- Email: [email protected]
Application of the revised WHO causality assessment protocol for adverse events following immunization in India
Vaccine xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Application of the revised WHO causality assessment protocol for adverse events following immunization in India Awnish Kumar Singh a,b,⇑, Abram L. Wagner c, Jyoti Joshi a,d, Bradley F. Carlson c, Satinder Aneja e, Matthew L. Boulton c,f a
Former National AEFI Secretariat, Immunization Technical Support Unit, Public Health Foundation of India, New Delhi, India National Technical Advisory Group on Immunization Secretariat, Ministry of Health and Family Welfare, National Institute of Health and Family Welfare, New Delhi, India Department of Epidemiology, School of Public Health, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109, USA d Centre for Disease Dynamics, Economics and Policy, New Delhi, India e Lady Hardinge Medical College, New Delhi, India f Department of Internal Medicine, Division of Infectious Diseases, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA b c
a r t i c l e
i n f o
Article history: Received 14 March 2017 Received in revised form 30 May 2017 Accepted 9 June 2017 Available online xxxx Keywords: Immunization programs India Adverse events
a b s t r a c t Background: In 2013, the World Health Organization (WHO) and CIOMS introduced a revised Causality Assessment Protocol (CAP) for Adverse Events following Immunization (AEFI). India is one of the first countries to adopt the revised CAP. This study describes the application of the revised CAP in India. Methods: We describe use of CAP by India’s AEFI surveillance program to assess reported AEFIs. Using publicly available results of causality assessment for reported AEFIs, we describe the results by demographic characteristics and review the trends for the results of the causality assessment. Results: A total of 771 reports of AEFI between January 2012 and January 2015, completed causality review by August 2016. The cases were reported as belonging to a cluster (54%; n = 302), hospitalized or requiring hospitalization (41%; n = 270), death (25%; n = 195), or resulting in disability (0.4%; n = 3). The most common combinations of vaccines leading to report of an AEFI were DTwP, Hepatitis B, and OPV (14%; n = 106), followed by Pentavalent and OPV (13%; n = 103), and JE vaccine (13%; n = 101). Using the WHO Algorithm, most AEFI reports (89%, n = 683) were classifiable. Classifiable AEFI reports included those with a consistent causal association (53%; n = 407), an inconsistent causal association (29%; n = 226) or were indeterminate causal association with implicated vaccine(s) or vaccination process (6.5%; n = 50) (Fig. 1); 88 reports remained unclassifiable. Conclusions: The revised CAP was informative and useful in classifying most of the reviewed AEFIs in India. Unclassifiable reports could be minimized with more complete information from health records. Improvements in causality assessment, and standardization in reporting between countries, can improve public confidence in vaccine system performance and identify important vaccine safety signals. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Vaccines have proven to be one of the most effective public health interventions available globally [1]. However, dramatic improvements in immunization coverage and the substantial declines in vaccine preventable diseases (VPDs), have also
⇑ Corresponding author at: National Technical Advisory Group on Immunization Secretariat, Ministry of Health and Family Welfare, National Institute of Health and Family Welfare, Baba Gang Nath Marg, Munirka, New Delhi, India. E-mail addresses: [email protected] (A.K. Singh), [email protected] (A.L. Wagner), [email protected] (J. Joshi), [email protected] (B.F. Carlson), [email protected] (S. Aneja), [email protected] (M.L. Boulton).
increasingly been accompanied by a shift in the public’s focus from the benefits of vaccination to the safety of vaccines [2]. Relatively rare adverse events following immunization (AEFIs) now often attract disproportionate media and public attention compared to the burden of disease they successfully prevent although the association between vaccination and adverse event is often purely temporal, likely coincidental, and usually not causally attributable to the vaccine [3]. Nevertheless, AEFI can create misperceptions about vaccine safety and can affect vaccine confidence in the community [4]. Vaccines protect individuals from a wide variety of VPDs, and are subjected to some of the most intense scrutiny of any medical therapeutic, requiring high standards for testing and safety, even
http://dx.doi.org/10.1016/j.vaccine.2017.06.027 0264-410X/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Singh AK et al. Application of the revised WHO causality assessment protocol for adverse events following immunization in India. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.027
2
A.K. Singh et al. / Vaccine xxx (2017) xxx–xxx
after receiving approval and licensure for marketing [2]. Postlicensure AEFI surveillance at the global, national, and regional levels is essential for continuous monitoring of the safety of marketed vaccines. AEFI surveillance can reveal increases in the frequency or severity of known vaccine product-related reactions [5], identify vaccine quality-related flaws or immunization program-related weaknesses, and bring to light previously unknown adverse events not detected during clinical trials. An AEFI is defined as any untoward medical occurrence following vaccination which may or may not have a causal relationship with the vaccine or vaccination process [6]. Occurrence of an AEFI depends upon individuals’ characteristics (age, preexisting illness, genetic expression, social conditions and environmental conditions), vaccine-related factors (vaccine product, manufacturer, lot, quality), and the immunization process itself (cold chain and handling, dose administered, type of vaccine in combination or alone) [6]. Timely investigation of adverse events and thorough collection of evidence are critical components of AEFI surveillance and vaccine pharmacovigilance [7]. Based on available data, reported adverse events are assessed for a causal association with the vaccine or vaccination process. A formal protocol for causality assessment of AEFIs can be used to identify vaccine safety signals in a standardized manner [8]. Many World Health Organization (WHO) member countries have national or local AEFI surveillance programs in place [9]. A recent study by Cassidy et al. has shown that passive AEFI surveillance in 39 WHO member countries covers up to 56% of the global birth cohort [9]. India, which has the largest birth cohort in the world at 26 million births annually [10], has a national AEFI surveillance system within the auspices of the Universal Immunization Program (UIP) and is managed by the Immunization Division, Ministry of Health and Family Welfare [11]. In India, vaccines that are a part of the UIP are administered for free (e.g., Bacillus Calmette-Guérin (BCG), oral polio vaccine (OPV), diphtheria-tetanus-whole cell pertussis (DTwP), hepatitis B vaccine, Haemophilus Influenza type B (HiB) in pentavalent vaccine (DPwT + hepatitis B + HiB), Inactivated Polio Vaccine (IPV), measles vaccine (being replaced phase wise with Measles Rubella (MR) vaccine) and rotavirus vaccine (RVV). These and many other vaccines are also available from the private sector for a fee [12]. Childhood vaccinations are administered both through routine immunization services and through mass immunization campaigns, e.g., Supplementary Immunization Activities (SIAs) for OPV, measles, and Japanese Encephalitis (JE). AEFI reports for any vaccine whether taken from the public or private sector and administered either during routine vaccination or SIAs, are to be reported, investigated and assessed as per the National AEFI Surveillance Guidelines. Reporting to the AEFI surveillance program is passive and any healthcare provider (public or private) can report an AEFI. All cases reported to the national AEFI surveillance program are shared with the National Regulatory Authority (NRA) to contribute to the larger goal of improving vaccine pharmacovigilance in the country. AEFI surveillance in India started along with the UIP in 1985 and initially focused on reporting and investigation of serious AEFIs [13]. It gained momentum in 2012, following the establishment of National AEFI Secretariat for the National AEFI Committee at Immunization Technical Support Unit, Ministry of Health and Family Welfare [11]. The National AEFI guidelines were first published in 2005, revised in 2010, and recently in 2015. According to the latest version of Operational Guidelines for AEFI Surveillance, all reported serious and severe AEFIs need to be assessed for causality using the WHO and CIOMS consensus Causality Assessment Protocol (CAP) that was revised in 2013 [14,15]. According to standard WHO definition an AEFI is considered ‘serious’, if it includes meeting any of the following criteria: results in death, is
life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, requires intervention to prevent permanent impairment or damage [6]. As per the 2015 national AEFI surveillance guidelines ‘severe’ is used to describe the intensity of a specific event (as in mild, moderate or severe). The event itself, however, may be of relatively minor medical significance [6,11]. India was one of the first countries to actively adopt this revised CAP and maybe the first to publicly release information about the results of the CAP. The CAP comprises four components: (a) the eligibility criteria for application of the tool, (b) a data review checklist, (c) a causality assessment algorithm and (d) classification of adverse event. Tafuri et al.’s review of the revised CAP revealed a dearth of information on actual use of the algorithm in both developed and developing countries [16]. Causality assessment of the reported serious/severe AEFI cases is performed by medical specialists trained in standardized WHO causality assessment methods and represent wide range of expertise including pediatrics, infectious diseases, public heath, forensic medicine, pathology, microbiology, vaccinology, community medicine and pharmacology. The objective of this study is to describe the application of the revised CAP in India, and characterize the AEFIs which underwent a review based on the revised CAP.
