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The sample comprised 384 patients with HFRS from January 2006 to February 2017.
•
A new scoring system specifically for HFRS was formulated, named H-SOFA.
•
PLT, PCT, TB, and FOBT were independent predictors of severe HFRS.
•
SAPS II, SOFA, and H-SOFA had high predictive value for the progression of severe HFRS, with H-SOFA being the highest.
Abstract
Background
Hemorrhagic Fever with Renal Syndrome (HFRS), caused by the hantavirus, is a natural infectious disease characterized by fever, hemorrhage and renal damage. China is the most severely endemic area for HFRS in the world. In recent years, critical scoring systems based on quantitative classification have become an important clinical tool for predicting and evaluating the prognosis of critical illness, and provide guidelines for clinical practice.
Methods
The sample comprised 384 patients with HFRS treated in the Taizhou Hospital from January 2006 to February 2017. The patients were divided into the severe group and the mild group according to their clinical characteristics. By comparing the differences in clinical symptoms, signs and laboratory data between the two groups, the clinically relevant indicators of severe HFRS were explored. According to the previous studies, we incorporated the positive fecal occult blood test (FOBT) into the sepsis-related organ failure assessment (SOFA) tool and formulated a new scoring system specifically for HFRS, named H-SOFA. By comparing the simplified acute physiology score II (SAPS II), SOFA and H-SOFA scores of the two groups, their predictive values for the progression of HFRS were assessed.
Results
Compared to the mild group, patients in the severe group had longer hospital stays; higher frequencies of nausea, vomiting, abdomen pain, signs of congestion and hemorrhage; and more pronounced impairment of liver and renal function. The levels of PLT, PCT, TB, and FOBT were positively correlated with the progression of HFRS (P < 0.001). Patients with HFRS in the severe group got significantly higher scores on the SAPS II, SOFA, and H-SOFA scoring systems (P < 0.001). The values of SAPS II, SOFA and H-SOFA, were significantly correlated with the severity of HFRS, and the AUC values were 0.90, 0.96, and 0.98, respectively.
Conclusion
PLT, PCT, TB, and FOBT were independent predictors of severe HFRS; SAPS II, SOFA, and H-SOFA had high predictive value for the progression of severe HFRS, with H-SOFA being the highest.
Hemorrhagic fever with renal syndrome (HFRS), caused by hantaviruses, is a natural infectious disease characterized by fever, hemorrhage and kidney damage (
). HFRS has been a major epidemic mainly in Asia and Europe; about 100,000 cases of HFRS are documented annually, most of which occur in China, Korea, and Russia (
). Due to positive prevention efforts of the government, the prevalence of HFRS had been lowered in recent years, but the high incidence persisted in some areas (
). The prevalence of HFRS in China is characterized by a large number of affected patients and high mortality of critical cases. Also, the incidence of atypical cases with unusual clinical manifestations has increased, and some new hantavirus genotypes have been found recently, hindering the early diagnosis and treatment of HFRS (
). Similar to other critical illnesses, exploring early and new biomarkers, and combining clinical features with laboratory parameters to detect the severity and prognosis of HFRS in advance are very important to guide clinicians to initiate effective treatment and improve the remedy achievement ratio.
In recent years, severity scoring systems based on quantitative classification have become an important clinical tool for the prediction and evaluation of the prognosis of critically ill patients, and serve as a guide to clinical practice (
). The scoring systems commonly used in clinical settings include the Simplified Acute Physiology Score II (SAPS II) and the Sepsis-related Organ Failure Assessment (SOFA) score, which is widely used in many Western countries. For example, it has been reported that whereas the SAPS II is positively associated with mortality in acute renal failure (ARF) (
). Some studies showed that although both the SAPS II and SOFA score could predict the prognosis of septic shock, the SAPS II was a little worse in doing so compared to the SOFA score, which was more reflective of the patient’s circulatory system (
). Currently, there are few reports about the application of the SAPS II and SOFA in the prediction of HFRS.
Methods
Study participants
384 patients with HFRS who were treated in the Affiliated Taizhou Hospital of Wenzhou Medical University from January 2006 to February 2017 were selected randomly and reviewed. The diagnosis of HFRS was made based on the detection of specific IgM antibodies to hantavirus by enzyme-linked immunosorbent assay (ELISA).
Based on the criteria for the clinical classification of HFRS (
), the patients were divided into two groups: the severe group consisted of serious and critical cases, and the mild group consisted of mild and moderate cases (Table 1).
Table 1The criteria for the clinical classification of HFRS.
