Clinical characteristics and outcomes in critical patients with hemorrhagic fever with renal syndrome

Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused by Hantavirus [1, 2]. Hantaviruses are carried by rodents, and transmission to humans is caused by the inhalation of infected rodent excreta [3]. China is the most severe endemic area of HFRS in the world, with 30,000-50,000 cases reported annually, which account for > 90% of total numbers worldwide [4, 5]. Shaanxi province is one of the most severely affected provinces in China. Xi’an is the center district of Shaanxi province and has had an increased incidence and mortality rate in the last three years [6]. Until now, it has been reported that all HFRS cases in this district are caused by hantaan virus (HTNV), a major serotype of Hantavirus [6], and the disease usually occurs in the spring and autumn/winter, with two incidence peaks [7]. Furthermore, a large number of patients in this epidemic area were adults, which was in sharp contrast to the predominantly pediatric cases seen in the dengue epidemics in southeast Asia [8, 9].

The clinical course of HFRS is primarily characterized by fever, circulatory collapse with hypotension, hemorrhage and acute kidney injury (AKI) [2, 10]. The typical disease progresses through five phases: febrile, hypotensive, oliguric, diuretic, and convalescent [11, 12]. A hallmark of HFRS is capillary leak syndrome, which causes edema and hemorrhage, suggesting that the vascular endothelium is the primary target of virus infection [13, 14]. In view of the rapidly expanding population and high mortality rate of infection in this district [6], it is essential to obtain a more comprehensive and better understanding of the clinical characteristics and outcomes in critical patients with this disease and to help clinicians engage in timely monitoring and effective supportive therapy in the early stages of the disease to improve the final survival rate.

To our knowledge, this is the first clinical study on the clinical characteristics and outcomes in critical patients with HFRS, with the largest sample enrolled in China. In the 75 critical patients enrolled, 29 cases died, with a hospital fatality of 38.7%. The Kaplan-Meier analysis revealed that the cumulative proportion surviving was 70.7% at the second week interval, with a 28-day mortality rate of 36.3% (Figure 1). This observation indicated that the fatality of critical patients with HFRS was high and was similar to the mortality rate of severe septic shock patients in the intensive care unit (ICU) [18‐20]. In this study, a majority of patients enrolled were male and farmers, with high incidence and obvious seasonal distribution (Table 1). These data are consistent with the biological and epidemical characteristics of the primary natural host (Apodemus agrarius) of HTNV and the susceptibility of the patients working in certain surroundings that are the natural habitat of rodents in Xi'an city [6, 7, 21]. Until now, the hantavirus strains from host rodents and patients in Xi’an only belong to the HTNV, and SEOV strains have not been found [6].

In this study, the survivors tended to have prolonged hospital stays (Table 1), which were consistent with the clinical course of HFRS. Generally, the hypotensive phase of HFRS (e.g., low blood pressure and circulation collapse) usually occurs between day 3 and day 7 of the clinical course, and some critical patients even exhibit overlapping hypotensive and oliguric phases combined with various fatal complications. During this period, timely and systematically supportive treatment, including mechanical ventilation combined with continuous blood purification (CBP), vasoactive drugs and nutritional supplement, are necessary to ensure survival. However, some critical patients still died of refractory shock, ARDS, multiorgan bleeding, disseminated intravascular coagulation (DIC) or multiple organ dysfunction syndrome (MODS). Patients who have passed through the critical phase may manifest obvious oliguria with AKI. The durations of the oliguric phase in patients with HFRS are obviously different based upon the degree of AKI [16] and the influence on applications of RRT including continuous renal replacement therapy (CRRT) and intermittent hemodialysis (IHD) [22, 23]; only a minority of critical patients die during this phase. Furthermore, it is an unfortunate truth that in addition to the critical condition of the disease on admission, the patient’s economic status may also influence the prognosis directly or indirectly.