1.1. Methods Information about the causality classification of serious AEFI reports is now being regularly published on the website of the Ministry of Health and Family Welfare. This dataset includes information on age, gender, vaccines received (temporally), date of vaccine receipt, reason for reporting, and vaccination session type (routine or SIA). Using the database available as of August 2016 from the Ministry of Health and Family Welfare [17–19], we retrieved information about the serious AEFIs cases who had been vaccinated between January 2012 and January 2015 and whose AEFI had undergone the causality assessment process. Information about the components of AEFI surveillance-serious/severe AEFI reporting, investigation and causality assessment are described below: (i) Reporting and investigation of a serious/severe AEFI Any serious or severe AEFI can be notified by the frontline health workers health workers to the health care provider who has the responsibility of reporting the AEFI in standardized forms. All severe/serious AEFIs are reported by filling an AEFI Case Reporting Form (CRF), formerly known as First Information Report (FIR), within 48 h of notification to the appropriate authorities at the district and simultaneously the national level. Investigation of the AEFI is conducted by a District Immunization Officer assisted by the District AEFI committee with the goal to collect evidence related to the notified adverse event, which may help in framing clinical diagnosis. Investigation details are filled in a Preliminary Case Investigation Form (PCIF) formerly known as Preliminary Information Report (PIR) within 10 days of notification and in a Final Case Investigation form (FCIF), formerly known as Detailed Information Report (DIR), within 70 days after notification of the event [11]. Complete and timely investigations help in confirming or refuting causal association of the event with the suspected vaccines or the immunization program. Some of the reported cases occur as clusters. A cluster of AEFIs is defined as two or more cases of the same adverse event related by time, place, or vaccine. For example, a cluster may occur within the same geographical location or be associated with use of the same vaccine, the same batch number administered, or the same vaccinator.
Please cite this article in press as: Singh AK et al. Application of the revised WHO causality assessment protocol for adverse events following immunization in India. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.027
3
A.K. Singh et al. / Vaccine xxx (2017) xxx–xxx
(ii) Assessment for eligibility of serious/severe AEFI case for causality assessment All reported adverse events are evaluated for eligibility to conduct causality assessment on the basis availability of AEFI reporting and investigation forms i.e. CRF, PCIF, FCIF, completeness of filled information and availability of other relevant documents such as hospital records, laboratory investigation reports, autopsy report, verbal autopsy report, clinical consultation and any other relevant information about the case and/or event on a case to case basis. (iii) WHO’s revised AEFI causality assessment tool This tool introduced in 2013, aids in classifying a reported individual adverse event in relation to a vaccine(s) or vaccination process into one of four main categories as a: consistent causal, inconsistent causal (coincidental), indeterminate or unclassifiable [14]. AEFIs showing consistent causal association are further categorized into A1 (vaccine product-related reactions), A2 (vaccine quality defect-related reactions), A3 (immunization error-related reactions) and A4 (immunization anxiety-related reactions). Indeterminate adverse events are further categorized into B1 (consistent temporal relationship but insufficient definitive evidence for vaccine causing the event) and B2 (reviewing factors result in conflicting trends of consistency and inconsistency with causal association to immunization). Reports which require additional information for causality classification are categorized as unclassifiable (D). (iv) Process of causality assessment of a serious/severe AEFI Serious/severe AEFIs with completed forms and supporting information are reviewed by a committee of trained experts, comprising pediatricians, forensic experts, public health professionals, pharmacologists, and microbiologists. A valid diagnosis is made for the event by the committee by using standard medical literature, available national or clinical guidelines as well as standardized AEFI case definitions by Brighton collaboration [20]. After a review of all the available data of an individual AEFI case and framing of valid diagnosis, the checklist of the causality assessment tool is filled by the trained experts followed by [21] classification of the individual AEFI case into the final category based on the information reviewed, the observation notes, and the completed algorithm [11]. 1.2. Descriptive analysis In this exploratory study, we present descriptive statistics on the year the vaccination occurred, sub region, age, gender, reason for reporting, session type, vaccine combinations and causal classification of serious AEFI reports from 2012 to 2015. Because reports from this study only extended into January 2015, we grouped 2015 reports with 2014 reports in the analysis. All data were analyzed in SPSS version 20 (IBM, Armonk, NY). 1.3. Ethical approval This study is limited to publicly available, de-identified data, which is collected as part of routine public health surveillance efforts and therefore is exempt for review and approval from an Ethical oversight by Institutional Review Board. 2. Results A total of 771 serious AEFIs had completed causality assessment by August 2016. The 771 cases were reported from 22 Indian states
Table 1 Demographic characteristics of Adverse Events following Immunization (AEFIs) in India which have undergone a causality assessment. Variables
Frequency (N = 771)
Proportion
Year 2012 2013 2014–2015
301 284 186
39.0 37.0 34.0
Age of the vaccine recipients 1 Month 1–9 Months 9–12 Months 1–2 Years 2–5 Years 5–15 Years >15 Years Missing Information
59 328 27 96 81 170 2 8
7.7 42.5 3.5 12.5 10.5 22.0 0.3 1.0
Gender Female Male Missing Information
385 385 1
49.9 49.9 0.1
Reason for reporting the case/event Cluster Case (Non Hospitalized) Cluster Case (Hospitalized) Cluster Case (Death) Death Disability Hospitalized Others
62 235 5 195 3 270 1
9.0 30.4 0.7 25.3 0.4 41.1 0.1
472 299
61.2 38.8
Type of vaccination session Routine Mass Immunization Campaign (e.g.: Supplementary Immunization Activity)
and 4 union territories (Table 1). The proportion of the reports from 2012 (39%; n = 301), 2013 (37%; n = 284), and 2014–15 (34%; n = 186) were similar. The AEFI cases assessed had an age range from newborn to 65 years. Most of the cases were in age group of 1–9 months (42.5%; n = 328), followed by 5–15 years (22.0%, n = 170), and the proportion of cases were equally distributed among male and female gender. Most of the reported cases were vaccinated as part of routine immunization services (61%; n = 472) versus vaccination as part of a mass immunization campaign (39%; n = 299). Two-third of them were reported hospitalizations (65%; n = 505), 26% (n = 200) reported deaths and 0.4% (n = 3) reported disability. Among the total causally assessed reported death cases (n = 200), proportion of infants was 92% (n = 183). A large proportion of reports were reported as cluster (39%; n = 302). Overall there were 21 clusters comprising 302 serious AEFI cases. The largest cluster had 88 cases following JE vaccine in 2014, followed by 80 cases after Hepatitis B vaccine in 2013. Of the 302 serious AEFI cases in clusters, 161 (53%) were classified as A4 and 32% (n = 97) were classified as A3. 154 cluster cases were found in school age group children 5–15 years of age. None of these causally assessed cases were reported as severe. There were over 45 different combinations of vaccines reported for the AEFI cases which were assessed for causality (Table 2). As expected based on the number of doses given as part of the UIP schedule, the most common combinations of vaccines reported in an AEFI report were DTwP, hepatitis B, and OPV (14%; n = 106); followed by the pentavalent and OPV (13%; n = 103), and the JE vaccine alone (13%; n = 101). In India, DTwP, hepatitis B, and OPV are usually administered during routine services (UIP) at 6, 10 and 14 weeks whereas JE vaccine is typically administered as part of SIAs in endemic areas of India. Additionally, 4.5% (n = 35) of the cases received vitamin A (in combination with one or more vaccines), as part of UIP at 9 months. In addition to UIP vaccines, AEFI
