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Tropical Viral Infections *

Tsai, Theodore F.a; Halstead, Scott B.b

Infectious Disease in Clinical Practice: February 2001 - Volume 10 - Issue 2 - p 107-115
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This section should be of particular interest to the travel medicine physician as it reports many new manifestations of exotic viral infections, both in terms of new clinical expression or extension to new geographical territory. Included are descriptions of improved diagnostic methodologies for arboviral diseases, a discussion of safety issues involving a licensed travel medicine vaccine and a randomized placebocontrolled trial of a drug widely prescribed to reduce vascular permeability in dengue hemorrhagic fever.

a Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, PO Box 2087, Fort Collins, CO 80522, USA; and b Division of Medical Science and Technology, Office of Naval Research, 800 North Quincy Street, Arlington, VA 22217-5660, USA

* This article first appeared in Current Opinion in Infectious Diseases, 1998;11:547–553.

Correspondence to Theodore F. Tsai at above address Tel: 11 970 221 6407; fax: 11 970 221 6476; e-mail: tft1@cdc.gov

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Introduction

Abbreviations:CCHF Crimean–Congo hemorrhagic fever, CSF cerebrospinal fluid, DHF dengue hemorrhagic fever, HFRS hemorrhagic fever with renal syndrome, JE Japanese encephalitis, KFD Kyasanur Forest disease, PCR polymerase chain reaction, RSSE Russian spring–summer encephalitis, TBE tick-borne encephalitis, UAE United Arab Emirates, VEE Venezuelan equine encephalitis, YF yellow fever

The 1997–1998 literature surveyed reports a startling array of new or unusual outbreaks of tropical and exotic viral diseases: a West Nile encephalitis outbreak in the city of Bucharest, Romania (encephalitis had rarely been associated with West Nile viral infections previously); at one end of Asia Japanese encephalitis (JE) virus reached Australia, and at the other the Kathmandu Valley in Nepal, all for the first time; the first case of indigenous tick-borne encephalitis (TBE) was reported from Japan; a first-ever occurrence of Kyasanur Forest Disease (KFD) virus in Saudi Arabia; endemic Toscana viral meningitis in central Italy; the first large outbreak of Venezuelan equine encephalitis (VEE) in 20 years; Crimean–Congo hemorrhagic fever (CCHF) in the United Arab Republics; sylvatic yellow fever (YF) south of the mouth of the Amazon; and the recurrence of secondary dengue 2-related dengue hemorrhagic fever (DHF) in Cuba 20 years after primary infections with dengue type 1. The clinical manifestations of viral infections were enlarged: JE was associated with flaccid paralysis, congenital transmission of dengue was reported and a major pulmonary component described in hemorrhagic fever with renal syndrome (HFRS). New, rapid diagnostic tests are now commercially available for dengue and JE. Ultrasound promises to provide more objective measurement of vascular permeability during dengue viral infections.

Contributions to knowledge about the pathogenesis and prevention of the viral hemorrhagic fevers are found in the Editorial Comment at the beginning of this section (pp. 515–518).

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Epidemiology

West Nile encephalitis

West Nile fever is a mosquito-borne infection in Africa and Asia that produces an undifferentiated febrile illness, often with rash and arthralgias. Infrequently, the illness is complicated by neurological infection. An unusual outbreak in 1996, in the lower Danube valley of southeastern Romania and centered in the city of Bucharest, was the first major epidemic in Europe, the first occurring in an urban area and was unprecedented in producing more than 350 meningoencephalitis cases; 17 patients, all over 50 years old, died [1 ••]. In many respects, the outbreak recalled past urban outbreaks of St Louis encephalitis in the United States: the probable vector was Culex pipiens, which was highly abundant in areas of the city needing repair, and the risk of acquiring the illness increased with age. It was speculated that the virus was introduced from a local transmission cycle in the Danube delta or by infected birds migrating from Africa. Clinicians should consider West Nile infection in the differential diagnosis of acute encephalitis occurring in Europe, the Middle East, Africa and south Asia.

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Japanese encephalitis

JE, the most important cause of viral encephalitis in Asia, has recently emerged in new areas where it had not been recognized previously. In 1995, three JE cases occurred in Australian territory for the first time, in residents of the Torres Strait Islands between the Cape York Peninsula and Papua New Guinea. In subsequent years, continued transmission on some islands was demonstrated, and in 1998 two more cases occurred [2]. Among them, a fisherman who was apparently infected on the western aspect of the Cape York Peninsula was the first case to occur on the Australian mainland. In 1998, JE cases were also reported for the first time in Papua New Guinea and Irian Jaya, Indonesia [3 •• ,4 •]. It appears that we are witnessing a true disease emergence in the spread of JE in the Australoasian region. In 1995, JE was also confirmed for the first time in the Kathmandu valley of Nepal [5 •]. Although the disease has been hyperendemic in the lowland Terai, both laboratory-confirmed patients in the Kathmandu outbreak of 15 cases were elderly, suggesting a recent viral introduction.

