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Synonyms: epidemic typhus, rickettsaemia, louse-borne typhus, classical typhus, jail fever, recrudescent typhus (Brill-Zinsser disease), scrub typhus, Shichito fever, Hatsuka fever
Typhus is an acute febrile illness with more than one form. It is caused by rickettsial infection, which is endemic in many parts of the world, and is acquired via lice and fleas from other humans and small mammals such as rats, cats and squirrels (most commonly rats).
There are two major types: epidemic typhus, and endemic (or murine) typhus. Epidemic typhus is the more serious condition, which has historically been responsible for vast numbers of deaths, particularly in times of war and hardship. Today, if caught early and treated, it is not usually fatal.
Scrub typhus, technically a separate condition, is also described here due to its clinical and epidemiological similarity to typhus proper.
The causative rickettsial bacteria are Gram-negative coccobacilli. These are obligate intracellular parasites which are found in many animals, including rats and mice:
- Rickettsia prowazekii causes epidemic typhus, the more severe form, and is spread mainly by lice, although sylvatic typhus (also due to R. prowazekii) is found in the USA and associated with bites from the fleas of a flying squirrel.
- Rickettsia typhi causes endemic typhus and is transmitted by fleas. The term endemic refers to the fact that there is an animal reservoir of disease maintaining the presence of typhus in a particular area.
- Rickettsia felis is found in cats and has also been linked to endemic typhus.
- Recrudescent typhus (Brill-Zinsser disease) occurs when latent infection reactivates, and is found in about 15% of cases (even where previously treated). It may trigger new epidemics through infection of a new generation of lice.
- Scrub typhus is caused by the organism Orientia tsutsugamushi, which is not classified with the other rickettsiae. However, whilst technically classified separately to epidemic and endemic typhus, it is in presentation and treatment so closely related as to be considered here.
The bacteria which cause endemic and epidemic typhus are not transmitted directly by bites, but by contamination of the bite site with infected louse faeces which are then inoculated by human excoriation. They then parasitise the endothelial cells of blood vessels, causing a multisystem vasculitis. Orientia tsutsugamushi is transmitted by the ovaries of trombiculid mites. The offspring infected mites are known as chiggers, and pass the infection directly to humans.
Epidemic typhus fever
This mainly occurs in cooler regions of Africa, South America and Asia. Most recently, outbreaks have mainly taken place in Burundi, Ethiopia and Rwanda. Outbreaks occur where poverty, homelessness, close human contact and lack of opportunity for washing and laundry co-exist, favouring the person-to-person spread of the human body louse. Tick-associated reservoirs of R. prowazekii have been described in Ethiopia, Mexico and Brazil. Epidemic typhus is considered a potential bioterrorism agent and was tested as such in the former USSR during the 1930s.
This is found in the USA and is associated with bites from the fleas of a flying squirrel.
Endemic (murine) typhus
A milder form of disease compared to epidemic typhus. It occurs globally - in temperate climates, usually during the summer months and, in tropical countries, throughout the year. It remains fairly widespread, including parts of the USA. Homelessness, poverty and situations which promote close contact between rats and people favour its spread.
Active foci of endemic typhus are known in the Andes' regions of South America and in Burundi and Ethiopia. There is an appreciable incidence of endemic typhus in parts of southern Europe. For example, 83 cases of murine typhus were documented in the city of Chania, on the island of Crete, over a five-year period from 1993-1997.
Scrub typhus is endemic to the tsutsugamushi triangle of the South/Southeast Asian Pacific extending from Japan and Eastern Russia to India and Pakistan, across Southeast Asia and Oceania to the Solomon Sea and northern Australia. The mites are particularly prevalent in areas of scrub vegetation - hence the name - and breeding is most rife during the rainy season and near water. In developing countries the disease remains rife - in northern Thailand and Laos around a quarter of all adults presenting with fever and negative blood cultures have scrub typhus, and incidence continues to increase all over India.The recent marked increase in incidence in India is thought to be due to the population explosion, causing a strain on sanitation, and also increased diversion of forest land for agricultural use[6, 7].
