Rickettsial Diseases



Rickettsial Diseases


Ralph D. Feigin

Anthony M. Hlavacek



The rickettsial diseases are caused by microorganisms that have characteristics common to both bacteria and viruses. Rickettsiae depend on the intracellular milieu of animal cells for growth and reproduction and are considered to occupy a position between bacteria and viruses. They are, however, predominantly bacterial in character, as indicated by the following properties: They contain both DNA and RNA; they multiply by transverse binary fission; they possess enzymes of Krebs cycle, of protein synthesis, and of electron transport; at least one species contains muramic acid; they are retained by a filter; and their growth can be inhibited by a variety of antibacterial agents. They resemble viruses primarily because they grow only within living cells.

Rickettsiae also are agents that are similar in size and shape to one another, and they can be seen under light microscopy as coccobacillary forms. The characteristic pathologic lesion in all rickettsial diseases is a widespread vasculitis of small blood vessels. The exception is Q fever, in which pneumonitis assumes equal import. The rickettsial agents multiply within cells of susceptible hosts.

All rickettsial diseases are characterized clinically by fever, headache, and rash, with the exception of Q fever (which has no rash) and ehrlichiosis (which frequently has no rash). In the early stages of rickettsial diseases, all infections are susceptible to numerous broad-spectrum antibiotics. All rickettsiae assume a characteristic red when they are stained by the Gimenez method (Table 144.1).

All rickettsiae infections, with the exception of rickettsialpox, Q fever, and ehrlichiosis, induce agglutinins against strains of the bacillus Proteus vulgaris, such as OX19, OX2, or OXK (Weil-Felix reaction). Rickettsial organisms all exist under natural conditions in insects such as lice and fleas or arachnids such as ticks and mites. These arthropods serve as vectors for the transmission of all rickettsiae diseases, with the exception of Q fever, to humans.

All rickettsial organisms, with the exception of those that cause ehrlichiosis and the heterogeneic strains of scrub typhus, produce complement-fixing antibodies. The clinical and epidemiologic features of the disease in an individual case, supplemented by the measurement of complement fixation titers, constitute the principal means for establishing the diagnosis of rickettsial infection.

Immunity produced by any one of the rickettsial infections usually is of long duration against reinfection by the same agent. The single exception to this rule is scrub typhus.

Four major groups of rickettsial disease occur within the tribe Rickettsiae. Ehrlichiosis is caused by organisms within a separate rickettsial tribe, Ehrlichieae. With the exception of ehrlichiosis, infection caused by an organism belonging to one of these groups confers partial or complete immunity against infection caused by any of the other rickettsiae belonging to the same group. In contrast, little or no immunity is conferred by infections that are caused by rickettsiae belonging to different groups. However, a minor degree of serologic cross-reaction

exists between some rickettsiae of the spotted fever groups and typhus. Generally, immunity that develops after natural infection is more prolonged than that which follows immunization.








TABLE 144.1. CLINICAL MANIFESTATION OF RICKETTSIAL DISEASES



































































































Disease Fever Rash Headache Liver and Spleen Enlarged Central Nervous System Involvement Cardiac Involvement Pulmonary Involvement
Rocky Mountain spotted fever (transmission by tick) Yes
100–104°F
Maculopapular, petechial and/or purpuric. Extremities first, then trunk Yes Unusual Yes (Common) Yes (Frequent) 10–40% of cases
Mediterranean spotted fever (transmission tick or mite) Yes
100–104°F
Local skin lesion (tache noire) at site of bite, rash on extremities which spreads to trunk Yes Liver (33%)
Spleen (20%)
Unusual Bradycardia Unusual
Rickettsialpox (transmission by mite) Yes
100–101°F
Red papule at site of mite bite-evolves into vesicle then scab. Yes No Very rare No No
Then scattered nonpruritic macules noted on trunk, face and extremities Yes No Yes (Common) Myocarditis and pericarditis occur, but uncommon Occasional
Epidemic typhus (louse borne) Yes
100–104°F or higher
Maculopapular rash on trunk, spreading to extremities Yes Uncommon Yes (Common) May occur May occur
Endemic typhus (transmission by fleas) Yes
100–102°F
Maculopapular rash on trunk, spreading to extremities Yes (mild) No Uncommon Rare Rare
Tsutsugamushi fever (transmission by chiggers) Yes
100–102°F
Maculopapular rash on trunk, spreading to extremities Yes Yes (Common) Deafness and tinnitus may occur Occasional Sometimes
Q Fever (airborne) Yes
100–104°F
No Yes Yes (Frequent) Unusual Endocarditis, Pericarditis Almost always is primary characteristic
Ehrlichiosis (human monocytic) (transmission by tick) Yes
100–103°F
Macular, petechial Yes Yes (30–40%) Uncommon but does occur Uncommon Uncommon
Ehrlichiiosis (human granulcyte) (transmission by tick) Yes
100–103°F
Yes (only 10%) Yes Uncommon Uncommon Uncommon Uncommon

