In vivo efficacy and safety of artemether–lumefantrine and amodiaquine–artesunate for uncomplicated Plasmodium falciparum malaria in Mozambique, 2018

Background Artemisinin-based combination therapy (ACT) has been the recommended first-line treatment for uncomplicated malaria in Mozambique since 2006, with artemether–lumefantrine (AL) and amodiaquine–artesunate (AS–AQ) as the first choice. To assess efficacy of currently used ACT, an in vivo therapeutic efficacy study was conducted. Methods The study was conducted in four sentinel sites: Montepuez, Moatize, Mopeia and Massinga. Patients between 6 and 59 months old with uncomplicated Plasmodium falciparum malaria (2000–200,000 parasites/µl) were enrolled between February and September of 2018, assigned to either an AL or AS–AQ treatment arm, and monitored for 28 days. A Bayesian algorithm was applied to differentiate recrudescence from new infection using genotyping data of seven neutral microsatellites. Uncorrected and PCR-corrected efficacy results at day 28 were calculated. Results Totals of 368 and 273 patients were enrolled in the AL and AS–AQ arms, respectively. Of these, 9.5% (35/368) and 5.1% (14/273) were lost to follow-up in the AL and AS–AQ arms, respectively. There were 48 and 3 recurrent malaria infections (late clinical and late parasitological failures) in the AL and AS–AQ arms, respectively. The day 28 uncorrected efficacy was 85.6% (95% confidence interval (CI) 81.3–89.2%) for AL and 98.8% (95% CI 96.7–99.8%) for AS–AQ, whereas day 28 PCR-corrected efficacy was 97.9% (95% CI 95.6–99.2%) for AL and 99.6% (95% CI 97.9–100%) for AS–AQ. Molecular testing confirmed that 87.4% (42/48) and 33.3% (1/3) of participants with a recurrent malaria infection in the AL and AS–AQ arms were new infections; an expected finding in a high malaria transmission area. Adverse events were documented in less than 2% of participants for both drugs. Conclusion Both AL and AS–AQ have therapeutic efficacies well above the 90% WHO recommended threshold and remain well-tolerated in Mozambique. Routine monitoring of therapeutic efficacy should continue to ensure the treatments remain efficacious. Trial registration Clinicaltrials.gov: NCT04370977

Unraveling the Complexity of Imported Malaria Infections by Amplicon Deep Sequencing

Imported malaria and recurrent infections are becoming an emerging issue in many malaria non-endemic countries. This study aimed to determine the molecular patterns of the imported malaria infections and recurrence. Blood samples were collected from patients with imported malaria infections during 2016–2018 in Guangxi Zhuang Autonomous Region, China. Next-generation amplicon deep-sequencing approaches were used to assess parasite genetic diversity, multiplexity of infection, relapse, recrudescence, and antimalarial drug resistance. A total of 44 imported malaria cases were examined during the study, of which 35 (79.5%) had recurrent malaria infections within 1 year. The majority (91.4%) had one recurrent malaria episode, whereas two patients had two recurrences and one patient had three recurrences. A total of 19 recurrence patterns (the species responsible for primary and successive clinical episodes) were found in patients returning from malaria epidemic countries. Four parasite species were detected with a higher than usual proportion (46.2%) of non-falciparum infections or mixed-species infections. An increasing trend of recurrence infections and reduced drug treatment efficacy were observed among the cases of imported malaria. The high recurrence rate and complex patterns of imported malaria from Africa to non-endemic countries have the potential to initiate local transmission, thereby undermining efforts to eliminate locally acquired malaria. Our findings highlight the power of amplicon deep-sequencing applications in molecular epidemiological studies of the imported malaria recurrences.

787Multistate modelling to investigate the impact of recurrent malaria episodes on hospital admissions and mortality

Background Inadequate prevention and treatment of malaria can lead to reinfections and recurrent episodes, and for vivax malaria, further recurrences from the dormant liver stage. This study quantified the impact of recurrent malaria episodes on morbidity and mortality. Methods Routinely collected data were available from 68,381 malaria patients presenting to the primary referral hospital in Papua, Indonesia. A multi-state modelling framework, with Cox regression for transition rates, was employed to determine the risks of re-presentation to hospital, receiving in-patient treatment, and early (≤14 days post treatment)/late death following multiple malaria episodes. Results The risk of re-presentation to hospital increased from 34.7% (95%CI: 34.4%–35.1%) at first episode to 58.6% (57.5%–59.6%) following the third episode. Infection with vivax malaria increased the rate of re-presentation to hospital by 1.48-fold (Hazard Ratio 1.48; 95%CI 1.44–1.51) and late hospital in-patient admission by 1.17-fold (1.11–1.22), compared to falciparum. Falciparum malaria caused a higher overall rate of early death (1.54 (1.25–1.92)), however, after multiple episodes, there was a trend towards a greater rate of early death for vivax infection (1.91 (0.73–4.97)). Conclusions Recurrent episodes of malaria can cause substantial morbidity and mortality, highlighting the importance of prevention and effective treatments for both falciparum and vivax malaria. Key messages To achieve elimination of malaria in South-East Asia, where prevalence of vivax malaria is high, we must prioritise the radical cure of vivax to eliminate the liver-stage of this species that causes relapses of infection.

