Portal de Periódicos da CAPES

Changes in Malaria Epidemiology in Africa and New Challenges for Elimination

2016; Elsevier BV; Volume: 33; Issue: 2 Linguagem: Inglês

10.1016/j.pt.2016.11.006

1471-5007

Irene N. Nkumama, Wendy Prudhomme O’Meara, Faith Osier,

Zoonotic diseases and public health

Malaria is declining in Africa overall but there is considerable uncertainty around reported estimates. In some areas, the burden of malaria has remained unchanged or increased. More time is spent estimating rather than measuring the malaria burden. Changes in malaria transmission intensity have brought to the fore emerging populations at risk. Sustaining the gains in malaria control is a major challenge for elimination. More extensive and high-quality data on the actual malaria burden is vital to guide control on the path to elimination. Although the burden of Plasmodium falciparum malaria is gradually declining in many parts of Africa, it is characterized by spatial and temporal variability that presents new and evolving challenges for malaria control programs. Reductions in the malaria burden need to be sustained in the face of changing epidemiology whilst simultaneously tackling significant pockets of sustained or increasing transmission. Large-scale, robust surveillance mechanisms that measure rather than estimate the actual burden of malaria over time from large areas of the continent where such data are lacking need to be prioritized. We review these fascinating developments, caution against complacency, and make the case that improving the extent and quality of malaria surveillance is vital for Africa as she marches on towards elimination. Although the burden of Plasmodium falciparum malaria is gradually declining in many parts of Africa, it is characterized by spatial and temporal variability that presents new and evolving challenges for malaria control programs. Reductions in the malaria burden need to be sustained in the face of changing epidemiology whilst simultaneously tackling significant pockets of sustained or increasing transmission. Large-scale, robust surveillance mechanisms that measure rather than estimate the actual burden of malaria over time from large areas of the continent where such data are lacking need to be prioritized. We review these fascinating developments, caution against complacency, and make the case that improving the extent and quality of malaria surveillance is vital for Africa as she marches on towards elimination. Malaria is caused by infection with protozoan parasites of the Plasmodium species. Plasmodium falciparum is widespread in Africa while P. vivax, P. ovale, and P. malariae infections are less common and geographically restricted [1Howes R.E. et al.Plasmodium vivax transmission in Africa.PLoS Negl. Trop. Dis. 2015; 9: e0004222Crossref PubMed Scopus (79) Google Scholar, 2Roucher C. et al.A 20-year longitudinal study of Plasmodium ovale and Plasmodium malariae prevalence and morbidity in a West African population.PLoS One. 2014; 9: e87169Crossref PubMed Scopus (68) Google Scholar]. The parasites are transmitted by Anopheles mosquitoes, with An. gambiae sensu stricto, An. funestus, and An. arabiensis being the most prevalent in Africa [3Sinka M.E. et al.The dominant Anopheles vectors of human malaria in Africa, Europe and the Middle East: occurrence data, distribution maps and bionomic précis.Parasites Vectors. 2010; 3: 1-34Crossref PubMed Scopus (36) Google Scholar]. Patients present with nonspecific symptoms, including fever, rigors, and chills, and the majority will not require hospital admission. Severe malaria develops in a minority, and in children it may manifest as a fever, impaired consciousness, severe anaemia, respiratory distress, convulsions, and hypoglycemia, among other symptoms [4Marsh K. et al.Indicators of life-threatening malaria in African children.N. Engl. J. Med. 1995; 332: 1399-1404Crossref PubMed Scopus (862) Google Scholar]. The epidemiology of malaria varies geographically depending on the local malaria transmission intensity or endemicity class (Box 1) [5Snow R.W. Marsh K. The consequences of reducing transmission of Plasmodium falciparum in Africa.Adv. Parasitol. 2002; 52: 235-264Crossref PubMed Scopus (172) Google Scholar]. While the exact numbers may be uncertain and underreporting is inevitable, 395 000 deaths were estimated in Africa in 2015 [6WHO World Malaria Report. World Health Organization, 2015Google Scholar]. Infection with P. falciparum in the absence of overt clinical symptoms is also common [7Lindblade K.A. et al.The silent threat: asymptomatic parasitemia and malaria transmission.Expert Rev. Anti. Infect. Ther. 2013; 11: 623-639Crossref PubMed Scopus (299) Google Scholar]. It is often referred to as being asymptomatic, but may be better termed chronic and is probably not as benign as the former term might suggest [8Chen I. et al.'Asymptomatic' malaria: a chronic and debilitating infection that should be treated.PLoS Med. 2016; 13: e1001942Crossref PubMed Scopus (198) Google Scholar]. Pregnant women often harbor chronic low-density infections with adverse outcomes for both mother and child [9Steketee R.W. et al.The burden of malaria in pregnancy in malaria-endemic areas.Am. J. Trop. Med. Hyg. 2001; 64: 28-35Crossref PubMed Scopus (758) Google Scholar]. The impact of malaria extends beyond health facilities to homes and everyday lives: children may develop long-term neurological sequelae following severe malaria attacks [10Mishra S.K. Newton C.R. Diagnosis and management of the neurological complications of falciparum malaria.Nat. Rev. Neurol. 