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Rift Valley fever (RVF) or enzootic hepatitis is caused by a mosquito-borne Phlebovirus primarily affecting sheep, goat, cattle and several other species including human beings. The disease is characterized by high fever, abortion storms, neonatal mortality and diffuse necrosis of the liver.
Geographic distribution
The first report of a novel acute, and fatal epizootic in lambs was made in the Rift Valley of Kenya in 1912. Eighteen years later a second virulent epizootic affected sheep, cattle and humans in the same location and its aetiology was identified as a previously unknown virus (1). The third epizootic emerged in South Africa 20 years later (2). Thereafter, enzootics and epizootics were detected in most countries of sub-Saharan Africa. In 1977 it emerged in Egypt affecting ruminants, camels, rats and caused 600 deaths in human males (3). In 1987 hundreds of human deaths occurred in Mauritania and Senegal (4) and in 1993 it re-emerged in Egypt (5). In 1998 a major epizootic spread out of Africa from Somalia into Yemen (6) overspilling into Saudi Arabia in 2000 (7).
In India, in August 1994, an outbreak of a fulminant, neonatal disease occurred in flocks of indigenous sheep in the Chengai-MGR district of Tamil Nadu. The features were reminiscent of published accounts of RVF (8,9). A similar episode was observed in November 1995 among sheep and goats in the district of Thiruvannamalai in Tamil Nadu. Sero-surveillance revealed the presence of RVF-antibodies (10).
Epidemiology
Mosquitoes are the important vectors, Aedes mcintoshi being the main vector between animals and Culex pipeno the human vector (11). Nevertheless, most human infections occur when handling infected tissues or viral samples in the laboratory (12). Although many RVF viruses have been isolated from - Aedes, Eretmapodites and Culicoides spp. survival of the virus depends upon floodwater mosquitoes (13).
The rare rampant epizootics of RVF in Africa south of the Sahara are linked to heavy rainfall that raises ground water-tables to flood shallow depressions called “dambos” in forest edges. Transovarian transmission of the virus in Aedes mcintoshi occurs when they lay their infected eggs on the dambo vegetation. Nothing happens until the eggs are immersed in floodwater. Years later when they hatch, new virus-infected mosquitoes are released. The virus is not known to persist in animal hosts between epizootics but there is evidence of an enzootic inter-epizootic maintenance cycle in cattle and wildlife (14).
Clinical signs
Clinical signs in animals vary according to the course of the disease. RVF occurrs as a peracute, acute, subacute, mild or inapparent infection (15). The peracute form was noticed in newborn and very young lambs, wherein death occurred without any clinical signs within 24 to 36 hours with a mortality of 95 to 100 per cent. The acute form was observed in young lambs, kids and calves characterized by pyrexia, vomiting, mucopurulent nasal discharge and unsteady gait. The subacute form was seen in adult sheep and goats, which often, showed clinical signs like pyrexia, anorexia, general weakness and abortion. In mild and inapparent forms, only adult sheep are affected developing slight febrile reactions. Muralimanohar et al. (8) while investigating RVF like disease among sheep in India recorded pyrexia, anorexia, sneezing, dry cough, bilateral mucopurulent nasal discharge, vomiting, erosions on the buccal commissures, disinclination to move, diarrhoea mixed with traces of blood and abortion.
Symptomatically, human RVF has features reminiscent of Dengue fever and sandfly fever. The incubation period ranges from 3-6 days and was followed by a sudden onset of pyrexia, headache, myalgia, arthralgia, debility and photophobia. In severe cases, pyrexia was prolonged and intermittent and associated with supraorbital pain and intraocular alteration such as unilateral or bilateral patchy retinitis near the macula, retinal haemorrhage and detachment, iritis and papillitis. There was also meningo-encephalitis manifested as choreiform movements, convulsions, stupor, grinding of teeth and visual hallucinations (16). A haemorrhagic state was also observed in some patients. The features were epistaxis, haematemesis, haematuria, cutaneous petechiae and moderate to marked jaundice. The salient clinical signs observed in human cases during RVF outbreak in Saudi Arabia were fever, lethargy, diarrhoea, abdominal pain, nausea, vomiting, head ache, jaundice, abortion, bleeding and neurologic manifestations.
