Hemorrhagic Fever with Renal Syndrome: Past Accomplishments and Future Challenges

James. W. LeDuc, James E. Childs, Greg E. Glass, and A. J. Watson *

Hemorrhagic fever with renal syndrome (HFRS) is a disease which has not gained widespread recognition among clinicians in the United States, but which is, in fact, of considerable significance in many parts of the world. This syndrome is caused by a newly recognized genus of viruses, the genus Hantavirus, of the family Bunyaviridae 1 , and these viruses are of special interest, as they clearly cause acute renal failure, and there is growing evidence that they may predispose a person to subsequent development of chronic renal disease.

Human disease due to hantaviral infections first came to the attention of Western medicine during the Korean Conflict, when a mysterious “new” disease, Korean hemorrhagic fever, was seen among the United Nations forces. At that time, over 2,000 U.S. troops were infected, and many deaths occurred 2 . In spite of intense investigations by some of the most prominent medical scientists of the era, the causative agent was not identified, and it wasn't until 1976, just over a decade ago, that the etiologic agent was finally discovered 3 .

*  

James W. LeDuc is with the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Ft. Detrick, Frederick, Maryland; James E. Childs and Greg E. Glass are with the Department of Immunology and Infectious Diseases, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland; and A. J. Watson is with the Division of Nephrology, Johns Hopkins University, Baltimore, Maryland. Correspondence to James W. LeDuc, Disease Assessment Division, USAMRIID, Ft. Detrick, Frederick, MD 21701-5011. The views of the author(s) do not purport to reflect the positions of the Department of the Army or the Department of Defense, who have approved this report for public release with unlimited distribution.



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Epidemiology in Military and Veteran Populations: Proceedings of the Second Biennial Conference March 7, 1990 Hemorrhagic Fever with Renal Syndrome: Past Accomplishments and Future Challenges James. W. LeDuc, James E. Childs, Greg E. Glass, and A. J. Watson * Hemorrhagic fever with renal syndrome (HFRS) is a disease which has not gained widespread recognition among clinicians in the United States, but which is, in fact, of considerable significance in many parts of the world. This syndrome is caused by a newly recognized genus of viruses, the genus Hantavirus, of the family Bunyaviridae 1 , and these viruses are of special interest, as they clearly cause acute renal failure, and there is growing evidence that they may predispose a person to subsequent development of chronic renal disease. Human disease due to hantaviral infections first came to the attention of Western medicine during the Korean Conflict, when a mysterious “new” disease, Korean hemorrhagic fever, was seen among the United Nations forces. At that time, over 2,000 U.S. troops were infected, and many deaths occurred 2 . In spite of intense investigations by some of the most prominent medical scientists of the era, the causative agent was not identified, and it wasn't until 1976, just over a decade ago, that the etiologic agent was finally discovered 3 . *   James W. LeDuc is with the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Ft. Detrick, Frederick, Maryland; James E. Childs and Greg E. Glass are with the Department of Immunology and Infectious Diseases, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland; and A. J. Watson is with the Division of Nephrology, Johns Hopkins University, Baltimore, Maryland. Correspondence to James W. LeDuc, Disease Assessment Division, USAMRIID, Ft. Detrick, Frederick, MD 21701-5011. The views of the author(s) do not purport to reflect the positions of the Department of the Army or the Department of Defense, who have approved this report for public release with unlimited distribution.