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Tickborne encephalitis

TBE and Russian spring–summer encephalitis (RSSE) viruses, are well-recognized causes of encephalitis across the Eurasian continent, in central Europe and in eastern Siberia and northeastern China. The first RSSE case in Japan, occurring on Hokkaido, the northernmost of that country’s principal islands, was reported in 1997 [6 •]. The serologically confirmed case was in a dairy farmer’s wife who developed severe encephalitis with residual upper limb paralysis typical of RSSE. A neighbor who had a similar illness 25 years earlier retained a high antibody titer to the virus, suggesting previous unrecognized viral transmission on the island. Several dogs were also seropositive. The patient’s occupation raised the possibility of oral milkborne infection, a frequent mode of TBE transmission; however cows were seronegative. Although the usual vector of RSSE in mainland Asia is Ixodes persulcatus, Ixodes ovatus was more prevalent on the island and several RSSE viral strains were isolated from the tick and from dogs [7]. RSSE and Japanese encephalitis overlap in their geographical distributions in northern Asia and the diseases cannot be differentiated clinically; however, serology can provide a specific diagnosis.

In western and central Europe, a single species of tick, Ixodes ricinus, is the principal vector of TBE, Borrelia burgdorferi, Ehrlichia phagocytophila and several species of rickettsia. Infection with various combinations of these agents have increasingly been reported. Although a fatal case of dual Lyme disease and TBE had suggested that this combination was associated with a more severe course of illness, 12 dual infection cases reported from Slovenia followed a typical acute neurological illness consistent with TBE, with subsequent signs of Lyme borreliosis in eight [8 •]. Because both infections can produce acute meningitis and cranial and peripheral neuroradiculitis, in some cases, clinical differentiation can be difficult and the possibility of dual infection should always be considered.

An analogous situation obtains in the United States where Ixodes scapularis ticks transmit Lyme disease, babesiosis and granulocyte ehrlichiosis. In addition, experimental studies indicate that the tick can transmit Powassan virus, the North American analogue of TBE virus. A Powassan-like virus has been isolated from I. scapularis but its pathogenic potential is unknown [9]. Why a Powassan epidemic has not occurred in the northeastern United States in parallel with the spread of Lyme disease is unclear. Tick viral infection rates are 10–100-fold lower than are borrelia infection rates, which in turn may be explained by the brief viremia of infected rodent hosts compared with their chronic borrelial infection. Numerous tickborne pathogenic agents can potentially be transmitted in the same geographical location, and clinicians should remain open to the possibility of dual or multiple concomitant infection in patients with a history of tick exposure.

Another novel flavivirus, related to KFD virus in the TBE group, was recently isolated from blood of ill abattoir workers in Saudi Arabia [10 ••]. The patients were acutely ill with fever, myalgias, and vomiting, and two patients developed a morbilliform rash. Purpuric lesions, melena, and signs of a bleeding diathesis were observed in one case, and one patient had clinical encephalitis. Leucopenia, thrombocytopenia, elevated liver enzymes and creatine phosphokinase were recorded in most cases. The virus has not been fully characterized but its genomic sequence suggests a relationship to KFD virus, which has previously been recognized only in areas of Karnataka State, India. Unexplained KFD viral antibodies previously observed in northwestern India, however, suggests the possibility of an unrecognized sheep, livestock or tick-related zoonosis transmitted in middle Asia.

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Toscana meningoencephalitis

Sandfly-transmitted phleboviruses cause brief non-specific febrile illnesses (sandfly fever) in Africa, Asia and Europe, especially in the Mediterranean littoral. Sandfly-borne Toscana virus has become recognized as a frequent cause of aseptic meningitis or meningoencephalitis in Italy, Spain, Portugal, Egypt, southern France, Greece and Cyprus, often occurring in tourists. Recent studies have shown that the infection is endemic in central Italy (Siena), and that the virus is the most common identifiable cause of hospitalized acute aseptic meningitis or encephalitis in children, accounting for 24% of cases throughout the year and 80% in the summer [11 •• ,12]. The illness usually produced acute aseptic meningitis, although some cases had clinical encephalitis; the virus was isolated from the cerebrospinal fluid (CSF) in two out of 14 cases. Rapid and sensitive laboratory diagnosis is provided by polymerase chain reaction (PCR) examination of the CSF. In another study [13 •], 56 out of 106 summertime meningoencephalitis cases (53%) in adults and children were diagnosed in this way. Tourists travelling to the Mediterranean in the summer should be made aware of this and other sandfly-borne infections, and should be advised to use repellents and other personal protective measures. Sandflies are smaller and peskier than mosquitoes and can penetrate ordinary window screens.

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Venezuelan equine encephalitis

Mosquito-borne VEE occurs in two forms: in extensive outbreaks of human and horse cases caused by epidemic strains; and in a sylvatic form, in which antigenically distinguishable sylvatic strains are transmitted in cryptic foci but rarely to humans and horses. In 1995, the first major outbreak of VEE in 22 years occurred in northern Colombia and Venezuela, leading to an estimated 75 000 human cases, 300 of which were fatal [14 ••]. An increased rate of spontaneous abortion was observed in the epidemic area, confirming previous observations that the virus is teratogenic. Heavy rains and the emergence of an epidemic viral strain from a sylvatic reservoir probably brought on the outbreak. Recent outbreaks have occurred in politically unstable areas that are not typical tourist destinations, and some forewarning of epidemic activity is often available because of the considerable disease toll in animals. Travellers who cannot avoid an area with active transmission should use precautions against mosquitoes.

