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Hospital Practice

NO EVIDENCE FOR INCREASED RISK OFLASSA FEVER INFECTION IN HOSPITAL

STAFF

CHARLES G. HELMICKCURTIS L. SCRIBNER

PATRICIA A. WEBB

JOHN W. KREBSJOSEPH B. MCCORMICK

Special Pathogens Branch, Division of Viral Diseases,Center for Infectious Daseases, Centers for Disease Control,

Atlanta, GA 30333, USA

Summary A prospective serological study was

undertaken in hospital personnel who carefor Lassa fever (LF) patients in an endemic region of SierraLeone, West Africa. Among personnel from three hospitalswhere barrier nursing is practised, antibody prevalence andseroconversion by age and sex were consistently equal to orlower than those of persons in nearby village populations.No group among hospital personnel evaluated by age, sex,contact, or occupational exposure was at higher risk thananother. Hospital staff in Sierra Leone who care for LFpatients using simple barrier nursing methods have nohigher risk of infection than the local population. Thesefindings support the proposal that patients with LF innon-endemic countries need not be confined to isolators.

INTRODUCTION

THE early history of Lassa fever (LF) was associated withperson-to-person transmission of a virus, especially in ahospital setting, and a high mortality rate (40-50%) inpatients admitted to hospital. 1-3 The transmissibility amonghuman beings, the high mortality rate, and the death of alaboratory worker in the United States promoted thedesignation of the virus as a biosafety level 4 virus forlaboratory work.4There remains, however, the issue of how to care safely

for patients suspected of having LF, especially in countrieswhere the disease is non-endemic and where immune

hospital staff would not be available. Until lately, guidelinesin the United States and elsewhere have required isolation ofsuch patients in a high-containment clinical facility ,5,6 whichmost hospitals do not possess. Recent experience hassuggested that the danger from such patients is less than wasoriginally supposed7-9 and some modifications of thefacilities required for hospital care of these patients havebeen suggested. 10

In a highly endemic area of Sierra Leone, West Africa, wehave assessed antibody prevalence to and rate of infectionwith Lassa virus among hospital staff who care for LFpatients. These individuals were compared with staff whohad less contact with LF patients and with people in anearby community.

METHODS

The Lassa Fever Research Project was established to study theclinical, epidemiological, ecological, and public health aspects of LFin an endemic area of the Eastern Province of Sierra Leone." 13 Weundertook a prospective serological study of staff from hospitals thatcare for LF patients in three towns-Segbwema (Nixon MemorialHospital), Panguma (Panguma Hospital), and Kenema (KenemaGovernment Hospital). These study hospitals have 100-200 bedseach and provide medical, surgical, paediatric, and obstetrical

services. The medical and surgical services have separate wards formen and women. Patients are admitted to the wards from outpatientclinics or as emergencies. The services and material resources of thehospitals are sparse. Much of the patient care is undertaken by thefamilies. LF patients are admitted to cohort isolation rooms whenpossible; otherwise they are placed on open wards with cloth"barriers" around the bed. Policy requires that hospital personneluse simple isolation techniques (gloves, gowns, masks), but

compliance varies.Hospital staff were surveyed at irregular intervals from 1972,

1977, or 1978 until 1983 to obtain multiple serum specimens and toenter new staff into the study. At entry, staff were bled and aquestionnaire was administered to obtain information includingage, sex, language, occupation, degree of contact with LF patients,and date of starting work at the hospital. At follow-up they gaveadditional serum specimens and were questioned about interveningfebrile illnesses.

For a comparison group we used persons from Niahun andKonia, two rural farming villages in the same area that had beenstudied intensively for 2-year periods from 1978 to 1981 as part of aseparate project." The villages are typical of those in the endemiccatchment area of the three hospitals but few hospital staff live inthem. The villager data had only two characteristics (age, sex) incommon with the hospital staff. For analysis, ages of villagers andhospital staff were divided into three ranges, 15-24, 25-34, and35-65, based on roughly equal numbers in these categories amonghospital staff.

In addition, we looked at three variables in the hospital staff.Self-reported contact with LF patients was classified as: none;possible (patient contact, but not with known LF patients);occasional; or frequent. Occupational exposure (determined a priorifrom 22 occupation groups) was classified as none (eg, officeworkers, drivers); indirect (eg, laboratory workers, cleaners,plumbers, launderers); or direct (nurses and physicians). And yearsworked at the hospital were grouped as 0-3 and 4 +, on the basis of anatural division seen among hospital staff examined for LFinfection.

