Journal of Infection (2007) 54, 381e386
Clinical and laboratory predictors of oliguric renal failure in haemorrhagic fever with renal syndrome caused by Hantaan virus Young Keun Kim a, Sang Cheol Lee b, Changsoo Kim c, Sang Taek Heo d, Changmin Choi e, June Myung Kim a,* a
Department of Internal Medicine, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemun-Gu, Seoul 120-752, South Korea b Department of Internal Medicine, Kwandong University College of Medicine, Goyang, South Korea c Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, South Korea d Department of Internal Medicine, Cheju National University College of Medicine, Cheju, South Korea e Department of Internal Medicine, Armed Forces Capital Hospital, Sungnam, South Korea Accepted 18 July 2006 Available online 23 August 2006
KEYWORDS Acute renal failure; Haemorrhagic fever with renal syndrome; Hantaan virus; Oliguria; Risk factor
Summary Objective: Haemorrhagic fever with renal syndrome (HFRS), caused by hantavirus infection, develops into acute renal failure (ARF) of variable degrees of severity. We investigated the early predictive markers for oliguric ARF in HFRS patients. Methods: A retrospective cohort study was performed of 61 patients with HFRS between 2000 and 2004. These patients were categorized into either oliguric or non-oliguric ARF groups according to their urine output (<400 ml/24 h). The clinical characteristics were compared between the two groups. Results: Of the 61 patients, 24 (39.3%) were classified as oliguric ARF and 37 (60.7%) as nonoliguric ARF. The peak serum Cr was 10.8 (IQR 9.1e12.4) mg/dl in oliguric ARF and 4.4 (IQR 3.1e6.0) mg/dl in non-oliguric ARF (p < 0.001). The risk for developing oliguric ARF significantly increased in the cases with leukocyte count (14 109/L, aOR 2.2, 95% CI 1.0e4.9; p Z 0.039), elevated aspartate aminotransferase (110 U/L, aOR 11.0, 95% CI 2.1e57.9; p Z 0.005) and the presence of microscopic haematuria (5/HPF, aOR 9.2, 95% CI 1.4e60.3; p Z 0.021) at the time of admission. Conclusion: The leukocyte count, level of aspartate aminotransferase and microscopic haematuria at admission would be useful to predict for the subsequent development of oliguric ARF in HFRS. ª 2006 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: þ82 2 2228 1946; fax: þ82 2 393 6884. E-mail address: [email protected]
(J.M. Kim). 0163-4453/$30 ª 2006 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2006.07.006
Y.K. Kim et al.
Since the isolation of Hantaan virus, the first recognized etiological agent of haemorrhagic fever with renal syndrome (HFRS),1 infection with other hantaviruses such as Puumala virus, Dobrava virus and Seoul virus have been linked to HFRS. After it was reported that hantavirus pulmonary syndrome (HPS) is caused by Sin Nombre virus, the interest in hantavirus infections has risen.2e4 While only 1000 HPS cases have been reported so far, approximately 150,000 HFRS cases are estimated to occur annually worldwide.4,5 HFRS is an acute infectious disease characterized by symptoms such as high fever, headache, abdominal and back pain, bleeding tendency, and renal failure, and it produces typical chronological phases including febrile phase, hypotensive phase, oliguric phase, diuretic phase, and convalescent phase.5,6 Acute renal failure (ARF) accompanying HFRS could be classified as either the oliguric type or the non-oliguric type according to urine output.7,8 In cases of acute oliguric renal failure, the possibility of developing complications and requiring dialysis is high. Therefore, early discrimination between oliguric and non-oliguric HFRS is very important in the management of HFRS patients. Therefore, we investigated the characteristics of HFRS patients with oliguric ARF and the early predictive markers for the subsequent development of oliguric ARF in HFRS.
Serologic testing was performed using a Hantadia (GreenCross SangA, Yong In, Korea) high-density particle agglutination assay kit for the detection of antibody to the Hantaan virus antigen. A titre higher than 1:640 or a titre that was raised more than four times during follow-up was determined to be positive.