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Epidemiology in Military and Veteran Populations: Proceedings of the Second Biennial Conference March 7, 1990 Dr. Ho Wang Lee and collaborators, working in Seoul, Korea, were the first to isolate the virus that causes Korean hemorrhagic fever. They named it “Hantaan virus” in recognition of the Hantaan River, which transsects the endemic region of Korea near the demilitarized zone. The virus was isolated from lung tissues of the striped field mouse, Apodemus agrarius, and this species is now recognized as the major rodent host of the virus 3 . Within a year or two of its initial isolation, Hantaan virus was adapted to grow in cell culture, which allowed for development of a serologic test 4 . The availability of both the virus and a serologic test allowed experimental infection of natural rodent hosts to be undertaken, and through these studies, one of the key characteristics of the hantaviruses was discovered. A brief viremia follows experimental inoculation of seronegative Apodemus agrarius. Subsequently, hantaviral antigen is detectable for weeks to months in many major organs, but, most importantly, infectious virus is shed in saliva, feces, and especially urine, perhaps for the duration of the rodent's life. This virus shedding occurs in spite of the presence of both indirect immunofluorescent antibody (IFA) and neutralizing antibody in serum 5 . Thus, the infected rodent becomes a persistent source of infectious virus, and we suspect that it is through aerosolized virus that is excreted in infected rodent urine and feces that most human infections occur. This persistent shedding of infectious virus by chronically infected rodents appears to be a general characteristic of all the hantaviruses and their rodent hosts, and is a critical aspect in the epidemiology of this group of viruses 6 . Acute hantaviral infections cause a wide spectrum of illness, which typically includes abrupt onset, fever, renal dysfunction, and often hemorrhagic manifestations 7 . The name hemorrhagic fever with renal syndrome has been proposed by the World Health Organization to cover all human disease due to hantaviral infections 8 . In Asia and some parts of Europe where inadequate treatment facilities exist, mortality rates may exceed 10%, and, even with modern treatment, mortality rates of 5% or greater are not uncommon for some forms of HFRS. A very interesting set of sera was collected by the Hemorrhagic Fever Commission during the Korean Conflict. This commission was formed by the Army to investigate the “new” hemorrhagic fever that was seen among the forces in Korea. While they were ultimately unable to isolate the causative agent, they did develop a considerable body of knowledge about both the clinical disease and its treatment. They also systematically collected acute and convalescent sera from patients studied. This collection remains intact, and we recently tested these sera for evidence of past hantaviral infection 9 .

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Epidemiology in Military and Veteran Populations: Proceedings of the Second Biennial Conference March 7, 1990 The sera were stored in three metal trunks over the years. The collection was very carefully packed, and surprisingly, almost none of the tubes was broken during their many years in storage. The collection contains three sizes of preserved sera, with each tube labeled with the patient 's name and number, date of collection, volume, and a “DD” number, which we believe represents the day of disease. The information on the labels is the only patient data that we have located, so we used this to calculate days post-onset when presenting our results. Each serum sample was tested by enzyme immunoassay for the presence of hantaviral antigen, and IgM and IgG antibodies. The last serum for each patient was also tested by plaque-reduction neutralization test to determine which strain of hantavirus was responsible for the infection. We tested over 600 sera from 245 patients, and only 15 patients failed to develop anti-hantaviral antibodies over the course of their illnesses. A few of these sera were from patients where only one sample was obtained, and could perhaps represent patients who died early in disease; but most of the negative sera were from patients where more than one sample was obtained and appear to represent infections with other than hantaviruses. Using the worst-case figures, the Commission clinicians were then accurate in their clinical diagnosis at least 94% of the time. These results demonstrate the utility of the IgM capture assay as the method of choice for diagnosis of acute HFRS. This was further enforced when we were unsuccessful in our attempts to detect hantaviral antigen in early sera. When we tested the last serum drawn from each patient by plaque-reduction neutralization tests, we found highest titers to prototype Hantaan virus, indicating that this virus was the likely infecting agent. These results confirm that the disease seen among U.S. forces during the Korean Conflict was indeed due to Hantaan virus infection. This confirmation of the clinical diagnosis, and the availability of sera drawn during acute illness, will prove very useful in some follow-up studies that we will propose later. Nephropathia epidemica is a less severe form of hemorrhagic fever with renal syndrome that is found in Scandinavia, the western Soviet Union, and much of Europe. This disease was first described in the medical literature during the 1930's 10 , 11 , and the similarities between it and the Asian forms of hemorrhagic fever with renal syndrome have been known for some time 12 . Like Hantaan virus in Asia, Puumala virus, the cause of nephropathia epidemica, is also associated with a rodent host, in this case the bank vole, Clethrionomys glareolus 13 , 14 . The clinical details of nephropathia epidemica are very similar to the Asian forms, with renal dysfunction as a prominent characteristic, but generally lacking the serious

