The surveillance paradox: Why biological breakthroughs fail without a global data map

“ Several different forms of the parasites have been found, corresponding to different203 varieties of malaria. Parasites of a very similar nature exist abundantly in birds. Ross, an army surgeon in India, found that the spread of this parasite from bird to bird was effected through the intervention of the mosquito. The parasites reach maturity in certain cells of the coats of the stomach of these insects, and develop into peculiar thread-like bodies, many of which ultimately reach the salivary glands, from which, as the insect bites, they pass with the secretion of the glands into the wound. ”

“ By a series of most interesting experiments, conducted by them and by other scientists in other parts of the world, it has been definitely proved that when a mosquito bites an individual suffering from malaria, the mosquito draws up into his body, along with the blood of the bitten person, some of the malarial parasites. In the body of the mosquito, the parasite develops, requiring for a full-grown specimen about seven days; then, if the mosquito bites another person, the parasite is injected into the skin of the victim, and in the course of about a week a good case of malaria ensues. ”

“ The malaria-parasite undergoes, in its passage through the body of the Anopheles, many and varied phases of its life-history. As the Frenchman said of the pork, which goes into one end of the machine in the Chicago meat factories as live pig, and comes out at the other in the form of sausages, ‘Il est diablement changé en route.’ The mosquito is as truly a host of the malarial parasite as man, and is as necessary for its full development as is man. ”

“ In accordance with this definition malaria is not a contagious disease in the sense that it is acquired by contact with the sick, which is not the case, but it is derived from contact with certain kinds of mosquitoes, and can be contracted in no other way, despite the many popular notions to the contrary. Mosquitoes, in their turn, acquire the malarial parasite by biting human beings suffering from malaria. It thus becomes possible for one malarial patient, coming to a region hitherto free from the disease, to infect the whole [Pg 248] district with malaria through the medium of mosquitoes. ”

“ As far as we know, the parasite of malaria exists only in infected man and in infected mosquito. Perpetuation of the disease is due to the perpetuation of the cycle, man to mosquito, mosquito to man. If the parasite is destroyed in man or the Anopheles is not allowed to breed, the disease disappears. ”

“ Thirdly, our knowledge of the parasite is invaluable in directing treatment. Lastly, a knowledge of the life-history of the malarial parasite is of extreme value for the prevention of malarial disease, for could we by mechanical or other arrangements prevent the mosquito attacking the human body, we could prevent the malarial parasites from entering the human body; or if we could abolish the mosquito by drainage or other means from a country, then we might be sure that we would abolish the malaria of that country also. ”

“ Typhoid fever is carried by water or by contaminated milk, and in various other ways, as well as by the house-fly. Kill all the house-flies and typhoid would still exist. On the other hand, malaria is carried only by the mosquito, because an essential part of the development of the malarial parasite is undergone in this insect. Exterminate all of the mosquitoes of certain species and the dissemination of human malaria is absolutely prevented. ”

“ Knowing the cause, we can now guard against malaria; mosquito-nets and wire-protected windows and doors are a sufficient check on the access of Anopheles to man. If the mosquito and man could only be kept permanently apart, we might hope for the disappearance of the parasite from our fauna. In relieving man from this world-wide pest, all genuine lovers of animals will rejoice that we are also relieving the far more serious lesions of one of the most delicate and beautiful insects that we know. ”

“ This increase in the parasitic burden causes malaria's characteristic symptoms—debilitating and recurring fevers and chills. Infected red blood cells also release gametocytes, which infect mosquitoes when they take a blood meal. In the mosquito, the gametocytes multiply and develop into sporozoites, thus completing the parasite's life cycle. Malaria can be prevented by controlling the mosquitoes that spread the parasite and by avoiding mosquito bites. Effective treatment with antimalarial drugs also helps to reduce malaria transmission. ”