Group
Type
Temperature
Effusion
Hemorrhage
Shock
Kidney Injury
Mild Group
Mild
<39 °C
mild
skin and mucous membranes
none
albuminuria+−++ without oliguria
Moderate
39–40 °C
moderate chemosis
ecchymosis
hypotension susceptibility
albuminuria ++−+++ and oliguria
Severe Group
Serious
≥40 °C
serious and toxic psychiatric symptoms
ecchymosis and gastrointestinal hemorrhage
shock
oliguria ≤5 days anuria ≤2 days
Critical
have one or more of the following complications in addition to the criteria for serious cases: refractory shock ≥2days, visceral hemorrhage; oliguria >5 days or anuria >2 days, BUN >42.84 mmol/L; pulmonary edema; heart failure; severe infection; cerebral hemorrhage, brain edema or herniation.
The positive symptoms and signs of two groups were compared and analyzed, including cough, nausea and vomiting, dizziness and headache, abdominal pain, backache, diarrhea, conjunctival congestion, pharynges congestion, flush, subconjunctival hemorrhage, cervico-thoracic hemorrhage, underarm hemorrhage, renal percussive pain, and abdominal tenderness.
Laboratory parameters
Twenty-seven clinical laboratory parameters were detected and analyzed, including blood tests performed using an autoanalyzer (Sysmex-2100, Sysmex Corp., Japan), biochemical and immune examination performed using an autoanalyzer (Architect ci16200, Abbott Corp., USA), blood coagulation detected by hematology analyzers (STA Compact, Stago Corp., France), lymphocyte subgroup examination detected by flow cytometry (Becton-Dickinson FACSCalibur, BD Biosciences, CA, USA), and routine urine performed using an autoanalyzer (UF-1000i, Sysmex Corp., Japan). The detailed laboratory parameters were white blood cell (WBC) count; platelet count (PLT); levels of hemoglobin (HB); C-reactive protein (CRP), procalcitonin (PCT), alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TB), serum sodium (Na), serum potassium (K), serum calcium (Ca), albumin (ALB), uric acid (UA), creatine kinase (CK), lactate dehydrogenase (LDH), urea, serum creatinine (SCr), glomerular filtration rate (GFR), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), cluster of differentiation 3 (CD3), cluster of differentiation 4 (CD4), and cluster of differentiation 8 (CD8); albuminuria; urine occult blood test (UOBT); and fecal occult blood test (FOBT).
SAPS II
The SAPS II includes 17 variables, including age, physiological variables (heart rate, blood pressure, temperature, PaO2/FiO2 ratio, urine volume, blood urea nitrogen (BUN), WBC, K, Na, bicarbonate ion (HCO3−), TB, and Glasgow coma scale (GCS) score), type of admission (emergency surgery, elective surgery, medical patient), and chronic diseases (acquired immunodeficiency syndrome (AIDS), metastatic cancer, hematological malignancy) (
). The score for each item ranges from 0-26 points, and the total score is 0-163 points. The SAPS II scores of the two groups were collected respectively, then compared and analyzed by statistical tools.
SOFA Score
The SOFA scoring system comprises 7 indexes, including the respiratory system (PaO2/FiO2), hematological system (PLT), liver function (TB), cardiovascular system (systolic blood pressure and application of vasoactive drugs), central nervous system (GCS), renal function (SCr and urine volume) (
The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.
). The score for each item ranges from 0-4 points, and the total score is 0-28 points. According to our previous studies, a positive FOBT was significantly correlated with the progression of HFRS. Thus, we constituted a new scoring system specifically for HFRS by juxtaposing the grade of FOBT positivity on the SOFA system, called the H-SOFA. The quantitative graduation for points is as follows: the result ‘-’ for FOBT equals 0 points, ‘+’ equals 1 point, ‘++’ equals 2 points, ‘+++’ equals 3 points, and ‘++++’ equals 4 points. The SOFA and H-SOFA scores for the two groups were collected respectively, then compared and analyzed by statistical tools.
Statistical analysis
Statistical analysis was performed using SPSS version 22.0 (IBM Inc., Armonk, NY, USA). The tables were created using Microsoft® Excel® 2016 (Microsoft Corp., USA). Continuous variables were presented as a mean ± standard deviation (SD). The variables with homogeneity of variance were analyzed by student’s t test, and variables with heterogeneity of variance were analyzed by the Welch-Satterthwaite t test. The frequencies and percentages were given for qualitative variables. Significant differences were tested by the chi-square test, and Fisher’s exact test was used when the numbers were too small. Binary logistic regression analysis was used to identify the clinical risk factors and scoring systems which correlated with the progression of HFRS. The predicting values were tested with receiver operating characteristic (ROC) curves, and quantified by calculating the area under the curve (AUC) and the 95% confidence interval (CI). A two-tailed P < 0.05 was considered to indicate a statistically significant difference.
