LABORATORY OUTBREAK OF Q FEVER ACQUIRED FROM SHEEP

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farms where there were infected and excreting animals, or that contamination of the environment was caused by wild birds or other animals. It is difficult to imagine how wild birds or animals could selectively contaminate one area of Newport. It is far more likely that C. burneti was brought out of farms on dust, straw, and manure, either on farm vehicles or by farm animals using the roads.4 Presumably infection would result from inhalation of infected dust particles. The features of this outbreak do not indicate that one farm premises was the source of infection. Farming contact which could be ascertained from the patients involved at least ten establishments. A survey of farms was attempted but proved to be unsuccessful. There were no reports of Q fever occurring amongst farm animals during the outbreak but C. burneti is almost always a symptomless infection of cattle and sheep. Vast numbers of organisms may be excreted in faeces, urine, and products of parturition by apparently healthy animals. The main group of patients in this outbreak had been exposed to infection between the last week of May and the middle of June. This was well after lambing had finished but just before the winter barley was harvested, and so farms may have been short of straw. Localreports suggested that LABORATORY OUTBREAK OF Q FEVER ACQUIRED FROM SHEEP CHRISTOPHER J. HALL SHIRLEY E. OWEN CAUL

J.

RICHMOND

Public Health Laboratory, Bristol

NORMAN H. PEARCE

Safety Office, University of Bristol IAN A. SILVER

Department of Pathology, University of Bristol In April and May, 1981, an outbreak of Q fever occurred in a university department which used gravid sheep for fetal respiratory studies. During the subsequent investigation 91 people were studied and 28 were found to have complement-fixing antibodies to the phase II antigen of Coxiella burneti in their serum. Symptoms compatible with C. burneti infection occurred in 14 of the seropositive patients. The majority of symptomatic infections could be related to the delivery of twin fetuses in one laboratory, but some people remote from this incident who were exposed to sheep in other parts of the building also showed evidence of infection. Those people with serological evidence of recent infection were treated with tetracycline for 4 weeks. Defects were apparent in the facilities being used for the research, and the risk of Q fever infection should be borne in mind by groups engaged in work with pregnant sheep.

Summary

INTRODUCTION

THERE have been several reports of human infection with Coxiella burneti acquired from sheep in research institutions in the U.S.A.’-4 We report here a laboratory outbreak of Q fever in England, associated with the use of gravid sheep for fetal respiratory studies. OUTBREAK AND INVESTIGATION

May 8, 1981, Q fever was diagnosed in a worker at the University of Bristol on the basis ofacomplement-fixing (CF) On

large quantities of straw had been moved through the area during this period. Furthermore, when visiting patients in one area of Newport, we saw the roadsides strewn with loose which had fallen from farm vehicles. Contamination of bales may have occurred during storage or when they were used for pens during lambing. The difficulties encountered when pursuing these possibilities within the farming community were disappointing and precluded a full investigation of the source of this zoonosis. straw

straw

We thank all patients, employers, and staff who helped us in the survey; and Mr R. A. Carson, assistant director of environmental health and Mr J. B. Williams, director of environmental health, Newport, for their invaluable support.

Correspondence should be addressed to S. R. P., Communicable Disease Surveillance Centre, 61 Colindale Avenue, London NW9 5EQ. REFERENCES

JB. Q fever in Great

Britain. Clinical account

of eight cases. Lancet 1949; ii; 1028-30. 2. Marmion BP, Stoker MGP. The epidemiology of Q fever in Great Britain. An analysis of the findings and some conclusions. Br Med J 1958; ii: 809-16. 3. Evans AD, Baird TT. An interim account of an autumnal outbreak of Q fever in Cardiff. Proc Roy Soc Med 1959; 52: 616-20. 4. Lennette EH, Clark WH. Observations on the epidemiology of Q fever in Northern California. JAMA 1951; 145: 306-09. 1. Harman

antibody titre of 1500 against C.

