Chapter 294. Rickettsial Infections

Rickettsial infections are caused by pleomorphic gram-negative organisms that contain both DNA and RNA. They are obligate intracellular parasites, have typical bacterial cell walls and cytoplasmic membranes, and divide by binary fission. The taxonomy of rickettsiae continues to undergo an extensive reorganization. The order Rickettsiales has changed and now includes only two families, the Anaplasmataceae and the Rickettsiaceae.1,2 Three groups of disease are still commonly classified as rickettsial diseases: (1) the spotted fever and the typhus group from the family Rickettsiaceae, (2) ehrlichioses and anaplasmoses from the family Anaplasmataceae, and (3) scrub typhus (Orientia tsutsugamushi).3

Rickettsial infections have many features in common, including multiplication of the organism in an arthropod host; geographic and seasonal occurrences that are related to the arthropod life cycle, activity, and distribution; zoonotic illnesses with humans as incidental hosts (except for louse-borne typhus); and fever, rash (except some cases of ehrlichiosis and anaplasmosis), headache, myalgias, and respiratory tract symptoms. These organisms produce a vasculitis following replication within the endothelial lining and smooth-muscle cells of blood vessels leading to generalized capillary and small-vessel endothelial damage, increased vascular permeability, thrombus formations, and tissue necrosis.4,5 This process consumes platelets and results in the characteristic thrombocytopenia. Many of the other initial symptoms and signs are referable to this pathogenesis, which can affect any organ system. Although the thrombus mediated vascular occlusion that occurs may play a role in severe rickettsial infections, disseminated intravascular coagulation (DIC) occurs rarely.5 Hyponatremia, which is another laboratory hallmark of many rickettsial infections, is the result of initial active secretion of salt into renal tubules. Subsequently, the syndrome of inappropriate production of antidiuretic hormone (SIADH) can further aggravate the hyponatremic state. Organisms from the typhus (except scrub typhus) and spotted fever groups contain endotoxins, and most will survive only briefly outside of a host (reservoir or vector).

The epidemiology, clinical manifestations and outcomes of each rickettsial disease are discussed below. Because diagnostic methods and treatment are similar for most rickettsial disorders, these are discussed at the end of the chapter.

From 1999 to 2006 there was a mean of 1237 cases per year (range: 495–2236) of Rocky Mountain spotted fever (RMSF) reported in the United States.7,8 Of these cases, approximately 90% occur between April and September. Approximately two thirds of the cases occur in children under age 15 years, with the highest age-specific incidence occurring between ages 5 and 9 years.9 Although the disease is rare in infants, RMSF has been described to occur in more than one family member at the same time. The geographic connotation of its name notwithstanding, RMSF is endemic to much of the western hemisphere, including Mexico, Costa Rica, Argentina, Panama, Colombia, and the continental United States.10-14 In the United States, RMSF is most common in the south Atlantic states (eg, North Carolina, South Carolina, Georgia, Virginia, and Maryland), as well as Tennessee, Mississippi, Missouri, Arkansas, and Oklahoma. Ticks that transmit the disease vary by region. In the western United States, wood ticks (Dermacentor andersoni) are primary carriers and vectors of infection, whereas in the eastern United States, the dog tick (D. variabilis), and in the south-central region, the Lone Star tick (Amblyomma americanum), represent the most common arthropod hosts.1 Even in areas where most human cases are reported, only approximately 1% to 3% of the tick population will carry the causative agent, Rickettsia rickettsii, and very few humans actually become infected despite suffering a tick bite.9 Ticks become infected by feeding on the blood of infected animals, through fertilization, or by transovarial passage. Once attached, the infected tick is able to transmit the disease to humans during feeding. After attachment to humans has occurred (6–24 hours), rickettsiae are released from the salivary glands and multiply in the endothelial cells lining the small blood vessels, resulting in cell damage. For all age groups, reported risk factors include exposure to dogs, residence in a wooded area, and male sex.