Another general characteristic is that arthropods and mammals serve as natural hosts for rickettsiae. However, infection also can occur by an airborne route when infectious microorganisms acquire access to respiratory surfaces or the conjunctivae. The airborne route appears to be the most common method of spread when the infection occurs in laboratories. Humans are an accidental blind-end host for rickettsiae and do not contribute to the survival of the rickettsial species, except for louse-borne typhus.

Rickettsial diseases vary markedly in severity, from benign and self-limited to severe, fulminating diseases. The survival of the patient depends on a prompt establishment of diagnosis and the institution of appropriate therapy.


SPOTTED FEVERS

The spotted fevers are a group of infectious diseases caused predominantly by Rickettsia rickettsii. Because most are transmitted by ticks, they are called tick typhuses.

Rocky Mountain spotted fever is the most severe and important of the spotted fever group that appears in the temperate zones of North America. An illness almost identical to Rocky Mountain spotted fever occurs in South America, where it is called Sao Paulo disease. Other less severe forms of tick typhus occur in Asia, Africa, Australia, and Europe. They can be distinguished by geographic location as well as by differences in the spotted fever rickettsiae that cause them. Important epidemiologic characteristics of the spotted fever group and of other rickettsiae diseases are provided in Table 144.2.


Rocky Mountain Spotted Fever

Rocky Mountain spotted fever is a disease caused by R. rickettsii; it was recognized first in areas of Idaho and Montana, around the turn of the twentieth century. Its occurrence is not limited to the Rocky Mountain area, however; the disease actually is most prevalent in the southeastern United States. The incidence of Rocky Mountain spotted fever in the Rocky Mountain region began a steady decline before the introduction of antibiotic therapy in the 1950s and, by 1988, fewer than 20 cases of Rocky Mountain spotted fever were reported
in the Rocky Mountain and Pacific coast areas. Most of the cases that have occurred in the past 20 years have been reported from the southeastern United States. Between 1993 and 1996, the Centers for Disease Control and Prevention collected and summarized 2,313 cases of Rocky Mountain spotted fever. During that time, the annual incidence per 1 million U.S. population rose from a low of 1.8 in 1993 to 3.3 in 1996. (The overall incidence has dropped, however, over the last 20 years from a high of 5.8 per million in 1981.) Fifty percent of confirmed cases were reported from only three states (Oklahoma, North Carolina, and Virginia). The incidence of confirmed cases was highest among children 5 to 9 years of age (3.7 per million).








TABLE 144.2. IMPORTANT EPIDEMIOLOGIC CHARACTERISTICS OF RICKETTSIAL DISEASES




















































































Disease Agent Epidemiologic Features Mammalian Host
Geographic Occurrence Usual Mode of Human Transmission
Typhus Group
Epidemic typhus R. prowazekii Worldwide Infected louse feces rubbed into broken skin or as aerosol to mucous membranes Humans, flying squirrels
Brill-Zinsser disease R. prowazekii Worldwide Recrudescence months or years after primary attack of epidemic typhus Humans
Murine typhus R. typhi Scattered pockets, worldwide Flea bite Rodents
Murine typhus-like R. felis United States Flea bite Opossums
Spotted Fever Group
Rocky Mountain spotted fever R. rickettsii Western Hemisphere Tick bite Wild rodents, dogs
Tick typhuses (Mediterranean spotted fever) R. conorii* Mediterranean, Caspian, and Black sea coastal regions; Africa; Southeast Asia Tick bite Wild rodents, dogs
Rickettsialpox R. akari Worldwide Mite bite Mice
Scrub Typhus Orientia tsutsugamushi Japan, Southeast Asia, west and southwest Pacific Mite bite Wild rodents
Q Fever Coxiella burnetii Worldwide Inhalation of infected particles from environment of infected animals Mammals
Ehrlichiosis Group*
Human monocytic ehrlichiosis Ehrlichia chaffeensis Worldwide Tick bite Deer, dogs, humans
Human granulocytopenic ehrlichiosis Anaplasma phagocytophila United States, Europe Tick bite Deer, humans, other mammals
*In addition, Rickettsia australis (Queensland tick typhus) in Australia, Rickettsia siberica (Siberian tick typhus) in North Asia, and Rickettsia japonica (Oriental spotted fever) in Japan are antigenically and geographically distinct entities.
Ehrlichia ewingii, which causes a variant of human granulocytic ehrlichiosis, and Neorickettsia sennetsu, the cause of Sennetsu fever, also are included in this group.
Adapted with permission from Edwards MS, Feigin RD. Rickettsial diseases. In: Feigin RD, Cherry JD, eds. Textbook of pediatric infectious diseases, 5th ed. Philadelphia: Saunders.