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Epidemiology in Military and Veteran Populations: Proceedings of the Second Biennial Conference March 7, 1990 hemorrhagic manifestations and marked mortality characteristic of hantaviral infections in Asia 15 . A severe form of hemorrhagic fever with renal syndrome occurs in the Balkan region of Europe, with documented mortality rates of around 15% in Greece 16 . The clinical disease more closely resembles that due to Hantaan virus, as seen in Asia, rather than the milder nephropathia epidemica of Scandinavia and Western Europe. A virus has been isolated from an acutely ill Greek patient, and it has been shown to be antigenically similar to prototype Hantaan virus, but sufficiently distinct to allow specific recognition; we have proposed the name Porogia virus for this apparently new hantavirus 17 . Investigations of the natural host of this virus indicate that the yellow-necked mouse, Apodemus flavicollis, is the most likely reservoir of Porogia virus 18 . To summarize briefly with regard to the hantaviruses discussed so far, three distinct hantaviruses are recognized that are regionally associated with hemorrhagic fever with renal syndrome. Hantaan virus is found in Asia and is responsible for a moderate to severe form of hemorrhagic fever with renal syndrome locally called Korean hemorrhagic fever or epidemic hemorrhagic fever. Puumala virus is found in Scandinavia, the western Soviet Union, and much of Europe, and causes a less severe form of HFRS called nephropathia epidemica. Porogia virus, and perhaps some other closely related strains, are found in the Balkan region and cause a severe form of HFRS. Seoul virus is another distinct hantavirus that is associated with domestic rats. The story of Seoul virus begins in the early 1980 's, and again, Ho Wang Lee and his Korean colleagues played a prominent role in its discovery 19 . With the aid of the serologic test developed for Hantaan virus, they diagnosed hemorrhagic fever with renal syndrome among patients who resided in the urban centers of Korea, far from the recognized endemic region of Korean hemorrhagic fever. The patients were city dwellers, people with no history of travel outside the city. When attempts were made to collect small rodents around patients' houses, no Apodemus could be found; however, domestic rats (Rattus rattus, R. norvegicus) were present, and both antigen and antibody to what appeared to be Hantaan virus were detected. Subsequent study with more specific techniques, however, found that the virus in domestic rats was a distinct agent, closely related to prototype Hantaan virus. It was named Seoul virus, after the Korean city where it was first isolated. Soon thereafter we began a global serosurvey of domestic rats to determine the distribution of this newly recognized virus 20 . Antibody-positive rats were found in many parts of the world, suggesting that the virus itself was not new, but rather, our ability to detect it had changed.

