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A spectrum of viral diseases in Odisha state, eastern India: An evidence-based analysis from 2010–2017 J Sabat1, S Subhadra1, LM Ho1, B Dwibedi21 VRDL, ICMR-Regional Medical Research Centre, Bhubaneswar, Odisha, India 2 Department of Pediatrics, AIIMS, Bhubaneswar, Odisha, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpgm.jpgm_1152_21
Keywords: Disease burden, fever of unknown origin, Odisha state, RT-PCR
Any country's disease burden data plays a crucial role in addressing the threat of seasonal diseases, helps in strengthening national and global preparedness/alertness, prevention, and control efforts. It helps the policymakers in planning the execution of health policies in the country. Emerging and re-emerging virus diseases are a major threat to human and veterinary public health. Every year a new virus is added to the existing list, and surprisingly, the majority of them originate from an animal host.[1] There are many factors like changes to local ecosystems perturbing the balance between pathogens and host species, increasing urbanization, and changes in human behavior. Emergence is hard to predict, although knowledge of spatial epidemiology and mathematical modeling has helped to improve the prediction of where disease emergence may occur. However, much needs to be done to ensure that adequate disease surveillance data is maintained to create general alertness among physicians, veterinarians, and policymakers. Importantly, better tools are required to identify and control emerging diseases in the regions where interaction between humans and animals is high, and many of these diseases have originated from those places. It has been estimated that out of the 20 emerging/re-emerging infections all over the world, 14 are of viral origin.[2] Global disease burden with special reference to infectious diseases varies from country to country. There is limited data from a publication point of view as it is seen that the country having the highest disease burden is not availing adequate opportunities, which may be due to inaccessibility to technological advancement tools to contribute sufficiently to the scientific world. The global disease burden also estimates the number of early death and life years compromised by disease and disability (DALYs). It had been estimated that the countries having 20,000 DALYs per 100,000 are in the best health condition, achieved by many European countries and Canada, Israel, South Korea, Taiwan, Japan, Australia, etc., India had 39,559.7 DALYs per 100,000 as of the year 2017, whereas Africa had 80,000 DALYs per 100,000.[3] As per WHO, at a global level, >60% of the disease burden was due to non-communicable diseases, 28% due to communicable diseases, and 10% from injuries. Among chronic liver diseases, worldwide 500 million people were infected with Hepatitis B or C, and two-third of the total infected people live in Eastern Europe and Central Asia regions. Dengue is still considered one of the fatal and neglected tropical diseases, endemic to 125 countries with 3.6 billion people at risk mostly residing in Africa, Asia, and the Indian subcontinent.[4] The global disease burden was estimated to be a 15-times greater burden of infectious diseases per person in India than in the UK in 2004. Disease burden due to the infectious cause has contributed to around 30% of the total disease burden in India. Among the viral diseases, first being the lower respiratory tract infection contributing 25.8% followed by diarrhoeal diseases- 21.5%, Measles- 6.1%, Hepatitis B- 0.6%, JE- 0.4%, and Dengue- 0.2%.[5] There is a paucity of data on viral disease burden not only in the state of Odisha but also in the eastern part of India. Odisha is situated on the coastal belt of the Bay of Bengal. Due to its geographical location, the state is always at the risk of natural calamities like flood and cyclone that poses a higher risk of infectious diseases. This is the first report on viral disease burden in the state of Odisha and bordering regions which are presented here.
