This week started with articles that drew attention to the challenges of malaria in low transmission areas and with low density infections. Malaria Journal has provided several insightful articles toward this end.
Being an island has certainly helped Zanzibar make progress toward malaria elimination as witness the fact that malaria prevalence has remained below 1% for the past decade. Not only does Zanzibar still face threats of infection from the mainland, it may also experience an upsurge locally if residual transmission and the role of human behavior and community actions are not well understood. April Monroe et al. conducted in-depth interviews with community members and local leaders across six sites on Unguja, Zanzibar as well as semi-structured community observations of night-time activities and special events to learn more.
While there was high reported ITN use, there were also times when people were exposed t mosquitoes while being outdoors during biting times. This could be around the house, or at special night events like such as weddings, funerals, and religious ceremonies. Men spent more time outdoors than women. Clearly appropriate interventions and needed and should be promoted in culturally appropriate ways in order to further reduce and eventually eliminate transmission.
Angela Early and colleagues presented findings on a diagnostic process of deep sequencing for understanding the dynamics and complexity of Plasmodium infections, but stress that knowing the lower limit of detection is challenging. They present “a new amplicon analysis tool, the Parallel Amplicon Sequencing Error Correction (PASEC) pipeline, is used to evaluate the performance of amplicon sequencing on low-density Plasmodium DNA samples.”
The authors learned that, “four state-of-the-art tools resolved known haplotype mixtures with similar sensitivity and precision.” They also cautioned that, “Samples with very low parasitemia and very low read count have higher false positive rates and call for read count thresholds that are higher than current default recommendations.” Better understanding of the genetic mix of plasmodium infections as countries move toward low transmission and elimination is crucial for selecting appropriate interventions and evaluating their outcomes.
Hannah Edwards and co-researchers examined conditions for malaria transmission along the Thailand-Myanmar border in areas approaching malaria elimination. While prevalence may be less than 1%, residual transmission still occurs. Transmission occurs not only around residences but in the forests where people work. The researchers therefore looked at the behavior of both humans and insects. Overall, they found that, “Community members frequently stayed overnight at subsistence farm huts or in the forest. Entomological collections showed higher biting rates of primary vectors in forested farm hut sites and in a more forested village setting compared to a village with clustered housing and better infrastructure.”
While mosquitoes preferred to bite inside huts, their threat was magnified by those who did not use long lasting insecticide-treated nets (LLINs). While out in the farms and forests, people tended to wake early and increase their likelihood of being bitten. The authors discuss the challenges of dual residences in terms of LLIN ownership and even concerning the potential access to indoor residual spraying. The definition for universal net coverage needs to expand from one net per two people to include adequate nets wherever people are located.
The Amazonian area of Brazil is another area working toward malaria elimination, in particular, Plasmodium vivax. Felipe Leão Gomes Murta et al. also looked at the human side of the equation and identified misperceptions by both community members and health workers that could inhibit elimination efforts. They found, “many myths regarding malaria transmission and treatment that may hinder the sensitization of the population of this region in relation to the use of current control tools and elimination strategies, such as mass drug administration (MDA),” and LLINs.
Problematic perceptions included mention by both groups that the use of insecticide-treated nets, may cause skin irritations and allergies. Both community members and health professionals said malaria is “an impossible disease to eliminate because it is intrinsically associated with forest landscapes.” They concluded that such perceptions can be a barrier to control and elimination.
Efforts to eliminate malaria from low transmission settings are an essential to the overall global goals. These four articles tell us that close attention to and better understanding of humans, parasites and mosquitoes is still needed to achieve these goals.
If all it took to eradicate a disease was a well proven drug, vaccine or technology, we would not be still reporting on polio, measles and guinea worm, to name a few. In the past week Afghanistan reported 2 wild poliovirus type 1 (WPV1) cases, and Pakistan had 3 WPV1 cases. Circulating vaccine-derived poliovirus type 2 (cVDPV2) was reported in Nigeria (1), DRC (4) and Ethiopia (3) from healthy community contacts.
Pacific Standard explained the differences in Ebola outbreaks between DRC today and the West Africa outbreak of 2014-16. On the positive side are new drugs used in organized trials for the current outbreak. The most important factor is safe, effective vaccine that has been tested in 2014-16, but is now a standard intervention in the DRC. While both Liberia and Sierra Leone had health systems and political weaknesses as post-conflict countries, DRC’s North Kivu and Ituri provinces are currently a war zone, effectively so for the past generation. Ebola treatment centers and response teams are being attacked. There are even cultural complications, a refusal to believe that Ebola exists. So even with widespread availability of improved technologies, teams may not be able to reach those in need.
To further complicate matters in the DRC, Doctors Without Borders (MSF) “highlighted ‘unprecedented’ multiple crises in the outbreak region in northeastern DRC. Ebola is coursing through a region that is also seeing the forced migration of thousands of people fleeing regional violence and is dealing with another epidemic. Moussa Ousman, MSF head of mission in the DRC, said, ‘This time we are seeing not only mass displacement due to violence but also a rapidly spreading measles outbreak and an Ebola epidemic that shows no signs of slowing down, all at the same time.’”
NIPAH and Bats
Like Ebola, NIPAH is zoonotic, and also involves bats, but the viruses differ. CDC explains that, “Nipah virus (NiV) is a member of the family Paramyxoviridae, genus Henipavirus. NiV was initially isolated and identified in 1999 during an outbreak of encephalitis and respiratory illness among pig farmers and people with close contact with pigs in Malaysia and Singapore. Its name originated from Sungai Nipah, a village in the Malaysian Peninsula where pig farmers became ill with encephalitis.
