Epidemiology

Currently, Lyme disease is a global illness. Cases have been reported on all continents except Antarctica. Since its original description more than 25 years ago, Lyme disease has become the most commonly reported (95%) vector-borne illness in the United States. This infection has emerged as a major health hazard for human beings and domestic animals. In 2011, it was the sixth most common nationally notifiable disease. It is endemic in more than 15 states in the United States and in Europe and Asia.

In some patients, Lyme disease may be transitory and of little consequence, but in others it may become chronic and severely disabling. Accurate diagnosis is therefore essential, although better laboratory techniques are still needed.

Retrospectively, the first symptom of Lyme disease apparently was recognized as early as 1908 in Sweden. In the decades that followed, the rash produced by the disease erythema chronicum migrans (ECM) was noted elsewhere in Europe, as were other symptoms that seemed to follow ECM’s eruption. Secondary symptoms, such as impairment of the nervous system, were described in France, Germany, and again in Sweden.

In the United States the European rash was almost unknown until 1969, when a case of a physician bitten by a tick while hunting in Wisconsin was reported. Although a few ECM cases were seen in Americans who had traveled to Europe, there were no further native American cases until 1975, when physicians at the U.S. Navy base in Groton, Connecticut, reported seeing four patients with a rash similar to that of ECM. At the same time, an epidemiologist at the Connecticut State Department of Health and a rheumatologist at Yale University were notified of an unusual cluster of cases of arthritis occurring in children in Lyme, Connecticut.

It was not until 1982 that Burgdorfer and Barbour isolated a previously unrecognized spirochete, now called B. burgdorferi, from I. scapularis ticks, and Lyme disease became a recognized vector-borne, infectious disease. Two factors influence the chance that a bitten patient will contract the disease, the likelihood that local ixodid ticks carry the Lyme spirochete and the likelihood of infection after a bite by an infected tick. The probability of infection after an ixodid tick bite in an area of endemic disease is about 3%, but varies in different regions from less than 1% to as high as 5%. It has been suggested that human leukocyte antigen (HLA)–DR4 (HLA-DR4) and, secondarily, HLA-DR2, may increase the risk that Lyme arthritis will become chronic and fail to respond to antibiotics.

Lyme disease does not occur nationwide and is concentrated heavily in the northeast and upper midwest. The highest number of confirmed cases of Lyme disease to date was 29,959 in 2009 (Fig. 19-3). Persons of all ages and both genders are equally susceptible. In 2011, 96% of Lyme disease cases were reported from 13 states (Fig. 19-4):

Lyme disease is considered an emerging infectious disease because of the impact of changing environmental and socioeconomic factors, such as the transformation of farmland into suburban woodlots favorable for deer and deer ticks. Although pets may represent a spirochete reservoir, it is unlikely that humans can be infected directly by them. In areas of endemic Lyme disease, however, both adult and nymphal ticks, carried into the household by dogs and cats, may infect humans.

Signs and Symptoms

The basic features of Lyme disease are similar worldwide, but there are regional variations, primarily between the illness in America and that in Europe and Asia. In at least 60% to 80% of U.S. patients, Lyme disease begins with a slowly expanding skin lesion, EM, which occurs at the site of the tick bite. The skin lesion is frequently accompanied by flulike symptoms.

The Centers for Disease Control and Prevention (CDC) clinical case definition for Lyme disease includes the presence of EM or at least one objective, late manifesting sign of musculoskeletal, neurologic, or cardiovascular disease and a positive serologic test for antibodies to B. burgdorferi. Many misdiagnosed patients actually have chronic fatigue syndrome or fibromyalgia, both of which can cause similar symptoms, such as joint stiffness or pain, fatigue, and sleep disturbance.

Lyme borreliosis is a multisystem illness that primarily involves the skin, nervous system, heart, and joints (Table 19-2). Lyme disease usually begins during the summer months with EM and flulike symptoms and may be accompanied by right upper quadrant tenderness and a mild hepatitis (stage 1). This stage is followed weeks to months later by acute cardiac or neurologic disease in a minority of untreated individuals (stage 2) and then by arthritis and chronic neurologic disease (stage 3) in many untreated patients weeks to years after disease onset. There is considerable overlap of these stages, but Lyme disease is best characterized as an illness that evolves from early to late disease without reference to an arbitrary staging system. However, a patient may have one or all of the stages, and the infection may not become symptomatic until stage 2 or 3. Most affected patients have EM and 25% manifest arthritis; neurologic manifestations and cardiac involvement are uncommon.