2009; 5: 189-198Crossref PubMed Scopus (125) Google Scholar], more subtle developmental and cognitive impairments as a result of both severe and uncomplicated episodes [11Holding P.A. Kitsao-Wekulo P.K. Describing the burden of malaria on child development: what should we be measuring and how should we be measuring it?.Am. J. Trop. Med. Hyg. 2004; 71: 71-79PubMed Google Scholar], and families face substantial economic consequences [12Sicuri E. et al.The economic costs of malaria in children in three sub-Saharan countries: Ghana, Tanzania and Kenya.Malaria J. 2013; 12: 307Crossref PubMed Scopus (60) Google Scholar].Box 1Malaria Endemicity ClassesThese give an indication of the burden of malaria in a given locale; areas are classified as holo-, hyper-, meso-, and hypo- endemic.Classification as Proposed in the WHO 1951 Report on the Malaria Conference in Equatorial Africa [90Malaria Conference in Equatorial Africa (1950: Kampala, Uganda), World Health Organization, Commission for Technical Co-operation in Africa South of the Sahara Report on the Malaria Conference in Equatorial Africa, held under the joint auspices of the World Health Organization and the Commission for Technical Co-operation in Africa South of the Sahara, Kampala, Uganda, 27 November-9 December 1950.Wld Hlth Organ. Tech. Rep. Ser. 1951; 38: 1-72PubMed Google Scholar]•Hypoendemic malaria: spleen-rate in children 2–10 years of age, 0–10%•Mesoendemic malaria: spleen-rate in children 2–10 years of age, 11–50%•Hyperendemic malaria: spleen-rate in children 2–10 years of age, constantly over 50%; spleen-rate in adults, high•Holoendemic malaria: spleen-rate in children 2–10 years of age, constantly over 50%; spleen-rate in adults, low; it is in this type of endemicity that the strongest adult tolerance is found.Classification Based on Parasite Prevalence•Hypoendemic malaria: parasite rate in children 2–10 years of age, 0–10%•Mesoendemic malaria: parasite rate in children 2–10 years of age, 10–50%•Hyperendemic malaria: parasite rate in children 2–10 years of age, 50–75%•Holoendemic malaria: parasite rate in children 2–10 years of age, >75% These give an indication of the burden of malaria in a given locale; areas are classified as holo-, hyper-, meso-, and hypo- endemic. •Hypoendemic malaria: spleen-rate in children 2–10 years of age, 0–10%•Mesoendemic malaria: spleen-rate in children 2–10 years of age, 11–50%•Hyperendemic malaria: spleen-rate in children 2–10 years of age, constantly over 50%; spleen-rate in adults, high•Holoendemic malaria: spleen-rate in children 2–10 years of age, constantly over 50%; spleen-rate in adults, low; it is in this type of endemicity that the strongest adult tolerance is found. •Hypoendemic malaria: parasite rate in children 2–10 years of age, 0–10%•Mesoendemic malaria: parasite rate in children 2–10 years of age, 10–50%•Hyperendemic malaria: parasite rate in children 2–10 years of age, 50–75%•Holoendemic malaria: parasite rate in children 2–10 years of age, >75% Given the current momentum and enthusiasm for malaria elimination in Africa, we contrast recently published modeled trends of the burden against those from empirical studies and show that much more remains to be achieved. We review new challenges for elimination where control has been successful and consider challenges where it has been limited, highlighting research gaps. Given the broad range of possible clinical presentations of malaria, it is not obvious what aspect(s) of the disease can and should be measured in order to accurately monitor changing epidemiology. On the face of it, making a diagnosis of malaria should be relatively simple based on readily defined clinical features and supported by positive identification of parasites in peripheral blood smears. In practice in endemic areas, this seemingly straightforward situation is problematic because of the high prevalence of chronic P. falciparum infections (Box 2), and the potential for many other conditions to cause fever and/or symptoms similar to severe malaria. Confirming that the parasitaemia one detects is the cause of the presenting symptoms in a patient remains challenging [13Koram K.A. Molyneux M.E. When is 'malaria' malaria? The different burdens of malaria infection, malaria disease, and malaria-like illnesses.Am. J. Trop. Med. Hyg. 2007; 77: 1-5PubMed Google Scholar], even in well-resourced research centres. The malaria-positive fraction (MPF, Box 3) of hospital admissions or outpatient attendees [14O'Meara W.P. et al.Changes in the burden of malaria in sub-Saharan Africa.Lancet Infect. Dis. 2010; 10: 545-555Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar, 15Ceesay S.J. et al.Changes in malaria indices between 1999 and 2007 in The Gambia: a retrospective analysis.Lancet. 