Burden of Rotavirus Diarrhea in under- five Indian Children: A Systematic Review Sriparna Basu,...

Burden of Rotavirus Diarrhea in under-five Indian Children: A Systematic Review

Sriparna Basu, Associate Professor, Department of Pediatrics, Institute of Medical Sciences,

Banaras Hindu University, VaranasiAshok Kumar, Professor, Department of

Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi

Address correspondence:Ashok Kumar, Professor & Head, Department of Pediatrics, Institute of Medical Sciences, Banaras

Hindu University, VaranasiE-mail: [email protected]

Introduction• Rotavirus is the most common cause of severe diarrhea in infants and

young children worldwide. Globally it is responsible for 611,000 childhood deaths [1], and another 2 million hospitalizations [2] every year.

• More than 80% deaths occur in low-income countries [1], and India records the highest mortality [3].

• Rotavirus diarrhea accounts for 2,000,000 outpatient visits, 457,000 - 884,000 hospitalizations, and 122,000-153,000 deaths in under-5 children in India annually.

• There is huge economic impact of rotavirus diarrhea.

• It is estimated that India spends approximately Rs 1.8–3.2 billion (US$ 37.4 to 66.8 million) in direct medical costs annually and Rs 107–176 million (US$ 2.2–3.7 million) in direct non-medical costs for the treatment of rotavirus diarrhea in children <5 years of age, with a total burden of Rs 2.0–3.4 billion (US$ 41–72 million) [4].

Epidemiology

• Rotaviruses are double stranded RNA viruses comprising a genus within the family Reoviridae.

• The primary mode of transmission is via the fecal-oral route with symptoms typically developing after an incubation period of one to two days.

• Majority of children become infected with rotavirus within the first three years of life, with a peak incidence of rotavirus diarrhea between six to 24 months of age [5,6].

Rotavirus detection and strain characterization

• Laboratory procedures for diagnosis of rotavirus include electron microscopy (EM), passive latex agglutination assays (LA), electropherotyping using polyacylamide gel electrophoresis (PAGE), enzyme-linked immunosorbent assays (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) [18].

• ELISA is the method of choice for routine screening.

• The sensitivity of routine tests are high since the amount of virus excreted by a child with rotavirus diarrhea (~1010 viruses/g of stool) far exceeds the level of detection (~107 viruses/g of stool) [19].

• For genotyping, newer methods like multiplex RT-PCR based genotyping, hybridization assays and nucleotide sequencing have greatly improved data on circulating rotavirus strains.

Molecular epidemiology• The mature virus particles are triple layered, with an approximate

diameter of 70 nm and icosahedral symmetry.

• The rotavirus genome consists of 11 segments of double-stranded RNA, which code for 6 structural viral proteins, VP1, VP2, VP3, VP4, VP6 and VP7 and 6 non-structural proteins, NSP1-NSP6 [20], where gene segment 11 encodes both NSP5 and 6.

• Genome is encompassed by an inner core consisting of VP2, VP1 and VP3 proteins. Intermediate layer or inner capsid is made of VP6 determining group and subgroup specificities.

• The outer capsid layer is composed of two proteins, VP7 and VP4 eliciting neutralizing antibody responses.

• Rotaviruses are classified into seven different groups (A-G) which is based on the antigenic specificity of the VP6 capsid proteins, as well as on the pattern of electrophoretic mobility of the 11 RNA segments of the viral genome.

Molecular epidemiology• Groups A, B and C are known to infect humans. Severe, life-

threatening disease in children worldwide is caused predominantly by group A rotaviruses.

• Within group A, four different subgroups (SG); SGI, SGII, SGI and II, and nonI/nonII, have been distinguished on the basis of VP6 diversity, among which possibly SGI or SGII are the only humans strains [21].

• Further typing schemes to describe rotavirus strains are based on the proteins of the outer capsid eliciting neutralizing antibodies, VP7 (G serotypes) and VP4 (P serotypes).

• G and P serotypes are defined on the basis of their reactivity to specific monoclonal antibodies.

• Variability in the genes encoding the two outer capsid proteins VP7 and VP4 form the basis of the current strain typing of group A rotaviruses into G and P genotypes.

• All known G serotypes correspond with genotypes; though, more P genotypes than serotypes have been identified.

Molecular epidemiology

• Current practice is to identify a rotavirus strain by a G genotype, indicated by a number, followed by its P type.

• To distinguish strains identified by P genotyping from those identified by P serotyping, the dual serotype/genotype nomenclature is used.

• P genotypes are expressed as P followed by a number in square brackets whereas P serotypes are designated as P with serotype number, followed by corresponding genotype in square brackets (e.g., the same strain could be represented as G9P[6], when both G and P genotypes are used, or G9P2A[6] when G genotype is followed by P serotype/genotype classification).

• Till date, at least 15 G genotypes and 25 P genotypes have been identified [22].

