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Reappearance of viral hemorrhagic fever with renal syndrome in northwestern Greece
International Journal of Infectious Diseases (2010) 14, e13—e15
http://intl.elsevierhealth.com/journals/ijid
Reappearance of viral hemorrhagic fever with renal syndrome in northwestern Greece N. Akritidis a,*, C. Boboyianni b, G. Pappas c a
Internal Medicine Department, General Hospital ‘‘G. Hatzikosta’’, Makrygianni Avenue, Ioannina, 45110, Greece Department of Microbiology, University Hospital of Ioannina, Ioannina, Greece c Institute of Continuing Medical Education of Ioannina, Ioannina, Greece b
Received 30 September 2008; received in revised form 31 October 2008; accepted 18 November 2008 Corresponding Editor: William Cameron, Ottawa, Canada
KEYWORDS Viral hemorrhagic fever; Hanta virus; Greece
Summary Background: Minor outbreaks of viral hemorrhagic fever (VHF) with renal failure have occurred in northwestern Greece over past decades. However, during the most recent decade, there has been a paucity of human cases despite the detection of hantavirus in rodents of this area. Case reports: We present herein the cases of two patients with VHF, arising in the same area, hospitalized for a short period of time. One patient presented with renal failure, while severe hepatic involvement was predominant in the other. Significantly high ELISA antibody titers for hantavirus established the diagnosis. Supportive treatment led to a successful outcome in both cases. We further discuss the difficulties in differential diagnosis of VHF from other zoonoses with similar endemicity, such as leptospirosis. Conclusions: Awareness of the continuing presence of VHF in rural Greece is needed, and a rapid diagnosis is important for the correct therapeutic approach. Continuous surveillance for such diseases, at both the animal (rodents) and human level, is warranted. # 2009 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
Introduction Minor outbreaks of viral hemorrhagic fever (VHF) with renal failure have occurred in northwestern Greece over past decades,1—4 particularly in the period 1984—1994, with more than 30 cases detected and attributed to hantavirus. The district of Epirus in northwestern Greece is one of the poorest regions of the European Union, with a largely rural population and a known endemicity for various zoonoses, including
* Corresponding author. Tel.: +30 26510 80746. E-mail address: [email protected] (N. Akritidis).
brucellosis, rickettsioses, and leptospirosis.5—7 In recent years, other hemorrhagic fevers, such as Crimean-Congo hemorrhagic fever (CCHF),8 have been a major concern in the Balkan Peninsula, with a recent case of CCHF documented in northeastern Greece underlining this concern.9 An outbreak of VHF with renal failure was recently described in Serbia,10 to the northwest of Greece, though hantavirus was absent. However, in more recent years, the presence of the disease has only been documented in animal vectors in the region.11 We report herein two new cases of hantavirus VHF emerging during a period of 3 months from the same area of northwestern Greece.
