Rickettsiae are very small bacteria (0.8 x 0.4 m m). These coccobacilli are closely related to Bartonella, Wolbachia, Cowdria and Anaplasma. They multiply intracellularly. They have a Gram-negative cell wall structure, but cannot be detected by Gram staining, although they can be by Giemsa staining - with difficulty. They derive their name from the American researcher, Howard Ricketts, who discovered them in 1909 in Montana, USA, as the source of a serious disease (Rocky Mountain Spotted Fever = RMSF). He himself died from typhus in an epidemic in Mexico some years later. Typhus has played an important historical role in various armed conflicts. Napoleon Bonaparte lost tens of thousands of soldiers from epidemic typhus during the invasion of Russia. During the Crimean War (1854-56) between Russia on the one hand and England and France on the other, typhus took a high toll. Florence Nightingale was famous for her help to the wounded during this dreadful conflict. Nowadays there are occasional flare-ups of epidemic typhus, as in 1997 in Burundi (an estimated 24,000 cases in the first half of the year).

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The complete genome of R. prowazekii has been mapped. This organism is genetically similar to mitochondria. Mitochondria might possibly have originated over time from a symbiotic relationship between eukaryotic cells and a rickettsia-like bacterium.

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Different classifications may be found in many manuals, e.g. the "Spotted Fever" group, the typhus group and scrub typhus. The division is based on intracellular growth characteristics and on antigenic differences between the various micro-organisms. Thus, organisms of the spotted fever group cause rapid cell lysis and spread rapidly from cell to cell, while R. prowazekii - belonging to the typhus group - grows to enormous numbers intracellularly before causing the host cell to burst. Spotted fever group Rickettsiae are found in both the nucleus and the cytoplasm, whereas R. prowazekii is found in the cytoplasm only. In practical terms, however, these divisions are not so useful. They can give rise to confusion rather than clarification. New Rickettsiae and various subtypes are still regularly being discovered. It is easier just to state that there are various sorts of Rickettsiae and that they cause a range of diseases of varying severity. Furthermore, not all Rickettsiae occur everywhere. Thus, RMSF is not found in Asia, nor does scrub typhus exist in America.

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With the exception of epidemic typhus, rickettsiosis are zoonoses. Transmission to humans occurs via arthropods. Ticks and mites infect humans through their bite. Lice and fleas infect humans through their faeces. Louse faeces can remain contagious for months. Ticks and mites transmit the organisms to their progeny (transovarial transmission). Mites and ticks are thus both vector and reservoir. In mites, infection with Orientia tsutsugamushi causes a shift in the sex-ratio in the offspring of the mites so that the female mites predominate in the following generation. This can be prevented by treating mites with tetracyclines.

In 1906 Charles Nicolle demonstrated that infection can be transmitted by body lice (head lice are not important). At the time he was working at the Pasteur Institute in Tunis. There were numerous cases of typhus and the hospitals were over-full. In 1909 he observed that personnel in the laundry became infected when they had washed the clothing of people who had been admitted. There were, however, no secondary infections originating in the over-full hospital wards. Hospitalised patients were given a hot bath with soap and clean hospital clothing on their admission. Dr Nicolle suspected a pathogenic agent in the patients’ dirty clothing and underwear. He injected a chimpanzee with a patient's blood. After a few days he collected some lice from the animal and introduced these insects into another, non-injected healthy chimpanzee. This second animal in turn became ill after ten days. Control experiments confirmed the results. Afterwards it was shown that louse faeces were infectious. Transmission is also possible when dry louse faeces are inhaled via aerosol.

People who have previously survived epidemic typhus (R. prowazekii) often harbour the bacteria in their body for life, even though they are asymptomatic (chronic carriers). In the event of immunosuppression, this can result in a mild flare-up of the infection, even after many years (Brill-Zinsser disease). When such a person is in the "right" circumstances, this can cause epidemic louse-borne typhus. As transmission of epidemic typhus occurs through lice, epidemics occur in conditions of poverty, overpopulation and poor hygiene (war, prisons, starvation, natural disasters, the homeless, refugee camps). The louse takes a contaminated blood meal and the bacteria proliferate in its intestinal epithelium. After 3-5 days, the infected cells burst. The intestine and faeces contain very large numbers of the bacteria. The haemolymph of the insect turns red from the passage of the intestinal contents (blood) into the body cavity. The louse itself does not survive infection with R. prowazekii and dies after 1 to 3 weeks. It does not form a reservoir. The importance of the American flying squirrel (Glaucomys volans) as a possible animal reservoir is not yet clear. Seemingly identical (?) Rickettsiae have been found in these animals. At this moment, these animals are not considered to be a reservoir, but this might change in the future. N.B.: the body louse is also the vector of recurrent fever (see borreliosis).

