Abstract
Viral hepatitis is a considerable public health burden affecting millions of people throughout the world. The incidence of viral hepatitis varies greatly depending upon geographic locations, age and gender. Exploring the etiological spectrum and clinic-epidemiological profile of acute viral hepatitis (AVH) becomes essential for strategizing the preventive measures to control the diseases. An epidemiological data depicting AVH situation and its etiologies is missing from central India. With the aim of fulfilling this lacuna, the present analysis was done on samples tested over a period of 2 years from July 2015 to June 2017. Of the 1901 hepatitis cases, 597 individuals (31.4%) were positive for AVH infection and HEV was the predominant cause followed by HBV, HAV and HCV. Co-infections of hepatitis viruses were detected in 42 cases. Co-infection of HEV with HBV was the commonest pattern. Male preponderance was observed among AVH positive cases and the age group of 26–45 years was the most susceptible to the viral hepatitis infections, except hepatitis A, which was the most frequent among children. Two hundred patients (33.45%) required hospitalization and 51 deaths were attributed to AVH infections. The analysis for the first time reports intricacies and viral etiologies of AVH in central India. Regular diagnosis of AVH etiology and monitoring of cases will help in patient management and assist disease control programs to take policy decisions.
Electronic supplementary material
The online version of this article (10.1007/s13337-019-00541-6) contains supplementary material, which is available to authorized users.
Keywords: Acute viral hepatitis, Central India, Laboratory diagnosis, Epidemiology
Introduction
Viral hepatitis is a global public health burden that accounts for about 1.45 million deaths worldwide [32]. In India, viral hepatitis is now documented as a serious public health concern affecting the socioeconomic conditions of the country (http://www.searo.who.int/india/topics/hepatitis/en/). Central Bureau of Health Intelligence (CBHI), Government of India had reported a total of 111,025 hepatitis cases with 574 deaths and estimated 139,662 cases with 407 deaths in the year 2013 and 2014, respectively (https://www.thehinducentre.com/multimedia/archive/02557/National_Health_Pr_2557764a.pdf). The most common cause of viral hepatitis is a specific group of hepatitis viruses A, B, C and E (HAV, HBV, HCV and HEV) and their infections lead to clinical manifestations ranging from asymptomatic to acute and fulminant hepatitis or chronic hepatitis in the case of HBV, HCV and HEV [31].
Both HAV and HEV are the enterically transmissible viruses spread primarily via faecally contaminated food and water [6, 26]. Infection by HAV causes mild to acute illness with jaundice, but very rarely leads to acute liver failure. An estimated 1.4 million morbidity cases (http://www.who.int/immunization/diseases/hepatitisA/en/) and 102,000 deaths are attributable to HAV throughout the world [17]. HAV is highly prevalent among pediatric age groups with high infection rates in India [9]. HEV, the commonest causative agent of AVH, is responsible for epidemics, outbreaks as well as sporadic infections [8]. It causes mild or self limiting acute hepatitis, but occasionally leads to the development of fulminant hepatitis, particularly in pregnant women [27] with high case fatality rate (20–25%) (http://www.who.int/news-room/fact-sheets/detail/hepatitis-e).
Hepatitis B and C are blood-borne viral diseases that can manifest as an acute illness, but are commonly associated with severe liver diseases such as liver cirrhosis and hepatocellular carcinoma (HCC) [25]. Both infectious agents affect 325 million people worldwide and cause 1.34 million deaths every year (https://www.who.int/who-campaigns/world-hepatitis-day/2018), thus, constituting a major proportion of the viral hepatitis disease burden (https://www.who.int/hepatitis/publications/hep-elimination-by-2030-brief/en/).
Despite being a major health challenge in developing country like India, not many studies exploring the prevalence, etiology and clinic-epidemiological profile of AVH are available. Further, information regarding the co-infection of hepatotropic viruses among AVH cases from India is scanty [8, 12, 24]. Moreover better patient management and scaling up preventive measures of viral hepatitis burden mandate the exploration of epidemiological data on the pattern of etiologies, clinical picture, seasonal variability and distribution of AVH based on age and gender. Though few studies describing the incidence or etiology of viral hepatitis have been reported from different parts of the country [8, 10, 19, 24], there is no such data reported from central India. The present analysis elucidates the frequency, seasonal distribution, pattern of viral hepatitis infection and associated clinical features among clinically suspected AVH cases in central India.