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Epidemiology in Military and Veteran Populations: Proceedings of the Second Biennial Conference March 7, 1990 We then focused our efforts locally to investigate the maintenance of this virus among domestic rats. We concentrated on the inner-city neighborhoods of Baltimore, Maryland, in areas where litter and trash abound, and rats are common. We have studied hantaviruses in the rat populations in these neighborhoods for several years, and we have found Seoul-like viruses especially common among rats in this environment 21 . We have isolated strains of Seoul-like virus from rats captured there, and we have monitored the hantaviral antibody prevalence rates in these populations 22 . We examined the percent seropositive by various bodymass groupings, which is a good estimator of age, and found that about a third of the animals in the lowest mass group, or youngest age group, had antibody to hantaviruses 22 . We suspect that this was maternal antibody, which was lost over the next several weeks, and is reflected in the dip in prevalence rates at about the 200-g mass group. As the rats aged, the prevalence rates increased, until virtually all were positive in the heaviest mass groups, representing the oldest segment of the population. With such an abundance of infected rats coexisting with the resident human population, and recognition in Asia that Seoul virus is capable of causing overt human disease, we next attempted to document human infection among Baltimore residents. We first sampled 2,470 persons visiting a venereal disease clinic located in a neighborhood where many infected rats were found ( Table 1 ). The population sampled here was young, in their mid-20's, predominantly black males, of lower socio-economic status 23 . Six persons from this sample clearly had been infected with the local rat-borne strain of hantavirus, yielding an antibody prevalence rate of 2.4 per thousand. We next examined 1,250 patients seen at the Johns Hopkins Hospital who had proteinuria of greater than 250 mg/24 hr ( Table 1 ). This population was also drawn from inner-city Baltimore locations where infected rats are common. Persons sampled in this group were typically older, in their mid-40's, predominantly black females, and again from lower socio-economic neighborhoods. We found 15 persons antibody positive in this group, for a prevalence rate fivefold higher, at 12 per thousand. None of the seropositive patients had evidence of acute HFRS, but all had some form of chronic disease 24 . When we attempted to match each seropositive by age and sex to five seronegative controls from this same population, we found that seropositive persons were significantly more likely to suffer from hypertension, chronic renal disease, or have a history of cerebrovascular accidents, although rates of diabetes were not significantly different ( Table 2 ). A nephrologist from Johns Hopkins Hospital then reviewed the charts for the primary diagnosis underlying their renal disease, without knowledge of their serological status. Diagnosis was based on reported histories, examinations, laboratory tests

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Epidemiology in Military and Veteran Populations: Proceedings of the Second Biennial Conference March 7, 1990 and radiography, and biopsies when available. Hypertensive renal disease was the most common diagnosis among the seropositives. These results differed significantly from those of the matched controls, where diabetes mellitus was the most common cause of renal disease; other factors such as drug abuse, polycystic disease, and glomerulonephritis were secondary ( Table 3 ). The differences seen could not be explained on the basis of race alone. Finally, a serological survey targeted 402 patients utilizing chronic renal dialysis units in Baltimore ( Table 1 ). Individual identifiers and personal histories were not available for these sera, but the population age distribution and sex ratio were similar to those of the Johns Hopkins Hospital population. The confirmed seroprevalence rate in this group was 20/1,000, the highest of any group sampled. While these serological results are drawn from differing segments of the Baltimore population, they do share several common characteristics, and suggest that strains of Seoul-like virus found in the United States may predispose individuals to later development of chronic renal disease, at least among lower socio-economic segments of inner-city populations. The possibility of long-term renal dysfunction after a hantaviral infection has not been well studied. One of the earliest studies was done by Rubini and his colleagues, including staff of the Medical Follow-up Agency 25 . They examined Korean War veterans who had suffered hantaviral infections, and a group of matched controls, in 1956, about 3 to 5 years after most cases would have been infected. This study was noteworthy in that they found a significant increase in the rate of genitourinary hospital admissions among the HFRS cases, at rates which increased with the severity of their original disease. Other findings included hyposthenuria, persistent mild albuminuria, and a suggestion of incipient hypertension among some examined. These early indications of chronic renal dysfunction are consistent with the hypothesis that the patients ' conditions could evolve over time to conditions similar to those seen among the Baltimore residents. Interestingly, the files from this study still exist at the Follow-up Agency. Clearly, another look at this population is desperately needed, and a collaborative study with the Follow-up Agency and USAMRIID is now being developed. We also encouraged our colleagues in the Balkan region of Europe to examine their serologically confirmed HFRS patients for evidence of chronic renal insufficiency, and their results are shown in Table 4 26 , 27 , 28 , 29 . About 10% of those who survived acute disease were left with evidence of chronic renal insufficiency. These figures are based on renal function evaluations taken anytime between discharge from hospital to about 5 years post-onset. Five years represents about the longest period of time that