“ What can be done to diminish malaria? A few years ago, before we understood the cause of the disease, much had been done to lessen it. While aiming at other objects, we drove malaria out of England by draining. Now that we know the secret of the disease we can direct our efforts more intelligently. There are two points exposed to attack. The first is the sporulating organism in the blood of man, the second is the insect. If we could eliminate the organism from man, the mosquito would be saved much suffering, and would be powerless to infect man ”

“ In short, science is prepared to say to the community: "I have done my part in the problem of malaria. It is for you to do the rest." There is literally no neighborhood in the temperate zone, and exceedingly few in the tropics, which cannot, by intelligent coöperation and a moderate expense, be absolutely rid first of malaria, and second of all mosquito-pests. ”

“ Whilst this 2010 map draws on a hugely expanded evidence-base, the distribution of information on endemicity affecting local communities remains profoundly uneven and, thus, so too does the capacity to precisely enumerate local levels of risk. Unfortunately, it remains the case that some of the largest populations, exposed to the highest levels of risk, are those about which the least is known. As resources to combat malaria increase, it is essential that these are matched by commensurate efforts to collect the data required to evaluate risk and monitor how it changes. ”

“ The design, financing and implementation of malaria control demand a quantitative approach to the definition of anti-malarial commodity requirements of populations living under varied malaria transmission risks. The geographic extent of effective intervention coverage and how this relates to the dominant local Anopheles vector species and, in turn, their sensitivity to insecticides, is necessary to design appropriate vector control. Information on the prevalence of drug resistance and population spatial access to medicines is required to devise adequate clinical disease management strategies. ”

“ Transmission intensity affects almost all aspects of malaria epidemiology and the impact of malaria on human populations. Maps of transmission intensity are necessary to identify populations at different levels of risk and to evaluate objectively options for disease control. To remain relevant operationally, such maps must be updated frequently. Following the first global effort to map Plasmodium falciparummalaria endemicity in 2007, this paper describes the generation of a new world map for the year 2010. ”

“ At a societal level, mismanagement of fever erodes patient's faith in the health system, wastes drug resources, augments drug pressure toward resistance [ [14] , and contributes to ignorance of the true causes of illness in these populations. In the face of this, it should be disturbing that less than 20% of suspected malaria cases receive a confirmatory diagnosis in 75% of African countries [ [10] .
High mortality at 10 Tanzanian hospitals among patients admitted with severe disease and treated for malaria. ”

“ This momentum has been captured by a new call for malaria elimination. Without wide implementation of accurate and discriminating diagnostic testing, and reporting of results, most fever will be inappropriately managed, millions of doses of ACT will be wasted, and malaria control programmes will be blindfolded to the impact of their efforts. ”

“ There is no perfect post-hoc correction to compensate for poor malaria surveillance. Both methods using routine HMIS adjusted for nonattendance, poor reporting, and inadequate diagnostics, and those presented here, have limitations with respect to coverage and quality of the input data for each model, and with respect to underlying modelling assumptions. Both approaches to burden estimation result in wide margins of confidence and the inevitable plea from any such analysis is for accurate national reporting systems or more empirical epidemiological data. ”

“ The epidemiology of malaria makes surveillance-based methods of estimating its disease burden problematic. Cartographic approaches have provided alternative malaria burden estimates, but there remains widespread misunderstanding about their derivation and fidelity. The aims of this study are to present a new cartographic technique and its application for deriving global clinical burden estimates of Plasmodium falciparum malaria for 2007, and to compare these estimates and their likely precision with those derived under existing surveillance-based approaches. ”

“ These metrics underpin mathematical models of transmission that are central to contemporary questions in malaria control [9] : identifying optimal intervention suites and coverage levels, predicting timelines of declining endemicity, and assessing the regional feasibility of elimination [2] , [10] - [11] . If these values exceed one, infection prevalence increases to a steady state, and if less than one, prevalence declines. Thus, if sustained disease control reduces transmission intensity by a factor that exceeds PfR0, the parasite will eventually be eliminated. ”

