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As of March 22, 1995 this article has been rewritten.

A 41-year-old animal caretaker at a medical research facility suddenly developed symptoms, including fever, chills, headache, general malaise, myalgia, and nausea. When there was no improvement after several days, he went to his physician. A blood sample was sent to the state health department, where it was tested for antibodies against several antigens, including influenza virus, cytomegalovirus, hepatitis virus, Chlamydia spp, Coxiella burnetii, and Mycoplasma spp. Serologic testing confirmed infection with C burnetii. The patient was treated with tetracycline and returned to work after a few weeks. He learned that several other persons at the facility had become ill at about the same time, with one fatality.

An epidemiologic investigation indicated that there had been an epidemic of Q fever at the facility. The probable source was traced to pregnant ewes that were used for laboratory research.

The caretaker lived on a small ranch where he maintained a flock of sheep. On occasion, he had furnished pregnant ewes and newborn lambs to the facility for research. When he learned that sheep were a possible source of infections he asked his veterinarian the following questions.

Q: What is Q fever?

A: Q fever is a disease of human beings, which is caused by C burnetii, a rickettsial agent. It is an obligate intracellular organism, but in contrast to other members of the genus Rickettsia, it completes its life cycle in the phagosomes of the nucleated cells (a location that kills most organisms), induces no typhus-like rash, and is not dependent on arthropod transmission. During replication, it forms a large cell variant and a sporelike small cell variant.¹ The organism also has phase I and phase II states that relate to its cell coating and antigenic, pathogenic, and immunogenic properties.² Human beings are the only host of C burnetii known to develop obvious illness as a result of infection. However, it can cause abortions in goats, sheep,^3-6 and occasionally, in cattle.⁷

Q: Why is C burnetii infection called Q fever?

A: In the past, the disease has been known as abattoir fever (because of an epidemic among slaughterhouse workers), Rickettsia diaporica infection (because it passes through filters that ordinarily retain rickettsia), the Balkan grippe (because of an epidemic among soldiers in the Balkans), goat boat fever (because the disease occurred among the crew of a boat transporting infected goats), and R burnetii infection. The name Q fever was introduced in a 1937 report of an epidemic of fever of unknown origin among workers in a meat plant in Queensland, Australia; the Q standing for "query," because the investigators had many unanswered questions about the disease.⁸ At about the same time, the agent was isolated from ticks in Montana. The organism was eventually named C burnetii for 2 of its early investigators, H. R. Cox and F. M. Burnet; it is the only member of its genus.

Q: How is the organism spread?

A: Goats, sheep, and cattle are the primary reservoirs for Q fever.⁹ Many other domestic and wildlife species, including birds, also are infected throughout the world.^10,11 The rickettsial organism is excreted in urine, feces, milk, and especially, in birth products. Coxiella burnetti organisms are found in huge numbers in birth fluids, especially amniotic fluid, placenta (up to 10¹²/g), and fetal membranes of parturient ewes, goats, or cows.¹² The birth fluids of cats also have been implicated in infecting human beings in few family episodes of the disease in North America.^13-15 Human infection also has been attributed to a intrauterine infection and breast feeding (C burnetii was isolated from placentas and breast milk).^16,17 Human beings usually are infected by inhalation of the organism from contaminated environments.¹⁸ Air-sampling studies have detected the organism at considerable distances from parturient ewes, and that a single inhaled organism is sufficient to initiate infection.¹⁹ In recent years, disease episodes were associated with infection of medical personal working with pregnant ewes in medical research facilities.¹⁴ The organism is extremely resistant to physical and chemical agents and survives for long periods in the environment.²⁰ There are many potential sources of infection, including contaminated wool, zoo animals, soiled laundry, livestock trucks, livestock at county fairs, air conditioner ducts in common with animal quarters, or inhalation of contaminated airborne dust particles from premises with infected animals.

In recent years, disease episodes have been associated with exposure to parturient cats^13-15 and wild rabbits,²¹ and urban exposure to manure brought as fertilizer from farms.²² Contaminated water has been shown to be a vehicle for dissemination of C burnetii.

Q: Is C burnetii infection an occupational disease?

A: Coxiella burnetii infection is a well-documented occupational disease affecting farmers raising sheep and goats in endemic areas, as well as in livestock industry, especially in abattoirs and people working in medical research facilities.²³ In the United States, occupational exposure in abattoirs and research facilities still accounts for most reported cases.^24,25

Q: Are there any control measures against being infected in the workplace?

