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A first step in bringing typhoid fever out of the closet

2012; Elsevier BV; Volume: 379; Issue: 9817 Linguagem: Inglês

10.1016/s0140-6736(12)60294-3

1474-547X

John Maurice,

Salmonella and Campylobacter epidemiology

A recent expert meeting marks one of the first attempts to jolt governments into action against a disease that is thriving largely unnoticed in many developing countries. John Maurice reports. Whoever invented the phrase “out of sight, out of mind” must have been thinking of typhoid fever. With the exception of a few hardy travellers, the disease has dropped out of sight and out of mind in the rich countries of the world. Gone are the days when the disease decimated armies and rampaged through the filthy streets of 19th century London, New York, and other large cities of the western world, taking the lives of rich and poor alike. Today, it is the poor, the poorest of the poor, living in the slums of the developing world, who bear the full brunt of the mortality and morbidity—216 000 deaths and about 21 million cases a year—wrought by Salmonella typhi. The bacillus infects mainly children. Its hunting grounds cover a vast swathe of the globe, spanning Asia, Africa, and Latin America (figure). Three countries—Pakistan, India, and Bangladesh—together account for about 85% of the world's cases. The main problem with typhoid fever is that it has dropped out of the minds of the international health community and, sadly, also of the many health officials of the developing countries where the disease is rife. “The disease”, says Chris Nelson, who heads the Coalition against Typhoid (CaT) secretariat at the Sabin Vaccine Institute in Washington, DC, USA, “has become so omnipresent in the developing world as to be invisible”. Bringing typhoid fever into visibility was one of the aims of a CaT meeting held in WHO's Geneva headquarters at the end of January, 2012. The meeting brought together some 30 leading epidemiologists, clinicians, vaccine industry representatives, and mathematical modellers to make a start in putting typhoid fever onto the agendas of international and national health policy makers. The main focus of the meeting was on modelling the epidemiology of the disease and on identifying the best ways of combating it. Combating a disease that keeps a low profile will not be easy, meeting participants agreed. “Typhoid fever is a disease that is under the radar screen of the global health community”, said Jeremy Farrar, professor of Tropical Medicine and director of the Oxford University Clinical Research Unit in Vietnam. “One reason is that with the inadequate diagnostic tools at our disposal it has always been difficult to know just how many deaths and cases typhoid fever is causing in any given area. Another is that it is a disease of true poverty. It's a disease that is part of the underground and the underclass.” For another participant, Zulfiqar Bhutta, chair of the Women and Child Health Division at the Aga Khan University in Karachi, Pakistan, “typhoid fever is an orphan disease because it has never had champions in health organisations. Most international health organisations give more attention to such infectious diseases as rotavirus disease, Haemophilus influenzae type b (Hib), meningitis, pneumonia, dengue, and cervical cancer, that are as much a burden or even less of a burden than typhoid fever. It is truly a neglected disease of neglected populations.” The CaT meeting explored how mathematical models of typhoid fever might tackle the main cause of this neglect, namely, the paucity of information available to governments about the magnitude of the typhoid fever burden in their countries, districts, cities, and towns and about the most feasible, cost-effective means of reducing that burden. These means are available. There are vaccines, however imperfect, that could reduce the typhoid burden and there are data, however limited, that could inform government decision making. To take vaccines first: there are two, one given orally, the other by injection. They have been available for nearly two decades. They are inexpensive and safe and have been licensed for use in virtually all countries. In countries where they have been tested they have substantially reduced the incidence of the disease. Since 2000, WHO has been urging countries to use them in combating endemic disease and outbreaks. And in November, 2011, WHO's prequalification procedure gave its stamp of approval for the injectable vaccine to be bought by developing countries at a relatively low cost through the UN vaccine procurement system. Yet, of the 16 countries, all in Asia, where typhoid fever is highly endemic, only three have used a typhoid vaccine to protect their child populations—India (in New Delhi), Vietnam, and Thailand. What are the reasons for the low uptake? Low government priority given to typhoid and insufficient data on vaccine cost-effectiveness in specific populations and settings, according to meeting participants. Another reason is that these typhoid vaccines have shortcomings. They are