The reservoirs of endemic or so-called murine typhus (R. typhi) are rodents (mice, rats). The infection is transmitted to humans by rodent fleas such as the oriental rat flea, Xenopsylla cheopis. In certain circumstances, e.g. markets, grain stores, forest fires, there is increased contact with rodents and their fleas and transmission can occur. In contrast to R. prowazekii, R. typhi does not kill the vector. A closely related organism, R. felis, is transmitted by cat fleas (Ctenocephalides felis). The reservoir for this bacterium is the opossum (California).

Fièvre boutonneuse and Rocky Mountain spotted fever are transmitted by the bite of hard ticks. Dermacentor variabilis (dog tick) is notorious in the eastern USA, while in the western USA Dermacentor andersoni is the principal vector (Rocky Mountain wood tick). In Africa Rhipicephalus species are responsible for transmission of R. conori and Amblyomma species for R. africae. In Brazil Amblyomma cajennense is responsible for transmission, while in Mexico Rhipicephalus sanguineus serves as the vector. A wide variety of mammals constitute the reservoir. Queensland Spotted Fever, Japanese SF, Astrakhan SF, Israeli SF, Flinders Island SF and Siberian SF are also transmitted by hard ticks. Rickettsia slovaca was first identified in Dermacentor ticks from Slovakia, and has subsequently been found in Dermacentor marginatus and D. reticulatus in France, Switzerland, Portugal, Spain, Armenia and Germany. The geographical areas where certain species occur, is not well known. E.g. in 2002, the first case of infection with R. aeschlimannii was detected in South Africa. Transmission of this bacterium can occur via the bite of Hyalomma ticks and Rhipicephalus ticks. This bacterium must have existed before, but was previously not identified.

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The bacteria enter the tick as part of its blood meal and multiply. The organisms are transmitted with the saliva during the next bite. Transovarial transmission in ticks can be 100%, but other factors also play an important role in determining the final infectious state of the vector. In the USA < 1% of Dermacentor ticks in the wild are infected with R. rickettsii. This may be explained by an interference phenomenon in which infection of the tick with the very commonly occurring, non-pathogenic R. peacockii, R. belli, R. montana or R. rhipicephali prevents R. rickettsii from becoming established in tick ovaries. Naturally occurring double infections (two species of Rickettsia in 1 tick) have yet to be observed.

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Scrub typhus is caused by Orientia tsutsugamushi [Japanese "tsutsuga" = sick; "mushi" = insect]. The organism was classified in the past as Rickettsia tsutsugamushi. There are several antigenic variants (Gilliam, Karp, Kato, Shimokoshi, Kuroki, etc.). The organism is only transmitted by the bite of mite larvae, known as "chiggers" (Leptotrombidium sp.). In nature the larvae feed on rats and other rodents while the adults feed on small invertebrate animals and insect eggs. The infection occurs focally in Asia where there is a specific ecological habitat of transitional vegetation (sides of roads, overgrown agricultural areas, disturbed rain forests, river banks, etc.). The larvae secrete an enzyme that dissolves animal tissue, after which the mite can suck up the fluid. This causes local irritation. When Orientia tsutsugamushi is introduced into the skin, an inoculation chancre often occurs.

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Infections with R. akari are not often seen in clinical practice and the condition "Rickettsialpox" is more of a curiosity. Transmission occurs via mite bites: Allodermanyssus or Liponyssoides sanguineus. These mites parasitise mice.

The lesions appear in:

• Skin: At the site of the arthropod bite there is sometimes a papulovesicular lesion with local necrosis: inoculation chancre (tache noire [black spot]). The regional lymph nodes can enlarge subsequently. A chancre occurs in fièvre boutonneuse, South American RMSF ("Sao Paulo tick fever") and also frequently in scrub typhus (but not necessarily). The chancre is almost always absent in North American RMSF and never present in epidemic and endemic typhus. The rash should be distinguished from severe measles, severe dengue and septicaemic purpura, e.g. due to meningococci. With a mild rash, a distinction must be made from typhoid fever (treatment differs).
• Brain: Meningo-encephalitis with confusion ("tuphos"), delirium and coma. Distinction from cerebral malaria is important. Often occurs with scrub typhus, epidemic typhus and RMSF. Hemiplegia can occur. In general there are features of aseptic meningitis, but in RMSF there can also be an increase in the number of neutrophils in the cerebrospinal fluid. Deafness may persist for months in scrub typhus.
• Myocardium: Myocarditis, heart failure, hypotension and shock. Hypovolaemia as a result of bleeding and increased vascular permeability contributes to low blood pressure.
• Blood vessels: Occlusion of arteries results in gangrene, possibly late onset (toes, fingers) and occurs predominantly in epidemic typhus and RMSF. Thrombophlebitis occurs as a result of vasculitis and stasis in severely ill patients.
• Kidney: kidney failure from vasculitis and interstitial nephritis, promoted by hypotension; albuminuria, oliguria.
• Eyes: Conjunctivitis, papilloedema (with cerebral involvement). Enlargement of the blind spot and scotomas occur frequently in scrub typhus.
• Lungs: Cough, tachypnoea, dyspnoea.