Rocky Mountain spotted fever is the most common fatal tick-borne disease in the United States (more than 600 people died from Rocky Mountain spotted fever between 1983 and 1998). Rocky Mountain spotted fever also is the most prevalent rickettsial disease in the United States.

Despite the use of chloramphenicol or tetracyclines, Rocky Mountain spotted fever has an overall case fatality rate of 3.9%. A considerable number of the deaths can be attributed to failure to consider and establish the diagnosis early enough for appropriate therapy to be beneficial.


Etiology, Epidemiology, and Transmission

R. rickettsii is a small coccobacillary microorganism measuring 0.3 to 0.4 μm in length and 0.3 to 0.5 μm in diameter. The organisms usually occur singly or in strands. In stained specimens, a diplobacillus with pointed ends and a transparent band between the two bacilli are noted. Rickettsiae must penetrate cells to grow and multiply. They can be grown most readily in the yolk sacs of embryonated eggs. Rickettsiae may remain viable for several days in blood at 4°C; thus, a specimen of blood from a patient suspected to have rickettsial disease can be held for more days in a refrigerator before a definitive isolation procedure is performed. The Gimenez stain turns Rickettsiae red. R. rickettsii organisms have a soluble antigenic moiety shared with all the antigenic variants in the spotted fever group, as well as with rickettsialpox.

Because Rocky Mountain spotted fever rickettsiae primarily are parasites of ticks, human disease generally is associated with the biology of the ticks that transmit it. However, disease can be transmitted by the aerosol route in the laboratory or by blood transfusion.

The wood tick (Dermacentor andersoni) in the West, the Lone Star tick (Amblyomma americanum) in the Southwest, and the dog tick (Dermacentor variabilis) in the East all are carriers and vectors of this disease. Rocky Mountain spotted fever rickettsiae do not kill the arthropod host, but they can be passed from generation to generation of ticks transovarially. Congenitally acquired rickettsiae in tick eggs can persist through the various larval and nymph stages into the adult stage of a 2-year cycle of the tick. Infected adult ticks may survive for as long as 4 years.

The important epidemiologic features of Rocky Mountain spotted fever include seasonal characteristics because most cases occur during the period of greatest tick activity between April and September. Two-thirds of the cases in the United States occur in children younger than 15 years of age. The disease also is focal (i.e., relatively small areas within a state may account for a high percentage of that state’s recorded cases of Rocky Mountain spotted fever).


Pathogenesis

The principal pathologic lesion of Rocky Mountain spotted fever is a vasculitis that develops after the bite of an infected tick. Rickettsiae multiply within the endothelial cells lining small blood vessels and are disseminated widely by the bloodstream. The rickettsiae can be demonstrated in both the cytoplasm and the nucleus of cells. Numerous mechanisms for cellular injury that have been suggested include injury to cell membranes resulting from penetration by multiple rickettsiae; depletion of adenosine triphosphate by intracellular rickettsiae, causing failure of the sodium pump and an influx of water; damage to the cell by toxic products of the rickettsial metabolism; and competition by R. rickettsii for crucial metabolic substrates.

Vascular lesions account for the more prominent clinical features noted, including rash, mental confusion, headache, heart failure, and shock. Pneumonia can be acquired by laboratory inhalation.

The vascular lesions are found everywhere, but they are appreciated most readily in the skin, adrenal glands, and gonads. Inflammation accompanies vasculitis of the heart and nervous system. Interstitial myocarditis is demonstrated readily in the location of the rickettsiae by immunofluorescence, which coincides with the distribution of the myocarditis. In neural tissue, both proliferative glial nodules (which usually are related topographically to inflamed blood vessels) and mononuclear infiltrations are seen. In the kidney, inflammation involves vessels of the interstitium, and acute tubular necrosis may occur in some patients. In the lung, rickettsial involvement of the pulmonary microcirculation results in interstitial pneumonia. Hepatic lesions include portal triaditis, portal vasculitis, and sinusoidal leukocytosis.

