examination of biopsy specimens. A serum assay that detects a galactomannan antigen produced by Aspergillus spp. is useful in the diagnosis of invasive pulmonary aspergillosis. Serum assays for circulating ®-D-glucan may also be useful for detecting invasive fungal infections.

The clinical findings associated with systemic mycotic infections are shown in Table 5–27 along with the microbiologic evaluation and histopathology findings.

Description

Many different viruses can cause upper and lower respiratory infections. Respiratory syncytial virus (RSV) and influenza viruses cause large numbers of infections in the winter months. RSV is the major cause of bronchiolitis in infants, and it can also cause serious infections in the elderly. Influenza is often thought of as an infection of adults (in whom it causes a syndrome characterized by rapid onset of fever, headache, and myalgias followed by upper respiratory symptoms). However, it also commonly infects children and may resemble RSV. Primary influenza pneumonia is a rare but dangerous form of the infection. More commonly, the typical influenza syndrome described above is followed several days later by a secondary bacterial pneumonia. Parainfluenza viruses classically cause croup (tracheobronchitis), the clinical manifestations of which often overlap those caused by RSV and influenza. Other important respiratory viruses include adenoviruses, metapneumovirus, and coronaviruses, including the agent of SARS. Because of the availability of antiviral agents that target influenza viruses, it has become important to establish the specific cause of virus-like respiratory particularly in severely ill patients and those with underlying cardiac and pulmonary diseases. Identification of the cause of severe respiratory infections may also be needed for infection control activities. Immunosuppressed patients are susceptible to all of the viruses described above. They are also at increased risk of developing CMV pneumonitis.

Diagnosis

The common respiratory viruses can be identified by detecting specific viral antigens in nasopharyngeal specimens (aspirates, washes, or swabs). Rapid tests for influenza can provide an answer in less than 30 minutes, but their sensitivity is only 40% to 70% (specificity is >90%). Immunofluorescent assays in which a slide preparation is stained with labeled antibodies are much more sensitive. However, they are more labor intensive and require a skilled observer. Isolation of respiratory viruses requires proper specimen collection to prevent the loss of viability of the viruses before arrival in the laboratory. Traditional viral culture methods are sensitive, but respiratory viruses typically require 3 to 10 days in culture before they can be detected. Centrifugation-enhanced culture, in which the organisms are centrifuged onto the cultured cells, can detect viruses in 1 to 2 days. Commercially available multiplexed nucleic acid amplification assays (eg, RT-PCR) can detect several respiratory viruses in 1 to 8 hours and rival or exceed the sensitivity of viral culture.

Laboratory methods for detecting respiratory viruses are summarized in Table 5–22.

Overview

Although many organisms can cause infectious gastroenteritis, the clinical setting usually makes it possible to focus on a small group of likely pathogens. This is particularly important since no 1 laboratory test can detect all of the potential agents, which include viruses, bacteria, and parasites. Key factors to consider are whether the infection was acquired in the community or in a health care facility, duration of symptoms, travel history, and whether the patient is immunosuppressed.

Description

In immunocompetent hosts, the majority of cases of community-acquired self-limited nausea, vomiting, and/or diarrhea are caused by viruses (primarily rotaviruses, noroviruses, and enteric adenoviruses [types 40 and 41]). Laboratory testing is usually not performed unless there are large outbreaks that have epidemiologic significance, for example, outbreaks on cruise ships or in health care facilities. Although enteroviruses are usually acquired by fecal–oral transmission, they generally cause systemic infections; gastroenteritis is not a prominent clinical manifestation. CMV, especially in immunocompromised patients, can produce an explosive, watery diarrhea.

Diagnosis

Table 5–28 summarizes the clinical, radiologic, histopathologic, and laboratory findings associated with the gastrointestinal illnesses produced by rotavirus, adenovirus, CMV, and noroviruses.