Cutaneous Manifestations

Cutaneous manifestations can be demonstrated as early ECM (Fig. 19-5), secondary lesions (disseminated lesions and lymphocytoma), and late lesions (ACA). Except for the late lesions, cutaneous manifestations generally resolve spontaneously over weeks to months. The red papule at the site of the tick bite is most often located on the thigh, groin, or axilla. Facial EM is seen more frequently in children.

Several days to weeks after the onset of EM, almost 50% of untreated patients develop secondary skin lesions. A rare early manifestation of Lyme disease is Borrelia lymphocytoma, a violaceous, tumor-like swelling or nodule at the base of the earlobe or nipple caused by a dense lymphocytic infiltrate of the dermis. This lesion occurs at the site of a tick bite and in conjunction with other symptoms; it may be confused with lymphoma.

ACA is a late skin manifestation of Lyme disease more prevalent in Europe than in the United States. Lesions display bluish red discoloration, doughy swelling, and fibrotic nodules. Eventually, striking atrophy of the skin and subcutaneous tissues follows. Polyneuropathy coexists in 30% to 45% of patients.

Diagnostic Evaluation

The culture of B. burgdorferi from specimens in Barbour-Stoenner-Kelly medium permits a definitive diagnosis. With a few exceptions, positive cultures have only been obtained early in the illness, primarily from biopsy samples of EM lesions, less often from plasma samples, and only occasionally from CSF samples in patients with meningitis. Later in the infection, polymerase chain reaction (PCR) testing is superior to culture for the detection of B. burgdorferi in joint fluid.

In the United States, the diagnosis is usually based on the recognition of the characteristic clinical findings, a history of exposure in an area in which the disease is endemic and, except in patients with EM, an antibody response to B. burgdorferi. In more than 50% of cases, physicians are comfortable making the diagnosis based on symptoms and patient history. Testing becomes important when the telltale bull’s eye rash or other symptoms characteristic of Lyme disease do not appear (Table 19-3).

Western Blot Analysis

Western blot analysis can verify reactivity of antibody to major surface or flagellar proteins of B. burgdorferi (Fig. 19-6). The Western blot test is helpful in determining borderline negative or weakly positive results obtained from other tests, but the values are not always reliable. This procedure is more definitive in later Lyme disease when multiple antibody bands specific for B. burgdorferi appear. Reported results from Western blot tests for Lyme disease in its late phase indicates reactive bands for IgM levels. The 41-kDa bands are the earliest to appear, but can cross-react with other spirochetes. The 18-, 23- to 25- (Osp C), 31- (Osp A), 34- (Osp B), 37-, 39-, 83-, and 93-kDa bands are the most specific, but may appear later or not appear at all.

Treatment and Prevention

Treatment decisions after a tick bite are influenced by the following factors:

Etiology

Tickborne rickettsiae of the genus Ehrlichia have been recognized as a cause of human illness in the United States. Ehrlichia spp. belong to the same family as the organism that causes Rocky Mountain spotted fever. Ehrlichia chaffeensis, the etiologic agent of human monocytic ehrlichiosis in the United States, was demonstrated to cause disease in a patient from Arkansas with tick bites in 1987. Since then, two more Ehrlichia spp., Ehrlichia ewingii and an Ehrlichia phagocytophila–like agent that differs antigenically and genetically from E. chaffeensis, have been identified as the cause of anaplasmosis (human granulocytic ehrlichiosis).

Epidemiology

Although the prevalence rates are low, human ehrlichiosis is endemic in the United States. Some fatalities have been reported. Incidence rates increase with age and are higher in men than women. Human ehrlichiosis occurs most frequently in the southern Mid-Atlantic and south central states during spring and summer.

The major vector for E. chaffeensis is the lone star tick, Amblyomma americanum. The principal reservoir for E. chaffeensis is the white-tailed deer, which hosts all stages of A. americanum. The primary tick vector for the agent of human granulocytic ehrlichiosis is I. scapularis in the eastern United States and I. pacificus in California. Dermacentor variabilis represents a second tick vector in the United States. The major reservoir for infection may be the white-footed mouse in the eastern United States. The onset of illness in spring and early summer for most cases parallels the time when A. americanum and D. variabilis ticks are most active.