There are many historical references to outbreaks of epidemic typhus. It has also been called gaol (or jail) fever and it caused more prison deaths than execution in the eighteenth century, even though capital punishment was common. It also killed several prominent judges. During the First World War there were over three million deaths from epidemic typhus, despite intensive attempts at delousing. During the Second World War, epidemic typhus was present across Central and Eastern Europe, with terrible outbreaks occurring in concentration camps: Anne Frank was one of many who died of typhus. After the war, DDT was used to kill lice and the incidence of typhus reduced. There have been a few epidemics since then. Typhus is rarely reported in international travellers: those who stay in budget-type accommodation or who may have close contact with louse-infested humans, especially during outbreaks or in refugee settings, may be at increased risk of infection.
Scrub typhus was a notorious risk to US troops in the Pacific during the Second World War when epidemics of the disease caused many deaths. There was no effective antibiotic treatment prior to 1944. It was also a problem for US troops stationed in Japan after the surrender.
The rash of typhus is initially often described as rose-coloured, although this will only be its appearance on fair skin. Initially it is a blanching rash, although later as it reddens and darkens it becomes non-blanching. In severe cases of typhus, where haemorrhagic elements are seen, bleeding into the skin (petechiae) may be present.
The incubation period is 10-14 days, after which symptoms last around two weeks in total and may include some or all of:
- Prodromal malaise lasting 1-3 days.
- Severe headache.
- Fever (40°C) for up to two weeks.
- Myalgia (those affected may adopt a crouching posture), photophobia and neurological abnormalities (seizures, confusion, drowsiness, coma and hearing loss).
- Nausea, vomiting and diarrhoea.
- Joint pain.
- Abdominal pain.
- Cough and sneeze.
- Rash, which usually develops 4-7 days into the illness, normally starting on the chest. Initially there is a non-confluent, erythematous, blanching rash commencing centrally (axilla, trunk) and spreading centrifugally to the extremities.
- Peripheral gangrene and necrosis.
The rash does not involve the face, palms and soles and there are no eschars. It may cover the rest of the entire body. Patients may develop additional symptoms of petechiae, delirium, stupor, hypotension, and shock, which can cause their death. The rash becomes petechial and unblanching within 1-2 days of appearing. Purpura occur in a third of patients.
Recrudescent typhus (Brill-Zinsser disease) is recurrent typhus and is clinically milder than the epidemic form.
The incubation period of endemic typhus is 1-2 weeks with an average of 12 days after which symptoms last about two weeks. These include (the most common first):
- Dull red rash starting on the chest (in 80% of fair-skinned and 20% of dark-skinned people).
- Very high fever for up to two weeks.
- Nausea and vomiting.
- Abdominal pain and diarrhoea.
- Dry cough.
- Joint pain.
- Approximately 10% of those admitted to hospital have acute renal failure, and respiratory failure.
- There is a small possibility of neurological features, including altered consciousness, ataxia and seizures.
Infection with scrub typhus is most often self-limiting but can occasionally be severe and even fatal. Mortality, untreated, ranges from 4-40%.
The incubation period is up to ten days. Common features are:
- Papule followed by black eschar at bite site.
- Gastrointestinal symptoms - pain, vomiting.
- Maculopapular rash.
More virulent forms of the disease can also cause:
- Interstitial pneumonia.
- Disseminated intravascular coagulation.
- Multi-organ failure.
Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at increased risk of a more severe form. Post-infection immunity lasts only a few years and infection with one strain of Orientia tsutsugamushi does not confer immunity against other strains.
- Meningococcal disease.
- Infectious mononucleosis.
- Idiopathic/autoimmune vasculitis.
- Rocky Mountain spotted fever (RMSF).
- Kawasaki disease.
- Relapsing fever.
- Toxic shock syndrome.
- Diagnosis is usually made clinically on the basis of characteristic onset and progression of illness.
- Investigations are used mainly to confirm clinical suspicions and to assess severity.
- Where the condition is suspected then antimicrobial therapy should be given whilst waiting for confirmatory serological tests, which can take up to a week to complete.
- FBC can show leukopenia ± thrombocytopenia, but WCC can be elevated or normal; atypical lymphocytes may be seen in blood film.
- U&E may reveal hyponatraemia or raised creatinine/urea.