Patients and methods Study subjects Seventy patients were admitted to the Armed Forces Capital Hospital, Sungnam, Korea, from 1 October, 2000 to 31 December, 2004, with typical clinical features of HFRS and serologically confirmed Hantaan virus infection. Among these patients, 61 were enrolled as the final study subjects after the exclusion of nine patients; two had superimposed infections, six were admitted after the diuretic phase, and one patient had died. The immediate cause of his death was pulmonary haemorrhage. All enrolled patients had a decrease in urine output (<1000 ml/day) and subsequent creatinine elevation (>1.5 mg/dl). The clinical data such as clinical symptoms and signs, vaccination status, laboratory findings, and clinical courses were obtained through medical record review. The status of Hantaan virus vaccination was assessed in 52 cases. If a patient had to be vaccinated at least 3 months before onset of symptoms, he was determined to be vaccinated. Haemodialysis was started in patients with severe dyspnea due to pulmonary oedema or hyperkalaemia (>6.0 mmol/L). Patients with thrombocytopenia (<20 109/L) were transfused with platelet concentration and patients with any sign of bleeding were transfused with plasma concentration. In the Republic of Korea (ROK) Military, all HFRS patients are admitted to the Armed Forces Capital Hospital for management. Therefore, all cases of HFRS that occurred during the study period in the ROK Military were included in this study.
Definition The patients whose 24-h urine volume was less than 400 ml even once during their admission were classified in the oliguric ARF group, and the others were placed in the nonoliguric ARF group. The clinical symptoms of the initial phase included fever, headache, myalgia, abdominal and back pain, nausea, vomiting and diarrhoea. A day in this study describes a 24-h time period starting from the onset of fever. If a patient was transferred from another hospital, the duration from onset of symptoms to hospital admission was calculated to the date of the first admission. The laboratory findings at time of admission were defined as those of first admission.
Statistical analysis The symptoms and signs, vaccination status, laboratory findings at time of admission, and clinical courses were compared between the oliguric and non-oliguric groups using nonparametric tests for continuous values and c2 test or a Fisher’s Exact test for categorical values. To determine the independent risk factors for developing oliguric ARF, a multiple logistic regression model was used to control for the effects of confounding variables. The results of these logistic regression analyses were reported as adjusted odds ratio with 95% confidence intervals. All p values were two-tailed, and p < 0.05 was considered to be statistically significant. All analyses were performed using SPSS 11.0 (SPSS Inc., Chicago, IL, USA).
Results Baseline characteristics of patients and their clinical symptoms and signs Of the 61 cases, 51 occurred in Gyeongi and Gangwon provinces (northern part of the ROK where Hantaan river runs through), and 10 cases occurred in the southern part of the ROK. Most cases occurred in the fall and the winterdOctober (18.0%), November (39.3%), December (26.2%), and January (4.9%)dalthough disease also occurred during the spring and the summer. Of the 61 patients, 56 cases had a value higher than 1:640 in the serological tests (1:640; 4 cases, more than 1:1280; 52 cases), and in the follow-up tests, there were five cases in which the titre increased more than fourfold. Twenty-four patients (39.3%) met the criteria for oliguric ARF, and 37 (60.7%) were placed in the non-oliguric ARF group. All patients were male and the median age was 21 years (IQR 20e22). A statistically significant difference
Oliguric ARF in Hantaan virus infection
in age, the time interval from onset of symptoms until admission, and the clinical symptoms and signs between the two groups was not observed (Table 1). The number of patients who were vaccinated against Hantaan virus was similar in the two groups.
Laboratory findings at the time of admission In comparison with the non-oliguric group, the leukocyte count, serum creatinine, serum potassium, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and the frequency of microscopic haematuria (5/HPF) were high in the oliguric group, but their platelet count and serum sodium levels were low (Table 1). A statistically significant difference in levels of hematocrit, serum protein and albumin was not observed.