Nosocomial diarrhea

• The Centers of Disease Control and Prevention defines nosocomial diarrhea as an acute onset of diarrhea in hospitalized patient, characterized by liquid stool for more than 12 hr with or without vomiting and/or fever or the occurrence of symptoms like nausea, vomiting, abdominal pain in conjunction with objective evidence of enteric infection obtained by stool culture, antigen or antibody assay of feces or blood, routine microscopic examination of stool or toxin assay.

• A period of at least 3 days of hospitalization prior to the

onset of diarrhea is necessary to term it as nosocomial diarrhea [23].

Objective

• The high burden of rotavirus disease in India requires that there is an urgent need to summarize and critically evaluate all available information related to the prevalence of rotavirus diarrhea in India.

• Comprehensive national estimates of the burden of diarrheal diseases caused by rotavirus in India are still lacking.

• The objective of this systematic review is to estimate the burden of rotavirus diarrhea in the community and in hospital in children <5 years of age in India.

Methods

Study Design • We reviewed the epidemiology of rotavirus

diarrhea in under-5 Indian children. The standard methodology for conducting a narrative systematic review was used [12].

• Our primary research question was

‘epidemiology of rotavirus diarrhea in under-5 children of India’.

Secondary research questions

(1) Epidemiology of rotavirus diarrhea in under-5 hospitalized children from different parts of India

(2) Epidemiology of rotavirus diarrhea in under-5 children in community from different parts of India

(3) Demographic profile of rotavirus diarrhea in under-5 Indian children (4) Identification of molecular epidemiology of rotavirus diarrhea in

under-5 children from different parts of India

(5) Incidence of rotavirus infection as a cause of nosocomial diarrhea in under-5 Indian children, and

(6) Mortality from rotavirus diarrhea in under-5 Indian children

• The primary databases searched were Medline through PubMed (www.pubmed.com) and IndMed (http://indmed.nic.in/).

• Other sources including World Health Organization (WHO) reports available online (www.who.int), documents of the UNICEF available online (www.unicef.org/india/), National Family Health Survey (http://www.nfhsindia.org/), and documents of the Ministry of Health and Family Welfare, Government of India (www.mohfw.nic.in) available online were also accessed.

• We also searched the related articles and the reference lists

of included publications to identify additional studies.

Inclusion and Exclusion Criteria

• We included all types of publications available in scientific public domain and reporting on rotavirus infection in India by direct data collection through clinical examination, and/or laboratory testing.

• No particular time frame was set. • We limited our search in humans, and articles published in

English language.

Participants• Children: 1 month to 5 years.

Searching the Literature

• For searching the PubMed, a search string was devised by converting each research question into problem, intervention, comparison, outcome (PICO) format.

• MeSH headings were looked for the research theme in question and added to the PubMed search builder.

• Salient keywords were included during search.

• A search for MeSH headings for ‘rotavirus’, revealed ‘Rotavirus, infections’, which was relevant and yielded 31 subheadings from which we selected ‘rotavirus diarrhea’, ‘rotavirus gastroenteritis’, and ‘rotavirus disease’.


• For assessing the epidemiology of rotavirus diarrhea in India, we searched PubMed using the search string: “(epidemiology* OR burden OR morbidity OR mortality or incidence OR prevalence OR profile) AND (rotavirus OR rotavirus diarrhea OR rotavirus gastroenteritis OR rotavirus disease) AND India.

• An additional search was made for the secondary research questions by combining keywords/MeSH terms for the secondary research question using the search string “(*) AND (rotavirus, infections) AND India”, where the asterisk represents the MeSH term/keywords for the secondary research question.


• To search the IndMed, the search string was kept simple using search keywords.

• The search date, search terms, search string and search output were recorded and saved.

• In the next step, we scrutinized all titles and excluding the titles which were obviously not relevant; the remaining articles were studied further.


• The next step involved examination of the abstract or the introduction (where the abstract was not published) of the short-listed titles; the ones which were not found relevant were excluded and the remaining articles were processed further.

• In the next step examination of full-text articles were done.

• Related articles and cross-references in identified articles were also reviewed and similar steps were performed before short listing the cross-references.

Results• Initial search in PubMed (initially accessed on 19th August

2012 and updated on 15th November 2012.) using ‘rotavirus’ yielded 3905 articles.

• While searching, filters activated were: Humans, English, Infant: 1-23 months, Preschool Child: 2-5 years. Search with ‘rotavirus diarrhea’ yielded 2123 articles and search with ‘rotavirus gastroenteritis’ yielded 1871 articles.

• Details of search strings and yield of articles have been summarized in Table I.

• All included studies were observational with GRADE quality of evidence ‘moderate’.

TABLE I: Results of Literature SearchQ. No.

