Category Archives: Diagnosis

Asymptomatic Malaria – we need to eliminate what we can’t see

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 achieve elimination.”[i] Here we examine the challenge of asymptomatic malaria infections.

Background

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 [5.62, 8.22])
  • 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 infection.

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 interventions.

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 phenomenon.


[i] Björkman 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 (2019) 17:14, https://doi.org/10.1186/s12916-018-1243-z

[ii] Global Malaria Programme. Universal access to malaria diagnostic testing – An operational manual. World Health Organization. November 2011 (rev. February 2013). https://www.who.int/malaria/publications/atoz/9789241502092/en/

[iii] Global Malaria Programme. World malaria report 2018. World Health Organization. 19 November 2018. https://www.who.int/malaria/publications/world-malaria-report-2018/en/

[iv] Peprah S, Tenge C, Genga IO, Mumia M, Were PA, Kuremu RT, Wekes WN,  Sumba PO, Kinyera T, Otim T, Legason ID, Biddle J, Reynolds SJ, Talisuna AO, Biggar1 RJ, Bhatia K, Goedert JJ, Pfeiffer RM, Mbulaiteye SM. A Cross-Sectional Population Study of Geographic, Age-Specific, and Household Risk Factors for Asymptomatic Plasmodium falciparum Malaria Infection in Western Kenya. The American Journal of Tropical Medicine and Hygiene, Volume 100, Issue 1, Jan 2019, p.54-65. DOI: https://doi.org/10.4269/ajtmh.18-0481.

[v] Ouédraogo M, Samadoulougou S, Rouamba T, Hien H, Sawadogo JEM Tinto H, Alegana VA, Speybroeck N and Kirakoya?Samadoulougou F. Spatial distribution and determinants of asymptomatic malaria risk among children under 5 years in 24 districts in Burkina Faso. Malaria Journal 2018; 17:460 https://doi.org/10.1186/s12936-018-2606-9

[vi] Lamptey H, Ofori MF, Kusi KA, Adu B, Owusu-Yeboa E, Kyei-Baafour E, Arku AT, Bosomprah S, Alifrangis M, Quakyi IA. The prevalence of submicroscopic Plasmodium falciparum gametocyte carriage and multiplicity of infection in children, pregnant women and adults in a low malaria transmission area in Southern Ghana. Malar J. 2018 Sep 17;17(1):331. doi: 10.1186/s12936-018-2479-y.

[vii] Mapua MI, Hans-Peter Fuehrer HP, Petrželková KJ, Todd A, Noedl H, Qablan MA, and Modrý D. Plasmodium ovale wallikeri in Western Lowland Gorillas and Humans Central African Republic. Emerging Infectious Disease journal. Volume 24, Number 8—August 2018. https://wwwnc.cdc.gov/eid/article/24/8/18-0010_article

[viii] Global Malaria Programme. A framework for malaria elimination. ISBN 978-92-4-151198-8. World Health Organization 2017, http://www.who.int/malaria/publications/atoz/9789241511988/en/

[ix] Kobayashi T, Kanyangarara M, Laban NM, Phiri M, Hamapumbu H, Searle KM, Stevenson JC, Thuma PE, Moss WJ and the Southern Africa International Centers of Excellence for Malaria Research. Characteristics of Subpatent Malaria in a Pre-Elimination Setting in Southern Zambia. The American Journal of Tropical Medicine and Hygiene, 10 December 2018, DOI: https://doi.org/10.4269/ajtmh.18-0399

[x] McCreesh P, Mumbengegwi D, Roberts K, Tambo M, Smith J, Whittemore B, Kelly G, Moe C, Murphy M, Chisenga M, Greenhouse B, Ntuku H, Kleinschmidt I, Sturrock H, Uusiku P, Gosling R, Bennett A, Hsiang MS. Subpatent malaria in a low transmission African setting: a cross-sectional study using rapid diagnostic testing (RDT) and loop-mediated isothermal amplification (LAMP) from Zambezi region, Namibia. Malar J. 2018 Dec 19;17(1):480. doi: 10.1186/s12936-018-2626-5.

