Diagnosis of Lassa fever and the isolationand management of patientsT. P. MONATH 1 & J. CASALS 2

The clinical spectrum ofLassa fever is described and discussed in terms of the possiblepathophysiological events involved. Early diagnosis is essential to permitprompt isolation ofthe potentially infectious patient. Lassa fever may be suspected on clinical grounds, butspecific early diagnosis depends upon isolation of the virus. Virus isolation is bestaccomplished from serum obtained during the first 2 weeks of illness. The patterns ofviraemia and virus excretion described in thispaper are useful guidelinesfor determining theduration of patient isolation. Problems encountered in the isolation, management, andtransport of the patient with Lassa fever are discussed.

Lassa virus infection in man may be followed by aspectrum of disease that varies from a mild acutefebrile illness of brief duration to a prolonged fataldisease with severe toxaemia, capillary leakage,haemorrhagic phenomena, shock, and dysfunctionof many organ systems. Establishing a clinical diag-nosis at an early stage is especially important be-cause of the transmissibility of infection from per-son to person and the need for effective isolationof the patient and for containment of potentiallyinfectious specimens during virological and clinico-pathological testing.

In this paper we attempt to review the clinicalfeatures of Lassa fever in relationship to the pre-sumed pathophysiological events involved and toprovide a basis for clinical diagnosis and therapeuticmanagement. In addition, the patterns of viraemiaand virus excretion are described in order to formu-late measures for isolating the patient.

CLINICAL FEATURES

The symptomatology of Lassa fever is often non-specific, especially early in the disease, and con-sequently the diagnosis may be difficult until mul-tiple similar cases appear in the setting of an epi-

1 Director, Vector-Borne Diseases Division, Bureau ofLaboratories, Center for Disease Control, US Public HealthService, Department of Health, Education, and Welfare,Post Office Box 2087, Fort Collins, CO 80522, USA.

' Professor of Epidemiology, Department of Epidemi-ology and Public Health, Yale University School of Medicine,New Haven, CT, USA.

demic or until the consummate and severe clinicalsyndrome becomes apparent in an individual pa-tient.The incubation period is generally between 7 and

10 days, but may be as short as 3 days or as longas 17. A prodrome has not been defined, but theonset of illness is usually insidious rather thansudden. The acute phase has lasted 2 to 4 weeks inpatients who have entered hospital, but is probablyshorter in mild cases escaping medical attention. Thefrequency of symptoms and signs is shown inTable 1 and the chronology in Fig. 1. Initial symp-toms include feverishness, chills, generalized malaise,diffuse muscle aching, and headache. During the firstweek other symptoms that may be present includesore throat, dysphagia, nausea, vomiting, diarrhoea,cough, and pains in the chest and abdomen. Diar-rhoea tends to cease at the end of the first week,whereas other gastrointestinal symptoms (abdominalpain and vomiting) may persist into the second weekof illness. Chest pain, often pleuritic in nature,increases in intensity during the first week and maybe present during the second and third weeks.Dizziness, tinnitus, and unilateral or bilateral hear-ing loss are less frequent and later symptoms appear-ing during the second week of illness.On physical examination, the patient is febrile,

appears toxic, and may be dehydrated. The bloodand pulse pressures are low, and there may be aslower pulse than is normal with fever. Abnormalsigns include conjunctival inflammation; coatedtongue; lymphadenopathy; exudative pharyngitis;

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T. P. MONATH & J. CASALS

Table 1. Lassa fever; frequency of symptoms andsigns in patients observed during epidemics at Jos,Nigeria (1970), Zorzor, Liberia (1972), and Panguma,Sierra Leone (1972).