1201-9712/$36.00 # 2009 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. doi:10.1016/j.ijid.2008.11.029
e14
Case presentation The first patient, a 40-year-old male shepherd from a village in a mountainous area, presented to the emergency department of the General Hospital ‘‘G. Hatzikosta’’, Ioannina, in June 2007, complaining of a recently initiated spiking fever, headache, and vomiting. On admission, the patient appeared mildly jaundiced; his temperature was 39 8C and blood pressure was 120/80 mmHg. Nuchal rigidity was present, and a brain computerized tomography scan showed mild brain edema. No signs of focal infection were elicited during physical examination. Laboratory tests revealed thrombocytopenia (54 109/l) and an increased prothrombin time (international normalized ratio (INR) 2.9) and D-dimers. His white blood cell (WBC) count was normal, with a mild relative increase in polymorphonuclear leukocytes. A mild increase in serum creatinine was noted (1.8 mg/dl). The liver biochemistry profile showed increases in total and direct bilirubin, reaching 7.7 and 4.1 mg/dl, respectively, a massive increase in alanine and aspartate aminotransferase values (6220 and 6790 U/l, respectively; normal values 5—40), rhabdomyolysis (serum creatine phosphokinase 3160 U/l; normal values 0—220), and hypokalemia (3.2 mEq/l). Urine analysis showed the presence of albuminuria. A lumbar puncture was performed as diagnostically critical, and elicited an acellular fluid with normal glucose and protein values. The patient was started empirically on doxycycline, due to the possibility of leptospirosis. Subsequently, serology results for IgM antibodies for hepatitis A virus, antibodies for hepatitis C virus, hepatitis B surface antigen and hepatitis B anti-core IgM antibodies, HIV, and Leptospira antibodies were negative. ELISA IgG antibody titers for hantavirus were two times the normal limit (3 units; considered positive when above 1.5 units, indeterminate when between 1 and 1.5 units, and negative when below 1 unit) and confirmed the diagnosis of VHF. Doxycycline was discontinued, and supportive treatment with plasma transfusion and fluid and electrolyte balancing was initiated; the patient was eventually discharged after normalization of hepatic and renal function and platelet number. The second patient, a 54-year-old male shepherd from the same village as the first patient, presented to the emergency department 3 months later, complaining of fever of 7 days’ duration for which he had already received azithromycin with no response. On admission, his temperature was 37 8C and blood pressure was 120/80 mmHg. The patient complained of tenderness in both costovertebral angles. There were no clinical signs of a focal infection in the remainder of the physical examination. Laboratory tests revealed thrombocytopenia (43 109/l), renal failure (creatinine 3.5 mg/dl, urea 171 mg/dl), mild rhabdomyolysis (creatine phosphokinase 387 U/l), and hypokalemia (3.1 mEq/l). The WBC count was normal, with a mild relative mononucleosis noted. Urine analysis showed albuminuria, later quantified to 2 g/24 h. An abdominal ultrasound revealed liver enlargement and inflammation surrounding the gallbladder. Antibodies to Leptospira were negative. The ELISA antibody titer for hantavirus was highly positive, both for IgM and IgG antibodies (4.6 and 18.2 units; considered positive when above 2 for both antibodies), and confirmed the diagnosis of VHF with renal failure. Treatment was supportive to fluid and electrolyte balance, with gradual
N. Akritidis et al. evolution from the initial, oliguric phase, to a brief polyuric phase and renal function improvement. In addition, the patient received a 2-day regimen of corticosteroids at high doses; this was in accordance with our previous experience, which has shown the beneficial effect of this approach (N. Akritidis, unpublished data). The patient was discharged with normal creatinine and urea values (1.1 and 40 mg/dl, respectively), reversal of thrombocytopenia (162 109/l), and in good health.