Sera from hospital staff and villagers were separated andrefrigerated within 2 h of venepuncture, stored at 4°C, and testedwithin two weeks. Titres were determined by the indirectfluorescent antibody (IFA) test.14 Prevalence of antibody wasdetermined from the first serum titre. Infection was judged to haveoccurred when an initially negative subject seroconverted to a titreof at least 16 or when there was a 4-fold rise in antibody titre. Titresof 4 and 8 were regarded as uninterpretable.

Prevalences of antibody at entry were compared among variousgroups by use of odds ratios with 95 % confidence limits, chi-squareand Fisher’s exact tests, and estimates of power.’-’ Infection ratesamong study groups were compared by survival analysis, because ofthe variable times of entry into and participation in the study.Probability values were calculated with the generalised Wilcoxontest/6 power cannot be determined for survival analyses. The termsignificant in the text indicates a p value of 0 05.

RESULTS

695 hospital staff at the three hospitals-85-90% of staffpresent at the time of the surveys-were entered into the

study. Of these, 175 who did not supply the questionnaireinformation and 24 who had uninterpretable serologicalresults were excluded from the analysis, leaving 496 hospitalstaff. At entry these 496 had worked in the hospital a medianof 9 months (mean 38 months) and represented 22 possibleoccupation groups. The numbers of persons studied fromeach of the hospitals were Segbwema 234, Panguma 164,and Kenema 98.

1906 villagers, a 95 + % sample of persons in the twovillages, were entered. Because all hospital staff were 15-65years old at entry, 775 villagers who were outside this agerange, along with 107 villagers who had uninterpretableserological results, were excluded from the analysis. Theremaining 1024 were all doing unskilled jobs, mainly

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TABLE I—CHARACTERISTICS OF THE POPULATIONS USED FOR

ANALYSES OF ANTIBODY PREVALENCE

TABLE II-PREVALENCE OF ANTIBODY TO LASSA VIRUS AT ENTRY

INTO STUDY FOR SELECTED CHARACTERISTICS, VILLAGERS

VERSUS HOSPITAL STAFF

*p0’0001; tpower (one-sided) =1.0; &plusmn;p<0.02.

farming. In table 1 the characteristics of hospital staff andvillagers are compared.22% of hospital staff had antibody to Lassa virus,

compared with 35% of villagers (p<0-0001), and the

antibody prevalence remained significantly lower whenadjusted for age or sex (table II). In addition, no subcategoryof hospital staff (contact, occupational exposure, or yearsworked) had a higher prevalence than the villagers overall.Only 6 of the 22 occupation groups-probationary nurses(36%, 5/14), cleaners (38%, 9/24), foremen/labourers(33%, 15/46), drivers (40%, 2/5), registration clerks (50%,1/2), and "other" (39%, 7/18)---had a higher prevalencethan that in the villagers overall. Among hospital staff, thosewith self-reported frequent, occasional, or possible contactwith Lassa fever patients were compared with staff lackingsuch contact and were found to have a lower antibodyprevalence, even when it was adjusted for number of yearsworked, occupational exposure, age range, or sex (table III).To study infections among villagers and hospital staff, we

further restricted the data to include only those with at leastone follow-up blood specimen obtained 14 or more daysafter the first. This left 305 hospital staff who provided fromtwo to six specimens (median two) over a median of 633(range 34-3905) days of observation. 48 (16%) of theseshowed serological evidence of infection. The same criterionleft 750 villagers who provided from two to six specimens(median two) over a median of 421 (range 20 - 508) days ofobservation. Of these, 69 (9%) showed serological evidenceof infection. The distributions of age, sex, and tribe were

TABLE III&mdash;PREVALENCE OF ANTIBODY TO LASSA VIRUS AT ENTRY

INTO STUDY, BY SELF-REPORTED DEGREE OF CONTACT WITH

LASSA FEVER PATIENTS: ANALYSIS OF HOSPITAL STAFF DATA

Comparison of survival curves for Lassa virus infection in villagersand hospital staff.

