1. Q Fever: A Public Health Paradox Emerging Zoonotic Diseases Summit, August 23, 2005 Jennifer H. McQuiston, Viral and Rickettsial Zoonoses Branch Division of Viral and Rickettsial Diseases Centers for Disease Control and Prevention, Atlanta, GA

2. Background “Query fever” Worldwide zoonosis Caused by Coxiella burnetii - Gram-negative coccobacillus - replicates in host macrophages and monocytes Shed in birthing fluids, excreta, milk Humans infected via inhalation, ingestion

3. Electron micrograph showing an infected monkey cell with one large vacuole harboring about 20 Coxiella burnetii bacteria. [Credit: R Heinzen, NIAID]

4. Environmental Persistence Shed in the environment in a small cell form that is very hardy (“spore-like”) Resistant to pH changes, desiccation, UV light Resistant to some common disinfectants Remains viable in soil, dust for months to years - isolated from barns, soil – culture, PCR Raises questions regarding: - environmental contamination - appropriate cleaning/disinfection

5. Transmission Ruminants most common source of human infection - Cattle, sheep, goats Domestic animals - Cats Wild Animals (rodents) Birds (pigeons) Ticks Wind-borne environmental spread - Can be spread several miles down-wind from farms Contact with contaminated products - Straw - Fertilizer - Farm equipment Human-to-human rare (OB/GYN, sexual)

6. Acute Q fever 1-3 week incubation Asymptomatic infections occur Nonspecific signs and symptoms fever severe headache myalgias cough fatigue night sweats rigors nausea/vomiting

7. Nonspecific flu-like illness Pulmonary Syndrome (~30%) Hepatitis (30-60%) Myocarditis, meningoencephalitis (rare) Antibiotics may shorten course Low mortality (< 1 %) Treatment: Doxycycline Chronic fatigue-like illness - following acute infection in Australian slaughterhouse workers (10%) Acute Q fever

8. Chronic Q fever Endocarditis - latent infection - < 1-2% of acute cases - immunocompromised, heart valve disorders at greater risk - life-threatening, heart valve replacement may be required - treament: 18 months doxycycline, hydroxychloroquine Granulomatous hepatitis, osteomyelitis

9. Diagnosis Serology IFA, paired sera Phase 2 antibody: acute infection Phase I > Phase 2 antibody: chronic infection Antibody can persist for a long time, or take a while to develop Commercial labs may incorrectly report low titers as positive Culture Requires BSL-3, Select Agent PCR, Immunohistochemistry

10. Q fever and Bioterrorism Category B bioterrorism agent - high morbidity - inhalation route of transmission - extreme persistence in environment Previous development as an agent of biowarfare Accessible – obtain from environment

11. History of Q fever Bioweapons Research First agent studied by Fort Detrick’s bioweapons program in 1954 Successfully developed an aerosol dispersion model - demonstrated infectivity for animal subjects and human volunteers in the “8-ball” - successfully field-tested via aerosol dispersion to human volunteers located > 0.5 miles downwind - developed dosage curves (1-10 units infective dose)

12. The “8-Ball” Ft. Detrick, MD ca. 1968

13. Q fever Outbreaks in the United States Occupational exposures most frequently cited research facilities using parturient ruminants slaughterhouses farms factories Sheep implicated more frequently than other animals in outbreaks

14. Q fever Seroprevalence in the United States Human Seroprevalence Studies : - persons with livestock contact 7.8% - general population 0.8% - Risk Ratio 10.3 [95% CI 9.0-11.8]) Ruminant Seroprevalence Studies: - bovine bulk tank: 26.3% - cattle: 3.4% - sheep: 16.5% - goats: 41.6% Vet school dairy herds, antibodies in milk - 9/22 (38%) had titers ≥ 1:256

15. Q fever Surveillance in the United States: Human Cases Reported by State Health Departments, 1978-1999 2 17 181 67 1 (CT) 1 (DC) 3 12 2 1 11 13 18 7 5 5 4 10 3 3 23 19 1 5 15 7 n=436 Mean: 20 per year

16. Current Surveillance for Q fever in the United States Q fever in animals is not reportable Human disease was made reportable in 1999 - states report cases to CDC via NETSS - data available for 2000-2004

17. Cases of Q fever in Humans Reported by State Health Departments, 1978-2004 * Years in which Q fever was a Nationally Reportable Disease

18. National Reporting, 2000-2004 Demographics n = 255, Mean 64 cases per year Gender: 195 (77%) Male Age: mean, median 51 years Race White: 92% Black: 6% Asian: 2% Hispanic: 13.4% No significant difference in gender distribution among age groups