“ The most commonly measured metric of malaria transmission is the parasite rate: the proportion of individuals infected at a given point in time. In 2009, the Malaria Atlas Project (MAP) assembled all available data from Plasmodium falciparumparasite rate (PfPR) surveys, and used model-based geostatistics (MBG) to generate a global map of estimated PfPR for the year 2007 [3] . That map provided new insights into global patterns of malaria endemicity and, through the careful handling of uncertainty, a framework for assessing those areas where knowledge of endemicity is inadequate. ”

“ The most commonly recorded measure of malaria risk remains the parasite rate (PR) . PR surveys are more frequently reported in bibliographic archives than all of the other epidemiological metrics combined (Table 1) . It was, therefore, justified to focus the initial information searches of MAP on the retrieval and archive of PR surveys undertaken across MECs. This paper presents the methods and approaches used to assemble a global database on this key measure of malaria endemicity and risk. ”

“ The global ubiquity of PfPR surveys means that they are the only feasible data source for large-scale malaria mapping [1] , [2] . Other metrics of malaria transmission, however, have distinct and crucial roles in informing control decisions. The basic reproductive number for malaria, PfR0, quantifies the potential for the disease to spread within a naive population [6] , [7] . The same metric for scenarios moderated by malaria control has been termed PfRc [8] . ”

“ Open access to databases of information generated by the research community can synergize individual efforts and are epitomized by the genome mapping projects. Open source models for outputs of scientific research funded by tax-payers and charities are becoming the norm. This has yet to be extended to malaria epidemiology and control.
Methods
The exhaustive searches and assembly process for a global database of malaria parasite prevalence as part of the Malaria Atlas Project (MAP) are described. ”

“ Once robust spatial estimates of global malaria endemicity have been developed, the integration of further epidemiological data to exploit the applicability of these maps is anticipated, including monitoring progress towards international malaria control targets and the projection of financial and commodity needs for MECs. Without publicly available information, national and international agencies will continue to assume that entire regions or countries share similar epidemiological characteristics and that they must share one prescribed menu for control. ”

“ To estimate stable transmission intensity, a Bayesian space-time geostatistical modelling framework was developed to interpolate empirical estimates of age-corrected parasite prevalence derived from 7,953 community surveys undertaken between 1985 and 2008 across 83 malaria-endemic countries. This model has been described in detail elsewhere [22] and its output allows for a continuous, urban-adjusted, contemporary estimate of parasite prevalence in children aged from 2 up to 10 years (PfPR2–10) at a pixel spatial resolution of 5×5 km for the year 2007 (Figure 2) . ”

“ In the MBG framework, PfPR2-10 values were modelled as a function of nearby survey data - which were weighted in each prediction according to their spatial and temporal proximity - and of a large suite of environmental covariates. Candidate spatial covariates were chosen based on factors known to interact with, and influence, the epidemiology of P. falciparumincluding climatology surfaces interpolated from networks of meteorological stations [32] and remotely sensed data from Earth observation satellites in their raw form and used as input into categorical global land cover products [33] . ”

“ Globally, this is likely to be of particular utility in those areas of low and unstable transmission where surveillance capabilities are often more robust and correspondingly where prevalence data are often rare as the number of people needed to be sampled to find infections is prohibitive [5] .
The malaria clinical burden estimates presented in this paper are driven by the underlying model of global prevalence [22] . This global malaria map is, to our knowledge, the first evidence-based attempt to define populations at risk of different levels of parasite transmission. ”

“ Whilst the spatial variation in risk mandates the generation of robust maps that can guide disease control, the dynamic nature of malaria endemicity means that such maps must be continually updated if they are to remain relevant. The ongoing scale-up of major malaria control initiatives represents the largest potential perturbation to local and regional malaria transmission systems for many decades, and heightens the requirement for regular assessments of risk. ”

“ Malaria control has recently seen a long-overdue resurgence in interest and funding, a belated recognition that malaria is still dominating the lives and health of millions, and holding whole populations in poverty. In places where these renewed efforts have been systematically applied, insecticide-treated bed nets, indoor residual spraying, and artemisinin-based combination therapy (ACT) have demonstrated their capacity to reduce both incidence and mortality from malaria. ”