burneti phase II antigen in a taken 12 days after the onset of a "flu-like" illness. He worked in a laboratory in which experimental procedures were performed on gravid ewes; the laboratory was on the first floor of a two-storey building. 6 other workers in that laboratory could recall pyrexial illnesses during April, and sera from these and 2 symptomless colleagues all had CF antibody titres of 64 or more. Since it has been recommended that all acute cases of Q fever should be treated with an antibiotic to reduce the likelihood of chronic infection,5 blood samples, clinical histories, and epidemiological information were obtained from all people who between mid-March and mid-April were in parts of the building that contained sheep. This investigation was carried out during the latter half of May and early June. When possible, second serum samples were taken approximately 2 weeks after the first from all people who were seropositive, and acute and convalescent sera were taken from anyone in whom symptoms compatible with Q fever developed during the investigation. Two gravid ewes housed in a side-room of the implicated laboratory were destroyed on May 21, and sera and tissue samples were taken for microbiological investigations. The records of sheep movements and laboratory procedures were scrutinised. The laboratory and associated side-room were fumigated with serum

sample

formaldehyde gas on May 22. Serological results and reasons for the investigation were given by the medical officer for environmental health to the general practitioner of each person tested. Unless contraindicated, oxytetracycline, 500 mg 8 hourly for 4 weeks, was recommended for all people showing evidence of recent infection-i.e., seroconversion or a stable CF antibody titre of more than 32. This level of antibody was chosen because seroconversion to a stable convalescent titre of only 64 was demonstrated in paired sera from a sheep handler with symptoms.

Serology The complement fixation test was used to measure antibody to C. burneti phase II antigen; any reactive sera (titre 8) were subsequently tested for CF antibodies to the phase I antigen. All sera were heat inactivated before testing by the

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standard four-volume overnight complement fixation test in microtitre plates. Titres were expressed as reciprocals of the dilutions giving 50% fixation. Antigens were provided by the division of ’microbiological reagents and quality control, Public Health Laboratory Service, Colindale. RESULTS

Human Data Five groups of people could have been exposed to C. burneti

infection, either through contact with the laboratory (F69) on the first floor or through contact with animal facilities on the ground floor. The serological and clinical evidence for infection in these groups is given in table 1. Of the 91 people TABLE I-SEROLOGICAL AND CLINICAL EVIDENCE OF COXIELLA BURNETI INFECTION AMONG

91

PEOPLE AT RISK r---

seropositive (titre>8) (tablesI & II). 3 symptomless seropositive people had stable titres32, which were regarded as indicating previous rather than recent infection. Serum antibody titres and symptoms in the seropositive cases are shown in table II. Symptoms varied, but the usual findings were acute onset of fever and chills with sweating, myalgia, and headache. Most symptoms resolved within 7-10 days, although malaise often persisted for several weeks. Symptoms recalled by people who were seronegative (titre<8) were generally of a mild upper respiratory nature (colds and sore throats). All sera tested for the presence of CF antibody against phase I antigen were negative (titre<8). Workers in laboratory F69.-4 of the 5 people directly involved with the sheep experiments were seropositive, and 3 of these 4 people had been ill. A serum sample had been taken during the acute phase of illness from 1 of these workers and tested 28

were

seroconversion

was

demonstrated,

whilst

another

seropositive person with symptoms had been seronegative in October, 1980. 9 other people used the same laboratory but were not directly involved with the sheep experiments. 5 of these people were seropositive, and 4 of these 5 had been ill. All illness occurred between April 19 and 24, those actually involved with sheep experiments becoming ill a few days

*CF antibody titre 8 against C. burneti phase II antigen. f CF antibody titre <8 against C. burneti phase II antigen. TABLE II-DETAILS OF ILLNESS AND ANTIBODY TITRES IN THE

28 SEROPOSITIVE PEOPLE

before the other workers. Visitors to F69. -The 3 seropositive people in this group were regular visitors to the laboratory, whereas the 8 seronegative visitors visited only occasionally. 1 visitor, who became ill on May 23 and subsequently seroconverted, was also closely associated domestically with a symptomatic seropositive sheep worker who had been ill 1 month earlier, so case-to-case spread may have occurred in this instance. Other workers on the first floor. -The 3 seropositive people in this group all worked in a room (F71) which adjoined and was the main route of entry into F69. The 5 workers who were seronegative worked in rooms further away from the

implicated laboratory. Ground floor animal facility users.