Few human cases caused by sylvatic strains of VEE virus have been reported, and those have occurred principally in soldiers or others venturing into remote locations. A sylvatic VEE viral strain (I-D) was shown to be the cause of 3% of undifferentiated febrile illnesses in persons presenting to clinics in the Peruvian Amazon basin city of Iquitos, the first reported association of this viral strain with human disease in Peru [15].

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O’nyong-nyong

The only arbovirus thought to be transmitted by anopheline species, presumably enzootic in eastern and southern Africa and responsible for a large human epidemic in 1959–1961, O’nyong-nyong fever again struck east Africa, this time southwestern Uganda in June–August, 1996 [16]. Symptoms and signs included the sudden onset of high fever with crippling arthritis, primarily of the large joints. Cases tended to cluster in families with attack rates as high as 60–80%.

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Crimean–Congo hemorrhagic fever

An unusual cluster of highly fatal CCHF cases among butchers and livestock handlers was observed in the United Arab Emirates (UAE) in November, 1994 [17–19]. CCHF is an acute viral hemorrhagic fever distributed from Africa to central Russia, caused by a nairovirus of the family Bunyaviridae and transmitted to humans by ticks. Scattered outbreaks of disease have been reported predominantly from rural areas in west Asia. CCHF may result in high rates of hospital transmission. As described by Khan et al. [17], 35 suspected cases of CCHF were hospitalized between August 1994 and March 1995, fortunately with no transmission to hospital personnel. The introduction of IgM capture antibody tests and the direct detection of antigen in blood samples increased the early diagnosis of cases. Normally, one third of CCHF patients may die before mounting an antibody response. Ribivirin is effective in treating CCHF, so prompt diagnosis of cases is essential.

During the outbreak, ruminants had been imported into the UAE predominantly from Somalia and Iran for processing by several abattoirs located in Oman, Qatar or Dubai. Livestock market employees, abattoir workers and animal skin processors accounted for about one half of cases. Nineteen of 268 animals sampled in the abattoir were positive for CCHF virus antibodies, including 12 ruminants from Somalia and Iran. In addition, ticks taken from Somali cattle and goats were positive for CCHF viral antigen. Normally, it would have been assumed that the UAE had experienced a single-source importation of virus from a zoonotic outbreak, probably in Somalia. Unexpectedly, a phylogenetic analysis of partial small segment nucleotide sequences from four tick and five human viral samples showed that one cluster of viruses was of Pakistan/Madagascar lineage, but another imported virus was related to CCHF viruses from Nigeria. In other words, CCHF viruses causing the 1994–1995 outbreak were imported many times. Large and widely dispersed reservoirs of CCHF are predicted because the UAE has reported four or more cases of CCHF annually for some years. A small cluster of CCHF cases was also reported from Saudi Arabia during the same time period [20]. It was recommended that all imported ruminants be dipped to kill ticks and quarantined for 2 weeks to permit the resolution of CCHF viremia.

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Yellow fever

An unusual outbreak of sylvatic YF occurred in 1993–1994 in the state of Maranhao, Brazil [21]. Citing reduced YF vaccination coverage, the authors report 74 cases diagnosed clinically, virologically or serologically in 1993 and another 16 cases in 1994. Thirteen fatal cases were recorded. YF viruses circulate in at least two genotypes and one sub-genotype [22]. E Type I viruses are zoonotically transmitted in central Africa between subhuman primates and occasionally to humans by species of the genus Aedes. E Type IIA viruses are zoonotic in West Africa circulating in subhuman primates, but possessing the ability to be transmitted in an urban cycle between humans by Aedes aegypti. E Type IIB viruses are zoonotic in South America and are transmitted among subhuman primates and occasionally to humans by species of the genus Haemagogus. In the Maranhao outbreak, 17 YF virus strains were isolated from Haemagogus mosquitoes. Earlier this century, sylvatic YF was reported in eastern and southern Brazil but an outbreak of jungle YF has never previously occurred in Maranhao. YF in Maranhao may have occurred in an ecological zone where human YF cases could be exposed to Ae. aegypti in rural communities, posing an imminent threat of epidemic urban YF.

A fatal case of YF was reported in a 45-year-old American man who toured rain forests for 9 days along the Rio Negro and Amazon Rivers in 1996 [23 • ?]. The patient had not received yellow fever vaccine, partly due to the inconvenience of attending a health department immunization clinic located 25 miles distant.