effective in only 65–70% of recipients, the protection they afford is of relatively short duration, and they have little or no efficacy in children younger than 2 years of age. Some governments are waiting for a better vaccine. A new-generation vaccine that is linked (conjugated) to an immunity provoking carrier molecule (a protein polysaccharide), has been in the industry pipeline for over a decade. It provides strong, long-lasting protection in recipients of all age groups. A version of this conjugate vaccine developed by the US National Institutes of Health has been tested in an advanced-stage (phase 3) trial in Vietnam, where it protected more than 90% of recipients, including infants younger than 2 years of age. Vaccine manufacturers, however, are waiting before taking the conjugate vaccine to the licensing stage. The limited uptake of existing typhoid vaccines by governments of countries where the disease is highly endemic does little to convince vaccine developers that there will be a strong market demand for the new vaccine. The GAVI Alliance has considerable experience in creating reliable markets for vaccines in developing countries. But GAVI, too, is waiting for the conjugate vaccine. GAVI head Seth Berkley explains why the Alliance is not adopting the currently available vaccines: “The current vaccines provide protection for only 1 to 3 years, which means revaccination is needed every so often. Also, neither of the two vaccines has been approved for use in children under 2 years of age, the age-group on which GAVI concentrates most of its efforts. And finally, alternative treatments do exist for typhoid fever.” As for paucity of data on typhoid fever, research teams from the International Vaccine Institute in Seoul, South Korea, have been collecting information about typhoid fever in five Asian countries. New data are also emerging from Africa, where typhoid fever has historically been thought to occur more often in the form of outbreaks than as an endemic disease (Zimbabwe is currently in the throes of a large outbreak). Surprising many typhoid watchers, a study reported in January, 2012, by Robert Breiman and his team at the Kenya office of the US Centers for Disease Control and Prevention in Nairobi found typhoid fever in about 2% of all children 2–9 years of age in a Nairobi slum area. A US team from Michigan State University found similar typhoid infection rates in Abuja, Nigeria, where 20% of children 0–5 years of age who tested positive for bacterial infection were infected with S typhi. There are, however, formidable obstacles to reducing the burden of typhoid fever. Providing populations with safe water and basic sanitation would bring down the incidence of the disease but the massive capital investment needed would be prohibitive. Antibiotics have for long been the standard treatment for typhoid fever. Where health-care services exist in the developing world, antibiotics have brought case fatality rates down from over 25% to around 1%. But in recent years, multidrug-resistant S typhi strains have been spreading rapidly throughout the developing world. In many places, 50% of typhoid patients are infected with multidrug-resistant strains. Drug resistance, formerly found only in Asia, has recently appeared in Africa. In the Nairobi study, Breiman's team found 75% of the infected children to be resistant to antibiotics. Differential diagnosis of typhoid fever is difficult. Onset of the disease, marked by high-grade fever, malaise and anorexia, stomach pain, liver and spleen enlargement, and constipation or less commonly diarrhoea, is insidious. Often it is misdiagnosed as malaria, dengue, or pneumonia. Accurate diagnosis, therefore, calls for the finding of S typhi in blood or stool specimens. Current standard culture methods are positive in only 40–60% of true cases. Bone marrow cultures are more sensitive but difficult to obtain and therefore not suitable for use in public health settings. Moreover, where the disease is present, laboratory facilities tend to be absent. Since accurate diagnosis is the mainstay of disease surveillance and since reliable surveillance data are the mainstay of informed policy decisions, the absence of reliable diagnostic methods generally hampers estimation of the true magnitude of the typhoid fever burden. Moreover, the potentially life-threatening complications of typhoid fever add urgency to the need for early accurate diagnosis and early treatment. Complications arise in 10–15% of untreated patients and include rupture and haemorrhage of the intestine followed by shock and death. Mathematical modelling, the CaT meeting concluded, could give health officials the information they need to take action against typhoid fever. Participants at the meeting discussed various modelling strategies and what information—on disease epidemiology, costs of illness, and the effectiveness of vaccination and other interventions—should be fed into a model to enable health officials to decide how best to deal with typhoid fever. How best, in other words, to put typhoid fever out of sight by keeping it well in mind.