[xi] Kobayashi T, Kanyangarara M, Laban NM, Phiri M, Hamapumbu H, Searle KM, Stevenson JC, Thuma PE, Moss WJ, For The Southern Africa International Centers Of Excellence For Malaria Research.Characteristics of Subpatent Malaria in a Pre-Elimination Setting in Southern Zambia. Am J Trop Med Hyg. 2018 Dec 10. doi: 10.4269/ajtmh.18-0399. [Epub ahead of print]

[xii] Thera MA, Konea AK, Tangaraa B, Diarraa E, Niarea A, Dembeleb A, Sissokoa MS, Doumboa OK. School-aged children based seasonal malaria chemoprevention using artesunate-amodiaquine in Mali. Parasite Epidemiology and Control 3 (2018) 96–105. https://doi.org/10.1016/j.parepi.2018.02.001

[xiii] Smit MR, Ochomo EO, Aljayyoussi G, Kwambai TK, Abong’o BO, Chen T, Bousema T, Slater HC, Waterhouse D, Bayoh NM, Gimnig JE, Samuels AM, Desai MR, Phillips-Howard PA, Kariuki SK, Wang D, Ward SA, ter Kuile FO. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine. www.thelancet.com/infection Published online March 27, 2018 http://dx.doi.org/10.1016/S1473-3099(18)30163-4

Improving the efficacy of reactive screen-and-treat for malaria elimination in southern Zambia

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 – Where is Malaria?

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.

Performance assessment of laboratory technicians on Malaria Microscopy in 5 high endemic districts of Rwanda

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.

Asymptomatic and Sub-Microscopic Malaria: a Challenge to Elimination Efforts

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.

Nepal on the Path to Malaria Elimination

Jhpiego’s Emmanuel Le Perru has been placed with Nepal’s malaria control program by the Maternal and Child Survival Program (USAID) to strengthen the agency’s overall response to malaria as well as ensure top performance of Nepal’s Global Fund Malaria grant. Emmanuel shares his experiences with us here.

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.

World Health Workers Week, a Time to Recognize Health Worker Contributions to Malaria Care

Since the beginning of the Roll Back malaria Partnership in 1998 there has been strong awareness that malaria control success is inextricably tied to the quality of health systems. Achieving coverage of malaria interventions involves all aspects of the health system but most particularly the human resources who plan, deliver and assess these services. World Health Worker Week is a good opportunity to recognize health worker contributions to ridding the world of malaria.

We can start with community health workers who may be informal but trained volunteers or front line formal health staff.  According to the Frontline Health Workers Coalition, “Frontline health workers provide immunizations and treat common infections. They are on the frontlines of battling deadly diseases like Ebola and HIV/AIDS, and many families rely on them as trusted sources of information for preventing, treating and managing a variety of leading killers including diarrhea, pneumonia, malaria and tuberculosis.”

The presence of CHWs exemplifies the ideal of a partnership between communities and the health system. With appropriate training and supervision CHWs ensure that malaria cases are diagnosed and treated promptly and appropriately, malaria prevention activities like long lasting insecticide-treated nets are implemented and pregnant women are protected from the dangers of the disease. CHWs save lives according to Nkonki and colleagues who “found evidence of cost-effectiveness of community health worker (CHW) interventions in reducing malaria and asthma, decreasing mortality of neonates and children, improving maternal health, increasing exclusive breastfeeding and improving malnutrition, and positively impacting physical health and psychomotor development amongst children.”

CHWs do not act in isolation but depend on health workers at the facility and district levels for training, supervision and maintenance of supplies and inventories. These health staff benefit from capacity building – when they are capable of performing malaria tasks, they can better help others learn and practice.