Research question

Search engine Total After title screening

After abstract screening

After reading full text

From cross reference

Additional search

Finally included

1 Epidemiology of rotavirus diarrhea in under-5 hospitalized children from different parts of India

(epidemiology* OR burden OR morbidity OR mortality or incidence OR prevalence OR profile OR hospital) AND (rotavirus OR rotavirus diarrhea OR rotavirus gastroenteritis OR rotavirus disease) AND india

167 93 84 45 4 0 49

2 Epidemiology of rotavirus diarrhea in under-5 children in community from different parts of India

(epidemiology* OR burden OR morbidity OR mortality or incidence OR prevalence OR profile OR community) AND (rotavirus OR rotavirus diarrhea OR rotavirus gastroenteritis OR rotavirus disease) AND india

152 82 27 15 0 0 15

3 Demographic profile of rotavirus diarrhea in under-5 Indian children

(epidemiology* OR demography OR profile OR hospital OR community) AND (rotavirus OR rotavirus diarrhea OR rotavirus gastroenteritis OR rotavirus disease) AND india

138 95 46 35 0 0 35

4 Molecular epidemiology of rotavirus diarrhea in under-five children of India

(classification* OR genetics OR phylogeny OR virology OR genotype OR classification OR genetic variation OR molecular epidemiology) AND (rotavirus OR rotavirus diarrhea OR rotavirus gastroenteritis OR rotavirus disease) AND india

134 97 51 43 2 1 46

5 Incidence of rotavirus infection as a cause of nosocomial diarrhea

(epidemiology* OR burden OR morbidity OR mortality or incidence OR prevalence OR profile OR hospital OR nosocomial) AND (rotavirus OR rotavirus diarrhea OR rotavirus gastroenteritis OR rotavirus disease) AND india

122 18 9 5 0 0 5

6 Mortality from rotavirus infection in under-5 children from different parts of India

(epidemiology* OR burden OR morbidity OR morbidity OR mortality or incidence OR prevalence OR profile OR hospital OR community OR case fatality) AND (rotavirus OR rotavirus diarrhea OR rotavirus gastroenteritis OR rotavirus disease) AND india

168 38 22 14 0 1 15

Burden of Rotavirus diarrhea in hospitalized children from different parts of India

• A total of 49 studies [24-72], carried out using samples obtained from under-5 Indian children hospitalized with rotavirus diarrhea were included (Table II, Fig. 1A, Fig. 1B).

• The studies were conducted in various geographic

locations. Eighteen studies were carried in Northern India, 7 in Western India, 8 in Eastern India and 11 in Southern India.

• Six studies involved multiple geographical locations. • Most of the studies used ELISA/PAGE for the screening

of rotavirus although latex agglutination assay, immunoblot and electron microscopy were also used in a limited number of studies.

Burden of Rotavirus diarrhea in hospitalized children from different parts of India

• A total of 34397 stool samples were tested, of which 7448 (21.7%) tested positive.

• Rates of rotavirus positivity ranged from 4.6% in Kolkata, Ghosh, et al.[51] to 89.8% in Manipur, Sengupta, et al.[54].

• Largest number of samples came from Northern India (9430), followed by Southern India (8840), multicentric studies (7428), Western India (5927) and Eastern India (2782).

• Region-wise, highest positivity was recoded from Eastern India (31.7%), followed by Western India (20.8%), Northern India (17.4%) and Southern India (17.2%).

• Studies conducted in multiple locations recorded an incidence of 21.4%, replicating the overall incidence of rotavirus diarrhea in hospitalized children in India.

• Details of studies have been summarized in Web Table I.

TABLE II: Rotavirus Positivity in Children Hospitalized with Diarrhea from Different Parts of India

S. No.

Reference Place of study

Study period (year)

Age group (years)

Detection method

Stool samples collected from children admitted with diarrhea (n)

Positive, n (%)

Northern India 1 Broor, et al.[24] Chandigarh 1982-

1983 <5 ELISA 242 44 (18.2)

2 Singh, et al.[25] Chandigarh

1982 - 1985

<5 ELISA 694 111 (15.9)

3 Ram, et al.[26] Chandigarh 1984-1987

<3 ELISA 1024 120 (11.72)

4 Samantaray, et al.[27]

Delhi 1980-1981

<5 ELISA 99 32(32.3)

5 Aggarwal, et al [28]

Delhi 1985 <5 ELISA 256 19(7.4)

6 Chakravarthi, et al.[29]

Delhi 1987 - 1989

<5 ELISA 978 176 (18.0)

7 Chakravarti, et al.[30]

Delhi 1987 - 1988

<5 ELISA 288 44 (15.3)

8 Broor, et al.[31] Delhi 1988 - 1990

<5 ELISA 990 104 (10.5)

9 Patwari, et al.[32] Delhi 1989 - 1990

<3 Immunodot

400 23 (6.0)

10 Husain, et al.[33] Delhi 1990 - 1991

<5 ELISA/PAGE

450 60 (13.3)

11 Chatterjee, et al.[18]

Delhi 1990 <5 ELISA 157 71 (45.0)


Delhi 1998 - 2000

<5 ELISA/PAGE

1172 158 (13.5)