-9 of 2people who had had little or no association with F69 showed serological evidence of infection. 3 of these seropositive people were animal attendants in contact with both gravid and non-gravid sheep and other animals. 1 person in this group complained of symptoms on May 25 and subsequently seroconverted, but she also kept her own lambing flock, which may have been the source of her infection. Ancillary staff.-4 of 35 domestic, maintenance, and portering staffinvestigated were found to be seropositive, only 1 of whom regularly visited F69. 1 of the seropositive people had visited the building only once, on April 4, when he passed through some ground floor rooms, whilst another had only been in the building on April 1, 25, and 26.

A=symptomless. *Symptoms: F=fever; LR=Iower respiratory; UR=upper respiratory; M=myatgia; S=sweats; H=headache; T=tiredness. tPeople involved with experiments with gravid sheep. Seronegative (<8) in October, 1980. Human-to-human transmission possible. Infection may have been acquired from subject’s own sheep. -

Sheep Data Gravid sheep used during 1981 had been purchased in September, 1980, from a farm in South Wales. They were mixed with the general flock at the University farm, and sent to the university in batches of two or three. They spent several days in mixed animal housing on the ground floor of the veterinary school, and when required each ewe was walked on a halter along corridors and up two flights of stairs to F69. During March and April, 1981, eight sheep had been studied in F69. After an anaesthetic, the uterus was opened and cannulae and electrical leads were inserted to allow fetal monitoring. After surgery the sheep were kept in a side-room but were returned to the laboratory for observations. When

1006 labour began the animals were killed and taken to the necropsy room on the ground floor where the fetuses were removed and returned to F69. However, an unusual procedure was used on April 3 when, after their intrauterine death, twin fetuses were surgically removed from one sheep (no. 993) in F69. Two gravid sheep present in F69 at the onset of this investigation were killed and examined at the Veterinary Investigation Laboratory, Langford. No CF antibody to phase II antigen was detected in the sheeps’ sera but their placental tissue contained C. burneti, demonstrated by seroconversion of guinea pigs inoculated with this material. DISCUSSION

_

An outbreak of Q fever associated with contamination of laboratory F69 with C. burneti occurred in late April and early May. The contamination was probably responsible for the infections in 15 people, of whom 11 (75%) were ill. Surgical delivery of twin fetuses from sheep 993 was the most likely event to have caused this contamination, although other surgical procedures performed on sheep in F69 early in April may also have been relevant. 13 people who had little or no association with F69 also showed serological evidence of infection. These people probably acquired infection from contaminated animal quarters on the ground floor rather than from F69, but since only 3 of them (23%) were ill, it is impossible to be certain of the exact date or source of the majority of these infections. All infections may have been acquired from organisms excreted by sheep 993 before transfer to F69; the one infection in late May being acquired either from organisms persisting in the environment or from the patient’s own sheep. Alternatively, since two sheep from the same source as sheep 993 were shown post mortem to be infected with C. burneti, it is possible that these and other experimental sheep had also been excreting organisms whilst on the ground floor and that they were the source of some infections. Several defects were apparent in the protocol used for the laboratory procedures conducted on pregnant sheep; rectification of the defects according to recommendations made after similar outbreaksl-4 might have reduced the number of infections, although it would probably not have prevented them totally. The main defects were: the use of a general laboratory for surgical procedures rather than a properly equipped and ventilated operating theatre; the large number of people in the vicinity of the experiments yet not involved with them; and the general lack of awareness of infections which can be acquired from sheep. The use of only sheep free of C. burneti may be difficult to achieve since investigation showed that CF antibodies cannot always be demonstrated in infected animals. We had difficulty in deciding whether the presence of antibodies in symptomless people represented recent or previous infection. Great variation in primary CF antibody responses occur in acute Q fever,6 and these antibodies may be detectable for 2 years or more after infection.6 Therefore titres we regarded as indicating recent infection may have represented past infection and vice versa. A method of detecting specific IgM has recently been described,’ and we are assessing the value of this technique in resolving these difficulties. The decision to treat recently infected people with oxytetracycline was made upon the recommendation of BrownS and, although such action has not been shown to prevent chronic Q fever, we thought it a sensible precaution

