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Postgrad Med J 2000;76:269–272 269

Rickettsial : the group of —a Postgrad Med J: first published as 10.1136/pmj.76.895.269 on 1 May 2000. Downloaded from review

George Cowan

Epidemic borne typhus has historically (3) The “spotted ” group of rickettsiae, caused massive mortality in the wake of war, which contains a large number of species famine, and great migrations.1 In the four years transmitted from rodents, dogs, and wild from 1918 in and there animals by ticks: were up to 30 million cases, and three million (A) R rickettsii, the agent of Rocky Mountain deaths. In the recent past in typhus , so-called because of the area of has infected prison inmates before spreading to its discovery, but now mainly occurring in the the wider community.2 It remains a risk among eastern Atlantic states of USA, especially in populations in all parts of the world, trekkers and hunters exposed to wild animal 9 despite its omission from a recent review of ticks, and with the potential for a severe health care in refugee camps.3 haemorrhagic illness. Tick borne typhus is a significant risk to (B) R conorii, the cause of tick typhus in the Mediterranean area and in India, which is human health, especially in the Eastern United transmitted by the brown dog tick Rhipicepha- States, Brazil, the Mediterranean basin, the lus sanguineus—the tick is brown, the dog not African veld, India, and Australia. Endemic necessarily so. A recent human case in Lille in flea borne typhus occurs sporadically wherever northern was caused by a tick from a rats and man live closely together. Scrub dog imported from .10 typhus is a hazard in many parts of South East (C) R africae, which is found in the African Asia and beyond, and is the first of the rickett- veld, is transmitted in game park areas by ticks sial infections to show evidence of resistance to living on cattle, hippo, and rhino.11 4 standard . No useful are (D) R japonica, R australis, and a variety of currently available for any of the rickettsial other similar organisms, which are widely infections. distributed in Asia and Australia,12 13 and infect man through various species of animal ticks. Pathogenesis (4) R tsutsugamushi, recently renamed as a The are a family of obligate new genus with only one species, Orientia intracellular small Gram negative coccobacilli tsutsugamushi,14 the agent of , which infect humans chiefly through insect acquired from the bite of larval trombiculid vectors, mostly from animal hosts, but some- living on the waist high Imperata grass times by transovarial transmission in the growing in previously cleared jungle around http://pmj.bmj.com/ insects themselves.5 villages and in plantations. The area of risk The genus is divided into: includes South East Asia, the Indian subconti- (1) R prowazekii, the agent of classical nent, Sri Lanka, and other Indian Ocean typhus, transmitted by the human islands, Papua New Guinea, and North body (clothing) louse, Pediculus humanus (but Queensland. not by head lice) from active human cases or The rickettsial fevers are acute bacteraemic illnesses characterised by headache, mental

from healthy carriers or subclinical cases, on October 1, 2021 by guest. Protected copyright. so-called Brill-Zinsser .6 Typical cir- confusion (and, in severe cases, meningoen- cumstances were evident in the Burundi cephalitis), a macular rash, mainly on the outbreak,2 which started in a prison at N’Gozi trunk, with, in some types, a small black scab or eschar at the site of the insect bite, with local or in 1995 and spread to the malnourished inhab- general . itants of refugee camps in the central highlands Rickettsial proliferation on the endothelium (over 1500 m), causing over 50 000 cases with of small blood vessels releases cytokines which a mortality of 2.6%. The infectious agent in the damage endothelial integrity, with consequent faeces of the is usually inoculated by scratching of the site of the louse bite, but in in closed communities an aerosol of dried louse faeces may be inhaled. The genome University of of the organism has recently been sequenced, —North providing new evidence of an evolutionary Thames, 33 Millman Street, London relationship between rickettsiae and intracellu- 7 WC1N 3EJ, UK lar mitochondria in general. (2) R mooseri (R typhi), the causal agent of Correspondence to: endemic typhus, is carried by the rat flea Dr Cowan, Dean of Postgraduate Medicine Xenopsylla cheopis, and typically infects man in (e-mail: markets, grain stores, breweries, and garbage [email protected]) depots. It is often a mild illness, but can Submitted 24 March 1999 become more aggressive in refugee camps, and Accepted 13 August 1999 a fatal case in the UK was infected in Spain.8 Figure 1 Scrub typhus: axillary eschar. 270 Cowan