Ethics statement
This retrospective study was reviewed and approved by the Institutional Review Board of the Affiliated Taizhou Hospital of Wenzhou Medical University.
Results
Of the 384 HFRS patients, 334 patients belonged to the mild group, and 50 patients belonged to the severe group. Compared to the mild group, patients in the severe group had longer hospital stays (P < 0.001). Also, the differences between the two groups in other parameters, like gender, age, career, the interval from onset to arrival at the hospital, duration of the febrile phase, and hospital stay, were not significant (P > 0.05) (Table 2). Compared to the mild group, patients in the severe group had higher frequencies of nausea and vomiting, abdominal pain, signs of congestion and hemorrhage, and abdominal tenderness (P < 0.05). However, there were no statistically significant differences in the other parameters between the two groups, like cough, dizziness and headache, backache, diarrhea, and renal percussive pain (P > 0.05) (Table 3).
Table 2The characteristics of HFRS patients, and the differences between two groups.
Compared to the mild group, patients in the severe group had higher levels of WBC, CRP, PCT, ALT, AST, TB, UA, CK, LDH, urea, SCr, PT, and APTT, as well as lower levels of PLT, Na, Ca, and GFR (P < 0.05). However, there were no statistical differences in the other parameters between the two groups, like HB, K, Fib, CD3, CD4, and CD8 (P > 0.05) (Table 4). Compared to the mild group, patients in the severe group had higher frequencies of albuminuria, and positive UOBT and FOBT (P < 0.01) (Table 5).
Table 4The Laboratory parameters of HFRS patients, and a statistical analysis of the differences between the two groups.
We selected the symptoms, signs, and laboratory parameters with significant differences between the two groups, which consisted of 30 variables. Assignment of the dependent and independent variables were performed as follows: the severe and mild cases were defined as ‘1’ and ‘0’ respectively; the positive and negative symptoms and signs were defined as ‘1’ and ‘0’ respectively; and the laboratory parameters were defined as ‘1’, ‘2’, ‘3’ according to their respective levels. Single-factor binary logistic regression analysis was first used to explore the correlation between the variables and severe or mild HFRS. Only 10 indicators, nausea and vomiting, cervico-thoracic hemorrhage, axillary hemorrhage, PLT, PCT, Ca, TB, SCr, GFR, and FOBT yielded statistically significant results. Then multi-factor binary logistic regression analysis was used, and finally, low PLT and high levels of PCT, TB, and FOBT were identified as risk factors for the progression of HFRS (Table 6).
Table 6Independent risk factors for the progression of HFRS.
Parameters
B
SE
Wald
df
P value
OR
95% CI for OR
Lower
Upper
PLT
2.646
0.454
33.960
1
<0.001
14.091
5.788
34.304
PCT
0.837
0.290
8.367
1
0.004
2.310
1.310
4.075
TB
0.948
0.445
4.529
1
0.033
2.580
1.078
6.176
FOBT
1.056
0.274
14.838
1
<0.001
2.873
1.679
4.916
Constant
−12.006
1.593
56.80
1
<0.001
0.001
Abbreviations: B, Independent variable coefficient; SE, standard error; df, degrees of freedom; OR, odds ratio; CI, confidence interval; PLT, platelet; PCT, procalcitonin; TB, total bilirubin; FOBT, fecal occult blood test.
To explore the predictive value of the risk factors, ROC analysis with AUC measurement was used. The analysis revealed that the AUC values for PLT, PCT, TB, and FOBT were 0.814, 0.712, 0.657, and 0.782, respectively. By combining the 4 factors, the AUC value rose to 0.890, and the sensitivity and specificity were 72.0%, 89.25%, respectively (Table 7, Figure 1).
Table 7Predictive values for progression based on laboratory parameters in patients with HFRS.
Parameters
AUC
P value
Cut-off value
Sensitivity
Specificity
95% CI for AUC
Lower
Upper
PLT
0.814
<0.001
2
68.00
91.94
0.758
0.861
PCT
0.712
<0.001
2
46.00
93.55
0.649
0.769
TB
0.657
<0.001
1
46.00
85.41
0.593
0.718
FOBT
0.782
<0.001
1
82.00
67.74
0.724
0.833
Combination
0.890
<0.001
7
72.00
89.25
0.843
0.927
Combination means combining of the 4 risk factors, the level of PLT, PCT, TB, and FOBT. Abbreviations: AUC, area under the ROC curve; CI, confidence interval; PLT, platelet; PCT, procalcitonin; TB, total bilirubin; FOBT, fecal occult blood test.