In vivo Efficacy and Safety of Artemether-Lumefantrine and Amodiaquine-Artesunate for Uncomplicated Plasmodium Falciparum Malaria in Mozambique, 2018

Background : Artemisinin-based combination therapy has been the recommended treatment for uncomplicated malaria in Mozambique since 2006, with artemether-lumefantrine (AL) and amodiaquine-artesunate (AS-AQ) as first-line treatments. To assess efficacy of currently used artemisinin-based combination therapy, an in vivo therapeutic efficacy study was conducted. Methods : The study was conducted in four sentinel sites: Montepuez, Moatize, Mopeia and Massinga. Patients between 6 to 59 months old with uncomplicated Plasmodium falciparum malaria (2,000–200,000 parasites/µl) were enrolled between February and September of 2018, assigned to either an AL or AS-AQ treatment arm, and monitored for 28 days. A Bayesian algorithm was applied to differentiate recrudescence from new infection using genotyping data of seven neutral microsatellites. Uncorrected and PCR-corrected efficacy results at day 28 were calculated. Results : Totals of 368 and 273 patients were enrolled in the AL and AS-AQ arms, respectively. Of these, 9.5% (35/368) and 5.1% (14/273) were lost to follow-up in the AL and AS-AQ arms, respectively. There were 48 and 3 recurrent malaria infections (late clinical and late parasitological failures) in the AL and AS-AQ arms, respectively. The day 28 uncorrected efficacy was 85.3% (95% CI: 81.1–88.9%) for AL and 98.8% (95% CI: 96.7–99.8%) for AS-AQ, whereas day 28 PCR-corrected efficacy was 97.9% (95% CI: 95.6–99.2%) for AL and 99.6 % (95% CI: 97.9–100%) for AS-AQ. Molecular testing confirmed that 87.4% (42/48) and 33.3% (1/3) of participants with a recurrent malaria infection in the AL and AS-AQ arms were new infections; an expected finding in a high malaria transmission area. Adverse events were documented in less than 2% of participants for both drugs. Conclusion : Both AL and AS-AQ have therapeutic efficacies well above the 90% WHO recommended threshold and remain well-tolerated in Mozambique. Routine monitoring of therapeutic efficacy should continue to ensure the treatments remain efficacious. Trial registration: Clinicaltrials.gov: NCT04370977

Co-infection of COVID-19 and recurrent malaria

In tropical countries, endemic diseases such as malaria can be challenging to distinguish from COVID-19 because of the similarities in presenting symptoms. Here we reported a case of a young soldier with fever and myalgia six days before admission, with non-productive cough, chills, nausea and vomiting, dizziness, and headache for two days. Previously, he had experienced four times of malaria infection. He had a history of positive non-falciparum malaria rapid diagnostic test (RDT) two days before admission. Significant findings were epigastric tenderness, splenomegaly, and severe thrombocytopenia of 36×103 cells / µL. A naso-oropharyngeal swab examination revealed a positive SARS-CoV-2 infection. Consequently, he was hospitalized for 12 days, successfully treated, and discharged without sequelae. Thus, in light of a pandemic, physicians need to raise the suspicion of concurrent COVID-19 infection with other tropical diseases, especially at-risk patients, because malaria and COVID-19 may share similar manifestations. Moreover, further ancillary testing, such as RDT, may be warranted.