TABLE IV-COMPARISON OF SURVIVAL CURVES FOR LASSA VIRUS

INFECTION, OVERALL AND BY AGE, SEX, AND AGE/SEX CATEGORIES:

VILLAGERS VERSUS HOSPITAL STAFF

nearly identical to those observed in the originalpopulations.The accompanying figure and table IV show that overall

or by age, sex, or age/sex category, no group of hospital staffwas at higher risk for infection than the comparable villagegroup; in fact, hospital staff were at significantly lower risk ofinfection. When each category of contact, occupationalexposure, and years worked among hospital staff was

compared with that of the 750 villagers overall, no categorywas at significantly increased risk; in fact, those with thegreatest contact, the most patient care, and the longestemployment were at lower risk (table v). When the 22occupation groups were compared with the villagers overall,only two-office workers and registration clerks-were atincreased risk (p = 00025 and 0-0166, respectively), butneither had hospital exposure to LF patients.Among hospital staff, those with self-reported frequent,

occasional, or possible contact with LF patients werecompared with staff who lacked contact with LF patientsand proved to have no significantly increased risk ofinfection. Similarly, no differences were found amongcategories of occupational exposure, age range, or sex.

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TABLE V--COMPARISON OF SURVIVAL CURVES FOR LASSA VIRUS

INFECTION, BY CONTACT, OCCUPATION, AND YEARS EMPLOYED:

VILLAGERS VERSUS HOSPITAL STAFF

*Generalised Wilcoxon (Breslow).

However, those who had worked 0-3 years at the hospitalshad a higher risk of infection than those who had worked 4 ormore years (p=00002), even when data were adjusted byage range, sex, occupational exposure, or contact.No significantly different pattern of antibody prevalence

or infection was found among the three hospitals. In

addition, results of a reanalysis confined to the Mendetribe, the primary ethnic group of the area, were fullyconsistent with the above findings.

DISCUSSION

The presence or acquisition of antibody to Lassa virus inhospital personnel in a highly Lassa-endemic area was notsignificantly different from that of populations in the

surrounding villages. This observation was true of variousage and sex strata of the populations and persisted evenwhen possible confounding variables, such as patientcontact, occupational exposure, or years worked in thehospital, were considered. Contrary to our expectations,persons with the greatest contact with patients with LF hadlower rates of antibody prevalence and infection. In theanalysis of antibody prevalence there was a strongprobability of detecting a difference if one existed, so a highdegree of confidence can be placed in this analysis. A similarmeasure of statistical power was unfortunately not availablefor application to the survival analysis for rates of infection.No data are available to explain the lower infection rates in

persons (primarily nurses) with frequent contact with LFpatients. We can only speculate that perhaps a slightlyhigher socioeconomic status and a heightened awareness ofthe disease and its consequences make these personsgenerally more careful about both domestic hazards (eg,rodent infestations) and professional hygiene, so that theyare at lower risk even from endemic, non-hospital sources.

This study was not likely to be compromised by selectionbiases, because a very high proportion of the hospital staffand village population participated. Also, it was staffturnover and movement of village population that seemed toaccount for losses to follow-up, rather than any factorassociated with Lassa virus infection. Similarly, antibody toLassa virus may be detectable for years," so it is unlikely thattrue infections were missed in the hospital group because ofa longer period of observation between serum samples.We found that hospital personnel who had worked less

than 4 years had a significantly higher frequency of infectionto Lassa virus than staff members who had worked 4 ormore years. Although the difference persisted when theanalysis was adjusted by several variables, the absolute risk

in those working less than 4 years remained lower than thatof local populations. Once again we have no data to explainthis observation, and can only guess that inexperience, lowersocioeconomic status, poor living conditions, or some lessapparent factor accounts for the difference in infection rates

by duration of hospital employment.These data indicate that simple isolation techniques are

effective in preventing excess risk of infection by Lassa virusin hospital staff. Some previous observations have suggestedthat the risk of nosocomial transmission is low, even withoutspecial precautions. In London, 159 contacts of an importedcase of LF showed no serological evidence of infection,’ and74 contacts of another patient had no clinical evidence of LFduring subsequent surveillance.8 In Sierra Leone, 20 closecontacts of an extremely ill patient managed with gloves,gowns, and masks remained seronegative.9 In westernLiberia, Frame et all’ found that the prevalence of antibodyamong those with patient contacts was the same as thatamong those without direct patient contact, so theyconcluded that most LF infections were acquired fromsources other than patients in the hospital.17