A recent human outbreak in southern India has been followed up with a study of local bats. In a report shared by ProMED, out of 36 Pteropus species bats tested for Nipah, 12 (33%) were found to be positive for anti-Nipah bat IgG antibodies. Unlike Ebola there are currently no experimental drugs or vaccines.
Climate Change and Dengue
Climate change is expected to heighten the threat of many neglected tropical diseases, especially arboviral infections. For example, the New York Times reports that increases in the geographical spread of dengue fever. Annually “there are 100 million cases of dengue infections severe enough to cause symptoms, which may include fever, debilitating joint pain and internal bleeding,” and an estimated 10,000 deaths. Dengue is transmitted by Aedes mosquitoes that also spread Zika and chikungunya. A study, published Monday in the journal Nature Microbiology, found that in a warming world there is a strong likelihood for significant expansion of dengue in the southeastern United States, coastal areas of China and Japan, as well as to inland regions of Australia. “Globally, the study estimated that more than two billion additional people could be at risk for dengue in 2080 compared with 2015 under a warming scenario.”
Schistosomiasis – MDA Is Not Enough, and Neither Are Supplementary Interventions
Schistosomiasis is one of the five neglected tropical diseases (NTDs) that are being controlled and potentially eliminated through mass drug administration (MDA) of preventive chemotherapy (PCT), in this case praziquantel. In The Lancet Knopp et al. reported that biannual MDA substantially reduced Schistosomiasis haematobium prevalence and infection intensity but was insufficient to interrupt transmission in Zanzibar. In addition, neither supplementary snail control or behaviour change activities did not significantly boost the effect of MDA. Most MDA programs focus on school aged children, and so other groups in the community who have regular water contact would not be reached. Water and sanitation activities also have limitations. This raises the question about whether control is acceptable for public health, or if there needs to be a broader intervention to reach elimination?
Trachoma on the Way to Elimination
Speaking of elimination, WHO has announced major “sustained progress” on trachoma efforts. “The number of people at risk of trachoma – the world’s leading infectious cause of blindness – has fallen from 1.5 billion in 2002 to just over 142 million in 2019, a reduction of 91%.” Trachoma is another NTD that uses the MDA strategy.
The news about NTDs from Dengue to Schistosomiasis to Trachoma is complicated and demonstrates that putting diseases together in a category does not result in an easy choice of strategies. Do we control or eliminate or simply manage illness? Can our health systems handle the needs for disease elimination? Is the public ready to get on board?
And concerning being complicated, malaria this week again shows many facets of challenges ranging from how to recognize and deal with asymptomatic infection to preventing reintroduction of the disease once elimination has been achieved. Several reports this week showed the particular needs for malaria intervention ranging from high burden areas to low transmission verging on elimination to preventing re-introduction in areas declared free from the disease.
In South West, Nigeria Dokunmu et al. studied 535 individuals aged from 6 months were screened during the epidemiological survey evaluating asymptomatic transmission. Parasite prevalence was determined by histidine-rich protein II rapid detection kit (RDT) in healthy individuals. They found that, “malaria parasites were detected by RDT in 204 (38.1%) individuals. Asymptomatic infection was detected in 117 (57.3%) and symptomatic malaria confirmed in 87 individuals (42.6%).
Overall, detectable malaria by RDT was significantly higher in individuals with symptoms (87 of 197/44.2%), than asymptomatic persons (117 of 338/34.6%)., p = 0.02. In a sub-set of 75 isolates, 18(24%) and 14 (18.6%) individuals had Pfmdr1 86Y and 1246Y mutations. Presence of mutations on Pfmdr1 did not differ by group. It would be useful for future study to look at the effect of interventions such as bednet coverage. While Southwest Nigeria is a high burden area, the problem of asymptomatic malaria will become an even bigger challenge as prevalence reduces and elimination is in sight.
Sri Lanka provides a completely different challenge from high burden areas. There has been no local transmission of malaria in Sri Lanka for 6 years following elimination of the disease in 2012. Karunasena et al. report the first case of introduced vivax malaria in the country by diagnosing malaria based on microscopy and rapid diagnostic tests. “The imported vivax malaria case was detected in a foreign migrant followed by a Plasmodium vivax infection in a Sri Lankan national who visited the residence of the former. The link between the two cases was established by tracing the occurrence of events and by demonstrating genetic identity between the parasite isolates. Effective surveillance was conducted, and a prompt response was mounted by the Anti Malaria Campaign. No further transmission occurred as a result.”
Bangladesh has few but focused areas of malaria transmission and hopes to achieve elimination of local transmission by 2030. A particular group for targeting interventions is the population of slash and burn cultivators in the Rangamati District. Respondents in this area had general knowledge about malaria transmission and modes of prevention and treatment was good according to Saha and the other authors. “However, there were some gaps regarding knowledge about specific aspects of malaria transmission and in particular about the increased risk associated with their occupation. Despite a much-reduced incidence of malaria in the study area, the respondents perceived the disease as life-threatening and knew that it needs rapid attention from a health worker. Moreover, the specific services offered by the local community health workers for malaria diagnosis and treatment were highly appreciated. Finally, the use of insecticide-treated mosquito nets (ITN) was considered as important and this intervention was uniformly stated as the main malaria prevention method.”
Kenya offers some lessons about low transmission areas but also areas where transmission may increase due to climate change. A matched case–control study undertaken in the Western Kenya highlands. Essendi et al. recruited clinical malaria cases from health facilities and matched to asymptomatic individuals from the community who served as controls in order to identify epidemiological risk factors for clinical malaria infection in the highlands of Western Kenya.