Changes in nitrogen balance are extreme. Early in this infection, large amounts of nitrogen may be excreted in the urine. Subsequently, nitrogen imbalances are related to an insufficient intake of protein. The serum albumin concentration is depressed as the result of losses of protein, hepatic dysfunction related to the disease process itself, and leakage of protein through the damaged endothelium of blood vessels.

Hyponatremia may be profound. Reported causes of the hyponatremia include a loss of sodium in the urine, a shift in water from the intracellular to the extracellular space, and an exchange of sodium for potassium at the cellular level. The intracellular sodium level increases slightly. The destruction of cells results in an increase in the serum concentration of potassium and in enormous losses of potassium in the urine. Plasma concentrations of antidiuretic hormone and aldosterone have been increased in some individuals with this disease.


Clinical Manifestations

Fever, headache, and rash are the hallmarks of Rocky Mountain spotted fever, as well as of other rickettsial diseases, although the complete triad may be present in only 45% to 62% of all cases. Mental confusion and myalgia also are common features of Rocky Mountain spotted fever. The onset of disease in children usually occurs 2 to 8 days after a bite is sustained from an infected tick. The onset of clinical manifestations may be gradual or abrupt. Body temperature increases rapidly to 40°C, with a pattern that is characterized by persistence, although many patients do have temperature oscillations of 1.8° to 2.8°C over several hours (Fig. 144.1).

The rash associated with Rocky Mountain spotted fever is one of the more pathognomonic features of this disease. It generally appears by the second or third day of illness, although it may be delayed for a week. Initially, the lesions are erythematous macules that can blanch on pressure. The lesions rapidly become petechial and, in untreated patients, even hemorrhagic (Fig. 144.2). Sometimes skin necrosis occurs. The rash appears peripherally on the wrists and ankles, spreading within hours up to the extremities and onto the trunk. The rash also appears frequently on the palms and soles. The absence of rash, however, does not exclude a diagnosis of Rocky Mountain spotted fever.






FIGURE 144.1. Patient with Rocky Mountain Spotted Fever. Rash is most extensive on extremities, with lesser intensity on trunk. Lesions are maculopapular, petechial, and purpuric. Facial edema and swelling of feet are evident. The protuberant abdomen is related to enlargement of the liver and spleen in this patient.


Headache in older children and adults is a characteristic finding. The headache is persistent night and day and is intractable. Young children, however, may not complain of this symptom. Signs of meningoencephalitis are common findings and may be appreciated because the patient is irritable, apprehensive, or restless or exhibits signs of mental confusion or delirium. Occasionally, children may become comatose. Meningismus may be present, but it is not accompanied always by abnormalities in the cerebrospinal fluid (CSF). In fact, the CSF generally is clear, with minor elevations seen in the lymphocyte count (less than 10 cells per microliter). Seizures (grand mal or focal) have been observed. Central deafness (persistent or transient) and cortical blindness have been described. Other reported neurologic involvement includes sixth-nerve paralysis, spastic paralysis, and ataxia. Rocky Mountain spotted fever also seems to exert a consistent effect on intellectual function, and several investigators have suggested that a higher probability of disability and difficulty in school performance exists in children who have had this disease.

Cardiac involvement is a frequent finding, and it requires an evaluation of each patient with clinically defined illness by electrocardiography, echocardiography, and other techniques, if necessary. Congestive heart failure and arrhythmias are common occurrences.






FIGURE 144.2. Close-up picture of extremity showing intense rash with many maculopapular, petechial, and purpuric lesions.

Muscle tenderness is a common feature of Rocky Mountain spotted fever. Characteristically, the patient complains when the calf or thigh muscles are squeezed.

Pulmonary involvement occurs in 10% to 40% of reported cases and may be associated with abnormal chest radiographic results and abnormal arterial blood gas measurements. Chest radiography may reveal cardiomegaly, focal infiltrates, or pulmonary edema.

Generalized edema of the face and extremities usually occurs and, in occasional cases, nuchal rigidity and conjunctival suffusion are seen. Acute tubular necrosis and glomerulonephritis can occur. Enlargement of the liver and spleen infrequently develops. Other gastrointestinal symptoms and signs, including nausea, vomiting, abdominal pain, and diarrhea, arise frequently during the early course of Rocky Mountain spotted fever. Icterus has been reported, but it is a relatively rare event, except in severe cases.