Discussion The presence of VHF with renal failure is unsurprising in an area like northwestern Greece, given the documented presence of the virus in animals of the region. Furthermore, northwestern Greece is an area that has hosted the largest outbreak of VHF in the recent past,1—4 is endemic for brucellosis,5 and systematically reports other zoonotic infections such as leptospirosis and rickettsioses.6,7 The neighboring of an area with Albania, considered a zoonotic reservoir, has been demonstrated to be a significant cause of persistence of certain zoonoses in the area.5 The VHF outbreak of the 1980 s gradually subsided through the 1990 s, although the virus remained present in rodents.11 The reappearance of the disease in two patients from the same area possesses important epidemiologic parameters and raises the need for a new awareness of the disease and further studies on the virus ecology. Of interest in our cases was the significant resemblance of both to severe leptospirosis, also endemic in the area. The first patient in particular could easily have been misdiagnosed with the icterohemorrhagic form of leptospirosis. Furthermore, both cases had hypokalemia, which has been considered as a useful diagnostic index for leptospirosis in such cases.12 A rapid diagnosis, when possible through serology, allows for optimization of treatment in the patient with leptospirosis,13 and sparing of unwarranted antibacterial administration to patients with VHF. Also of interest is the favorable outcome of the first patient, despite the severe liver involvement, which has been shown to be an adverse survival index in previous studies in the area.14 A similar clinical picture might also be induced by CCHF, yet the recently reported Greek case arose in the northeast, more than 400 km away from this area. One may wonder if there are any specific environmental or climate-related parameters related to the reappearance of the virus, as shown in other endemic areas.8 It is more likely though, that the new cases of human disease are related to an accidental bypassing of the human—animal carrier barrier; epidemiologic surveillance in the village of the two patients might shed light in the near future on any specific underlying causes for this barrier bypass. No other cases have been reported in the subsequent 12 months though. In conclusion, awareness of the continuing presence of VHF in rural Greece is needed, especially in light of the other endemic bacterial, rickettsial and viral infectious diseases resembling VHF, and the arrival of novel (for the area) pathogens, such as CCHF virus. Rapid diagnosis is important for a correct therapeutic approach. Awareness should extend beyond the medical differential diagnostic process to health literacy in the susceptible populations. With regard to public
VHF with renal syndrome, northwestern Greece health interventions, continuous surveillance for such diseases, at both the animal (rodents) and human level, is warranted. Conflict of interest: No conflict of interest to declare.
References 1. Siamopoulos K, Antoniades A, Acritidis N, Constantopoulos S, Tsianos E, Papapanagiotou I, et al. Outbreak of hemorrhagic fever with renal syndrome in Greece. Eur J Clin Microbiol 1985;4:132—4. 2. Siamopoulos KC, Elisaf M, Antoniadis A, Moutsopoulos HM. Hemorrhagic fever with renal syndrome in an endemic area of Greece. Am J Nephrol 1992;12:170—3. 3. LeDuc JW, Antoniades A, Siamopoulos K. Epidemiological investigations following an outbreak of hemorrhagic fever with renal syndrome in Greece. Am J Trop Med Hyg 1986;35:654—9. 4. Antoniades A, Grekas D, Rossi CA, LeDuc JW. Isolation of a hantavirus from a severely ill patient with hemorrhagic fever with renal syndrome in Greece. J Infect Dis 1987;156:1010—3. 5. Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV. The new global map of human brucellosis. Lancet Infect Dis 2006;6:91—9.
e15 6. Raptis L, Pappas G, Akritidis N. Use of ceftriaxone in patients with severe leptospirosis. Int J Antimicrob Agents 2006;28:259—61. 7. Pappas G, Akritidis N, Christou L, Mastora M, Tsianos E. Unusual causes of reactive arthritis: Leptospira and Coxiella burnetii. Clin Rheumatol 2003;22:343—6. 8. Vapalahti O, Mustonen J, Lundkvist A, Henttonen H, Plyusnin A, Vaheri A. Hantavirus infections in Europe. Lancet Infect Dis 2003;3:653—61. 9. Papa A, Maltezou HC, Tsiodras S, Dalla VG, Papadimitriou T, Pierroutsakos I, et al. A case of Crimean-Congo hemorrhagic fever in Greece, June 2008. Euro Surveill 2008;13. pii: 18952. 10. Papa A, Bojovic B, Antoniadis A. Hantaviruses in Serbia and Montenegro. Emerg Infect Dis 2006;12:1015—8. 11. Papa A, Mills JN, Kouidou S, Ma B, Papadimitriou E, Antoniadis A. Preliminary characterization and natural history of hantaviruses in rodents in northern Greece. Emerg Infect Dis 2000;6:654—5. 12. Visith S, Kearkiat P. Nephropathy in leptospirosis. J Postgrad Med 2005;51:184—8. 13. Pappas G, Cascio A. Optimal treatment of leptospirosis: queries and projections. Int J Antimicrob Agents 2006;28:491—6. 14. Elisaf M, Stefanaki S, Repanti M, Korakis H, Tsianos E, Siamopoulos KC. Liver involvement in hemorrhagic fever with renal syndrome. J Clin Gastroenterol 1993;17:33—7.
