Outbreak of poliomyelitis due to type 3 poliovirus, northern India, 1999–2000: injections a major contributing factor

Kathryn A Kohler1, W Gary Hlady2, Kaushik Banerjee2,3 and Roland W Sutter1

1 Global Immunization Division, National Immunization Program, Centers for Disease Control and Prevention, Atlanta, GA, USA.
2 National Polio Surveillance Project, World Health Organization, New Delhi, India.
3 World Health Organization, Southeast Asia Regional Office.

Correspondence: Kathryn A Kohler, Global Immunization Division (E05), National Immunization Program, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. E-mail: kik9{at}cdc.gov


    Abstract
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 Abstract
 Methods
 Results
 Discussion
 References
 
Background A large outbreak of poliomyelitis due to poliovirus type 3 (P3) occurred in India in 1999. This raised concerns about oral poliovirus vaccine (OPV) effectiveness, particularly the type 3 component, in preventing clinical disease and offered an opportunity to describe the epidemiology of a P3 outbreak.

Methods We reviewed data collected by the National Polio Surveillance Project to describe the outbreak and conducted a case-control study to determine risk factors for the development of paralytic poliomyelitis. The P3 cases with paralysis onset in 2000 were enrolled with four controls per case, matched for age and neighbourhood.

Results Of 1126 virologically confirmed poliomyelitis cases reported in 1999, 719 (64%) were due to P3. We enrolled 48 (80%) of 60 cases and 175 matched controls. Age (30.6 months, cases versus 30.4 months, controls) and vaccination status (median 5.8 OPV doses, cases versus 6.1 OPV doses, controls) were similar among cases and controls. The only significant difference between the groups was the proportion that received any injection in the last 30 days prior to paralysis onset or the corresponding reference date for controls (35.4% versus 12.3%, adjusted odds ratio [OR] = 3.9, 95% CI: 1.8–12.5).

Conclusions Cases and controls had similar vaccination histories. The only significant risk factor for paralytic illness was having received any injection in the 30 days before onset. Our study confirms that injections administered during the poliovirus incubation period can provoke paralytic poliomyelitis. Injections in polio-endemic countries should only be indicated when other therapeutic options have failed or are not available.


Keywords Poliomyelitis, poliovirus type 3, injections, India, case-control study

Accepted 5 September 2002

Massive worldwide efforts, including the widespread administration of oral poliovirus vaccine (OPV) via national immunization days (NID), have led to substantial progress toward achieving the goal of global poliomyelitis eradication adopted by the World Health Assembly in 1988.1 In 1999, the only remaining poliovirus reservoirs were in south Asia and sub-Saharan Africa. India, the major poliovirus reservoir in the Southeast Asia Region of the World Health Organization (WHO), accounted for over half of all cases worldwide.2

In 1999 the estimated population of India was approximately 1 billion people (34% under age 15) with an annual birth cohort of approximately 25 million children. The recommended routine OPV schedule in India is a birth dose for institutional births, and doses at 6, 10, and 14 weeks of age. To achieve the goal of polio eradication, India began mass OPV immunization campaigns in 1994 in Delhi, targeting children under age 3 years. Annual NID have continued and since December 1996 have targeted all children under age 5 years, regardless of previous vaccination status.3 In 1999, an unprecedented five rounds of NID were conducted in northern India (January, March, October, November, and December). Approximately 133 million children were vaccinated in 1999 through these campaigns; however, pockets of unvaccinated children persist.

The transmission of wild poliovirus in India has been dramatically reduced as a result of intensified polio eradication efforts throughout the country. However, a large outbreak of poliomyelitis due to type 3 poliovirus (P3) occurred in northern India in 1999. This article describes the P3 epidemic in northern India in 1999 and presents the results of a case-control study to investigate risk factors for paralytic poliomyelitis due to P3.


    Methods
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 Abstract
 Methods
 Results
 Discussion
 References
 
Surveillance data
Active acute flaccid paralysis (AFP) surveillance began in India in October 1997 with the posting of 59 trained Surveillance Medical Officers (SMO) throughout the country.2 The number of SMO increased to approximately 210 by 2000. International performance standards were met and then surpassed starting in May 1998 (i.e. a non-polio AFP rate >=1.0 case per 100 000 population <15 years of age). Acute flaccid paralysis cases are detected by active surveillance through over 8500 healthcare institutions and providers reporting weekly. The SMO visit these reporting units on a regular basis to elicit weekly reports, including zero reports in weeks when no AFP cases are seen. Cases of AFP in children <15 years are reported and investigated, and two stool samples are taken for poliovirus isolation and intratypic differentiation of wild and vaccine-derived strains. Virologically confirmed poliomyelitis cases are those AFP cases with wild poliovirus isolated in at least one stool sample. An AFP surveillance database is maintained by the National Polio Surveillance Unit (NPSU) in New Delhi; these data were used as the basis for the analyses in this study.