Please cite this article in press as: Singh AK et al. Application of the revised WHO causality assessment protocol for adverse events following immunization in India. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.027
4
A.K. Singh et al. / Vaccine xxx (2017) xxx–xxx
Table 2 Suspected vaccine combinations of Adverse Events following Immunization (AEFIs) in India which have undergone a causality assessment. Vaccines
Frequency (N = 771)
Percent
Rabies vaccine BCG BCG HEP-B OPV BCG HEP-B BCG OPV BCG HEP-B DTwP BCG DTwP BCG OPV DTwP BCG OPV DTwP HEP-B BCG OPV DTwP MEASLES BCG OPV DTwP HEP-B MEASLES BCG OPV PENTA BCG MEASLES DTaP DTwP DTwP HEP-B DTwP MEASLES DTwP VIT-A DTwP OPV VIT-A DTwP OPV DTwP OPV HEP-B DTwP OPV JE DTwP OPV JE VIT-A DTwP OPV MEASLES DTwP OPV MEASLES JE DTwP OPV MEASLES VIT-A DTwP OPV VIT-A DTwP OPV VIT-A JE DTwP OPV HEP-B MEASLES VIT-A OPV OPV HEP OPV JE OPV OTHER PENTA PENTA OPV PENTA OPV MEASLES HEP-B JE MEASLES MEASLES JE MEASLES VIT-A MMR RUBELLA TT TYPHOID VACCINE
5 15 8 1 14 1 1 1 6 2 1 5 2 1 22 12 5 2 1 24 106 1 1 11 1 7 7 4 1 39 1 1 1 48 103 1 96 101 83 2 13 3 1 8 1
0.6 1.9 1 0.1 1.8 0.1 0.1 0.1 0.7 0.3 0.1 0.7 0.3 0.1 2.9 1.6 0.6 0.3 0.1 3.1 13.7 0.1 0.1 1.4 0.1 0.8 0.9 0.5 0.1 5.1 0.1 0.1 0.1 6.2 13.4 0.1 12.5 13.1 10.8 0.3 1.7 0.4 0.1 1.0 0.1
reports had also been received for e few non-UIP vaccines (e.g., rubella, rabies, and typhoid). Most classified reports comprised a consistent causal association (53%; n = 407), inconsistent causal association (29%; n = 226), or indeterminate (6.5%; n = 50) causal association with implicated vaccine or vaccines (Fig. 1). Unclassifiable reports (n = 88) are those which have had insufficient medical evidence to make a decision on causality, a designation of unclassifiable requires further investigations so that eventually the case could be classified as A, B or C.
3. Discussion Populations with high vaccine coverage and a correspondingly lower incidence of disease, now take greater notice of AEFIs [3]. Recent measles outbreaks in Europe have been attributed to misinformation about adverse events following measles vaccinations [22]. Effective AEFI surveillance and timely causality assessment of reported serious events can play an important role in assuaging concerns about vaccine safety. The World Health Organization published an aide-memoire in 2005 to assist in the systematic and standardized causality assessment of individual case of serious
adverse events [23]. In the subsequent seven years, certain limitations were identified in the tool, which led to development of the revised CAP, published in March 2013. We are unaware of other countries that have published results of reported AEFIs using the revised CAP. India seems to be the only country that has published the results of the causality assessment for reported AEFIs. Within India, it is difficult to make interpretations about the rates of AEFIs because the total number of children vaccinated annually is not known, nor is information about the total number of AEFIs reported annually is publicly available. Moreover, AEFI causality assessment is an on-going process and there are many reports for the past period (2012–15) still being assessed, which plausibly could fall in one demographic group more than another. In reviewing the causality assessment reports, we found that most reported AEFIs were either in the infant or adolescent age groups. This is perhaps not surprising as within UIP the primary series of vaccines such as DTwP, hepatitis B, and OPV are given <1 year age. Though we did not find differences in gender distribution of reported AEFIs, this may be an important indirect finding as there have been examples of gender disparities in reported AEFIs in other countries. For example, female infants in Senegal receiving a special high-titer measles vaccine had higher rates of death than male infants [24]. Among all reported serious AEFIs, clusters require immediate investigation and causality assessment for corrective action. Often the clusters result from mass anxiety reactions, minor AEFIs, or immunization error. In rare cases, a cluster may result due to defect in vaccine quality in a particular lot, although there has been no case of vaccine quality defect among all causally assessed reports. Clusters are commonly seen in schoolchildren and most of them are of anxiety related reactions. Such events could be prevented through strategic information, education, and communication (IEC) activities. Overall, the algorithm classified almost 90% of reports. Unclassifiable cases occur when more medical evidence is needed. For example, in the case of insufficient social or medical information or records, making a valid diagnosis may not be possible, as is very common in cases of reported AEFI deaths at home. Moreover, many families refuse an autopsy, making it difficult to investigate such AEFI death reports. AEFIs falling in the indeterminate category maybe are potential new signals or arise due to conflicting evidence of consistent and inconsistent causal association – e.g., seizure occurring after receipt of pertussis or measles vaccine but also accompanied by hypocalcemia, Furthermore, AEFIs falling in inconsistent causal association category, are coincidental events having temporal association with vaccines – e.g., high grade fever after vaccination and isolation of the malarial parasite in blood investigation. Global standardization of AEFI surveillance can better inform studies that compare vaccine rollout in different countries. To address vaccine safety across countries and to provide guidance to developing countries, the WHO established an independent Global Advisory Committee on Vaccine Safety (GACVS) in 1999 [2]. Since its establishment, GACVS has provided support in the development of different tools and methods for assessing vaccine safety. In 2014, the Global Manual on Surveillance of Adverse Events Following Immunization was published and in the same year the WHO facilitated a South East Asia Regional Workshop for strengthening the investigation and causality assessment of AEFIs at both country and regional level [6,21,25]. National AEFI committees of different countries can be linked to GACVS to address global needs and modifying assessment tools such as CAP that could be applied at regional and national level. Completeness of the information and timeliness in sharing and collating that information is critical for conducting causality assessment. Timely feedback from the causality assessment
Please cite this article in press as: Singh AK et al. Application of the revised WHO causality assessment protocol for adverse events following immunization in India. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.027
5
A.K. Singh et al. / Vaccine xxx (2017) xxx–xxx
226
N=771 170
122
115 88
38 12 A1
A3
A4
B1
B2
C
D
Fig. 1. Causality classification of Adverse Events following Immunization (AEFIs) in India. Notes: A1, Vaccine product-related reactions; A3, Immunization error-related reactions; A4, Immunization anxiety-related reactions; B1, Consistent temporal relationship but insufficient definitive evidence for vaccine causing the event; B2, Reviewing factors result in conflicting trends of consistency and inconsistency with causal association to immunization; C, Coincidental events; D, Unclassifiable.