“A greater percentage of people in the control group without malaria (64.6%) used insecticide-treated bed nets (ITNs) compared to the families of malaria cases (48.3%). Low income was the most important factor associated with higher malaria infections (adj. OR 4.70). Houses with open eaves was an important malaria risk factor (adj OR 1.72).” Other socio-demographic factors were examined. The authors stress the need to use local malaria epidemiology to more effectively targeted use of malaria control measures.
The key lesson arising from the forgoing studies and news is that disease control needs strong global partnerships but also local community investment and adaptation of strategies to community characteristics and culture.
For almost 20 years we have been maintaining an email list where current news and articles have been shared with those interested in tropical health and malaria. The listserve host we have been using is changing to a paid model. While there are still some free listserve options, these are cumbersome to produce. Since we are already maintaining this blog, we thought it best to provide a weekly summary of key news events through this medium.
Mapping Plasmodium Vivax
The Malaria Atlas Project has published in The Lancet a global burden of Plasmodium Vivax mapping study. The authors describe the contribution of this study as: “Our study highlights important spatial and temporal patterns in the clinical burden and prevalence of P vivax. Amid substantial progress worldwide, plateauing gains and areas of increased burden signal the potential for challenges that are greater than expected on the road to malaria elimination. These results support global monitoring systems and can inform the optimisation of diagnosis and treatment where P vivax has most impact.”
Ebola Spread from DRC to Uganda
Since the major ongoing outbreak of Ebola Virus Disease in North Kivu and Ituri Provinces of the Democratic Republic of Congo (DRC) started nearly a year ago, there has been concern that the disease might spread to neighboring countries like Uganda, Rwanda, South Sudan and the Central African Republic. This fear same true recently when a family affected by Ebola crossed from DRC into Uganda to connect with relatives in Kasese District Uganda. Uganda has had many years’ experience dealing with Ebola and was able to contain the situation.
A press release this week noted that, “As of today (21 June 2019), Uganda has not registered any new confirmed Ebola Virus Disease (EVD) case in Kasese District or any other part of Uganda since the last registered case one week ago. There are no new suspect cases under admission. Currently, 110 contacts to the confirmed Ebola cases in Kagando and Bwera are being followed up daily. A total of 456 individuals have been vaccinated against EVD using the Ebola-rVSV vaccine in Kasese District, Western Uganda.”
Although many people expected that the meeting of the “International Health Regulations (2005) Emergency Committee} for Ebola virus disease in the Democratic Republic of the Congo would finally declare the current outbreak a Public Health Emergency of International Concern (PHEIC) because it crossed a border, the result was noting that the challenge was still an emergency only for DRC. WHO did note that there were serious funding gaps and support from other countries for the DRC’s predicament. Ironically, such gaps make it more likely that Ebola can spread more widely.
As of 21 June 2019, the DRC reported a total of 2,211 cases since the start of the epidemic last year, of which 2,117 have been confirmed and 94 are probable. There have been 1,489 deaths. To date 139,027 persons have been vaccine with the Merck rVSV-ZEBOV vaccine.
Progress toward Eliminating Malaria – the E-2020 Countries
The process of eliminating malaria from the world needs to start in a step-by-step fashion. WHO explained that, “Creating a malaria-free world is a bold and important public health and sustainable development goal. It is also the vision of the Global technical strategy for malaria 2016-2030, which calls for the elimination of malaria in at least 10 countries by the year 2020.”
Actually, WHO identified 21 countries, spanning 5 regions, that could defeat malaria by 2020. The progress report charts the effort. During the recent World Health Assembly two countries received recognition for being certified malaria-free, Argentina and Algeria. This week WHO also announced that 5 more countries have not had malaria cases in the past year. There was also release of a downloadable report on progress toward the 2020 target for selected countries.
Reconsidering Yaws Eradication
In the 1950s and 1960s the world focused on the possibility of eradicating Yaws through screening and treatment interventions. Like the early malaria eradication programs from the same period, the Yaws effort slowed, stopped and experienced a resurgence. The Telegraph reported that, “Between 1952 and 1964, Unicef and the WHO screened some 300 million people for the illness, in a coordinated programme which treated more than 50 million cases. Yaws was on the brink of being wiped out and reports of the disease dropped by 95 per cent.” WHO continues to work on treatment strategies with azithromycin and for resistant cases, benzathine benzylpenicillin injection.
WHO noted that there were 80,472 cases reported in 2018, although this figure is likely to be much higher in actuality. The challenge of case detection exists but may be overcome, according to the Telegraph with a new molecular rapid diagnostic test which detects yaws within 30 minutes, and thus could allow on-the-spot diagnosis in remote regions.
Measles Cases Continue to Increase
The problem of measles in the DRC may not be receiving much attention because of the Ebola epidemic. Ironically, Outbreak News Today reports that, “In a follow-up on the measles outbreak in the Democratic Republic of the Congo (DRC), UN health officials report an additional 7500 suspect cases in the past 2 weeks, bringing the total cases since the beginning of the year to 106,870. The death toll due to the measles outbreak has reached 1815 deaths (case fatality ratio 1.7%).”
Vaccine coverage challenges in the DRC result from health systems weaknesses. Unfortunately, a global study has shown that increasing cases in the Global North are not due to weak systems, but ‘vaccine hesitancy.’ The Guardian reports that a global survey has revealed the scale of the crisis of confidence in vaccines in Europe, “showing that only 59% of people in western Europe and 50% in the east think vaccines are safe, compared with 79% worldwide.” The Guardian observes that, “In spite of good healthcare and education systems, in parts of Europe there is low trust in vaccines. France has the highest levels of distrust, at 33%.”