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Epidemiology in Military and Veteran Populations: Proceedings of the Second Biennial Conference March 7, 1990 HFRS has been diagnosed accurately in this area, so we haven't known infected patients for longer follow-up. Nonetheless, there is a striking similarity in the results from several different medical centers, which suggests that chronic renal insufficiency is not an uncommon sequela among patients sick enough to be hospitalized during acute illness. We are continuing to examine these patients over time, and we are trying to determine if there is a correlation between seropositivity and chronic renal disease or hypertension among long-term residents of the area as seen in Baltimore. To summarize, the past decade has yielded a wealth of new knowledge regarding hemorrhagic fever with renal syndrome. We now know that several different viruses are capable of causing clinically similar diseases, which are called collectively hemorrhagic fever with renal syndrome. These viruses are maintained in nature by chronically infected rodents, and they are distributed much more widely than once suspected. We are in a position to diagnose acute HFRS rapidly and accurately, and we have preliminary evidence to suggest that past hantaviral infection may be associated with subsequent development of chronic renal disease. Providing the proof of this association represents an exceptional challenge, and the resources of the Follow-up Agency, the Department of Defense, and the Veterans Administration are especially well suited to answer this question definitively. Hantaviral infections can be acquired either overseas, including as part of military service, or right here in the United States, from local infected rats; but regardless of the source of infection, there is growing evidence that some patients will progress to chronic renal disease and perhaps end-stage kidney failure. It has been estimated that the United States spends more than $30 billion a year for medical care for kidney and urologic diseases, and about $3 billion is Medicare payments for dialysis and transplantation for people with end-stage kidney disease. If even a small portion of this burden is due to hantaviral infections, say, the 2% we found in our Baltimore dialysis units, then we, as a nation, are spending about $60 million a year on this disease. Clearly, we cannot afford to let this question remain unresolved. REFERENCES 1. Schmaljohn, C.S. Hasty, S.E. Dalrymple, J.M. LeDuc, J.W. Lee, H.W. von Bonsdorff, C.H. Brummer-Korvenkontio, M. Vaheri, A. Tsai, T.F. Regnery, H.L. Goldgaber, D. Lee, P.W. 1985 Antigenic and genetic properties of viruses linked to hemorrhagic fever with renal syndrome Science 227 : 1041-1044 2. Earle, D.P. 1954 Symposium on epidemic hemorrhagic fever Am. J. Med. 16 : 617-709 3. Lee, H.W. Lee, P.W. Johnson, K.M. 1978 Isolation of the etiologic agent of Korean hemorrhagic fever J. Infect. Dis. 137 : 298-308

