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SOUTH AMERICAN HAEMORRHAGIC FEVERS

LUIS VALVERDE CHINEL
Instituto National de Laboratorios de Salud "Nestor Morales Villazon", Casilla 842, La Paz, Bolivia

ANTECEDENTS

In 1953/54 epidemic outbreaks of Argentine Haemorrhagic Fever were discovered in the north-west of Buenos Aires Province. This humid Pampa is the richest farming land of Argentine, the climate is temperate and the average annual rainfall is about 1,000mm. The geographical extension was formerly recognized as 16,274 km 2 with 268,049 inhabitants in 1958. At the present time it covers more than 100,000 km2 with a population of more than 1,000,000 people (1).

Bolivian Haemorrhagic Fever was first observed around San Joaquin, in Agua Clara, in September of 1959, in Yutiole in July 1960, in Yoatre in August and in Las Moscas in December. In May 1961 the first cases appeared in San Joaquin and Barranquita.

Another epidemic outbreak was also reported in Orobayaya 115 km to the East of San Joaquin. The island was abandoned by its 600 inhabitants. In 1962 there were only 15 persons at Orobayaya. At the present time after rodent control was initiated in 1964 in San Joaquin, new cases were found in other human settlements far from the first focus such as Magdalena, La Cayoba, Chaco Lejos, Rio Negro, Fortaliza (Fig. 1).

ETIOLOGY

Junin virus is the etiologic agent of Argentine Haemorrhagic Fever and was isolated in human clinical cases independently by Parodi et al. (2) and Piroski et al. (3) in 1958-59.

Machupo virus is the etiologic agent of Bolivian Haemorrhagic Fever and the initial isolation was on May 19, 1963, in a typical clinical human case by Johnson (4). It was also isolated from the wild rodent Calomys Callosus in San Joaquin (5).



Fig. 1 Geographical distribution of Bolivian Haemorrhagic Fever outbreaks.

TABLE 1


BIOLOGICAL CHARACTERS OF MACHUPO, LATINO AND JUNIN VIRUSES


NATURAL HOSTS


Machupo & Latino Viruses


Junin Virus


Calomys Callosus


Calomys Musculinus

Calomys Laucha (Hesperomys)

Akodon Arenicus (A. Azarae)

Akodon Obscurus

Akodon ArenicoZa

Oryzomys Flavescens

WS musouzus


Cavia Sp.


EXPERIMENTAL HOSTS


Saguinus Geoffroyi

Macaca MuZata

Macaca Fascioularis

Cavia Porcella

C-13


(strain)


Cavia Porcella

Mus musculus

Calomys Musculinus


Biological properties. Intracerebral (Table 1) inoculation of infant hamsters and mice is the more adequate method for isolation of Machupo virus; both develop neurologic signs and die 6-15 days later. In low dilutions infected suckling hamsters frequently do not exhibit illness or death. The survivors appear stunted and develop antibodies. In adult hamsters and mice illness was rarely observed. Calomys callosus is the critecine rodent naturally infected with Machupo and Latino viruses in enzootic foci. No other cricetidae such as Oryzomys, Zygodontomys, Holochilus and Nectomys or Muridae as Mus musculus, Rattus rattus, Rattus norvegicus, Echimydae as Proechimys and Marsupials were positive for virus isolation.

Calomys callosus, above 9 days of age, inoculated with Machupo virus gives a "split response" (6).

In type A, occurring in 50% of inoculated animals, the animals are "immunotolerant", with persistent viraemia, little or no neutralizing and immunofluorescent antibodies, viruria, splenomegaly microcytic-hyprochromic anaemia and reduced fertility. In type B animals are "immunocompetent"; there is clearance of viraemia, presence of N, CF and immunofluorescent antibodies, minimal or no viruria, and no anaemia or splenomegaly.

In suckling Calomys, Machupo virus induces a viraemic immunotolerant infection. Latino virus produces chronic but non-tolerant infection. Apparently it only infects suckling hamsters. In the guinea-pig, Machupo virus produces little or no viraemia and there is no evidence of haemorrhagic lesions (6).