13 Bahl, et al.[35] Delhi 2000 - 2001

<5 ELISA 584 137 (23.5)


Delhi 1998 - 2000

<3 ELISA/PAGE

560 100 (17.8)


Delhi 2005 - 2007

<2 ELISA 862 318(36.9)

16 Sharma, et al.[38] North India Not mentioned

Not mentioned

ELISA 172 32 (19.0)

17 Nag, et al.[39] Lucknow 2003-2004

<2 ELISA/PAGE

90 14(15.6)

18 Mishra, et al.[40] Lucknow 2004 - 2008

<3 ELISA 412 79(19.2)

Total 9430 1642(17.4)

TABLE II: Rotavirus Positivity in Children Hospitalized with Diarrhea from Different Parts of India contd…

S. No.


Study period (year)

Age group (years)

Detection method


Positive, n (%)

Western India 19 Desai, et al.[41] Mumbai 1984 –

1986 Not mentioned

LA /EM / ELISA

273 63 (21.0)

20 Kelkar, et al.[42] Pune 1990 – 1993

Not mentioned

ELISA 722 188 (26.0)

21 Kelkar, et al.[43] Pune 1992 – 1996

<5 ELISA 945 266 (28.2)

22 Kelkar, et al.[44] Pune 1990-1997

<5 ELISA 3064 432 (14.1)

23 Kelkar, et al.[45] Pune 1993-1996

<5 ELISA 628 177 (28.3)

24 Borade, et al.[46] Pune 2009-2010 (?)

<5 ELISA 246 88 (35.8)

25 Kelkar, et al.[47] Thane 2000-2001

<5 ELISA 39 27 (69.2)

Total 5917 1241 (20.8)


S. No.


Study period (year)

Age group (years)

Detection method


Positive, n (%)

Eastern India 26 Phukan, et al.[48] Dibrugarh 1999 -

2000 <5 ELISA 202 47 (23.3)

27 Saha, et al.[49] Kolkata 1979-1981

<12 ELISA 245 55 (22.4)

28 Sen, et al.[50] Kolkata 1979-1981

Not mentioned

ELISA 356 27 (7.6)

29 Ghosh, et al.[51] Kolkata 1986-1988

<6 months

ELISA 218 10 (4.6)

30 Samajdar, et al.[52]

Kolkata and Berhampur

2003-2005

<4 ELISA 545 198 (36.3)

31 Samajdar, et al.[53]

Kolkata 2005 - 2006

<4 ELISA 668 249 (37.3)

32 Sengupta, et al.[54]

Manipur 1979 Not mentioned

ELISA 59 53 (89.8)

33 Mukherjee, et al.[55]

Manipur 2005 - 2008

<5 ELISA 489 244 (49.9)

Total 2782 883 (31.7)


S. No.


Study period (year)

Age group (years)

Detection method


Positive, n (%)

Southern India Aijaz, et al.[56] Bangalore 1988 -

1994 Not mentioned

PAGE 694 150 (21.6) 34

Aijaz, et al.[56] Mysore 1993 - 1994

Not mentioned

PAGE 447 50 (11.2)

35 Ananthan, et al.[57]

Chennai 1997 - 1999

0 - 2, >2

ELISA 245 51 (20.8)

36 Saravanan, et al.[58]

Chennai 1995 - 1999

<3 ELISA/PAGE

745 168 (22.6)

37 Anand, et al.[59] Hyderabad 1998 - 1999

<2 PAGE 352 57 (16.2)

37 Shetty, et al.[60] Karnataka Not mentioned

<5 LA 106 19 (18)

38 Ballal, et al.[61] Karnataka 1995-2000

<5 LA 780 40 (19.9)

39 Anand, et al.[62] Tirupati 1991 <2 ELISA 170 40 (23.5) 40 Kang, et al.[63] Vellore 1995 -

1998 <5 ELISA /

LA 602 126 (20.9)

41 Banerjee, et al.[64]

Vellore 2002 - 2004

<5 ELISA/ LA

343 94 (27.1)

42 Sowmyanarayanan, et al.[65]

Vellore 2005-2008

<5 EIA/PCR 1001 354 (35.4)

43 Paniker, et al.[66] Calicut 1976-1978

<5 EM 3355 368 (70.7)

Total 8840 1517 (17.2)


S. No.


Study period (year)

Age group (years)

Detection method


Positive, n (%)

Multiple locations 44 Ramachandran, et

al.[67] Multiple 1 1993 6 mo

to <5 yr

ELISA 458 63 (13.7)

45 Jain, et al.[68] Multiple 2 1996 - 1998

<5 ELISA 1502 313 (20.8)

46 Kang, et al.[69] Multiple 3 1998 - 1999

<5 LA /EM / ELISA

365 82 (22.5)

47 Das, et al.[70] Multiple 4a 1998 - 2000

<4 PAGE 406 141 (34.7)

48 Das, et al.[71] Multiple 5 2001 <4/allb PAGE 454 161 (35.4) 49 Kang, et al.[72] Multiple 6 2005 -

2007 <5 RT-PCR 4243 1405

(39.2) Total 7428 2165

(21.4) All India total 34397 7448

(21.7)


• LA, latex agglutination; EM, electron microscopy; PAGE, polyacrylamide gel electrophoresis; ELISA, enzyme linked immunosorbent assay.