A: Personnel in animal facilities should recognize and understand that Q fever is a biohazard. Signs and protocols should be posted.²⁶ Pregnant ewes are an extreme risk and should be kept in a containment facility with limited access; autoclaving of contaminated tissue, laundry, and equipment and the proper disposal of bedding should be observed. Coxiella burnetii is highly resistant to chemical agents and physical conditions, but fomites and small areas can be partially decontaminated with 2% house bleach. In an experiment, liquid suspensions of 108 C burnetii in 0.5 sodium hypochlorite, 5% Lysol were infective after 24 hours at 25 C.²⁷ Five percent Enviro-Chem (a mixture of N-alkyl dimethyl benzil (2.25%) and ethylbenzal (2.25%) ammonium chlorides), 5% chloroform, and 70% ethylalcohol resulted in the inactivation of C burnetii within 30 minutes.

Serologic monitoring of animals, personnel working in care-taking units, and researchers who work with the animals or their products should be done routinely.^24,28,29 Vaccination of personnel at risk should also be considered.³⁰

Q: How common is C burnetii infection in livestock?

A: Clinically relevant signs of infection rarely seem to develop in livestock infected with C burnetii,²⁵ and latent infection is the rule. In sheep, goats, and cattle, abortion can be one of the major clinical manifestations of infection. Economic losses caused by C burnetii have never been accurately evaluated. Estimates indicate losses ranging from 5 to 15% of abortions in cattle, sheep, and goats.²⁵

Infection in dairy herds is almost universal. A survey of 1,052 dairy cattle in California indicated an overall serum antibody (greater than or equal to 1:8 by the complement-fixation test) prevalence of 82%. Among individual herds, the prevalence ranged from 0% for heifers on open range to 100% among cows in densely populated dairies. The antibody prevalence depended on age, geographic location, size of herd, and stage of gestation. Of 840 cows, 23% were determined to be shedding C burnetii in their milk.³¹ A recent cross-sectional survey in California revealed serum antibody prevalences of 24% among 2,097 sheep and 57% among 1,475 goats.³²

A longitudinal study of 306 ewes indicated a seasonal cycle of C burnetii infection. The prevalence of detectable antibodies was highest (55%) 8 to 12 weeks after the lambing period and lowest (18%) 6 months later (September), just before the breeding period.³³

In Nova Scotia, Canada, a serosurvey of domestic animals, using a microimmunofluorescence test, indicated that 24% of the 214 cattle and 216 cats tested had antibodies to phase-I antigen. Only 7% of the 329 sheep tested and none of the dogs had antibodies.³⁴ In France and Germany, prevalence rates of 5 to 7% have been reported in cattle.³⁵

Q: If Coxiella burnetii is excreted by cows, goats, and sheep, can human beings become infected from drinking milk?

A: Large numbers of C burnetii can be shed in the milk of infected cows, especially at the beginning of the milking period, after parturition. Although raw milk also contains specific antibodies, the agent remains infective. Contamination after consumption of raw milk or nonpasteurized milk products in human beings has been reported from Europe (Great Britain, France, Spain), and the United States.³⁶ In many instances, infected persons seroconverted and did not manifest clinical signs of infection (1 to 35 seropositive people who drank unpasteurized milk).³⁷

The original minimal pasteurization temperatures of milk were those that inactivated the tuberculosis bacteria, but C burnetii was not inactivated and could be recovered from commercial dairy products. Because of this, pasteurization temperatures were increased to 62.8 C (145 F) for 30 minutes or 71.7 C (161 F) for 15 seconds to eliminate viable C burnetii from whole milk.³⁸ It is recommended that only pasteurized dairy products be consumed.

Q: Is it possible to maintain an uninfected flock of ewes for research?

A: Episodes of Q fever in the United States develop principally in occupational settings, including research facilities that conduct experimental research on sheep. In 1979, an episode occurred in San Francisco, and resulted in 19 confirmed cases (one fatality) and more than 68 presumptive cases among researchers and employees, owing to exposure to C burnetii during research on pregnant ewes.²⁹ Because of frequent subclinical infection of the flocks, it is difficult to claim an infection-free flock. Flocks used for research should consistently be monitored for C burnetii infection. Serological surveillance (using ELISA or immunofluorescent antibody techniques, IFA) must be prepared on a regular basis, but there is no warranty that the flock will remain free of infection; C burnetii can sometimes be recovered form seronegative ewes.¹¹ The dissociation between seropositivity and shedding of the organism is another concern for infection control. Use of sophisticated diagnosis tools, such as polymerase chain reaction (PCR), may help to partially solve the limitations of serologic methods. However, this test still will be reserved for specialized laboratories and cannot be performed as a screening test.