Figure 1ROC analysis of PLT, PCT, TB, and FOBT revealed that the 4 parameters reached statistical significance for predicting HFRS progression (P < 0.001). By combining the 4 factors, the AUC value was increased. Combination means combining of the 4 risk factors, the level of PLT, PCT, TB, and FOBT. Abbreviations: ROC, receiver operating characteristic; PLT, platelet; PCT, procalcitonin; TB, total bilirubin; FOBT, fecal occult blood test.
Compared to the mild group, patients with HFRS in the severe group got significantly higher scores on the SAPS II, SOFA, and H-SOFA scoring systems (P < 0.001) (Table 8). Single-factor binary logistic regression analysis was used to explore the correlation between the scoring systems and severe or mild HFRS. High scores on the SAPS II, SOFA, and H-SOFA scoring systems were identified as risk factors for the progression of HFRS (P < 0.001) (Table 9). Finally, the ROC analysis of the SAPS II, SOFA and H-SOFA scoring systems revealed that the values of the SAPS II, SOFA and H-SOFA significantly correlated with the severity of HFRS (P < 0.001), and the AUC values were 0.90, 0.96, and 0.98, respectively (Table 10, Figure 2).
Table 8Scores on the SAPS II, SOFA, and H-SOFA scoring systems for HFRS patients, and a statistical analysis of the differences between the two groups.
Scoring systems, mean ± SD
Severe group (n = 50)
Mild group (n = 334)
t value
P value
SAPS II
48.14 ± 27.18
19.78 ± 9.23
7.265
<0.001
SOFA
13.06 ± 5.69
4.34 ± 2.18
10.629
<0.001
H-SOFA
15.86 ± 5.97
5.06 ± 2.60
12.472
<0.001
H-SOFA was a new version of the SOFA scoring system specifically for HFRS, which was incorporated with the level of fecal occult blood test according to the previous studies. Abbreviations: SAPS II, simplified acute physiology score II; SOFA, sepsis-related organ failure assessment.
Table 10Predictive values for disease progression based on scoring systems in patients with HFRS.
Scoring systems
AUC
P value
Cut-off value
Sensitivity
Specificity
95%CI for AUC
Lower
Upper
SAPS II
0.900
<0.001
30
80.00
87.10
0.855
0.936
SOFA
0.960
<0.001
6
96.00
83.87
0.927
0.981
H-SOFA
0.980
<0.001
9
92.00
93.55
0.953
0.994
Abbreviations: AUC, area under the ROC curve; CI, confidence interval; SAPS II, simplified acute physiology score II; SOFA, sepsis-related organ failure assessment.
Figure 2The ROC analysis revealed that the values of the SAPS II, SOFA, and H-SOFA were significantly correlated with the severity of HFRS (P < 0.001). H-SOFA was a new version of the SOFA scoring system specifically for HFRS, which was incorporated with the level of fecal occult blood test according to the previous studies. Abbreviations: ROC, receiver operating characteristic; SAPS II, simplified acute physiology score II; SOFA, sepsis-related organ failure assessment.
In this study, there was no significant correlation between severe HFRS and patient characteristics such as age and duration of the febrile phase. However, patients in the severe group had longer hospital stays; higher frequencies of nausea, vomiting, abdominal pain, signs of congestion, and hemorrhage; and more pronounced impairment of liver and renal function compared to the mild group. Patients with mild HFRS without shock and oliguria usually have mild signs of toxicity, and commonly enter the polyuric stage directly after the onset of fever. Such patients usually have a quick resolution of the condition with a good prognosis and short hospital stay. Patients with severe HFRS with an overlap of the second and third stages usually have more serious signs of toxicity and extensive damage to the capillaries and small vessels. This is usually accompanied by nausea and vomiting, abdominal pain, and other gastrointestinal symptoms, as well as obvious signs of congestion and hemorrhage (
). The kidneys are the most commonly damaged organs in HFRS, with the underlying pathological mechanisms including the direct damage caused by the hantavirus, hypoxic-ischemic renal damage, renal tubular obstruction, and immunologic injury caused by the renal deposition of immune complexes (
). Parameters such as urine volume, BUN, and albuminuria are all important indices in the clinical classification of the serious or critical type of HFRS in China (
). HFRS with liver function impairment is also very common; some patients suffer mainly from liver damage, and since the renal injury is not obvious, are easily misdiagnosed as having acute viral hepatitis (
). It has been reported that a disproportionality in T lymphocyte subsets, the obvious decrease in the absolute count and ratio of CD4+ T cells, and a dysfunction of the immune system, might be associated with the pathogenesis of HFRS. However, there were no significant differences in the levels of CD3, CD4 and CD8 between the mild and severe groups in our study (P > 0.05).