For more news and daily updates check our other services, a closed/private Facebook Group and a Twitter feed. For those who do not use social media, please check here each weekend to find a summary of some of the stories we have shared during the week.
April hosts several important global health days or observances. On World Health Day 2019 WHO stressed that, “Universal health coverage (UHC) is WHO’s number one goal. Key to achieving it is ensuring that everyone can obtain the care they need, when they need it, right in the heart of the community.” Nationwide monitoring through the Demographic and Health Surveys (DHS), the Malaria Indicator Surveys (MIS) and the Multi-Indicator Cluster Surveys (MICS) can document the status of appropriate malaria treatment and intermittent preventive treatment in pregnant women (IPTp).
Definitions of indicators have evolved for treatment-related malaria interventions. When Intermittent Preventive Treatment for pregnant women (IPTp) began in the early 2000s, the recommended dosing was twice during pregnancy after the first trimester one month apart in high and/or stable transmission areas. Due to lessening efficacy of sulfadoxine-pyrimethamine (SP), the dosage recommendation has changed to at least three times, still a month apart from the beginning of the second trimester.
This updated policy was broadcast widely between 2012 and 2013, but it took countries some time to build capacity and scale up for the expanded coverage goals. UNICEF Data5 again show that between 2014 and 2017 coverage was far below either 80% of pregnant women, let alone reaching them universally (Figure 2). Most countries achieved 30% or less coverage. Zambia at 50% was the highest. Low coverage leaves both pregnant women and the unborn child at risk for anemia and death in the former and low birth weight, still birth or miscarriage for the latter. The World Malaria Report of 2018 estimates that three doses of IPTp were received by only 22% of pregnant women in the target countries in 2017.
The SMC delivery process was not linked to immunization but provided by community health workers and volunteers. SP and Amodiaquine (SP-AQ) were used in combination and provided monthly, three or four times during the rainy/high transmission season. Coverage was targeted at children below school age. It is only recently that SMC has been scaled up to reach all eligible countries or states and regions within designated countries.
WHO states that SMC focuses on, “children aged 3–59 months (and) reduces the incidence of clinical attacks and severe malaria by about 75%.” In some countries the coverage is extended to primary school aged children, making comparisons and calculations of coverage (universal por otherwise) challenging.
The World Malaria Report of 2018 notes that, “In 2017, 15.7 million children in 12 countries in Africa’s Sahel subregion were protected through seasonal malaria chemoprevention (SMC) programs. However, about 13.6 million children who could have benefited from this intervention were not covered, mainly due to a lack of funding.” This implies that 54% of eligible children were reached. Coverage of SMC can refer to receiving any of the doses or as having received all the monthly doses offered by a nation’s malaria control program. Specifically, the World Malaria Report 2018 drew on surveys in 7 countries that provided 4 monthly doses to determine that 53% of children received all doses.
Determining coverage for malaria treatment for sick people is not as straightforward as finding out the numbers who slept under an ITN or swallowed IPTp doses, and even those are not simple. As defined, correct treatment first consists of parasitological diagnosis, which at the primary care level could be by microscopy or rapid diagnostic test (RDT). The next issue is treating only those with positive tests. Finally, the treatment must consist of age- or weight-specific doses of an approved artemisinin-based combination therapy (ACT) drug. Very few clinic records or surveys document whether the treatment given is ‘correct’ by these standards.
WHO addresses the need for achieving universal access to malaria diagnostic testing and notes this will not be easy. They provide a successful example of Senegal, where following the introduction of malaria RDTs in 2007, malaria diagnostic testing rates rose rapidly from 4% to 86% (by 2009). Logistics, funding, training and supportive supervision complicate implementation.
UNICEF Data report that performance of malaria diagnostics in febrile children in surveys between 2014-17 was approximately 30% on average for countries with national surveys within that time frame (Figure 3). Only 4 countries achieved 50% or better. Most surveys then go on to report the number of febrile children who received ACTs, but do not necessary indicate how many who were correctly diagnoses were given ACTs vs those who received ACT but did not receive a test or tested negative.
The Nigeria 2015 Malaria Indicator Survey Illustrates this dilemma. Among 2600 children who reported having a fever in the two weeks preceding the survey, 66.1% sought advice (or care). Overall, 12.6% of febrile children received a diagnostic test as defined in the question as to whether the child was stuck on the finger or heel to obtain blood. Among the febrile children 37.6% reportedly were given some type of antimalarial drug. Overall 15.5% of febrile children were given an ACT. Even if ACTs were given only to tested children, not all tests would have been positive.
The overall implication of measuring treatment without a link to testing is that if more children receive any, let alone the correct drugs, is that evidence for actual presence of disease. We have a long way to go to measure malaria treatment coverage correctly, not to mention achieving universal coverage with appropriate treatment. Different malaria treatment-related interventions with different steps and different target groups in different regions of Africa and the World make defining, no less achieving UHC, a huge challenge.
After the World’s first attempt at eradicating the
complicated disease malaria mainly through a single tool, a period of control
set in where the aim was to reduce mortality through prompt and presumptive
treatment of fevers with anti-malarials, particularly in young children. During
this period in the 1980s and 1990s it was recognized that parasite-based
diagnostic capabilities in the form of microscopy were limited, so in malaria
endemic areas, it was worth providing inexpensive medicines like chloroquine
(CQ) and sulfadoxine-pyrimethamine (SP) to febrile children in order to save lives.
When the fevers did not resolve, other illnesses explored.