A good example of this capacity building is the Improving Malaria Care (IMC) project in Burkina Faso, implemented by Jhpiego and supported by USAID and the US President’s malaria Initiative. IMC builds capacity of health workers at facility and district level to improve malaria prevention service delivery and enhance accuracy in malaria diagnosis and treatment. Additionally capacity building is provided to health staff in the National Malaria Control Program to plan, design, manage and coordinate a comprehensive malaria control program. As a result of capacity building there has been a large increase in malaria cases diagnosed using parasitological techniques and in the number of women getting more doses of intermittent preventive treatment to prevent malaria during pregnancy.

Malaria care is much more than drugs, tests and nets. Health worker capacity is required to get the job done and move us forward on the pathway to eliminate malaria.

Leadership and Support for Malaria Pre-Elimination in Nepal

Emmanuel Le Perru, Jhpiego field staff in Nepal, shared his experiences in aiding the malaria pre-elimination efforts in the country during a retreat that preceded the 65th Annual Meeting of the American Society of Tropical Medicine and Hygiene in Atlanta. Here are some highlights of his talk.

risk-mapMalaria Pre-Elimination efforts are targeting 0 deaths as well as investigation of 100% of confirmed cases in Nepal. Systematic entomology investigation/interventions are required. Glucose-6-Phosphate Dehydrogenase deficiency (enzyme genetic defect causing hemolysis with primaquine) testing for Plasmodium vivax in high G6PDd prevalence communities is required. Cases should receive treatment within 72 hours of symptoms for Pf (to quickly prevent transmission and gametocyte reservoir). There is also a need to distinguish between indigenous and imported cases.

Jhpiego is providing technical assistance and capacity building for Nepal’s Ministry of Health pre-elimination efforts as follows:

  • Integrated Vector Management
  • Micro-stratification
  • Entomology curriculum to be conducted in medical college (need new positions)
  • Case-based Surveillance guidelines
  • Private-sector engagement (for increased reporting and product quality control/procurement such as Antigen RDTs)
  • Capacity Assessments in 9 health systems strengthening components at central and district levels (Jhpiego Malaria Implementation Guide)
  • Human resources: clear job descriptions and performance goals
  • Leadership & Management development program

gfatm-bednets-distProgram highlights include the fact that the Global Fund malaria grant rating improved from B2 (inadequate but demonstrating potential) in January 2016, but now A2 (meeting expectations) in November 2016. Concept note for operational research at 2 or 3 border check points has been developed in order to determine whether such intervention (communication & voluntary screening) is cost-effective and relevant to catch/target imported cases, raise awareness on malaria available services, detect/prevent sources of potential outbreaks. This will inform GFATM on the relevance to fund such intervention. A similar approach was done at the China-Myanmar border but was not recognized by not WHO.

Nepal's Global Fund Grant Indicators for Malaria Case Management

Nepal’s Global Fund Grant Indicators for Malaria Case Management

Although the National Malaria Strategic Plan refers to high risk groups (forest workers, national parks security personnel, refugees, prisoners, etc.) evidence is needed to back this up. A study or improved investigation forms are needed to identify such groups and use this information to design appropriate behavior change communications and other interventions.

Special Programming Highlights include proposing a focus on Closed/Isolated Settings/Foci (limited migration, duration and population) to WHO and GFATM. Considering a targeted mass drug administration (MDA) Plasmodium vivax (not yes recommended by WHO) with Primaquine/G6PD testing. Consideration is being given to new drugs in the pipeline such as Ivermectin. Molecular Testing using Polymerase Chain Reaction (PCR) to detect low parasitemia, asymptomatic or re-infection cases (Pv includes inactive/dormant sporozoites known as hypnozoites) is being proposed.

Community based testing as proposed in the Global Fund grant needs strengthening. Therefore RDT use by Female Community Health Volunteer is being considered. Active case detection is another possibility for those areas moving toward pre-elimination. As mentioned, there is also need for studies of asymptomatic infection.

Lessons learned so far for best practices for efforts in identifying specific pre-elimination interventions include the value of getting consensus at national level through the Malaria Technical Working Group. There is also need to challenge WHO recommendations and engage dialogue to get creative. At present there is a risk of a Catch 22 situation wherein the GFATM asks for innovative interventions but at the same time tries to adhere strictly WHO to existing guidance.