Fre- Fre-Symptom quency Sign quency

(%) a (%) a

nausea/vomiting 80 fever 100

sore throat 80 pharyngitis 79

cough 68 reduced blood pressure 66and pulse pressure

headache 57abdominal tenderness 53

abdominal pain 57lymphadenopathy 48

myalgia 46puffiness of face or neck 36

diarrhoea 43coated tongue 36

chest pain 39conjunctivitis 34

dizziness 25bleeding 32

deafness 18rales 25

tinnitus 16muscle tenderness 21

constipation 5petechiae 12

rash 7

convulsions 5

leukopenia (<4000/mm3) 41

albuminuria (>2+) 52

a Based on 34-44 patients; denominator variable because ofincomplete recording of information on specific symptoms or signs.

pulmonary rales; tenderness of intercostal, lumbar,or other muscles; abdominal tenderness (particularlyover the liver) and, occasionally, a maculopapularrash. Pharyngitis has been noted in approximately80% of the cases and is characterized by patchyexudates varying in size from 1 mm to a coalescentpseudomembrane. Dizziness has been associatedwith nystagmoid eye movements in one case (1), butnystagmus has been absent in others. Hearing loss isdemonstrable on gross examination. Jaundice hasnot been reported. Spiking low-grade fevers with nodefinite pattern have been noted in survivingcases (2); high persistent fever appears to correlatewith severe disease and a poor prognosis. In surviv-ing cases, fever breaks by lysis as symptoms andsigns gradually subside between the second andfourth weeks of illness.

Convalescence may be accompanied by com-plaints of generalized weakness lasting several-weeks. After a severe infection, one patient hadprolonged generalized neurologic dysfunction, withtremulousness, involuntary eye movements, un-

Fever

Generalizedmalaise

Myalgia

Headache

Sore throat

Chest pain

Cough

Abdominal pain

Vomiting

Diarrhoea

Dizziness

Hearing loss

Shock syndromehaemorrhagedeath

Viranmia

Viroria

p~~~~

p.

p~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

1 2Week of illness

3 4

Fig. 1. Diagramatic scheme of the chronology of symp-toms of Lassa fever.

steady gait, and episodic dizziness (1). Deafnessdeveloping during the acute illness has been irre-versible in some patients. Loss of scalp hair duringthe convalescent period has not been infrequent.Two instances of relapse of fever and symptomshave been reported (2, 3).

In 35-50% of hospitalized cases the disease mayprogress to its severe form, with persistent highfever, signs of increasing toxicity, diffuse capillaryleakage, a haemorrhagic diathesis, central nervoussystem disturbances, respiratory distress, oliguria,and shock. Such cases tend to have a fatal outcome,generally in the second week of illness. Capillaryleakage is manifested by the appearance of serouseffusions, oedema of the face and neck, petechiae,rales, and haemodynamic instability.

Respiratory distress has been associated withsevere Lassa fever in several settings: (a) airwayobstruction by cervicofacial, pharyngeal, or laryn-geal oedema; (b) pleural effusions with or without

708

DIAGNOSIS OF LASSA FEVER

painful pleuritis, which cause a reduction in lungvolumes; (c) pulmonary oedema, congestion, atel-ectasis, or haemorrhage associated with a diffusecapillary leak syndrome and shock; (d) dyspnoeadue to arterial acidaemia; and (e) congestive heartfailure due to overhydration in the face of dimin-ished renal function and/or myocarditis.

Metabolic acidosis, though for technical reasonsnot yet documented, is almost certainly an importantpathophysiological event in patients with severeLassa fever and shock. The difficulty in managementof acidosis and attendant serum potassium im-balance without the benefit of blood gas analysis hasprobably contributed to the high mortality of Lassafever in Africa.

Renal failure has been noted in severely ill patientswho develop shock, possibly due both to reducedrenal perfusion and to direct viral injury. Develop-ment of acute tubular necrosis has not been recog-nized, since patients have not survived the develop-ment of shock.

Haemorrhage, which has taken the form of ec-chymoses and oozing from needle puncture sites andminor gastrointestinal bleeding, has not been clin-ically important.CNS disturbances have been quite striking in

some cases and include tremor, alterations in con-sciousness, and generalized convulsions. Cerebro-spinal fluids have shown no abnormalities. Theseencephalopathic manifestations have coincided withprofound physiological alterations in other organsystems and probably systemic metabolic derange-ments; without further study they cannot be con-sidered as primary results of Lassa virus infection.The localizing neurological signs noted in an out-break (not confirmed as Lassa fever) in Sierra Leonein 1956 (4) have not been described in reports ofsubsequent epidemics.

Characteristically, the body temperature falls tosubnormal levels an hour or more before death.