The study was conducted at India Council of Medical Research (ICMR) Virology Grade 1 Laboratory of Regional Medical Research Centre (RMRC), Bhubaneswar. We looked into sporadic outbreaks of viral diseases, investigating their etiology and clinico-epidemiology in coordination with the state health system. The laboratory was networked with different health facilities established in both government and private set up in Odisha for hospital-based surveillance of suspected viral diseases that included major tertiary care hospitals/medical colleges and district hospitals. The detailed methodology is outlined below. Plan of Investigation We conducted hospital-based case enrolment and outbreak investigation of suspected viral diseases reported in the region. Tertiary level hospitals/medical colleges of Cuttack and Bhubaneswar and district hospitals of Odisha were included for case enrolment. The geographical catchment area included Odisha and neighboring states like West Bengal, Jharkhand, and Chhattisgarh, as many patients from the bordering states seek referral service at the hospitals of Bhubaneswar and Cuttack. We used a uniform clinical data recording format and criteria for subject enrolment for viral disease investigation from hospitalized patients. Coordination meetings were held with the clinicians at the outset, and electronic contact was maintained throughout the process. The state health cooperation was sought as per situational requirements, especially for outbreak investigations. The sample collection and transport process was supervised to maintain uniformity as per the laboratory diagnosis Standard Operating Procedure. This study followed a surveillance approach to include the majority of clinically suspected cases from sporadic hospital admission as well as reported outbreaks. Suspected patients were included from around 55 government and private health facilities located at different places in the state of Odisha. Detailed demographic and clinical information was recorded from each patient, and samples were collected as per requirement. The samples were transported to the centralized laboratory set up at RMRC, Bhubaneswar, following the cold chain. Investigation (serological and/or molecular) was undertaken as per the specific virus/group of viruses suspected following laboratory methodology. The investigation reports were shared with treating clinicians and/or public health authorities immediately after laboratory testing on ethical grounds to support case management and public health action. The cumulative data has been analyzed and presented in this report to provide summative information that would help both case management and public health control through early suspicion and sensitization. Study area and population The study was intended to explore the pattern of different viral diseases in the state of Odisha, which is situated in the eastern region of the country. The state of Odisha is situated on the coastal belt of the Bay of Bengal sea, spreading over 480 km across the coastal belt. The state of Odisha is located on the East coast of India between 17° 48' and 22° 34' North latitude and 81° 24' and 87° 29' East longitude. Besides, the above patients were also included from bordering states who attended the hospitals in Odisha covered under the study. A total of 43,397 patients were screened for different viral diseases from 2010–2017. This included 938 patients from outside Odisha, bordering states like West Bengal, Jharkhand, and Chattisgarh. Laboratory investigation Patients were included for evaluation of suspected viral diseases with Dengue (DENV), Chikungunya, Japanese Encephalitis (JEV), Hepatitis A, B, C and E virus (HAV, HEV, HBV, HCV), Herpes simplex-1 and 2 viruses (HSV-1, HSV-2), Epstein-Bar virus (EBV), Cytomegalovirus (CMV), Respiratory viruses, and Viral diarrhea were also included in atypical/unsolved clinical settings suspected of a viral infection. The samples included blood, Cerebro Spinal Fluid (CSF), throat/nasal swab, pericardial fluid, stool/rectal swab and tissue samples. Samples were processed in biosafety laboratory level-II (BSL-II), aliquoted, and stored at –20/–80° C for further use. About 5 ml of serum was transported in an icebox maintained at 2–8°C and processed within 24–48 hours. Samples were subjected to Enzyme-Linked Immune Sorbent Assay (ELISA) as per the requirement of clinical investigation and history of disease as recorded by the clinician. ELISA was done by using standard and recommended kits. The ELISA kits used were: Chikungunya IgM and Den IgM (NIV, Pune), DEN NS1 (Panbio, USA), HAV and HEV (MP Biomedicals, USA), HBV (HBsAg) and HCV (J. Mitra, India), HSV1 and 2 IgM, Measles IgM, Rubella IgM (EuroImmun, Germany). For patients suspected of DENV infections having a history of fever <5 days, Dengue NS1 antigen ELISA was performed. Hepatitis C Virus (HCV) testing was done for the presence of total antibodies. Samples from patients with a history of recent infection (within one week of disease onset) were preferred for molecular testing. Molecular tests include RealTime RT-PCR for respiratory viruses like Flu A, H1N1, Adeno, Human Metapneumovirus virus (HMPV), Rhino, Corona, Entero, Respiratory Syncytial Virus A B (RSV AB), Human Boca Virus (HBoV), and Para Influenza viruses (1-4). For these respiratory viruses ready-to-use RT-PCR kit from Fast Track Diagnostics, Luxenberg was used as per manufacturer instruction for master mix preparation and setting of PCR conditions. During the study, standard guidelines of GCP and GLP were followed, and approval of the human ethical committee was obtained. Written informed consent from the patients/guardians was taken before enrolment and sample collection. The report of the laboratory diagnosis was provided to the patient/treating physician for patient care free of cost on ethical grounds. Statistical analysis Data were entered and analyzed in Microsoft Excel. The percentage prevalence for different variables was calculated as the percentage of the number of samples positive for a particular viral infection out of the total suspected cases investigated.
