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Hemorrhagic fever with renal syndrome imported to Hawaii from West Germany
Hemorrhagic Fever with Renal Syndrome Imported to Hawaii from West Germany LTC PHILIP BRUNO, MC. USA, LTC L. Tripler
Army
Medical
Center,
HARRISON
HASSELL,
MC. USA,
A
mild form of hemorrhagic fever with renal syndrome (HFRS) caused by the Puumala virus is endemic to Scandinavia, the Soviet Union west of the Ural mountains, and northwestern Europe. This disease is also known as nephropathica epidemica. To the best of our knowledge, no cases of HFRS have been reported in the United States. We describe the case of a U.S. soldier who developed HFRS in Hawaii shortly after arriving from West Germany. CASEREPORT During November 1988, a healthy 24-year-old U.S. Army pilot completed 2 weeks of field training exercises at Hohenfels Training Area, Bavaria, West Germany. He spent another week at his home in Giebelstadt, West Germany, preparing for a trip to Hawaii. The soldier left West Germany via a commercial airline on December 1, and arrived in Honolulu, Hawaii, 18 hours later. Soon thereafter, he experienced restlessness, difficulty sleeping, anorexia, and constipation. He attributed these symptoms to jet lag. During a 2mile run on December 5, the soldier became nauseated, weak, and unsteady. Later that evening, he became acutely ill and presented to Tripler Army Medical Center for evaluation of fever, chills, sweats, vomiting, blurred vision, and severe abdominal pain. This illness began 28 days after the start of the field exercise. Physical examination revealed the young man to be acutely ill and clutching his abdomen in pain. He was alert and lucid. His temperature was 38.7”C, blood pressure 128/70 mm Hg, respiratory rate 24 breaths/ minute, and pulse 98 beats/minute. A conjunctival hemorrhage was present in the left eye. Scattered petechiae were located on the face, soft palate, tympanic membranes, and chest. The abdomen was diffusely tender. The remainder of the examination was normal. Admission laboratory findings included a hematocrit of 0.50; leukocyte count, 16 X 10s/L, with 0.56 neutrophils, 0.13 band forms, 0.13 lymphocytes, 0.10 monocytes, and 0.08 atypical lymphocytes; and platelet count, 73 X 10s/L. Pheripheral blood smear confirmed thrombocytopenia without platelet clumping. Schistocytes were absent. The serum creatinine level was 200 pmol/L (normal, 44 to 130 pmol/L), and the blood urea nitrogen 6.4 mmol/L (normal, 2.9 to 9.3 From the Department of Medicine, Tripler Army Medical Center, Tripler Army Medical Center, Hawaii. The views of the authors do not purport to reflect the positions of the Department of the Army or the Department of Defense. Requests for reprints should be addressed to Philip Bruno, D.O., Lieutenant Colonel, M.C.. USA, Department of Medicine, Tripler Army Medical Center, Tripler Army Medical Center, Hawaii 96859-5000. Manuscript submitted February 15. 1990, and accepted in revised form April 30, 1990.
232
August
1990
CPT
JAMES
QIJAN,
MC, USA, COL
JOEL
BROWN,
MC, uSA,
Hawaii
The American
Journal
of Medicine
Volume 89
mmol/L). Urinalysis demonstrated proteinuria and microscopic hematuria without red cell casts. Standard chest and abdominal radiographs, serum transaminases, alkaline phosphatase, amylase, bilirubin, and creatine phosphokinase levels were normal. Rapid plasma reagin, rheumatoid factor, and antinucler antibody studies were negative. Blood and urine bacterial cultures were negative. Serum CH50 and C3 levels were normal, but the serum C4 level was reduced to 0.13 g/L (normal, 0.15 to 0.45 g/L). A non-contrast computed tomographic abdominal scan showed bilateral nephromegaly (Figure 1). Treatment consisted of intravenous fluids and analgesics. Symptoms rapidly improved. The platelet count rose to 155 X 10s/L, and the serum creatinine and urea nitrogen values reached peak levels of 430 rcrnol/L and 15.0 mmol/L, respectively, on the third hospital day. Renal function returned to normal by the seventh hospital day. The clinical course was otherwise uncomplicated. The soldier was asymptomatic at discharge on December 13. He returned to duty 8 days later. Acute and convalescent serology for Leptospira species was negative. IgM antibody for Hantavirus was positive; plaque reduction neutralization tests confirmed infection due to Puumala virus. COMMENTS Puumala, Hantaan, and Seoul viruses, a group of closely related Hantaviruses within the Bunyaviridae family, are the etiologic agents for HFRS throughout Eurasia [l]. Hantaan virus causes a severe and often life-threatening form of HFRS. Although primarily found in Korea, China, Japan, and the eastern Soviet Union, cases have also been reported in several European countries, including France, Germany, and the Balkan peninsula [2-4]. It is transmitted to humans from the infected field mouse, Apodemus agrarius. Seoul virus is responsible for HFRS in urban areas of Korea and China. The vector is the domestic rat. Laboratory rats have also transmitted Seoul virus to laboratory workers in Asia and Europe [2]. Puumala virus is the causative agent of nephropathica epidemica in Scandinavia, the western Soviet Union, and northwestern Europe. People contract Puumala virus infection after exposure to its natural reservoir, the bank vole, Clethrionomys glareolus. Other rodent species may also play a role in virus transmission. The clinical manifestations of nephropathica epidemica include fever, abdominal or back pain, gastrointestinal symptoms, headache, myalgia, and blurred vision. Hemorrhagic manifestations are usually mild and may include epistaxis, conjunctival hemorrhage, metrorrhagia, melena, hematemesis, petechiae, and ecchymoses. Principal laboratory abnormalities are
HEMORRHAGIC
Figure 1. Non-contrast abdominal tomogram teral nephromegaly.