CLINICAL PATHOLOGY

Clinical laboratory examinations may be of diag-nostic aid, either in helping to establish other eti-ologies or in supporting the suspicion of Lassa fever.It should be emphasized that the information atpresent available is derived from studies on a fewhospitalized, severely ill patients.A moderate leukopenia has been noted early in

the disease, especially between the fourth and tenthdays (Table 2), but absence of a low white cell count

Tab le 2. White blood counts in patients with Lassa fever

Number of determinations with white cell count ofTime after

onset (days) 2000-2500 2501-4000 >4000(wbc/mm3) (wbc/mm3) (wbc/mm3)

0-3 1 4

4-7 3 5 4

8-10 1 6 8

11-14 1 5

15+ 6

is not a helpful diagnostic criterion. Late in illness, amarked leukocytosis may occur. Abnormalities inthe platelet count, prothrombin time, and clottingtimes sometimes occur (9, 10). Increased amounts ofalbumin in the urine and abnormal urinary sediment(cells and granular casts) have been reported inapproximately half of the patients, especially insevere or fatal cases (9).

Elevations of serum enzymes (creatine phospho-kinase, lactic dehydrogenase, and glutamic-oxalo-acetic transaminase) have been found in a few cases.These changes are nonspecific and may reflect dam-age to the liver, myocardium, and/or skeletal muscle.The cerebrospinal fluid has been normal (1, 3).Electrocardiographic examinations have been in-

frequently made; conduction defects, ST-T wavechanges, and abnormal Q waves have been described(10, 11), suggesting myocardial injury. In severalinstances, the chest X-ray has shown infiltrates con-sistent with pneumonitis (1).

PATHOPHYSIOLOGICAL CORRELATIONS

The pathology of human Lassa virus infection hasbeen reviewed by Winn & Walker during this Sym-posium (5) and by previous authors (1, 6, 7, 8). Thepathophysiological alterations in severe Lassa feverremain obscure and are certainly complex. Clinicalobservations suggest that alterations in capillarypermeability, possibly due to direct viral injury,pharmacological mediators, or complement splitproducts, may be a central event. A schematicrepresentation of the presumed pathophysiologicalmechanisms is shown in Fig. 2.

Secondary results of capillary leakage and reducedeffective circulating blood volume may include in-crease in sympathetic tone, local tissue acidosis andanoxia, and further reduction in tissue blood flow,thus generating the shock syndrome. Pre-renal fail-

709

T. P. MONATH & J. CASALS

Fig. 2. Hypothetical mechanisms involved in the patho-physiology of Lassa fever infection.

ure, lactic acidaemia, hyperkalaemia, and reducedperfusion and oxygenation of vital tissues ensue andprogress to a fatal outcome. Other secondary effectsof microvascular damage include alterations in pul-monary function due to several mechanisms. Respi-ratory failure may contribute to the anoxia andacidosis associated with the shock syndrome. Dis-seminated intravascular coagulation has not beenconfirmed by laboratory tests, but may play a role inthe haemorrhagic diathesis, renal damage, and thegeneration of shock. In addition to the secondaryeffects, direct viral damage to vital organs, such as

the liver (5-8), heart, and kidney, play an undeter-mined role in the pathogenesis of the severe syn-drome.

Since both the haemodynamic and metabolicdisturbances may be amenable to specific therapeuticmeasures, future efforts should be directed towardsdocumentation of these abnormalities in the patient.The lack of relatively advanced monitoring equip-ment makes such studies difficult in hospitals inremote rural areas.

CLINICAL AND DIFFERENTIAL DIAGNOSIS

The diagnosis of Lassa fever must be seriouslyconsidered for a patient living in or travelling fromendemic areas of West Africa who presents with thetriad of fever, exudative pharyngitis, and a low or

slightly subnormal white cell count. Streptococcalpharyngitis and viral illness due to adenoviruses,coxsackieviruses, and herpesvirus generally have asudden onset and a briefer febrile course (less than3-4 days). Diphtheria must be considered whenpharyngeal lesions are severe. Bacteriological ex-amination of the throat and measurement of theperipheral white blood count may be useful indifferentiating infections due to bacterial organisms.

