Epidemic Typhus

1. Epidemic Typhus Maria Salas October 22, 2001

2. Epidemic Typhus • Agent: R. prowazekii • Vector: human body louse • Disease of war and poverty • Plague of Athens (5th c. BC) • Napoleonic Wars • WWI and WWII • Modern refugee camps

3. The Rickettsiae • Gram-negative, obligate intracellular bacteria • Pleomorphic coccobacilli, ~ 2 um in length • Includes Rickettsia, Ehrlichia,Orientia, and Coxiella genera • 2 antigenic groups (based on LPS) of Rickettsia species: • spotted fever group (SFG) • typhus group (TG)

5. Pathogenesis • Enter through skin -> bloodstream • Infect endothelial cells by inducing phagocytosis and escaping phagolysosome -> replicate in cytosol • Can also infect m, PMNs, and fibroblasts in vitro • R. prowazekii escapes by cell lysis • May lyse cells extracelluarly via phospholipase A production -> increased vascular permeability and hypotension

7. Clinical Manifestations • 7-14 day incubation • Fever (~ 2 weeks), chills, headache • Macropapular rash after ~ 7 days, centrifugal spread (unlike RMSF) • Myocarditis, stupor and delirium • “typhos” (Greek) = smoke or haze

8. Clinical Manifestations • Both humoral response and CMI crucial to recovery. One attack usually confers long-lasting immunity. • There are asymptomatic carriers • Complications include vascular collapse, pneumonia, encephalitis • Mortality up to 70% in epidemics, mortality increasing with age

9. Brill-Zinsser Disease • Recrudescent epidemic typhus • Establish latency in lymph nodes • Occurs in elderly or immunocompromised persons -> malnourishment, poverty, and war! • Milder disease (including absence of fever) and lower mortality • RESERVOIR FOR NEW TYPHUS EPIDEMICS!

10. Findings from sequencing the R. prowazekii genome • Completed in 1998 in Sweden by Kurland, et al. • 1.1 million bp, 834 genes • Toxic polysaccharides may be vaccine targets • R. prowazekii has genes similar to those found in yeast nucleus but used by mitochondria -> mitochondrial ancestor “off-loaded” genes to host cell? • High percentage of non-functional genes in R. prowazekii

11. The Vector: Pediculus humanus humanus (body louse) “It was not so long ago, indeed, that [the louse’s] prevalence extended to the highest orders of society, and was accepted as an inevitable part of existence – like baptism, or the smallpox.” Hans Zinsser Rats, Lice, and History

12. The Vector: Pediculus humanus humanus (body louse) • Order Anoplura • Life cycle (egg to egg) takes 22-28 days • Eggs hatch in 5-9 days • Prefers 82-86oF -> remains on human host until death or high fever (can live 5-8 days away from host) • Prefers areas in direct contact with clothing -> neck, armpits, crotch • Lays eggs on clothing

13. Life cycle of body lice

14. Transmission • Rickettsiae invade and destroy louse gut epithelial cells • Rickettsiae released from lysed cells into gut lumen • Louse deposits rickettsiae into bite wound via infected feces • Louse dies of GI tract disease after ~2 weeks, not significant reservoir for rickettsiae (no transovarial transmission) • BZ patients can serve as sources of infection for 1-5% of feeding lice!

15. Diagnosis • Clinical manifestations often confused with measles, meningococcemia, typhoid fever • Weil-Felix reaction: IgM cross-reactive with Proteus antigens (doesn’t work for BZ, non-specific, insensitive) • Specific serology: IFA • Animal inoculation with patient’s blood (yolk sac, guinea pig) • Xenodiagnosis (infect previously uninfected vectors) • PCR of ticks found in clothing (Raoult, et al)

16. Diagnosis

17. Treatment Doxycycline, tetracycline, or chloramphenicol are very effective! • Single dose of 200 mg doxycycline

18. Control and Prevention • Sanitation!!! • Delousing of clothing, bedding with insecticide dust or temperatures >70oC for over 1 hour • Whole killed vaccine confers imperfect immunity • Live attenuated vaccine has been more successful in producing CMI, but has side effects, including mild disease

19. Typhus in History • 430 BC - Plague of Athens during Peloponnesian War? 1/3 of population died!

20. Clinical Manifestations • 7-14 day incubation • Fever (~ 2 weeks), chills, headache • Macropapular rash after ~ 7 days, centrifugal spread (unlike RMSF) • Myocarditis, stupor and delirium • “typhos” (Greek) = smoke or haze

21. Typhus in History • Napoleon in Moscow • WWI – epidemic in Russia (3 mil. deaths!), Poland, and Balkan States. • 1909 – Charles Nicholle shows body louse is sole vector, influences improvements in sanitation during WWI (1928 Nobel Prize)

24. Typhus in History • WWII • Vaccine used in armed forces • Use of DDT significantly decreased prevalence of typhus (1948 Nobel Prize goes to Paul Müller for discover of DDT) • Typhus rampant in concentration camps

26. Typhus Today • Since WWII, typhus decreased to a few foci, primarily in Burundi, Rwanda, and Ethiopia • HOWEVER, epidemics occurring in refugee camps and impoverished populations (Burundi, Russia)

27. Burundi, 1997 • 1993 – Civil war erupts, displacing over 760,000 refugees internally and throughout neighboring countries • 1995 – “Jail Fever” outbreak in N’Gozi • 1997 – 100,000 persons estimated to be infected throughout refugee camps in Burundi

28. Lessons from Burundi • Military blockades and civil war severely impaired investigation and management of epidemic • Rapid diagnostic techniques needed in the field to distinguish epidemic typhus in transient population • Treatment is cost-effective and essential, as delousing is difficult in transient populations • An effective and available vaccine is needed (all refugees in Burundi could be vaccinated in 2 months!)

29. “ Typhus is not dead. It will live on for centuries, and it will continue to break into the open whenever human stupidity and brutality give it a chance, as most likely they occasionally will.” Hans Zinsser Rats, Lice, and History (1934)