2008; 372: 1545-1554Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar] is used as an index of transmission intensity but may be confounded by variability in its denominator. It can be deceptively high when the denominator comprises cases selected based on a high index of suspicion, and is more accurate when all cases presenting to a facility are tested. Additionally, the utilization of formal health services is variable and can be low [16Geldsetzer P. et al.The recognition of and care seeking behaviour for childhood illness in developing countries: a systematic review.PLoS One. 2014; 9: e93427Crossref PubMed Scopus (139) Google Scholar]. Community surveys of parasite prevalence give a broader picture of the overall parasite burden in the population by including asymptomatic individuals of all ages, but the relationship between parasite prevalence and disease incidence is complex and nonlinear [5Snow R.W. Marsh K. The consequences of reducing transmission of Plasmodium falciparum in Africa.Adv. Parasitol. 2002; 52: 235-264Crossref PubMed Scopus (172) Google Scholar]. Furthermore, parasite prevalence surveys are often opportunistic, prone to observer bias, nonstandardized, and affected by a multitude of factors including the age-structure of the sample, the timing of sampling in relation to local malaria transmission seasons, and the methodology and rigor applied to parasite detection [17Tusting L.S. et al.Measuring changes in Plasmodium falciparum transmission: precision, accuracy and costs of metrics.Adv. Parasitol. 2014; 84: 151-208Crossref PubMed Scopus (116) Google Scholar, 18Mappin B. et al.Standardizing Plasmodium falciparum infection prevalence measured via microscopy versus rapid diagnostic test.Malaria J. 2015; 14: 460Crossref PubMed Scopus (15) Google Scholar] (Box 2). Serological markers show promise, particularly in low-transmission settings, but need further validation [19Helb D.A. et al.Novel serologic biomarkers provide accurate estimates of recent Plasmodium falciparum exposure for individuals and communities.Proc. Natl. Acad. Sci. U.S.A. 2015; 112: E4438-E4447Crossref PubMed Scopus (131) Google Scholar] and are not yet widely used. Furthermore, data are either lacking [20Gething P.W. et al.Declining malaria in Africa: improving the measurement of progress.Malaria J. 2014; 13: 39Crossref PubMed Scopus (35) Google Scholar] or have questionable quality from many parts of the continent: thus the malaria burden may be underestimated in areas where it is greatest for a host of reasons, not least poverty and political instability [14O'Meara W.P. et al.Changes in the burden of malaria in sub-Saharan Africa.Lancet Infect. Dis. 2010; 10: 545-555Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar, 21WHO The World Malaria Report. World Health Organization, 2014Google Scholar].Box 2Diagnosing MalariaInfection with Plasmodium parasites may or may not lead to symptoms recognizable as an acute infection prompting care. On the other hand, those presenting with fever and malaria-like symptoms may or may not be infected with Plasmodium, and even when they are infected the parasites may not always be the cause of the acute symptoms.Presumptive or Clinical DiagnosisFor decades, presentation with a fever, particularly in children, was assumed to be malaria and treated with antimalarials. This practice continues when diagnostic tools are not available (e.g., underresourced clinics, retail outlets). Although the presence of fever is highly sensitive for malaria, it lacks specificity which leads to overdiagnosis. These cases are counted as malaria cases although they may be designated 'unconfirmed' or 'clinical' malaria.Diagnosis by Light MicroscopyExamination of stained blood smears by light microscopy has been used to detect parasites in the peripheral blood since the late 1800s. Microscopy is inexpensive and, when done well, can be very sensitive and specific. The quality of microscopic diagnosis is often compromised by poor equipment, underqualified staff, high workload, and limited availability of electricity and reagents.Diagnosis by Rapid Diagnostic Test (RDT)Immunochromatographic antigen-based single-use tests detect circulating antigen in an active infection. Tests can have excellent sensitivity and specificity compared to light microscopy, with some loss of sensitivity at very low parasite densities. Tests based on the HRP2 antigen do exhibit reduced specificity since HRP2 can circulate in the bloodstream for a week after