Fever lasting more than 3-4 days accompanied bypulmonary symptoms (cough, pleurisy, effusions)and signs may suggest viral, chlamydial, or bacterialpneumonia. Examination of the sputum, chest X-ray, white blood count, and response to antimicro-bial therapy may assist in the diagnosis. Tuber-culosis, relapsing fever, pulmonary infarction, andother diagnoses may also be considered.

Fever, lumbar pain and tenderness, and gastro-intestinal symptoms may mimic acute pyelonephri-tis. The demonstration of bacteria and numerousleukocytes in the urine, a polymorphonuclear leuko-cytosis, and a response to antibiotic therapy arehelpful in distinguishing this disease from Lassafever.Blood smears should be examined for malaria

parasites, but it is emphasized that the presence ofplasmodia does not exclude concurrent infection withLassa virus; antimalarials may be administered rou-tinely as a therapeutic trial.A number of diseases (e.g., typhoid, early infec-

tious hepatitis, influenza, yellow fever, dengue, infec-tious mononucleosis, leptospirosis, relapsing fever,typhus, and rheumatic fever) may produce a clinicalpicture resembling that of Lassa fever. Similaritiesbetween Lassa and typhoid fevers include insidiousonset, prolonged fever, headache, rash, lymphadeno-pathy, relative bradycardia, gastrointestinal symp-toms, cough, leukopenia, sore throat, vascular col-lapse, hypothermic death, and residual deafness.Culture of the blood (if available) during the firstweek of illness may be extremely helpful in thediagnosis of typhoid; response to chloramphenicolmay distinguish the disease.

VIROLOGICAL AND SEROLOGICAL DIAGNOSIS

Specific diagnosis requires isolation and identifica-tion of the virus or demonstration of an antibodyrise using paired serum samples.The pattern of viraemia and virus excretion in

patients studied to date (Fig. 3), provides guidelinesboth for attempts at early virological diagnosis andfor instituting and continuing the isolation of pa-

710

DIAGNOSIS OF LASSA FEVER

5~~~~R'

h tSH-FiR..,_;-,_ _I0 1:

sods_~~~~n7

Fig. 3. Results of virus isolation attempts from serum,throat swabs, urine, and other body fluids obtained fromLassa fever patients studied between 1969 and 1974.

tients. Virus isolations are best accomplished fromserum collected within 14 days from onset. Of 44sera collected during this period, 36 (82%) werepositive; 6 of the 8 negative sera were obtained frompatients who had been transfused with Lassa im-mune plasma shortly before. The longest docu-mented viraemia is 19 days.

Virus has been isolated from approximately halfof the throat washings or swabs tested during thefirst 14 days of illness. The duration of pharyngealexcretion parallels the viraemia. In 2 patients whoreceived transfusions of immune plasma, viraemiaceased but throat washings remained positive (2, 10).

Viruria has been less frequently demonstrated, butit may be present for more prolonged periods despitethe administration of immune plasma (Fig. 3).

Present constraints on the early specific diagnosisof Lassa fever by virus isolation include: (1) the timeand practical obstacles encountered in the shipmentof specimens from West Africa to a diagnosticlaboratory with biocontainment facilities and (2) thetime required in the laboratory for demonstration ofthe virus.

Serological diagnosis by conversion of the comple-ment-fixation (CF) test from negative to positive inpaired serum samples is not an efficient means ofestablishing an early diagnosis. Of 29 sera takenbetween days 3 and 14 after onset from patientswhose diagnosis was proved by virus isolation or

serological conversion, only 3 (10%) were CF-posi-tive; and of 28 sera taken between days 15 and 28, 19(68 %) were positive. The presence of CF antibody inserum has been demonstrated in patients from whomvirus was simultaneously recovered from thepharynx (2).

The indirect fluorescent antibody (IFA) test isapparently more sensitive than the CF test and maydetect antibody earlier following infection. Furtherstudies are required.