Laboratory procedures
Nine WHO-accredited laboratories conduct poliovirus isolation studies on AFP stool specimens and two of these laboratories are used for intratypic differentiation of polioviruses as wild or vaccine-derived.4 Standard procedures were used to isolate viruses from stool suspensions by culture in a rhabdomyosarcoma (RD) and HEp-2C cell monolayer;5second half of 1999.6 Neutralization tests used high-titre equine sera to determine serotypes; subsequently, poliovirus isolates were further characterized as vaccine-related or wild by hybridization with genotypic probes7 and by polymerase chain reaction analyses.8

Case-control study
We conducted a matched case-control study to examine risk factors for paralytic poliomyelitis. Cases were any Indian child: (1) with virologically confirmed poliomyelitis with onset between 1 January 2000 and 30 May 2000, (2) wild type 3 poliovirus isolated from at least one stool sample, (3) residing in the northern states of Uttar Pradesh or Bihar at the time of paralysis onset, and (4) aged <=5 years at the time of paralysis onset. All cases were identified using the India AFP surveillance system (see above). Each case was individually matched by sex and age to up to four neighbourhood controls. Controls were matched for age within ± 1 month for cases aged <1 year, ± 3 months for cases aged >=1 year, and were selected from the neighbourhood where the case resided at the time of paralysis onset.

A reference date, the date of paralysis onset for each case, was set for each case-control set. Using a standard questionnaire, face-to-face interviews were completed with the primary caregiver(s) of all cases and controls to obtain a detailed OPV vaccination history (prior to the reference date) for each child. Surveillance medical officers (n = 21) assigned to the districts with P3 cases, WHO short-term consultants (n = 2) and members of the Stop Transmission of Polio (STOP) team (n = 5) posted in these districts conducted all interviews. The exposure of interest was OPV vaccination history, collected by caregiver recall using a standard questionnaire. If a vaccination card was available, all information about OPV routine vaccination history (e.g. number and dates of doses) was abstracted onto a separate form. In the case of discrepancies between the number of routine OPV doses based on caregiver recall and the number on the vaccination card, the number on the vaccination card was used as the number of routine OPV doses.

The total number of OPV doses was defined as the total number of routine OPV doses plus the total number of OPV doses from NID. If the caregiver was able to produce the child’s vaccination card, then this record was used to determine the number of routine OPV doses; otherwise, number of routine OPV doses was based on caregiver recall. Total number of NID doses was based completely on caregiver recall since these are generally not recorded on vaccination cards. If the caregiver gave only the number of routine doses, then this number was used for the total number of OPV doses; similarly, if only the number of NID doses was given, then this number was used as the total number of OPV doses. If the total OPV doses calculated from routine plus NID doses was different than the number of total OPV doses recalled by the parent, then the smaller of these two numbers was used as a minimum number of total OPV doses received.

After completing the case interview, the interviewer went to the household nearest that of the case and looked for any children meeting the matching criteria. If more than one child in the household met the matching criteria, one was chosen randomly and the mother or primary caretaker was interviewed. The interviewer then visited successive households, increasingly further away from the case household, until four appropriate control children were selected and interviewed. If four matched controls could not be found, the interviewer completed interviews with as many matched controls as possible.

Because the primary objective of this study was programme assessment and identification of factors contributing to the P3 outbreak, and the objective was not primarily research, formal institutional review board clearance from the Centers for Disease Control and Prevention was not required.

Statistical methods
Data analysis was done using EPI INFO (v. 6.04, Centers for Disease Control, Atlanta, GA, USA) and SAS (v. 6.12, Cary, NC, USA). Data are presented as ± SD or medians with ranges. Comparisons between cases and controls were made by calculating odds ratios (OR) and their corresponding 95% CI. Exact conditional logistic regression was used for the matched analysis. Statistical significance was defined as P < 0.05.