treatment. RDTs are simple, do not require electricity, and their availability has greatly expanded the reach of diagnosis.New technologies, including urine and saliva tests, are under development. Highly sensitive PCR methods are used primarily for research. However, the recently developed loop-mediated isothermal amplification (LAMP), a nucleic acid-based diagnostic tool that is cheaper, faster, and easier than PCR but with equal sensitivity, has potential for application in targeting the malaria infectious reservoir through mass screening and treatment (MSAT).In Africa, case numbers obtained through routine health information systems are confounded by two main problems: (i) incomplete reporting (low reporting from the public sector, and lack of engagement of private sector in government reporting), and (ii) inclusion of both unconfirmed cases and diagnostically confirmed cases in the totals. Because clinical diagnosis has very low specificity, when diagnosis is scaled up the total malaria case numbers may be observed to decline (Figure 3).Box 3Malaria MetricsThe epidemiology of malaria is closely linked to its transmission intensity. Malaria metrics often either focus on the clinical disease burden, for example case numbers, or may be more generalized to detect how many people in a given locale are infected with parasites regardless of whether or not they have overt clinical symptoms, for example parasite prevalence. The entomological inoculation rate (EIR) is a more direct measure of transmission intensity. Malaria control is guided both by estimates of the clinical burden and transmission intensity.•Spleen rate: the incidence of splenic enlargement in children between 2 and 10 years of age, and thought to reflect intensity of malaria transmission. This metric is not commonly used at the present time.•Parasite prevalence/parasite rate: the proportion of the population in a given locale with detectable parasites in blood, and thought to reflect the intensity of malaria transmission.•Entomological inoculation rate: the number of infectious mosquito bites per person per unit time and the traditional gold standard for measuring the intensity of transmission.•Seroconversion rate: the frequency by which seronegative individuals become seropositive upon malaria exposure per unit of time. It is thought to be a good indicator of exposure to infectious mosquitoes and reflect the intensity of transmission. This measure has particular promise as a surveillance tool in low-transmission settings, and there are efforts to identify serological biomarkers that can better discriminate between cumulative malaria exposure and recent infection.•Malaria-positive fraction: the proportion of children admitted to hospital or seen at outpatient health facilities who are positive for malaria parasites. Its denominator could be all patients or those selected based on a high index of suspicion. It is thought to be an indicator of malaria transmission intensity.•Incidence rate: the proportion of new cases of malaria diagnosed within a given period of time in a defined population.•Case numbers: the total number of clinical cases of malaria reported over a given time frame in a given area.•Deaths: the numbers of deaths attributable to malaria is often estimated from verbal autopsies.•Slide positivity rate: the number of laboratory-confirmed malaria cases per 100 suspected cases examined and thought to reflect changes in clinical disease incidence. Its denominator is usually suspected malaria cases rather than all patients as in the MPF. Infection with Plasmodium parasites may or may not lead to symptoms recognizable as an acute infection prompting care. On the other hand, those presenting with fever and malaria-like symptoms may or may not be infected with Plasmodium, and even when they are infected the parasites may not always be the cause of the acute symptoms. For decades, presentation with a fever, particularly in children, was assumed to be malaria and treated with antimalarials. This practice continues when diagnostic tools are not available (e.g., underresourced clinics, retail outlets). Although the presence of fever is highly sensitive for malaria, it lacks specificity which leads to overdiagnosis. These cases are counted as malaria cases although they may be designated 'unconfirmed' or 'clinical' malaria. Examination of stained blood smears by light microscopy has been used to detect parasites in the peripheral blood since the late 1800s. Microscopy is inexpensive and, when done well, can be very sensitive and specific. The quality of microscopic diagnosis is often compromised by poor equipment, underqualified staff, high workload, and limited availability of electricity and reagents. Immunochromatographic antigen-based single-use tests detect circulating antigen in an active infection. Tests can have excellent sensitivity and specificity compared to light microscopy, with some loss of sensitivity at