Signs and Symptoms

Ehrlichiosis is a general term for human granulocytic ehrlichiosis, now called anaplasmosis, and human monocytic ehrlichiosis (HME). The syndrome of human ehrlichiosis is not typically recognized by physicians, but should be considered in patients with a history of tick exposure and an acute febrile, flulike illness. Most patients are not suspected of having a rickettsial infection. Because ehrlichiosis can cause fatal infections in humans, early detection and treatment with tetracycline or chloramphenicol appear to offer the best chance for complete recovery.

Symptoms are nonspecific and include fever, chills, and headache. Fever and skin rashes are the most common physical findings. In children, fever and headache are universal. Myalgias, nausea, vomiting, and anorexia are also common.

Diagnostic Evaluation

Laboratory studies have indicated that the hematologic, hepatic, and central nervous systems are usually involved in human ehrlichiosis. Definitive diagnosis is based on inclusion in leukocytes (Fig. 19-7). Ehrlichia spp. undergo three developmental stages, as follows:

For anaplasmosis, direct observation of intraleukocytic morulae in Wright-Giemsa–stained peripheral blood or buffy coat smears is a rapid and inexpensive laboratory test. If clinical symptoms and the epidemiologic history are compatible with rickettsial infections, the following diagnostic tests should be used during the acute stage of illness and when antibiotic treatment is initiated:

In anaplasmosis, the diagnosis is confirmed by seroconversion or by a single serologic titer higher than 1:80 in patients with a supporting history and clinical symptoms. Seroconversion is defined as a fourfold rise in the titer of paired acute and convalescent sera. Detection of IgM class antibody alone should not be interpreted as recent exposure to the rickettsial agents and should be confirmed by detection of IgG or, preferably, IgG seroconversion by parallel evaluation with a convalescent phase serum collected 4 to 6 weeks after onset of the illness.

In HME the diagnosis is confirmed by seroconversion or by a serologic titer higher than 1:128 in patients with a supporting history and clinical symptoms. Serum or CSF can be analyzed for IgM and IgG antibodies to Ehrlichia spp.

PCR-based detection of the E. phagocytophila–like agent of anaplasmosis represents the most sensitive and direct approach to diagnosis. PCR detection of E. chaffeensis includes the amplification of sequences with 16SrDNA.

Treatment and Prevention

HME patients and those with anaplasmosis are treated with doxycycline. No established guidelines have been established for long-term therapy. Prevention consists of reducing the risk of exposure to ticks (see earlier discussion of Lyme disease prevention).

Epidemiology

The CDC has noted that the geographic distribution of RMSF correlates with the type of tick found in that area. For example, American dog tick is found in the eastern, central, and Pacific coastal United States; the Rocky Mountain wood tick resides in the western United States. In 2005, the brown dog tick, a vector of RMSF in Mexico was implicated as a vector of this disease in a confined geographic area in Arizona. The cayenne tick (Amblyomma cajennense) is a common vector for RMSF in Central and South America and its range extends into the United States in Texas.

During 1997 to 2002, the estimated average annual incidence of RMSF, based on passive surveillance, was 2.2 cases/million persons. More than half (56%) of reported cases of RMSF were from only five states—North Carolina, South Carolina, Tennessee, Oklahoma, and Arkansas—but cases have been reported from each of the contiguous 48 states, except Vermont and Maine. RMSF is also endemic throughout several countries in Central and South America, including Argentina, Brazil, Columbia, Costa Rica, Mexico, and Panama.

Signs and Symptoms

The first symptoms of RMSF typically begin 2 to 14 days after the bite of an infected tick. A tick bite is usually painless and about 50% of those who develop RMSF do not remember being bitten. The disease frequently begins as a sudden onset of fever and headache. Most patients with RMSF (90%) have some type of rash during the course of the illness. The number and combination of symptoms vary greatly from person to person. Symptoms can include fever, rash (occurs 2 to 5 days after fever; may be absent in some cases), headache, nausea, and vomiting.

