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Epidemiology Indian Pediatrics 2000;37: 728-738 |
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DiphtheriaDown But Not Out |
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Tanu Singhal
E-mail: [email protected] The decline in incidence of diphtheria has been so remarkable that it has now supposedly become a medical curiosity from a major public health problem in the past. The clinical index of suspicion is fairly low and many young physicians have never seen a case. Additionally, facilities for microbiologic diagnosis are scarce and antidiphtheritic serum is not readily available(1). However, recently over a six weeks period (September and October 1999) ten children aged 1½-10 years from slums in Delhi and rural areas of neighboring states presented with diphtheria at All India Institute of Medical Sciences, New Delhi. Six of them presented in the acute phase of the illness and the rest in the latter phase with cardiac and/or neurologic complications. These children were either unimmunized (seven) or partially immunized (three). Their clinical characteristics are men-tioned in Table I. Direct smears and cultures were taken from the pharynx and processed according to standard methods(2). Micro-biologic confirmation could be established in six cases. In one case presenting on the 10th day of the illness with a typical membrane, smear and culture were negative possibly due to prior antibiotic therapy. In three children who presented late the organisms could not be isolated. Four children died, two were dis-charged after prolonged hospital stay and four were referred to the Infectious Disease Hospital. Review of prior eight years available records did not reveal any case of micro-biologically confirmed diphtheria at this insti-tute. The clustering of ten cases over a short period of six weeks is, therefore, a matter of considerable concern. This is particularly rele-vant in view of the recent resurgence of diphtheria in several countries(1). We have, therefore, attempted to review disease epi-demiology, principles of immunization and the immune status of the Indian population against diphtheria. The aim of this review is to increase awareness and to caution against possible outbreaks.
Prevaccine Era In the prevaccination era, diphtheria was a leading cause of childhood mortality(3,4). Most children acquired immunity by natural infection, 15% of these infections being symptomatic and the rest subclinical(3,5,6). Forty per cent of the cases occurred in children below 5 years and 70% below 15 years of age(3). There was widespread circulation of toxigenic strains, which resulted in frequent boosting of adult immunity; henceforth disease in adults was rare(3-5). Vaccine Era With the introduction of routine childhood immunization the disease has been almost completely eliminated in certain developed countries. Many European countries have not reported cases for almost a decade and in the USA, only 41 cases were reported during 1980-1995(1).Widespread immunization has also reduced circulation of toxigenic strains, which in turn has resulted in less natural boosting of adult immunity(4-6). Consequently, the adult population in countries with high childhood immunization coverage has become susceptible to the disease(4,5). The few cases that are reported have usually been in adults(1,4,5). In developing countries, with increasing immunization coverage (46% in 1985 to 79% in 1992) the incidence of disease too has declined(1). Though reliable incidence data on diphtheria from these countries is not available, developing countries still account for 80-90% of the global burden of diphtheria cases(1). As the pool of immunized children is not large, infection of skin lesions with C. diphtheriae and respiratory tract carriage are important in development and boosting of natural immu-nity(4,5). Disease in these countries affects both children and young adults(4). Resurgence of Diphtheria The last decade has seen resurgence of diphtheria in both developed and developing countries where it was previously well controlled. An epidemic that began in 1990 in the Newly Independent States of the former Soviet Union caused more than 1,50,000 reported cases and 5000 deaths by the end of 1996(1,3,7). Most of the cases (60-77%) and fatalities occurred in adults. The proportion of cases that were microbiologically confirmed ranged from 29-95% (varying in different geographic regions). The case fatality rate ranged from 3%-23%(7). Increased adult susceptibility was an important factor responsible for the epidemic. Successful childhood vaccination programs in the past had reduced the opportunity to acquire natural immunity, additonally there was waning of previously acquired immunity in the absence of natural boosting/adult vaccination program. Equally important in facilitating disease spread was the decline in childhood immuniza-tion coverage (which ranged between 60-80%)(3). This drop was attributed to decreased public support to immunization programs, deteriorating health infrastructure and deferring immunization for trivial reasons. Other factors responsible for the decline in childhood immunity were adoption of an alternative schedule of fewer doses of lower antigenic strength and administration of the second childhood booster at nine years instead of six years(3,7,8). Coexistence of susceptible adults and children, turbulent socioeconomic conditions and mass population movements (consequent to the breaking up of the Soviet Union) caused explosive spread of the disease(3,7). Developing countries such as Ecuador, Algeria have also reported recent outbreaks, characterized by occurrence in both children and adults, and high case fatality rates(1,4).
The incidence of diphtheria has declined in India over the years with only 1326 cases being reported in 1997(9). No details about the age distribution, immunization status, disease severity and outcome of these cases are available. Outbreaks have not been reported in recent times. The figures quoted above may possibly be a gross underestimate due to lack of a good surveillance system and facilities for microbiologic diagnosis(1). In a recent case series of 616 cases over a period of 5 years (1989-1993) from West Bengal, the diagnosis of diphtheria was clinical, microbiologic con-firmation being available in only 7%(10). The series demonstrated an age shift, as 40% of the cases occurred above the age of 5 years. Details about the immunization status of the cases were not available. An earlier study from a South Indian district hospital also discovered a similar age shift with occurrence of 45% of cases in children more than five years of age(11). No data about disease in adults is available.