Materials and methods
Study period, area and sample collection
This cross sectional observational study was conducted at the Virus Research and Diagnostic Laboratory (VRDL) of the Indian Council of Medical Research-National Institute of Research in Tribal Health (ICMR-NIRTH), Jabalpur, Madhya Pradesh (M.P.) India from July 2015 to June 2017.
AVH suspected patients presenting clinical symptoms such as jaundice, fever, malaise, headache, nausea, vomiting, anorexia, diarrhea, and abdominal pain for more than a week were examined by clinicians at Netaji Subhash Chandra Bose Medical College and Hospital (NSCB MC and H), a tertiary health care unit at Jabalpur (23°10′N 79°56′E) and blood sample (2 ml) of both in- and out-door patients along with clinical and demographic information recorded in predesigned format were referred to this laboratory for diagnosis. The patients from the both sexes and all ages were included in the analysis. The written informed consent was obtained from patients or their parents/guardians prior to enrollment. The samples of the patients with chronic hepatitis were excluded from the analysis. Serum was separated as per the laboratory protocols, and subjected to serological assay.
Serological tests
Serological tests were performed preferably on the same day of receipt for diagnosis of hepatitis A, B, C and E viral infections. Enzyme Linked Immunosorbent Assay (ELISA) of anti-HAV IgM (DRG diagnostics, Germany and Cat. No. EIA-5837), hepatitis B surface antigen (HBsAg) using HBsAg ELISA kit (J. Mitra & Co., India and Cat. IR020096), anti-HCV antibodies (J. Mitra & Co., India and Cat. No. HC-023096) and anti-HEV IgM antibodies (MP Diagnostics, Singapore and Cat. No. 21160-096T) were performed according to the manufacturer’s instructions. The test reports were handed over to the patients/their relatives/treating physician. The AVH positive cases were followed up for 3 months telephonically to find out the duration of hospital stay, clinical outcome etc.
Statistical analysis
The demographic details and clinical data related to viral hepatitis were entered into Microsoft (MS) Excel 2007 to calculate the frequency distribution of categorical variables and mean ± standard deviation of continuous variables. Comparison between proportions of two independent groups were analyzed using odds ratio (OR) and risk ratio (RR) with 95% confidence interval. Comparison of two independent mean values was done using student’s t test. The statistical analysis was done using the MedCalc medical calculator available online and p value of < 0.05 was considered significant (https://www.medcalc.org/calc/odds_ratio.php).
Ethical considerations
The study was conducted under the project “Establishment of Grade II virus research and diagnostic laboratory” and this project had an ethical clearance of the institutional ethical committee (RMRCT/Ethics Committee/2725/2011).
Results and discussions
Etiologies of AVH cases
We received total 1959 samples of AVH during the study period. Owing to the limited quantity of 58 samples, only 1901 samples could be tested for all four hepatic viral markers and were considered for further analysis. The overall percentage positivity of acute viral hepatitis was 31.4% (597/1901). Viral hepatitis mono-infection was observed in 555 patients (29.2%). HEV was the most common etiological agent among mono-infected AVH positive cases 260 (13.7%) followed by HBV in 186 cases (9.8%), HAV in 97 cases (5.1%) and HCV in 12 cases (0.6%). Studies from different parts of the country also reported HEV as a predominant etiological agent of viral hepatitis [8, 10, 19]. While Jain et al. [14] found HAV as the dominant cause of acute hepatitis in their hospital based study conducted in north India. The etiology of viral hepatitis and their associated clinical outcomes differ geographically owing to different social, cultural economical and environmental factors and varying prevalence of HAV (1.7–67%), HBV (7.3–42%), HCV (1.16–10.6%) and HEV (16.3–66.3%) was reported from different regions of India.
The predominance of HEV infection (n = 38) was also seen among co-infected cases 2.2% (n = 42) in the study. This virus was commonly observed with HBV (25 cases), then with HAV (8 cases) and HCV (4 cases). In one AVH positive case, HEV was found to be co-infected with HAV and HBV. Co-infection of HBV with HCV was observed among four AVH positive cases (Supplementary Table 1). The forty-two patients of total AVH positive cases (n = 597) were detected with more than one hepatitis virus infection, therefore, the overall sero-positivity of anti-HEV IgM, HBsAg, anti-HAV IgM and anti-HCV antibodies have increased i.e. 15.7% (298/1901), 11.4% (216/1901), 5.6% (106/1901) and 1.1% (20/1901), respectively (Supplementary Table 2).