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Epidemiology in Military and Veteran Populations: Proceedings of the Second Biennial Conference March 7, 1990 4. French, G.R. Foulke, R.S. Brand, O.A. 1981 Korean hemorrhagic fever. Propagation of the etiologic agent in a cell line of human origin Science 211 : 1046-1048 5. Lee, H.W. Lee, P.W. Baek, L.J. 1981 Intraspecific transmission of Hantaan virus, etiologic agent of Korean hemorrhagic fever, in the rodent Apodemus agrarius . Am. J. Trop. Med. Hyg. 30 : 1106-1112 6. LeDuc, J.W. 1987 Epidemiology of hantaan and related viruses Lab. Anim. Sci. 37 : 413-418 7. McKee, K.T. MacDonald, C. LeDuc, J.W. Peters, C.J. 1985 Hemorrhagic fever with renal syndrome Mil. Med. 150 : 640-647 8. World Health Organization 1985 Haemorrhagic fever with renal syndrome: memorandum from a WHO meeting Bull. WHO 61 : 269-275 9. LeDuc, J.W. Ksiazek, T.G. Rossi, C.A. Dalrymple, J.M. 1990 A retrospective analysis of sera collected by the Hemorrhagic Fever Commission during the Korean Conflict J. Infect. Dis. (submitted) 10. Zetterholm, S.G. 1934 Akata nefriter simulerande adata bukfall Svenska Lakartidningen 31 : 425-429 11. Myhrman G. 1934 En njursjukdom med egenartad symptombild Nord. Med. Tidskr. 7 : 793-794 12. Gajdusek, D.C. 1953 Acute infections hemorrhagic fevers and mycotoxicoses in the Union of Soviet Socialist Republics Medical Science Graduate School, Walter Reed Army Medical Center, Washington, D.C. 13. Brummer-Korvenkontio M Vaheri, A. Hovi T. von Bonsdorff, C.H. Vuormies, J. Manni, T. Penttinen, K. Oker-Blom, N. Lahdevirta, J. 1980 Nephropathia epidemica: detection of antigen in bank voles and serologic diagnosis of human infection J. Infect. Dis. 141 : 131-134 14. Niklasson, B LeDuc, J.W. 1987 Epidemiology of nephropathia epidemica in Sweden J. Infect. Dis. 155 : 269-276 15. Lahdevirta, J. 1971 Nephropathia epidemica in Finland. A clinical, histological, and epidemiological study Ann. Clin. Res. 3 : 1-154 16. Antoniadis, A. LeDuc, J.W. Acritidis, N. Alexiou-Daniel, A. Kyparissi, A. Saviolakis, G.A. 1989 Hemorrhagic fever with renal syndrome in Greece: clinical and laboratory characteristics of the disease Rev. infect. Dis. 11 : S891-S896 17. Antoniadis, A. Grekas, D. Rossi, C.A. LeDuc, J.W. 1987 Isolation of a hantavirus from a severely ill patient with hemorrhagic fever with renal syndrome in Greece J. Infect. Dis. 156 : 010-1013 18. LeDuc, J.W. Antoniadis, A. Siamopoulus, K. 1986 Epidemiological investigations following an outbreak of hemorrhagic fever with renal syndrome in Greece Am. J. Trop. Med. Hyg. 35 : 654-659 19. Lee, H.W. Baek, L.J. Johnson, K.M. 1982 Isolation of Hantaan virus, the etiologic agent of Korean hemorrhagic fever, from wild urban rats J. Infect. Dis. 146 : 638-644 20. LeDuc, J.W. Smith, G.A. Childs, J.E. Pinheiro, F.P. Maiztegui, J.I. Niklasson, B. Antoniadis, A. Robinson, D.M. Khin, M. Shortridge, K.F. Wooster, M.T. Elwell, M.R. Ilbery, P.L.T. Koech, D. Rosa, E. Salbe, T. Rosen, L. 1986 Global survey of antibody to Hantaan related viruses among peridomestic rodents Bull. WHO 64 : 139-144 21. Childs, J.E. Korch, G.W. Smith, G.A. Terry, A.D. LeDuc, J.W. 1985 Geographic distribution and age related prevalence of antibody to Hantaan-like virus in rat populations of Baltimore Am. J. Trop. Med. Hyg. 34 : 385-387 22. Childs, J.E. Korch, G.W. Glass, G.E. LeDuc, J.W. Shah, K.V. 1987 Epizootiology of Hantavirus infections in Baltimore: isolation of a virus from Norway rats and characteristics of infected rat populations Am. J. Epidemiol. 126 : 55-68 23. Childs, J.E. Glass, G.E. Korch, G.W. Arthur, R.R. Shah, K.V. Glasser, D. Rossi, C. LeDuc, J.W. 1988 Evidence of human infection with a rat-associated Hantavirus in Baltimore, Maryland Am. J. Epidemiol. 127 : 875-878