The difficulty arose in identifying cases that did not offer
clinical clues that they might be malaria. Today countries approaching malaria
elimination face challenges, such as seen in Zanzibar where, “outdoor
transmission, a large asymptomatic parasite reservoir and imported infections,
require novel tools and reoriented strategies to prevent a rebound effect and
Here we examine the challenge of asymptomatic malaria infections.
By 1998 when the Roll Back Malaria partnership formed, there
had been enough research done so that the malaria community had a better
arsenal of interventions including insecticide-treated bed nets,
artemisinin-based combination therapy (ACT) and intermittent preventive
treatment with SP during pregnancy. The Abuja Declaration of 2000 set a target
of 80% coverage of these interventions by the year 2010.
While ACTs overcame the challenges of parasite resistance
that had developed for the single drugs, CQ and SP, it cost several times more
than those medicines. The need for easy-to-use, inexpensive, point-of-care
diagnostics was recognized so that not only would ACTs be targeted only to
parasitologically confirmed malaria cases, but also in the process, overuse and
misuse would not contribute to parasite resistance of these new drugs.[ii]
Unfortunately, the development and dissemination of antigen-based rapid
diagnostic tests (RDTs), lagged behind the availability of ACTs meaning that
health workers unfortunately continued their business as usual with presumptive
treatment using ACTs.
The benefits of RDTs were generally two-fold. First, they
could be used by front-line, auxiliary and community-based health workers.
Secondly, they tended to identify more cases than microscopy. The big challenge
was convincing health workers to use them and trust the results, because the
era of presumptive treatment had given these staff a false sense of confidence
in their own clinical diagnostic abilities.
Although reaching the 2010 coverage targets has remained
illusive for most endemic countries, there has been enough progress for major
reductions in incidence (despite a recent upsurge).[iii]
As the proportion of actual malaria cases among febrile illness patients
declines, concern has risen that transmission might continue among people with
subclinical or asymptomatic malaria. Here we explore the extent of this problem
and new directions in parasitological testing needed to ensure continued
progress toward elimination in each endemic country.
Understanding the Risk of Asymptomatic Malaria
Risk can relate to geographical, epidemiological, and socio-demographic factors as well as history of malaria interventions. Kenya has stratified the country by higher and lower malaria transmission areas. Even the higher areas are comparatively low compared to its higher transmission neighbors. Studying the prevalence of asymptomatic malaria in some of these higher transmission areas in the west of the country was seen as a way to better identify people at risk and learn about intervention effectiveness. An examination of apparently healthy children (no symptoms) revealed a Plasmodium falciparum malaria prevalence 36.0% (27.5%, 44.5%) by RDT and 22.3% (16.0%, 28.6%) by thick film microscopy.[iv] Living in a household with electricity was protective but the adjusted odds ratio of prevalence comparing households with and without indoor residual spray showed only borderline benefit. Unfortunately, in Zanzibar, asymptomatic malaria infection was not associated “with use of any vector control.”1
A major challenge in detecting cases through routine health
care systems is care seeking patterns of care seeking for fever. The 2018 World
Malaria Report acknowledges that there are major equity challenges in care
seeking wherein families with higher incomes, better education and living in
urban areas are more likely to seek help for their febrile children that rural,
poor and less educated families who would be more at risk. Care seeking without
the signs of fever is more challenging. A dual strategy of enabling better
service utilization as well as outreach to detect cases will be necessary to
detect asymptomatic cases.3
In Burkina Faso, the prevalence of asymptomatic malaria
infection in children under 5 years of age was estimated at 38.2% in 24 of its
70 health districts. Those at most risk for asymptomatic malaria infection
included the following:[v]
older children (48–59 vs < 6 months: OR: 6.79
children from very poor households (Richest vs
poorest: OR: 0.85 [0.74–0.96])
households located more than 5 km from a health
facility (< 5 km vs ? 5 km: OR: 1.14 [1.04–1.25])
localities with inadequate number of nurses
(< 3 vs ? 3: 0.72 [0.62, 0.82]
rural areas (OR: 1.67 [1.39–2.01])
Nine districts reported significantly higher risks (Batié,
Boromo, Dano, Diébougou, Gaoua, Ouahigouya, Ouargaye, Sapouy and Toma. The
researchers concluded that, “Such national spatial analysis should help to
prioritize areas for increased malaria control activities.”
A study in Ghana found that, “children and pregnant women had higher prevalence of submicroscopic gametocytes (39.5% and 29.7%, respectively) compared to adults (17.4%).”[vi]
An additional concern is emerging in terms of sharing of malaria parasite species between humans and primates, especially as urbanization and deforestation push these two populations into closer contact. For example Mapua and colleagues working in Central Africa Republic, “found the human malaria parasite P. ovale wallikeri in both asymptomatic humans and western lowland gorillas in Dzanga Sangha Protected Areas. Molecular analysis revealed that the genotype of the P. ovale wallikeri DNA found in a gorilla was genetically identical to that of a human isolate within the mt cytb and mt cox 1 genes, indicating potential human–ape transmission.”[vii] They noted similar sharing of parasites in the region between humans and chimpanzees.
Detecting and Responding to Asymptomatic Cases
WHO’s Framework for Malaria Elimination[viii]
recognizes the important role of case detection and subsequent treatment as
well as broader community level preventive responses around detected cases. In
the context of elimination WHO notes that case detection “requires use of
a diagnostic test to identify asymptomatic malaria infections.” WHO
stresses that a case is a case, regardless of whether it is symptomatic or
asymptomatic, as long as the diagnostic process confirms presence of malaria
It is important to monitor Plasmodium parasitemia in areas where malaria
transmission has declined and efforts to achieve malaria elimination are
underway, such as Zambia, where 3,863 household members were tested.[ix]
Only 2.6% were positive by either microscopy, RDT, or PCR. Of these, 48 (47%)
had subpatent parasitemia, and 85% of those with subpatent parasitemia were
asymptomatic. “Compared with individuals without parasitemia, individuals with
subpatent parasitemia were significantly more likely to be aged 5–25 years.”