    Results
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 Abstract
 Methods
 Results
 Discussion
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Poliomyelitis in India, 1998–2000
The transmission of wild poliovirus in India has been dramatically reduced as a result of intensified polio eradication efforts throughout the country. In 2000, India reported 265 virologically confirmed poliomyelitis cases, compared with 1126 cases in 1999 and 1934 cases in 1998 (Figure 1Go). However, the progress of poliomyelitis eradication has not been uniform throughout India. Acute flaccid paralysis surveillance data show that eradication has progressed more slowly in Delhi and the northern states of Uttar Pradesh, Bihar, and West Bengal. From 1998 to 1999, the number of polio cases in these states declined by 11%, compared with a decline of 83% in the remaining states during the same time period. These four states accounted for 88% of all reported poliomyelitis cases in India in 1999. Routine vaccination coverage with three OPV doses in children aged 12–23 months has been estimated at 50% in Uttar Pradesh and 21% in Bihar in 2000–2001 (UNICEF coverage evaluation survey), which may be one factor contributing to slower progress of polio eradication in these states.



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Figure 1 Number of reported poliomyelitis cases, India, 1994–2000

Reported incidence adjusted for surveillance sensitivity of 10% before June 1997: as per non-polio AFP rate from June 1997 onward.

NIDS—National Immunization Days; IPPI—Intensified Pulse Polio Immunization; HRA—High Risk Area; HRS—High Risk States; HBZ—High Burden Zone; MBZ—Medium Burden Zone.

Data as on 20th May 2001.

 
In 1999, 9586 AFP cases were reported to the surveillance system in India. Of these, 2816 were classified as poliomyelitis and 6770 were classified as non-polio AFP. Of the 2816 poliomyelitis cases, 1126 were virologically confirmed poliomyelitis (poliovirus isolated from at least one stool sample) and the remaining 1690 were clinically classified as poliomyelitis. Poliovirus type 3 was most commonly isolated from the virologically confirmed cases (64%), followed by type 1 (n = 34%) and type 2 (1%). Both P1 and P3 were isolated in 12 cases (1%).

Poliomyelitis due to poliovirus type 3
The number of P3 cases increased dramatically from 190 (10% of all virologically confirmed cases) in 1998 to 730 (65% of all virologically confirmed cases) in 1999. These P3 cases include 12 ‘mixture’ cases in which P3 was isolated in combination with at least one other poliovirus type (32 mixture cases in 1998 versus 12 in 1999). All 12 of these cases occurred in Uttar Pradesh (10 districts) and were mixtures of poliovirus type 1 and poliovirus type 3.

Poliovirus type 3 cases (n = 730) were reported in 13 states. Most of the P3 cases occurred in Uttar Pradesh (72%, 57 districts), Delhi (9%), and Bihar (9%, 27 districts). The P3 cases occurred in every month, with peaks in September and October, and very few cases (n = 15, 2%) occurring from February through to April (Figure 2Go).



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Figure 2 Monthly incidence of P1 and P3 wild poliovirus, India, 1998–2000

 
The median number of OPV doses for all 1999 P3 cases was 3 (range: 0–14); 11% had received no OPV doses before paralysis onset and 62% had received >=3 OPV doses. The median age at paralysis onset was 16 months (range: 1 month–14 years), compared with 18 months (range: 1 month–12 years) for type 1 cases. Most (85%) of the cases had fever at the time of paralysis onset, 76% presented with asymmetric paralysis, and 86% had residual paralysis 60 days after paralysis onset.

Case-control study
From 18 to 28 July 2000, 48 (80%) of the 60 eligible cases were located and interviews were completed with their primary caregivers and those of up to four neighbourhood age- and sex-matched controls. The total number in the matched case-control analysis was 223 (175 controls, 48 cases). Three of the 48 cases had died between the time of initial case investigation and the case-control study in July; cause of death was unknown, as these data are not routinely collected. Interviews were completed with their primary caregivers and with four matched neighbourhood controls. By definition, all controls were alive at the time of the case-control study.

Unmatched analysis
The median age of all study participants was 30 months (range: 11–69 months) (Table 1Go). Of the 223 total cases and controls, 155 (70%) were male, 105 (47%) were Muslim, and 31% had vaccination cards (40% cases versus 29% controls). According to caregiver recall, 90 of the 223 (40%) had never received routine immunizations (49% cases versus 40% controls). The proportion receiving at least one injection in the month before the reference date was significantly higher among cases (35%) than among controls (12%) (OR = 3.9, 95% CI: 1.7–9.1). When analysis was restricted to the 19 cases and 51 controls with vaccination cards, cases remained more likely to have received an injection in this time frame than controls (OR = 2.2, 95% CI: 1.1–25.0).