ISOLATION OF THE PATIENT

The principles and practice of isolation are beyondthe scope of this paper and may be found in a USGovernment publication, which is readily available(12). Once the clinical suspicion of Lassa fever isentertained, the physician must turn to account hisunderstanding of the source of infection and routesof transmission of Lassa virus (13) in order to adaptthe ideal principles of isolation to the more limitedlocal capabilities. Procedures within the capabilitiesof many, though certainly not all, hospitals in WestAfrica include the use of a private room and toiletfacility, protection of staff against contact spread bythe use of gowns, gloves, and masks, and disinfec-tion of objects coming in contact with the patient.To date Lassa virus has not been transmitted from

a patient in isolation to a medical attendant orvisitor. Although routine isolation techniques areprobably effective, one cannot be certain that theyhave prevented tertiary infections, since observationsin the nosocomial outbreaks suggest that only theoccasional patient is highly infectious (13-15).

In the setting of an epidemic, the physician isoften faced with the problem of misdiagnosis whendeciding to isolate a patient with symptoms andsigns resembling, but not clinically diagnostic of,Lassa fever. Where facilities are limited, this decisionmay result in an exposure of an uninfected patient toLassa virus. Whenever possible, patients with thequestionable diagnosis of Lassa fever should beisolated in separate rooms rather than in an isolationward. Where two or more patients must be isolatedtogether, beds should be placed as far apart aspossible (10-12 feet; 3-3.5 m), to minimize directcontact and droplet spread.The duration of isolation cannot be rigidly speci-

fied. In practice, it will be determined by the lengthof time necessary for clinical recovery. Most patientswill not feel well enough to be discharged until 3-4weeks after onset, by which time viraemia andpharyngeal virus excretion will probably have sub-sided. Viruria may persist longer, and dischargedpatients should be advised of simple preventivemeasures to reduce the exposure of others to urine.For patients in hospitals with access to rapid viro-logical analysis, the date of discharge may be deter-

711

T. P. MONATH & J. CASALS

mined by the cessation of virus excretion; viruriamay be intermittent (2, 10), however, and sequentialsamples must be tested.An unresolved problem is that of the safe handling

of specimens for clinical diagnostic tests. Determina-tion of haematological and chemical parameters maybe helpful diagnostically, and certain tests (in parti-cular, electrolytes and blood gases) may be essentialto the care of the severely ill patient. In a fewspecialized centres, it may be possible to carry outthe necessary clinical examinations in a virologicallaboratory or other laboratory with biocontainmentfacilities. This is not, however, a practical solution tothe general problem.For some determinations, clinical specimens can

probably be rendered non-infectious. For example,the addition of blood to dilute acetic acid(20 mg/litre; pH 2.9) for leukocyte counting wouldbe expected to inactivate Lassa virus. Blood smearsused for differential cell counts or detection ofmalarial organisms can be fixed with glutaraldehyde.Although the thermal inactivation kinetics of Lassavirus have not been definitely measured, it appearsthat heating at 60°C for 1 hour is sufficient toinactivate the agent (H. Wulff, personal communica-tion). Samples for measurement of electrolytes,creatinine, febrile agglutinins, or other thermostablecomponents could thus be heated before they areused.

CLINICAL MANAGEMENT

Because of the uncertain prognosis for any patientin the early acute phase of Lassa fever, close ob-servation is recommended in a hospital.

Supportive measures include bedrest, sedativeanalgesic drugs when required, paracetamol or tepidwater-sponging to reduce fever and metabolic de-mands, and small amounts of viscous lidocaineswallowed to reduce sore throat when dysphagia issevere. Nausea and vomiting occur frequently andmay require specific measures to relieve discomfortand reduce the risks of dehydration and electrolyteimbalance.

Vital functions, especially blood and pulse pres-sure, pulse, and intake and output, should be closelymonitored. Serial measurements of haematocrit,urine specific gravity, and electrolytes, if available,will be useful in managing fluid balance. Dehydra-tion or extracellular fluid volume depletion, which ispresent in a high proportion of cases, should becorrected and fluid balance maintained by appro-priate fluid administration; the oral or rectal routes

are preferred when biochemical tests are not avail-able. Extreme vigilance must be maintained for signsof diffuse capillary leakage, extracellular volumeexcess, and reduced effective blood volume, whichindicate progression of the disease to its severe form.A rising haematocrit or haemoglobin level and in-creasing albuminuria may provide early clues tothese events.The patient with shock and the capillary leak

syndrome requires the constant attention of a physi-cian and trained nurse and continuous monitoring ofvital functions, including central venous pressure, ona bedside flow chart. Administration of salt andwater should be curtailed and a cautious attemptmade to expand intravascular volume with colloids.The use of vasoactive drugs (isoprenaline, norepin-ephrine), digitalis, and diuretics (furosemide) may beindicated.