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Dengue

Certainly the most important dengue activity in recent history has been the sharp outbreak of DHF, in January–August 1997, in Santiago de Cuba [24 ••]. Since World War II, Cuba has been involved in only three dengue virus introductions, dengue 1 in 1977–1979, dengue 2 in 1981, and dengue 2 in 1997. This outbreak, involving 3000 hospitalized persons, 205 with DHF and 12 deaths, was caused by a dengue 2 virus belonging to the Jamaica 1981 genotype, a virus of recent southeast Asia origin, which has repeatedly been associated with DHF in the American tropics [25 ••]. The youngest DHF patient was 17 years old, and virtually all hospital-diagnosed DHF cases experienced secondary-type dengue antibody responses. This outbreak provides the first evidence that DHF may occur at virtually any interval after a primary dengue infection. Only the 1977–1979 dengue 1 epidemic could have provided the antibody responsible for modifying 1997 dengue 2 infections from mild to severe. Of great importance was the fact that the severe and fatal clinical syndrome seen in adult patients was identical to the increased vascular permeability syndrome described in children in southeast Asia. No patients were observed who had severe bleeding in the absence of increased vascular permeability.

Each year dengue increases as a travel medicine problem. In 1996, 43 laboratory-confirmed cases of dengue in travellers returning to the USA were reported to the Centers for Disease Control [26]. The most frequent travel destinations resulting in dengue infections were the Caribbean and southeast Asia. It is not known what proportion of total cases are not reported. Many travel clinics, however, report a rising incidence of dengue infection among travellers [27] or in expatriates with prolonged residence overseas [28]. Of interest, US military personnel experienced extremely high attack rates of dengue infection shortly after being deployed to policing operations on Haiti in 1994 [29]. Dengue types 1, 2 and 4 were recovered.

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Clinical features

Viral encephalitis

JE and other flaviviral encephalitides cause disseminated infection of the brain and spinal cord and it has been known that some cases can present with lower motor neurone paralysis alone, without encephalopathic changes. Four decades ago, when epidemics of arboviral encephalitis and poliomyelitis frequently overlapped, it was common wisdom that the differentiation of individual cases on clinical features alone was often impossible. Recent reports from India and Vietnam of JE cases presenting with cranial nerve, limb or urinary bladder paralysis, suggesting acute olio or Guillain–Barré syndrome, are reminders that JE does not always produce an encephalitis syndrome [30 •• ,31 ••].

Numerous reports of brain imaging studies in JE patients have been published in recent years. Magnetic resonance imaging is more sensitive than computed tomography in disclosing multiple lesions involving the cerebrum, cerebellum, brainstem, basal ganglia and especially the thalamus, which often appears hemorrhagic [32 ••]. Single photon emission computed tomography was helpful in differentiating JE patients, who had a marked increase in 99mTc hexamethylpropyleaneamine oxime uptake, from patients with encephalitis due to other causes [33 •].

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Dengue

From reports to the WHO, it may be estimated that dengue viruses are endemic in countries or portions of countries with a total population of 2.5 billion, 1 billion of whom are children under 15 years of age. From estimates of dengue antibody prevalence, annual infection rates of between 5 and 10% can be predicted [34]. Considering infections only in children in countries with multiple viruses circulating, annual dengue infections could involve 50–100 million individuals. Only in DHF-endemic countries are dengue infections in children clinically apparent. Adults bear the largest burden of dengue illness because nearly all dengue infections in adults are overt. Without better global serological data it is difficult to estimate the annual infection rates in adults. Even when a relatively small percentage of adults are infected, however, because of their high clinical attack rates very large numbers seek medical attention. Furthermore, dengue infections in adults are prone to complications. In Bangkok, where dengue infection rates have been declining for two decades, for the first time this century large numbers of adults are susceptible, and dengue is increasing as an infectious disease problem. In a recent report, dengue infections were described in three women before, during and after birth [35]. One patient with severe preeclampsia requried a cesarean delivery to produce a normal infant. For other patients conservative management resulted in good outcome. In Malaysia, two mothers had dengue 2 virus infections shortly before birth with apparent congenital transmission [36]. Dengue infection in one mother resulted in the worsening of her eclampsia and the delivery of a male infant with respiratory distress, uncontrollable intracerebral hemorrhage and fatal outcome. A second mother delivered a female infant who developed fever and thrombocytopenia immediately after birth without other complications and in convalescence developed IgM dengue antibodies.

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Hemorrhagic fever with renal syndrome

HFRS is a disease complex caused by four closely related viruses, occurring across Asia and involving most of Scandinavia and eastern Europe. A more remotely related hantavirus, Sin Nombre, is found in the western hemisphere, where it causes the hantaviral pulmonary syndrome. The two groups of hantaviruses seem to have evolved separately as parasites of various rodent species to cause quite different human disease syndromes. Swedish workers have studied pulmonary function in 13 patients hospitalized with nephropathia epidemica, the European variant of HFRS [36]. As compared with reference values, diffusion capacity for carbon monoxide was decreased. Four out of 11 patients had reduced partial pressure of oxygen and three patients had interstitial infiltrates or pleural effusion. These changes are best explained as being caused by an alveolocapillary lesion. This is the first evidence that hantavirus syndromes may share pulmonary pathology.