Clinical course and laboratory findings after admission The highest leukocyte count and lowest platelet count occurred on the same day post symptom onset for both the oliguric and non-oliguric groups. In the oliguric group, however, the highest leukocyte count was high and the lowest platelet count was low compared to the non-oliguric group. Serum creatinine reached peak levels on the ninth day after the onset of symptoms in the oliguric group and on the seventh day in the non-oliguric group (p < 0.001). In addition, the peak value of serum creatinine was higher in the oliguric group. A difference between the two groups was not detected in the serum albumin levels (Table 2). In the oliguric group, oliguria developed on the fifth day (IQR 5e6), and the oliguric period was 5 days (IQR 4e7) in
duration. Twenty-one patients required haemodialysis in the oliguric group (87.5%) and two needed dialysis in the non-oliguric group (5.4%). Median frequency of haemodialysis was 3 (range 1e6) in the oliguric group and 2 in the non-oliguric group. Fifty-nine (96.7%) patients had total recovery of renal function (<1.5 mg/dl) within 28 days. Median duration was 14 days (range 8e26 days). Two patients were not followed up.
Risk of developing oliguric ARF At the time of admission, the leukocyte count (14 109/L), platelet count (38 109/L), serum creatinine (2.0 mg/ dl), AST (110 U/L) and the presence of microscopic haematuria (5/HPF) were identified as the predictive markers for the subsequent development of oliguric ARF in HFRS by univariate analysis (Table 3). These parameters were significant after adjustment of age and the time interval from onset of symptoms until admission. Multivariate analysis using a logistic regression model identified the leukocyte count (14 109/L), the level of AST (110 U/L), and the presence of microscopic haematuria (5/HPF) as the independent predictive markers for the subsequent development of oliguric ARF in HFRS (Table 4).
Discussion HFRS caused by the hantavirus showed diverse clinical patterns from mild to fatal.6,7 Although the intravenous administration of ribavirin has been reported to be effective in reducing the incidence of renal failure, the tendency to haemorrhage and the mortality rate, it is limited in that it must be administered within 4 days of the onset of
Comparative characteristics of patients with HFRS both with and without oliguric ARF at time of admission
Characteristics Age (years) Durations from onset of symptom to hospital admission (days) Vaccinationa Conjunctival haemorrhage Petechiae Shock, <90/60 mmHg Haematocrit Leukocyte count (109/L) Platelet count (109/L) Serum sodium (mmol/L) Serum potassium (mmol/L) Serum creatinine (mg/dl) Aspartate aminotransferase (U/L) Alanine aminotransferase (U/L) Serum protein (g/L) Serum albumin (g/L) Microscopic haematuria, 5/HPF
Non-oliguric ARF (n Z 37) 21 (20e23) 4 (3e5)
12/30 11 10 6 45.8 11.1 46 134 4.0 1.6 84 45 57 33 19
(40.0%) (29.7%) (27.0%) (16.2%) (43.0e50.6) (6.1e16.5) (23e83) (131e136) (3.7e4.4) (1.1e2.5) (65e120) (32e70) (50e61) (28e38) (51.4%)
Oliguric ARF (n Z 24) 21 (21e22) 4 (3e5)
8/22 8 11 6 48.5 22.7 20 131 4.5 3.4 148 70 55 31 21
(36.4%) (33.3%) (45.8%) (25.0%) (44.2e53.9) (14.2e31.1) (14e44) (126e134) (3.9e4.8) (2.0e4.8) (110e197) (42e93) (50e59) (28e34) (87.5%)
P Value 0.661 0.383
0.790 0.767 0.131 0.738 0.226 0.001 0.001 0.010 0.023 0.001 0.002 0.026 0.359 0.303 0.004
Values are expressed as the median (interquartile range) or number (percentage) unless otherwise indicated. HFRS, haemorrhagic fever with renal syndrome; ARF, acute renal failure; HPF, high-power field. a Patients with previous hantavirus vaccination/total number of known vaccination status.