Clinical pathology
Following the onset of the disease, there was an initial increase in neutrophils and monocytes, which decreased rapidly within 24 hours. In adult sheep, the lowest count of leukocytes coincided with the maximal rectal temperature and maximal amount of virus in the blood (1). The consistent haematological and pathophysiological changes observed were leukopenia, thrombocytopenia, decreased level of prothrombin and elevated levels of bilirubin, urea and aspartate and alanine aminotransferases. Similarly during the outbreak of RVF in Saudi Arabia, affected patients had decreased levels of haemoglobin, platelets and increased levels of LDH (Isoform 2), creatinine and Creatinine Phospho Kinase.
Pathology
Daubney et aI. (1) were the first to describe the lesions of RVF in sheep and lambs. RVF produces similar pathological changes in most susceptible animals. The most striking feature in all carcasses was jaundice. Liver was the most frequent organ affected which showed characteristic lesion of RVF namely necrotic foci of less than 1 mm diameter. Subcutaneous, serosal and mucosal haemorrhages were also seen along with hepatic lesions (17). Death was associated with haemorrhages, massive necrosis in the liver, haemorrhages in the adrenal, spleen, lung and gastro-intestinal tract (18). In other species, the hepatic lesions tended to be focal (19). Experimentally, infected lambs revealed enlarged, mottled, yellow or orange brown and red livers with greyish white foci scattered in the liver parenchyma (20). In India, Muralimanohar et al. (8) also recorded similar liver lesions accompanied with petechiae in the soft palate and frenum linguae, congestion and haemorrhages in the intestine in sheep, which died of RVF-like disease.
Severe liver necrosis, interstitial pneumonia, myocardial degeneration, ocular lesions characterised by haemorrhages, edema and retinitis were observed in fatal human cases during 1977 RVF epidemic in Egypt (21). Ocular complications of RVF have also been recorded (22,23). Histopathological lesions were seen consistently in the infected livers of both natural as well as experimental animals. Liver showed multifocal coagulative necrosis which was predominantly centrilobular (1) with dissociation of the cords of Billroth, swollen hepatocytes showing various stages of degeneration. Findlay (17) observed that the liver lesions in yellow fever and RVF were similar but fatty changes were totally absent in RVF. The hepatic lesions varied with species, being diffuse or multiple in sheep while in other species these tended to be focal (18). The degenerating hepatocytes contained intranuclear eosinophilic inclusion bodies surrounded by a halo. Margination of nuclear chromatin along the nuclear membrane was evident. The hepatic lesions in dogs and cats were identical to those observed in other species but intranuclear inclusions were not well defined. Different strains of RVF virus caused identical changes in liver and brain of mice. However, inclusion bodies were not consistently seen with all strains and there was no correlation between virus titres and severity of histological changes observed (24). Easterday et al. (18) studied the sequential development of hepatic lesions in lambs. The presence of eosinophilic intranuclear inclusion bodies was a cytological hallmark. Viral antigen contained in these inclusions was detectable in indirect fluorescent antibody test using purified hyperimmune sheep anti-serum.
Two types of inclusions have been described, the spherical and the filamentous. In the development of the former, the nucleoplasm separated into small portions, each having some marginated chromatin with eosinophilic core (25). Filamentous inclusions thickened and branched and sometimes assumed a rod shaped structure surrounded by a clear unstained halo (26, 27). Multifocal hepatocellular necrosis and presence of intranuclear acidophilic inclusions with a clear halo and margination of chromatin were observed in sheep which died due to RVF-like disease (8).
A finding of considerable molecular virological interest has been the demonstration of the non-structural protein in the nuclei of infected cells during viral morphogenesis (28). Lymphoid organs like spleen and lymph nodes revealed extensive destruction of lymphocytes. Extensive haemorrhages, vasculitis and edema were observed in different organs along with meningo-encephalitis. Development of retinopathy and lesions in the fundus region were also reported (16, 21).
