Rickettsia , Ehrlichia , and Anaplasma Infections

Prevalence and Etiology

Epidemic typhus is caused by Rickettsia prowazekii, a louse-transmitted endotheliotropic rickettsia in the typhus group of the genus Rickettsia . Although humans have been thought to be the sole reservoir, some data suggest that other vectors, such as ticks, are competent for transmission and that other natural reservoirs, such as flying squirrels, could exist. The disease occurs as outbreaks owing to the obligatory relationship between its vector, the human body louse Pediculus humanis corporis and the reservoir, humans. In times and places of peace and good personal hygiene, prevalence and incidence is low. With war, famine, strife, or other conditions that predispose to louse infestations, outbreaks of immense proportions can occur, as observed in Burundi in the mid-1990s where as many as 100,000 infections occurred within 1 to 2 years.

Clinical Signs and Symptoms

Epidemic typhus is a disease chiefly characterized by fever, headache, and severe myalgias; rash is reported in up to 50% of infections, but it is less frequent before day 3 of illness and may be difficult to detect in individuals with dark skin. The rash is distributed on both the trunk and extremities. An outbreak of epidemic typhus in Africa between 1995 and 1997 had a lower prevalence of rash; however, nearly half of those with rash developed purpuric lesions. Of Wohlbach’s 37 fatal cases of epidemic typhus, all had rash. There is a high frequency of central nervous system (CNS) involvement; in the Burundi outbreak, over 80% had delirium and 4% became comatose. Although abdominal pain and vomiting are common, diarrhea occurs in less than 20% of cases. Prior to the availability of antibiotics, pneumonia was often observed; among those with epidemic typhus in Burundi, 70% had cough, and most who were examined had radiographic evidence of pneumonia. Severe vascular compromise and shock occur in about 7%, and a small proportion develops sufficient vascular injury such that toes and fingers become ischemic and gangrenous. Important laboratory findings include thrombocytopenia in 40%, elevated serum aminotransferase levels in 35% to 63%, hyperbilirubinemia in 20%, and elevated serum urea nitrogen levels in 31%. Leukocyte counts vary and the prothrombin time is normal in 70% of infections.

Diagnosis

Diagnosis is based on clinical suspicion and routinely confirmed by comparing acute and convalescent serology using a specific test such as indirect immunofluorescence and R. prowazekii antigen. Rickettsia prowazekii is serologically cross-reactive with the other typhus group rickettsia, R. typhi .

Rickettsia typhi: Murine Typhus

Prevalence and Etiology

Rickettsia typhi is the cause of murine typhus and is transmitted by fleas, chiefly the rat flea Xenopsylla cheopis, and in some regions the cat flea, Ctenocephalides felis . Murine typhus is considered a rare infection in the United States except in south Texas and southern California. Worldwide, murine typhus has been implicated as an important cause of fever of unknown origin, including attack rates of up to 185 cases per 100,000 population in some regions of Southeast Asia.

Clinical Signs and Symptoms

For murine typhus, the chief presentation is with fever and headache. Rash is less frequent, occurring as macules, papules, and maculopapules in 50% to 80% of patients. Petechiae can occur but are infrequent. Gastrointestinal involvement, including abdominal pain, nausea, vomiting, anorexia, and diarrhea, occurs in 25% to 50% of patients, whereas cough and abnormal chest radiographs may be found in 20% of patients. Unlike the situation for epidemic typhus caused by R. prowazekii, murine typhus is associated with CNS manifestations in only 10% of infections; seizure is the most common abnormality, whereas delirium and coma are infrequent. Laboratory studies reveal that the leukocyte counts are usually normal to low with a significant left shift, often accompanied by thrombocytopenia. Approximately 80% to 90% of adult patients will have elevations in serum transaminase activities suggesting liver involvement, and approximately 20% will have hyponatremia. In general, the course of the disease is considered mild compared with that of epidemic typhus; however, the mean length of hospitalization is 6 days. The case fatality rate is approximately 1%.

Diagnosis

Diagnosis is based largely on clinical suspicion coupled with appropriate exposure history, and it is confirmed with paired acute-convalescent serology demonstrating a fourfold increase in antibody titer or seroconversion. The rickettsiae can be demonstrated in tissues using immunofluorescent or immunohistochemical stains.

Prevalence and Etiology

RMSF, also known by other geographic names such as Brazilian spotted fever, is caused by R. rickettsii, the prototype member of the spotted fever group of the Rickettsia genus. This bacterium is tick-transmitted, typically by the American dog tick ( Dermacentor variabilis ) in the eastern United States, by the Rocky Mountain wood tick ( Dermacentor andersoni ) in the western United States, and by Amblyomma cajennense in Central and South America. The brown dog tick ( Rhipicephalus sanguineus ), which is highly adapted to domestic environments such as kennels and homes, is now recognized as an important vector in areas where RMSF had not been previously found.

Arguably one of the most deadly infectious diseases to affect humans, RMSF was associated with mortality rates as high as 75% when first investigated in regions of Montana and Idaho. Despite knowledge of geography, ecology, clinical presentation, and the availability of highly effective therapy, the modern-day case fatality rate remains as high as 8%. The incidence of infection cycles over years, with unprecedented rates reported in the early 2000s. Owing to serologic cross-reactivity with other spotted fever group rickettsial infections, there is controversy as to the accuracy of incidence data.