to

take, bearing in mind the difficulties experienced in

treating this rare but serious complication. Except for residual malaise no symptoms lasted longer than 2 weeks, and the only person admitted to hospital was a diabetic requiring stabilisation. Other groups engaged in research with pregnant sheep should be reminded of the risk of acquiring Q fever. We thank Dr S. K. R. Clarke for her advice during the investigation and her help in the preparation of this manuscript; Dr R. Buttery of Avon Area Health Authority for his assistance in the investigation; Dr A. Goodship for his assistance, particularly in the tracing of sheep movements; the Veterinary Investigation Centre, Langford, and the Central Veterinary Laboratory, Weybridge, for providing details and results of their sheep investigations; and all members of the University of Bristol who cooperated in this investigation. Correspondence should be addressed to C. J. H., Public Health Laboratory, Royal United Hospital, Combe Park, Bath BA1 3NG. REFERENCES 1. Schachter 2.

3. 4. 5. 6. 7.

J, Sung M, Meyer KF. Potential danger of Q fever in a university hospital environment. J Infect Dis 1971; 123: 301-04. Curet LB, Paust JC. Transmission of Q fever from experimental sheep to laboratory personnel. Am JObstet Gynecol 1972; 114: 566-68. Center for Disease Control. Q fever at a university research center-California. Morbid Mortal Wkly Rep 1979; 28: 333-34. Meiklejohn G, Reimer LG, Graves PS, Helmick C. Cryptic epidemic of Q fever ina medical school. J Infect Dis 1981; 144: 107-13. Brown GL. Q fever. Br Med J 1973; ii: 41-43. Murphy AM, Field PR. The persistence of complement fixing antibodies to Q fever (Coxiella burneti) after infection. Med J Aust 1970; 1: 1148-50. Murphy AM, Magro L. IgM globulin response in Q fever (Coxiella burneti) infections. Pathology 1980; 12: 391-96.

Personal

Paper

CHEMOTHERAPY FROM AN INSIDER’S PERSPECTIVE KENNETH H. COHN Harvard Surgical Service/New

England Deaconess Hospital,

Boston, Massachusetts, U.S.A. THIS paper is based on my experience of receiving chemotherapy from November, 1980, to July, 1981. I was well until Oct. 15, 1980, when I discovered a 3 cm mass in my left mid-neck. Apart from intermittent pruritus and an intertriginous fungus infection at the end of August, 1980,I had had no symptoms. I had not noticed any masses before Oct. 15, and I had not lost weight or experienced night sweats. A sonogram showed the mass to be cystic. With the preoperative diagnosis of cystic hygroma, I underwent a cervical exploration on Oct. 20, 1980, and was informed in the recovery room that the frozen section was malignant. Because of a normal bone-marrow aspiration, as well as a negative computerised tomographic scan of the abdomen and pelvis, I was designated stage IA, diffuse undifferentiated lymphoma. After sperm-banking had been completed I began, on Nov. 17, 1980, a 37-week course of chemotherapy

(including bleomycin, adriamycin, cyclophosphamide, oncovin, dexamethasone, methotrexate, and citrovorum). PROBLEMS CONFRONTING PHYSICIANS WHO BECOME PATIENTS -

The abrupt change from being a surgical resident to becoming a patient gave rise to six problems: 1. Reaction of Health-care Workers to their own Mortality The first difficulty stemmed from the realisation by the health-care team that people of their own age and profession