Immunology
The various strains isolated appear to be closely related antigenically. Antisera and colostrum have prophylactic and therapeutic value and they may be used to induce passive immunity in lambs and calves. Resistance to RVF was transmitted to calves by ingestion of colostrum and lasted for five months after weaning (29). The immunity produced in human beings by an outbreak of RVF persists for life. Humans are vaccinated with a vaccine prepared from Rhesus and African green monkey kidneys (30). Vaccine prepared from lamb kidney or hamster kidney primary cell culture virus inactivated by formalin also proved effective (31).
Such inactivated tissue culture vaccine was also found effective in sheep against challenge (32). Two ml of formalin inactivated alum adjuvanted vaccine protected sheep against illness as well as viraemia, when the animals were challenged with RVF several months later.
In cattle, the antibody responses to a single injection of modified and inactivated vaccines were poor when measured by the serum-virus neutralization and haemagglutination inhibition tests. A booster dose of the inactivated vaccine however, produced a good anamnestic response. Baskerville et al. (33) used a live attenuated mutant RVF virus MVP12 to study the usefulness of this strain as a vaccine by inoculating it into pregnant ewes. They concluded that MVP12 might be used successfully as a live attenuated vaccine.
El-Karamany et al. (34) have stated that inactivated RVF vaccine prepared from CEF cell cultures infected with the pantropic strain with aluminum hydroxide gel adjuvant was safe and effective for immunization of goats, lambs, pregnant ewes and adult sheep. It induced a high level of neutralizing antibody and prevented viraemia.
Diagnosis
Tentative diagnosis of RVF may be made based on history, clinical signs and lesions. A history of clinical illness, short incubation period with a storm of abortions and a high mortality in lambs, kids and to a lesser extent in calves and a much lower incidence of mortality in adults, presence of focal or multifocal necrotic foci in the liver with presence of intranuclear eosinophilic inclusion bodies in the hepatocytes and meningo-encephalitis and illness or febrile reactions in human beings involved in examination of the infected carcasses may be regarded as highly suspicious of RVF. The disease can be confirmed by isolation and identification of the virus or by serological examination of acute and convalescent phase sera. For viral isolation, blood preferably collected during febrile stage from ailing animals, tissue suspensions of brain, liver or spleen may be used. These materials are diluted ten-fold in phosphate buffer containing one per cent peptone, five per cent lactose, 500 units of penicillin and 500 mg of streptomycin per ml and 0.03 ml of the suspension is given to day-old albino mice by intracerebral route. Mice usually die within one to four days. The brains of these mice may be used as antigen for identification of virus in a neutralization test (35). The serum-virus neutralization (SVN) and haemagglutination inhibition tests are used for serological diagnosis. In the SVN test neurotropic virus is used as antigen using day-old mice. A plaque inhibition test in Vero cells may also be used. The haemagglutination-inhibition technique of Clarke and Casals (36) is also used for determining antibody titres. A sucrose acetone extract of infected mouse brain and goose red cells are employed in the test, which must be performed at pH 6.4.
Control
The recent emergence of Rift Valley Fever (RVF)-like disease in flocks of indigenous sheep in Chengai-MGR and Thiruvannamalai districts of Tamil Nadu (8,9) is a matter of grave concern to sheep and goat farmers in the state. It is also a matter of national and international importance. Though no virus could be isolated from sheep or mosquitoes from the outbreak which occurred in Veerapuram in India (8), haemagglutination inhibition (HI) antibodies to RVF virus antigen were detected in 14 of 28 convalescent sera, 7 of which showed anti-RVF IgG antibodies by ELISA (10). These disturbing reports are adequate to institute stringent measures. Strict animal movement restriction has to be enforced. Importation of animals from countries where this disease has been reported should be banned. Other preventive measures which may be adopted to avoid its penetration and establishment in India include: strict animal movement restriction within and in between states; educating veterinarians and medicos about clinical features of the disease; provision of diagnostic facilities; serological and entomological surveillance; virological examination of suspected foeti and insects and establishment of a speedy reporting system in collaboration with the public health authority. It is pertinent to mention in this context that non-vectoral transmission through direct contact with infected fomites and animal tissues has been clearly established as the cause of human disease in several African countries. Transfer of infection from man to animals has not been reported so far.
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