Distribution of patients suspected of a viral disease according to clinical presentation (or syndrome) In the present study, a total of 43,397 patients were included from different health care units in Odisha. Patients were enrolled as per the syndrome of viral diseases, and samples were tested on the basis of symptoms and preferred viral testing. As per the presenting symptom/syndrome, the patients were categorized under six broad groups like diarrhea, acute encephalitis, fever with rash, fever cases without any confirmed etiology/Fever of unknown origin, jaundice syndrome, and respiratory illness [Table 1]. Out of the total cases the highest number of patients, i.e., 32.24%, were enrolled under fever with rash, followed by 24.55% under suspected viral encephalitis [Figure 1]. Though the least number of cases were enrolled for fever of unknown origin (2.56%), the total number (n = 1,113) was considerable.
The number of males was more in different clinical presentations/syndromes, except fever with rash, where females (53.34%) were more than males (46.66%). Children <16 years of age were found to be the predominant age group for suspected viral diarrhea (85.26%), encephalitis (76.96%), fever of unknown origin (40.16%), and respiratory illness (27.23%). The majority of patients in the age group 16–30 years were presented with jaundice and fever with rash, i.e., 45.71% and 30.45%, respectively [Table 1]. Distribution of patients confirmed with a viral etiology among those suspects Laboratory analysis of each group of viral illnesses was done as per the symptoms and signs mentioned in the clinical proforma filled up during sample collection. The distribution of different viruses identified among different syndromic groups is depicted in [Figure 2]. Rotavirus infection was predominant contributing 29.94% towards childhood diarrhea in comparison to Adeno, Astro, and Norovirus infection. In the case of Acute Encephalitis Syndrome, IgM antibody to HSV was present in 13.22% of cases, followed by Japanese Encephalitis (JE) virus detected in 9.91% of cases. Cases of JE included 65% children of <15 years of age. Among the cases presenting with fever and rash, varicella was the most predominant (49.85%) among the studied population, followed by dengue (45.92%), measles (32.38%), mumps (16.48%), chikungunya (13.26%), and enteroviruses (11.90%). Among the total cases enrolled for fever of unknown etiology, 21.91% EBV IgM was detected, followed by CMV IgM in 19.08%. Viral hepatitis was another major illness reported in the region. The major contributor to acute viral hepatitis was the Hepatitis A virus, with an IgM antibody prevalence of 35.49%, followed by 26.56% for HEV IgM. Hepatitis B was found to be the major contributor to chronic hepatitis (HB antigen-11.28%) in comparison to HCV (2.21%). Respiratory illness contributed 9.04% of the total viral illness studied in this population. Among the respiratory viruses, the pandemic H1N1 virus contributed 18.48%, followed by the Flu A virus, i.e., 10.82%, which was detected as a seasonal virus. Other respiratory viruses like Adeno, HMPV, Rhino, Corona, Entero, RSV, HBoV, and Parainfluenza viruses were detected in low prevalence (1–4%).
Proportion of males was higher in almost all the studied viruses; Rota (63.74%), JE (55.73%), HSV 1 (52.97%), Dengue (63%), Varicella (55.75%), Measles (51.92%), Mumps (59.57%), EBV (51.82%), HAV (58.49%), HEV (62.03%), HBV (71.50%), and Flu A (59.36%) as compared to their female counterparts. However, Chikungunya (52.16%), CMV (59.26%), and H1N1 (50.08%) had a female predominance. The mean age varied between 2.4 years (Rota) and 49.67 years (H1N1), and the median age was between 1 year (Rota) and 53.5 years (H1N1) [Table 2]. The Standard Deviation (SD) value ranged between 3.87 and 22.33.