FEVER / BRUNO
ET AL
computed showing bila-
thrombocytopenia, an elevated serum creatinine level, proteinuria, and hematuria. The acute illness usually lasts 1 to 3 weeks, followed by a prolonged convalescent period of several months. Conservative medical management, directed toward pain relief and strict attention to fluid and electrolyte balance, is usually adequate therapy for Puumala virus infection. Shock and severe hemorrhage are uncommon. Hemodialysis is seldom required. Recovery is the rule, and fatalities are rare [5,6]. The management of HFRS caused by Hantaan virus is more complex. Shock and significant hemorrhagic manifestations occur more frequently. Hemodialysis is often required to treat uremia, pulmonary edema, or electrolyte disturbances. Sepsis and intracranial hemorrhage are significant causes of death during the diuretic phase of renal failure. Despite modern medical management, death from shock and renal failure occur in 5% to 10% of patients [2,7]. Antiviral therapy with ribavirin appears promising; it has been shown to significantly reduce the mortality of HFRS in China [8]. Although no cases of indigenous symptomatic Hantavirus infections have been reported within the United States, serosurveys of human populations in the U.S. and Canada have identified Hantavirus antibodies. Further, urban rat populations in coastal cities of the U.S. have been shown to carry Hantaviruses [9]. This suggests that asymptomatic or unrecognized cases of Hantavirus infection do occur in North America [lO,ll]. Because most western physicians are not familiar with HFRS, the disease will remain unrecognized until its protean manifestations are appreciated and serodiagnostic tests applied in appropriate clinical settings. Serologic testing for Hantavirus infection should be considered in undiagnosed cases of abacteremit septic shock, acute renal failure with thrombocytopenia, and undifferentiated febrile illnesses with thrombocytopenia. This case of nephropathica epidemica was diagnosed because the infection was considered in the differential diagnosis of renal failure with thrombocytopenia, and confirmed by ordering serodi-
agnostic tests for IgM and IgG Hantavirus antibodies. This case could have easily been misdiagnosed as leptospirosis, glomerulonephritis, or heat injury. The serologic demonstration of IgM antibodies, or a fourfold rise in IgG antibodies to Hantaviruses, by either enzyme-linked immunosorbent assay or the indirect immunofluorescent antibody test, is currently the diagnostic method of choice. The type of Hantavirus responsible for the infection can then be determined by plaque-reduction neutralization tests [2]. The recent availability of these serodiagnostic tests for Hantaviruses should make the diagnosis of HFRS easier and further define the extent of its geographic distribution. Serologic testing for Hantavirus antibody in the U.S. is available from the Centers for Disease Control Special Pathogens Branch by arrangement through state health departments. This report illustrates the concept that HFRS can be an emporiatric illness. The combination of modern air transportation, fewer travel restrictions to eastern Europe and the Far East, and the relatively long incubation period for HFRS (4 to 42 days) create a situation in which an unsuspecting physician may be confronted with an imported case of HFRS. Such infections may be misdiagnosed by unsuspecting physicians, leading to potentially harmful diagnostic and therapeutic errors.
ACKNOWLEDGMENT We thank J.W. LeDuc, Ph.D., United States Army MedIcal Research lnstltute of lnfectlous Diseases, Frederick, Maryland, for performlng the Hantavirus serodiagnostic tests, and Richard A. Yamamoto for the photography.