Respiratory distress is often apparent; its etiologyshould be ascertained (see Clinical features) andtherapy guided accordingly.

Metabolic (lactic) acidosis and hyperkalaemia un-doubtedly accompany the shock syndrome. Electro-cardiographic monitoring may be helpful. Whereblood gas analysis is not available, it may be prudentto administer bicarbonate on an empirical basis.

Corticosteroids have been used in the severely ill;no information is available regarding their efficacy(or possible deleterious effects) in Lassa fever. Theuse of pharmacological doses to counteract shock isstill controversial.

Since intensive care facilities do not exist inregions where Lassa fever is endemic, emphasisshould be placed on measures to reduce the factorscontributing to the development of the shock syn-drome. Correction of fluid balance during the earlyacute phase, and the administration of immuneplasma, which may limit the extent of microvascularinjury, are at present considered to be the mostimportant measures.

SPECIFIC TREATMENT

Administration of plasma containing antibodies toLassa virus has now been tried in a number ofacutely ill patients. Five are well documented; afavourable response was observed in 4 and anadverse effect was suspected in 1 case. Patients withLassa fever who have received immune plasma maycontinue to excrete virus by the respiratory andurinary routes; isolation procedures should remainin effect after transfusion. Further clinical trials and

712

DIAGNOSIS OF LASSA FEVER

observations in individual patients receiving sero-therapy should be carefully recorded.Under emergency conditions, the use of con-

valescent plasma of undetermined potency andsafety may be contemplated. The principal hazard isthe transfusion of plasma containing Lassa virus to apatient with disease suspected on clinical groundsbut not proved to be Lassa fever. Since viraemia hasbeen documented 19 days after onset and the devel-opment of antibody is often delayed, plasma to beused for transfusion therapy should never be ob-tained earlier than 3 weeks after onset and preferablyshould be obtained 6 weeks or more after onset.The world's supply ofstored immune plasma is very

limited. The World Health Organization and othersare attempting to identify potential immune donors byserosurveys of hospital workers and missionaries inAfrica. A small cadre of cooperative persons willingto undergo plasmapheresis could generate a volumeof plasma large enough to allow the preparation ofspecific immunoglobulin. In the endemo-epidemicregion of Sierra Leone, where the need for immuno-therapy is at present great, a selective blood donorprogramme is precluded by the difficulties involvedin locating and obtaining blood from specific in-digenous immune individuals. Because the pre-valence of antibody in the general population maybe as high as 10%, an alternative plan is currentlyunder consideration: plasma would be routinelyseparated from all blood units used for patients withconditions requiring the transfusion of packed redblood cells (e.g., anaemic patients). Potent plasmaunits, identified by serological tests and screened forhepatitis antigen, would be stored frozen and wouldbe available for use in the endemic region.

TRANSFER AND EVACUATION OF PATIENTS

Since the treatment of patients with Lassa feverrequires the use of isolation facilities and advancedclinical resources, evacuation from rural primary-care hospitals to better equipped medical centreswithin the endemic area or country may be desirable.It seems certain that Lassa fever will be a continuingpublic health problem in parts of West Africa;health authorities should therefore consider theselection and designation of regional hospitals asLassa fever treatment centres. These hospitalsshould be suitably equipped and selected personnelshould be trained in isolation techniques and in themanagement of patients with severe illness.

International air transfer, generally to the countryof national origin, has occurred in a number of casesinvolving expatriates. Precautions taken to avoidcross-contamination of crew and passengers havevaried from none to the use of a charter flight and aplane with a specially equipped air-conditioningsystem. Epidemiologically the use of a special flightis the only acceptable method, though costs are veryhigh. International transfer should be undertakenonly with the specific agreement of the health admin-istration and clinical centre of the receiving country.Organizations such as missionary groups and foreignhealth agencies that have medical personnel sta-tioned in endemic areas should consider in advancetheir responsibilities to the individuals concernedand to the international community. The need foroverseas transfer would be obviated by the establish-ment of an intensive care unit and immune plasmabank available to nationals and expatriates through-out the whole of West Africa.