- LFTs may show mild elevation of transaminases and low albumin levels.
- Prothrombin time is usually normal.
- Serology shows rising IgM titre in acute infection and rising IgG titre in recrudescent disease.
- PCR amplification and analysis of rickettsial DNA from serum or skin biopsy specimens can be used to diagnose the condition.
- Indirect immunoperoxidase assay (IPA) and immunofluorescence assay (IFA) are the gold standard tests but are not universally available.
Rickettsial (and closely related) infections may cause several other disease entities such as:
- RMSF (USA).
- Mediterranean spotted fever (boutonneuse fever - Europe, Africa and elsewhere).
- When the disease is suspected, treat with moderate- to high-dose oral doxycycline or tetracycline.
- Scrub typhus can also be treated with doxycycline, as well as tetracycline and azithromycin. Chloramphenicol is used in more severe cases. Resistance is becoming widespread in Thailand in particular, where azithromycin remains effective. Azithromycin is also safe in pregnant women and children.
- Patients with epidemic typhus may need IV antibiotics and oxygen.
- Antibiotics should be initiated as soon as possible, usually before serological confirmation of the diagnosis. Most patients improve dramatically within 48 hours of starting treatment.
- Chloramphenicol is also effective but is less commonly used.
- The duration of treatment will depend on the antibiotic, but is often continued for 2-4 days after fever has subsided.
- An alternative strategy in outbreak situations is to give patients a single 200 mg dose of doxycycline, although there may be a higher risk of relapse with this approach.
- In patients with severe, acute disease, management on a high-dependency area with support measures may be needed.
- Recrudescent cases of epidemic typhus will usually be cured by a single further course of antibiotics.
- End organ damage (affecting the central nervous, musculoskeletal, cardiovascular, pulmonary and renal systems and the skin).
- Electrolyte disturbance.
- Peripheral gangrene.
- Secondary infections, particularly bacterial pneumonia.
- Without treatment, death may occur in 10-50% with epidemic typhus, 4-40% with scrub typhus, and around 2% with endemic typhus.
- Uncomplicated cases that are promptly diagnosed and treated do very well and usually make a full recovery.
- Complicated or delayed cases have a higher risk of complications but still do well on the whole, dependent on comorbidity and degree of immunity from previous infections.
- Untreated, mortality for epidemic typhus can be as high as 60%. Howard Taylor Ricketts (after whom the genus Rickettsia is named) died of typhus after exposure during his laboratory work. Prompt antibiotic treatment results in cure in almost all patients if correct treatment is given - deaths still occur due to delayed diagnosis. Murine typhus has a mortality rate of between 0-1%.
- The highest mortality is seen in adults, particularly the elderly and malnourished.
- No vaccine or chemoprophylaxis is available.
- Avoidance of endemic areas and crowding.
- Avoiding contact with vectors (fleas and rats in particular).
- Treatment of domestic animals to eradicate fleas.
- Weekly doses of doxycycline in those entering endemic areas.
- Long-sleeved shirts and long trousers should be worn in endemic areas and changed regularly with attention to good personal hygiene.
- Infested clothing should be exposed to 70°C for >1 hour.
- Where water and fuel are in short supply, insecticides may be used to treat clothing - eg, 0.5% permethrin; one treatment is sufficient unless re-infestation is expected. Treating clothing with diluted permethrin gives protection for six weeks.
- An alternative is to remove and leave infested clothing unworn for a week (body lice can only survive for five days if deprived of blood).
- Complete eradication of epidemic typhus may be impossible because of the lifelong nature of infection with R. prowazekii and risk of reactivation.
- Control of populations of rats and other biting arthropod-bearing animals can reduce the overall incidence of endemic typhus.
- An inactivated vaccine offering partial protection against R. prowazekii has been available in the past but is not currently recommended. DNA vaccines are now under development.
- In areas where endemic typhus is found, or in outbreaks of epidemic typhus, efforts to treat domestic animals to rid them of fleas are good preventive measures.
- Boil clothing during outbreaks, if possible. If not, avoid any physical contact with infested clothing for five days to allow the lice to die.