REFERENCES 1. Schmaljohn CS. Hasty SE, Dalrymple JM. eta/. Antigenic and genetic properties of viruses linked to hemorrhagic-fever with renal syndrome. Science i98$ 227: 10414. 2. Lee HW. Hemorrhagic fever with renal syndrome In Korea. Rev Infect Dis 1989; ll(Suppl4): S864-76. 3. Gartner L. Emmench P, Schmitz H. Hantaan virus Infections as a cause of acute kidney failure 3 cases in West Germany. Dtsch Med Wochenschr 1988: 113: 93740.
August
1990
The American
Journal
of Medicine
Volume
89
233
HEMORRHAGIC
FEVER / BRUNO
ET AL
4. Antoniadis A, LeDuc JW. Acritidis N. et al. Hemorrhagic fever with renal syndrome in Greece: clinical and laboratory characteristics. Rev Infect Dis 1989; 1 l(Suppl 4): S891-6. 5. Settergren B, Juto P. Trollfors B. et al. Hemorrhagic complications and other clinical findings in nephropathia epidemica in Sweden: a study of 355 serologically verified cases. J Infect Dis 1988; 157: 380-Z. 6. Settergren B. Juto P, Trollfors B. Wadell G, Norby SR. Clinical characteristics of nephropathia epidemica in Sweden: prospective study of 74 cases. Rev Infect Dis 1989: 11: 921-7. 7. Cosgriff TM. Hemorrhagic fever with renal syndrome: four decades of research. Ann Intern Med 1989; 110: 313-6.
234
August
1990
The American
Journal
of Medicine
Volume
6. Huggins JW. Prospects for treatment of viral hemorrhagrc fevers with ribavirin, a broad-spectrum antiviral drug. Rev Infect Dis 1989; ll(Suppl 4):S750-61. 9. Tsai TF. Bauer SP. Sasso DR, et al. Preliminary evidence that Hantaan or a closely related virus is enzootic rn domestic rodents [Letter]. N Engl J Med 1982;
307:623-5. 10. Lee PW, Gibbs CJ. Gajdusek DC, Svedmyr A. Antibody to Korean hemorrhagic fever virus In man in parts of the world where hemorrhagic fever with renal syndrome is not known. Lancet 1981; 1: 256-7. 11. Lee HW, Seong IW. Baek LJ, et a/. Positive serological evidence that Hantaan virus, the etiologrc agent of hemorrhagic fever with renal syndrome, is endemic in Canada. Can J Microbial 1984; 30: 1137-40.
89
Army
Medical
Center,
HARRISON
HASSELL,
MC. USA,
A
mild form of hemorrhagic fever with renal syndrome (HFRS) caused by the Puumala virus is endemic to Scandinavia, the Soviet Union west of the Ural mountains, and northwestern Europe. This disease is also known as nephropathica epidemica. To the best of our knowledge, no cases of HFRS have been reported in the United States. We describe the case of a U.S. soldier who developed HFRS in Hawaii shortly after arriving from West Germany. CASEREPORT During November 1988, a healthy 24-year-old U.S. Army pilot completed 2 weeks of field training exercises at Hohenfels Training Area, Bavaria, West Germany. He spent another week at his home in Giebelstadt, West Germany, preparing for a trip to Hawaii. The soldier left West Germany via a commercial airline on December 1, and arrived in Honolulu, Hawaii, 18 hours later. Soon thereafter, he experienced restlessness, difficulty sleeping, anorexia, and constipation. He attributed these symptoms to jet lag. During a 2mile run on December 5, the soldier became nauseated, weak, and unsteady. Later that evening, he became acutely ill and presented to Tripler Army Medical Center for evaluation of fever, chills, sweats, vomiting, blurred vision, and severe abdominal pain. This illness began 28 days after the start of the field exercise. Physical examination revealed the young man to be acutely ill and clutching his abdomen in pain. He was alert and lucid. His temperature was 38.7”C, blood pressure 128/70 mm Hg, respiratory rate 24 breaths/ minute, and pulse 98 beats/minute. A conjunctival hemorrhage was present in the left eye. Scattered petechiae were located on the face, soft palate, tympanic membranes, and chest. The abdomen was diffusely tender. The remainder of the examination was normal. Admission laboratory findings included a hematocrit of 0.50; leukocyte count, 16 X 10s/L, with 0.56 neutrophils, 0.13 band forms, 0.13 lymphocytes, 0.10 monocytes, and 0.08 atypical lymphocytes; and platelet count, 73 X 10s/L. Pheripheral blood smear confirmed thrombocytopenia without platelet clumping. Schistocytes were absent. The serum creatinine level was 200 pmol/L (normal, 44 to 130 pmol/L), and the blood urea nitrogen 6.4 mmol/L (normal, 2.9 to 9.3 From the Department of Medicine, Tripler Army Medical Center, Tripler Army Medical Center, Hawaii. The views of the authors do not purport to reflect the positions of the Department of the Army or the Department of Defense. Requests for reprints should be addressed to Philip Bruno, D.O., Lieutenant Colonel, M.C.. USA, Department of Medicine, Tripler Army Medical Center, Tripler Army Medical Center, Hawaii 96859-5000. Manuscript submitted February 15. 1990, and accepted in revised form April 30, 1990.