• Multiple 1: Shimla, Lucknow, Bhopal, Nagpur, Davengere• Multiple 2: Shimla, Lucknow, Bhopal, Nagpur,

Davengere, Delhi, Hyderabad• Multiple 3: Vellore, Mysore, Jalandhar, Yamunagar• Multiple 4: Kolkata, Imphal, aData on disease burden from

Kolkata only• Multiple 5: Kolkata, Dibrugarh, Bhuvaneshwar,

Chandigarh• b<4/all: Samples collected from two groups: children <4

yr, patients of all age groups

Figure 1A: Overall Rotavirus positivity in Indian childrenhospitalized with diarrhea

Figure 1B: Region-wise breakup of Rotavirus positivity in children hospitalized with diarrhea

34397

7448 (21.7%)

0

5000

10000

15000

20000

25000

30000

35000

40000

Total stool samples Rotavirus positive

No. o

f sto

ol sa

mpl

es

9430

5917

2782

7428

8840

2165(21.4)

883(31.7%)

1241(20.8%)

1517(17.2%)

1642(17.4%)

0

2000

4000

6000

8000

10000

12000

NorthernIndia

SouthernIndia

WesternIndia

Eastern India Multiplelocations

No

. o

f st

oo

l sa

mp

les

Rotavirus positive

Total stool samples

Burden of Rotavirus diarrhea in the community from different parts of India

• A total of 15 studies, carried out using samples obtained from under-5 Indian children in community with rotavirus diarrhea were included (Table III, Fig. 2A, 2B).

• Nine studies were carried in Northern India, 2 in Western India, 1 in Eastern India and 3 in Southern India.

• A total of 7566 stool samples were tested in children with diarrhea and 2810 controls, 1504 (19.9%) were tested positive in children with diarrhea and 117 (4.2%) in controls.

• Rates of rotavirus positivity in diarrhea ranged from 33.7% in Manipur [83], to 4% in Delhi, [74].

• In controls, stool positivity ranged from 0 in Vellore [84] to 12.3% in North India [76].

• Details of studies have been summarized in Web Table II.

TABLE III: Burden of Rotavirus Diarrhea in the Community from Different Parts of India

S. No.


Community

Study period (yr)

Age (yr)

Detection method

Diarrhea Sample size (n)

Positive n (%)

Northern India 1 Samantara

y, et al [27]

Delhi Semi urban

1980-1981

<5 ELISA Yes No

212 82

45 (21.2) 2 (2.4)

2 Bhan, et al [73]

Delhi Semi urban

1985-1986

<5 ELISA Yes No

204 98

42 (20.6) 2 (2.0)

3 Raj, et al [74]

Delhi Semi urban

1985-1986

<3 ELISA Yes No

346 211

14 (4.0) 14 (6.6)

4 Bhan, et al [75]

Delhi Urban/rural

1985 <5 ELISA Yes No Yes No

Urban 330 319 Rural 340 315

50 (15.2) 6 (1.9) 56 (16.5) 9 (2.9)

5 Panigrahi, et al [76]

North India

Urban/rural

1982 - 1983

<5 ELISA Yes No

1050 350

44 (29.3) 43 (12.3)

6 Malik, et al [77]

Aligarh Semi urban

1982- 1983

<5

ELISA Yes No

216 216

40(18.5) 1(0.05)

7 Yachha, et al [78]

Chandigarh

Urban/peri-urban/rural

1988 - 1991

<5 ELISA Yes 218 25 (11.5) rural-14 periurban-7 urban -4

8 Nath, et al [79]

Varanasi Urban 1988 - 1989

<5 LA Yes No

376 299

67 (17.7) 12 (4)

9 Nath, et al [80]

Varanasi Urban 1988 - 1989

<5 LA Yes

607

100 (16.4)

Total Yes No

3899 1890

483 (12.4) 87 (4.6)

TABLE III: Burden of Rotavirus Diarrhea in the Community from Different Parts of India contd..