committee is important to build confidence in community. Like many developing countries, India is challenged by issues of incomplete information or delayed information, which in turn postpones causality assessment. More complete information in the medical records, laboratory examination, and obtained from observations, field investigation and physical examination are helpful in validation of the diagnosis. There are limitations to AEFI surveillance program in India. Since it constitutes passive surveillance, reports are limited to those reported by healthcare providers to medical officers and district immunization officers of government health facilities, and suffers from under-reporting. Also, we do not have information on whether the AEFI was reported from a public or private facility. Additionally, we are limited to the reports that have undergone causality assessment and available for public access, regular meetings from the review committee will result in continually more information. The status of unclassifiable reports can change in the future if additional information about a reported AEFI case is collected. To protect confidentiality of cases, there is limited demographic and medical information on the Ministry of Health and Family Welfare website, but this information could help inform the epidemiological picture of AEFI surveillance in India. Also, there is dearth of published articles from other countries to compare our findings. Nonetheless, despite these limitations, this is the first study to report on serious adverse events reported into a surveillance system that uses the revised CAP guidelines. Immunization managers of other countries should initiate culture of publishing results of causality assessment of reported AEFIs using the revised CAP. Moreover, the use of AEFI surveillance systems can identify rare events, such as rapid onset optic neuritis after measles vaccination [26]. 4. Conclusions The revised CAP from the WHO was insightful, informative, and useful in classifying AEFI reports. This algorithm is economical to use and aims to standardize for consistency across cases, countries, and experts. Unclassifiable cases could be minimized with more complete information from medical records, laboratory examinations, physical examinations, and field observations. All countries should be encouraged to use of the revised CAP to assure vaccine safety, improve causality assessment, help standardize reporting between countries, and ultimately contribute to improved public
confidence in vaccine system performance. Further research is warranted to understand variation between individual cases and among countries for CAP use, and ease of use. India faces the dual challenge of improving immunization coverage to protect at least 90% of children and setting up an effective AEFI surveillance system to insure community confidence in vaccines. As vaccine programs are expanded with addition of new vaccines and safety surveillance systems are simultaneously strengthened, it is essential that improving vaccine coverage and vaccine safety are optimally synergized as twin objectives in all countries and not one after the other. Conflict of interest statement The authors declare no conflict of interest. References [1] CDC. Ten great public health achievements — United States, ten great achievements — United States. MMWR Morb Mortal Wkly Rep 1999; 48: p. 243–8. [2] Asturias EJ, Wharton M, Pless R, MacDonald NE, Chen RT, Andrews N, et al. Contributions and challenges for worldwide vaccine safety: The Global Advisory Committee on Vaccine Safety at 15 years. Vaccine 2016;34:3342–9. http://dx.doi.org/10.1016/j.vaccine.2016.05.018. [3] Wilson CB, Marcuse EK. Vaccine safety – vaccine benefits: science and the public ’ s perception. Nat Rev Immunol 2001;1:160–5. http://dx.doi.org/ 10.1038/35100585. [4] Omer SB, Salmon DA, Orenstein WA, deHart MP, Halsey N. Vaccine refusal, mandatory immunization, and the risks of vaccine-preventable diseases. N Engl J Med 2009;360:1981–8. http://dx.doi.org/10.1056/NEJMsa0806477. [5] Law BJ, Laflèche J, Ahmadipour N, Anyoti H. Canadian Adverse Events Following Immunization Surveillance System (CAEFISS): annual report for vaccines administered in 2012 - ProQuest. Canada Commun Dis Report, Suppl Vaccine Saf 2014;40(S3):7. [6] World Health Organization. Global manual on surveillance of adverse events following immunization. World Heal Organ 2014. www.who.int/about/ licensing/copyright_form/en/index.html [accessed 28.11.16]. [7] Council for International Organizations of Medical Sciences. Vaccine pharmacovigilance definition; 2012. [8] WHO. Investigation of safety signals. WHO n.d. http://www.who.int/vaccine_ safety/initiative/investigation/en/ [accessed 11.03.17]. [9] Cassidy C, MacDonald NE, Steenbeek A, Ortiz JR, Zuber PLF, Top KA. A global survey of adverse event following immunization surveillance systems for pregnant women and their infants. Hum Vaccin Immunother 2016;5515:2010–6. http://dx.doi.org/10.1080/21645515.2016.1175697. [10] GAVI. Gavi country factsheet: India n.d. [11] Minsitry of Health and Family Welfare. Government of India. Adverse Events Following Immunization Surveillance and Response Operations Guidelines Guidelines; 2015.
Please cite this article in press as: Singh AK et al. Application of the revised WHO causality assessment protocol for adverse events following immunization in India. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.027
6
A.K. Singh et al. / Vaccine xxx (2017) xxx–xxx
[12] Minsitry of Health and Family Welfare. Government of India. Universal Immunization Program n.d. http://www.mohfw.nic.in/WriteReadData/l892s/ 5628564789562315.pdf [accessed 09.12.16]. [13] Chitakara AJ, Thacker N, Vashishtha VM, Bansal CPGS. Adverse Event Following Immunization (AEFI) surveillance in India: Position Paper of Indian Academy of Pediatrics; 2013. [14] World Health Organization. Causality assessment of an adverse event following immunization (AEFI) User manual for the revised WHO classification. World Heal Organ 2013. http://www.who.int/vaccine_safety/ en/ [accessed 28.11.16]. [15] Tozzi AE, Asturias EJ, Balakrishnan MR, Halsey NA, Law B, Zuber PLF. Assessment of causality of individual adverse events following immunization (AEFI): A WHO tool for global use. Vaccine 2013;31:5041–6. http://dx.doi.org/10.1016/j.vaccine.2013.08.087. [16] Tafuri S, Gallone MS, Calabrese G, Germinario C. Adverse events following immunization: is this time for the use of WHO causality assessment? Expert Rev Vaccines 2015;14:625–7. http://dx.doi.org/10.1586/ 14760584.2015.1029460. [17] Ministry of Health and Family Welfare. Government of India. Causality Assessment of 367 reported serious AEFI cases, approved by National AEFI committee:MoHFW n.d. http://www.mohfw.nic.in/showfile.php?lid=3172 [accessed 31.08.16]. [18] Ministry of Health and Family Welfare. Government of India. Causality Assessment of 296 reported serious AEFI cases, approved by National AEFI committee: MoHFW n.d. http://www.mohfw.nic.in/showfile.php?lid=3496 [accessed 31.08.16]. [19] Ministry of Health and Family Welfare. Government of India. Causality Assessment of 108 reportred serious AEFI cases, approved by National AEFI
[20]
[21]
[22] [23]
[24]
[25]
[26]
committee: MoHFW n.d. http://www.mohfw.nic.in/showfile.php?lid=3692 [accessed 31.08.16]. Kohl KS, Bonhoeffer J, Braun MM, Chen RT, Duclos P, Heijbel H, et al. The Brighton Collaboration: Creating a global standard for case definitions (and guidelines) for adverse events following immunization. AHRQ Adv Patient Safety Concepts Methodol Rockville, AHRQ 2005;2:87–102. doi:NBK20507 [bookaccession]. WHO. Adverse event following immunization Aide-Mémoire on causality assessment 2013. http://www.who.int/vaccine_safety/publications/ [accessed 09.12.16]. Muscat M. Who Gets Measles in Europe ? J Infect Dis 2011;1899:353–65. http://dx.doi.org/10.1093/infdis/jir067. WHO. Adverse Events Following Immunization (AEFI): Causality Assessment 2005. http://apps.who.int/iris/bitstream/10665/191391/1/a87773_eng.pdf [accessed 09.12.16]. Aaby P, Samb B, Simondon F, Knudsen K, Seck AMC, Bennett J, et al. Sexspecific differences in mortality after high- titre measles immunization in rural Senegal. Bull World Health Organ 1994:761–70. MacDonald NE, Guichard S, Amarasinghe A, Balakrishnan MR, Rahman S, Islam S, et al. Strengthening of causality assessment of adverse events following immunization in the WHO South East Asia and Western Pacific regions: Lessons from the 2014 SEAR inter-country workshop. Vaccine 2015;33:6902–7. http://dx.doi.org/10.1016/j.vaccine.2015.01.033. Joshi J, Seth A, Aneja S, Singh AK, Aggarwal MK, Gupta N. Rapid onset optic neuritis following measles vaccine in India: Case report. Vaccine Reports 2016;6:86–8. http://dx.doi.org/10.1016/j.vacrep.2017.01.001.