It is essential to consider the various forms of typhus as possible causes of fever in returning travellers[20, 21]. Whilst Plasmodium falciparum malaria remains the most common and dangerous disease to exclude, the increasing incidence of typhus, particularly scrub typhus, across South and Southeast Asia, together with increasing resistance to standard treatment regimes, mean that this intracellular pathogen must always be considered in the differential diagnosis, particularly in travellers presenting with fever within three weeks of their return.
Further reading and references
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Howard A, Fergie J; Murine Typhus in South Texas Children: An 18-year Review. Pediatr Infect Dis J. 2018 Nov37(11):1071-1076. doi: 10.1097/INF.0000000000001954.
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Typhus fever (Epidemic louse-borne typhus); World Health Organization, 2019
Bechah Y, Capo C, Mege JL, et al; Epidemic typhus. Lancet Infect Dis. 2008 Jul8(7):417-26.
Prusinski MA, White JL, Wong SJ, et al; Sylvatic typhus associated with flying squirrels (Glaucomys volans) in New York State, United States. Vector Borne Zoonotic Dis. 2014 Apr14(4):240-4. doi: 10.1089/vbz.2013.1392. Epub 2014 Apr 1.
Civen R, Ngo V; Murine typhus: an unrecognized suburban vectorborne disease. Clin Infect Dis. 2008 Mar 1546(6):913-8. doi: 10.1086/527443.
Xu G, Walker DH, Jupiter D, et al; A review of the global epidemiology of scrub typhus. PLoS Negl Trop Dis. 2017 Nov 311(11):e0006062. doi: 10.1371/journal.pntd.0006062. eCollection 2017 Nov.
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Ruang-Areerate T, Jeamwattanalert P, Rodkvamtook W, et al; Genotype diversity and distribution of Orientia tsutsugamushi causing scrub typhus in Thailand. J Clin Microbiol. 2011 Jul49(7):2584-9. doi: 10.1128/JCM.00355-11. Epub 2011 May 18.
Rahi M, Gupte MD, Bhargava A, et al; DHR-ICMR Guidelines for diagnosis & management of Rickettsial diseases in India. Indian J Med Res. 2015 Apr141(4):417-22. doi: 10.4103/0971-5916.159279.
Newton PN, Keolouangkhot V, Lee SJ, et al; A prospective, open-label, randomized trial of doxycycline versus azithromycin for the treatment of uncomplicated murine typhus. Clin Infect Dis. 2018 Jul 18. pii: 5055327. doi: 10.1093/cid/ciy563.
Wee I, Lo A, Rodrigo C; Drug treatment of scrub typhus: a systematic review and meta-analysis of controlled clinical trials. Trans R Soc Trop Med Hyg. 2017 Aug 1111(8):336-344. doi: 10.1093/trstmh/trx066.
El Sayed I, Liu Q, Wee I, et al; Antibiotics for treating scrub typhus. Cochrane Database Syst Rev. 2018 Sep 249:CD002150. doi: 10.1002/14651858.CD002150.pub2.
Akram S et al; Rickettsia Prowazekii (Epidemic Typhus)
Typhus; North Carolina Department of Health and Human Services, 2017
Peniche Lara G, Dzul-Rosado KR, Zavala Velazquez JE, et al; Murine Typhus: Clinical and epidemiological aspects. Colomb Med (Cali). 2012 Jun 3043(2):175-80. eCollection 2012 Apr.
Typhus; World Health Organization, 1997
Rapsang AG, Bhattacharyya P; Scrub typhus. Indian J Anaesth. 2013 Mar57(2):127-34. doi: 10.4103/0019-5049.111835.
Mendell NL, Bouyer DH, Walker DH; Murine models of scrub typhus associated with host control of Orientia tsutsugamushi infection. PLoS Negl Trop Dis. 2017 Mar 1011(3):e0005453. doi: 10.1371/journal.pntd.0005453. eCollection 2017 Mar.
Lo Re V 3rd, Gluckman SJ; Fever in the returned traveler. Am Fam Physician. 2003 Oct 168(7):1343-50.
Bell DJ; Fever in the returning traveller. J R Coll Physicians Edinb. 2012 Mar42(1):43-6