Clinical Manifestations

The incubation period for Rocky Mountain spotted fever (RMSF) is usually 7 days, but ranges from 1 to 14 days, depending on the size of the rickettsial inoculum.1,9 The illness is usually characterized by a short prodromal period with headache, malaise, and myalgias.15-18 The classic triad of fever, headache, and a centrifugal petechial rash, plus a history of exposure to ticks is present in only 3% to 18% of patients at their initial evaluation.15 The onset of fever is usually abrupt and high grade [40–40.5°C (104–104.9°F)]. The skin rash, however, begins to appear on average 2 to 3 days after the onset of illness as blanching, 1- to 4-mm macules that later become petechial (Fig. 294-1).1,9,14-18 The skin rash begins peripherally (eg, wrists, ankles) and spreads centrally; it is common to have involvement of the palms and soles. It is important to note, however, that only 50% of patients have a rash during the first 3 days of illness and as many as 20% of adults and 5% of children may never develop a rash.9,14,15,18 Care should also be taken when dealing with patients with darkly pigmented skin because the rash may not be appreciated. The absence of a rash should never delay the institution of appropriate antimicrobial therapy if the historical, clinical, and laboratory findings are compatible with the diagnosis of RMSF. Although physicians rely greatly on a history of tick exposure, in reported series such information was confirmed in only one half to two thirds of documented infections.15

Other clinical manifestations include headache, mental confusion, and myalgia.14-18 The headache is described by adults and older children as being the most severe headache they have ever experienced, persisting throughout the day and unresponsive to any pain medications. Most of the major complications of this illness occur as a result of a vasculitic mechanism of injury. Complications of severe illness include encephalitis; meningitis; pulmonary edema; respiratory distress syndrome; cardiac arrhythmias; coagulopathy; gastrointestinal bleeding; hepatitis; and skin necrosis.9,14-18

Diagnosis

The diagnosis of Rocky Mountain spotted fever (RMSF) must be based only on the history and physical examination findings, because specific laboratory tests may not become positive until the second week of infection. Although laboratory abnormalities such as thrombocytopenia, hyponatremia, leukopenia, and elevated liver function tests may be present in patients with RMSF,9,15 none are specific for this illness, and therefore cannot be used to confirm a diagnosis. Specific serologic testing should be performed to confirm a diagnosis of RMSF.6 This can be accomplished demonstrating a 4-fold increase in antibody titer between acute and convalescent sera using one or more of the specific serologic tests as determined by a number of methods, including complement fixation, immunofluorescent assays, latex agglutination, indirect hemagglutination, or microagglutination tests. Testing is available in most state and local laboratories in highly endemic regions, as well as at the Centers for Disease Control and Prevention (CDC) in Atlanta. A single titer greater than 1:128 can also be used to confirm the diagnosis. Rickettsia rickettsii have been identified by immunofluorescent staining of skin biopsy specimens obtained at the site of the rash with 70% sensitivity and 100% specificity.14 A polymerase chain reaction assay has been developed to detect R rickettsii in blood and biopsy specimens during the acute phase of illness but is not currently widely available and its use has been limited owing to its inferior sensitivity in detecting Rrickettsii in the blood.6,20

Outcome

Long-term sequelae that have been described include paraparesis; hearing loss; peripheral neuropathy; cerebellar, vestibular, and motor dysfunction; language disorders; behavioral disturbances; learning disabilities; bladder and bowel incontinence; and limb amputation.19-22 The mortality rate associated with RMSF is 20% to 25% if untreated, and 5% with appropriate antimicrobial therapy. Risk factors for an adverse outcome include nonwhite race; male gender; absence of headache; no history of tick attachment; delay in initiating therapy; gastrointestinal symptoms; and no treatment by the fifth day of illness.

Many new data on Rickettsia from the spotted fever group have accumulated over recent years. Prior to 1984, Mediterranean spotted fever (R conorii SPP conorii), Israeli spotted fever (R conorii subsp israelensis), Siberian tick typhus or North Asian tick typhus (R sibirica subsp sibirica), and Queensland tick typhus (R australis) were the only other spotted fevers described.1 Since 1984, new infections have been recognized and described, such as Japanese or Oriental spotted fever (R japonica), Astrakhan fever (R conorii subsp caspia), African tick bite fever (R africae), Flinders Island spotted fever (R honei), Indian tick typhus (R conorii subsp indica), as well as others. As our knowledge of Rickettsiae increase, new illnesses will be recognized.

