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Editorial Indian Pediatrics 2002; 39: 5-11 |
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Defining the Burden of Hib Disease in India |
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Infections due to the bacterium Haemophilus influenzae type b (Hib) represent a serious cause of vaccine-preventable morbidity and mortality among children worldwide(1). Hib is firmly established as the leading cause of bacterial meningitis among infants and young children, and is recognized as the second leading cause of bacterial pneumonia deaths among children <5 years old. Surveillance studies show Hib is responsible for 30-50% of confirmed bacterial meningitis cases in children(2). Two careful clinical trials of Hib conjugate vaccine have demonstrated that Hib vaccine can prevent 20-25% of radiographically confirmed pneumonia with consolidation(3,4). The World Health Organization (WHO) estimates that between 400,000-500,000 children <5 years old die each year from Hib infections(5). Hib is a Vaccine Preventable Infection Children do not have to die from Hib meningitis and pneumonia. Several Hib vaccines with proven effectiveness for prevention of Hib meningitis and pneumonia are available(1). The safety and immuno-genicity of these vaccines have been demonstrated in every region of the world. In many countries, the routine use of Hib conjugate vaccine has led to the near elimination of Hib disease in young children through the combined effects of direct protection against disease and the indirect protection of unvaccinated children as a consequence of reduced transmission of Hib organisms(6). These vaccines are available in combination with other existing vaccines and can be easily integrated into routine vaccine programs. Current Status of Hib Vaccine Use Globally The current WHO recommendations on use of Hib conjugate vaccines note that "In view of the demonstrated safety and efficacy of the Hib conjugate vaccines, Hib vaccine should be included, as appropriate to national capacities and priorities, in routine infant immunization program. In geographical regions where the burden of Hib disease is unclear, efforts should be made to evaluate the magnitude of this problem".(5) Currently, 73 (33%) of 216 countries and political units reporting data to WHO are routinely vaccinating infants with Hib vaccine (Fig. 1). Additional countries adopt the vaccine every year, and at least 7 more countries will use Hib conjugate vaccines provided by The Vaccine Fund by 2002.
Fig. 1. Global update: countries with routine Hib immunization, 2001. Black indicates countries that are routinely using Hib conjugate vaccine; Diagonal lines indicate countries that are introducing Hib conjugate vaccine with support from GAVI’s Vaccine Fund; White indicate countries that are not routinely using Hib conjugate vaccine. Obstacles to the Introduction of Hib Vaccine Economic and programmatic limitations are often cited as obstacles to introducing a new vaccine such as Hib conjugate(7). Although, Hib vaccines are relatively more expensive than existing vaccines, experience and recent studies have shown that the perceived burden of the disease is a primary concern for policy makers(7). For example, Princeton Survey Research Associates conducted a recent survey of key opinion leaders (medical and non-medical) in four countries – Nepal, Tanzania, Thailand and Zimbabwe – to determine the key issues of importance for new vaccine introduction. In this survey, ‘medical need or merit’ was identified as the most important factor for vaccine introduction, ahead of the vaccine price and the impact of introduction on the existing program. In sum, the local perception that Hib disease is not a problem frequently obstructs efforts to introduce Hib vaccine. A quick glance at the map of countries routinely using Hib vaccine shows a striking geographic pattern, with an obvious lack of routine use in Asia, including India (Fig.1). Economics alone could not possibly explain this observation. Countries like Japan, South Korea, Malaysia, Thailand and the Philippines (which have not introduced the vaccine) are as affluent or more so than the countries of Mexico, Chile, South Africa and Syria (which have introduced it). One major difference between these countries is the absence of data quantifying the burden of Hib disease in children and the subsequent perception that Hib disease is not a problem. In the regions where countries have taken up Hib vaccine, there is typically substantial evidence to show the importance of Hib disease in children. The economic obstacles to Hib vaccine introduction are rapidly diminishing. The creation of the Vaccine Fund (VF) represents a major step forward in overcoming these obstacles. The 74 countries with the lowest per capita gross domestic product (GDP per capita less than US$1000) are eligible for support through the VF (this includes India and its neighbors). To date, 52 eligible countries have applied for support and 36 have been approved for a total of US$600 million committed to these countries. (http://www.who.int/director-general/speeches/2001/english/20010 829_gavilunchaddress brazzaville.en.html). In short, economic obstacles to Hib vaccine introduction are vanishing and hence, there is a need to focus on the other key obstacle – defining the local burden of Hib disease. Defining the Local Burden of Hib Disease In India, as in many countries, the lack of local Hib disease burden data impedes taking a decision on whether to introduce Hib vaccines. Fortunately, a range of approaches are available to help determine the local burden of Hib disease. These methods vary in their complexity, the resources needed, and the precision of the estimates that they yield. They range from complex, expensive and highly precise clinical trial designs to relatively simple, inexpensive, less precise methods such as the recently developed WHO Hib rapid assessment tool (Hib tool) (available on the Internet at http://www. who.int/vaccines-documents/DocsPDF01/www625.pdf) The most comprehensive and precise method to measure the burden of Hib disease is a randomized, controlled clinical trial design. The biggest advantage of these studies is that they can yield accurate estimates of the burden of Hib disease that goes undetectable by routine culture methods, especially pneu-monia. Because the vaccine is known to be highly efficacious against Hib disease, one can measure the incidence of a clinically defined endpoint, such as radiographically-confirmed pneumonia, in both groups and then attribute the difference between the vaccinated and unvaccinated groups to Hib infections that were prevented by the vaccine. Clinical trials