Description and Diagnosis

Community-acquired diarrhea accompanied by abdominal pain or systemic symptoms should be evaluated for a select group of bacterial pathogens, consisting of Salmonella spp., Shigella spp., Campylobacter spp., Shiga toxin-producing E. coli, and Yersinia spp. Recent travel or consumption of raw shellfish would raise the possibility of Vibrio spp. All of these organisms are very unlikely to be the cause of gastroenteritis in a patient who has been hospitalized for more than 3 days. Mycobacterial infections would need to be considered in profoundly immunosuppressed patients. Table 5–29 describes some of the more common bacterial infections of the gastrointestinal tract. Many of these organisms also can produce infections outside of the gastrointestinal tract.

Description

C. difficile infection is frequently implicated in antibiotic-associated diarrhea and is responsible for most cases of pseudomembranous colitis, a potentially life-threatening condition that requires combined medical and surgical intervention. Antibiotics frequently implicated include ampicillin, amoxicillin, cephalosporins, and clindamycin. In C. difficile colitis, there is a disruption of the normal bacterial flora of the colon by the antibiotic treatment, after which there is colonization by C. difficile organisms. Colonization of the gastrointestinal tract occurs by the oral–fecal route. C. difficile elaborates toxins A and B that induce fluid secretion, mucosal damage, and intestinal inflammation and produces heat-resistant spores that persist for months in the environment. The organisms can be cultured from floors, toilets, bed pans, bedding, and all sites where patients with diarrhea from C. difficile infection have recently been treated.

C. difficile infection is typically acquired in the hospital by both infants and adults. Neonates have an asymptomatic colonization, and most are resistant to the toxic effects of C. difficile infection. Adults can also be asymptomatically colonized. Symptomatic C. difficile infection usually presents with mild-to-moderate diarrhea and lower abdominal cramping. Symptoms often begin with antibiotic therapy, but may be delayed for several weeks after antibiotic therapy is initiated. Patients who go on to develop pseudomembranous colitis experience more severe diarrhea, abdominal tenderness, and systemic symptoms. Patients with advanced disease may present with a fulminant life-threatening colitis that must be treated promptly to avoid perforation of the bowel wall.

Diagnosis

Since patients can be asymptomatically colonized with C. difficile, stool tests for toxigenic C. difficile should only be performed on patients with a compatible clinical presentation, such as those with 3 or more loose stools in 24 hours.Table 5–30 summarizes the evaluation of patients for C. difficile infection.

Description

Protozoa are a very diverse group of unicellular eukaryotic organisms that can be free-living or parasitic. Many have 2 morphologic stages—trophozoites and cysts. Trophozoites, which are metabolically active feeding forms of the organism, may encyst within a protective coating to tolerate harsh environments. The cyst is a dormant form of the protozoan, and can reemerge as a trophozoite (for asexually reproducing organisms) when exposed to favorable conditions. For protozoa that multiply by sexual reproduction, a zygote is formed from the fusion of 2 gametes. Encystation of a zygote produces an oocyst that may contain 2 or more sporocysts, each with its own cyst wall. Sporocysts contain sporozoites, infective forms of the organism.

The intestinal protozoa are divided into 5 main groups that differ in terms of epidemiology and clinical presentation. Several of the groups contain pathogenic as well as nonpathogenic species. Although the latter do not require treatment, their presence indicates that the individual has been exposed to oral–fecal contamination.

• Flagellates: Pathogenic species include Giardia lamblia and Dientamoeba fragilis. Giardia is the most common intestinal parasite in the United States. Sources of infection include ingestion of contaminated water and person-to-person transmission in day care centers. Giardia can cause diarrhea, abdominal cramps, bloating, and flatulence. Symptoms often persist for more than 1 week.

• Amebas: Entamoeba histolytica is a major cause of intestinal infections worldwide, particularly in tropical areas with limited sanitation facilities. Most infections in the United States are acquired elsewhere. Clinical manifestations range from asymptomatic colonization to diarrhea, amebic colitis/dysentery, or extraintestinal abscess formation (usually in the liver). The diagnosis of amebiasis is complicated by the fact that E. histolytica is morphologically indistinguishable from the nonpathogenic E. dispar. Other nonpathogenic amebas include E. coli and Endolimax nana.