In general, most of the spotted fever rickettsiosis syndromes have similar clinical courses as well as treatments. Those with distinctive clinical features include infections caused by R slovaca and R africae.5 Tickborne lymphadenopathy and Dermacentor-bornenecrosis-eschar lymphadenopathy are descriptive names applied to infections by R slovaca.23-49 Ticks frequently attach to the scalp, where an eschar appears 7 to 9 days later associated with painful cervical adenopathy. Alopecia at the eschar site may occur and persistent asthenia of the area may even be present after proper treatment. Fever and rash are seldom present in this disease. African tick fever differs from most other rickettsioses because it is of mild-to-moderate severity and it produces painful regional lymphadenopathy, has multiple eschars (Fig. 294-2), and occasionally, a sparse and sometimes vesicular rash.50 Those with distinctive clinical features include infections caused by R slovaca and R africae.5 Tickborne lymphadenopathy and Dermacentor-borne-necrosis-eschar lymphadenopathy are descriptive names applied to infections by R slovaca.23-49 Ticks frequently attach to the scalp, where an eschar appears 7 to 9 days later associated with painful cervical adenopathy. Alopecia at the eschar site may occur and persistent asthenia of the area may even be present after proper treatment. Fever and rash are seldom present in this disease. African tick fever differs from most other rickettsioses because it is of mild-to-moderate severity and it produces painful regional lymphadenopathy, has multiple eschars (Fig. 294-2), and occasionally, a sparse and sometimes vesicular rash.50

There are 5 members of the Anaplasmataceae family that infect humans: (1) Ehrlichia chaffeensis, (2) Ehrlichia ewingii, (3) Ehrlichia canis, (4) Anaplasma phagocytophilum, and (5) Neorickettsia sennetsu.23 Circulating white blood cells are the target of these organisms and the diseases they cause are often named after the infected white blood cell (eg, Echaffeensis infects monocytes and is called human monocytic ehrlichiosis). Human infections from Ecanis are rare, whereas Nsennetsu causes a mononucleosislike illness with fever, fatigue, malaise, and lymphadenopathy.24 Ehrlichia ewingii, although serologically similar to Echaffeensis, actually affects the neutrophils much like Aphagocytophilum and is usually referred to as human ewingii ehrlichiosis. Human ewingii ehrlichiosis occurs infrequently and is clinically indistinguishable from infections caused by Echaffeensis or Aphagocytophilum.25

Human monocytic ehrlichiosis (HME) in humans is caused by Echaffeensis. The exact incidence of human monocytic ehrlichiosis is unknown but has been described to be as high as 330 to 414/100,000 population in tick endemic regions of the United States.26,27 The geographic distribution of illness overlaps that of Rocky Mountain spotted fever (RMSF), as the tick vectors are identical (Amblyomma americanum, Dermacentor variabilis). From the first year it became a reportable disease in 1999 until 2006 there was a mean of 300 cases per year (range: 99–578) reported to the Centers for Disease Control and Prevention (CDC) in the United States.7,8 The majority of reported cases, however, are from Texas, Oklahoma, Arkansas, Missouri, and Georgia. Approximately 80% of reported cases occurred during the months of May and June. The interval from tick exposure to the development of the illness is from 2 days to 3 weeks. White-tailed deer and dogs have been proposed as potential reservoirs of infection from which the tick feeds. Current evidence suggests that E chaffeensis is introduced into the dermis of the host by the bite of an infected tick with subsequent hematogenous spread of the organism.

Human granulocytic anaplasmosis (HGA) is caused by Aphagocytophilum and is transmitted from the hard-bodied ticks that are members of the Ixodespersulcatus complex.28 Although the majority of illness has been recognized in the United States, HGA has been described in several European countries as well.7,8,29 The prevalence of HGA is not well documented, but rates as high as 52 to 58 cases/100,000 population have been described in highly endemic regions of Connecticut and Wisconsin in the United States.30,31 From 1999 to 2006, there was a mean of 457 cases/year (range: 203–786) of HGA reported to the Centers for Disease Control and Prevention (CDC).7,8 Most HGA infections are diagnosed between April and September and more than two thirds occur in rural residents. Tick and human studies suggest a potential coinfection with comorbidity for HGA and Lyme borreliosis or babesiosis.32 Human granulocytic anaplasmosis has also been demonstrated to be transmitted perinatally as well as by blood transfusion.33,34

Clinical Manifestations

Fever, rash, headache, myalgia, and hepatosplenomegaly are common abnormalities encountered on physical examination in children with human monocytic ehrlichiosis (HME).35-38 The rash associated with HME is more commonly encountered in children than in adults. The rash is generally distributed over the trunk or extremities and may be macular, maculopapular, petechial, or a combination of all three types. Life-threatening illness has been reported in children with up to 25% of all patients with HME required intensive-care therapy.37Long-term sequelae reported to date include foot drop, speech impediment, decreased school performance, renal failure, and hypertension.31,32

There are limited data available for the clinical presentation with human granulocytic anaplasmosis (HGA) in children. Symptoms similar to HME are found but the rash is usually absent (eTable 294.1). The most important feature of HGA is a lack of abnormal findings on physical examination. Peripheral neuropathies (eg, brachial plexus, demyelinating polyneuropathy, isolated facial palsy) can occur in HGA and may persist for weeks or months.23