Hepatitis B was the next most important cause of AVH and its sero-positivity, including mono- and co-infection was 11.4% among suspected patients. The finding is comparable with the data of the studies done previously in other parts of the country [11, 33]. India comes in the intermediate endemic zone for HBV infection with 2–8% prevalence among the general population [11]. In this study, low incidence of HAV (5.1%) was observed as compared to the studies reported from different parts of the country [14, 16]; probably because of higher mean age of the study population. Earlier study from central India reported 21% incidence with 7.3% HAV cases belonging to the adult age group [5]. In the present study, about 1% of AVH cases were due HCV infection, which is within the estimated prevalence of HCV (approximately 1–1.9%) in India [29].
Age and gender wise distribution of AVH cases
Among 1901 examined cases, the age/gender information of 12 patients was missing and the age and gender wise study was carried out by taking available information (n = 1889), which comprised of 1093 males and 796 females representing male predominance in the study group. In case of positive AVH cases, age/sex information of one HEV positive patient was not available. The mean age of the study group was 29.5 ± 18.4 years. The average age of males and females was 30.2 ± 18.8 years and 28.1 ± 17.9 years, respectively.
The high proportion of AVH positive cases [37.5% (224/597)] was observed in the age group of 26–45 years (Supplementary Table 1) and low in the age group (0–5 years) contributing 6.3% (38/597) of total sero-positivity. On gender wise analysis of AVH positive cases, the sero-positivity was higher among males [369/597 (61.8%)] than females [227/597 (38%)] (Supplementary Table 1) and the difference was statistically significant (OR 1.27; 95% CI 1.0 to 1.5, p = 0.015). The age group of 26–45 was identified as the most susceptible group for HEV (n = 117), HBV (n = 92) and HCV (n = 11) infections. On the other hand, a much larger proportion of HAV sero-positive cases belonged to the age group of 6–14 years, followed by age group of 0–5 years. The age groups above 14 years had 21 cases positive for anti-HAV IgM. The mean age of HAV, HBV, HCV and HEV positive cases was 11.2 (± 10.9), 38.2 (± 16.7), 41.4 (± 12.6), and 29.7 (± 15.7) years, respectively. The average age of HAV positive cases was almost three times less than that of HBV, HCV and HEV positive cases and this difference was statistically significant (p < 0.0001). Twenty-one cases of HAV (19.8%) were detected among adults during the present analysis, indicating an age shift from children to adolescent and adults. This age shift from children to adult has been observed with the improvement in socioeconomic conditions and maintenance of proper hygiene and it has been documented in other parts of the world and India [3, 14, 15].
The sero-positivity for anti-HAV IgM [61.3% (65/106)] and anti-HEV IgM [59.7% (178/298)] were higher in males than females (Supplementary Table 2), but the difference was not statistically significant (p = 0.4). The predominance of HEV (n = 117) was detected among age group of 26–45. The highest frequency of HEV was observed among males and adults, and similar findings were reported from other parts of the country [3]. The male dominance among HEV infected cases has been documented in endemic countries like Bangladesh, China and India [1, 13, 18]. Studies have shown that adults present more apparent symptoms than children [1, 23]. Higher prevalence among males and adults may be attributed to their greater risk of exposure to the contaminated water and travelling [2].
HBsAg sero-positivity was found higher among males [64.4% (139/216)] than females [35.6% (77/216)] and the difference was statistically significant (OR 1.3; 95% CI 1.0–1.8 p = 0.04). Most of the HBV infected cases in the study belonged to the adult age group (26–45 years). Similarly, a study by Antony and Celine [3] reported the highest frequency of HBV infection among the age group of 20–39 years, indicating adults are at greater risk of contracting HBV infection. Males (14/20) also outnumbered females (6/20) in case of HCV infection and its preponderance among adults was seen in the present study. This result is in accord with previous studies from India showing that males are more affected by HCV infection [22, 28]. The proportion of co-infections was higher in adults (34/42) than children (8/42). Among children, two cases of HBV + HEV and six cases of HAV + HEV co-infection were noted (Supplementary Table 1).
Seasonal distribution of AVH cases
Seasonal distribution of all four hepatotropic viruses was studied. The major etiological agent, HEV, was found to be circulating during all seasons, but maximum numbers of patients infected with HEV were seen in the monsoon season (July to October) followed by the summer season (March to June). The prevalence of HAV was higher in the summer season. The distribution of HBV and HCV was seen throughout the year (Fig. 1). The high prevalence HAV and HEV during the monsoon and summer period may be due to improper sewage management and water logging problems leading to drinking of contaminated water that is being a cause of infection and this is in agreement with other studies reported from India and other countries [8, 21]. On the other hand, the raised cases of enteric AVH in the summer could be due to contamination of potable water with sewage water, which is reported to occur due to the negative pressure created in water supply lines running in parallel with drainage lines [20]. The prevalence of HBV and HCV do not vary with seasonal changes. On the contrary, Chadha et al. [7] reported a high prevalence of HCV during the winter season.