• Coccidia: Human pathogens include Cryptosporidium spp., Cyclospora spp., and Isospora belli. These organisms are members of the apicomplexans family and are related to the tissue parasites T. gondii and Plasmodium spp. Cryptosporidium spp. are a relatively common cause of infection in the United States. Outbreaks have been caused by contamination of drinking water or recreational water such as pools or water parks. Cryptosporidium usually causes a self-limited diarrhea in immunocompetent hosts, but it can cause severe persistent diarrhea in AIDS patients. Cyclospora spp. have caused outbreaks linked to imported food, such as raspberries. Isospora infections are usually only diagnosed in immunosuppressed patients.

• Ciliates: Balantidium coli is the only pathogenic ciliate.

• Microsporidia: Although these organisms are included in the section on protozoans, recent phylogenetic analysis indicates that they are more closely related to the fungi. Enterocytozoon bienusi causes self-limited diarrhea in normal hosts and chronic diarrhea in AIDS patients in whom it can also spread to the biliary tract. Encephalitozoon spp. can cause diarrhea and a variety of extraintestinal infections in immunosuppressed hosts.

Diagnosis

Most intestinal protozoa are detected by examination of stained stool specimens. Sensitive immunoassays are available for detecting antigens produced by Giardia and Cryptosporidium. Serology can be useful for diagnosing invasive E. histolytica since E. dispar does not trigger an antibody response. Table 5–31 describes infections produced by selected pathogenic protozoa. Protozoal infections are commonly found within the gastrointestinal tract, but, as noted in the table, many other organs and tissues can be infected.

Description

Helminth (worm) infections in humans constitute a significant percentage of the global burden of illness caused by infectious diseases. The helminths are multicellular organisms that are divided into 3 groups: tapeworms (cestodes), roundworms (nematodes), and flukes (trematodes). Helminths are typically enclosed by a protective coat, inside of which may be differentiated organ systems for digestion, neuromuscular control, and reproduction. Many helminths have complex life cycles that involve 2 or more hosts. Helminths develop into adult worms and/or undergo sexual reproduction in the definitive host, and they do not develop past the larval stage in intermediate hosts. Infections in humans usually result from ingestion of eggs, penetration of intact skin by infective larvae, or bites by insect vectors. Many helminth life cycles involve a stage in which the larvae migrate through tissue. This migration can be relatively asymptomatic but can also have serious clinical consequences depending on the type of helminth. These principles are illustrated by the following 2 examples.

The definitive host for Echinococcus granulosis (a tapeworm) is the dog, which harbors the adult tapeworm in its intestinal tract and excretes eggs in the feces. When an intermediate host, such as sheep or humans, ingests these eggs, the eggs hatch in the intestinal tract and larvae penetrate the intestinal wall and eventually form slowly expanding cysts in visceral organs such as the liver or lungs.

Strongyloides stercoralis is 1 of the several nematodes that are acquired when infective larvae present in warm moist soil penetrate human skin. The larvae migrate through tissue into the venous circulation and are transported to the lungs where they invade the alveoli, are coughed up and swallowed, and then develop into mature worms in the intestinal tract. The adult worms produce larva that are shed in feces into the environment where they can complete their life cycle. Unlike other nematodes, however, S. stercoralis larvae can also penetrate the gut wall or perianal skin and initiate an autoinfective cycle that results in persistent low-level infection even after the host has left an endemic area. If an infected patient subsequently receives immunosuppressive therapy, particularly with corticosteroids, the patient can develop life-threatening Strongyloides hyperinfection syndrome in which large numbers of nematode larvae migrate into the lungs and extraintestinal tissues.

Diagnosis

Infections with intestinal helminths are usually diagnosed by detection of eggs or larvae in feces. For many of the helminths, the identification of the organism is based on the morphologic characteristics of the organism and/or the eggs. These characteristics include size, shape, and thickness of the egg wall, special structures such as knobs and spines, and the developmental stage of the egg contents (eg, undeveloped, developing, or embryonated).

Important information in the evaluation of a patient infected with helminths includes a history of possible exposure to the organism. Eosinophilia is commonly observed in patients with helminth infections due to larval migration through tissues. The clinical findings, mode of transmission to humans, aspects of microbiologic and serologic testing, and relevant radiologic findings for selected helminth infections are presented in Table 5–32.