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Table 1 Unmatched comparison of cases and controls. Data for age and total oral poliovirus vaccine (OPV) doses presented as mean ± SD and median (range)
 
Vaccination status
In all 42/47 (89%) cases and 145/165 (88%) controls had received >=3 OPV doses (excludes 1 case and 10 controls who reported ‘Don’t know‘). None of the 46 cases reported zero prior OPV doses, while 5/165 (3%) of the controls reported zero doses of OPV. The five controls with no previous OPV doses ranged in age from 14 to 39 months and all were Muslim; four of the five lived in Uttar Pradesh. Of 48 cases, 19 (40%) had vaccination cards compared with 51/175 (29%) controls. Cases were more likely to have never received OPV via routine immunization than controls (49% versus 40%), but this difference was not statistically significant.

Matched analysis
In matched analysis not controlling for other covariates, P3 cases were statistically significantly more likely to have received an injection in the month prior to the reference date than controls (OR = 3.9, 95% CI: 1.8–12.5), corresponding to an attributable risk percentage of 74%. Restricting the analysis to those children with vaccination cards gave OR = 1.4, 95% CI: 0.25–7.7. Using exact conditional logistic regression, the OR for having an injection in the month prior to the reference date, controlling for number of OPV doses, was 4.6 (95% CI: 1.6– 15.4); when not controlling for other covariates, OR = 4.0 (95% CI: 1.3–13.5). When OPV doses given within one month of the reference date were excluded and number of prior OPV doses was controlled for, OR = 5.3 (95% CI: 2.1–13.2).


    Discussion
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 Abstract
 Methods
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 References
 
Intensified poliomyelitis eradication activities have dramatically reduced the number of poliomyelitis cases occurring in India and confined wild poliovirus transmission to focal areas in the north, particularly in the heavily populated states of Uttar Pradesh and Bihar. In the face of this success, the sudden rise in the proportion of P3 cases in 1999 and identification of factors associated with this P3 outbreak was of major concern. Several possible reasons for the P3 outbreak were postulated, including cold chain deficiencies in affected areas and primary vaccine failure for the P3 component. While cold chain problems persist in many districts, the fact that there was no concurrent P1 outbreak suggested that cold chain failure was unlikely to be responsible for the P3 outbreak.

It has been demonstrated that P3 immunogenicity is frequently lower in tropical developing countries and that >3 OPV doses may be required to induce a sufficient immune response in children in these settings.9,10 This may be one explanation for the high proportion of outbreak cases that had received >3 OPV doses. The results of the case-control investigation confirmed that a high proportion of both cases and controls had received >=3 doses of OPV. In fact, the distribution of OPV doses was very similar for both cases and controls. As the eradication programme progresses and transmission of wild poliovirus declines, it is expected that a higher proportion of poliomyelitis cases will be vaccinated cases.11 The similar vaccination status of cases and controls may reflect the fact that controls were chosen from households near the cases and matched on age and sex; OPV coverage is likely to be similar among households in the same neighbourhood.

With little difference in the vaccination status of cases and controls, the only clear risk factor for type 3 poliomyelitis in this study was having at least one injection in the month prior to paralysis onset. This finding has been well documented in several studies in different populations and is explained as the phenomenon of provocation poliomyelitis.12–14 However, it is important to note that in our study the temporal association between these injections and onset of poliomyelitis symptoms is not clear because we did not know the date of the injection, only that at least one injection had been received by the child in the month before paralysis. Prior to paralysis onset, children infected with wild poliovirus may present with fever or other non-specific symptoms; in India, this is frequently an indication for therapeutic injections. Therapeutic injections are commonly given by traditional healers and private allopathic doctors in India, often to treat fever and diarrhoea.15,16 Injected substances may include antibiotics (e.g. gentamycin, tetracycline, penicillin), antihistamines, and other materials; it may not be possible to determine whether substances injected were used before the expiry date or what diluents were used. These therapeutic injections are often given in the gluteus muscles. In our study, information on the type of injection received or injection site was not collected; caregivers were asked solely whether their child had received any injections of any type during the month before the reference date.