In sheep, serum antibodies are detectable about 2 weeks after the initial infection. Antibody concentrations reach a maximum at 30 to 60 days, then rapidly decline and phase into the seasonal antibody cycle of the rest of the flock in relation to the lambing season.²⁰ Therefore, if the sheep were serotested during the lowpoint of the cycle, when antibody concentration is less than that detectable, claims of a seronegative flock would be misleading. The intracellular growth of C burnetii protects it from the effect of humoral antibodies and other body defense mechanisms. Therefore, the organism can be either recovered from the tissues of chronically infected animals by mouse passage,¹¹ or detected in the tissue by PCR.³⁹

The best policy would be to quarantine and serotest twice, at 2- to 3-week intervals, every sheep that enters a research facility. If any sheep are seropositive, they should be traced back to the flock of origin, and the entire flock should be serotested. Seropositive sheep should be discarded from any medical and experimental use.

Q: Were my symptoms typical of the disease?

A: Although your symptoms were quite typical, not everyone experiences the same syndrome. In human beings, infection can range from asymptomatic seroconversions, or mild to severe flu-like symptoms of variable duration, to chronic infection and endocarditis. After an incubation period of 2 to 6 weeks, patients typically have acute onset of high fever, chills, severe headaches, malaise, myalgia, and retro-orbital pain. Other symptoms, such as cough, chest pain, nausea, vomiting, and diarrhea can be observed, but fever (> 38.5 C) is always present.^16,40 Hepatomegaly and splenomegaly are often seen. Q Fever is usually described as an atypical pneumonia, and sometimes as hepatitis, but is diagnosed in only a few to 90% of the cases. Symptoms of acute infection are similar to those of influenza, brucellosis, viral pneumonia, chlamydia, and mycoplasmal infections, and infectious hepatitis or mononucleosis, which makes diagnoses difficult.

Most cases of Q fever are self-limiting, with symptoms resolving in 1 to 2 weeks. However, in less than 1% of the cases, endocarditis with infection of the heart valves may develop in 1 to several years after infection.

Q: How prevalent is C burnetii infection in human beings?

A: Q Fever has worldwide distribution. It usually occurs sporadically, but epidemics have been frequently observed. Occurrence of the disease in the United States is unusual, although public health reporting is required in only 24 states.¹⁶ Serologic surveys indicate antibody prevalence of 4 to 17% in human beings, depending on their activities.³⁰ Antibody prevalence of up to 40% was found among employees who were working in the corrals and exposed to dust and hides at a meat-processing plant in Brazil.⁴¹ Seroepidemiologic surveys conducted recently in various geographic regions indicate that the distribution of Q fever is essentially the same as that previously reported up to 1956.²⁵

In Nova Scotia, Q fever accounted for 20% of all cases of pneumonia admitted to regional hospitals in 1983.⁴² In Europe, human cases of Q fever are usually sporadic, but the infection is endemic in many countries: United Kingdom (1,656 cases reported for the period 1976-1985), southern France (300 cases from 1987 to 1990), Germany (between 27 and 100 officially reported cases per year), Czechoslovakia, and Switzerland. In 1983, Switzerland had one of the largest European episodes of acute Q fever, involving more than 400 persons.⁴³

Cellular immunity probably is the best indication of past infection and is detected by skin testing. Skin testing of previously exposed people results in erythema at the site of intradermal injection and usually is accompanied by a rebound in antibody concentration.⁴⁴ Antibody formation to phase II antigens begins soon after infection (IgM first, then IgG and IgA). Response to phase I antigen begins during convalescence and may persist for several months. Patients with chronic manifestations of active Q fever do not have detectable IgM responses, but have very high IgG and IgA responses to phase I antigen.⁴⁰ Previous exposure usually confers a lifetime immunity.

Q: How can C burnetii infection be diagnosed and what is the treatment?

A: The approach to diagnosis of acute Q fever is mainly serologic, based on the association of clinical syndromes and seroconversion, with antibodies specific to phase II and/or phase I antigens. The disease is difficult to diagnose clinically and can be confused with many other infectious diseases (brucellosis, influenza, hepatitis, mononucleosis). The method most widely used over the past 2 decades has been complement fixation (CF), but IFA tests and ELISA are now available. Of these methods, the IFA test is the most subjective, CF is the most tedious to perform, and ELISA is the most convenient to use on a large scale.⁴⁰ A diagnosis algorithm has been proposed by Harrison et al in occupational settings.²⁴

The treatment of acute Q fever depends on the clinical presentation. Pneumonia usually resolves without treatment within 2 weeks.⁴⁵ In severely ill patients, treatment must be started within the first 3 days of illness to be effective. Tetracycline compounds and especially doxycycline (200 mg for 15 to 21 days) are still the drugs currently recommended to treat acute Q fever. Chronic Q fever usually requires prolonged chemotherapy with doxycycline and rifampin. More recently, treatment of Q fever with 900 mg of chloroquine and 200 mg of doxycycline/d gave excellent results.⁴⁵

Antibiotic treatment of cattle does not seem to be effective in preventing shedding of the organism.⁴⁶

Q: Is there a vaccine against C burnetii infection?