Please cite this article in press as: Singh AK et al. Application of the revised WHO causality assessment protocol for adverse events following immunization in India. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.027
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Application of the revised WHO causality assessment protocol for adverse events following immunization in India Awnish Kumar Singh a,b,⇑, Abram L. Wagner c, Jyoti Joshi a,d, Bradley F. Carlson c, Satinder Aneja e, Matthew L. Boulton c,f a
Former National AEFI Secretariat, Immunization Technical Support Unit, Public Health Foundation of India, New Delhi, India National Technical Advisory Group on Immunization Secretariat, Ministry of Health and Family Welfare, National Institute of Health and Family Welfare, New Delhi, India Department of Epidemiology, School of Public Health, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109, USA d Centre for Disease Dynamics, Economics and Policy, New Delhi, India e Lady Hardinge Medical College, New Delhi, India f Department of Internal Medicine, Division of Infectious Diseases, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA b c
a r t i c l e
i n f o
Article history: Received 14 March 2017 Received in revised form 30 May 2017 Accepted 9 June 2017 Available online xxxx Keywords: Immunization programs India Adverse events
a b s t r a c t Background: In 2013, the World Health Organization (WHO) and CIOMS introduced a revised Causality Assessment Protocol (CAP) for Adverse Events following Immunization (AEFI). India is one of the first countries to adopt the revised CAP. This study describes the application of the revised CAP in India. Methods: We describe use of CAP by India’s AEFI surveillance program to assess reported AEFIs. Using publicly available results of causality assessment for reported AEFIs, we describe the results by demographic characteristics and review the trends for the results of the causality assessment. Results: A total of 771 reports of AEFI between January 2012 and January 2015, completed causality review by August 2016. The cases were reported as belonging to a cluster (54%; n = 302), hospitalized or requiring hospitalization (41%; n = 270), death (25%; n = 195), or resulting in disability (0.4%; n = 3). The most common combinations of vaccines leading to report of an AEFI were DTwP, Hepatitis B, and OPV (14%; n = 106), followed by Pentavalent and OPV (13%; n = 103), and JE vaccine (13%; n = 101). Using the WHO Algorithm, most AEFI reports (89%, n = 683) were classifiable. Classifiable AEFI reports included those with a consistent causal association (53%; n = 407), an inconsistent causal association (29%; n = 226) or were indeterminate causal association with implicated vaccine(s) or vaccination process (6.5%; n = 50) (Fig. 1); 88 reports remained unclassifiable. Conclusions: The revised CAP was informative and useful in classifying most of the reviewed AEFIs in India. Unclassifiable reports could be minimized with more complete information from health records. Improvements in causality assessment, and standardization in reporting between countries, can improve public confidence in vaccine system performance and identify important vaccine safety signals. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Vaccines have proven to be one of the most effective public health interventions available globally [1]. However, dramatic improvements in immunization coverage and the substantial declines in vaccine preventable diseases (VPDs), have also
⇑ Corresponding author at: National Technical Advisory Group on Immunization Secretariat, Ministry of Health and Family Welfare, National Institute of Health and Family Welfare, Baba Gang Nath Marg, Munirka, New Delhi, India. E-mail addresses: [email protected] (A.K. Singh), [email protected] (A.L. Wagner), [email protected] (J. Joshi), [email protected] (B.F. Carlson), [email protected] (S. Aneja), [email protected] (M.L. Boulton).
increasingly been accompanied by a shift in the public’s focus from the benefits of vaccination to the safety of vaccines [2]. Relatively rare adverse events following immunization (AEFIs) now often attract disproportionate media and public attention compared to the burden of disease they successfully prevent although the association between vaccination and adverse event is often purely temporal, likely coincidental, and usually not causally attributable to the vaccine [3]. Nevertheless, AEFI can create misperceptions about vaccine safety and can affect vaccine confidence in the community [4]. Vaccines protect individuals from a wide variety of VPDs, and are subjected to some of the most intense scrutiny of any medical therapeutic, requiring high standards for testing and safety, even
http://dx.doi.org/10.1016/j.vaccine.2017.06.027 0264-410X/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Singh AK et al. Application of the revised WHO causality assessment protocol for adverse events following immunization in India. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.027
2
A.K. Singh et al. / Vaccine xxx (2017) xxx–xxx
after receiving approval and licensure for marketing [2]. Postlicensure AEFI surveillance at the global, national, and regional levels is essential for continuous monitoring of the safety of marketed vaccines. AEFI surveillance can reveal increases in the frequency or severity of known vaccine product-related reactions [5], identify vaccine quality-related flaws or immunization program-related weaknesses, and bring to light previously unknown adverse events not detected during clinical trials. An AEFI is defined as any untoward medical occurrence following vaccination which may or may not have a causal relationship with the vaccine or vaccination process [6]. Occurrence of an AEFI depends upon individuals’ characteristics (age, preexisting illness, genetic expression, social conditions and environmental conditions), vaccine-related factors (vaccine product, manufacturer, lot, quality), and the immunization process itself (cold chain and handling, dose administered, type of vaccine in combination or alone) [6]. Timely investigation of adverse events and thorough collection of evidence are critical components of AEFI surveillance and vaccine pharmacovigilance [7]. Based on available data, reported adverse events are assessed for a causal association with the vaccine or vaccination process. A formal protocol for causality assessment of AEFIs can be used to identify vaccine safety signals in a standardized manner [8]. Many World Health Organization (WHO) member countries have national or local AEFI surveillance programs in place [9]. A recent study by Cassidy et al. has shown that passive AEFI surveillance in 39 WHO member countries covers up to 56% of the global birth cohort [9]. India, which has the largest birth cohort in the world at 26 million births annually [10], has a national AEFI surveillance system within the auspices of the Universal Immunization Program (UIP) and is managed by the Immunization Division, Ministry of Health and Family Welfare [11]. In India, vaccines that are a part of the UIP are administered for free (e.g., Bacillus Calmette-Guérin (BCG), oral polio vaccine (OPV), diphtheria-tetanus-whole cell pertussis (DTwP), hepatitis B vaccine, Haemophilus Influenza type B (HiB) in pentavalent vaccine (DPwT + hepatitis B + HiB), Inactivated Polio Vaccine (IPV), measles vaccine (being replaced phase wise with Measles Rubella (MR) vaccine) and rotavirus vaccine (RVV). These and many other vaccines are also available from the private sector for a fee [12]. Childhood vaccinations are administered both through routine immunization services and through mass immunization campaigns, e.g., Supplementary Immunization Activities (SIAs) for OPV, measles, and Japanese Encephalitis (JE). AEFI reports for any vaccine whether taken from the public or private sector and administered either during routine vaccination or SIAs, are to be reported, investigated and assessed as per the National AEFI Surveillance Guidelines. Reporting to the AEFI surveillance program is passive and any healthcare provider (public or private) can report an AEFI. All cases reported to the national AEFI surveillance program are shared with the National Regulatory Authority (NRA) to contribute to the larger goal of improving vaccine pharmacovigilance in the country. AEFI surveillance in India started along with the UIP in 1985 and initially focused on reporting and investigation of serious AEFIs [13]. It gained momentum in 2012, following the establishment of National AEFI Secretariat for the National AEFI Committee at Immunization Technical Support Unit, Ministry of Health and Family Welfare [11]. The National AEFI guidelines were first published in 2005, revised in 2010, and recently in 2015. According to the latest version of Operational Guidelines for AEFI Surveillance, all reported serious and severe AEFIs need to be assessed for causality using the WHO and CIOMS consensus Causality Assessment Protocol (CAP) that was revised in 2013 [14,15]. According to standard WHO definition an AEFI is considered ‘serious’, if it includes meeting any of the following criteria: results in death, is
life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, requires intervention to prevent permanent impairment or damage [6]. As per the 2015 national AEFI surveillance guidelines ‘severe’ is used to describe the intensity of a specific event (as in mild, moderate or severe). The event itself, however, may be of relatively minor medical significance [6,11]. India was one of the first countries to actively adopt this revised CAP and maybe the first to publicly release information about the results of the CAP. The CAP comprises four components: (a) the eligibility criteria for application of the tool, (b) a data review checklist, (c) a causality assessment algorithm and (d) classification of adverse event. Tafuri et al.’s review of the revised CAP revealed a dearth of information on actual use of the algorithm in both developed and developing countries [16]. Causality assessment of the reported serious/severe AEFI cases is performed by medical specialists trained in standardized WHO causality assessment methods and represent wide range of expertise including pediatrics, infectious diseases, public heath, forensic medicine, pathology, microbiology, vaccinology, community medicine and pharmacology. The objective of this study is to describe the application of the revised CAP in India, and characterize the AEFIs which underwent a review based on the revised CAP.