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Leptospirosis simulating Venezuelan hemorrhagic fever

Four years ago, a major outbreak of disease in children and adults characterized by pulmonary hemorrhages and occurring in rural areas of Nicaragua was initially confused as an outbreak of DHF [37]. In 1993, Australian physicians admitted to hospital a 48-year-old Ghanaian man who presented with severe jaundice and gastrointestinal hemorrhage [38]. Rather naturally the differential diagnosis included Lassa fever and Ebola with consequent panic among the hospital staff. Leptospira bataviae was isolated from this patient.

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Diagnostic Approaches

Viral encephalitis

Efforts to improve the laboratory diagnosis of arboviral encephalitis, like other central nervous system infections, have moved towards evaluating PCR as a means to provide a rapid diagnosis. Although PCR assays have been described to detect a broad range of neurotropic flaviviruses (e.g. JE, St Louis encephalitis and TBE viruses), alpha-viruses (e.g. eastern, western and VEE viruses) and various bunyaviruses (e.g. Toscana and California serogroup viruses), few clinical evaluations have been reported [39–41]. Previous studies of Toscana encephalitis (see below) and recent studies of JE cases suggest the utility of testing serum as well as the CSF, but results have been mixed and it is still too early to know what role PCR will eventually play in the routine laboratory diagnosis of these infections. At the other end of the spectrum of complexity and equipment requirements, simple, rapid and relatively inexpensive immunoblot tests for JE and dengue have undergone preliminary field evaluations that indicate a high correlation with standard enzyme-linked immunosorbent assay results [42 •]. These immunochromatographic tests are configured into a small folder (similar in appearance and size to an occult blood-test folder) and could make specific diagnostic testing available to remote locations as well as to physicians’ offices or small hospitals caring for returned travellers in developed countries.

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Dengue

An important problem in the diagnosis and management of DHF has been the early recognition of increased vascular permeability and the estimation of the amount of fluid loss from the circulatory system. Recently, ultra-sound has been applied to detect pleural or pericardial effusions or ascites. Indonesian workers have been in the forefront of applying these diagnostic techniques. Setiawan et al. [43] describe ultrasound findings in 148 virologically or serologically confirmed ‘DHF’ cases, allegedly conforming to the WHO diagnostic criteria and classification system. Pleural effusion on the right or right and left sides, ascites and gallbladder wall thickening were observed in 95% of 75 cases with hypotension or shock. Of the 73 milder cases, positive ultrasound findings were observed in only 34% of cases. Although patients had daily ultrasound examinations during hospitalization, the authors failed to state when in the course of the illness effusions could be detected. Furthermore, the apparent failure to detect vascular permeability in the majority of ‘DHF’ patients graded as I or II constitutes evidence that patients were incorrectly classified. Clinically significant hypovolemia is required to make a diagnosis of DHF. Although intriguing, that study fails to clarify the sensitivity and specificity of ultrasound for the early diagnosis and management of fluid losses during DHF.

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Prevention

Japanese encephalitis

The inactivated mouse brain-derived JE vaccine has been recommended only for travellers at high risk of exposure, because numerous allergic reactions were reported in preliminary observations. Two studies of approximately 110 000 [44 ••] and 35 000 [45 •] vaccinees, respectively, have disclosed rates of urticaria/angioedema between 0.6 and 2 per 1000. Numerous vaccine lots were implicated. Although the majority of cases were self-limited, 10 out of 68 Danish cases were hospitalized for monitoring and therapy. A remarkable and consistent feature of the allergic reactions was their delayed onset, 24–48 h after the first dose and 96 h after the second dose. As a practical matter, this observation has led to a recommendation to delay travelling until 7 days after vaccination, to avoid the onset of a potentially life-threatening reaction where medical care is inaccessible. The pathogenesis of the reactions is not well understood, but some cases have been associated with allergy to gelatin, which is a vaccine stabilizer [46 •]. Anecdotal cases of acute disseminated encephalomyelitis temporally associated with JE vaccination continue to be reported [47]. Although the incidence of this potential complication has been estimated to be as high as one per 50 000 vaccinees, controlled studies have not been done. These observations underscore that JE vaccine should not be given routinely to travellers to Asia, and that travellers should be offered the vaccine only after evaluating their risk factors for acquiring the disease.

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General protective measures against mosquitoes

Specific protection against arboviral infections with vaccines is available only for YE, JE and TBE, and chemical repellents are the principal means of protection against dengue and important vector-borne parasitic infections. N-N-diethyl 3-methylbenzamide is the most effective of the marketed repellents, but it has been associated with rare but serious neurological side-effects. Permethrin, a repellent and insecticide, is highly effective when applied to clothing, and various other commercially available lotions and repellents have various degrees of repellency. A timely review was recently published [48 ••].