“ Global malaria control efforts have been energized by the availability of new sources of funding, and by the rapid reduction in malaria prevalence in a number of settings where bed nets, indoor residual spraying with insecticides, and ACT have been systematically deployed. ”

“ To remain useful, however, these maps must remain contemporary. The year 2010 has a particular significance as an evaluation milestone for malaria global health policy [4] - [5] and a huge expansion in the availability of parasite rate surveys since 2007, as well as ongoing refinement in spatial modelling techniques, including the use of environmental covariates, has provided an opportunity to carry out a major revision of the map for this benchmark year. ”

“ The single largest difference between previous work and the present iteration of P. falciparum disease burden estimation is that neither previous approach was based upon an empirically defined risk map of malaria transmission [22] . Comparing estimates derived using these different techniques, over various time periods, is not a sound basis for investigating trends and should be avoided. ”

“ African Regional Office, AMRO – Americas Regional Office, EMRO – Eastern Mediterranean Regional Office, EURO – European Regional Office, SEARO – South East Asian Regional Office, WPRO – Western Pacific Regional Office. Spatial distribution of PR records
The number of records varies substantially amongst regions and countries, reflecting not necessarily where malaria is a more serious problem, but where more PR estimates are available, either because surveys are conducted more systematically or because data proved easier to access. ”

“ Cartographic approaches to burden estimation provide a globally consistent measure of malaria morbidity of known fidelity, and they represent the only plausible method in those malaria-endemic countries with nonfunctional national surveillance. Unacceptable uncertainty in the clinical burden of malaria in only four countries confounds our ability to evaluate needs and monitor progress toward international targets for malaria control at the global scale. National prevalence surveys in each nation would reduce this uncertainty profoundly. ”

“ Analysis of geographic variation in data availability and uncertainty must be tempered by a consideration of the underlying population: uncertainty matters more where populations are dense. The population-weighted index of uncertainty (Figure 3C) brings into stark relief the dearth of robust data in the high-endemicity and high-population regions of India, Myanmar, Nigeria, and DRC. In some currently under-surveyed regions, new national malaria surveys are either planned or completed, meaning that future iterations of this map will improve substantially. ”

“ It is worth reiterating that if the international community wishes to demonstrate progress in malaria control, then the quantity and timeliness of prevalence information and parasite-specific surveillance records must dramatically improve. This is true for all countries but is particularly important in India, Nigeria, DRC, and Myanmar because of the large populations at risk and the paucity of existing malariometric information. ”

“ Low rates of care-seeking for malaria in the formal health sector, unreliable diagnoses, poor record keeping, and inefficient data transfer and collation systems can all combine to make the number of cases formally reported a small fraction of the true number of cases in a population. ”

“ The most successful approach to identifying community specific estimates of parasite prevalence was through communications and contacts with malaria scientists identified from peer-reviewed literature sources. Assembling a comprehensive database of PR data cannot depend entirely on information available from peer-reviewed sources, therefore, as sources classified as 'journal' alone only provided 26.4% of the total number of records. ”

“ This source of information resulted in only 25 PR records. Smaller national conference proceedings might have yielded more comprehensive data, but these were not easily accessible with the exception of one conference proceeding in India, available from the National Institute of Malaria Research website [41] . By the very nature of national conferences, post-graduate theses, 'grey' literature reports and ministry of health survey data, these will not have been captured comprehensively by the MAP data searches. ”

“ Afghanistan, Tanzania, Kenya, Zimbabwe and Eritrea are the top five countries in terms of number of PR survey records. A more balanced picture of data availability by country was produced by weighting the number of points by the estimated area that is malarious derived from the global spatial limits of malaria (Figure 5) [25] , [26] . According to this ranking, the five countries for which the least PR records are available are Angola, Mexico, Namibia, Chad and Democratic Republic of the Congo.
The global distribution of P. falciparum PR points from the MAP database. ”