These infections usually have a very serious course. The incubation period is 5-10 days for scrub typhus and RMSF and ± 12 days for epidemic typhus. After a few days of generally not feeling well, a high fever occurs. It is associated with severe general malaise, severe headache, muscular pain, conjunctivitis, cough, hypotension, meningeal irritation, vomiting, epistaxis, confusion or coma. Hepatosplenomegaly occurs occasionally, but is rare. Lymphadenopathy occurs in approximately one in four patients. Rash appears around the 3^rd to the 7^th day after the onset of fever. The absence of a rash in the first few days often makes it difficult for the diagnosis to be suspected at an early stage. The skin rash in RMSF begins on the wrists, palms and soles and spreads centripetally to the trunk. In epidemic typhus and scrub typhus it is the reverse: beginning on the trunk (axilla), it spreads centrifugally over the rest of the body, sometimes sparing the face, hands and feet. The rash may develop into purpura and can rapidly become haemorrhagic. Gangrene of the fingers and toes can occur. Because of diffuse intravascular coagulation (fibrinogen consumption), there may be a pronounced bleeding tendency. O. tsutsugamushi has several subtypes and repeated infections with scrub typhus are possible. Scrub typhus in HIV patients follows the same course as in people with an intact immune system. One peculiarity has been recently observed, which is that during the acute phase the viral load falls markedly, sometimes to below the limit of detection of the assays. This fact is currently undergoing further study.

Rickettsia akari causes rickettsialpox. It is a rare infection which manifests as a self-limiting, febrile, vesicular skin rash, usually confused with varicella. The differential diagnosis includes monkeypox, a rare viral pox disease which to date is endemic in Central Africa.

In developing countries, the diagnosis of typhus is predominantly clinical. If scrub typhus (Southeast Asia) or boutonneuse fever (Africa, Mediterranean Sea basin) is suspected, a chancre should be sought. The rash should be distinguished from, among others, dengue, rat bite fever [infection with Spirillum minus or Streptobacillus moniliformis], secondary syphilis, meningococcal septicaemia, ehrlichiosis, varicella, herpes zoster, rubella, Epstein-Barr virus infection and severe measles. Q fever does not produce a rash. In RMSF, the cerebrospinal fluid is usually normal, although sometimes the neutrophil count is slightly raised. Scrub typhus and murine typhus can cause an increased number of lymphocytes in the cerebrospinal fluid in meningito-encephalitis so that the infections can resemble also (arbo)viral infections and leptospirosis. In the blood, the white blood cell count is normal or reduced (leukopenia). Diffuse intravascular coagulation often occurs with thrombocytopenia.

The diagnosis can be confirmed at a late stage by serology. Seroconverson however does not occur so fast. A 4-fold increase in titre between acute and convalescent sera must be detected. Rickettsiae have some antigens in common with Proteus vulgaris strains OX19, OX2 and OXK. On this basis, a flocculation test was developed: the Weil-Felix test [1916, Edmund Weil and Arthur Felix, Hungarian doctors]. The test is aspecific. Q fever tests negative in it. Scrub typhus only produces a positive result in 50% of cases. There are now many better tests but often they are not available under field conditions. Treatment must be started early without waiting for laboratory confirmation.

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Isolation of the organism by blood culture is not possible in practice in third world situations (even in most Western hospitals). Culture of rickettsia is difficult, laborious and dangerous (tissue culture or isolation on embryonated eggs). Guinea pigs can be inoculated with blood from a patient. After 4-5 days, the animals develop fever and male guinea pigs develop a swollen scrotum (Neil-Mooser reaction). Such techniques can only be performed in reference laboratories. There is a significant risk of laboratory infection. Recently, PCR technology became very important in identifying rickettsial species and strains.

Untreated, the mortality of RMSF is 20 to 40% and of epidemic typhus ± 20%. General status (malnutrition, etc) plays a role here. Endemic typhus follows a milder course (mortality 2%) and fièvre boutonneuse has a low mortality (< 1%). It is not necessary to wait for confirmation of the diagnosis for treatment. If the course is fulminant, antibiotics are relatively ineffective.

Disease duration and severity are probably reduced by the early short-term administration of steroids (dexamethasone). They should only be given to very sick patients. This is not yet a general adopted treatment strategy.

All patients and their clothing should be free from insects, ticks and mites. Delousing is of major importance in epidemics. The patient should be washed (removal of louse faeces on the skin and in the hair). Clothes and sheets should be decontaminated.

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