of Hib conjugate vaccine conducted in the Gambia and in Chile showed that Hib vaccine prevented about 5 times more radiographically confirmed pneumonia (regardless of the results of microbio- logic investigations) than culture-confirmed meningitis(3,4). Thus, a vaccine study that did not look at the efficacy against radiographic pneumonia would have missed the major impact of Hib vaccines. A major trial of this type is ongoing in Lombok, Indonesia and the results of the study are expected to be available by the end of 2002(8). The complexity and substantial resources required for these studies make them most appropriate for situations where there is substantial doubt over the role of Hib as a cause of child mortality and where the limitations of other approaches make them unlikely to yield accurate estimates of disease burden. A commonly used approach to measuring the local burden of Hib disease is to con- duct surveillance for laboratory-confirmed bacterial meningitis among children. Although it does nor quantify the total burden of Hib disease, population-based surveillance can yield an estimate of the incidence of childhood Hib meningitis(9), which is useful for extrapolating to broader populations such as countries and facilitates comparison with other countries that have introduced Hib vaccine. In some areas, population based surveil-lance may be difficult or impossible, and hospital-based surveillance (or surveillance networks) may be a useful alternative(10). These studies can yield information on the proportion of culture-confirmed bacterial meningitis due to Hib (and other meningitis pathogens), the case-fatality rate, and the pre-valence of antibiotic-resistant strains, data that may be useful to decision makers. The Invasive Bacterial Infections Surveillance network in India is one example of this approach. Preliminary data from this 6 centers in the surveillance network has shown that Hib meningitis is severe (case-fatality ratio = 25%), occurs primarily in infants (76% of cases), and that 40-50% of isolates are resistant to first-line antibiotics(11). Meningitis surveillance studies depend on isolation of the bacterium from cerebrospinal fluid specimens, and thus, these studies must be conducted in areas where lumbar punctures are routinely performed on all patients with signs and symptoms of meningitis and where there is a laboratory with the resources to consistently isolate H. influenzae from CSF(12). In many areas, not all of these criteria are met, and hence, existing data may underestimate the burden of Hib meningitis. Clearly, successful surveillance for meningitis can require substantial investments in laboratory resources and standardization of clinical practices. Recently it has become clear that some countries want an alternative method of disease burden estimation, one that could be conducted rapidly and inexpensively and that uses as much local data as possible. Estimates from this method will be less precise than those obtained by the other methods but also less time and resource intensive. In an effort to meet these criteria, the US Centers for Disease Control and Prevention and the WHO developed and evaluated an Hib rapid assessment tool. The Hib tool was specifically designed to help countries rapidly estimate Hib disease burden using as much local data as possible. The tool uses two separate methods to generate a range of estimates. The first method starts with an estimate of the incidence of Hib meningitis and its case-fatality rate among children aged <5 years. The second method uses local estimates of the under-5 mortality rate and other indicators of overall mortality in childhood. Together, the methods provide a range of possible disease burden estimates from more conservative to less conservative. The tool is designed to require no more than 7-10 days in the field to complete. Both methods involve substantial assumptions and extrapolations based on the results of clinical trials and other more precise surveillance studies. The tool was field tested in several countries of Africa and the Middle East and the assumptions of the tool were reviewed by a technical experts meeting (available on the Internet at http://www.who.int/vaccines-documents/DocsPDF01/www604.pdf). In India, a number of hospital-based studies have shown that, as in other parts of the world, Hib is generally the most common endemic cause of bacterial meningitis in children(13-17). Based on different assumptions from the ones used in the WHO Hib rapid tool, the incidence of Hib meningitis in Vellore in 1996 was estimated as 50-66 cases per 100,000 children <5 years old(18). Similarly, bacterial pneumonia is well known to be a leading killer of children in the areas of India where infant mortality rates remain high(19). These data show that Hib disease exists in India, and urgently needs addressing, since a useful vaccine exists. To define the local Hib disease burden in India the next steps are to match the appropriate methods to the local situation and to collect the data. This will require determination of the amount of precision needed, the outcomes of interest (e.g., meningitis, pneumonia, overall mortality), the resources available, and the feasibility of the various approaches. In areas where there is considerable controversy over the burden of Hib disease it seems prudent to favor the methods that yield more precise methods, even if they are more complex and expensive. Technical assistance, including documentation for conducting population-based meningitis surveillance and the rapid disease burden assessment, is available from WHO (see http://www.who.int/vaccines-documents/DoxGen/H3DoxList.htm). Linking Data to Policy Hib conjugate vaccines work. They have successfully prevented severe Hib disease everywhere that they have been tested. With the creation of the Global Alliance for Vaccines and Immunizations (GAVI), countries such as India will no longer face the same economic obstacles to vaccine procure-ment. Efforts to define the local burden of Hib disease are urgently needed. Experience has shown us, though, that the collection of disease burden data and the dissemination amongst professional groups is not enogh. It is important to recognize that ultimately the decision to introduce a new vaccine requires political commitment. Once disease burden data are generated, pediatricians and scientists must make an effort to generate advocacy and political will based on those data. With a firm political commitment to introduce and sustain Hib vaccination, the financing and logistical obstacles in India can be overcome. Funding: None. Competing interests: None stated. Orin S. Levine
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