384 Table 2
Y.K. Kim et al. Clinical course of patients with HFRS both with and without oliguric ARF
Characteristics Leukocyte Highest (109/L) Daya Platelet Lowest (109/L) Daya Serum creatinine Highest (mg/dl) Daya Serum albumin Lowest (g/L) Daya Dialysis required
Non-oliguric ARF (n Z 37)
Oliguric ARF (n Z 24)
17.3 (13.5e25.8) 6 (5e7)
28.9 (20.4e38.5) 5 (5e6)
p Value 0.002 0.397
30 (22e50) 5 (4e6)
15 (10e27) 5 (4e5)
4.4 (3.1e6.0) 7 (7e9)
10.8 (9.1e12.4) 9 (8e11)
29 (27e31) 7 (5e8) 2 (5.4%)
28 (26e30) 7 (6e9) 21 (87.5%)
0.316 0.186 <0.001
Values are expressed as a median (interquartile range) or number (percentage). HFRS, haemorrhagic fever with renal syndrome; ARF, acute renal failure. a A day represents the period of time from the onset of symptoms in 24-h units.
symptoms.9 Therefore, conservative management such as the correction of the bleeding tendency and the electrolyte imbalance and also renal replacement therapy are widely used in the management of HFRS. Appropriate dialysis also reduces the mortality rate from 5e15% to lower than 5%.2 The severity of HFRS has generally been evaluated according to haemorrhagic complications,6 but when considering renal failure and the subsequent importance of dialysis for its management, HFRS with oliguria must be considered as a severe form. In this study, most patients with oliguria required dialysis, and their maximum values of serum creatinine were much higher than those in the non-oliguric patients. In the oliguric group, haemorrhagic manifestations such as petechiae and the frequency of shock were slightly higher, but not statistically significant. Any differences in other symptoms and signs between the
two groups were not observed. This suggests that in HFRS the clinical symptoms and signs at the time of admission cannot be used as markers for predicting oliguric renal failure, although the haemorrhage and shock without adequate management may be associated with mortality. The ROK Army defines a ‘high-risk area’ for HFRS as an administrative district where HFRS cases have occurred during the previous 3 years. Vaccination programs focus on military units located in these high-risk areas, but vaccinating all personnel in those units is impossible because of budget limitations. Even though this study did investigate the protective effects of vaccinations on oliguria, a history of Hantaan virus vaccination was not associated with less oliguria in HFRS patients. This results suggests that the vaccination did not lessen the severity of the disease, as recent studies have suggested that the protective effectiveness of
The risk for developing oliguric ARF in HFRS according to laboratory findings at time of admission
Laboratory value on admission Leukocyte count (109/L) <14 14 Platelet count (109/L) >38 38 Serum creatinine (mg/dl) <2.0 2.0 Aspartate aminotransferase (U/L) <110 110 Microscopic haematuria <5/HPF 5/HPF
No. of patients with oliguric ARF/no. of patients (%)
OR (95% CI)
aOR (95% CI)a
5/29 (17) 19/32 (59)
1 7.0 (2.1e23.2)
1 7.4 (2.2e25.4)
7/30 (23) 17/31 (55)
1 4.0 (1.3e12.0)
1 4.1 (1.3e12.4)
6/29 (21) 18/32 (56)
1 4.9 (1.6e15.4)
1 4.7 (1.5e15.0)
6/31 (19) 18/30 (60)
1 6.3 (2.0e19.8)
1 6.2 (1.9e20.3)
3/21 (14) 21/40 (53)
1 6.6 (1.7e26.1)
1 6.9 (1.7e27.6)
ARF, acute renal failure; HFRS, haemorrhagic fever with renal syndrome; HPF, high-power field; OR, odds ratio; aOR, adjusted odds ratio; CI, confidence interval. a After adjustment for age and the time interval from onset of symptoms until admission.
Oliguric ARF in Hantaan virus infection
Table 4 The independent predictors for developing oliguric ARF in HFRS according to laboratory findings upon admissiona Variables
Adjusted OR (95% CI)
Aspartate aminotransferase (110 U/L) Microscopic haematuria (>5/HPF) Leukocyte count (14 109/L)
ARF, acute renal failure; HFRS, haemorrhagic fever with renal syndrome; HPF, high-power field; OR, odds ratio; CI, confidence interval. a Included variables as follows: leukocyte count, aspartate aminotransferase, microscopic haematuria, creatinine, shock, age, and the time interval from onset of symptoms until admission.