Marmosets develop anorexia, tremors, shock and die 8-20 days postinoculation. Virus multiplies in many tissues except in the brain. Histological lesions were cortical necrosis in lymph nodes, reticular hyperplasia with lymphoid depletion in the spleen.

In Rhesus monkeys, the virus causes a severe illness consisting of two clinical phases (7). After 6-7 days incubation all animals develop fever conjunctivitis, depression, anorexia, diarrhoea, clonic spasms, nasal haemorrhagic discharge, erythematous facial rash. Dehydration is maximal on 18-19th day, just before death occurring in 80% of the monkeys. In 20% of the monkeys surviving this first clinical phase, neurological signs develop after 26 to 40 days: intentional tremors, nystagmus, incoordination, paresis and coma. The pathology shows moderate to severe encephalitis with vasculitis.

In Cavia porcella, Junin virus produces a fatal disease resembling Argentine Haemorrhagic Fever in man. The animals develop fever on 5-8th day. Death occurs in hypothermic shock on the 11th to 15th day. Viraemia persists until death. The virus is located in the principal organs and is excreted with urine and saliva. Pathological findings are macroscopic and microscopic haemorrhagic lesions, in subcutaneous tissues, haemorrhagic lesions in the stomach wall, the small and large intestine, adrenals, lymph nodes, lung, peritoneum and thoracic cavity. Bone marrow shows moderate to massive necrosis. Homologous immune serum given 24 hours before or 5 days after infection, protects 55% of the guinea pigs.

Guinea pigs infected with XJ CL3 strain develop an inapparent infection detectable by the appearance of antibody. The virus is detected in spleen and lymph nodes only. Complementfixing and neutralizing antibodies appear after about 20 days and protect the guinea pigs against challenge with the pathogenic XJ strain (9). Tacaribe virus inoculated into guinea pigs induces resistance to high doses of the XJ Junin strain. When suckling Mus musculus are infected with Junin virus they develop typical viral encephalitis, mortality is 95-100%. Adult mice are resistant.

According to Sabattini et al. (10) field studies have been made indicating that Calomys musculinus is a natural host for Junin virus, exhibiting persistent viraemia with virus excretion in urine and saliva, without disease symptoms.

EPIDEMIOLOGY AND ECOLOGY

From 1958 through 1974 about 16,000 cases of Argentine Haemorrhagic Fever were diagnosed on clinical grounds. From 1965 to 1974 an epidemiological unit was established at Pergamino (3,000 km2, 75,000 inhabitants). In 1959, 3,075 patients were studied, whose diagnosis was confirmed by CF tests and a few virus isolations (1). Striking seasonal occurrence of the disease remains centered in the humid "pampa" of the Buenos Aires Province, about 200 km west of the capital city, where maize is the principal and intensively cultivated crop. The maize is harvested in April, May and June with peak incidence in May. The disease is four times more prevalent in males than in females and occurs especially in rural workers. The wild fauna of the area is composed of several species of Cricetidae and Muridae. Calomys musculinus and Calomys laucha are the principal reservoir host of Junin virus, both of them maintain a persistent and inapparent infection with prolonged viraemia and virus in saliva.

Bolivian haemorrhagic fever occurred from 1959 through 1962, on the island of Orobayaya, Province of Itenez, and in the communities surrounding San Joaquin. The population of these epidemic areas was about 4,500-5,000, there were an estimated number of 470 cases with a 30% mortality. Cases occurred chiefly among adult males who had recently been working on small farms. There also seemed to be a marked seasonal tendency with peaks in July-August. Because of the panic caused by the epidemic, most of the 600 inhabitants of Orobayaya fled to Magdalena by the middle of 1962, resulting in a sharp decrease in the incidence of cases in the Itenez Province. San Joaquin city with 3,000 people, located in Mamore province, became the principal active epidemic center until 1964. In the second semester of 1962 cases began to occur among residents who had not gone outside the town; age-sex groups were more uniformly affected, and there was evidence that Machupo virus was active within San Joaquin itself (11).

From January 1, 1963 through May 30, 1964, 778 suspected cases of haemorrhagic fever were hospitalized in San Joaquin, of whom 122 died. Of 656 survivors 336 of acute and convalescent serum samples were tested for complement fixing antibodies with Machupo virus and 282 samples were positive (84%), suggesting that 650 persons hospitalized had haemorrhagic fever with a fatality rate of 19%.