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Epidemiology in Military and Veteran Populations: Proceedings of the Second Biennial Conference March 7, 1990 24. Glass, G.E. Childs, J.E. Watson, A.J. LeDuc, J.W. 1990 Association of chronic renal disease, hypertension and infection with a rat-borne Hantavirus Arch. Virol. (in press) 25. Rubini, M.E. Jablon, S. McDowell, M.E. 1960 Renal residuals of acute epidemic hemorrhagic fever Arch. Int. Med. 106 : 378-387 26. Cizman, B. Ferluga, D. Avsic, T. Kaplan-Pavlovcic, S. Licina, A. Furlan, P. Gradecki, I. Drinovec, J. 1989 Clinico-laboratory evaluation of patients with HFRS-4 years of investigation.. 2nd Symposium on Arboviruses in the Mediterranean Countries, 24-29 September 1989, Dubrovnik, Yugoslavia, Abstract S19 27. Dmitrovic, R. Djordjevic, D. Djerkovic, V. Obradovic, M. Dimkovic, N. Dimitrijevic, Z. Ostric, V. Gligic, A. 1989 Epidemiological and clinical aspects of chronic renal insufficiency in patients who have had HFRS 2nd Symposium on Arboviruses in the Mediterranean Countries, 24-29 September 1989, Dubrovnik, Yugoslavia, Abstract S30 28. Ahmetic, S. Kufllovci, M. Baljosevic, S. Avdiu, S. 1989 Clinical and epidemiological characteristics of haemorrhagic fever with renal syndrome (HFRS) induring epidemic 1986 in SAP Kosora (sic) 2nd Symposium on Arboviruses in the Mediterranean Countries, 24-29 September 1989, Dubrovnik, Yugoslavia, Abstract S34 29. Siamopoulus, K.C. Elisaf, M. Antoniadis, A. 1989 Initial and long term evaluation of renal function in hemorrhagic fever with renal syndrome 2nd Symposium on Arboviruses in the Mediterranean Countries, 24-29 September 1989, Dubrovnik, Yugoslavia, Abstract S16

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Epidemiology in Military and Veteran Populations: Proceedings of the Second Biennial Conference March 7, 1990 TABLE 1 PREVALENCE OF ANTIBODIES TO HANTAVIRUSES AMONG SELECTED POPULATIONS OF BALTIMORE, MARYLAND Population Prevalence Young (mid-20's), predominantly black males seen at a sexual disease clinic 2.4/1000 Older (mid-40's), predominantly black patients seen at Johns Hopkins Hospital 12/1000 Patients using chronic renal dialysis units 20/1000

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Epidemiology in Military and Veteran Populations: Proceedings of the Second Biennial Conference March 7, 1990 TABLE 2 COMPARISON OF HANTAVIRUS-SEROPOSITIVE AND HANTAVIRUS-SERONEGATIVE PERSONS FOR PREVALENCE OF CHRONIC DISEASES IN BALTIMORE, MARYLAND, CASECONTROL STUDY, 1986-88 Disease Seropositive Seronegative P value * Chronic renal disease 12 (80%) 32 (44%) <0.025 Hypertension 14 (93%) 47 (64%) <0.05 Cerebrovascular accident 4 (27%) 5 (7%) <0.025 Diabetes mellitus 6 (40%) 35 (48%) ns Total 15 73   *Chi square analysis.

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Epidemiology in Military and Veteran Populations: Proceedings of the Second Biennial Conference March 7, 1990 TABLE 3 SPECIFIC CAUSES OF CHRONIC RENAL DISEASE IN BALTIMORE, MARYLAND, CASE-CONTROL STUDY, 1986-88 Condition Seropositive Seronegative P value Chronic renal disease 12 (80%) 32 (44%) <0.025 Hypertension 7 (47%) 3 (4%) <0.005 * Diabetes mellitus 2 (13%) + 16 (22%)   Drug induced 1 (7%) + 6 (8%)   Obstructive 0 3 (4%)   Autoimmune 0 4 (5%)   Unknown 1 (7%) 0   None 3 (20%) 41 (56%)   * Chi square analysis with 3 df. + Drug induced also with diabetes.

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Epidemiology in Military and Veteran Populations: Proceedings of the Second Biennial Conference March 7, 1990 TABLE 4 CHRONIC RENAL INSUFFICIENCY AS A SEQUELA OF HFRS AMONG SEROLOGICALLY CONFIRMED PATIENTS DIAGNOSED IN YUGOSLAVIA AND GREECE   No. Pos/No. Tested % Yugoslavia Ljubljana 2/20 10 Belgrade 3/19 16 Kosova 4/39 10 Greece 2/19 10 Total 11/97 11

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