The authors suggested that their findings pointed to the need for active or
reactive case detection to identify asymptomatic individuals and thus better
target individuals with subpatent parasitemia with appropriate malaria
WHO explains that active case detection (ACD) takes place in
areas of limited or under-utilization of health care services.4 It
may start with initial screening for symptoms, followed by appropriate
parasitological laboratory confirmation. In low-transmission settings or as
part of a focus investigation, “ACD may consist of testing of a defined
population group without prior symptom screening (population-wide or mass
testing) in order to identify asymptomatic infections.” Elimination cannot be
achieved until even asymptomatic infections have stopped. The challenge is the
expense of community-wide screening.
Reactive Case Detection (RCD), according to WHO, takes place
in settings low transmission intensity where the few “occurring malaria cases
are highly aggregated.”4 When a case is identified, usually through
identification of an actual infected patient at a local clinic, the community
where the patient comes from is visited and a “net is cast around the
index case” where household members and neighbors within a selected radius
are tested. In this process asymptomatic cases are also identified.
Our existing diagnostic tools may be inadequate. McCreesh
and colleagues reported on subpatent malaria in Namibia that, “fever
history and standard RDTs are not useful to address this burden. Achievement of
malaria elimination may require active case detection using more sensitive
point-of-care diagnostics or presumptive treatment and targeted to high-risk
groups.” This includes loop-mediated isothermal amplification (LAMP) using
dried blood spots, which they tested.[x]
Likewise from experience in a Zambian study, Kobayashi and co-researchers
suggest, “more sensitive diagnostic tests or focal drug administration may be
necessary to target individuals with subpatent parasitemia to achieve malaria elimination.”[xi]
Responses to detecting asymptomatic cases start at the
individual level with prompt treatment of those found through RCD to be
infected. Then focused preventive interventions such as distribution of
insecticide treated bednets can be provided to those in the cluster or village.
Follow-up would be needed for such ‘hot spots.’
On a broader basis we have Seasonal Malaria Chemoprevention
(SMC) as practiced in Sahelian countries where during the peak transmission
(rainy) season intermittent preventive treatment is given to children monthly
by community health workers and volunteers. Of course, many of these children
would be asymptomatic carriers and SMC could benefit the reduction of parasites
in circulation. At present SMC focuses on pre-school aged children, but Thera
and co-researchers stress the importance of reaching school aged children who
are also often asymptomatic carriers.[xii]
Another intervention being tested for mass drug
administration (MDA) use providing the community with ivermectin, a drug that
has been highly effective in controlling filarial diseases and also found to
kill mosquitoes who take a blood meal from a person who has recently taken it.[xiii]
This strategy is still being tested, but again MDA means all community members,
especially those with asymptomatic infection, would be reached.
A major question requires further research. To what extent
do asymptomatic, submicroscopic and subpatent parasitemia contribute to
continued malaria transmission? Another question is how can we address malaria
infection in other primates? We know that scientists recommend targeting of
malaria elimination interventions based on mapping of these infections.5
We therefore need to study the actual transmission potential of this
A, Shakely D, Ali AS, Morris U, Mkali H, Abbas AK, Al-Mafazy A-W, Haji KA, Mcha
J, Omar R, Cook J, Elfving K, Petzold M, Sachs MC, Aydin-Schmidt B, Drakeley V,
Msellem M and Mårtensson A. From high to low malaria transmission in
Zanzibar—challenges and opportunities to achieve elimination. BMC Medicine
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Global Health Day 2018 sponsored by the Johns Hopkins University Center for Global Health featured a poster presentation by several colleagues on Improving the efficacy of reactive screen-and-treat for malaria elimination in southern Zambia. Fiona Bhondoekhan, William Moss, Timothy Shields, Douglas Norris, Kelly Searle, Jennifer Stevenson, Harry Hamapumba, Mukuma Lubinda and Japhet Matoba (Southern Africa International Centers of Excellence in Malaria Research, the JHU Bloomberg School of Public Health, and the Macha Research Trust, Zambia) share their findings below.
Background: Malaria screen-and-treat (called Step D in Zambia) is a reactive case detection strategy in which cases detected at a health center trigger community health workers (CHWs) to screen for secondary malaria cases within a 140-meter radius of the index case household using PfHRP2 rapid diagnostic tests (RDTs). Few studies evaluated whether an evidence-based strategy using environmental features that characterize the immediate surroundings of a household, can improve the efficiency of secondary case identification.
Objective: This study utilized the Step D and extended the screening radius to 250-meters (termed Enhanced Step D or ESD) to assess which local environmental variables can guide CHWs to identify secondary cases more efficiently. As Zambia works toward eliminating malaria, more refined and targeted case detection strategies are required to find the untreated malaria cases that could serve as potentially asymptomatic sources of infection. This study can help guide and plan reactive case detection strategies in Zambia that allow community health workers/field teams to employ an evidence-based strategy to find malaria-positive secondary households situated near index case houses more efficiently.