Laboratory confirmed viral infections were geographically widespread over the state of Odisha. The mapping of districts with frequent reports of outbreaks or a larger number of sporadic hospital admissions associated with common viral agents is outlined in [Figure 3].
Common viruses identified in the region associated with presenting symptoms and age group Viral antibodies or molecular markers showing higher prevalence were further analyzed. It is evident from the study that children <5 years of age group are more susceptible to Rotavirus diarrhea with a prevalence of 93.09% of total rotavirus positive cases. Among the confirmed cases of viral encephalitis, the age group 5–15 years appeared to be most affected with JE (43.06%) and HSV-1 (40.79%). A significant number of cases have also been reported for dengue (39.98%) and chikungunya (27.78%) in the age group of 16–30 years. Mumps (62.50%), measles (62.36%), varicella (53.10%) were noted in the 5–15 years of age group. CMV (27.78%) among age group <5 years and EBV (22.73%) among 31–45 years were more prevalent. HAV (74.57%), and HEV (38.67%) were more prevalent among 5–15 years and 15–30 years, respectively. It was noted that the 46–60 years age group was affected with Flu A (25.40%) and H1N1 (29.42%) with the highest prevalence. Though the percent prevalence was not high for any viral disease in the age group >60 years, still a considerable proportion of Flu A (25.13%), H1N1 (18%), and Chikungunya (14.20%) were recorded [Table 3].
The genotype of common viruses circulating during the period During this period, some common viruses causing outbreaks or major sporadic infections were tested and phylogenetically analyzed. The genotype/serotype circulating in the region was found. For Dengue, all four serotypes were found to be circulating with genotype-III of serotypes 1 and 3, genotype-IV of Serotype 2. The ECSA genotype of Chikungunya was found to be a major genotype as per the E2 genetic region analysis. Genotype D8 of the measles virus was established as the prevalent genotype that caused many outbreaks during this period. Subtype A of Genotype 1 of HEV was found to be a cause of a major outbreak isolated from Sambalpur district of Odisha in 2014. Subsequent genotypic analysis for rotavirus revealed G1P[8] as the commonest genotype causing viral diarrhea in this region. Genotype D and genotype 1b were found to be present for HBV and HCV, respectively. H1N1 was found to be the major Flu strain circulating in this region. Co-infection detected for some major viruses Out of 619 dengue-positive samples tested for Chikungunya, 87 samples were found positive for both Dengue and Chikungunya IgM. Among JE positives, 11 were both positive for Dengue and JE out of 55 samples (Serum and CSF) tested for both Dengue and JE IgM. It was noted that out of 768 samples tested for both HAV and HEV, 90 samples were positive for both HAV and HEV IgM. For HSV-1 and 2 IgM, out of 387 samples tested, 119 were positive for both HSV-1 and 2 IgM antibodies. Similarly, 59 samples out of 135 were positive for both EBV and CMV IgM. This does not cover all co-infections, as every sample was not processed for investigating co-infections.