In our study population, Muslim children were overrepresented (47% of the P3 cases in this study compared with approximately 16% of the population of India). Reasons for the high proportion of Muslim cases are not clear and are beyond the scope of this discussion. Based on the availability of vaccination cards, routine immunization coverage was low both among cases and controls, though cases were somewhat more likely than controls to have received no routine immunization. The NID coverage was high, with all of the cases and 95% of the controls reporting having received at least one dose of OPV via NID. However, the fact that five children (all controls; age range 14–39 months) with zero previous OPV doses were found is evidence that pockets of no or low OPV coverage persist and may partially explain the continued circulation of poliovirus in northern India. Even if OPV coverage is high, conditions of high population density and poor sanitation may allow persistence of poliovirus transmission. The large population size and birth rate in India ensure rapid and continued accumulation of susceptible children.

This study was unable to address the question of vaccine effectiveness. Estimation of vaccine effectiveness for OPV requires the comparison of cases and controls with either zero OPV doses or three OPV doses. Because the number of cases and controls with either exactly zero or exactly three doses was small, and because no cases in this study had zero OPV doses, this comparison could not be made. Similarly, it was not possible to compare zero doses with >=3 doses because the matched OR could not be computed due to a denominator of zero. Several factors may have contributed to the inability to estimate vaccine effectiveness. One possibility is that matching on age and sex, and selecting neighbourhood controls, created too many similarities between cases and controls and thus too few matched sets that were discordant for exposure. A second concern is that OPV history based on caregiver recall, which was used to form exposure categories, is often unreliable. Caregivers may feel pressure to inflate the number of prior OPV doses given to their children.

The P3 outbreak in northern India appears to have been limited to 1999. In 2000, type 3 poliovirus accounted for 127 out of 265 (48%) of all virologically confirmed poliomyelitis cases reported through 31 December 2000, a marked decrease from the 730 P3 cases in 1999. To eliminate poliovirus completely from India, it is essential that AFP surveillance be maintained at its current high level of performance and that these surveillance data continue to be used to target susceptible populations and to plan supplemental immunization strategies. Additionally, this study supported the finding that injections administered during the incubation period of poliovirus can provoke paralytic poliomyelitis. Thus, in polio endemic countries, injections should only be indicated when other therapeutic options are not available or have failed.


KEY MESSAGES

  • An outbreak of poliomyelitis due to type 3 poliovirus (P3) occurred in northern India during 1999–2000.
  • We interviewed 48 of 60 P3 cases (January–May 2000) and 175 age- and sex-matched controls to investigate risk factors for the development of paralytic poliomyelitis.
  • Cases and controls were similar with respect to total doses of oral poliovirus vaccine (OPV) received and vaccine effectiveness could not be calculated.
  • Cases were more likely than controls to have received an injection in the 30 days prior to paralysis onset (or the corresponding reference date for controls): adjusted odds ratio [OR] = 3.9, 95% CI: 1.8–12.5.
  • Injections can provoke paralytic poliomyelitis and should only be indicated in polio-endemic countries when other therapeutic options have failed or are not available.

 


    Acknowledgments
 
We thank Dr Nihal Singh and Dr Saurabh Sharma, NPSP regional co-ordinators for Uttar Pradesh and Bihar, for their assistance in facilitating the case-control study. Sunita Durrani provided valuable help with data management. We thank the following Surveillance Medical Officers, WHO short-term consultants, and STOP team members for their dedication in conducting the field interviews: Dr S Anand, Dr RN Bhattacharya, Dr A Chakravarty, Dr S Dutta, Dr S Pall, Dr R Prasad, Dr D Roy, Dr BK Sarkar, Dr MP Sharma, Dr B Sibal, Dr MJ Aslam, Dr R Bhaskar, Dr CG Birla, Dr M Dabral, Dr S Ghosh, Dr MV Kiran, Dr JS Malik, Dr V Prakash, Dr K Singhal, Dr A Shukla, Dr N Malakmadze, Mr B Wheeler, Mr A Shahriari, Ms J Bass, Ms J Goff, Ms F Quiaiot, Ms M Lynders. Dr Stephen Cochi and Dr Susan Chu reviewed the manuscript.


    References
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 Abstract
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12 Strebel PM, Ion-Nedelcu N, Baughman AL, Sutter RW, Cochi SL. Intramuscular injections within 30 days of immunization with oral poliovirus vaccine—a risk factor for vaccine-associated paralytic poliomyelitis. N Engl J Med 1995;332:500–06.[Abstract/Free Full Text]

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