RltSUMtDIAGNOSTIC DE LA FIEVRE DE LASSA, ET ISOLEMENT ET TRAITEMENT DES MALADES

Le tableau clinique de l'infection due a la fievre deLassa couvre un large spectre, allant d'une affectionfebrile tres benigne A une longue maladie avec issue fatale.Le diagnostic precoce est essentiel car le virus est trans-missible A l'hopital. Les manifestations cliniques sontd'abord insidieuses avec acces febrile, frissons, myalgieset cephalees, suivis selon le cas par une pharyngite, dessympt6mes gastro-intestinaux, de la toux, des douleursthoraciques, des etourdissements et une diminution del'oule. Chez 35 A 50% des cas hospitalises, la maladieprogressejusqu'a la forme aigue, avec toxemie prononcee,syndrome d'epanchement diffus des capillaires, manifes-

tations hemorragiques, troubles respiratoires, perturba-tion du systeme nerveux central, oligurie et etat de choc.

II est indispensable de faire un parallle, avec la fievretypholde lors du diagnostic differentiel clinique; I'hemo-culture et l'administration de chloramph6nicol A titreexperimental peuvent se reveler utiles.Le diagnostic precoce specifique d6pend de l'isolement

du virus dans le serum, le pharynx, l'urine ou le liquidepleural. Parmi 44 specimens de serum recueillis pendantles 14 premiers jours de la maladie, la presence du virusde Lassa a ete confirmee dans 36 (82%). Le virus estmoins souvent observe, en revanche, dans le pharynx et

713

714 T. P. MONATH & J. CASALS

l'urine. La virurie peut persister jusqu'a 32 jours, et il estarriv6 que des serums et prelevements pharynges soientpositifs pendant 19 jours.

Les malades dont les sympt6mes cliniques permettentde diagnostiquer la fievre de Lassa doivent etre rigoureu-sement isoles. Dans la pratique, la duree de l'isolementd6pend dti retablissement clinique, mais on pourra s'ins-pirer a cet 6gard de 1'evolution de la viremie et des excre-tions virales d6crites plus haut. Des problemes particu-liers surgissent quand des specimens infectieux sontobtenus en vue d'epreuves anatomo-pathologiques cli-niques. Pour certaines etudes, il est possible d'inactiverle virus dans le serum ou l'urine avant l'epreuve enlaboratoire.Le traitement du malade comportera au premier chef

la surveillance du bilan des liquides organiques des ledebut de la phase aigue et l'on devra veiller aux signesd'instabilite hemodynamique et d'dpanchement des capil-laires. Le traitement specifique au plasma immun, quin'a e essaye que chez quelques malades, semble devoirdonner de bons resultats, mais il n'existe que des quan-tites tres faibles de plasma immun.

Du fait que le traitement des cas graves exige des ins-tallations cliniques perfectionnees, il peut s'averer neces-saire de transf6rer le malade dans un centre medicalbien equipe. II faudra affreter un avion special pourtransporter les malades dans un autre pays oui la fievrede Lassa n'est pas endemique, afin de r6duire le risqued'une contamination croisee.

REFERENCES

1. FRAME, J. E. ET AL. Lassa fever, a new virus disease ofman from West Africa. I. Clinical description andpathological findings. Amer J. trop. Med. Hyg., 19:670-676 (1970)

2. MONATH, T. P. ET AL. Lassa fever in the EasternProvince of Sierra Leone, 1970-1972. II. Clinicalobservations and virological studies. Amer. J. trop.Med. Hyg., 23: 1140-1149 (1974)

3. MERTENS, P. E. ET AL. Clinical presentation of Lassafever cases during the hospital epidemic at Zorzor,Liberia, March-April, 1972. Amer. J. trop. Med.Hyg., 22: 780-784 (1973)

4. ROSE, J. R. An outbreak of encephalomyelitis inSierra Leone. Lancet, 2: 914-916 (1957)

5. WINN, W. & WALKER, D. Pathology of human Lassafever. Bull. World Health Organ., 52: 535-545(1975)

6. ED1NGTON, G. M. & WHITE, H. A. The pathology ofLassa fever. Trans. roy. Soc. trop. Med. Hyg., 66:381-389 (1972)

7. WINN, W. ET AL. Lassa virus hepatitis. Observationson a fatal case from the 1972 Sierra Leone epidemic.Arch. Pathol., (in press) (1975)