Learning points Postgrad Med J: first published as 10.1136/pmj.76.895.269 on 1 May 2000. Downloaded from x The types of typhus fever are: (A) Epidemic louse borne: R prowazekii (B) Endemic flea borne: R typhi/R mooseri (C) Tick borne “spotted fever”: R rickettsii, R conorii, etc (D) borne scrub typhus: O tsutsugamushi x The typhus fevers all present with headache and a macular rash. A clinical diagnosis is often made, and a specific therapeutic trial undertaken, before serological confirmation is received. x Careful examination of the patient for the entry site eschar (insect bite) is helpful in the diagnosis of scrub and tick typhus, the commonest types in travellers. x In Thailand there is evidence of resistance of scrub typhus to and . Possible alternative treatments include rifampicin and ciprofloxacin. x Louse borne typhus epidemics are a risk in all refugee camps, especially in the cooler mountainous regions of tropical countries, but also in European settings. x Foci of scrub typhus in jungle areas of South East Asia are maintained by Figure 2 Classical typhus rash on trunk. vertical transmission in the mite vectors fluid leakage, platelet aggregation, and poly- without the need for mammal hosts. morph and monocyte proliferation, leading to focal occlusive endangiitis, causing microinf- arctions, as in the typical “typhus nodule” of Wolhbach.15 This process especially aVects the of cases, typically in the groin or axilla (see fig brain, cardiac and skeletal muscle, the skin, 1), and the potential for an acute brain lungs and kidneys, and may cause venous syndrome which can progress to coma and, thrombosis and peripheral . rarely, death. Occasional imported cases are reported in the UK.

Clinical presentations The clinical severity of is http://pmj.bmj.com/ The of all rickettsial infec- largely determined by the nutritional state of tions is 12 to 15 days on average, but can the population infected and in the most extend up to 28 days. extreme situations of malnutrition, such as in Murine and milder cases of scrub typhus the concentration camps at Bergen-Belsen in often present as non-specific fevers for a few 1945, a mortality of 50% and upwards may days’ duration,16 with a minimal macular rash, occur. After an incubation period of about 14 or no rash at all, and no eschar at the site of days, there is a sudden onset of high prostrating entry. Generalised lymphadenopathy was a fever with severe headache, limb pains, and on October 1, 2021 by guest. Protected copyright. characteristic feature of the milder cases seen vomiting. The face is suVused and the victim in US soldiers in Vietnam, where tetracycline appears vacant and semimute, with epistaxis was freely prescribed for cases of “pyrexia of and a dry cough. The classical rash appears on unknown origin” and the specific diagnosis was about the third day on the trunk (see fig 2) and made serologically in retrospect. proximal limbs, consisting of irregular pink Rocky Mountain spotted fever is a poten- macules, which darken and coalesce but are tially serious febrile illness with a haemorrhagic not haemorrhagic. Constipation is usual and rash and the possibility of diVuse intravascular paralytic ileus may ensue. Splenomegaly and coagulation and acute renal failure. Perhaps generalised lymphadenopathy are common. In surprisingly there is no eschar at the site of the severe cases a meningoencephalitic syndrome tick bite, although this is seen with the same develops, with meningism, tinnitus and hypera- organism in Brazil. Tick typhus in the Old cusis, followed by deafness, dysphoria, agita- World, with its many species types, varies in tion, and coma. Survivors may have hemipare- severity but can cause hepatorenal failure. The sis, acute transverse myelitis, or peripheral rash is macular and there is an eshcar (“tache neuropathy. Other possible complications in- noire”) at the entry site in the majority of cases. clude: (1) secondary bacterial infection, lead- Mediterranean tick typhus (“fièvre boutton- ing to bronchopneumonia, parotitis, or otitis neuse”) is the type most likely to be imported media; (2) , presenting as low into the UK but only a handful of cases are output cardiac failure or sudden collapse, typi- reported annually. cally when the generalised febrile illness is Scrub typhus is clinically similar to Old recovering; and (3) peripheral gangrene or World tick typhus, with an eschar in up to 80% venous thromboembolism. Rickettsial diseases: typhus 271