This study observed that the levels of PLT, PCT, TB, and FOBT were positively correlated with the progression of HFRS (P < 0.001), and the AUC values were 0.814, 0.712, 0.657, 0.782, respectively, which indicated the better predictive efficacy of PLT and FOBT. HFRS is usually associated with a sharp decrease in the level of PLT, the pathogenesis being the direct damage to megakaryocytes caused by the hantavirus, lysis, and death of platelets caused by the deposition of immune complexes, and massive depletion of platelets owing to vascular injury and DIC (
). Consistent with the results of our study, some scholars reported that the dynamic monitoring of the levels and function of PLT, as well as the increasing and declining patterns, were beneficial to assessing the condition of HFRS patients (
). Of course, there is the need for more studies to ascertain whether elevated PCT is positively correlated with the severity of HFRS. Hantavirus can damage the structural integrity of the intestinal wall directly, and induce immune injury by releasing inflammatory factors (
); therefore, patients with HFRS commonly suffer from gastrointestinal symptoms, such as nausea, vomiting, abdominal pain and diarrhea. Also, gastrointestinal bleeding, intestinal obstruction, and intestinal perforation may occur in severe cases. In our study, patients in the severe group had higher frequencies of positive FOBT compared to the mild group. Patients with positive FOBT had a higher probability of progression to severe HFRS.
The values of the SAPS II, SOFA, and H-SOFA systems were significantly correlated with the severity of HFRS (P < 0.001), and the AUC values were 0.90, 0.96, and 0.98, respectively. This indicated that all three scoring systems had good predictive value for progression to severe HFRS, with H-SOFA having the highest efficacy. The SAPS II is a system for assessing disease severity, monitoring intensive care unit (ICU) performance, and predicting prognosis. It has the advantages of convenient parameter assessment, relatively easy data acquisition, good operability, accuracy, and repeatability, and is not influenced by the kind of disease (
). As revealed in our study, patients with high SAPS II score had a higher probability of progression to severe HFRS, with the sensitivity and specificity of the diagnosis being 80.0% and 87.1%, respectively, and a cut-off value of 30 points. The SOFA scoring system is designed to assess the incidence and dynamics of single or multiple organ failure in patients, as well as the degree of organ failure (
). The SOFA has been widely used in western countries. Studies have shown that the maximum SOFA score after admission is consistent with the prognosis in critically ill patients, and is the most important predictor of patient outcome (
). In this study, the SOFA system was found to have a higher efficacy in predicting the progression to severe HFRS, the sensitivity, and specificity of the diagnosis being 96.0% and 87.1%, respectively, with a cut-off value of 6 points. Similarly, Kim et al. evaluated patients with severe organophosphate poisoning using the SOFA and SAPS II systems, and found that the SOFA score was simpler and more effective in predicting mortality (
). However, the SOFA scoring system lacks the ability to assess gastrointestinal function. In this study, we incorporated the FOBT results into the SOFA scoring system, to constitute a new H-SOFA scoring system specifically for HFRS. As revealed in this study, H-SOFA possessed the highest efficacy, with the sensitivity and specificity of the diagnosis of severe HFRS being 92.0% and 93.55%, respectively, and a cut-off value of 9 points. Of course, there is the need for large-scale, multicenter prospective studies to support the clinical use of the H-SOFA scoring system.
In summary, HFRS is still an important public health problem in China. The dynamic monitoring of the levels of PLT, PCT, TB, FOBT, and the clinical application of the SAPS II and SOFA systems will contribute to the early detection and recognition of severe HFRS. With the sustainable progress made in the development of supportive therapy in recent years, like continuous renal replacement therapy (CRRT), intermittent hemodialysis (IHD), blood purification treatment, and mechanical ventilation (MV), the treatment options available to patients with severe HFRS are continually improving, and are expected to increase the remedy achievement ratio.
Conflicts of interest
The authors have no conflicts of interest to declare.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgments
The authors would like to thank the staff of the Medical Research Center of Taizhou Hospital for their helpful advice and guidance.
Appendix A. Supplementary data
The following is Supplementary data to this article:
The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.
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