1.1. Methods Information about the causality classification of serious AEFI reports is now being regularly published on the website of the Ministry of Health and Family Welfare. This dataset includes information on age, gender, vaccines received (temporally), date of vaccine receipt, reason for reporting, and vaccination session type (routine or SIA). Using the database available as of August 2016 from the Ministry of Health and Family Welfare [17–19], we retrieved information about the serious AEFIs cases who had been vaccinated between January 2012 and January 2015 and whose AEFI had undergone the causality assessment process. Information about the components of AEFI surveillance-serious/severe AEFI reporting, investigation and causality assessment are described below: (i) Reporting and investigation of a serious/severe AEFI Any serious or severe AEFI can be notified by the frontline health workers health workers to the health care provider who has the responsibility of reporting the AEFI in standardized forms. All severe/serious AEFIs are reported by filling an AEFI Case Reporting Form (CRF), formerly known as First Information Report (FIR), within 48 h of notification to the appropriate authorities at the district and simultaneously the national level. Investigation of the AEFI is conducted by a District Immunization Officer assisted by the District AEFI committee with the goal to collect evidence related to the notified adverse event, which may help in framing clinical diagnosis. Investigation details are filled in a Preliminary Case Investigation Form (PCIF) formerly known as Preliminary Information Report (PIR) within 10 days of notification and in a Final Case Investigation form (FCIF), formerly known as Detailed Information Report (DIR), within 70 days after notification of the event [11]. Complete and timely investigations help in confirming or refuting causal association of the event with the suspected vaccines or the immunization program. Some of the reported cases occur as clusters. A cluster of AEFIs is defined as two or more cases of the same adverse event related by time, place, or vaccine. For example, a cluster may occur within the same geographical location or be associated with use of the same vaccine, the same batch number administered, or the same vaccinator.
Please cite this article in press as: Singh AK et al. Application of the revised WHO causality assessment protocol for adverse events following immunization in India. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.027
3
A.K. Singh et al. / Vaccine xxx (2017) xxx–xxx
(ii) Assessment for eligibility of serious/severe AEFI case for causality assessment All reported adverse events are evaluated for eligibility to conduct causality assessment on the basis availability of AEFI reporting and investigation forms i.e. CRF, PCIF, FCIF, completeness of filled information and availability of other relevant documents such as hospital records, laboratory investigation reports, autopsy report, verbal autopsy report, clinical consultation and any other relevant information about the case and/or event on a case to case basis. (iii) WHO’s revised AEFI causality assessment tool This tool introduced in 2013, aids in classifying a reported individual adverse event in relation to a vaccine(s) or vaccination process into one of four main categories as a: consistent causal, inconsistent causal (coincidental), indeterminate or unclassifiable [14]. AEFIs showing consistent causal association are further categorized into A1 (vaccine product-related reactions), A2 (vaccine quality defect-related reactions), A3 (immunization error-related reactions) and A4 (immunization anxiety-related reactions). Indeterminate adverse events are further categorized into B1 (consistent temporal relationship but insufficient definitive evidence for vaccine causing the event) and B2 (reviewing factors result in conflicting trends of consistency and inconsistency with causal association to immunization). Reports which require additional information for causality classification are categorized as unclassifiable (D). (iv) Process of causality assessment of a serious/severe AEFI Serious/severe AEFIs with completed forms and supporting information are reviewed by a committee of trained experts, comprising pediatricians, forensic experts, public health professionals, pharmacologists, and microbiologists. A valid diagnosis is made for the event by the committee by using standard medical literature, available national or clinical guidelines as well as standardized AEFI case definitions by Brighton collaboration [20]. After a review of all the available data of an individual AEFI case and framing of valid diagnosis, the checklist of the causality assessment tool is filled by the trained experts followed by [21] classification of the individual AEFI case into the final category based on the information reviewed, the observation notes, and the completed algorithm [11]. 1.2. Descriptive analysis In this exploratory study, we present descriptive statistics on the year the vaccination occurred, sub region, age, gender, reason for reporting, session type, vaccine combinations and causal classification of serious AEFI reports from 2012 to 2015. Because reports from this study only extended into January 2015, we grouped 2015 reports with 2014 reports in the analysis. All data were analyzed in SPSS version 20 (IBM, Armonk, NY). 1.3. Ethical approval This study is limited to publicly available, de-identified data, which is collected as part of routine public health surveillance efforts and therefore is exempt for review and approval from an Ethical oversight by Institutional Review Board. 2. Results A total of 771 serious AEFIs had completed causality assessment by August 2016. The 771 cases were reported from 22 Indian states
Table 1 Demographic characteristics of Adverse Events following Immunization (AEFIs) in India which have undergone a causality assessment. Variables
Frequency (N = 771)
Proportion
Year 2012 2013 2014–2015
301 284 186
39.0 37.0 34.0
Age of the vaccine recipients 1 Month 1–9 Months 9–12 Months 1–2 Years 2–5 Years 5–15 Years >15 Years Missing Information
59 328 27 96 81 170 2 8
7.7 42.5 3.5 12.5 10.5 22.0 0.3 1.0
Gender Female Male Missing Information
385 385 1
49.9 49.9 0.1
Reason for reporting the case/event Cluster Case (Non Hospitalized) Cluster Case (Hospitalized) Cluster Case (Death) Death Disability Hospitalized Others
62 235 5 195 3 270 1
9.0 30.4 0.7 25.3 0.4 41.1 0.1
472 299
61.2 38.8
Type of vaccination session Routine Mass Immunization Campaign (e.g.: Supplementary Immunization Activity)
and 4 union territories (Table 1). The proportion of the reports from 2012 (39%; n = 301), 2013 (37%; n = 284), and 2014–15 (34%; n = 186) were similar. The AEFI cases assessed had an age range from newborn to 65 years. Most of the cases were in age group of 1–9 months (42.5%; n = 328), followed by 5–15 years (22.0%, n = 170), and the proportion of cases were equally distributed among male and female gender. Most of the reported cases were vaccinated as part of routine immunization services (61%; n = 472) versus vaccination as part of a mass immunization campaign (39%; n = 299). Two-third of them were reported hospitalizations (65%; n = 505), 26% (n = 200) reported deaths and 0.4% (n = 3) reported disability. Among the total causally assessed reported death cases (n = 200), proportion of infants was 92% (n = 183). A large proportion of reports were reported as cluster (39%; n = 302). Overall there were 21 clusters comprising 302 serious AEFI cases. The largest cluster had 88 cases following JE vaccine in 2014, followed by 80 cases after Hepatitis B vaccine in 2013. Of the 302 serious AEFI cases in clusters, 161 (53%) were classified as A4 and 32% (n = 97) were classified as A3. 154 cluster cases were found in school age group children 5–15 years of age. None of these causally assessed cases were reported as severe. There were over 45 different combinations of vaccines reported for the AEFI cases which were assessed for causality (Table 2). As expected based on the number of doses given as part of the UIP schedule, the most common combinations of vaccines reported in an AEFI report were DTwP, hepatitis B, and OPV (14%; n = 106); followed by the pentavalent and OPV (13%; n = 103), and the JE vaccine alone (13%; n = 101). In India, DTwP, hepatitis B, and OPV are usually administered during routine services (UIP) at 6, 10 and 14 weeks whereas JE vaccine is typically administered as part of SIAs in endemic areas of India. Additionally, 4.5% (n = 35) of the cases received vitamin A (in combination with one or more vaccines), as part of UIP at 9 months. In addition to UIP vaccines, AEFI