Diagnostic Evaluation

Blood specimens are not always useful for detection of the organism through PCR assay or culture. If the patient has a rash, PCR testing or immunohistochemical (IHC) staining can be performed on a skin biopsy taken from the rash site or on autopsy specimens. This can yield rapid results with good sensitivity (70%) when applied to tissue specimens collected during the acute phase of illness and before antibiotic treatment has been started, but a negative result should not be used to guide treatment decisions.

During RMSF infection, a patient’s immune system develops antibodies to R. rickettsii, with detectable antibody titers usually observed within 7-10 days of illness onset. It is important to note that antibodies are not detectable in the first week of illness in 85% of patients; a negative test during this period does not rule out RMSF as a cause of illness.

The gold standard serologic test for diagnosis of RMSF is the IFA with R. rickettsii antigen, performed on two paired serum samples to demonstrate a significant (fourfold) rise in antibody titers. The first sample should be taken as early in the disease as possible, preferably in the first week of symptoms, and the second sample should be taken 2 to 4 weeks later.

Typically, in most RMSF cases, the first IgG IFA titer is low or negative and the second shows a significant (fourfold) increase in IgG antibody levels. IgM antibodies usually rise at the same time as IgG near the end of the first week of illness and remain elevated for months or even years. Also, IgM antibodies are less specific than IgG antibodies and more likely to yield a false-positive result. For these reasons, physicians requesting IgM serologic titers should also request a concurrent IgG titer.

Both IgM and IgG levels may remain elevated for months or longer after the disease has resolved or may be detected in persons who were previously exposed to antigenically related organisms. Up to 10% of currently healthy people in some areas may have elevated antibody titers due to past exposure to R. rickettsii or similar organisms. If only one sample is tested, it can be difficult to interpret, whereas two paired samples taken weeks apart that demonstrate a significant (fourfold) rise in antibody titer provide the best evidence for the correct diagnosis of RMSF.

Treatment and Prevention

The progression of the disease varies greatly. Patients who are treated early may recover quickly on outpatient medication, whereas those who experience a more severe course may require IV antibiotics, prolonged hospitalization, or intensive care.

Doxycycline is the first-line treatment for adults and children of all ages and is most effective if started before the fifth day of symptoms. Standard duration of treatment is 7 to 14 days.

Etiology

Babesiosis is a rare, severe, and sometimes fatal tickborne disease caused by various types of Babesia, a microscopic parasite that infects red blood cells (Fig. 19-8). The causative organism of babesiosis was first described by Babes in 1888. In New England and the eastern United States, the disease is caused by Babesia microti; in California, it is caused by Babesia equi. In Europe, the disease is caused by Babesia divergens and Babesia bovis. Babesia canis has been found to be responsible for several cases in Mexico and France.

Epidemiology

B. microti is transmitted by tick I. scapularis in the northeastern United States. The larvae of the tick feed mainly on the white-footed mouse (P. leucopus). When larvae develop into nymphs and adults, they feed on the white-tailed deer (Odocoileus virginianus), but may also choose a human host.

Babesiosis is seen most frequently in older individuals, splenectomized patients, or immunocompromised patients. In the 1970s, cases were primarily reported during the spring, summer, and fall in coastal areas in the northeastern United States, especially Nantucket Island off the coast of Massachusetts and on Long Island in New York. Cases have also been reported in Wisconsin, California, Georgia, and Missouri, as well as in some European countries. The organism has also been transmitted via blood transfusion from asymptomatic donors.

The U.S. blood supply is vulnerable to transfusion-transmitted Babesia. Between 1979 and 2009, 159 cases of transfusion-related babesiosis were identified. Most (77%) of the identified cases occurred between 2000 to 2009.

Signs and Symptoms

The incubation period is approximately 7 to 21 days. The clinical presentation is variable, ranging from asymptomatic to rapidly progressive and sometimes fatal. Infections caused by B. divergens tend to be more severe (frequently fatal if not appropriately treated) than those caused by B. microti (clinical recovery usually occurs).

The disease can cause fever, fatigue, and hemolytic anemia lasting several days to several months. It may take from 1 to 8 weeks, sometimes longer, for symptoms to appear. The disease course is characterized by high fever, massive hemolysis, hemoglobinemia, and hemoglobinuria.