8. SARRAT, H. ET AL. Diagnostic histopathologique desh6patites dues au virus Lassa. Bull. Soc. Pathol.exot., 65: 642-650 (1972)

9. WHrrE, H. A. Lassa fever. A study of 23 hospitalcases. Trans. roy. Soc. trop. Med. Hyg., 66: 390-401(1972)

10. LEIFER, E. ET AL. Lassa fever, a new virus disease ofman from West Africa. II. Report of a laboratory-acquired infection treated with plasma from a personrecently recovered from the disease. Amer. J. trop.Med. Hyg., 19: 677-679 (1970)

11. WOODRUFF, A. W. Handling patients with suspectedLassa fever entering Great Britain. Bull. WorldHealth Organ., 52: 717-721 (1975)

12. US DEPARTMENT OF HEALTH, EDUCATION, AND WEL-FARE. Isolation Techniques for use in hospitals,Washington, D.C., US Government Printing Office,(Publication No. (HSM) 71-8043).

13. MONATH, T. P. Lassa fever: Review of epidemiologyand epizootiology. Bull. World Health Organ., 52:577-592 (1975)

14. CAREY, D. E. ET AL. Lassa fever. Epidemiologicalaspects of the 1970 epidemic, Jos, Nigeria. Trans.roy. Soc. trop. Med. Hyg., 66: 402-408 (1972)

15. MONATH, T. P. ET AL. A hospital epidemic of Lassafever in Zorzor, Liberia, March-April, 1972. Amer. J.trop. Med. Hyg., 22: 773-779 (1973)

DISCUSSION

K. JOHNSON: Your clinical description of Lassa fever andthe handling of it correspond exactly to what we seewith Junin and Machupo disease. There is a big differ-ence, however, in the viraemia data, and I think this maybe one reason why Lassa fever presents such a differentproblem. In the case of Bolivian haemorrhagic fever, the

virus cannot be isolated from blood of the patients inmore than about one in four attempts at any time inthe course of the illness. In the care of well over 700patients, there has never been, in the original focus atleast, an instance of transmission to medical personnel.Since then there has been a small outbreak in Cocha-

DIAGNOSIS OF LASSA FEVER 715

bama where person-to-person transmission occurred.Lassa fever is exceptional in that such person-to-persontransmission occurs frequently.

MAIZTEGUI: I also think that your interpretation of theclinical events in Lassa fever can be applied to bothArgentine and Bolivian haemorrhagic fever. However,I would like to add that our recent electron microscopyand immunofluorescent studies in 9 cases ofAHF indicatea direct viral pathogenic effect. Finally, I wish to askhow low are the platelet and white cell counts duringthe acute phase of Lassa fever?

MONATH: The thrombocytopenia is not in the rangewhere one would expect major haemorrhagic problems.

SMITH: Do you think that mobile hospital units might beuseful in the treatment of Lassa fever, especially in veryremote areas that are relatively inaccessible?

MONATH: This is a question that we could talk aboutfor a long time. I think we have to look at Lassa feverin perspective, keeping in mind the myriad of other health

problems that are much more important in regard toyour part of the world than is Lassa fever. I do notbelieve that it would be desirable to put a lot of moneyinto equipping a mobile unit and so use up resourcesthat are needed to combat diseases like malaria and oncho-cerciasis; this would be a conceptual mistake. But to alterexisting health facilities by establishing isolation roomsand by training existing personnel is a reasonable ap-proach. I am not sure that you will ever be able to reachthe villages that are 10 miles off the road or even knowthat they had a case of Lassa fever in the first place.

SAMA BANYA: a In Africa, isolation wards readily becomeprivate wards, remote from the main block, and thismakes it difficult to provide adequate nursing coverage.It seems better to use barrier nursing on the main wardsof the hospital in order to assure that the patients areconstantly under care. I also believe that patients withLassa fever should not be moved at all. Perhaps it wouldbe better to improve the general care of these patientsin the areas where the disease is recognized.

a Kenema, Sierra Leone.