“ Defining Malaria Incidence in Areas of Unstable P. falciparum Malaria Transmission
We estimate that almost one billion people were living in areas where P. falciparum transmission was unstable in 2007 [21] (Figure 2) . Defining annualized disease risk in these areas from empirical data is difficult, as epidemiological investigations for research or survey purposes are rare. Nevertheless, in computing disease burdens it is important to impute some measure of completeness of formal malaria reporting within these marginal, unstable transmission areas. ”

“ In countries with unstable transmission, the researchers assumed a uniform annual clinical incidence rate of 0.1 cases per 1,000 people and multiplied this by population sizes to get disease burden estimates. In countries with stable transmission, they used a modeled relationship between clinical incidence (number of new cases in a population per year) and prevalence (the proportion of a population infected with malaria parasites) and a global malaria endemicity map (a map that indicates the risk of malaria infection in different countries) to estimate malaria incidences. ”

“ It is not possible to provide an evidence-based under-reporting correction factor that is specific for every national malaria information system. We have therefore elected to use a single worst-case rate of 10-fold under-reporting across all countries. We hence assume for all unstable areas a uniform incidence of 0.1 case per 1,000 PA, with a lower confidence bound of zero and an upper confidence bound assuming a 10-fold under-reporting rate ”

“ Finally, they note that improvements in the national prevalence surveys in India, Nigeria, the Democratic Republic of the Congo, and Myanmar would greatly reduce the uncertainty associated with their estimate of the global clinical burden of malaria, an observation that should encourage efforts to improve malaria surveillance in these countries. ”

“ It is clear that investing in radically improved surveillance and/or nationally representative malariometric surveys would substantially increase the fidelity of national and, by extension, global burden estimates. Because there are regional differences in the uncertain relationship between transmission intensity and disease outcome [23] , more information derived from active case detection studies would improve the precision in our estimates of disease incidence within these transmission ranges. ”

“ Potential explanations for quinine treatment failure Quinine resistance
Parasite drug resistance is probably the greatest problem faced by malaria control programs worldwide and is an important public health concern. Over the years, malaria parasites have developed resistance to a number of commonly used anti-malarial drugs. ”

“ This and the proposed future studies will substantially improve our understanding of malaria transmission in Djibouti, but without a carefully defined plan, staff or funding elimination of malaria in Djibouti remains only a biological possibility. The threshold of parasite prevalence seen as the benchmark for deciding whether to move on to malaria elimination or sustain low endemic control is seen as 1% parasite prevalence [3] , [11] . But to detect this level of prevalence requires large and expensive survey samples. ”

“ Defining P. falciparum Clinical Incidence in Areas of Reliable Case Detection
Paradoxically, where the incidence of clinical malaria events are rare, their rapid detection and notification becomes increasingly important as part of national malaria control strategies, demanding more sophisticated surveillance [35] , [34] – [36] . This is particularly true for countries aiming to attain or maintain WHO accredited elimination status [37] – [38] . ”

“ Countries aiming for malaria elimination require a detailed understanding of the current intensity of malaria transmission within their national borders. National household sample surveys are now being used to define infection prevalence but these are less efficient in areas of exceptionally low endemicity. Here we present the results of a national malaria indicator survey in the Republic of Djibouti, the first in sub-Saharan Africa to combine parasitological and serological markers of malaria, to evaluate the extent of transmission in the country and explore the potential for elimination. ”

“ The remaining aspect of uncertainty arises from spatial or temporal variation in transmission intensity that occurs over short spatial or temporal scales. The early cartography of malaria risk aimed to classify wide areas into risk strata [65] , and this has led to a tendency to think of endemicity as a smoothly varying phenomenon. In reality, however, an area considered to belong to a particular endemicity 'class' will likely display a huge amount of variation, with parasite rates sampled at nearby villages often differing dramatically regardless of sample size. ”

“ Progressive malaria elimination in Bhutan will require intensified efforts in case-based surveillance, with rapid notification, case investigation and case containment strategies. The expansion of parasitological and entomological surveillance is a priority, and must include the identification and mapping of local malaria foci, which is dependent upon the creation of district-level case investigation and rapid response teams. ”