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Treatment

Dengue

New and severe illnesses invite the application of new treatment modalities. The search for a ‘magic bullet’ has characterized the entire history of DHF. Among the compounds being touted as a specific for reducing vascular permeability is AC-17 (carbazochrome sodium sulfonate). Despite the absence of contemporary pharmaceutical rationale, this drug is widely sold in southeast Asia for the treatment of DHF. A randomized, placebo-controlled clinical treatment trial [49] of AC-17 was carried out in 95 Thai children who were stratified by age and sex. The drug was administered as recommended by the manufacturer. All patients, experimental and control, were given supportive intravenous fluids as indicated by careful physiological monitoring. Patients were admitted in the early, premonitory stage of DHF. In the AC-17 group, pleural effusion was detected on chest X-ray in 31% of patients compared with 28% of placebo controls. The incidence of shock in the experimental and control groups was 8.9 and 6.0%, respectively. It was concluded that AC-17 does not reduce vascular permeability and has no place in the treatment of DHF and dengue shock syndrome.

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Conclusion

The events described in this section occurred over the past 4–5 years. Taken collectively, they constitute a remarkable record of infectious disease activity, including obvious extension from an area of known endemicity to a completely new part of the world. It would be foolish to attempt to relate all of these occurrences to El Niño. Some of these emergence events may, however, well be caused by unusual rainfall or an increase in ambient temperature. Others probably reflect the simple fact that as global commerce grows, more and more species of all kinds are transported between countries.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