Methods: Demographic information, malaria diagnosis, bed-net use and ownership, cooking energy source, and household floor material were obtained from surveys. Households were stratified into malaria positive and negative secondary households using RDT and qPCR results. ArcGIS was used to generate the following local environmental variables: screening radius (140 vs. 250-meters), number of animal pens within 100-meters, distance to nearest animal pen, distance and elevation difference between index and secondary houses, as well as the following large scale environmental variables: distance to main road and nearest stream category. Generalized estimating equations (GEE) estimated the cross-sectional effect for the difference in odds of a positive vs. negative secondary household for each predictor. For the secondary analysis GEE with the same model specifications was used to estimate the cross-sectional difference in odds of a positive vs. negative household for each environmental predictor. Model fit was evaluated with the Hosmer-Lemeshow goodness of fit test and significance was evaluated as a p-value of 0.05. Statistical analyses were carried out using STATA 14.2.
Results: Screening within the index households yielded an overall parasite prevalence of 8.6%, which was higher by qPCR (8.1%) than RDT (2.7%) as seen in Table 1. Secondary households had an overall parasite prevalence of 1.9% with similar differences by test used. Key results from regression analysis seen in Table 2 include a difference in prevalence according to screening radius as well as by proximity to the nearest stream. Secondary analysis produced similar results but showed statistically significant higher odds for households where animal pens were present.
Conclusion: Screening for secondary households within low-transmission setting in Zambia could be optimized by using both local-scale indicators such as the presence of animal pens and large-scale indicators such as streams as environmental guiding tools.
Acknowledgements: This research was supported in part the Bloomberg Philanthropies and the Johns Hopkins Malaria Research Institute, and the NIH-sponsored Southern and Central Africa ICEMR 2U19AI089680.
Universal Health Coverage (UHC) is the theme of the 2018 World Health Day on April 7th. The concept was applied to malaria in 2009 regarding the provision of long lasting insecticide-treated nets (LLINs aka ITNs) with the definition of universal meaning one net for every two persons in a household. Up until that time coverage targets for malaria interventions set at the 2000 Abuja Declaration had focused on achieving by the year 2010, 80% of people (particularly pregnant women and children below the age of 5 years) sleeping under ITNs, 80% of children receiving appropriate malaria treatment with artemisinin-based combination therapy (ACTs) within 24 hours of onset of illness and 80% of pregnant women receiving two doses of Intermittent Preventive Treatment (IPTp) for malaria as part of antenatal care (ANC).
Definitions have evolved since the Abuja Declaration. The target for ITNs was extended to all household members (thus universal). The ACT target was modified to require treatment based on parasitological testing (microscopy or rapid diagnostic tests). IPTp targets were extended to achieving monthly dosing from the 13th week of pregnancy, which depending on the point in pregnancy when a women entered the ANC system could be 3, 4 or more doses. In addition to these changes, the US President’s malaria Initiative upped the Abuja targets from 80% to 85% in the countries where it supported national malaria programs.
We are eight years past 2010. It had been assumed that if scale up to 80% had been achieved by then and sustained for five or more years, malaria deaths would come close to zero and elimination of the disease would be in sight. National surveys have shown that reaching these targets has not been simple.
The example of ITNs is a good place to start, as is Nigeria with the highest burden of malaria. The attached chart shows findings from the Demographic and Health or Malaria Information Surveys in 2010, 2013 and 2015. Whether one measures universal coverage by the house possessing at least one net per two residents or by the proportion who actually use/sleep under the nets, we can see that UHC for this intervention is difficult to achieve. Even when households possess nets, not everyone sleeps under them either because of adequacy of nets, preferred sleeping arrangements, internal household power structure or other factors.
In 2015 the majority of nets that existed in households were obtained through campaigns (77%), 14% were acquired from the health services, and 7% were purchased. These systems are not keeping up with the need.
Four endemic countries reported a malaria Information Survey in 2016, Liberia, Ghana, Madagascar, and Sierra Leone. The chart shows that they too have had difficulty in achieving universal coverage of malaria interventions. Of note the chart only includes whether appropriate malaria parasitological diagnosis was done on children who had fever in the preceding two weeks. Data on provision of ACTs is based on fever, not test results, so there is no way to know whether it was appropriate. Generally 20-30% more febrile children received ACTs than were tested.
All three malaria interventions, ACTs, Diagnostics and ITNs, require contact with the health system (including community health workers). If malaria services are indicative of other health interventions, then universal coverage including seeking interventions, getting them and ultimately using them is still a distant goal. To achieve universal coverage there also needs to be universal commitment by countries, donors and technical partners.
Parasitological diagnosis plays an increasing role in malaria control and elimination. Noella Umulisa, Angelique Mugirente, Tharcisse Munyaneza, Aniceth Rucogoza, Aline Uwimana, Beata Mukarugwiro, Stephen Mutwiwa, Aimable and Mbituyumuremyi of the Maternal and Child Survival Program, Jhpiego, the National Reference Laboratory, Rwanda Biomedical Centre (RBC), and the Malaria and Other Parasitic Diseases Division (Mal & OPDD) in Rwanda will present their experiences building the capacity of lab technicians during Session 47 at the American Society of Tropical Medicine and Hygiene Annual Meeting on 6 November 2017. Their abstract is found below.
Accurate malaria diagnostics help to establish the true prevalence of each Plasmodium species and can ensure appropriate treatment. Light microscopy is the gold standard for malaria diagnosis and sufficient training of laboratory staff is paramount for the correct microscopy diagnosis of malaria. In Rwanda each of about 400 health centers has a laboratory able to perform malaria microscopy, at least 2 trained lab technicians and 1 to 2 functioning microscopes.
The objective of the study is to evaluate the performance of laboratory technicians in detecting and quantifying malaria parasites in 81 health centers from 5 highly endemic districts (Huye, Nyanza, Ngoma, Kirehe, Kayonza, Gatsibo). In October 2015 the Rwanda Biomedical Center and partners trained 1 lab technician per health center from these districts in malaria microscopy.
