Identifying risks for severity of neurological symptoms in Hungarian West Nile virus patients

West Nile virus (WNV) has become an endemic source of disease in a number of countries worldwide [1]. Although most human infections are asymptomatic or can be characterized as a mild disease, in rare cases WNV infections can lead to severe neuroinvasive disease and death [2]. Increasing trends in WNV infections have been reported in certain European countries, including Hungary, between 2014 and 2018 [3]. Compared to the average number of cases in preceding years, there was a 10-fold increase in 2018, with the Central and Eastern counties of Hungary being mostly affected [4, 5].

The WNV is a flavivirus and it is transmitted to humans by mosquito-bites, thus, causing a zoonotic disease [6]. Approximately 80% of patients infected by WNV remain asymptomatic and about 20% develop West Nile Fever, a mild, flu-like disease [2]. 1% of all infections results in West Nile neuroinvasive disease (WNND), which may manifest itself as meningitis, encephalitis, meningoencephalitis or acute flaccid paresis (AFP) [7]. WNND is a serious disease, with a mortality rate between 10 and 30%, and often leads to different forms of disability or deficit, even after recovery from the acute illness [2].

Studies investigating long-term prognosis after WNND, have shown that full neurological recovery could be as low as 37% after 12 months, and most patients (86%) who had suffered from encephalitis still had abnormal neurological exam findings up to 1–3 years later [8, 9].

Assessing risks for disease outcome is important for clinicians, particularly in WNND, where lack of timely or adequate supportive therapy may lead to lingering neurological symptoms and even long-term disabilities. Age, male gender and ongoing chronic illnesses, such as hypertension as risk factors, have been shown to be associated with developing WNND, while age, congestive heart failure, chronic hepatitis and neoplasm have been found to be risk factors for death [10, 11]. Investigations taking into account various parameters related to the patients and aimed at identifying potentially novel risk factors greatly enhance knowledge related to optimal medical care for WNND patients.

The goal of our study was to analyze the neurological status of West Nile Virus –infected patients upon hospital admission and to assess changes in their status after a short-term follow-up period, using one established and one novel neurological assessment tool. By collecting data regarding patients’ demographic, symptomatic, diagnostic and treatment-related characteristics, it was also our objective to identify potential risk factors as underlying reasons for severe neurological outcome.

Our study provided detailed data on the demographic and clinical characteristics of WNV infected patients from four regional medical centers in Hungary. The age and gender distribution as well as the presence of comorbidities was comparable with previous studies [26]. Symptoms of WNV infection often include fever, headache, malaise, muscle pain, chills, vomiting, eye pain, rash, and fatigue [6]. In our study population, fever, weakness/malaise and nausea/vomiting were the most common general symptoms.

Serological testing was carried out in all cases and was positive for either IgM or IgM and IgG in all of the patients’ serum or CSF samples. However, PCR testing was performed in only 84% of the cases and gave positive results in only 25.8% of all cases. The low proportion of PCR positivity can be explained by the short-term viremia and low viral load in humans. The length of elapsed time between symptom onset and date of sampling, and the storage and shipment conditions might also have an impact on the viral RNA stability in clinical specimens [27]. Lineage 1 and lineage 2 WNV, have been known as causative agents of human disease [28] and lineage 2 WNV was initially identified in Hungary outside of sub-Saharan Africa [29]. Lineage 2 WNV infections were identified in all of our PCR-positive cases, suggesting lineage 2 WNV circulation in Hungary, in accordance with sequence data [27]. Although, direct sequence data are not available from our PCR-negative cases, exposure to WNV lineage 2 infection was the most probable in their cases as well.

Treatment for WNND mostly includes supportive therapy, including administration of pain medication and the treatment of secondary infections, while treatment of seizures or respiratory insufficiency may even require intensive care [6, 8]. In our study population, administration of mannitol and steroid was the most common (19.7%) relevant medication, while analgesics and antibiotic or combination of antiviral (empiric acyclovir) and antibiotic therapy were given in the majority of the cases.

Meningitis, as WNND, can be typified by onset of fever, headache, meningeal signs and photophobia, while, encephalitis can manifest itself as a mild confusional state or as severe encephalopathy and coma [6]. Paralysis in WWND is usually caused by damage to the anterior horn cells of the spinal cord [6]. Although enrollment criteria in our study included all patients with confirmed WNV infection, the vast majority of our patients developed some form of WNND, that is, meningitis, encephalitis, meningoencephalitis or acute flaccid but all of the patients had some type of neurological symptom. The high proportion of WNND patients was unsurprising, since the symptoms of WNV infections are often mild and atypical, therefore patients often only present at a hospital with more severe symptoms, which are typical for neuroinvasive disease [2]. Almost a third of the patients suffered from muscle weakness after hospital admission, which in most cases was mild to moderate but reflex and sensory involvement was comparatively uncommon. Other frequent neurological symptoms were headache, vertigo and confusion following hospital admission which are in line with previous studies [2].