The Nepalese malaria program is in constant dialogue with the GFATM Fund Portfolio Manager and team on the local context and technical challenges in order to get them involved in looking for innovative solutions.

Challenges arise in malaria diagnostics. While systematic microscopy is the gold standard, quality can be poor because of low stain/re-agent quality, constant staff turnover and donor reluctance to fund additional training. Also microscopy confirmation and slide quality control are time consuming, and often this process is not clear or well followed. PCR require specific equipment, training and qualifications. Takes time to be operational.

There are opportunities moving forward.  Progress could be made if there were more “elimination experts” to position to influencer to WHO to seek and propose new interventions for the pre-elimination stage. Nepal provides an ideal opportunity to test new ideas. It will also be necessary for the national malaria program staff to receive regular technical updates on program issues such as new drugs (Ivermectin?) and on-going pilots of MDA.

Identifying a More Accurate Test for Schistosomiasis in The Gambia

During the recently concluded 65th Annual Meeting of the American Society of Tropical Meicine and Hygiene colleagues from The Gambian Ministry of Health and Social Welfare, the World Health Organization and the NTD Support Center presented a poster entitled, “Field Performance of a Circulating Cathodic Antigen Rapid Test at Point-Of-Care for Mapping Schistosomiasis-Endemic Districts in Gambia.” The authors included Bakary Sanneh, Kristen Renneker, Joof  Ebrima, Sanyang M. Abdoulie, Camara Yaya, Sambou M. Sana, Sey Alhagie Papa, Jagne Sherifo, Baldeh Ignacious, Louis-Albert Tchuem Tchuente, Patrick J Lammie, and Kisito Ogoussan. Their abstract appears below.

figureBackground: The traditional parasitological Kato Katz smears and urine filtration methods recommended by the World Health Organization (WHO) to implement mapping of schistosomiasis have been found to be less sensitive in the detection of light-intensity schistosomiasis infections. Field surveys in Sub-Sahara Africa have shown that the Circulating Cathodic Antigen (CCA) point-of-care (POC) test is more accurate for detecting Schistosoma mansonia than the microscopic Kato Katz technique.

Aim: To establish the field sensitivity and specificity of POC CCA as mapping tool to provide the endemicity of schistosomiasis in The Gambia.

Methods: A cross-section study …

  • Ten school per region in 4 regions with historical known risk
  • Fifty children aged 7 to 14 years: 25 boys and 25 girls (WHO Mapping sampling guide)
  • Stool, urine and finger pricks samples were examined for Schistosomiasis
  • Parasitological tests: 2 Kato-katz slides to read from each stool sample, and urine filtration technique, urine dip-stick and Circulating Cathodic Antigen (CCA) techniques,

table-1Discussion: The CCA prevalence in this study was 23.34% (95% CI, 21.51-25.26%) two times higher than the prevalence based on  egg-detection for S. haematobium and S.mansoni (10.13,95% CI 8.87-11.55; and 0.26%, (95% CI, 0.09-0.62, respectively).  Although The Gambia is thought to be endemic for only S. haematobium, yet 5 subjects were found to harbor S. mansoni. Three of the 5 individuals from the high endemic schistosomiasis regions were co-infected with S. haematobium and S. mansoni.

table-2The sensitivity of the POC-CCA proved to be relatively high (60.0%), using double Kato-Katz as a reference for S. mansoni detection, although few infections were found, 5 out 1954  tested. The specificity of the POC CCA was 76.8%, respectively.  Using urine filtration as reference standard for the detection of S. haematobium, the sensitivity of POC-CCA was 47.9% and the specificity was 79.4%.