S. No.


Community

Study period (yr)

Age (yr)

Detection method

Diarrhea Sample size (n)

Positive n (%)

Western India 10 Desai, et

al [81] Mumbai

Urban 1984-1986

<5 EM/LA/ELISA

Yes No

273 273

63 (23) 3 (1.1)

11 Kelkar, et al [82]

Pune 1993 - 1996

<5 ELISA Yes

489 76 (15.5)

Total Yes No

762 273

139 (18.2) 3 (0.01)

Eastern India 12 Krishnan,

et al [83] Manipur Urban

Semi urban

1989-1992

<5 ELISA Yes No

787 457

265 (33.7) 22 (4.8)

Total Yes No

787 457

265 (33.7) 22 (4.8)

Southern India 13 Maiya, et

al [84] Vellore* Urban 1974-

1975 <2 EM

Yes No

50 30

13 (26) 0 (0)

14 Mathew, et al [85]

Vellore

Urban, periurban, rural

1983-1985

<3 EM Yes No

916 587

95 (10.4) 5 (0.9)

15 Banerjee, et al [64]

Vellore

Urban 2002 - 2004

<5 ELISA Yes 1152 82 (7.1)

Total Yes No

2118 617

190 (9) 5 (0.01)

All India total Yes No

7566 2810

1504 (19.9) 117 (4.2)

Figure 2A: Overall Rotavirus positivity in Indian children from community

Figure 2B: Region-wise breakup of Rotavirus positivity in children with and without diarrhea from community

7566

2810

1504 (19.9%)

117(4.2%)

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

With diarrhea Without diarrhea

No. o

f sto

ol sa

mpl

es

Rotavirus positive

Total stool samples

1504(19.9%)

117(4.2%)

483(12.4%)

87(4.6%)

139(18.2%)

3(0.01%)

265(33.7%)

22(4.8%)

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

With d

iarr

hea

Without

dia

rrhea

With d

iarr

hea

Without

dia

rrhea

With d

iarr

hea

Without

dia

rrhea

With d

iarr

hea

Without

dia

rrhea

Northern India Southern India Eastern India Western India

No

. o

f sto

ol

sam

ple

s

Rotavirus positive

Total stool samples

Demographic profile of rotavirus diarrhea

• Demographic profile of rotavirus diarrhea has been summarized in Table IV and Web Table III.

• A total of 35 studies could be identified which described demographic profile of rotavirus diarrhea in children.

• Details of all the studies have been discussed in Web Table III, 27 have been summarized in Table IV .

• Most cases of rotavirus diarrhea were found to occur in the first two years of life, most commonly affected age group was 7-12 months both in hospital and community settings.

• Most of the authors have observed an increase in rotavirus-associated diarrhea during the winter months.

TABLE IV: Demographic Profile of Rotavirus Diarrhea

S.No.

Reference Place of study Peak age incidence (%) Gender affected Peak season

1 Broor, et al.[24] Chandigarh 7-12 mo Not mentioned Not mentioned

2 Ram, et al.[26] Chandigarh 10-12 mo M:F=3:1 November

3 Yachha, et al [78] Chandigarh 6-11 mo Not mentioned November-February

4 Samantaray, et al.[27] Delhi 0-6 mo M:F=26:19 October - June

5 Bhan, et al [73] Delhi 0-6 mo Not mentioned Not mentioned

6 Raj, et al [74] Delhi 13-24 mo Not mentioned October – December

7 Patwari, et al.[32] Delhi 7-12 mo M:F=256:144 February-April

8 Panigrahi, et al [76] North India 37-60 mo Not mentioned April-June

9 Malik, et al [77] Aligarh <1 yr M=F January-March

10 Nag, et al.[39] Lucknow 6-12 mo M:F=2.5:1 Not mentioned

11 Nath, et al [79] Varanasi <2 yr F>M November - February

12 Kelkar, et al.[43] Pune 6-12 mo (64.7) M>F Winter

13 Borade, et al.[46] Pune 11-20 mo M=F December - January

14 Kelkar, et al.[47] Thane 6-12 mo M>F Not mentioned

15 Saha, et al.[49] Kolkata 6-12 mo M=F January

TABLE IV: Demographic Profile of Rotavirus Diarrhea contd... S.No.

Reference Place of study Peak age incidence (%)

Gender affected Peak season

16 Sen, et al.[50] Kolkata <2 yr (25) Not mentioned Not mentioned

17 Sengupta, et al.[54]

Manipur Not mentioned M:F=1.9:1 November

18 Ananthan, et al.[57]

Chennai

7-12 mo (28.7) Not mentioned Not mentioned

19 Saravanan, et al.[58]

Chennai

7-12 mo (62.5) M:F=93:75 Sept-Feb

20 Shetty, et al.[60] Karnataka <2 yr-59(56) Not mentioned Winter (Dec-Feb)

21 Ballal, et al.[61] Karnataka 7-12 (65) Not mentioned Not mentioned

22 Anand, et al.[62] Tirupati 7-12 mo M>F Not mentioned

23 Kang, et al.[63] Vellore Mean age 19.5 mo Not mentioned Not mentioned

24 Banerjee, et al [64]

Vellore Not mentioned Not mentioned December-January

25 Sowmyanarayanan, et al.[65]

Vellore 6-12 mo M:F=75:51 January-February

26 Paniker, et al.[66] Calicut 6-23 mo M=F November - January

27 Kang, et al.[72] Multiple locations

Mean age 12.9±9.0mo

M>F Not mentioned

Rotavirus serotypes detected from various

parts of India • A total of 46 studies could be identified which dealt with

serotyping of rotavirus, of which G and P typing were done in 40 studies.