In recent years, globalization and ease of transportation have made the frequent movement of people across continents, which has impacted human health to a great extent. Human behaviur towards nature has also been changed, attributing to imbalance in the natural ecosystem. Simultaneously increased attention is paid to the changing patterns of infectious diseases all over the world. Now the factors that lead to the emergence or re-emergence of infectious diseases are given more importance to think and act immediately to curtail the interference in the animal world.[7] It is estimated that as high as 75% of these emerging diseases are derived from animals. These zoonoses spilled over from their natural reservoirs either through direct or indirect contacts and subsequently entered into the human population.[8] Diarrhea is the second leading infectious cause of childhood disease worldwide, and Rotavirus is the single most common cause of severe and fatal diarrhea in children <5 years of age.[6] Indian studies have shown a prevalence of 23.5%–49.4% among children of this age group which agrees with our study where 29.94% were reported, and 93.09% of this rotavirus antigen-positive cases belonged to children <5 years of age.[9] It was evident from different reports that viruses are the major cause of Acute Encephalitis Syndrome (AES) and the type of viruses markedly differ in different regions of the world. HSV is the most common viral agent for AES, as reported by many authors.[10] In eastern India, HSV-1 is the leading cause of viral encephalitis, with a reported prevalence of 34.6%[11] compared to our study, where a prevalence of 13.6% was recorded. For decades, JE had been considered to be the leading cause of AES in Asia, especially in North and North-west India. Our study detected 9.2% of JEV IgM, which is the 2nd leading cause of AES in comparison to the 16.2% prevalence observed in north India.[12],[13] Fever is a very common complaint among hospital attendees, and studies describing the epidemiology of fever are scarce, perhaps because it is considered a commonplace and non-specific finding. Still it may go up to 30% among non-surgical patients as per some studies done in the past.[14] Fever with an accompanying rash is a common symptom constellation in patients presenting to clinicians that may provide an early clue to an underlying infection.[15] The occurrence of generalized rashes is the most frequent condition seen by primary care physicians, which sometimes becomes a diagnostic challenge.[16] In our study leading number of cases were enrolled for febrile illness with any type of rash, which contributed to 32.24% of total cases. The differential diagnosis for febrile patients with a rash is extensive. Diseases that present with fever and rash are usually classified according to the morphology of the primary lesion. For classification, a thorough history and a careful physical examination are essential for making a correct diagnosis, although laboratory studies can be useful in confirming the diagnosis.[17] In most of the viral infections, males outnumbered females; however, this may be the representation of all the patients who visited the health care system to seek medical care rather than the truly infected population. Identification based on the type of rash and other associated clinical presentation is possible for Varicella Zoaster in comparison to Measles and Rubella. Among the group of patients who presented with fever and rash, seropositivity for Varicella IgM was the highest (49.89%) recorded. Though the incidence of the disease has been decreased in many countries after the introduction of the vaccine but it continues in outbreak form in developing countries like India.[18] A study in North India has shown an antibody prevalence of 76.5% in an outbreak in 2013.[19] Dengue is the most common mosquito-borne viral infection reported in many regions of the world. India has experienced a number of outbreaks and considerable mortality due to Dengue infection in the last few decades.[20] In India, dengue was also found to be one of the most common viral and mosquito-borne diseases studied in north India, contributing 55.7% of all viral diseases studied.[21] Odisha experienced its first Dengue infection in the year 2010 and continued each year in epidemic form during post-monsoon period, gradually becoming an endemic phenomenon.[22] This study reported 45.92% of the patients to be serologically positive for dengue infection, which can be correlated with other Indian studies reporting a prevalence ranging from 31.3% to 56.77%.[23] Measles is one of the world's most contagious and vaccine-preventable diseases. As per the WHO report (2019), 10,430 incidences were recorded, the leading disease being pertussis (11,875). Due to effective vaccination, global measles death has been decreased by 73%, from an estimated 536,000 in 2000 in comparison to 142,000 in 2018.[24] A high seropositivity for IgG antibody (91%) in comparison to IgM (11.1%) was recorded in a three years study from 2017–2019 in Mumbai.[25],[26] In our study Measles IgM was recorded in 32.38% of cases, out of which 62.36% of cases were detected among the 5–15 years of age group, which needs to be further analyzed for vaccinated and non-vaccinated cases. As reported by many authors, fever is the most common symptom observed in most clinical practices. It may be self-limiting or have some underlying etiology. When fever remains undiagnosed and persistent for a period of three weeks, it is called Fever of Unknown Origin (FUO).