232
August
1990
CPT
JAMES
QIJAN,
MC, USA, COL
JOEL
BROWN,
MC, uSA,
Hawaii
The American
Journal
of Medicine
Volume 89
mmol/L). Urinalysis demonstrated proteinuria and microscopic hematuria without red cell casts. Standard chest and abdominal radiographs, serum transaminases, alkaline phosphatase, amylase, bilirubin, and creatine phosphokinase levels were normal. Rapid plasma reagin, rheumatoid factor, and antinucler antibody studies were negative. Blood and urine bacterial cultures were negative. Serum CH50 and C3 levels were normal, but the serum C4 level was reduced to 0.13 g/L (normal, 0.15 to 0.45 g/L). A non-contrast computed tomographic abdominal scan showed bilateral nephromegaly (Figure 1). Treatment consisted of intravenous fluids and analgesics. Symptoms rapidly improved. The platelet count rose to 155 X 10s/L, and the serum creatinine and urea nitrogen values reached peak levels of 430 rcrnol/L and 15.0 mmol/L, respectively, on the third hospital day. Renal function returned to normal by the seventh hospital day. The clinical course was otherwise uncomplicated. The soldier was asymptomatic at discharge on December 13. He returned to duty 8 days later. Acute and convalescent serology for Leptospira species was negative. IgM antibody for Hantavirus was positive; plaque reduction neutralization tests confirmed infection due to Puumala virus. COMMENTS Puumala, Hantaan, and Seoul viruses, a group of closely related Hantaviruses within the Bunyaviridae family, are the etiologic agents for HFRS throughout Eurasia [l]. Hantaan virus causes a severe and often life-threatening form of HFRS. Although primarily found in Korea, China, Japan, and the eastern Soviet Union, cases have also been reported in several European countries, including France, Germany, and the Balkan peninsula [2-4]. It is transmitted to humans from the infected field mouse, Apodemus agrarius. Seoul virus is responsible for HFRS in urban areas of Korea and China. The vector is the domestic rat. Laboratory rats have also transmitted Seoul virus to laboratory workers in Asia and Europe [2]. Puumala virus is the causative agent of nephropathica epidemica in Scandinavia, the western Soviet Union, and northwestern Europe. People contract Puumala virus infection after exposure to its natural reservoir, the bank vole, Clethrionomys glareolus. Other rodent species may also play a role in virus transmission. The clinical manifestations of nephropathica epidemica include fever, abdominal or back pain, gastrointestinal symptoms, headache, myalgia, and blurred vision. Hemorrhagic manifestations are usually mild and may include epistaxis, conjunctival hemorrhage, metrorrhagia, melena, hematemesis, petechiae, and ecchymoses. Principal laboratory abnormalities are
HEMORRHAGIC
Figure 1. Non-contrast abdominal tomogram teral nephromegaly.