A: A vaccine is not commercially available in the United States, but the phase I Henzerling vaccine developed by the US Army may be obtained under an investigational new drug (IND) protocol. Vaccination of human beings is apparently effective, but care must be taken not to inoculate people who have had previous exposure.⁴⁷ In Australia, a Q fever vaccine has been licensed for vaccination of at-risk personnel in occupational groups principally affected (ie, abattoir and research workers).

Vaccination of cattle and sheep confers an antibody response and reduces but does not eliminate C burnetii shedding from milk and placenta tissues.^40,48 Vaccination of animals is an effective means of reducing the infection rate, but test-and-slaughter programs are not effective because of the high infectivity of C burnetii and the nature of the disease in animals.²⁵ Williams et al⁴⁹ reported the development of a chloroform:methanol residue subunit of phase I C burnetii, which could be of use in flock vaccination programs.⁴⁹

References

1. McCaul TF, Williams JC. Developmental cycle of Coxiella burnetii: structure and morphogenesis of vegetative and sporogenic differences. J Bacteriol 1981.

2. Williams JC, Peacock MG, McCaul TF. Immunological and biological characterization of Coxiella burnetii phases I and II, separated from host components. Infect Immun 1981; 32:840-851.

3. Spicer Al, Crowther KW, Vella EE, et al. Q fever and animal abortions in Cyprus. Trans R Soc Trop Med Hyg 1977.

4. Waldhalm DG, Stoenner HG, Simmons RE, et al. Abortion associated with Coxiella burnetii infection in dairy goats. J Am Vet Med Assoc 1978.

5. Palmer NC, Kierstead M, Key DW, et al. Placentitis and abortion in goats and sheep in Ontario caused by Coxiella burnetii. Can Vet J 1983.

6. Stanford SE, Josephson GKA, McDonald A. Coxiella burnetii (Q fever) abortion storms in goat herds after attendance at an annual fair. Can Vet J 1994.

7. Coche B. La fièvre Q bovine en France-aspect pratiques et importance de la sérologie. Le Point Vétérinaire 1981.

8. Wentworth BB. Historical review of the literature on Q fever. Bacterial Rev 1955.

9. Babudieri B. Q fever: a zoonosis. Adv Vet Sci 1959.

10. Riemann HP, Behymer DE, Franti CE, et al. Survey of Q fever agglutinins in birds and small rodents in northern California, 1975-76. J Wildl Dis 1979.

11. Enright IB, Longhurst WM, Franti CE, et al. Coxiella burnetii in wildlife-livestock environment. Isolation of rickettsiae from sheep and cattle. Am J Epidemiol 1971.

12. Stocker MGP, Morrison BP. The spread of Q fever from animals to man: the natural history of rickettsial disease. Bull WHO 1955.

13. Kosatsky T, Rideout V, Lagign P, et al. Household out-break of atypical pneumonia attributed to Q fever. N S Can Dis Week Rep 1982.

14. Langley JM, Marrie TJ, Covert A, et al. Poker players's pneumonia. An urban outbreak of Q fever following exposure to a parturient cat. N Engl J Med 1988.

15. Pinsky RL, Fishbein DB, Greene CR, et al. An outbreak of cat-associated Q fever in the United States. J Infect Dis 1991.

16. Sawyer LA, Fisbein DB, McDade JE. Q fever: current concepts. Rev Infect Dis 1987.

17. Fiset P, Wisseman CL, El Bataivi Y. Immunologic evidence of human fetal infection with Coxiella burnetii. Am J Epidemiol 1975.

18. Delay PD, Lennette EH, De Ome KB. Q fever in California. II. Recovery of Coxiella burnetii from naturally-infected air-borne dust. J Immunol 1950.

19. Tigertt WD, Benenso AS, Gochnour WS. Airborne Q fever. Bacterial Rev 1961.

20. McCaul TF, Hakstadt T, Williams JC. Ultrastructural and biological aspects of Coxiella burnetii under physical disruptions. In: Burgdorfer W, Anacker RL, eds. Rickettsiae and rickettsial diseases. New York: Harcourt Brace Jovanovich, 1981.