In 1963 a significant difference occurred between the south and north halves of San Joaquin with an incidence of 90% in the south. There was also a higher risk in warm houses. Mild or subclinical infections were rare. The peaks of the epidemic curve were not related to the rainy or dry season and seemed to depend on other factors.

In 1964 the northern half of the city showed more virus activity, meaning that the infection spread very slowly, needing a year for moving to the north.

We observed evidence of direct person to person transmission but this mechanism is not the common mode of transmission.

The epidemics were located in the immensely flat plain known as the "Llanos de Mojos" or "pampas" at an average altitude of 240 mt. which extends to the east of the Cordillera de los Andes. Rising about 2 mt. above the level of the pampas are the "alturas", some of which are covered by dense forest or by scattered low bushes. During the rainy season when the pampas may be flooded, these alturas can best be described as islands. The human settlements have been located on the border of the alturas. The climate is tropical. Temperature is about 25-32ºC, annual rainfall about 1500-2000 mm. The population in Itenez and Mamorb Provinces is 10,000 inhabitants. The principal activity is cattle raising and the harvest of corn, rice, yucca, bananas, cultivated in chacos on the alturas. The prevailing vegetation consists of open grassland and savanna interspersed with islands of climax and semideciduous forest.

Kuns (12) describes two types of grasslands. The "Bajios" or marsh which are low-lying grassy plains covered by a few inches of surface water during the first five months of each calendar year. Savannas occupy higher sites, namely the alturas, and are maintained by annual burning. The farms are usually located on the periphery of the fore islands overlooking the grass covered bajios, and in this ecological nest little villages and isolated settlements have been established where the epidemics of haemorrhagic fever have been observed.

In the vicinity of San Joaquin and in other special ecological settlements previously described, we find the habitat of various genera of rodents (table 2) Calomys Callosus is a pastoral species occurring in scrub forest when the canopy is sufficiently open to permit the growth of grass.

TABLE 2
HABITAT PREFERENCES OF RODENTS CAPTURED SURROUNDING SAN JOAQUIN, BENI, BOLIVIA

 

Marsh

Savanna

Fields Fallow

Brush Forest

Forest

Houses

Calomys Callosus

 

+

+

   

+

Holochilus Brasiliensis

+

 

+

 

+

 

Mus Musculus

         

+

Oryzomys Bicolor

     

+

+

+

Oryzomys Capito

     

+

+

 

Oryzomys con color

     

+

+

 

Oryzomys Subflavus

     

+

+

 

Oryzomys Migripes

       

+

 

Proechimys Guyannensis

   

+

+

+

 

Rattus Rattus

   

+

   

+

Zygodontomys Lasiurus

   

+

+

   

The study of the rodent fauna in ten localities during a survey of a large geographic area shows that Calomys prosper only on grasslands. Ectoparasites collected from wild and domestic mammals and from humans were species grouped and inoculated in suckling hamsters and mice. No machupo virus was isolated from 803 pools. Three of the most common species of bats, Myotis nigricans, Molossus major and Eumops sp. were negative for virus isolation. Only in Calomys callosus has Machupo virus been found in endemo-emidemic areas of Beni, Bolivia. Antibodies against Machupo virus in other rodents and marsupials in endemic and non endemic areas of B.H.F. were negative.

Rodent control was therefore initiated with traps and poisons: approximately 3,000 Calomys were estroyed in this manner. The rodent control program was followed in about fourteen days by a dramatic reduction in the incidence of human cases of haemorrhagic fever, first in the east part of the city and second in the entire town when the control was extended to the west sector of San Joaquin.

At the present time the epidemiologic pattern of surveillance has been extended to Yacuma and Moxos provinces of Beni. Two brigades permanently inspect the region, trap rodents and in certain circumstances use poisoned baits when the Calomys populations are increased. They check the size of spleen, notifying the authorities if they find them longer than 2 cm. Since 1971 less than fifty cases were notified in new places.