http://intl.elsevierhealth.com/journals/ijid
Reappearance of viral hemorrhagic fever with renal syndrome in northwestern Greece N. Akritidis a,*, C. Boboyianni b, G. Pappas c a
Internal Medicine Department, General Hospital ‘‘G. Hatzikosta’’, Makrygianni Avenue, Ioannina, 45110, Greece Department of Microbiology, University Hospital of Ioannina, Ioannina, Greece c Institute of Continuing Medical Education of Ioannina, Ioannina, Greece b
Received 30 September 2008; received in revised form 31 October 2008; accepted 18 November 2008 Corresponding Editor: William Cameron, Ottawa, Canada
KEYWORDS Viral hemorrhagic fever; Hanta virus; Greece
Summary Background: Minor outbreaks of viral hemorrhagic fever (VHF) with renal failure have occurred in northwestern Greece over past decades. However, during the most recent decade, there has been a paucity of human cases despite the detection of hantavirus in rodents of this area. Case reports: We present herein the cases of two patients with VHF, arising in the same area, hospitalized for a short period of time. One patient presented with renal failure, while severe hepatic involvement was predominant in the other. Significantly high ELISA antibody titers for hantavirus established the diagnosis. Supportive treatment led to a successful outcome in both cases. We further discuss the difficulties in differential diagnosis of VHF from other zoonoses with similar endemicity, such as leptospirosis. Conclusions: Awareness of the continuing presence of VHF in rural Greece is needed, and a rapid diagnosis is important for the correct therapeutic approach. Continuous surveillance for such diseases, at both the animal (rodents) and human level, is warranted. # 2009 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
Introduction Minor outbreaks of viral hemorrhagic fever (VHF) with renal failure have occurred in northwestern Greece over past decades,1—4 particularly in the period 1984—1994, with more than 30 cases detected and attributed to hantavirus. The district of Epirus in northwestern Greece is one of the poorest regions of the European Union, with a largely rural population and a known endemicity for various zoonoses, including
* Corresponding author. Tel.: +30 26510 80746. E-mail address: [email protected] (N. Akritidis).
brucellosis, rickettsioses, and leptospirosis.5—7 In recent years, other hemorrhagic fevers, such as Crimean-Congo hemorrhagic fever (CCHF),8 have been a major concern in the Balkan Peninsula, with a recent case of CCHF documented in northeastern Greece underlining this concern.9 An outbreak of VHF with renal failure was recently described in Serbia,10 to the northwest of Greece, though hantavirus was absent. However, in more recent years, the presence of the disease has only been documented in animal vectors in the region.11 We report herein two new cases of hantavirus VHF emerging during a period of 3 months from the same area of northwestern Greece.