Other reports have been more difficult to interpret. Forexample, the prevalence of serum antibodies in hospital staffand residents from nearby villages in Lofa County, Liberia,suggested a prevalence in hospital workers about times ashigh as that in the general village population.18,19 However,these data were not adjusted for age or sex or any othervariable. Since the village population included manychildren and adolescents, who have a lower antibodyprevalence, the data are difficult to interpret with regard torisk of transmission in the hospital setting.Keane and Gilles20 reported that 13/75 (17%) of hospital

staff had CF antibodies indicative of recent Lassa virus

infection, 3 of whom had been clinically ill; 2 others haddied. They suggested that the risk to hospital staff was lowand that familial person-to-person spread was limited andunimpressive, but concluded that high-security precautionsshould be maintained for medicolegal reasons until themode of transmission was better understood.2O Most cases inthat study were unconfirmed and the complement fixationtest used is far less sensitive than the fluorescent antibodytest now used.Taken with the conclusions of the London, Sierra Leone,

and Liberia reports, our studies suggest that nosocomialtransmission of Lassa virus occurs less frequently thanpreviously supposed, and that good hospital practice andsimple barrier nursing techniques are sufficient to preventsuch spread. Indeed, the hospital personnel in our studymay be at a lower risk both at work and at home than localinhabitants. These findings suggest that, if the nosocomialtransmission of Lassa virus is infrequent in the endemicsetting in Africa, then such transmission is even less likely ina modem Western hospital. It seems unnecessary,therefore, to require that patients with LF in non-endemiccountries be cared for in biosafety level 4 containment.

We thank Roy Baron, Ineke Bosman, Karl Johnson, George Komba-Kono, Sally Trippel, and Mariam Boone, Austin Demby, GabrielMohammed Kamar, James Kanu, Isabel King, Renee O’Sullivan, EtheleneSmith, Tony Tong, and the hospital staffs for their help in this project.

Correspondence should be addressed to J. B. McC.

REFERENCES

1. Frame JD, Baldwin JM Jr, Gocke DJ, Troup JM. Lassa fever, a new virus disease ofman from West Africa. I. Clinical description and pathological findings. Am J TropMed Hyg 1970; 19: 670-76.

2. Carey DE, Kemp GE, White JA, et al. Lassa fever Epidemiological aspects of the1970 epidemic, Jos, Nigeria. Trans R Soc Trop Med Hyg 1972; 66: 402-08.

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3. Monath TP, Mertens PE, Patton R, et al. A hospital epidemic of Lassa fever in Zorzor,Liberia, March-April, 1972. Am J Trop Med Hyg 1973; 22: 773-80.

4. Centers for Disease Control. Biosafety in microbiological and biomedical laboratories.HHS publication no. (CDC)84-8395. Atlanta: Centers for Disease Control, 1984.

5. CDC recommendation for initial management of suspected or confirmed cases ofLassa fever. MMWR 1980; 28 (suppl): 15-125.

6. Simpson DIH. Viral haemorrhagic fevers of man. Bull WHO 1978; 56: 819-32.7. Cooper CB, Gransden WR, Webster M, et al. A case of Lassa fever: Experience at St

Thomas’s Hospital. Br Med J 1982; 285: 1003-05.8. Public Health Laboratory Service. Lassa fever 1982. Commun Dis Rep 1983; 10: 3

(unpublished).9. Fisher-Hoch SP, Price ME, Craven RB, et al. Safe intensive care management of a

severe case of Lassa fever with simple barrier nursing techniques. Lancet 1985; ii:1227-29.

10. Viral hemorrhagic fever: Initial management of suspected and confirmed cases.MMWR 1983; 32: 27-39S.

11. McCormick JB, King IJ, Webb PA, et al. Lassa fever: A case-control study of theclinical diagnosis and course. J Infect Dis (in press).

12. McCormick JB, Webb PA, Krebs JW, et al. Lassa fever- A prospective study of itsepidemiology and ecology J Infect Dis (in press).

13. McCormick JB, King IJ, Webb PA, et al. Lassa fever: Effective therapy with ribavirinN Engl J Med 1985; 314: 20-26.

14. Johnson KM, McCormick JB, Webb PA, et al. Lassa fever in Sierra Leone: Clinicalvirology in hospitalized patients. J Infect Dis (in press)

15. Casagrande JT, Pike MC, Smith PG. An improved approximate formula for

calculating sample sizes for comparing two binomial distributions. Biometrics 1978;34: 483-86.

16. Survival analysis. In: Dixon WJ, Brown MB, Engelman L, et al. BMDPStatistical Software 1981. Berkeley: University of California Press, 1981:

555-94.17. Frame JD, Casals J, Dennis EA. Lassa virus antibodies in hospital personnel in

western Liberia. Trans R Soc Trop Med Hyg 1979; 73: 219-24.18. Frame JD, Yalley-Ogunro JE, Hanson AP. Endemic Lassa fever in Liberia. V.