Factors influencing severity of recurrent malaria in a conflict-affected State of south Sudan

Background South Sudan has borne the brunt of years of chronic warfare and remains endemic of malaria, with increasing mortality and morbidity. Limited data still exists on factors influencing the severity of recurrent malaria, especially in emergency context as South Sudan. This study therefore aimed to investigate factors influencing recurrence of severe malaria in selected primary healthcare centres in South Sudan. This would assist and guide in malaria prevention, treatment, and eradication efforts.Methods We conducted a retrospective study of routinely collected clinic data collected for individuals aged 1 year and above who received a diagnosis of severe malaria at 3 primary healthcare centres (PHCC); Malual Bab PHCC, Matangai PHCC and Malek PHCC between September 15, 2019 to December 15, 2019 in South Sudan. Patient characteristics were analyzed using simple descriptive statistics. Inferential statistics were also conducted to identify the associated factors influencing recurrence of severe malaria. All analyses were conducted using R Version 3.6.2.Results A total of 289 recurrent malaria cases were included in this study. More than half of the participants were female. Overall, the prevalence of severe recurrent malaria was 66.1% (191) while 74.4% (215) did not complete malaria treatment. Among those who did not complete malaria treatment, 76.7% (165) had severe recurrent malaria, while among those who completed malaria treatment 35.1% (26) had severe recurrent malaria (p<0.001). There is a significant association between marital status (OR= 0.33, 95% CI: 0.19-0.56, p<0.001), employment status (OR=0.35, 95% CI: 0.14-0.87, p=0.024), the use of preventive measures (OR=3.82, 95% CI: 1.81-8.43, p<0.001) and nutrition status (OR=0.22, 95% CI: 0.13-0.37, p<0.001). When adjusted for employment, marital status, nutritional and prevention measures in turns using Mantel-Haenszel test of association, this effect remained statistically significant.Conclusion Our study showed that there is a high prevalence of severe recurrent malaria in South Sudan and that significant relationship exists between severe recurrent malaria and antimalarial treatment dosage completion influenced by certain personal and social factors. Findings from our study would be useful for effective response to control and prevent malaria in endemic areas of South Sudan.

Admiral Nelson’s illnesses and injuries

Horatio Nelson is one of the greatest English heroes. His key exploits at the battles of the Nile and Trafalgar, which led to Britain’s maritime supremacy, are well known and celebrated in the 5.5m statue at the summit of Nelson’s column in Trafalgar Square, London. The statue also showcases his most famous injuries, the injury to his right eye and arm amputation. However, as well as these he had a number of other battle injuries and afflictions including recurrent malaria, yellow fever, scurvy, tuberculosis and dysentery, which, although he bore with stoicism, may have affected his professional performance at different times in his career. The exact cause of his death was probably a combination of blood loss, lung injury and spinal shock.

Recurrence of Falciparum Malaria under Coartem Treatment in the City of Mâncio Lima, Acre, Brazil: A Retrospective Study

Background: Malaria remains a health problem in the Amazon and since 2005 the state of Acre has high incidence of malaria. Treatment with Coartem® for cases of falciparum malaria was introduced in Acre in August 2012. In Brazil, there is still no published study on the effectiveness of Coartem in endemic areas. Methods: This study was conducted in Mâncio Lima, Acre, in the western Brazilian Amazon region. All malaria cases notified in Mâncio Lima between August 01st, 2012 and October 31st, 2013 were revised. The therapeutic response to Coartem in Mâncio Lima, Acre, was evaluated. A recurrence of falciparum malaria was defined as a malaria case occurring in the same patient in a maximum interval of 40 days between the day treatments was started and the day the next diagnosis was made. Results: All malaria cases (7,171) notified between August 2012 and July 2013 were revised. About 23.72% (n = 1,701) were falciparum malaria. There were six cases of recurrent falciparum malaria that can be classified as treatment failure. All cases had low parasitemia. The minimum and maximum interval between the first and the recurrent malaria episode was 17 days and 33 days. Age range was 9 to 50 years. Two patients were from rural areas, while all others were from riverine areas. Conclusion: Possible failure to Coartem treatment was identified, however causes are not clear. Further studies are needed.

Atypical B cells are a normal component of immune responses to vaccination and infection in humans

The full diversity of the circulating human B cell compartment is unknown. Flow cytometry analysis suggests that in addition to naïve and memory B cells, there exists a population of CD11c+, CD27− CD21− “atypical” B cells, that are associated with chronic or recurrent infection and autoimmunity. We used single cell RNA-seq approaches to examine the diversity of both antigen-specific B cells and total B cells in healthy subjects and individuals naturally-exposed to recurrent malaria infections. This analysis revealed two B cell lineages: a classical lineage of activated and resting memory B cells, and an atypical-like lineage. Surprisingly, the atypical lineage was common in both malaria exposed individuals and non-exposed healthy controls. Using barcoded antibodies in conjunction with our transcriptomic data, we found that atypical lineage cells in healthy individuals lack many atypical B markers and thus represent an undercounted cryptic population. We further determined using antigen specific probes that atypical cells can be induced by primary vaccination in humans and can be recalled upon boosting. Collectively these data suggest that atypical cells are not necessarily pathogenic but can be a normal component of B responses to antigen.