Full strength diphtheria toxoid containing 10-25 Lf doses (Indian vaccines-25 Lf/ 30Lf) usually in the form of DPT/DT vaccine is used for primary and booster immunization in children(12,13). For primary immunization, most develop-ing countries including India use the schedule recommended by the WHO, with three doses of DPT given at 6,10 and 14 weeks of age(12,13). Maternal antibodies may interfere with the immune response to the 1st two doses but the 3rd dose and the 1st booster obviate this effect. After primary immunization 94-100% of infants develop protective antibody titers(12). According to internationally accepted definitions and recent studies, an antibody titer of 0.1IU/ml or more gives full protection, a titer between 0.01U/ml and 0.1 IU/ml gives basic protection and a titer of less than 0.01U/ml is inadequately protective(14). During an epi-demic diphtheria may occur in individuals with antibody titers in the range of 0.01U-0.1 U/ml(5,6). In studies of vaccine efficacy (retro-spective case control studies during epidemics) the efficacy of three doses ranges between 82-96%(5). Disease in previously immunized individuals is milder and less likely to be fatal(5,8). The duration of immunity after primary immunization is limited and has been variously reported in different studies(12). In one study from the United States, infants had inadequately protective antibody titers at 16-20 months of age. Other studies from United Kingdom and Italy show longer duration of immunity lasting upto 6-8 years of age(12). Immunity after primary immunization lasts longer if frequency of exposure to C. diphtheriae is high(6). In view of this decline of antibodies administration of boosters is recommended at 1½ years and school entry(12,13). After booster doses, the mean antibody titers are higher and the rate of decline is slower; but may still decline to below protective levels in adulthood(12). The importance of childhood booster immunization can be appreciated from certain observations made during the Russian epidemic. Disease rates were very high in children aged 7-10 years as these children had not received their second childhood booster (age for the second booster had been changed from 6 years to 9 years on the basis of serological studies)(8). As mentioned earlier, the adult immune status and need for booster doses depends on the frequency of exposure to C. diphtheriae. In industrialized countries, 20-60% of the adult population is susceptible to diphtheria(12). Despite a high proportion of susceptible population, outbreaks have not occurred in many of these countries as high level of child-hood immunization has prevented disease spread (herd immunity)(5,6,12). Need for routine immunization of adults in these countries is therefore debated(15,16). It must however be remembered that any drop in childhood immunization coverage may trigger an epidemic (e.g., the Russian Epidemic). Hence, routine immunization of adults in these countries with appropriately spaced low strength (2Lf) booster doses is considered desirable by many(12,15). Table I__Characteristics of Children with Diphtheria Presenting at AIIMS
IDHInfectious Diseases Hospital.
Childhood Immunity Routine immunization against diphtheria was introduced in 1978 under EPI and inten-sified after introduction of UIP in 1985. The reported coverage of infants with 3 doses of DPT vaccine for 1997-1998 as stated by the annual report of Ministry of Health and Family Welfare stands at 90.1%(17). There has been a drop in coverage over the past 3 years (Table II). These official figures are in fact a proxy for actual coverage and are calculated on the basis of % achievement of a target, i.e., Total No. of infants vaccinated with 3 doses of
DPT The official report for 1997-98 also indi-cates a significant drop between the 1st and 3rd dose of OPV/DPT in certain states-27% in Delhi, 28% in Chandigarh and 18-36% in the north eastern states(17). Coverage for the 1½ year booster is not available but since there is a 44% drop out between the 3rd dose of OPV and 1½ year polio booster at the national level, a similar drop out rate for the DPT booster can be expected. The coverage for the 5 year DT booster is merely 60.8% for 1997-1998(17). The national coverage evaluation survey (1996-97) however estimated the coverage for 3 doses of DPT in children aged 12-23 months to be 73% (ranging from 2% in Bihar to 99% in Goa, coverage in Delhi being 85%). Details of boosters are not available(19). Contradicting the above-mentioned claims for immunization coverage is the information generated by the National Family Health Survey, 1992-1993(20). Children aged 12-23 months were evaluated and only 52% were immunized with 3 doses of DPT, and of these even fewer were immunized in their first year of life (47%). The reported official coverage for the same year was 90.6%(17). The vaccine coverage was lower in rural areas as compared to urban areas (46% and 69%, respectively) and varied throughout the country (30% in Bihar, 86% in Tamil Nadu, 89% in Delhi). The survey also reported a significant drop out between the 1st and 3rd dose of DPT (22%). Details about booster doses were not available in this survey. The results of other independent surveys are summarized in Table III. The data thus presented is very heterogeneous but allows some general conclusions: (i ) The vaccine coverage varies widely throughout the country and there are significant urban and rural differences; (ii ) There is paucity of recent data; (iii ) Independent surveys estimate the coverage to be considerably lower than official claims.This indicates a flaw in collection and compilation of data; (iv ) There is significant dropout between the 1st and 3rd dose of DPT; and (v ) The booster (1½ year and 5 year) coverage is extremely low. It is important to note that most of these coverage estimates have been based on parental recall, as immunization cards in most surveys have been largely unavailable (69% in the NFHS survey). Table II__Immunization Coverage with DPT Vaccine
Data cited from References 17,18.