• Details of studies have been summarized in Table V, VI,

VII, Figure 3 - 12 and Web Table IV.

• Maximum number of studies was reported from southern India (12), 8 from western India, 7 from eastern India and 6 studies were reported from northern India.

• Seven studies involved multiple locations.

Rotavirus G serotypes detected from various parts of India

• Overall, G1 was the most common serotype isolated in Indian studies (32%), followed by G2 (24%) and G-untypable (15%).

• On regional distribution, in northern India, G1 was the most common serotype isolated (32%), followed by G2 (20%), G-untypable (13%) and G9(11%).

• In western India, G2 was predominant (28%), closely followed by G-untypable (25%) and G1 (23%).

• In eastern India, G1 was detected in 40%, followed by G2 (30%).

• In southern India, G1 was predominant (31%), followed by G2 (23%) and G-untypable (21%).

All India G serotypes

32%

24%5%6%

8%

3%

7%15%

G1

G2

G3

G4

G9

G12

G-Mixed

G-UT

Figure 3

Figure 4-7: G serotyping

Northern India

32%

20%6%2%11%

8%

8%

13%G1

G2

G3

G4

G9

G12

G-mixed

G UT

Western India

23%

28%8%

7%

1%

0%

8%

25%

G1

G2

G3

G4

G9

G12

G-mixed

G UT

Eastern India

40%

30%0%

5%

6%

8%8% 3%

G1

G2

G3

G4

G9

G12

G-mixed

G UT

Southern India

31%

23%6%5%8%

1%

5%

21%G1

G2

G3

G4

G9

G12

G-mixed

G UT

Rotavirus P serotypes detected from various parts of India

• In P serotyping, P[4] was most prevalent (23%) all over India, followed by P[6] (20%) and P Untypable/others (13%).

• In northern India, P[6] was most common (22%), followed by P[4] (19%).

• Prevalence of P[4] was 43% in western India and 32% in

eastern India. • In southern India, untypable P type was documented in

40%, followed by P[8] (39%). • P[4] was documented in 17%.

All India P serotypes

23%

20%33%

11%

13%P[4]

P[6]

P[8]

P[Mixed]

P UT/others

Figure 8

Figure 9-12: P serotyping

Northern India

19%

22%

36%

11%

12%P[4]

P[6]

P[8]

P mixed

P UT/Other

Western India

43%

12%

45%

0%

0%P[4]

P[6]

P[8]

P mixed

P UT/Other

Eastern India

32%

8%41%

19% 0%

P[4]

P[6]

P[8]

P mixed

P UT/Other

Southern India

17%

2%

39%2%

40%P[4]

P[6]

P[8]

P mixed

P UT/Other

Nosocomial Rotavirus Infections

• Five studies were identified which dealt with nosocomial rotavirus infection.

• Two studies were done in Kolkata [111-112], one in Delhi [110], two

in Vellore [113,114]. • A total of 3810 children hospitalized for illnesses other than diarrhea

were included. • Among them 466 (12.2%) developed nosocomial diarrhea. Rotavirus

was identified as the etiological agent in 75 (16.1%) of them. • Details of the studies have been discussed in Table VIII, Figure 13

and Web Table V.

Figure 13: Nosocomial Rotavirus Infections

3810

75(16.1%)

466(12.2%)

0

500

1000

1500

2000

2500

3000

3500

4000

4500

No. of childrenadmitted

Nosocomialdiarrhea

Rotavirus positive

Nu

mb

er o

f sto

ol

sam

ple

s

Five studies were included in nosocomial rotavirus infection. One study was done in Delhi [110], two studies in Kolkata [111-112] and two in Vellore [113,114].

Rotavirus mortality• Indian Rotavirus Strain Surveillance Network (IRSSN)

data, which covered pediatric admissions to 10 hospitals in 7 cities of India from December 2005 to November 2007, showed that stool samples from 1405 (39%) of 3580 children hospitalized with diarrhea were positive for rotavirus [72].

• The Million Death Study, a nationally representative sample of 6.3 million people in 1.1 million households within the Sample Registration System, recorded approximately 334 000 diarrheal deaths in India during 2005, i.e., 1 in 82 Indian children died from diarrhea before the age of 5 years [128].

• As per the IRSSN data, rotavirus was estimated to cause approximately 34% (113,000; 99% confidence interval, CI: 86,000–155,000) of all diarrheal deaths in under-5 children.

Rotavirus mortality• As per the IRSSN data, rotavirus was estimated to cause

approximately 34% (113,000; 99% confidence interval, CI: 86,000–155,000) of all diarrheal deaths in under-5 children.

• Taken together, there was an estimated mortality rate of 4.14 (99% CI: 3.14–5.68) deaths per 1000 live births during 2005 suggesting that approximately 1 in 242 children will die from rotavirus infection before reaching their fifth birthday.