19. Age Distribution of Q fever Cases in the United States, NETSS 2000-2004 p< 0.0001

20. Month of Illness Onset, Q fever Cases in the United States, NETSS 2000-2004

21. Not Reportable 2000-2004 ≥ 0.28 per million < 0.28 per million 0.45 0.31 2.40 0.63 0.93 0.51 0.35 0.64 0.94 0.32 0.52 0.28 1.52 Average Annual Incidence of Q fever in Humans Reported by State Health Departments, 2000-2004 0.44 * Incidence calculated for years when Q fever was reportable. 0.28 0.42 (MA) 1.33 (DC)

22. Summary: Human Surveillance Incidence of Q fever in humans is highest in the midwestern and western states, and lower in the eastern U.S. - differences in livestock densities do not offer complete understanding - complex interplay of agricultural practices, human population density, and climactic factors Demographics similar to previously published studies - middle-aged male patients - exception: no evidence of gender difference between adolescent cases vs. adult cases

23. Why is Surveillance so difficult? Nonspecific clinical signs -resembles a variety of other common illnesses - self-limiting in most cases - poor physician recognition Requires laboratory confirmation for reporting Serology requires paired serum specimens - early specimens frequently negative - patients rarely return to provide convalescent samples Physicians must request appropriate tests

24. Why is Surveillance so important? Category B bioterrorism agent - vital to establish endemic baseline levels - need to understand background seroprevalence before a BT event takes place Current numbers of cases are under-reported - true level of disease unknown - level of serious disease (endocarditis) unknown - economic burden of Q fever in humans and animals is poorly assessed - in Australia, considered the most economically important zoonosis

25. Credit: Ralph A. Clevenger, 1999

26. Q fever: Investigation Challenges All human cases should be investigated and reported - Document geographic trends - Recognize persons at high risk for endocarditis - Assess source to determine outbreak potential Investigating animal infection may be problematic - Endemic in ruminants - Serologic assessment difficult - Phase 1 antibody may be more prominent - Historically, only Phase 2 antibody was examined - Cannot easily prevent or control infection in herds

27. Q fever: A Public Health Paradox Difficulties in clinical and laboratory diagnosis make adequate surveillance problematic. However, because of bioterrorism potential and possible serious outcomes in high-risk persons, surveillance and reporting are critical. Investigating sporadic human cases may not help reduce risk - there is often little that can be done to minimize transmission in farm settings.

28. Prevention Laboratory environments - vaccination when possible (IND in U.S.) - appropriate respiratory protection Research environments with parturient ruminants - Q fever-free animals - employee biomonitoring program - strict biocontainment Farm/slaughterhouse situations: - vaccine (Australia, not available in U.S.) - attention to hygiene - need for employee serologic monitoring? General Public - pasteurize milk products - limit contact with parturient animals, especially in public settings (petting zoos, etc)

29. Discussion Q fever in humans is likely substantially underreported - nonspecific clinical signs - poor physician recognition - difficult laboratory diagnosis Surveillance for Q fever in the U.S. is improving - made nationally reportable in 1999 - reporting increased by ~ 300% from 2000-2004 - reportable in 46 states in 2004 Future studies will improve our understanding of geographic patterns of infection and risk

30. Acknowledgments Bob Holman, Division of Viral and Rickettsial Diseases, CDC Viral and Rickettsial Zoonoses Branch, CDC Especially: Herb Thompson Vrinda Nargund Margaret Bowman Tracey McCracken Candace McCall Jamie Childs NETSS Staff State Health Departments U.S. Veterinary Schools

32. Not Reportable 2000-2004 ≥ 0.28 per million < 0.28 per million 0.45 0.31 2.40 0.63 0.93 0.51 0.35 0.64 0.94 0.32 0.52 0.28 1.52 Average Annual Incidence of Q fever in Humans Reported by State Health Departments, 2000-2004 0.44 * Incidence calculated for years when Q fever was reportable. 0.28 0.42 (MA) 1.33 (DC)

33. Dairy Cows per Square Mile In the United States, 1998 5.8 13.3 10.6 5.1 5.0 8.9 37.6 7.8 9.3 5.0 5.4 21.4 11.8 20.1 0.0-2.0 per square mile > 2.0 per square mile 6.5 24.1

34. 60.1 87.6 30.1 53.6 51.0. 78.6 33.2 57.4 30.9 Beef Cattle per Square Mile In the United States, 1998 46.3 > 0.0- 15.0 per square mile > 15 per square mile 59.5 76.7 38.2

35. 5.5 4.7 7.3 5.1 3.4 5.8 3.3 Sheep per Square Mile In the United States, 1998 5.4 0.0-1.5 per square mile > 1.5 per square mile No reports