of special interest

•• of outstanding interest

1. Tsai TF, Popovici F, Cernescu C, Campbell GL, Nedlelcu NI. West Nile encephalitis epidemic in Southeastern Romania. Lancet 1998; 352:767–771.•• A report of a unique outbreak and a good example of disease emergence.
2. Anonymous. Japanese encephalitis on the Australian mainland. Communicable Dis Intell 1998;22:80.
3. Mackenzie JS. Japanese encephalitis: an example of an emerging disease. Aust Epidemiologist 1998; 5:1–5.•• A scholarly review of the apparent spread of JE to Australia.
4. Spicer PE. Japanese encephalitis in Western Irian Jaya. J Travel Med 1997; 4:146–147. Few JE cases have ever been reported from Indonesia—this is the first from the easternmost island of Irian Jaya.
5. Zimmerman MD, McNair Scott R, Vaughn DW, Rajbhandari S, Nisalak A, Shrestha P. An outbreak of Japanese encephalitis in Kathmandu, Nepal. Am J Trop Med Hyg 1997; 57:283–284.•• The first recognized JE cases in the Kathmandu valley raise the question of whether the virus has spread within Nepal.
6. Takashima I, Morita K, Chiba M, Hayasaka D, Sato T, Takezawa C et al. A case of tick-borne encephalitis in Japan and isolation of the virus. J Clin Microbiol 1997; 35:1943–1947. Details of the first case of RSSE in Japan—an example of recent recognition but not recent introduction of disease in a new area.
7. Takeda T, Ito T, Chiba M, Takahashi K, Niioka T, Takashima I. Isolation of tick-borne encephalitis virus from Ixodes ovatus (Acari: Ixodidae) in Japan. J Med Entomol 1998; 35:227–231.
8. Cimperman J, Maraspin V, Lotric-Furlan S, Ruzic-Sablijic E, Avsic-Zupanc T, Picken RN, Strle F. Concomitant infection with tick-borne encephalitis virus and Borrelia burgdorferi sensu lato in patients with acute meningitis or meningoencephalitis. Infection 1997; 26:160–164. Clinical complications of dual tickborne infections deserve greater scrutiny—this series of 338 patients describes 12 with dual TBE and borrelia infection.
9. Telford SR, Armstrong PM, Katavolos P, Foppa I, Garcia ASO, Wilson ML, Spielman A. A new tick-borne encephalitis-like virus infecting New England deer ticks. Emerg Infect Dis 1997; 3:165–170.
10. Zaki AM. Isolation of a flavivirus related to the tick-borne encephalitis complex from human cases in Saudi Arabia. Trans R Soc Trop Med Hyg 1997; 91:179–181.•• The circumstances of this outbreak in an abattoir initially suggested CCHF, but it appears to be a new disease caused by a novel virus.
11. Braito A, Corbisiero R, Corradini S, Fiorentini C, Ciufolini MG. Toscana virus infections of the central nervous system in children: a report of 14 cases. J Pediatr 1998; 132:144–148.•• A revealing prospective study showing that this sandfly-borne infection is the most common cause of acute summertime neurological infection in central Italy.
12. Braito A, Corbisero R, Corradini S, Marchi B, Sancasciani N, Fiorentini C, Ciufolini MG. Evidence of Toscana virus infections without central nervous system involvement: a serological study. Eur J Epidemiol 1997; 13:761–764.
13. Valassina M, Cuppone AM, Bianchi S, Santini L, Cusi MG. Evidence of Toscana virus variants circulating in Tuscany, Italy, during the summers of 1995 to 1997. J Clin Microbiol 1998; 36:2103–2104. This study highlights the utility of PCR in the diagnosis of this infection.
14. Rivas F, Dias LA, Cardenas VM, Daza E, Bruzon L, Alcala A et al. Epidemic Venezuelan equine encephalitis in La Guajira, Colombia, 1995. J Infect Dis 1997; 175:828–832.•• VEE is among the most explosive of epidemic diseases, as exemplified by the most recent outbreak. The teratogenic potential of the infection and lack of person-to-person spread were shown in this investigation.
15. Watts DM, Callahan J, Rossi C, Oberste S, Roehrig JT, Wooster MT et al. Venezuelan equine encephalitis febrile cases among humans in the Peruvian Amazon River region. Am J Trop Med Hyg 1998; 58:35–40.
16. Rwaguma EB, Luttwama JJ, Sempala SDK, Kiwanuka N, Kamugisha J, Okwara S et al. Emergence of epidemic O’nyong-nyong fever in Southwestern Uganda after an absence of 35 years. Emerg Infect Dis 1997; 3:77.
17. Khan AS, Maukpin GO, Rollin PE, Noor AM, Shurie HH, Shalabi AG et al. An outbreak of Crimean–Congo hemorrhagic fever in the United Arab Emirates, 1994–1995. Am J Trop Med Hyg 1997; 57:519–525.
18. Schwarz TF, Nsanze H, Ameen AM. Clinical features of Crimean–Congo haemorrhagic fever in the United Arab Emirates. Infection 1997; 25:364–367.
19. Rodriguez LL, Maupin GO, Ksiazek TG, Rollin PE, Khan AS, Schwarz TF et al. Molecular investigation of a multisource outbreak of Crimean–Congo hemorrhagic fever in the United Arab Emirates. Am J Trop Med Hyg 1997; 57:512–518.
20. Hassanein KM, el-Azazy OM, Yousef HM. Detection of Crimean–Congo haemorrhagic fever virus antibodies in humans and imported livestock in Saudi Arabia. Trans R Soc Trop Med Hyg 1997; 91:536–537.
21. Vasconcelos PF, Rodrigues SG, Degallier N, Moraes MA, Travassos da Rosa JF, Travassos da Rosa ES et al. An epidemic of sylvatic yellow fever in the southeast region of Maranhao State, Brazil, 1993–1994: epidemiologic and entomologic findings. Am J Trop Med Hyg 1997; 57:132–137.
22. Chang GJ, Cropp BC, Kinney RM, Trent DW, Gubler DJ. Nucleotide sequence variation of the envelope protein gene identifies two distinct genotypes of yellow fever virus. J Virol 1995; 69:5773–5780.
23. McFarland JM, Baddour LM, Nelson JE, Elkins SK, Craven RB, Cropp BC et al. Imported yellow fever in a United States citizen. Clin Infect Dis 1997; 25:1143–1147. A cautionary tale to be taken to heart by tourists and their physicians. A valid yellow fever vaccination is required for travel to South America. Because of the limited distribution of immunization clinics, yellow fever vaccination requires effort and advanced planning.
24. Kouri G, Guzman MG, Valdes L, Carbonet I, del Rosario D, Vazquez S et al. Reemergence of dengue in Cuba: a 1997 epidemic in Santiago de Cuba. Emerg Infect Dis 1998; 4:89–92.•• A Jamaica-1981 genotype dengue 2 virus was introduced into Cuba probably late in 1996. Although 10 000 dengue ‘cases’ were reported, on serological testing 3000 were dengue etiologically. Nearly all observed disease was caused by secondary dengue infections, primary infections in children were silent.