the hantavirus vaccine is questionable.10,11 But it is impossible to conclude that the vaccinations are not associated with the severity of HFRS because (1) the sample size of this study might be small to find a benefit of vaccination on the severity of HFRS and (2) selection bias might exist; asymptomatic or mild HFRS cases might not be included. To evaluate the effect of Hantaan virus vaccination, further study is mandatory. The laboratory values at the time of admission between the two groups were different for diverse parameters. Compared to the non-oliguric group, the serum creatinine levels were high in the oliguric group, but the time it took between the onset of symptoms and the admission was similar between the two groups. This suggests that the serum creatinine levels abruptly increase in HFRS patients with oliguria. A difference in serum sodium and potassium levels was also observed. It was thought that these results were primarily due to more severe acute renal failure in oliguric patients. AST and ALT values were shown to be higher in the oliguric group, and the level of AST revealed the pattern of being high in the initial phase and then gradually decreasing with the progression of the disease. The level of ALT was low in the initial phase and then increased gradually as the disease progressed. In patients with HFRS, jaundice is rarely observed,12 and liver damage in pathologic findings was not marked, rather damage of renal medulla was characteristic.13 Therefore, it is possible that the increase in AST implies renal cell damage instead of damage to liver cells. The frequency of microscopic haematuria was much higher in the oliguric group. Haematuria in HFRS is due to extravasation of blood into the renal medulla or acute glomerulonephritis.12e14 Therefore, the presence of haematuria might imply renal injury. Although acute glomerulonephritis is rarely reported,14 the damage of renal medulla is marked and characteristic in renal biopsy findings in HFRS.12,13 In HFRS, it is likely that reduced blood flow in medullary vessels leads to the development of regional ischaemia, thereby producing ischaemic injury to renal tubular cells.12 This injury leads to decreased glomerular filtration rate and renal plasma flow by several
postulated mechanisms including simple obstruction of tubular lumina, back-leak of glomerular filtrate, and tubuloglomerular feedback.12 In HFRS, the loss of proteins appears because of proteinuria and the loss within the intestinal tract due to the increased permeability of blood vessels.15 It has been reported that the degree of hypoalbuminaemia is associated with the severity of HFRS.16 In this study, however, the serum albumin levels at the time of admission and the degree of hypoalbuminaemia were not different between the oliguric and non-oliguric groups. To determine the predictive factors for acute oliguric renal failure in HFRS, the relative risk was calculated using the laboratory parameters including the leukocyte count (14 109/L), platelet count (38 109/L), serum creatinine (2.0 mg/dl), AST (110 U/L) and the presence of microscopic haematuria (5/HPF) at the time of admission, which were significantly different (p < 0.01) between the oliguric and non-oliguric groups. The standard value was determined by the median value of each parameter. Although the highest leukocyte count and the lowest platelet count may become more reliable parameters than laboratory findings at the time of admission, it could not be useful as a predictor because the time from the onset of symptoms to either the appearance of the lowest platelet count or the highest leukocyte count was similar to the time of the development of oliguria. The present study suggests that at the time of admission, the leukocyte count (14 109/L), AST (110 U/L) and the presence of microscopic haematuria (5/HPF) constitute independent predictive markers for the subsequent development of oliguria ARF in HFRS. In recent studies, the degree of thrombocytopenia has been associated with systemic inflammatory reactions and the subsequent deterioration of renal function in HFRS,17,18 but in this study the degree of leukocytosis rather than the degree of thrombocytopenia was found to be significantly associated with the deterioration of renal function in HFRS. This may be because previous study was about nephropathica epidemica caused Puumala virus or other hantaviruses other than Hantaan virus. The level of AST and presence of microscopic haematuria might represent the degree of renal cell damage. Together with the leukocyte count (14 109/L), the AST (110 U/L) and the presence of microscopic haematuria (5/HPF) were important parameters predicting the development of oliguric renal failure in HFRS. This study has some limitations. Only HFRS cases caused by the Hantaan virus were included, the subjects were young adult males only, and the comparison of coagulation profiles and sequelae after the recovery of renal function such as hypertension were not performed. However, this study may be useful for early discrimination between oliguric and non-oliguric HFRS.
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