Clinical Signs and Symptoms

The most frequent early clinical presentation of RMSF includes fever, headache, malaise, and myalgias. Rash appears on average at day 6 to 7 after fever onset, usually with macules or maculopapules that evolve into petechiae in half of patients and into purpura when severe. The spectrum of clinical signs and symptoms includes fever (99%), rash (89%), and headache (86%). A history of tick bite is obtained in approximately 68%. The frequency of fever, rash, and tick bite at the first presentation is only 3%. Rash is found on both extremities and trunk, including the soles and palms in 77% of patients. Systemic manifestations are reported often, with gastrointestinal abnormalities in 41% to 57%, conjunctivitis in 30%, edema in 18%, pneumonitis in 12%, and severe central nervous system manifestations such as coma, stupor, or seizure in 24%.

The intense endothelial injury and confounding inflammation of the pulmonary and cerebral microvasculature lead to transudation of edema fluid into both the alveolar spaces and brain parenchyma, allowing noncardiogenic pulmonary or cerebral edema that is life threatening. Infection of capillaries of the myocardium, the renal interstitium, or gastrointestinal organs infrequently has clinically significant consequences, except as with severe systemic involvement where clinical manifestations lead to unwarranted abdominal surgery.

Laboratory findings show normal leukocyte and elevated band neutrophil counts in 72% and 69% of patients, respectively. Other frequent findings include thrombocytopenia < 150,000 and < 99,000/μL in 52% and 32%, hyponatremia in 52%, and elevated serum aspartate aminotransferase activities in 62%, whereas hyperbilirubinemia is present in 30% and a mononuclear or polymorphonuclear leukocyte CSF pleocytosis in approximately 50%. Nearly half of all persons with RMSF who recover will have long-term complications including paraparesis, hearing loss, peripheral neuropathy, bladder and bowel incontinence, cerebellar, vestibular, and motor dysfunction, language disorders, limb amputation, and scrotal pain after cutaneous necrosis.

Diagnosis

Diagnosis and early treatment is based on clinical suspicion and confirmed by serologic studies using R. rickettsii antigens. Immunohistochemical and immunofluorescent methods have been used to diagnose infection during the acute phase in skin biopsies of petechial lesions. Molecular diagnostic tests such as polymerase chain reaction (PCR) have yet to prove useful.

Prevalence and Etiology

Genetically and antigenically related to R. rickettsii, R. conorii causes MSF or Boutonneuse fever. The latter name is derived from the frequent occurrence of the “tache noire,” an eschar at the site of tick bite, a finding that is unusual in RMSF. As for RMSF and other forms of spotted fever group rickettsioses worldwide, the incidence of infection varies cyclically over many years, doubling or more in incidence in recent years in the Mediterranean basin. Most cases occur in June through October in association with tick exposure and bites.

Clinical Signs and Symptoms

Clinical presentation is similar to that of other rickettsioses with fever (100%), rash (97%), headache (56%), and myalgias (36%). A petechial rash is identified in only 10% of patients, whereas the eschar is present in 72%. Laboratory findings are as for RMSF with either normal leukocyte counts or with leukopenia in 20% and leukocytosis in 25%, thrombocytopenia in 35%, hyponatremia in 25%, and elevations in serum hepatic transaminase levels in approximately 40%. Severe complications include meningoencephalitis and pneumonitis. The case fatality rate for MSF is high, varying from 2.5% to 3.5%. In fact, severe infection occurs in approximately 6% overall and is most often documented in persons with underlying medical conditions such as diabetes, alcoholism, and heart failure.

Diagnosis

Diagnosis is based on clinical suspicion and can be confirmed by culture, serologic studies, or immunohistochemical or immunofluorescent demonstration of the organisms in skin biopsies at the time of illness.

Prevalence and Etiology

Orientia tsutsugamushi, the etiologic agent of scrub typhus, is genetically related to but distinct from classical members of the Rickettsia genus that are vasculotropic. Although O. tsutsugamushi infects endothelial cells to induce a typical vasculitis clinical and histopathologic picture, it also infects and disseminates within macrophages in tissues and monocytes in blood. The bacterium is transmitted by bites of larval trombiculid mites (chiggers) in the genus Leptotrombidium, the only life stage of these mites to take a blood meal. As for all rickettsioses, reporting and recognition of scrub typhus have increased markedly. The disease occurs in a region that holds 2 billion people, ranging from Pakistan in the west to northern Australia in the south to Korea in the northeast. It is estimated that there are more than 1 million infections yearly.

Clinical Signs and Symptoms

Fever and headache are the dominant clinical manifestations, with a skin rash, including an eschar at the site of the mite bite, occurring in about 50% of cases. Other manifestations include myalgia, gastrointestinal manifestations, and CNS involvement in about 10%. Laboratory findings are similar to those of other rickettsioses, including a normal or low leukocyte count accompanied by thrombocytopenia and evidence of hepatic injury.

Diagnosis

Diagnosis is based largely on clinical suspicion and can be confirmed at the time of illness by demonstration of bacteria in tissues by immunohistochemical or immunofluorescent methods, by PCR, or by demonstrating a seroconversion or fourfold increase in antibody titer between acute and convalescent sera.