1201-9712/$36.00 # 2009 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. doi:10.1016/j.ijid.2008.11.029
e14
Case presentation The first patient, a 40-year-old male shepherd from a village in a mountainous area, presented to the emergency department of the General Hospital ‘‘G. Hatzikosta’’, Ioannina, in June 2007, complaining of a recently initiated spiking fever, headache, and vomiting. On admission, the patient appeared mildly jaundiced; his temperature was 39 8C and blood pressure was 120/80 mmHg. Nuchal rigidity was present, and a brain computerized tomography scan showed mild brain edema. No signs of focal infection were elicited during physical examination. Laboratory tests revealed thrombocytopenia (54 109/l) and an increased prothrombin time (international normalized ratio (INR) 2.9) and D-dimers. His white blood cell (WBC) count was normal, with a mild relative increase in polymorphonuclear leukocytes. A mild increase in serum creatinine was noted (1.8 mg/dl). The liver biochemistry profile showed increases in total and direct bilirubin, reaching 7.7 and 4.1 mg/dl, respectively, a massive increase in alanine and aspartate aminotransferase values (6220 and 6790 U/l, respectively; normal values 5—40), rhabdomyolysis (serum creatine phosphokinase 3160 U/l; normal values 0—220), and hypokalemia (3.2 mEq/l). Urine analysis showed the presence of albuminuria. A lumbar puncture was performed as diagnostically critical, and elicited an acellular fluid with normal glucose and protein values. The patient was started empirically on doxycycline, due to the possibility of leptospirosis. Subsequently, serology results for IgM antibodies for hepatitis A virus, antibodies for hepatitis C virus, hepatitis B surface antigen and hepatitis B anti-core IgM antibodies, HIV, and Leptospira antibodies were negative. ELISA IgG antibody titers for hantavirus were two times the normal limit (3 units; considered positive when above 1.5 units, indeterminate when between 1 and 1.5 units, and negative when below 1 unit) and confirmed the diagnosis of VHF. Doxycycline was discontinued, and supportive treatment with plasma transfusion and fluid and electrolyte balancing was initiated; the patient was eventually discharged after normalization of hepatic and renal function and platelet number. The second patient, a 54-year-old male shepherd from the same village as the first patient, presented to the emergency department 3 months later, complaining of fever of 7 days’ duration for which he had already received azithromycin with no response. On admission, his temperature was 37 8C and blood pressure was 120/80 mmHg. The patient complained of tenderness in both costovertebral angles. There were no clinical signs of a focal infection in the remainder of the physical examination. Laboratory tests revealed thrombocytopenia (43 109/l), renal failure (creatinine 3.5 mg/dl, urea 171 mg/dl), mild rhabdomyolysis (creatine phosphokinase 387 U/l), and hypokalemia (3.1 mEq/l). The WBC count was normal, with a mild relative mononucleosis noted. Urine analysis showed albuminuria, later quantified to 2 g/24 h. An abdominal ultrasound revealed liver enlargement and inflammation surrounding the gallbladder. Antibodies to Leptospira were negative. The ELISA antibody titer for hantavirus was highly positive, both for IgM and IgG antibodies (4.6 and 18.2 units; considered positive when above 2 for both antibodies), and confirmed the diagnosis of VHF with renal failure. Treatment was supportive to fluid and electrolyte balance, with gradual
N. Akritidis et al. evolution from the initial, oliguric phase, to a brief polyuric phase and renal function improvement. In addition, the patient received a 2-day regimen of corticosteroids at high doses; this was in accordance with our previous experience, which has shown the beneficial effect of this approach (N. Akritidis, unpublished data). The patient was discharged with normal creatinine and urea values (1.1 and 40 mg/dl, respectively), reversal of thrombocytopenia (162 109/l), and in good health.
Discussion The presence of VHF with renal failure is unsurprising in an area like northwestern Greece, given the documented presence of the virus in animals of the region. Furthermore, northwestern Greece is an area that has hosted the largest outbreak of VHF in the recent past,1—4 is endemic for brucellosis,5 and systematically reports other zoonotic infections such as leptospirosis and rickettsioses.6,7 The neighboring of an area with Albania, considered a zoonotic reservoir, has been demonstrated to be a significant cause of persistence of certain zoonoses in the area.5 The VHF outbreak of the 1980 s gradually subsided through the 1990 s, although the virus remained present in rodents.11 The reappearance of the disease in two patients from the same area possesses important epidemiologic parameters and raises the need for a new awareness of the disease and further studies on the virus ecology. Of interest in our cases was the significant resemblance of both to severe leptospirosis, also endemic in the area. The first patient in particular could easily have been misdiagnosed with the icterohemorrhagic form of leptospirosis. Furthermore, both cases had hypokalemia, which has been considered as a useful diagnostic index for leptospirosis in such cases.12 A rapid diagnosis, when possible through serology, allows for optimization of treatment in the patient with leptospirosis,13 and sparing of unwarranted antibacterial administration to patients with VHF. Also of interest is the favorable outcome of the first patient, despite the severe liver involvement, which has been shown to be an adverse survival index in previous studies in the area.14 A similar clinical picture might also be induced by CCHF, yet the recently reported Greek case arose in the northeast, more than 400 km away from this area. One may wonder if there are any specific environmental or climate-related parameters related to the reappearance of the virus, as shown in other endemic areas.8 It is more likely though, that the new cases of human disease are related to an accidental bypassing of the human—animal carrier barrier; epidemiologic surveillance in the village of the two patients might shed light in the near future on any specific underlying causes for this barrier bypass. No other cases have been reported in the subsequent 12 months though. In conclusion, awareness of the continuing presence of VHF in rural Greece is needed, especially in light of the other endemic bacterial, rickettsial and viral infectious diseases resembling VHF, and the arrival of novel (for the area) pathogens, such as CCHF virus. Rapid diagnosis is important for a correct therapeutic approach. Awareness should extend beyond the medical differential diagnostic process to health literacy in the susceptible populations. With regard to public
VHF with renal syndrome, northwestern Greece health interventions, continuous surveillance for such diseases, at both the animal (rodents) and human level, is warranted. Conflict of interest: No conflict of interest to declare.