“ Djiboutian armed and police forces train in Ethiopia and are stationed as part of UN peace keeping in Cote D'Ivoire. Thousands of foreign military personnel are stationed in Djibouti Ville and engage in regional travel. Therefore the significance of human population movement for the risks of imported infectious diseases, including malaria, should not be under-estimated and may be an important contributor to disease hot spots in the country. ”

“ The low-lying southern region of Bhutan is at high-risk for malaria transmission [6] and has a highly porous border with India, through which there is significant population movement. In addition, large numbers of migrant workers enter the country to work in large-scale development projects in areas vulnerable to malaria transmission, creating a risk of continual importation and re-introduction of malaria into the area [7] . Given these and other challenges, the recent success in reducing malaria incidence may contain lessons for other countries [8] . ”

“ Combined, the results of these studies demonstrate the importance of population surveillance; to enable identification of routes of P. vivax introduction to, and transmission within, a given population. To achieve malaria elimination targets, the movement of P. vivax populations must be controlled to limit not only reintroduction of the disease into non-endemic countries, but also to restrict global genetic diversity and the spread of drug resistance. ”

“ Use of mobile phone data to track population movements internally and externally [ [60] ; screening arriving passengers for malaria at the border entry points and recording of their detailed travel history; and redesigning household survey sampling and questionnaires to capture detailed travel histories of individuals tested for malaria infections are possible approaches to assessing the impact of human population movement on malaria in Djibouti. ”

“ Sustained malaria control will depend on the global capacity to accurately detect malaria and map its distribution. The specific detection of malaria parasites is now possible even at the village level with high quality rapid diagnostic tests. Driven by the extent of over-diagnosis and misdiagnosis of malaria when syndromic approaches are used, global efforts are underway to increase the utilization of parasite-based diagnosis, and to ensure the quality of tests that are used. ”

“ This household sub-sample was also interviewed about travel histories in the last six months, duration and destination and the presence of fever in the last 14 days and on the day of survey.
Laboratory methods Serological measures
Serologic markers can be particularly useful in areas of low endemicity, where it may be easier to detect relatively long-lasting antibody responses than a low prevalence of malaria infections in the human population or infected mosquitoes [28] - [29] . ”

“ A drive towards malaria elimination will increase the need for broad use of quality assured diagnostics for malaria, and possibly the development of novel assays to address specific needs such as the sensitivity at low parasite densities and minimal invasiveness required for population-based surveys for parasite reservoirs. The imperative for parasitologic diagnosis will be dramatically increased where malaria incidence falls, and where reflex treatment of fever with antimalarial drugs would be ineffective and even harmful in the vast majority of cases. ”

“ As a consequence, we believe that until there is a universally reliable reporting system for malaria cases worldwide to support comprehensive surveillance-based estimates, a concerted effort to map the changing spatial extents and intensity of transmission will remain a valuable contribution to the future estimations of a changing disease burden worldwide. In the short term, measuring how the “denominator” changes with time is clearly easier and cheaper than improving the global state of health information systems. ”

“ Malaria surveillance also needs to become an up-regulated disease reporting system with the ability to detect, intervene and eliminate residual foci of malaria infections as and when they emerge. The round 9 proposal includes 0.48 million USD to strengthen surveillance but deciding on how best to develop and implement malaria surveillance systems for elimination has a much weaker evidence-based platform than ITN delivery [ [3] . ”

“ Eggs of Anopheles. After Howard.
Since that time there have been many practical demonstrations of the fact that malaria is transmitted exclusively by the bite of mosquitoes and that the destruction of the mosquitoes means the elimination of the disease.
We have said that the malarial parasite is able to undergo its development only in certain species of mosquitoes belonging to the Anopheline group. It is by no means certain that all of this group even, are capable of acting as the definitive host of the parasites, and much careful experiment work is still needed along this line. ”