25. Rico-Hesse R, Harrison LM, Salas RA, Tovar D, Nisalak A, Ramos C et al. Origins of dengue type 2 viruses associated with increased pathogenicity in the Americas. Virology 1997; 230:244–251.•• A large collection of dengue 2 viruses were sequenced at the E-NS-1 junction. They fall into four groups, the distantly related viruses recovered from African monkeys, a group of viruses first recognized in the Americas and not associated with DHF, and two closely related groups of viruses of recent southeast Asian origin, but with many strains recovered from recent dengue and DHF outbreaks in the Americas.
26. Imported dengue—United States, 1996. MMWR 1998;47:544–547.
27. Jelinek T, Dobler G, Holscheer M, Loscher T, Northdurft HD. Prevalence of infection with dengue virus among international travelers. Arch Intern Med 1997; 157:2367–2370.
28. Janisch T, Preiser W, Berger A, Niedrig M, Mikulicz U, Thoma B, Doerr HW. Emerging viral pathogens in long-term expatriates (II): dengue virus. Trop Med Int Health 1997; 2:934–940.
29. Trofa AF, De Fraites RF, Smoak BL, Kanesa-thasan N, King AD, Burrows JM et al. Dengue fever in US military personnel in Haiti. JAMA 1997; 277:1546–1548.
30. Solomon T, Kneen R, Dung NM, Khanh VC, Thuy TTN, Ha DQ et al. Poliomyelitis-like illness due to Japanese encephalitis virus. Lancet 1998; 351:1094–1097.•• Acute flaccid paralysis surveillance in the polio eradication effort disclosed several Japanese encephalitis cases that could not be differentiated clinically from polio and sporadic Guillain–Barré syndrome.
31. Misra UK, Kalita J. Anterior horn cells are also involved in Japanese encephalitis. Acta Neurol Scand 1997; 96:114–117.•• Weakness and residual muscular atrophy due to lower motor neurone involvement are well documented by electromyography and other studies.
32. Kumar S, Misra UK, Kalita J, Salwani V, Gupta RK, Gujral R. MRI in Japanese encephalitis. Neuroradiology 1997; 39:180–184.•• The distribution and time course of magnetic resonance imaging lesions in JE cases are described, underscoring the prediction for thalamic hemorrhages.
33. Kimura K, Dosaka A, Hashimoto Y, Yasunaga T, Uchino M, Ando M. Single photon emission CT findings in acute Japanese encephalitis. Am J Neuroradiol 1997; 18:465–469. Single photon emission computed tomography imaging was helpful in differentiating JE from other causes of encephalitis and may yield clues to its pathogenesis.
34. Bunyavejchevin S, Tanawattancharoen S, Taechakraichana N, Thisyakorn U, Tannirandorn Y, Limpaphayom K. Dengue hemorrhagic fever during pregnancy: antepartum, intrapartum and postpartum management. J Obstet Gynaecol Res 1997; 23:445–448.
35. Chye JK, Lim CT, Ng KB, George R, Lam SK. Vertical transmission of dengue. Clin Infect Dis 1997; 25:1374–1377.
36. Linderholm M, Sandstrum T, Rinnstrom O, Groth S, Blomberg A, Tarnvik A. Impaired pulmonary function in patients with hemorrhagic fever with renal syndrome. Clin Infect Dis 1997; 25:1084–1089.
37. Zaki S, Shieh WJ. Leptospirosis associated with outbreak of acute febrile illness and pulmonary haemorrhage, Nicaragua, 1995. The Epidemic Working Group at Ministry of Health in Nicaragua. Lancet 1996; 347:535–536.
38. Heron LG, Reiss-Levy EA, Jacques TC, Dickeson DJ, Smythe LD, Sorrell TC. Leptospirosis presenting as a haemorrhagic fever in a traveller from Africa. Med J Aust 1997; 167:477–479.
39. Kuno G. Universal diagnostic RT±PCR protocol for arboviruses. J Virol Methods 1998; 72:27–41.
40. Pfeffer M, Proebster B, Kinney RM, Kaaden OR. Genus-specific detection of alphaviruses by a semi-nested reverse transcription–polymerase chain reaction. Am J Trop Med Hyg 1997; 7:709–718.
41. Fang MY, Chen HS, Chen CH, Tian XD, Jiang LH, Peng YF et al. Detection of flaviviruses by reverse transcriptase– polymerase chain reaction with the universal primer set. Microbiol Immunol 1997; 41:209–213.
42. Solomon T, Thao LTT, Dung NM, Kneen R, Hung NT, Nisalak A et al. Rapid diagnosis of Japanese encephalitis by using an immunoglobulin M dot enzyme immunoassay. J Clin Microbiol 1998; 36:2030–2034. Immunochromatographic test kits for various infections are being developed and may soon make laboratory diagnosis of tropical infections available in remote locations.
43. Setiawan MW, Samsi TK, Wuler H, Sugianto D, Pool TN. Dengue haemorrhagic fever: ultrasound as an aid to predict the severity of the disease. Pediatr Radiol 1998; 28:1–4.
44. Plesner AM, Ronne T. Allergic mucocutaneous reactions to Japanese encephalitis vaccine. Vaccine 1997; 15:1239–1243.•• A review of the Danish State Serum Institut database over 13 years implicates JE vaccine in 62 allergic events. Numerous vaccine lots were involved.
45. Berg SB, Mitchell BS, Hanson RK, Olafson RP, Williams RP, Tueller JE et al. Systemic reactions in US Marine Corps personnel who received Japanese encephalitis vaccine. J Infect Dis 1997; 24:265–266. This prospective study of 35 000 Navy personnel and dependents provides the best data on the incidence of hypersensitivity events associated with JE vaccine.
46. Sakaguchi M, Yoshida M, Kuroda W, Harayama O, Matsunaga Y, Inouye S. Systemic immediate-type reactions to gelatin included in Japanese encephalitis vaccines. Vaccine 1998; 15:121–122. Gelatin allergy is now thought to be the cause of hypersensitivity to measles, varicella, and possibly JE vaccine.
47. Fukuda H, Umehara F, Kawahigashi N, Suehara M, Osame M. Acute disseminated myelitis after Japanese B vaccination. J Neurol Sci 1997; 148:113–115.
48. Fradin MS. Mosquitoes and mosquito repellents. Ann Intern Med 1998; 128:931–940. •• A thorough review of repellent safety and efficacy.
49. Tassniyom S, Vasanawathana S, Shiensiri T, Nisalak A, Chirawatkul A. Failure of carbazochrome sodium sulfonate (AC-17) to prevent dengue vascular permeability of shock: a randomized, controlled trial. J Pediatr 1997; 131:525–528.
© 2001 Lippincott Williams & Wilkins, Inc.