Table III__DPT Vaccination Coverage (Regional Surveys)
Adult Immunity Certain recent serological studies have demonstrated high antitoxin titers in adults in Delhi. Singh et al. in 1994 discovered that 94% of 121 full term pregnant women belonging to middle socioeconomic status (aged 18-38 years) had very high antitoxin titers (>0.125 U/ml) and none had titers below the protective level(31). In another study, Icchpujani et al. in 1993 reported that 87.5% of 574 adult males from Delhi had protective titers against diphtheria(32). Childhood immunization status of subjects in both studies was not ascertainable. These studies indirectly reflect on the low childhood immunization coverage and consequent widespread transmission of toxigenic strains. Conversely in another cross sectional study from Nagpur, antibody levels were estimated in 200 healthy immunized individuals(33). Fifty two per cent of individuals aged between 21-30 year and 82. 5% adults above 30 years had inadequate antibody titers. This was attributed to good childhood coverage in that area leading to inadequate boosting of natural immunity.
Various studies have implicated poor vaccination services and low awareness among parents as the major reasons for poor immuni-zation coverage(22-24,28,34-37). In certain areas health centers may not be easily accessible. However more significantly, the child may not be vaccinated despite a contact with the health facility. These so called "missed opportunities" may result from(31,33): (i ) Logistic problems-short supply of vaccines, poor clinic organization, non availability of immunization services on all days of the week; (ii ) Not screening adequately for immunization status of children who visit the health facility; (iii ) Reluctance to open a multi dose vial if enough children are not present, fearing wastage; and (iv ) Postponing/delaying vaccina-tion for minor childhood illnesses. In one study as many as 38% of eligible children approach-ing a tertiary hospital for curative services were not vaccinated(33). Inadequate and ineffective dissemination of health information compounded by widespread illiteracy results in low awareness in caregivers about utility of vaccination, vaccination sche-dules and vaccine preventable diseases(31,32). Lack of sufficient motivation, inappropriate concern about vaccine side effects and refusal of vaccination if the child is ill are other factors attributable to care givers(22-24,31). Additional factors that prevent completion of vaccination include ignorance about total doses required, no/improper counseling about next vaccination visit, loss of vaccination cards with incorrect recall about the childs immuni-zation status and vaccine side effects(31,32). There is no provision to enable tracing of vaccine drop outs(31). Migration of families may also prevent completion of vaccination. Apart from the above-mentioned reasons, few other factors have possibly assumed impor-tance in the present scenario. Recently, there has been a shift in priorities in the immunization program with pulse polio immunization taking a front seat. A recently conducted survey on the quality of vaccination services in India and other developing countries discovered that certain vaccines were in short supply when a national immunization day was to be held(31). Also though not documented, in the absence of adequate awareness about the complete immunization schedule, many families may accept pulse polio doses as a substitute for routine immunization. Administration of pulse polio may provide a false sense of security and lead parents to omit primary and booster doses of other vaccines. This observation needs objective documentation. This is not to imply that pulse polio should not be encouraged but "only" pulse polio should not be encouraged. The contact between the health system and the community during a pulse polio campaign should be utilized to counsel parents about the need to vaccinate against other diseases.
A recent who meeting concluded that to prevent spread of diphtheria, a minimum immunization coverage rate of 90% in children and 75% in adults is required(5). Evidence points to low childhood immunization coverage and continued transmission of C. diphtheriae in India. Serological studies that have assessed status of adult immunity indicate that the adult population is probably immune, though there may be regional variations(3133). In such a setting a widespread epidemic is unlikely, but focal outbreaks in children particularly in urban slums are highly probable. Overcrowding, presence of a migrant population with low immunization coverage are potential risk factors for these outbreaks.
Based on review of available literature immunization coverage of children against diphtheria is far from satisfactory. Serious efforts should therefore be made to increase immunization coverage, both primary doses and childhood boosters. At present immunization of adults in our country may not be necessary, as there is widespread circulation of toxigenic strains that boost adult immune status. After sufficient reduction of C. diphtheriae circulation with high immunization coverage, properly timed booster doses of vaccine among adolescents and adults may be needed to avoid possibility of outbreaks in adults in future(4,12). Serologic studies to monitor and detect this transition in immune status in adults are thus required. It is also important to establish a good surveillance system to enable generation of reliable data on disease morbidity and mortality and detect a potential outbreak at the outset. Contributors: TS and RL collected the data and helped in preparation of manuscript. YJ and SKK drafted the manuscript. SKK will act as guarantor for the paper. AK was responsible for microbiologic diagnosis and critical review of manuscript. Funding: None. Competing interests: None stated.
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