OTHER TROPICAL FEVERS

Uruma Fever. In the last months of 1954 and the first semester of 1955 a prolonged outbreak of febrile illness with devastating effects and high mortality appeared in the Okinawan colonist settlement of Uruma, a place located 80 km northeast of Santa Cruz city. Of about 400 Okinawan pioneers, 192 got sick with Uruma Fever, an attack rate of 47.6%. There were 15 deaths, mortality rate 7.8. Uruma virus was isolated, but according to Schaeffer (13), this virus was responsible for only 15% of cases.

Haemorrhagic Exanthem of Bolivia. In May of 1967 an epidemic of haemorrhagic exanthematous disease appeared in recruit soldiers that were sent from the Altiplano area (4,000 mt. above sea level) to a stationary training camp of Riberalta (183 mt. of altitude). The clinical picture was characterized by pronounced haemorrhagic manifestations: petechieae, ecchymosis and vesicles, bleeding from the gums, gastro-intestinal and conjunctival haemorrhages and hematuria. Mild temperature of 38-39ºC. After two weeks, 21 soldiers who had pronounced symptomatology were returned to active duty. There was one fatal case. Laboratory investigations were negative and the provisional diagnosis was Haemorrhagic vesicular syndrome following black fly bites (14).

Yungas Haemorrhagic Fever. In 1969 a new epidemic outbreak appeared among road workers residing in a camp in La Asunta, 150 km from La Paz. The clinical picture resembled B.H.F. but specimens were not collected. Four men died, a liver sample taken by viscerotomy, revealed pathological lesions not characteristic of yellow fever, but rather similar to those of B.H.F.

I brought a summary description of these syndromes to alert researches and to promote investigations in tropical areas of South America.

REFERENCES
1. Maiztegui, J.I. (1975) Clinical and epidemiological patterns of Argentine haemorrhagic fever. Bull. WHO 32, 567-575.
2. Parodi, A.S., et at. (1958) Sobre la etiologia del brote epidimico de Junin. Dia med. 30, 2300-2302.
3. Priosky, I., et al. (1969) Virosis hemorragica del noroeste bonaerense (endemo-epidemica, febril, enantematica y leucopénica). Orient. med. 8, 171-180.
4. Johnson, K.M., et al. (1965) Virus Isolations from Human Cases of Hemorrhagic Fever in Bolivia. Proc. Soc. exp. Biol. Med. 118, 113118.
5. Johnson, K.M., et al. (1966) Isolation of Machupo Virus from Wild Rodent Calomys Callosus. Am. J. Trop. Med. Hyg.,15, 103-106.
6. Webb, P.A. (1975) Infection of Wild and Laboratory Animals with Machupo and Latino Viruses. Bull. WHO 52, 493-499.
7. Eddy, G.A., et al. (1975) Pathogenesis of Machupo Virus Infection in Primates. Bull. WHO 52, 517-520.
8. Weissenbacher, M.C., et al. (1975) Experimental biology and pathogenesis of Junin virus infection in animals and man. Bull. WHO 52, 507-515.
9. Guerrero, L.B., et al. (1969) Inmunizacion contra la fiebre hemorragica Argentina con una cepa atenuada del virus Junin. Estudio de una cepa medificada del virus Junin. Immunizacion de cobayos. Medicina (B. Aires) 29, 1-5.
10. Sabattini, M.S., Maiztegui, J.I. (1970) Adelantos en medicina: Fiebre Hemorragica Argentina. Medicina (B.Aires) 30 supl.1, 111-128.
11. Mackenzie, R., et al. (1964) Epidemic Hemorrhagic Fever in Bolivia. Am. J. Trop. Med. Hyg.,13, 620-625.
12. Kuns, M.L. (1964) Ecological and Control Studies of Hemorrhagic Fever. Am. J. Trop. Med. Hyg.,14, 813-816.
13. Schaeffer, M., et al. (1959) Epidemic Jungle Fevers among Okinawan Colonists in the Bolivian Rain Forest. Am. J. Trop. Med. Hyg.,8, 372-396.
14. Noble, J., Valverde, L. (1973) Hemorrhagic Exanthem of Bolivia. Am. J. Epidem., 99, 123-130.

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