References 1. Siamopoulos K, Antoniades A, Acritidis N, Constantopoulos S, Tsianos E, Papapanagiotou I, et al. Outbreak of hemorrhagic fever with renal syndrome in Greece. Eur J Clin Microbiol 1985;4:132—4. 2. Siamopoulos KC, Elisaf M, Antoniadis A, Moutsopoulos HM. Hemorrhagic fever with renal syndrome in an endemic area of Greece. Am J Nephrol 1992;12:170—3. 3. LeDuc JW, Antoniades A, Siamopoulos K. Epidemiological investigations following an outbreak of hemorrhagic fever with renal syndrome in Greece. Am J Trop Med Hyg 1986;35:654—9. 4. Antoniades A, Grekas D, Rossi CA, LeDuc JW. Isolation of a hantavirus from a severely ill patient with hemorrhagic fever with renal syndrome in Greece. J Infect Dis 1987;156:1010—3. 5. Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV. The new global map of human brucellosis. Lancet Infect Dis 2006;6:91—9.
e15 6. Raptis L, Pappas G, Akritidis N. Use of ceftriaxone in patients with severe leptospirosis. Int J Antimicrob Agents 2006;28:259—61. 7. Pappas G, Akritidis N, Christou L, Mastora M, Tsianos E. Unusual causes of reactive arthritis: Leptospira and Coxiella burnetii. Clin Rheumatol 2003;22:343—6. 8. Vapalahti O, Mustonen J, Lundkvist A, Henttonen H, Plyusnin A, Vaheri A. Hantavirus infections in Europe. Lancet Infect Dis 2003;3:653—61. 9. Papa A, Maltezou HC, Tsiodras S, Dalla VG, Papadimitriou T, Pierroutsakos I, et al. A case of Crimean-Congo hemorrhagic fever in Greece, June 2008. Euro Surveill 2008;13. pii: 18952. 10. Papa A, Bojovic B, Antoniadis A. Hantaviruses in Serbia and Montenegro. Emerg Infect Dis 2006;12:1015—8. 11. Papa A, Mills JN, Kouidou S, Ma B, Papadimitriou E, Antoniadis A. Preliminary characterization and natural history of hantaviruses in rodents in northern Greece. Emerg Infect Dis 2000;6:654—5. 12. Visith S, Kearkiat P. Nephropathy in leptospirosis. J Postgrad Med 2005;51:184—8. 13. Pappas G, Cascio A. Optimal treatment of leptospirosis: queries and projections. Int J Antimicrob Agents 2006;28:491—6. 14. Elisaf M, Stefanaki S, Repanti M, Korakis H, Tsianos E, Siamopoulos KC. Liver involvement in hemorrhagic fever with renal syndrome. J Clin Gastroenterol 1993;17:33—7.