Diagnostic Evaluation

In symptomatic people, babesiosis usually is diagnosed by examining blood specimens under a microscope and observing Babesia parasites inside red blood cells. Multiple smears may need to be examined to detect low levels of parasites. Two rapid screening methods are used for the identification of Babesia organisms. The gold standard for their identification is the visualization of the intraerythrocytic organisms in thick or thin blood films. Sometimes, it is hard to distinguish Babesia spp. from Plasmodium falciparum (malaria) by blood smear examination. Also, some Babesia spp. (e.g., B. microti, B. duncani) appear identical; they cannot be distinguished from each other by microscopy.

Acute and convalescent antibody titers may be useful for diagnosis. A titer higher than 1:256 is considered diagnostic of acute infection. Only IgG antibody determinations are performed. PCR amplification can be used for diagnosis.

Molecular diagnosis can also be useful. In some infections with intraerythrocytic parasites, the morphologic characteristics observed on microscopic examination of blood smears do not allow an unambiguous differentiation between Babesia and Plasmodium organisms. In these cases, the diagnosis can be derived from molecular techniques such as PCR testing using the appropriate primers and single-step or the more sensitive nested PCR technique. In addition, molecular approaches are valuable for the investigation of new Babesia variants (or species) observed in recent human infections in the United States and Europe.

No Babesia test approved by the U.S. Food and Drug Administration (FDA) is currently available for screening prospective blood donors, who may feel healthy despite being infected. Some manufacturers are working with investigators at blood centers to develop FDA-approved tests for Babesia for donor screening.

Treatment and Prevention

Standardized treatments for babesiosis have not been developed. However, some drugs used for the treatment of malaria have been found to be effective in some patients with babesiosis.

Antimicrobial therapy is recommended for splenectomized or immunodeficient patients, older patients, and patients with severe infections. The usual regimen consists of a combination of clindamycin and oral quinine. An alternate treatment option is oral azithromycin and oral atovaquone. Exchange transfusion has been effective for patients with a high level of parasites (>10%), severe disease, or massive hemolysis.

Prevention requires vigilance when in tick-infested areas (see earlier discussion of Lyme disease prevention).

Epidemiology

The virus has been in the United States since at least the summer of 1999. Figure 19-9 shows the U.S. distribution of WNV in 2011. If WNV infection is reported to the CDC from any area of a state, the entire state is shaded.

Signs and Symptoms

West Nile virus infection is characterized by fever, headache, fatigue, aches, and sometimes a rash. Illness can last from a few days to several weeks.

Diagnostic Evaluation

Historically, flavivirus infections have been diagnosed by serologic tests or virus isolation. IgM antibody is evident in most infected patients 7 to 8 days after the onset of symptoms. IgM antibody has been shown to persist for longer than 500 days in approximately 60% of cases. Most patients demonstrate IgG antibody in 3 to 4 weeks after infection.

Several molecular techniques are available for diagnosis. Molecular detection of WNV is used for prevention of transmission by blood transfusion and transplantation. Laboratory diagnosis of WNV infection is generally accomplished by testing of serum or CSF to detect virus-specific IgM and neutralizing antibodies.

Four FDA-approved WNV IgM ELISA kits from different manufacturers are commercially available in the United States. According to the package inserts, each of these kits is indicated for use on serum to aid in the presumptive laboratory diagnosis of WNV infection in patients with clinical symptoms of meningitis or encephalitis. The package inserts also state that all positive results obtained with any of the commercially available WNV test kits should be confirmed by additional testing at a state health department laboratory or by the CDC.

In fatal cases, nucleic acid amplification, histopathology with immunohistochemistry and virus culture of autopsy tissues can also be useful. Only a few state laboratories or other specialized laboratories, including those at the CDC, can carry out this specialized testing.

Treatment and Prevention

There is no specific treatment for WNV infection. In patients with milder disease, symptoms resolve over time, although even healthy people have been sick for several weeks. In patients with more severe disease, hospitalization is usually required for supportive treatment, including IV fluids.

Prevention consists of avoiding mosquito bites.

Limitations

The positive predictive value of the test depends on the likelihood of Lyme disease being present. Testing should only be performed when clinical symptoms are present or exposure is suspected.

Clinical Applications

A positive result should only be interpreted as initial evidence for detection of antibodies to B. burgdorferi with the recommendation for second-step testing before reporting results to a clinician. A negative result may have a low predictive value early in the infection.