Fig. 1.
Seasonal trends of hepatitis viruses in the central India. Monsoon season (July to October) followed by winter (November to February) and summer (March to June) in this part of the country. Seasons are given on the X axis and numbers of cases are on the Y axis
Clinical presentation of AVH cases
AVH suspected cases presented with a spectrum of clinical symptoms i.e. fever, jaundice, dark colored urine, hepatomegaly, nausea, vomiting and abdominal pain. Clinical symptoms with their incidence rate among AVH positive cases (n = 597) was recorded. The majority of the cases had fever and jaundice followed other clinical signs (Supplementary Table 3). There were marginal differences between clinical symptoms presented by AVH suspected and confirmed cases. This could be due to the other clinical conditions and hepatopathic infections caused by non-hepatotropic viruses, parasites and other pathogens showing similar clinical symptoms suggestive of AVH. It is estimated that approximately 15% patients of viral hepatitis are accounted by a group of non-hepatotropic viruses [12]. Thus, these viruses and other hepatopathic pathogen/s need to be detected simultaneously with the viral hepatic panel for better patient management, particularly in areas like central India where other hepatopathic infections among populations are common [30].
Two hundred patients (33.5%) required hospitalization out of 597 confirmed viral hepatic patients, and HEV was the main cause of these hospitalized cases and responsible for 105 cases (52.5%). HBV was the second major etiological agent causing hospitalization of 77 cases (38.5%). HAV and HCV were attributed to 23 (11.5%) and 7 (3.5%) cases, respectively. The average hospital stay was significantly lower in HAV patients [7.9 (± 3.2) days] than in the case of HBV, HCV and HEV patients [15.6 (± 10.4) days] and this difference was statistically significant (p < 0.0001).
Case fatality rate of AVH in the present study was 8.5% (51/597). The majority of mortality cases (n = 21) were attributed to the mono-infection of HBV followed by HEV (n = 19), HAV (n = 3) and HCV (n = 2). Among fatal cases, four were pregnant women having HEV mono-infection. Six fatal cases were caused by dual infection, two cases were with HCV and HEV infections, and four had a co-infection of HBV + HEV. Case fatality rate was higher among co-infected AVH cases [14.3%, (6/42)] than positive cases with mono-infection [8.1%, (45/555)]. The dual/super-infections may usually lead to the development of severe form of infections [4, 12].
The present study has certain shortcomings as it included only sample subjects referred from the hospital and not from the community. The information about a few patients was missing and serum samples were not subjected to the other serological markers of HBV. Despite the limitations, the sufficient cases were evaluated for etiologies of viral hepatitis during a period of 2 years and AVH confirmed cases were followed up for clinical outcome in order to comprehend the clinical feature of the AVH in central India. The study lays ground and provides a baseline data for future studies.
To conclude, AVH is a considerable problem in the central part of India. HEV is the most important viral etiological agent causing a maximum number of hospitalized cases and the second major causative agent responsible for case mortality after HBV. However, the morbidities and mortalities due to HBV are expected to reduce over a period of time with an inclusion of the HBV vaccine in the recently launched “Indradhanush” vaccination program in India (https://mohfw.gov.in/sites/default/files/216846291201489665182.pdf). Taking safety measures, including vaccination, improving sanitation and proper blood screening prior to the blood transfusion can reduce the incidence rate of viral hepatitis and limit their spread. Further, timely diagnosis of viral hepatitis can help in patient treatment and outbreak mitigation.
Electronic supplementary material
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Acknowledgements
The authors sincerely thank the Secretary of the Government of India, DHR, MoH and FW and the Director General, ICMR for financial support under the Viral Diagnostic Network Project (Grant No. VIR/43/2011-ECD-I). The authors thank Late Dr. Neeru Singh, Director, National Institute of Research in Tribal Health for her kind support and encouragement during the study. We thank the doctors and technical staffs at NSCB MC and H, Jabalpur for referring samples and co-operation for data collection. We acknowledge the assistance of Mr. Piyush Joshi, TA (R) in data analysis. We also thank The technical staff (Mr. Ritesh Dwivedi) at the Department of Virology at NIRTH, Jabalpur for their timely reporting and details of the test outcomes during the study period.
Compliance with ethical standards
Conflicts of interest
Authors declare that there is no conflict of interest.
Footnotes
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