The present study demonstrated that the non-survivors had higher frequencies of dyspnea, agitation, conjunctival hemorrhage, coma, cardiac failure, ARDS and encephalopathy compared to the survivors (Tables 2, 3, 4 and 5). The agitation, conjunctival hemorrhage, coma, cardiac failure, ARDS and encephalopathy were all negatively correlated with the survival outcome (Table 7). Although there was no significant relationship, the difference was obvious in pleural effusion and pericardial effusion found in the survivors vs. non-survivors (Table 4). According to the pathophysiologic characteristics of HFRS, the pleural and pericardial effusion can reflect the degree of body edema and may increase the risk of the occurrence of pulmonary infection, ARDS and heart failure. All of these findings highlight that it would be dangerous to ignore the critical condition of the disease and the increased probability of death when patients exhibit clinical manifestations of ARDS and encephalopathy, and conjunctival hemorrhage can be considered to be a local manifestation of severe organ bleeding with poor outcome. Furthermore, ARDS, conjunctival hemorrhage and coma were identified as risk factors for prognosis by binary logistic regression analysis (Table 8), which underscores the importance of clinicians’ alertness to the occurrence of potentially fatal complications. Additionally, although cardiac failure was not a risk factor for death in the present report, it deserves further study in larger samples of critical patients, especially the cases of deaths.

Kidney is a major organ that is damaged during HFRS, with the most prominent pathological presentation being acute tubulointerstitial nephritis following the infiltration of inflammatory cells [24]. In this study, a majority of the patients had humoral abnormalities with obvious urine protein and urine occult blood (Table 4), which may reflect the degree of severity of AKI. In this study, all the critical patients had different stages of AKI, and 62 cases (82.7%) exhibited ARF, the third stage of AKI [16] (Table 5). Interestingly, we observed that the frequency of ARF in the survivors was obviously higher than that of the non-survivors (Table 5). ARF and Scr were positively correlated with the survival outcome (Table 7); non-survivors were also found to have lower Scr levels (Table 6).These results can be explained by the fact that some critical patients died during the overlapping phase because of other fatal complications when ARF was not obviously detected. According to the data, we can conclude that the stage of AKI and the duration of the oliguric phase during the acute stage are not a directly influential factor for prognosis because of the application of RRT.

This study observed that the levels of WBC, HGB, ALT, BUN, Scr, glucose, PT, APTT and TT in the critical patients were higher or longer than the reference value, while the levels of PLT and ALB were lower than the reference value (Table 6), which indicated that critical patients with HFRS usually had obvious hepatic and kidney injury, and stress hyperglycemia and hypermetabolism were also common during the clinical course. According to the pathophysiologic mechanism of HFRS, it has been widely accepted that severe plasma leakage, massive bleeding and/or profound shock may lead to tissue hypoperfusion, potentially rendering AKI and hepatic injury [25]; the high level of HGB was closely related to the degree of pachyhemia; the low level of PLT was related to the decreased platelet production or increased platelet destruction [26‐28]; the low level of ALB correlates with degree of the loss of vascular integrity and enhanced vascular permeability, which also usually appears in patients with dengue hemorrhagic fever (DHF) [3, 29]. Compared to the survivors, the non-survivors were found to be more critical, with a higher degree of inflammatory reaction and coagulation abnormality, which is in line with the previous reports on patients with DHF [30‐32]. Furthermore, although the AUCs were not higher than 0.900 and would be influenced by small samples or treatments, ROC analysis still revealed that the WBC levels, PT and APTT times were statistically significant for predicting death (Table 9, Figure 2). In total, the laboratory results may reflect the severity of the disease to a degree, and clinicians should be alert to their dynamic changes during the acute stage, ensure close monitoring and thereby initiate a timely management as necessary.

As a retrospective study, some limitations must be addressed. First, this study was conducted at the largest center for infectious diseases in the northwest region of China. Most patients with severe clinical conditions were sent to our medical center, but it is likely that outside of our center, there were still a significant number of critical HFRS patients who were admitted to local hospitals. Therefore, the demographic, epidemiological characteristics and mortality rate in critical patients may have been biased. Second, the clinical manifestations may be biased by clinicians based on his or her personal recognition of the clinical severity. In this study, we were unable to calculate the acute physiology, age, chronic health evaluation (APACHE II) score, sepsis related organ failure assessment (SOFA) and simplified acute physiology score (SAPS II) of the critical patients on admission because of the loss of detailed clinical data on central nervous system dysfunction. These data may be very important for predicting the prognosis. Third, the relatively small number of cases made the statistical power quite small, especially for multivariate logistic regression analysis used for identifying risk factors for death in the critical patients. Finally, the clinical outcomes and classifications of HFRS patients might be biased by the lack of a more standardized protocol for the management of patients with HFRS.

The high fatality in critical patients with HFRS underscores the importance of clinicians’ alertness to the occurrence of potentially fatal complications and changes in biochemical status to ensure that timely and systematically supportive treatment can be initiated when necessary.