very low parasite densities. Tests based on the HRP2 antigen do exhibit reduced specificity since HRP2 can circulate in the bloodstream for a week after treatment. RDTs are simple, do not require electricity, and their availability has greatly expanded the reach of diagnosis. New technologies, including urine and saliva tests, are under development. Highly sensitive PCR methods are used primarily for research. However, the recently developed loop-mediated isothermal amplification (LAMP), a nucleic acid-based diagnostic tool that is cheaper, faster, and easier than PCR but with equal sensitivity, has potential for application in targeting the malaria infectious reservoir through mass screening and treatment (MSAT). In Africa, case numbers obtained through routine health information systems are confounded by two main problems: (i) incomplete reporting (low reporting from the public sector, and lack of engagement of private sector in government reporting), and (ii) inclusion of both unconfirmed cases and diagnostically confirmed cases in the totals. Because clinical diagnosis has very low specificity, when diagnosis is scaled up the total malaria case numbers may be observed to decline (Figure 3). The epidemiology of malaria is closely linked to its transmission intensity. Malaria metrics often either focus on the clinical disease burden, for example case numbers, or may be more generalized to detect how many people in a given locale are infected with parasites regardless of whether or not they have overt clinical symptoms, for example parasite prevalence. The entomological inoculation rate (EIR) is a more direct measure of transmission intensity. Malaria control is guided both by estimates of the clinical burden and transmission intensity. •Spleen rate: the incidence of splenic enlargement in children between 2 and 10 years of age, and thought to reflect intensity of malaria transmission. This metric is not commonly used at the present time.•Parasite prevalence/parasite rate: the proportion of the population in a given locale with detectable parasites in blood, and thought to reflect the intensity of malaria transmission.•Entomological inoculation rate: the number of infectious mosquito bites per person per unit time and the traditional gold standard for measuring the intensity of transmission.•Seroconversion rate: the frequency by which seronegative individuals become seropositive upon malaria exposure per unit of time. It is thought to be a good indicator of exposure to infectious mosquitoes and reflect the intensity of transmission. This measure has particular promise as a surveillance tool in low-transmission settings, and there are efforts to identify serological biomarkers that can better discriminate between cumulative malaria exposure and recent infection.•Malaria-positive fraction: the proportion of children admitted to hospital or seen at outpatient health facilities who are positive for malaria parasites. Its denominator could be all patients or those selected based on a high index of suspicion. It is thought to be an indicator of malaria transmission intensity.•Incidence rate: the proportion of new cases of malaria diagnosed within a given period of time in a defined population.•Case numbers: the total number of clinical cases of malaria reported over a given time frame in a given area.•Deaths: the numbers of deaths attributable to malaria is often estimated from verbal autopsies.•Slide positivity rate: the number of laboratory-confirmed malaria cases per 100 suspected cases examined and thought to reflect changes in clinical disease incidence. Its denominator is usually suspected malaria cases rather than all patients as in the MPF. Monitoring malaria is thus challenging in the clinic and community. The array of metrics utilized further compounds the situation (Box 3). There is no consensus on which is best, and whilst many of them are correlated, these relationships are not absolute and one metric may not accurately reflect another in different transmission settings. Importantly, estimates of the malaria burden ought to be interpreted with an appreciation of the variability that arises through methodological differences between studies, and the inevitable limitations of aggregating such data. The above challenges notwithstanding, independent research groups have applied different large-scale modeling techniques to estimate a range of malaria metrics and arrived at the unanimous conclusion that the burden of malaria in Africa is decreasing (Figure 1A). In the last 10 years the population at risk of infection has shrunk [22Noor A.M. et al.The changing risk of Plasmodium falciparum malaria infection in Africa: 2000-10: a spatial and temporal analysis of transmission intensity.Lancet. 2014; 383: 1739-1747Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar], malaria deaths have declined [23Murray C.J. et al.Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.Lancet. 