Diagnosis Because of the lack of clues from routine labo- Multiple choice questions (answers at Postgrad Med J: first published as 10.1136/pmj.76.895.269 on 1 May 2000. Downloaded from ratory investigations, which are usually normal, end of paper) and the facts that rickettsiae are dangerous 1. Scrub typhus in South East Asia is pathogens and specific serological tests are only transmitted by: available from a few specialised laboratories, (A) Ticks from wild animals often in retrospect, it is advisable to make a (B) Rat fleas clinical diagnosis of the typhus fevers based on (C) Larval mites on long grass a detailed travel and occupational history and (D) Head lice the physical signs. In these circumstances a (E) Sandflies therapeutic trial of specific treatment is justi- 2. Epidemic louse borne typhus: fied, as rapid defervescence is strongly sugges- (A) Typically has a haemorrhagic rash tive of a correct diagnosis. and evidence of diVuse intravascular The diVerential clinical diagnosis includes coagulation typhoid (enteric) fever, viral haemorrhagic (B) In tropical countries occurs most in fever, meningococcal infection, louse borne seaside areas of high temperature relapsing fever, and, as for all and humidity fevers acquired in the tropics, malaria, which (C) In undernourished is likely should always be excluded by the examination to carry a high mortality if untreated of blood films. (D) Can lead to peripheral gangrene Specific diagnosis can be made by: and loss of digits in severe cases (1) The Weil-Felix test, involving the dem- (E) Should be controlled by the onstration of heterophile antibodies to strains widespread prescription of of (OX-19, OK-2, OX-K); this ciprofloxacin in the community at risk test is, however, negative in up to 50% of cases. 3. Possible treatments for the typhus fevers (2) Group specific microagglutination test or include: species specific immunofluorescent antibody (A) test (IFAT) or enzyme linked immunoabsorb- (B) Ciprofloxacin ent assay (ELISA). (C) Chloramphenicol An indirect immunoperoxidase version of (D) Erythromycin the IFAT is highly sensitive,2 and the ELISA (E) Coamoxiclav can be applied to filter paper for field use. 4. Recognised eVective methods of (3) Polymerase chain reaction techniques.17 prevention of scrub and tick typhus include: Management (A) The wearing of clothing Good general care of the patient is essential, impregnated with DEET emphasising fluid balance, oral toilet, analge- (B) Specific vaccination sia, mild sedation if needed, and appropriate (C) The use of bed nets impregnated antibiotics for secondary infections. Acute with

renal failure needs appropriate management (D) The wearing of stout boots, gaiters, http://pmj.bmj.com/ and modification of the regimen. and long trousers Specific chemotherapy with chlorampheni- (E) Daily oral doxycycline 100 mg col, first used in scrub typhus in 1947,18 is with 5. Areas of risk of tick borne typhus 500 mg six hourly orally or intravenously for include: seven to 10 days in adults, or 12.5 mg/kg six (A) Queensland, Australia hourly for children. If tetracycline is preferred, (B) Rocky Mountains, USA the same dosages are used. In all mild to mod- (C) Game parks in Zimbabwe erate cases, however, the treatment of choice is (D) Mediterranean coast of France on October 1, 2021 by guest. Protected copyright. oral doxycycline 200 mg for adults, 100 mg for (E) Scottish Highlands children, in a single dose, with one further dose in five to seven days if relapse of fever occurs. There are now reliable reports4 of partial Endemic flea borne typhus can be controlled resistance to chloramphenicol and tetracycline, by antirodent measures, and individual use of for O tsutsagamushi only, in northern Thailand. insect repellent creams. Both are bacteriostatic agents so that in cases Measures to reduce the risk of tick typhus acquired there it may be wise to treat scrub include the control of dog ticks, “buddy” typhus ab initio with rifampicin or a quinolone inspection for ticks after visits to game parks or antibiotic, for example ciprofloxacin. forests, insect repellents, and the impregnation of clothing with DEET (diethyl toluamide) or Prevention and control permethrin. In epidemics of louse borne typhus it is essen- Scrub typhus control depends on the clear- tial to treat all cases with doxycycline, and ing of secondary jungle grass within and near indeed to consider mass prophylaxis with this villages, and, in travellers, the use of jungle agent in the whole population at risk and for boots and gaiters with long trousers, permeth- carers and medical workers on a weekly basis. rin or DEET impregnation of clothing, and All those at risk should initially be issued with consideration of the use of prophylactic oral clean clothes, which are dusted with powder doxycycline 200 mg weekly in those who have containing 1% or 1% permethrin. to travel through areas of known high risk, Again, this should include medical attendants, for example soldiers, policemen, plantation since history shows that they are at high risk. workers. 272 Cowan

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