Please cite this article in press as: Singh AK et al. Application of the revised WHO causality assessment protocol for adverse events following immunization in India. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.027
4
A.K. Singh et al. / Vaccine xxx (2017) xxx–xxx
Table 2 Suspected vaccine combinations of Adverse Events following Immunization (AEFIs) in India which have undergone a causality assessment. Vaccines
Frequency (N = 771)
Percent
Rabies vaccine BCG BCG HEP-B OPV BCG HEP-B BCG OPV BCG HEP-B DTwP BCG DTwP BCG OPV DTwP BCG OPV DTwP HEP-B BCG OPV DTwP MEASLES BCG OPV DTwP HEP-B MEASLES BCG OPV PENTA BCG MEASLES DTaP DTwP DTwP HEP-B DTwP MEASLES DTwP VIT-A DTwP OPV VIT-A DTwP OPV DTwP OPV HEP-B DTwP OPV JE DTwP OPV JE VIT-A DTwP OPV MEASLES DTwP OPV MEASLES JE DTwP OPV MEASLES VIT-A DTwP OPV VIT-A DTwP OPV VIT-A JE DTwP OPV HEP-B MEASLES VIT-A OPV OPV HEP OPV JE OPV OTHER PENTA PENTA OPV PENTA OPV MEASLES HEP-B JE MEASLES MEASLES JE MEASLES VIT-A MMR RUBELLA TT TYPHOID VACCINE
5 15 8 1 14 1 1 1 6 2 1 5 2 1 22 12 5 2 1 24 106 1 1 11 1 7 7 4 1 39 1 1 1 48 103 1 96 101 83 2 13 3 1 8 1
0.6 1.9 1 0.1 1.8 0.1 0.1 0.1 0.7 0.3 0.1 0.7 0.3 0.1 2.9 1.6 0.6 0.3 0.1 3.1 13.7 0.1 0.1 1.4 0.1 0.8 0.9 0.5 0.1 5.1 0.1 0.1 0.1 6.2 13.4 0.1 12.5 13.1 10.8 0.3 1.7 0.4 0.1 1.0 0.1
reports had also been received for e few non-UIP vaccines (e.g., rubella, rabies, and typhoid). Most classified reports comprised a consistent causal association (53%; n = 407), inconsistent causal association (29%; n = 226), or indeterminate (6.5%; n = 50) causal association with implicated vaccine or vaccines (Fig. 1). Unclassifiable reports (n = 88) are those which have had insufficient medical evidence to make a decision on causality, a designation of unclassifiable requires further investigations so that eventually the case could be classified as A, B or C.
3. Discussion Populations with high vaccine coverage and a correspondingly lower incidence of disease, now take greater notice of AEFIs [3]. Recent measles outbreaks in Europe have been attributed to misinformation about adverse events following measles vaccinations [22]. Effective AEFI surveillance and timely causality assessment of reported serious events can play an important role in assuaging concerns about vaccine safety. The World Health Organization published an aide-memoire in 2005 to assist in the systematic and standardized causality assessment of individual case of serious
adverse events [23]. In the subsequent seven years, certain limitations were identified in the tool, which led to development of the revised CAP, published in March 2013. We are unaware of other countries that have published results of reported AEFIs using the revised CAP. India seems to be the only country that has published the results of the causality assessment for reported AEFIs. Within India, it is difficult to make interpretations about the rates of AEFIs because the total number of children vaccinated annually is not known, nor is information about the total number of AEFIs reported annually is publicly available. Moreover, AEFI causality assessment is an on-going process and there are many reports for the past period (2012–15) still being assessed, which plausibly could fall in one demographic group more than another. In reviewing the causality assessment reports, we found that most reported AEFIs were either in the infant or adolescent age groups. This is perhaps not surprising as within UIP the primary series of vaccines such as DTwP, hepatitis B, and OPV are given <1 year age. Though we did not find differences in gender distribution of reported AEFIs, this may be an important indirect finding as there have been examples of gender disparities in reported AEFIs in other countries. For example, female infants in Senegal receiving a special high-titer measles vaccine had higher rates of death than male infants [24]. Among all reported serious AEFIs, clusters require immediate investigation and causality assessment for corrective action. Often the clusters result from mass anxiety reactions, minor AEFIs, or immunization error. In rare cases, a cluster may result due to defect in vaccine quality in a particular lot, although there has been no case of vaccine quality defect among all causally assessed reports. Clusters are commonly seen in schoolchildren and most of them are of anxiety related reactions. Such events could be prevented through strategic information, education, and communication (IEC) activities. Overall, the algorithm classified almost 90% of reports. Unclassifiable cases occur when more medical evidence is needed. For example, in the case of insufficient social or medical information or records, making a valid diagnosis may not be possible, as is very common in cases of reported AEFI deaths at home. Moreover, many families refuse an autopsy, making it difficult to investigate such AEFI death reports. AEFIs falling in the indeterminate category maybe are potential new signals or arise due to conflicting evidence of consistent and inconsistent causal association – e.g., seizure occurring after receipt of pertussis or measles vaccine but also accompanied by hypocalcemia, Furthermore, AEFIs falling in inconsistent causal association category, are coincidental events having temporal association with vaccines – e.g., high grade fever after vaccination and isolation of the malarial parasite in blood investigation. Global standardization of AEFI surveillance can better inform studies that compare vaccine rollout in different countries. To address vaccine safety across countries and to provide guidance to developing countries, the WHO established an independent Global Advisory Committee on Vaccine Safety (GACVS) in 1999 [2]. Since its establishment, GACVS has provided support in the development of different tools and methods for assessing vaccine safety. In 2014, the Global Manual on Surveillance of Adverse Events Following Immunization was published and in the same year the WHO facilitated a South East Asia Regional Workshop for strengthening the investigation and causality assessment of AEFIs at both country and regional level [6,21,25]. National AEFI committees of different countries can be linked to GACVS to address global needs and modifying assessment tools such as CAP that could be applied at regional and national level. Completeness of the information and timeliness in sharing and collating that information is critical for conducting causality assessment. Timely feedback from the causality assessment
Please cite this article in press as: Singh AK et al. Application of the revised WHO causality assessment protocol for adverse events following immunization in India. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.027
5
A.K. Singh et al. / Vaccine xxx (2017) xxx–xxx
226
N=771 170
122
115 88
38 12 A1
A3
A4
B1
B2
C
D
Fig. 1. Causality classification of Adverse Events following Immunization (AEFIs) in India. Notes: A1, Vaccine product-related reactions; A3, Immunization error-related reactions; A4, Immunization anxiety-related reactions; B1, Consistent temporal relationship but insufficient definitive evidence for vaccine causing the event; B2, Reviewing factors result in conflicting trends of consistency and inconsistency with causal association to immunization; C, Coincidental events; D, Unclassifiable.