• Rotavirus-associated mortality rate varied by gender, age and region during 2005 [129].

• The rate among girls (4.89 deaths per 1000 live births; 99% CI: 3.75–6.79) was 42% higher than among boys (3.45 deaths per 1000 live births; 99% CI: 2.58–4.66).

Rotavirus mortality• Region-wise, most rotavirus-associated deaths during 2005

occurred in the central India and eastern India (56,400 vs. 28,900, respectively).

• State-wise mortality rate per 1000 live births due to rotavirus infection among Indian under-5 children during 2005 is shown in Fig. 14.

• The mortality rate from rota virus associated gastroenteritis among under-5 children ranged from a low of 1.64 deaths per 1000 live births in western India to as high as 5.49 deaths per 1000 live births in central India.

• Overall mortality rate was 4.1 per 1000 live births.

Rotavirus mortality• Highest mortality rate was observed in Bihar (6.3)

followed by Uttar Pradesh (6.2). • Lowest rate was recorded by Maharashtra (1.1). • In absolute figures, more than half (64,400) of deaths were

estimated to occur in three states, Uttar Pradesh recording the highest number (35,700), followed by Bihar (17,800) and Madhya Pradesh (10,900) [127].

• The age distribution of deaths from rotavirus infection was similar for boys across the country, but age of death was lower in girls in the northern and southern India compared to other regions.

Figure 14: State-wise estimated mortality rate due to rotavirus

infection among Indian under-5 children during 2005

6.3 6.2

5.4

4.9 4.8

4.24

3.4

2.8 2.8 2.82.5

2.1

1.7

1.1

3.3

0

1

2

3

4

5

6

7

Mo

rtality

rate

fro

m r

ota

vir

us in

fecti

on

/1000 liv

e b

irth

s

Discussion • Limitations• Lack of data from many geographical locations,

particularly central India, where the burden of diarrheal disease is particularly heavy.

• There are many gaps in our understanding of the epidemiology of rotavirus diarrhea in under-5 children particularly at the community level.

• Most of the studies were confined to few places in each region except southern India and sample size differed widely in individual studies. Another shortcoming is use of different methodologies employed for virus detection.

• The limitation is particularly applicable to the period prior to 1994 when molecular methods for serotyping were not available.

• Lastly, we did not perform any formal quality assessment of the individual studies beyond selection criteria requirements.

Discussion • The burden of rotavirus diarrhea is high in India (GRADE

quality of evidence moderate)• Incidence of rotavirus positive diarrhea is higher in

hospitalized children than in the community settings. • Rotavirus infection is most common below 2 years of age,

7-12 months being the most commonly affected age group. • Maximum infection occurs in winter months, from

October– February. • Mortality from rotavirus is still very high in India. • There are large regional differences in the pattern of

circulating rotavirus strains. • Overall, G1 was the most common serotype isolated in

Indian studies (32%), followed by G2 (24%) and G-untypable (15%).

Discussion • Beyond the common G1, G2, G3 and G4, more unusual

strains like G9 and G12 are appearing as causative agents. • Mixed infections, along with human-animal reassortments,

unusual G-types (G6 and G8) and strains (G3P[11] and G9P[10]) had been described which highlights the wide genetic and antigenic diversity of strains circulating in different regions.

• Even group B and group C rotavirus have been incriminated to cause diarrhea.

• Such variation necessitates continuous surveillance. • In view of continuing high morbidity and mortality from

rotavirus diarrhea and enormous economic consequences thereof, there is a strong case for immunization against rotavirus infection.

• It is also crucial to assess and consider the strain variability in the design of a new candidate vaccines and its clinical evaluation in regions with high strain diversity.

Discussion • Also after introduction of immunization, it is important to

have ongoing surveillance to measure the impact of large-scale vaccination program on rotavirus diarrhea hospitalization and mortality rates.

• As per latest WHO estimate, India as a country records highest rotavirus deaths in under-5 children (22%).

• Unfortunately, very few studies dealt with mortality from rotavirus diarrhea. Particularly, there is no study from Bihar and very few studies in Uttar Pradesh, the states which record highest mortality rate from rotavirus diarrhea.

• More studies are needed at the community level to better define the epidemiology of rotavirus diarrhea.

Conclusions • Rotavirus diarrhea is a significant public health problem in

India (GRADE quality of evidence moderate). • The incidence of rotavirus positive diarrhea is higher in

hospitalized children than in community, indicating thereby that rotavirus accounts for more severe dehydrating diarrhea in children.

• Most cases of rotavirus diarrhea in India are caused by G1, G2, and G untypable strains with distinct regional variations.

• Rotavirus is also an important cause of nosocomial diarrhea in children.

• In view of continuing high morbidity and mortality from rotavirus diarrhea and enormous economic consequences thereof, there is a strong case for immunization against rotavirus infection in India.

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Burden of Rotavirus Diarrhea in under- five Indian Children: A Systematic Review Sriparna Basu,...

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