FEVER / BRUNO
ET AL
computed showing bila-
thrombocytopenia, an elevated serum creatinine level, proteinuria, and hematuria. The acute illness usually lasts 1 to 3 weeks, followed by a prolonged convalescent period of several months. Conservative medical management, directed toward pain relief and strict attention to fluid and electrolyte balance, is usually adequate therapy for Puumala virus infection. Shock and severe hemorrhage are uncommon. Hemodialysis is seldom required. Recovery is the rule, and fatalities are rare [5,6]. The management of HFRS caused by Hantaan virus is more complex. Shock and significant hemorrhagic manifestations occur more frequently. Hemodialysis is often required to treat uremia, pulmonary edema, or electrolyte disturbances. Sepsis and intracranial hemorrhage are significant causes of death during the diuretic phase of renal failure. Despite modern medical management, death from shock and renal failure occur in 5% to 10% of patients [2,7]. Antiviral therapy with ribavirin appears promising; it has been shown to significantly reduce the mortality of HFRS in China [8]. Although no cases of indigenous symptomatic Hantavirus infections have been reported within the United States, serosurveys of human populations in the U.S. and Canada have identified Hantavirus antibodies. Further, urban rat populations in coastal cities of the U.S. have been shown to carry Hantaviruses [9]. This suggests that asymptomatic or unrecognized cases of Hantavirus infection do occur in North America [lO,ll]. Because most western physicians are not familiar with HFRS, the disease will remain unrecognized until its protean manifestations are appreciated and serodiagnostic tests applied in appropriate clinical settings. Serologic testing for Hantavirus infection should be considered in undiagnosed cases of abacteremit septic shock, acute renal failure with thrombocytopenia, and undifferentiated febrile illnesses with thrombocytopenia. This case of nephropathica epidemica was diagnosed because the infection was considered in the differential diagnosis of renal failure with thrombocytopenia, and confirmed by ordering serodi-
agnostic tests for IgM and IgG Hantavirus antibodies. This case could have easily been misdiagnosed as leptospirosis, glomerulonephritis, or heat injury. The serologic demonstration of IgM antibodies, or a fourfold rise in IgG antibodies to Hantaviruses, by either enzyme-linked immunosorbent assay or the indirect immunofluorescent antibody test, is currently the diagnostic method of choice. The type of Hantavirus responsible for the infection can then be determined by plaque-reduction neutralization tests [2]. The recent availability of these serodiagnostic tests for Hantaviruses should make the diagnosis of HFRS easier and further define the extent of its geographic distribution. Serologic testing for Hantavirus antibody in the U.S. is available from the Centers for Disease Control Special Pathogens Branch by arrangement through state health departments. This report illustrates the concept that HFRS can be an emporiatric illness. The combination of modern air transportation, fewer travel restrictions to eastern Europe and the Far East, and the relatively long incubation period for HFRS (4 to 42 days) create a situation in which an unsuspecting physician may be confronted with an imported case of HFRS. Such infections may be misdiagnosed by unsuspecting physicians, leading to potentially harmful diagnostic and therapeutic errors.
ACKNOWLEDGMENT We thank J.W. LeDuc, Ph.D., United States Army MedIcal Research lnstltute of lnfectlous Diseases, Frederick, Maryland, for performlng the Hantavirus serodiagnostic tests, and Richard A. Yamamoto for the photography.
REFERENCES 1. Schmaljohn CS. Hasty SE, Dalrymple JM. eta/. Antigenic and genetic properties of viruses linked to hemorrhagic-fever with renal syndrome. Science i98$ 227: 10414. 2. Lee HW. Hemorrhagic fever with renal syndrome In Korea. Rev Infect Dis 1989; ll(Suppl4): S864-76. 3. Gartner L. Emmench P, Schmitz H. Hantaan virus Infections as a cause of acute kidney failure 3 cases in West Germany. Dtsch Med Wochenschr 1988: 113: 93740.
August
1990
The American
Journal
of Medicine
Volume
89
233
HEMORRHAGIC
FEVER / BRUNO
ET AL
4. Antoniadis A, LeDuc JW. Acritidis N. et al. Hemorrhagic fever with renal syndrome in Greece: clinical and laboratory characteristics. Rev Infect Dis 1989; 1 l(Suppl 4): S891-6. 5. Settergren B, Juto P. Trollfors B. et al. Hemorrhagic complications and other clinical findings in nephropathia epidemica in Sweden: a study of 355 serologically verified cases. J Infect Dis 1988; 157: 380-Z. 6. Settergren B. Juto P, Trollfors B. Wadell G, Norby SR. Clinical characteristics of nephropathia epidemica in Sweden: prospective study of 74 cases. Rev Infect Dis 1989: 11: 921-7. 7. Cosgriff TM. Hemorrhagic fever with renal syndrome: four decades of research. Ann Intern Med 1989; 110: 313-6.
234
August
1990
The American
Journal
of Medicine
Volume
6. Huggins JW. Prospects for treatment of viral hemorrhagrc fevers with ribavirin, a broad-spectrum antiviral drug. Rev Infect Dis 1989; ll(Suppl 4):S750-61. 9. Tsai TF. Bauer SP. Sasso DR, et al. Preliminary evidence that Hantaan or a closely related virus is enzootic rn domestic rodents [Letter]. N Engl J Med 1982;
307:623-5. 10. Lee PW, Gibbs CJ. Gajdusek DC, Svedmyr A. Antibody to Korean hemorrhagic fever virus In man in parts of the world where hemorrhagic fever with renal syndrome is not known. Lancet 1981; 1: 256-7. 11. Lee HW, Seong IW. Baek LJ, et a/. Positive serological evidence that Hantaan virus, the etiologrc agent of hemorrhagic fever with renal syndrome, is endemic in Canada. Can J Microbial 1984; 30: 1137-40.
89