Distribution of Lassa virus activity in Liberia: Hospital staff surveys. Trans R SocTrop Med Hyg 1984; 78: 761-63.

19. Yalley-Ogunro JE, Frame JD, Hanson AP. Endemic Lassa fever in Liberia. VI.Village serological surveys for evidence of Lassa virus activity in Lofa County,Liberia Trans R Soc Trop Med Hyg 1984; 78: 764-70.

20. Keane E, Gilles HM. Lassa fever in Panguma Hospital, Sierra Leone, 1973-6. Br MedJ 1977; i: 1399-402.

Environmental Physiology

SLEEP AFTER TRANSMERIDIAN FLIGHTS

A. N. NICHOLSONM. B. SPENCER

PETA A. PASCOEBARBARA M. STONE

Royal Air Force Institute of Aviation Medicine, Farnborough,Hampshire

T. ROEHRS T. ROTH

Sleep Disorders and Research Center, Henry Ford Hospital, Detroit,Michigan, USA

Summary Nocturnal sleep and daytime sleeplatencies, recorded electroencephalo-

graphically after westward and eastward flights across theNorth Atlantic involving time zone shifts of 5 h, wereinfluenced by the time of the flight and by subsequentdisplacement of the rest period. After the westward flightthere was sleep disturbance during the latter part of the firstnight. However, there was persistent disturbance of sleepafter the eastward flight. A rapidly eliminated hypnotic maybe useful for the first night or two after a westward flight andfor a few nights after an overnight eastward flight.

INTRODUCTION

TRANSMERIDIAN flights usually lead to sleep disturb-ance, but, though many studies have been carried out on thedisplacement of circadian rhythms and the subsequentrealignment of rhythms with the new time zone, less isknown about the nature of the sleep disturbance and theappropriate use of hypnotics. Sleep disturbance aftertransmeridian flights is probably an important factor inbehavioural inefficiency in a new time zone,l and specificchanges in sleep seem to be related to the direction oftravel. 2,3We now report our electroencephalographic studies of

sleep and daytime alertness in travellers who have crossedthe North Atlantic in both directions and our assessment ofthe potential use of a hypnotic drug (brotizolam, BoehringerIngelheim) in the management of sleep disturbance duringthe adaptation phase.

METHODS

The subjects were six healthy male volunteers aged between 19and 27 (mean 21 8) years. Overnight sleep (2330-0730 h) was

recorded with electroencephalogram, bilateral electro-oculograms,and submental electromyogram. Daytime sleep latencies4 weremeasured at 2-hourly intervals from 1000 to 2000 h. The latency tostage 1 (drowsy) sleep was determined electroencephalographically,and each test was terminated after sleep onset or after 20 minutes ifsleep was not achieved.

The Schedule ’

Control studies were carried out at the Institute of AviationMedicine, Famborough, for 2 days before the westward,flight (fig1). The flight from London departed at 1100 h Greenwich MeanTime (GMT). After arrival in Detroit at 2130 h GMT (1630 hEastern Standard Time [EST]), sleep was recorded for 5 nights anddaytime sleep latencies were measured for 4 days at the same localtimes as in the United Kingdom. The next 2 days were free ofrecordings, though the subjects remained within EST and on thesame sleep-wake schedule.

Sleep latency recordings in Detroit were resumed on day 7. Afterovernight sleep and recording of sleep latencies during the morningand early afternoon (1000-1400 h) subjects returned to London onan overnight flight which departed from Detroit at 1700 h EST(2200 h GMT). Sleep was not allowed during the flight or duringthe next day. On arrival in London (0830 h GMT) daytime sleeplatencies were measured from 1200 h. Sleep was recorded for 5nights and sleep latencies were measured during each of theintervening 4 days.The effect of a benzodiazepine hypnotic, brotizolam, on sleep

patterns was assessed in a double-blind crossover trial. Placebo was

given before all sleep periods in one direction and 0-25 mgbrotizolam for the 3 nights after the flight (with placebo before allother sleeps) in the other direction. Each subject undertook tworeturn schedules separated by at least 3 months, the order ofbrotizolam and placebo ingestion being reversed for the repeatjourney. -

Fig I-Schedule of sleep recordings before and after thetransatlantic flights.

Before the westward flight sleep was recorded for 2 nights (control). Sleepwas recorded (hatched areas) for 5 nights after the westward flight and, after abreak of 2 nights, preceding the return eastward flight and for 5 more nightsafter the flight.