Diagnosis

The recognition of ehrlichiosis can be difficult. Patients who are evaluated during the summer with a history of tick attachment should be considered to be at risk. Elevated liver function tests, thrombocytopenia, and leukopenia [with lymphopenia (HME) or neutropenia (HGA)] are the most common laboratory abnormalities noted.23,35-38 Patients may also have hyponatremia, anemia, and cerebrospinal fluid abnormalities (ie, pleocytosis with a predominance of lymphocytes and an elevated total protein concentration), but none of these laboratory tests are specific for the diagnosis. Although examination of the peripheral smear with a Wright stain looking for intracytoplasmic inclusions (morulae) in the monocytes (HME) or neutrophils (HGA) has been described, it is a very insensitive method for establishing the diagnosis.23 In addition, doxycycline treatment will adversely affect the ability to detect these inclusions. Likewise in vitro cultivation of the organism, immunohistologic or immunocytologic, or polymerase chain reaction is not widely available. The use of serologic testing is therefore required for confirmation in patients with compatible history and clinical findings.6 Human monocytic ehrlichiosis can be diagnosed with a minimum antibody titer greater than or equal to1:64 to E chaffeensis or a 4-fold or greater change in antibody titers from acute and convalescent sera using indirect fluorescent antibody testing. Currently, testing for human granulocytic anaplasmosis requires identification of indirect fluorescent antibodies to preparations of A phagocytophila. A 4-fold increase in titer between acute and convalescent sera.

If a rash is present, ehrlichiosis may be indistinguishable from Rocky Mountain spotted fever (RMSF). Other tickborne infections that should be considered include tularemia, babesiosis, Lyme disease, murine typhus, and Colorado tick fever. Bacterial cultures can help exclude meningococcemia, other bacterial organisms causing sepsis, or endocarditis, whereas viral etiologies such as enterovirus, adenovirus, and Epstein-Barr virus can also be considered. Patients with Kawasaki syndrome are more likely to have conjunctivitis, mucous membrane involvement, and extremity changes as compared with those children with ehrlichiosis.

The incidence of murine typhus (also called endemic typhus or fleaborne typhus) in the United States is unknown since it is not a nationally reportable disease, although it is reportable in some states (eg, California, Texas, Hawaii).39 Murine typhus is transmitted to human beings by infected feces from the rat flea or the cat flea. Either the flea bite or subsequent scratching by the host inoculates Rickettsia typhi or R felis into human tissue. The incubation for murine typhus is 1 to 2 weeks, and the illness usually begins with the abrupt onset of fever. Other important signs and symptoms of infection include headache, chills, rash, nausea, myalgias, arthralgia, and vomiting.39,40 Compared with adult populations, children complain less frequently of headaches. The rash begins 6 to 7 days after onset of fever and is usually macular, maculopapular, or papular in appearance. Although a hallmark of rickettsial disease, the presence of rash in endemic typhus is variable and can be found in 20% to 80% of patients.39,40

Historically, epidemic (louseborne) typhus (R prowazekii) has been a significant pathogen, causing massive epidemics of disease during periods of war and famine, accounting for thousands of deaths in prison camps during and after World War II.41 There have been recent outbreaks in Africa and Central and South America, but not in the United States.

Epidemic typhus has an acute onset beginning 7 to 14 days after exposure to an infected louse. High fever [39–40°C (102.2–104°F)] and headache precede by 3 to 7 days a rash, which has a central distribution, spreading to the extremities, but usually sparing the palms and soles. This rash progresses from blanching macules to papules, petechiae, and occasionally ecchymoses. Patients who have recovered from epidemic typhus may retain the organism for an extended period of time, relapsing years later with Brill-Zinsser disease, a milder illness.

Scrub typhus (Orientia tsutsugamushi) is a disease transmitted by chiggers and is endemic in Southeast Asia and the southwestern Pacific. The chigger bite results in a papule, enlarging to a bulla that rapidly sloughs, leaving a shallow ulcer. A black crust surrounded by a 1- to 2-cm erythematous, raised circle then forms. At this time, other systemic symptoms begin, at first insidiously with a low-grade fever, headache, chills, and anorexia. Within 5 days, an unremitting fever to 40°C (104°F) accompanied by a severe headache are seen in virtually all patients.42 Generalized lymphadenopathy is the most consistent physical finding, occurring in 80% to 90% of patients. The characteristic rash of scrub typhus is maculopapular and generalized but most apparent on nonexposed skin surfaces.