A few studies have focused on analyzing the neurological outcomes of WNV-infected patients [8, 9]. According to one investigation, long-term neurological abnormalities were most frequently found in WNND patients with primary WNV encephalitis, while another study reported that younger age was the only significant predictor for neurological recovery [8, 9]. Investigations based on previous post-stroke studies have shown that motor function improved rapidly in the first 6–8 weeks following neural injury and reached a plateau around 3 months [30]. Therefore, we believed it reasonable to follow-up our patients - whose motor function had been impaired in the majority of the cases - within a 2–6 month interval. The occurrence of muscle weakness has been reported to be typical of WNV-associated acute flaccid paresis and is thought to be due to a poliomyelitis-like process, a pure motor impairment [31‐33]. As expected, the proportion of neurological symptoms in our study population and patients’ status severity decreased by the 1st and 2nd follow-up intervals.

In a number of studies, advanced age, immunosuppression, hypertension, diabetes mellitus, cerebrovascular disease and other comorbidities have been shown to be associated with neuroinvasive infection and long-term sequelae [2, 10, 34, 35]. Accordingly, we found, that age above 65 years and having 2 or more comorbidities significantly increased the odds of severe neurological status after hospital admission. Among the presenting symptoms, “weakness/malaise” and “uncertain gait” were associated with higher ORs for severe neurological status. Although the reason for this finding is unclear, we hypothesize that “uncertain gait” as a symptom may imply consequent muscle weakness or vertigo and “weakness/malaise” may be a forerunner of neuroinvasive disease. A recent study showed that admission to the intensive care unit (ICU) predicted longer hospital stay, in-hospital death and survival with inability to walk independently in WNND patients [7]. Furthermore, 81% of these patients admitted to the ICU developed some kind of complication [7]. Accordingly, in our study, the occurrence of complications significantly increased the odds of patients having a severe neurological status at 1st follow-up, underlining the importance of supportive care in WNND in order to avoid complications.

Only a few studies have reported the number of days between the onset of neurological symptoms and hospital admission [36], however, to our knowledge, none have investigated their association with neurological symptom severity. Our most prominent finding, therefore, was that the time between the onset of symptoms and hospital admission influenced the severity of the neurological status in WNV-infected patients and shorter time intervals served as a protective factor. The longer the interval, the greater patients’ chances were for having severe neurological status after hospital admission.

Our findings regarding the above-described risk factors have several implications. Since elapsed time between neurological symptom onset and hospital admission affects symptom severity, it would be vital that patients with neurological symptoms present at their health care provider in time. Clinicians vat emergency departments are often the first to meet patients with a suspicion of WNV-infection. Thus, they need to be prepared to make timely care-related decisions when their patients present with various neurological symptoms, which often cause differential diagnostic difficulties due to the varied manifestations of WNV infection [5]. As reported previously, WNV infection can be an occupational hazard, affecting the younger, active population [37, 38], and a recent investigation found that younger patients were more at risk of developing critical WNND since age below 60 years predicted ICU admission [7]. In our study, two-thirds of the patients were below 65 years, indicating that the young, active population, particularly with comorbidities, was also a high-risk population. Thus, epidemiologic preventive measures, such as the prevention of mosquito bites and public education about the symptoms of WNV infections, among the general population appears important [7, 39].

Assessment of risks and the use of evaluation scales help clinicians make timely decisions regarding diagnostic and therapeutic interventions, especially in emergency settings where optimal allocation of resources is vital. The modified Rankin scale has been used for the assessment of functional assessment after stroke and meningitis [40] and also in WNND patients in a previous study [7], therefore we considered it convenient for assessing neurological status severity in our sample of patients. In comparison to the mRS, our scoring system, the WNV-N Index, took into account neurological symptoms typical for WNV neuroinvasive disease. Throughout the investigation, the two scores moved parallel with each other. Based on our observations, the use of assessment tools should be considered for patients presenting with neurological symptoms indicating neuroinvasive disease. However, further investigations are warranted for the development of the optimal WNV neurological assessment tool.

Our study was conducted on a sample of WNV-infected Hungarian patients with neurological symptoms, in a country among a few in Europe, where the incidence and prevalence of WNV infections has significantly increased over the past years.

Age, comorbidities, and complications during hospital stay significantly and independently increased the risks for severe neurological status in patients, during their hospital stay or short-term follow-up. We also identified a novel risk factor, longer time between onset of neurological symptoms and hospital admission, for the occurrence of severe neurological symptoms in patients.

Our findings imply that awareness regarding WNV infections and related neurological symptoms should be raised among the general population in WNV-affected areas. Clinicians need to be aware of their patients’ risk factors when the suspicion of a WNV-infection arises. Furthermore, the development of an optimal tool for assessing neurological status in WNV infection could be an important step for improving outcome for WNND patients.