committee is important to build confidence in community. Like many developing countries, India is challenged by issues of incomplete information or delayed information, which in turn postpones causality assessment. More complete information in the medical records, laboratory examination, and obtained from observations, field investigation and physical examination are helpful in validation of the diagnosis. There are limitations to AEFI surveillance program in India. Since it constitutes passive surveillance, reports are limited to those reported by healthcare providers to medical officers and district immunization officers of government health facilities, and suffers from under-reporting. Also, we do not have information on whether the AEFI was reported from a public or private facility. Additionally, we are limited to the reports that have undergone causality assessment and available for public access, regular meetings from the review committee will result in continually more information. The status of unclassifiable reports can change in the future if additional information about a reported AEFI case is collected. To protect confidentiality of cases, there is limited demographic and medical information on the Ministry of Health and Family Welfare website, but this information could help inform the epidemiological picture of AEFI surveillance in India. Also, there is dearth of published articles from other countries to compare our findings. Nonetheless, despite these limitations, this is the first study to report on serious adverse events reported into a surveillance system that uses the revised CAP guidelines. Immunization managers of other countries should initiate culture of publishing results of causality assessment of reported AEFIs using the revised CAP. Moreover, the use of AEFI surveillance systems can identify rare events, such as rapid onset optic neuritis after measles vaccination [26]. 4. Conclusions The revised CAP from the WHO was insightful, informative, and useful in classifying AEFI reports. This algorithm is economical to use and aims to standardize for consistency across cases, countries, and experts. Unclassifiable cases could be minimized with more complete information from medical records, laboratory examinations, physical examinations, and field observations. All countries should be encouraged to use of the revised CAP to assure vaccine safety, improve causality assessment, help standardize reporting between countries, and ultimately contribute to improved public
confidence in vaccine system performance. Further research is warranted to understand variation between individual cases and among countries for CAP use, and ease of use. India faces the dual challenge of improving immunization coverage to protect at least 90% of children and setting up an effective AEFI surveillance system to insure community confidence in vaccines. As vaccine programs are expanded with addition of new vaccines and safety surveillance systems are simultaneously strengthened, it is essential that improving vaccine coverage and vaccine safety are optimally synergized as twin objectives in all countries and not one after the other. Conflict of interest statement The authors declare no conflict of interest. References [1] CDC. Ten great public health achievements — United States, ten great achievements — United States. MMWR Morb Mortal Wkly Rep 1999; 48: p. 243–8. [2] Asturias EJ, Wharton M, Pless R, MacDonald NE, Chen RT, Andrews N, et al. Contributions and challenges for worldwide vaccine safety: The Global Advisory Committee on Vaccine Safety at 15 years. Vaccine 2016;34:3342–9. http://dx.doi.org/10.1016/j.vaccine.2016.05.018. [3] Wilson CB, Marcuse EK. Vaccine safety – vaccine benefits: science and the public ’ s perception. Nat Rev Immunol 2001;1:160–5. http://dx.doi.org/ 10.1038/35100585. [4] Omer SB, Salmon DA, Orenstein WA, deHart MP, Halsey N. Vaccine refusal, mandatory immunization, and the risks of vaccine-preventable diseases. N Engl J Med 2009;360:1981–8. http://dx.doi.org/10.1056/NEJMsa0806477. [5] Law BJ, Laflèche J, Ahmadipour N, Anyoti H. Canadian Adverse Events Following Immunization Surveillance System (CAEFISS): annual report for vaccines administered in 2012 - ProQuest. Canada Commun Dis Report, Suppl Vaccine Saf 2014;40(S3):7. [6] World Health Organization. Global manual on surveillance of adverse events following immunization. World Heal Organ 2014. www.who.int/about/ licensing/copyright_form/en/index.html [accessed 28.11.16]. [7] Council for International Organizations of Medical Sciences. Vaccine pharmacovigilance definition; 2012. [8] WHO. Investigation of safety signals. WHO n.d. http://www.who.int/vaccine_ safety/initiative/investigation/en/ [accessed 11.03.17]. [9] Cassidy C, MacDonald NE, Steenbeek A, Ortiz JR, Zuber PLF, Top KA. A global survey of adverse event following immunization surveillance systems for pregnant women and their infants. Hum Vaccin Immunother 2016;5515:2010–6. http://dx.doi.org/10.1080/21645515.2016.1175697. [10] GAVI. Gavi country factsheet: India n.d. [11] Minsitry of Health and Family Welfare. Government of India. Adverse Events Following Immunization Surveillance and Response Operations Guidelines Guidelines; 2015.
Please cite this article in press as: Singh AK et al. Application of the revised WHO causality assessment protocol for adverse events following immunization in India. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.027
6
A.K. Singh et al. / Vaccine xxx (2017) xxx–xxx
[12] Minsitry of Health and Family Welfare. Government of India. Universal Immunization Program n.d. http://www.mohfw.nic.in/WriteReadData/l892s/ 5628564789562315.pdf [accessed 09.12.16]. [13] Chitakara AJ, Thacker N, Vashishtha VM, Bansal CPGS. Adverse Event Following Immunization (AEFI) surveillance in India: Position Paper of Indian Academy of Pediatrics; 2013. [14] World Health Organization. Causality assessment of an adverse event following immunization (AEFI) User manual for the revised WHO classification. World Heal Organ 2013. http://www.who.int/vaccine_safety/ en/ [accessed 28.11.16]. [15] Tozzi AE, Asturias EJ, Balakrishnan MR, Halsey NA, Law B, Zuber PLF. Assessment of causality of individual adverse events following immunization (AEFI): A WHO tool for global use. Vaccine 2013;31:5041–6. http://dx.doi.org/10.1016/j.vaccine.2013.08.087. [16] Tafuri S, Gallone MS, Calabrese G, Germinario C. Adverse events following immunization: is this time for the use of WHO causality assessment? Expert Rev Vaccines 2015;14:625–7. http://dx.doi.org/10.1586/ 14760584.2015.1029460. [17] Ministry of Health and Family Welfare. Government of India. Causality Assessment of 367 reported serious AEFI cases, approved by National AEFI committee:MoHFW n.d. http://www.mohfw.nic.in/showfile.php?lid=3172 [accessed 31.08.16]. [18] Ministry of Health and Family Welfare. Government of India. Causality Assessment of 296 reported serious AEFI cases, approved by National AEFI committee: MoHFW n.d. http://www.mohfw.nic.in/showfile.php?lid=3496 [accessed 31.08.16]. [19] Ministry of Health and Family Welfare. Government of India. Causality Assessment of 108 reportred serious AEFI cases, approved by National AEFI
[20]
[21]
[22] [23]
[24]
[25]
[26]
committee: MoHFW n.d. http://www.mohfw.nic.in/showfile.php?lid=3692 [accessed 31.08.16]. Kohl KS, Bonhoeffer J, Braun MM, Chen RT, Duclos P, Heijbel H, et al. The Brighton Collaboration: Creating a global standard for case definitions (and guidelines) for adverse events following immunization. AHRQ Adv Patient Safety Concepts Methodol Rockville, AHRQ 2005;2:87–102. doi:NBK20507 [bookaccession]. WHO. Adverse event following immunization Aide-Mémoire on causality assessment 2013. http://www.who.int/vaccine_safety/publications/ [accessed 09.12.16]. Muscat M. Who Gets Measles in Europe ? J Infect Dis 2011;1899:353–65. http://dx.doi.org/10.1093/infdis/jir067. WHO. Adverse Events Following Immunization (AEFI): Causality Assessment 2005. http://apps.who.int/iris/bitstream/10665/191391/1/a87773_eng.pdf [accessed 09.12.16]. Aaby P, Samb B, Simondon F, Knudsen K, Seck AMC, Bennett J, et al. Sexspecific differences in mortality after high- titre measles immunization in rural Senegal. Bull World Health Organ 1994:761–70. MacDonald NE, Guichard S, Amarasinghe A, Balakrishnan MR, Rahman S, Islam S, et al. Strengthening of causality assessment of adverse events following immunization in the WHO South East Asia and Western Pacific regions: Lessons from the 2014 SEAR inter-country workshop. Vaccine 2015;33:6902–7. http://dx.doi.org/10.1016/j.vaccine.2015.01.033. Joshi J, Seth A, Aneja S, Singh AK, Aggarwal MK, Gupta N. Rapid onset optic neuritis following measles vaccine in India: Case report. Vaccine Reports 2016;6:86–8. http://dx.doi.org/10.1016/j.vacrep.2017.01.001.
Please cite this article in press as: Singh AK et al. Application of the revised WHO causality assessment protocol for adverse events following immunization in India. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.027