21. Marrie TJ, Schlech WF, Williams JC, et al. Q fever pneumonia associated with exposure to wild rabbits. Lancet 1986.

22. Salmon MM, Howells B, Blencross EJG, et al. Q fever in an urban area. Lancet 1982.

23. Stoenner HG. Occupational hazards of Q fever. Ind Med Surg 1964.

24. Harrison RJ, Vugia DJ, Ascher MS. Occupational health guidelines for control of Q fever in sheep research. Ann NY Acad Sci 1990.

25. Williams JC, Sanchez V. Q fever and coxiellosis. In: Beran GW, ed. Handbook of zoonoses. 2nd ed. Section A. Boca Raton, Florida: CRC Press, 1994.

26. Spinelli JS, Ascher MS, Brooks DL. Q fever crisis in San Francisco: controlling a sheep zoonosis in a lab animal facility. Lab Anim 1981.

27. Scott GH, Williams JC. Susceptibility of Coxiella burnetii to chemical disinfectants. Ann NY Acad Sci 1990.

28. Simor AE, Brunton JL, Salit IE, et al. Q fever: hazard from sheep used in research. Can Med Assoc J 1984.

29. CDC. Q fever at a university research center: California. MMWR Morbid Mortal Wkly Rep 1979.

30. Bernard KW, Parham GL, Winkler WG, et al. Q fever control measures: recommendations for research facilities using sheep. Infect Control 1982.

31. Biberstein EL, Behymer DE, Bushnell R, et al. A survey of Q fever (Coxiella burnetii) in California dairy cows. Am J Vet Res 1974.

32. Ruppanner R, Brooks D, Franti CE, et al. Q feverhazards from sheep and goats used in research. Arch Environ Health 1982.

33. Enright JB, Franti CE, Longhurst WM, et al. Coxiella burnetii in a wildlife-livestock environment. Antibody response of ewes and lambs in an endemic Q fever area. Am J Epidemiol 1971.

34. Marrie TJ, Van Buren J, Fraser J, et al. Seroepidemiology of Q fever among domestic animals in Nova Scotia. Am J Public Health 1985.

35. Krauss H, Schmeer N, Schiefer HG. Epidemiology and significance of Q fever in the federal Republic of Germany. Zentralbl Mikrobiol 1987.

36. Benson WW, Brock DW, Mather J. Serologic analysis of a penitentiary group using raw milk from a Q fever infected herd. Public Health Rep 1963.

37. Marmion BP, Stoker GP. The epidemiology of Q fever in Great Britain. Br Med J 1958.

38. Enright JB, Sadler WW, Thomas RC. Thermal inactivation of Coxiella burnetii in milk pasteurization. Public Health Monogr 1957.

39. Frazier ME, Mallavia LP, Samuel JE, et al. DNA probes for the identification of Coxiella burnetii strains. Ann NY Acad Sci 1990.

40. Reimer LG. Q fever. Clin Microbiol Rev 1993.

41. Riemann HP, Brant PC, Behymer DE et al. Toxoplasma gondii and Coxiella burnetii antibodies among Brazilian slaughterhouse employees. Am J Epidemiol 1975.

42. Marrie TJ, Haldane EV, Faulkner RS, et al. The importance of Coxiella burnetii as causes of pneumonia in Nova Scotia. Can J Publ Hlth 1985.

43. Macellaro A, Akesson A, Norlander L. A survey of Q-fever in Sweden. Eur J Epidemiol 1993.

44. Izzo M, Marmion BP, Worswick DA. Markers of cell-mediated immunity after vaccination with an in activated whole-cell Q fever vaccine. J Infect Dis 1988.

45. Rhoult D. Treatment of Q fever. Antimicrob Agents Chemother 1993.

46. Behymer DE, Ruppanner R, Riemann HP, et al. Observations on chemotherapy in cows chronically infected with Coxiella burnetii (Q fever). Folia Vet Lat 1977.

47. Lackman DB, Philip RN, Casper EA, et al. Q fever immunity in man. Health Lab Sci 1967.

48. Behymer DE, Biberstein EL, Riemann HP, et al. Q fever (Coxiella burnetii) investigations in dairy cattle:challenge of immunity after vaccination. Am J Vet Res 1976.

49. Williams JC, Peacock MG, Waag DM, et al. Vaccines against coxiellosis and Q fever. Development of a chloroform:methanol residue subunit of phase I Coxiella burnetii for the immunization of animals. Ann N Y Acad Sci 1992.