Rotavirus gastroenteritis in Indian children < 5 years hospitalized for diarrhoea, 2012 to 2016

Rotavirus is a genus of the Reoviridae family, and is classified into 7 groups (A-G) [1]. Of the seven groups, group A rotavirus is the most important cause of severe acute diarrhoea in infants and young children globally [1]. Rotavirus consists of 11 segments of double stranded RNA, surrounded by 3 layers of proteins. The outer capsid consists of VP7 (G type) and VP4 (P type) proteins, which are essential for the binary system of rotavirus classification [1]. The four common G types (G1-G4), along with G9 and G12, in association with P[6] and P[8], comprise the common circulating rotavirus genotypes globally [1].

Rotavirus causes an estimated 11.37 million episodes of acute gastroenteritis (AGE) in children < 5 years annually in India, requiring 3.27 million outpatient visits and 872,000 inpatient admissions resulting in total direct costs of Indian Rupee (INR) 10.37 billion per year [2]. In 2011, it is estimated that there were 78,000 deaths due to rotavirus associated AGE in India, with the majority (75.6%, 59,000) in the first 2 years in life [2].

The Indian Rotavirus Strain Surveillance Network, comprising of 10 representative hospitals from 7 Indian cities, estimated rotavirus to cause 40% of hospitalizations due to AGE in children < 5 years during 2005–2009 [3]. The study demonstrated regional trends in rotavirus strain diversity along with the emergence of new strains [3]. A few other prospective hospital based surveillance studies in < 5 years children, conducted between 2009 to 2012, found rotavirus to be associated with approximately 26–39% of AGE cases [4, 5]. The climate in north India varies from that in south India. The northern sites have more temperate climate, with a substantial fall in temperature during the winter months. In contrast, south India has a tropical climate. A difference in the seasonal trend in rotavirus associated diarrhoea across northern and southern sites in India has been reported in a few surveillance studies from India [4, 6].

For the prevention of rotavirus associated AGE, two oral rotavirus vaccines, Rotarix (RV1; monovalent G1P[8]; GlaxoSmithKline Biologicals, Belgium) and RotaTeq (RV5; pentavalent G1, G2, G3, G4, P[8], Merck Vaccines, NJ, USA), have been commercially available in India since 2006 [7]. In 2015, the ROTAVAC vaccine (Bharat Biotech, India), containing the live 116E rotavirus strain (G9P[11]), was introduced as the first indigenously developed vaccine at a substantially lower price [8]. In April 2016, the vaccine was introduced into the Universal Immunization Programme (UIP) by the Government of India in 4 states (Andhra Pradesh, Haryana, Himachal Pradesh, Odisha), with the subsequent introduction in 5 additional states by September 2017 (Rajasthan, Madhya Pradesh, Assam, Tripura, Tamil Nadu).

Pre- vaccine surveillance data is crucial to study the potential change in admission rates for gastroenteritis and circulating rotavirus genotypes after vaccine introduction. We report the findings of a multicentre hospital-based surveillance from July 2012 to June 2016 from 7 Indian sites on the clinical, epidemiological, and virological features of severe rotavirus disease among Indian children < 5 years of age, with the use of standardized protocols for enrolment and diagnostic evaluation.

This 4 year study emphasizes the role of rotavirus as a major cause for acute gastroenteritis in children < 5 years in India before the introduction of the oral rotavirus vaccine into the national immunization programme. In more than 5800 stool samples, rotavirus was detected in 35.5%, comparable to the 2005–2009 period when rotavirus was detected in stools of 40% of children hospitalized for diarrhoea [3] An earlier review of studies on rotavirus disease in India found approximately 34% (inter study variation: 19–50%) of all AGE related hospitalizations to be due to rotavirus infections [7].

The study also demonstrates the early prevalence of rotavirus gastroenteritis in India, with most disease in the first 2 years of life. Although the percentage of rotavirus-associated diarrhoea remained similar from 2012 to 2016, significant changes in rotavirus strain diversity were observed across all sites. G1P[8] (49.9%) and G2P[4] (9.8%) were the two most common genotypes in this study, which is similar to the previous multi-centre surveillance studies conducted in India between 2005 to 2012 [3, 4] Other studies from India have also found these two genotypes as common rotavirus strains causing diarrhoea in children (Table 4). Similar to the surveillance study from 2005 to 2009, an increase in G12 strains, particularly G12P[6], was observed in the southern (Kolenchery, 10.7%) and northern (New Delhi, 12.8%) regions [3] G12 strains were detected first in Philippines in 1987, following which they have been reported from other Asian countries [1, 14, 15] In India, G12 was reported first in 2003 from the eastern region, and since then it has been reported to cause AGE in children from other regions [3, 13, 16, 17] G9, in association with P[4], P[6], and P[8], was detected in 13.2% of the samples, which is higher than reported in the Indian Rotavirus Network Surveillance study from 2005 to 2009 (7.5%) [3]. G9 was first detected in Philadelphia in 1983, and is now the fifth most common G type worldwide [1, 15]. G9 is the most successful among the currently circulating reassortant human rotavirus strains. Similar to G9 rotaviruses, G12 rotavirus strains also exhibit reassortment activity [15]. The emergence of G12 rotaviruses might be similar to the pattern of evolutionary events that led to the emergence of G9 as a dominant human rotavirus genotype. This view is strengthened by the fact that G12 rotavirus strains are increasingly being detected in Argentina, Nepal, Bangladesh, Japan, and other countries globally [15].

The emergence of G3P[8] in our study across southern and northern sites from 2015 onwards emphasizes the rapid temporal changes in circulating rotavirus strains. The circulation of uncommon genotypes, such as G1P[4], G1P[6], G2P[6], G2P[8], G3P[4], G3P[6], G4P[6], G9P[6], G12P[4], and G12P[11], and the high proportion of mixed infections (8%) indicate that the children probably acquire infections from a variety of sources, and could serve as sources of new global strains.

We did not find any association between the severity of diarrhoea and genotypes of the rotavirus, unlike previous studies which reported that children infected with G1 strains had a greater risk of developing severe diarrhoea than children infected with other rotavirus strains [5, 18].

The strengths of this study include the use of a standardized protocol across the sites and laboratory confirmation of rotavirus diarrhoea in a single reference laboratory. The difficulty in extrapolating the data from 7 sites to the whole Indian population can be a potential limitation of the study, but previous studies have shown that data tend to be similar across the country [3].

To summarize, this study highlights the ongoing high prevalence of rotavirus disease in India and the change in circulating rotavirus strains across sites. The study demonstrates the continued circulation of G9 and G12 strains and the emergence of G3P[8] from 2015 onwards. With new vaccines and the recent introduction of the indigenous oral rotavirus vaccine into the national immunization schedule in nine Indian states by the Government of India, ongoing surveillance is important to interpret the rotavirus epidemiology and evaluation of vaccine effectiveness against a broad range of serotypes, thus assessing the impact of vaccination.