The training emphasized determining parasite density and detection of malaria species. From August to September 2016 a follow-up assessment was conducted. Of the 81 technicians trained, 30 were randomly chosen and assessed at their health facilities.
A standardized pre-validated slide panel of 5 slides was distributed, a comprehensive checklist used to collect information and conduct visual inspection and maneuvers used in routine malaria diagnosis. During the training a significant increase was found between pre and post tests with median scores improving from 47% to 85%.
As part of the assessment 150 lab tech-prepared slides were analyzed to evaluate the quality of thick and thin blood smears. There was a significant increase in quality of both blood smear types. The sensitivity and specificity of participants in detection of malaria parasites were 100% and 86% respectively, while species identification and parasite quantification accuracy were 79% and 75% respectively.
The findings of this assessment support the need for continuous capacity building for laboratory staff to ensure accurate malaria diagnosis for appropriate treatment and suggest that District hospitals may benefit from conducting regular malaria microscopy diagnosis quality control/assurance activities at health center laboratories.
WHO says that, “In settings where malaria is actively being eliminated or has been eliminated, a “case” is the occurrence of any confirmed malaria infection with or without symptoms.” Several recent studies describe the importance of paying attention to asymptomatic infections.
In the Bagamoyo District of Tanzania Sumari and colleagues collected blood samples and examined them for Plasmodium falciparum prevalence using rapid diagnostic test (RDT), light microscopy (LM) and reverse transcription quantitative PCR. While overall prevalence was higher in symptomatic children using all three methods, asymptomatic children had a higher prevalence of gametocytes using light microscopy and PCR. They concluded that, “The higher gametocytemia observed in asymptomatic children indicates the reservoir infections and points to the need for detection and treatment of both asymptomatic and symptomatic malaria.”
The health effects of asymptomatic plasmodial infections (API) on children were documented in Rwanda. These included “Plasmodium infection was associated with anaemia, fever, underweight, clinically assessed malnutrition and histories of fever, tiredness, weakness, poor appetite, abdominal pain, and vomiting” and were generally more common with submicroscopic infection.
Besides children other groups are at risk from API. Malaria during pregnancy is a life and health threat to both the pregnant woman and the unborn child. Thirty-seven percent of asymptomatic pregnant women who had just delivered in Colombia were found to have parasitemia. Using microscopy only 8% were identified, such that without PCR the true extent of the problem would not have been identified. Thus, there is also concern for submicroscopic malaria and well as API generally. Asymptomatic and submicroscopic infections in areas co-endemic for P. falciparum and P. vivax are major contributors to anemia, not only in children but also in adults.
Working along the China-Myanmar border area, Zhao et al. explained that, “Sensitive methods for detecting asymptomatic malaria infections are essential for identifying potential transmission reservoirs and obtaining an accurate assessment of malaria epidemiology in low-endemicity areas aiming to eliminate malaria.” Thus they tried three molecular detection methods side-by-side, namely nested PCR targeting the rRNA genes, nested RT-PCR to detect parasite rRNA, and CLIP-PCR to detect parasite rRNA.
Interestingly the presence of fever is no guarantee that malaria parasites will be found. A study in Gabon demonstrated that among febrile patients only 1% had parasites found through microscopy compared to 32% through molecular testing. These studies have demonstrated the need for a better understanding of malaria transmission across different zones and strata in a country in the light of asymptomatic and submicroscopic malaria, especially gametocytemia. This should lead to better targeting of case detection, improved treatment and better compliance with preventive measures.
From 3,000 cases in 2010, Nepal reported around 1,000 cases in 2016, including 85% Plasmodium vivax cases. However private sector reporting is almost null so number of total cases may be the double. Nepal’s National Malaria Strategic Plan (NMSP) targets Elimination by 2022 (0 indigenous cases) with WHO certification by 2026.
Ward Level Micro-stratification is an important step for targeting appropriate interventions. Key interventions in the NMSP include case notification system by SMS (from health post workers or district vector control inspectors) to a Malaria Disease Information System, later to be merged with DHIS2. Case investigation teams conduct case and foci profiling as well as “passive cases” active detection and treatment (including staff from district such as surveillance coordinator, vector control inspector, and entomologist).
Malaria Mobile Clinics actively search/treat new cases in high risk areas (slums, brick factories, river villages or flooded areas, migrant workers villages, etc.). PCR diagnosis with Dry Blood Spot or Whole Blood is used to identify low density parasite cases, relapses or re-introduction. Coming up in April-June 2018 will be a Pilot of MDA (primaquine) for Plasmodium vivax in isolated settings (80% of cases in the country are P vivax).
Recent successes in the national malaria effort include the number of cases notified by SMS went from 0% to 45%. Also the number of cases fully investigated went from 22% to 52%, though this needs to go up to 95% for elimination. 73% of districts are now submitting timely malaria data reports per national guidelines, an increase from 52% in November 2015.
The border runs right through this town making importation of malaria cases easy
The Global Fund (GFATM) malaria grant rating went from B2 to A2. Nepal Epidemiology Disease Control Division (EDCD), WHO and GFATM are keen to pilot MDA for P vivax in isolated setting which MCSP/Jhpiego Advisor taking the lead.
Moving forward the malaria elimination effort needs to address Indo-Nepal Cross boarder collaboration since 45% cases are imported. Hopefully WHO will help EDCD Nepal to propose a plan of action to India. The program still needs to convince partners of relevance of malaria mobile clinics vs community testing and of the relevance of MDA for P vivax. More entomological and PCR/laboratory expertise is needed. With these measures malaria elimination should be in sight.