Conclusion: The Gambia is endemic for both urinary and intestinal schistosomiasis although most of the infections are due to S. haematobium in the 4 regions investigated. The results of the study showed a low sensitivity of the POC-CCA test in detecting S. haematobium and therefore we conclude further research is needed  to develop an ideal rapid diagnosis tool for urinary schistosomiasis.

schisto-acknowledgementAcknowledgement: Thanks to the Mapping Team,  Consultants, MoHSW, WHO,  Task Force for Global Health (TFGH) for all their support. For questions please contact: Dr. Kisito Ogoussan, kogoussan@taskforce.org; or Mr. Bakary Sanneh, sheikbakary@yahoo.com

Mobile suitcase laboratory: A tool for the rapid detection of emerging and endemic infectious disease

Ahmed Abd El Wahed who is based at Georg-August University, Goettingen, Germany shares his experiences with development and use of field diagnostics that can fit in a suitcase. This work received support from the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, Geneva, Switzerland. He explains the concept here …

Laboratory diagnosis mainly depends on nucleic acid detection by real-time polymerase chain reaction (PCR), which is available in central laboratories and has a turnaround time of more than two hours. Since real-time RT-PCR assays are not suitable for on-site screening, samples collected from local hospitals, treatment center or at the site of an outbreak have to be sent to laboratories over long distances for testing.

In developing countries, the necessary equipment for diagnosis is only available in few central laboratories, which are not accessible and of limited capacity to test large numbers of incoming samples. Moreover, transport conditions of samples are inadequate and therefore lead to unreliable results.

lab-in-a-suitcaseFor decentralizing of the molecular diagnostics, there is a need for a simple molecular point-of-need test. We have developed a mobile suitcase laboratory (62+49+30 cm) containing all reagents and equipment for the detection of the nucleic acid of infectious agents using the recombinase polymerase amplification (RPA) technology. The RPA assay run at a constant temperature (42°C) for a maximum of 15 minutes.

Moreover, all reagents are cold-chain independent and the mobile laboratory is operated by a solar power battery. The nucleic acid extraction is performed by a magnetic bead based method, in which a simple fast lysis protocol is applied. In case of highly infectious agents such as Ebola virus, the inactivation step was performed in a glovebox.

The suitcase lab is designed to detect almost 30 pathogens such as Dengue, Zika, Chikungunya, Ebola, Coronaviruses as well as Tuberculosis, Leptospira, Salmonella typhi and paratyphi, malaria, avian influenza, and Leishmania.

The suitcase lab featured in a presentation at the 65th Annual Meeting of the American Society of Tropical Medicine in Atlanta under the title of “Novel Extraction Protocol and Recombinase Polymerase Amplification Assay for Detection of Leishmania Donovani In 30 Minutes.” Authors/presenters included Dinesh Mondal, Prakash Ghosh, Md. Anik Ashfaq Khan, Faria Hossain, Susanne Böhlken-Fascher, Greg Matlashewski, Axel Kroeger, Piero Olliaro, and Ahmed Abd El Wahed.

Their work highlighted Leishmania donovani (LD), a protozoan parasite transmitted to humans by sand flies, which causes Visceral Leishmaniasis (VL). Currently, diagnosis is based on presence of anti-LD antibodies and clinical symptoms. Molecular diagnosis would require real-time PCR, which is not easy to implement at field settings.

In this study, we report on the development and testing of a novel extraction protocol in combination with recombinase polymerase amplification (RPA) assay for the detection of LD. The LD RPA assay detected equivalent to one LD genomic DNA. The RPA assay was performed at constant temperature (42°C) and the total assay runtime including the extraction procedure was 30 minutes.

The RPA assay also detected other Leishmania species (L. major, L. aethiopica and L. infantum), but did not identify nucleic acid of other pathogens. Forty-eight samples from VL, asymptomatic and post-kala-azar dermal leishmaniasis subjects were detected positive and 48 LD negative samples were negative by both LD RPA and real-time PCR assays, which indicates 100% agreement.

To allow the use of the assay at field settings, a mobile suitcase laboratory (56+45.5+26.5 cm) was developed and operated at the local hospital in Mymensingh, Bangladesh by using a solar-powered battery. DNA extraction was performed by a novel magnetic bead based method, in which a simple fast lysis protocol was applied.