[27] The etiology for FUO may differ in different countries. The present study reported an EBV IgM prevalence of 21.91%, with a higher prevalence of 22.73% among 31–45 years of age. Some studies have shown 44.4% of EBV IgM antibody prevalence,[28] whereas others have shown it as highest (55%) in the third year of life and remained between 30% and 40% thereafter.[29],[30] Our study reported CMV IgM in 19% of cases with fever of unknown origin. There is a very scanty report on CMV as a major viral etiology in FUO. Sero-prevalence of CMV was reported from 50 to 90% in different studies with an increasing prevalence with advancing age as much as high as 90.8% among >80 years of patients.[31],[32] Manfredi et al.[28] found in a cohort of patients with fever of unknown origin that approximately 14% were positive for CMV infection where the symptoms associated with primary CMV infection are prolonged, with fever lasting three weeks or more. Hepatitis A and Hepatitis E viruses contribute significantly towards acute hepatitis in humans transmitting feco-orally. They pose a major health problem in developing countries like India in terms of sporadic infection and outbreaks.[33] India reported high seroprevalence ranging from 26.96% to 97.6% among acute viral hepatitis cases in southern and northern India.[34],[35] It was also noted that the seropositivity of HAV was closely linked to the educational and socioeconomic status of the people. Sero-prevalence of HEV in India is reported as low as 10.54% and as high as 92% in different studies in comparison to our study (26.56%).[36],[37],[38] It is believed that HAV infection is a disease in infants and young children, and the same was found in our study, with 74.57% of total HAV positivity in children within the 5–15 years age group. On the other side, maximum positivity in HEV (38.67%) was found in the population 16–30 years of age group with more number of males than females. This justifies the preponderance of HEV infection in older children and young adults.[39] These findings, along with other studies, indicate that HEV infection has now emerged as a global health burden requiring the implementation of specific control measures.[40] In 2009, the world encountered a pandemic due to a novel Influenza A (H1N1) pdm09. The first case was reported from Mexico in 2009, which was characterized by rapid spread and high morbidity.[41] The first cases of pandemic A (H1N1) pdm09 were reported in Hyderabad city in 2009 in India that spread rapidly within a short span of time. During this period, a large population of Odisha was also affected, where H1N1 positivity of 21.1% was reported.[42] The current prevalence of 18.48% was lower in comparison to the reported prevalence of 21.1%, indicating the population affected during 2009 was naive to H1N1 infection, and gradually, it became endemic in nature. It was seen that the distribution of cases was disproportionate among all age groups but the patients belonging to the 46–60 years followed by the 30–45 years of age group were found to be more affected than the other age groups, which was also reflected in previous studies.[43] The above observations reported here provided baseline evidence and/or information on a relatively proportionate burden of different viral infections in the region during 2010–2017. More importantly, it covers all the major viral disease manifestations with laboratory-confirmed evidence, which was not available prior to 2010. Besides few reports on outbreak/sporadic disease investigation indicating circulation of chikungunya infection (2006–07),[44] Japanese encephalitis (1989-90),[45] Hand Foot Mouth disease (2009),[46] and Chandipura virus causing encephalitis (2009),[47] Hepatitis B and C seroprevalence in the tribal population (2007–2009),[48],[49] there is no comprehensive record of viral diseases in the region. The report would sensitize the public health system in undertaking a multi-prong approach to meeting the challenges of patient care and public health prevention. This report on the proportionate contribution of different viral agents and genotypes in circulation will also help to keep track of the changing epidemiology in the post-vaccination era, especially in the scenario where vaccines against Hepatitis B, Rotavirus, and JE were introduced in the health program of the region in the last decade.
The state of Odisha, which reported viral diseases like Dengue, Chikungunya, Hepatitis A, and Hepatitis E before 2010, has now witnessed many other diseases of viral etiology after the establishment of the network of laboratories in the country for diagnosis and research in viral diseases. Odisha being one of the coastal states in the country, harbors many viral illnesses, which was evident from the present study. Initially, it was thought that only vector-borne diseases posed a threat to the eastern part of the country, but subsequently, other viral diseases like respiratory infections, viral diarrhea, jaundice, etc., were also diagnosed with the etiological agent and reported. The viral disease burden was definitely a challenge from the public health perspective, at the same time as laboratory diagnosis at the proper time to support the clinicians for better patient management. This report will help to plan a comprehensive ongoing viral disease control measure, including environment control, vaccination promotion, early diagnosis, and promoting healthy behavior. Acknowledgements The authors wish to thank DHR-ICMR for funding the scheme. Also, authors are grateful to the state IDSP and NVBDCP for providing support for the influx of the samples for this study. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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