Rickettsialpox, a mild infection produced by Rickettsia akari, has been reported primarily in New York City, but has been observed in a number of other large cities, especially during periods when large mice populations were being exterminated. Infected mite vectors of R akari then attach to human beings, the most available alternative host, and produce disease. Because the skin rash resembles chickenpox, this infectious process was named rickettsialpox. Incubation is estimated at 9 to 14 days as determined by the time period following documented attachment of arthropod vectors. Initially, a red papule appears at the site of the mite bite. This lesion enlarges to form a black eschar, at which time fever is first observed.43 The rash begins as diffuse nonpruritic macules, progressing to maculopapules and to papulovesicles, resembling chickenpox. The palms, soles, and mucous membranes are occasionally involved, but distribution of lesions is quite variable. Fever, chills, and headache persist for about 5 days, but rarely more than 10 days. Upper respiratory and gastrointestinal symptoms are common. Untreated, recovery is still universal, but appropriate antibiotics may shorten duration of symptoms in more severe illness.

Treatment

The most important issue when treating rickettsial infections is to avoid delays in treatment. One should not wait for a rash to develop to suspect the diagnosis, nor should one exclude the diagnosis because there is no history of tick bite, or based solely on geographic or seasonal reasons. Therapy should be administered when one is clinically suspicious of the infection (eTable 294.2).

Doxycycline and tetracycline are the antimicrobial agents of choice for most rickettsial infections and its use should not be delayed in suspected cases, regardless of age.6,9,44 Despite years of intensive education, clinicians in tick-endemic regions still delay in starting empiric antirickettsial therapy.15,45 In the past, chloramphenicol was used for children younger than age 9 years because of the side effects (eg, teeth staining) attributed to the use of tetracycline agents. Data now demonstrate that in patients with Rocky Mountain spotted fever (RMSF), the mortality is higher for those treated with chloramphenicol as compared to those treated with doxycycline.11 Therefore, in children with life-threatening rickettsial illnesses, most experts now choose to treat patients with doxycycline regardless of the patient’s age. The family should be informed of the risks of staining, which appear to be less with doxycycline than tetracycline, of permanent teeth. The optimal duration of antimicrobial therapy has not been well established for any of the rickettsial diseases because very few comparative clinical trials have examined short-course versus conventional antibiotic management. Patients should, therefore, be managed individually, reserving a briefer course for those with mild illness or for those with a rapid response to therapy. But, as a general approach for more difficult patients, therapy should be continued until patients have been afebrile for 48 to 72 hours and clinically improved.

Meningococcemia is an important consideration for any toxic patient with a petechial or ecchymotic skin rash. For this reason empiric therapy often includes coverage for Neisseria meningitidis as well as for RMSF. Other pathogens that can produce high fever and petechial rash are enteroviruses, Epstein-Barr virus, group A streptococci, measles virus, and other rickettsiae. It is important to remember that ehrlichiosis can be clinically indistinguishable from RMSF.

Prevention

Avoidance or control of arthropod vectors remains the first line of defense against rickettsial disease. If high-risk areas cannot be avoided, protective clothing that covers the arms and legs provides an excellent physical barrier to these biting arthropods. Insect repellents on skin containing N,N-diethyl-m-toluamide (DEET) or those impregnated in clothing containing permethrin become important defense mechanisms against these vectors.47 Avoidance of high-risk areas is still the most prudent approach for infants younger than age 1 year because of the potential for systemic reactions with repeated applications of DEET-containing compounds. In general, the higher the DEET concentration in the repellent formulation, the longer will be the duration of protection; however, this reaches a plateau at about 30% to 35%. DEET and sunscreen combinations are also not recommend because DEET decreases the efficacy of sunscreen and the recommendations for the use of sunscreen (eg, liberally and often) differ from those of DEET (eg, sparingly and only as required), especially among young children. Although natural-based products such as oil of citronella may have some effects against mosquitoes, the data supporting their use against ticks are lacking.

Ticks must be attached to the human host for at least 6 hours before transmitting the rickettsial organism. Rapid removal of ticks and disinfecting bedding for lice also lessens the possibility of disease transmission. The best method of removing all species of ticks is gentle traction of the attached arthropod using tweezers or similar blunt devices.48 After removal the site of attachment should be cleaned with alcohol. Because only a small percentage of ticks are infected with Rickettsia rickettsii, prophylactic antimicrobial agents are not indicated for asymptomatic individuals after a tick bite.