2014; 384: 1005-1070Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar], as has the age-standardized prevalence of infection in children 2–10 years old [22Noor A.M. et al.The changing risk of Plasmodium falciparum malaria infection in Africa: 2000-10: a spatial and temporal analysis of transmission intensity.Lancet. 2014; 383: 1739-1747Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 24Bhatt S. et al.The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015.Nature. 2015; 526: 207-211Crossref PubMed Scopus (1555) Google Scholar]. However, the magnitude of both the absolute burden and the change vary considerably between reports. For example, estimates of cases in Africa differ by as much as 100–200 million episodes in a single year (Figure 1B and [25Cibulskis R.E. et al.Worldwide incidence of malaria in 2009: estimates, time trends, and a critique of methods.PLoS Med. 2011; 8: e1001142Crossref PubMed Scopus (91) Google Scholar]). Careful scrutiny of the published estimates reveals that the magnitude of the decline in case numbers falls within the margins of error between yearly estimates, thus requiring judicious interpretation. Not surprisingly, the greatest uncertainty coincides with the areas of highest burden and the areas with highest predicted decline (Figure 2A), somewhat obscuring the picture.Figure 2Uncertainty in the Estimates of Total Malaria Case Burden in Africa. (A) The difference between the upper and lower 95% credible intervals for total estimated malaria cases per country in 2015. Malaria Atlas Project (MAP) (www.map.ox.ac.uk). Briefly, estimates are derived from inputting prevalence values extrapolated from survey data into functions describing the modeled relationship between prevalence and incidence. Case counts are generated by multiplying incidence and population data. (B) Trends in malaria burden in WHO African region from 2006 to 2015. Studies on malaria burden in Africa with data for more than two consecutive years were obtained from Pubmed (https://www.ncbi.nlm.nih.gov/pubmed). Studies with data from before 2006 and those designed specifically to test an intervention were excluded. A total of 51 longitudinal studies from 22 countries were included (see Table S1 in the supplemental information online for a complete list of studies). The trend in malaria cases, admissions, and/or parasite prevalence in each country was summarized year-by-year and indicated as: decline (green), increase (red), or as differing between studies (yellow). The island of Zanzibar is part of Tanzania but was shown separately as it has experienced a sustained decline in transmission.View Large Image Figure ViewerDownload Hi-res image Download (PPT) We analyzed trends in the malaria burden from recently published empirical studies and found that, despite the overall decline, a sobering pattern marked by a limited number of studies and spatial as well as temporal heterogeneity was apparent. One in four countries (82%) from the WHO African region published trends in the malaria burden that were either inconsistent (rising in some parts of the country and declining in others) or showed evidence of a temporal increase or resurgence (Figure 2B). A sustained decline was reported from only four countries (and the island of Zanzibar), but in most of these there was only one study available (Figure 2B). Together, these studies represent just 22 of 45 countries that comprise the WHO African region, and the bulk of the research covered the years 2006–2011, presumably a reflection of the time lag between data collection and publication. We limited our analysis to studies showing trends over two consecutive years in the last decade. Nevertheless, the predominantly heterogeneous success of malaria control suggests that the situation is potentially fragile. A major challenge will be the ability to achieve and sustain gains in all areas until elimination becomes a reality because history is clear: malaria can and does come back [26Cohen J.M. et al.Malaria resurgence: a systematic review and assessment of its causes.Malaria J. 2012; 11: 122Crossref PubMed Scopus (318) Google Scholar]. Empirical studies showing a reduction in the malaria burden (Figure 2B) attributed it to a scale-up of combinations of control strategies. In the main, these were long-lasting insecticide-treated nets (LLINs) or insecticide treated nets (ITNs), indoor residual spraying (IRS) and intermittent preventive therapy (see Glossary) for pregnant women (IPTp) for prevention, better diagnostics for case ascertainment, and effective treatments using artemisinin-based combination therapies (ACTs). The majority of directly observed studies did not generally single out ITNs as the sole or major driver of the decline as recently suggested [24Bhatt S. et al.The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015.Nature. 2015; 526: 207-211Crossref PubMed Scopus (1555) Google Scholar]. In sub-Saharan Africa the proportion of children