Diagnosis

Specific treatment should be initiated promptly because, in most cases, laboratory evaluations do not permit a specific cause to be identified before therapy must be instituted. R. rickettsii, however, can be identified by fluorescent or peroxidase-tagged antibody technique of a skin specimen obtained by biopsy on days 4 through 8 of the illness, and sometimes for a longer period. This technique is a practical means of confirming the diagnosis during the stages of the disease before positive serologic reactions can be obtained. One must recognize, however, that an experienced technologist usually is needed to interpret the immunofluorescent test result and that false-positive and false-negative results do occur. A negative immunofluorescent test result never excludes the diagnosis of Rocky Mountain spotted fever.

Specific serologic results usually are not positive before day 10 or 12 of the illness. Twenty percent of untreated patients with Rocky Mountain spotted fever die, most within the first 10 to 12 days of illness. For this reason, the provision of appropriate therapy never can await a definitive diagnosis.

Selected laboratory clues may be helpful. During the first 4 or 5 days after the onset of disease, the white blood cell (WBC) count is normal or may reveal a leukopenia. As the disease progresses, secondary bacterial infections may occur, and leukocyte counts may increase to as high as 30,000 cells per microliter. Thrombocytopenia of varying severity develops in most cases.

Historically, the Weil-Felix test was used in the diagnosis of Rocky Mountain spotted fever. This test, however, is insensitive and nonspecific, and it should not be used as a diagnostic tool in rickettsial diseases.

Tests available for establishing a specific diagnosis include an enzyme immunoassay, a complement fixation test, an indirect hemagglutination reaction test, microimmunofluorescence tests, and latex agglutination and microagglutination tests. Each of these tests has limitations with regard to sensitivity or specificity. The complement fixation and microagglutination tests are highly specific but lack sensitivity. Indirect hemagglutination and latex agglutination tests are highly sensitive and specific but are not suitable for seroepidemiologic diagnosis because the immunoglobulins detected by these tests (IgM) are short-lived. The microimmunofluorescence test is the most specific and sensitive test available, but it is subject to observer bias.

A microtiter enzyme-linked immunosorbent assay (ELISA) has been developed to characterize the IgG and IgM response in Rocky Mountain spotted fever. The ELISA is both sensitive and accurate. The value of this test is limited, however, because IgG and IgM seroconversions cannot be demonstrated until 6 days after the onset of illness. This test is useful in seroepidemiologic studies.


Investigators have shown that serum from patients with Rocky Mountain spotted fever has a unique profile when analyzed by frequency-pulsed electron capture-gas-liquid chromatography. Typical profiles can be noted as early as 1 day after the onset of disease and before any antibody test result becomes positive. A polymerase chain reaction (PCR) assay that enables the detection of specific sequences of DNA at the theoretic limit of one organism has been developed. The assay is a specific and useful screening test and diagnostic tool for the most common rickettsial illnesses in the United States. This test detects as few as 30 organisms per sample and can be completed in 48 hours, thus permitting therapeutic intervention during the acute illness.

The diagnosis of Rocky Mountain spotted fever can be confirmed by isolation of R. rickettsii in embryonated eggs of guinea pigs from blood drawn during the first week of illness before specific antibodies have developed. The isolation techniques are expensive, usually unavailable, and consequently rarely utilized.


Differential Diagnosis

Meningococcemia and measles are the disorders confused most frequently with Rocky Mountain spotted fever. A petechial rash involving the palms and soles that spreads in a centripetal manner suggests a diagnosis of Rocky Mountain spotted fever. The atypical measles syndrome can produce a similar rash. Therefore, a history of receiving previous measles immunization, particularly with a killed vaccine preparation, is important. One should note that killed measles virus vaccine has not been used in the United States for many years. Differentiating from meningococcemia can be difficult because WBC counts may be low or normal and signs of meningeal irritation and moderate pleocytosis may be seen in both diseases. The inability to differentiate meningococcemia from Rocky Mountain spotted fever does not justify delaying the administration of antimicrobial therapy because both diseases potentially are fatal. Treatment should be initiated promptly with one of the tetracyclines or chloramphenicol and penicillin G if the diagnosis of either disease is entertained and neither can be excluded immediately. When the appropriate diagnosis is certain, the inappropriate drug can be discontinued.

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