Malaria: elimination tale from Yunnan Province of China and new challenges for reintroduction.

BACKGROUND: Eradication of infectious disease is the sanctified public health and sustainable development goal around the world. MAIN BODY: Three antimalarial barriers were developed to control imported malarial cases, and an effective surveillance strategy known as the "1-3-7 approach" was developed to eliminate malaria from the Chinese population. From 2011 to 2019, 5254 confirmed malaria cases were reported and treated in Yunnan Province, China. Among them, 4566 cases were imported from other countries, and 688 cases were indigenous from 2011 to 2016. Since 2017, no new local malarial case has been reported in China. Thus, malaria has been completely eliminated in Yunnan Province. However, malaria is detected in overseas travellers on a regular basis, such as visitors from neighbouring Myanmar. CONCLUSION: Hence, the strategies should be further strengthened to maintain a robust public health infrastructure for disease surveillance and vector control programs in border areas. Such programs should be supported technically and financially by the government to avert the possibility of a malarial resurgence in Yunnan Province.

Seven decades towards malaria elimination in Yunnan, China.

BACKGROUND: Yunnan Province was considered the most difficult place in China for malaria elimination because of its complex malaria epidemiology, heterogeneous ecological features, relatively modest economic development, and long, porous border with three malaria endemic countries: Lao People's Democratic Republic, Myanmar, and Viet Nam. METHODS: Academic publications and grey literature relevant to malaria elimination in Yunnan covering the period from 1950 until 2020 inclusive were considered. The following academic indexes were searched: China Science Periodical Database, China National Knowledge Infrastructure Database, and MEDLINE. Grey literature sources were mainly available from the National Institute of Parasitic Diseases (NIPD), the Chinese Center for Diseases Control and Prevention, and the Yunnan Institute of Parasitic Diseases (YIPD). RESULTS: A malaria elimination campaign in the 1950-1960s, based mainly on mass administration of antimalarial drugs and large-scale vector control, reduced morbidity and mortality from malaria and interrupted transmission in some areas, although elimination was not achieved. Similar strategies were used to contain outbreaks and a resurgence of disease during the 1970s, when malaria services were discontinued. From the 1980s, malaria incidence declined, despite the challenges of large numbers of mobile and migrant populations and an unstable primary health care system in rural areas following economic transformation. Launch of the national malaria elimination programme in 2010 led to adoption of the '1-3-7' surveillance and response strategy specifying timely detection of and response for every case, supported by the establishment of a real-time web-based disease surveillance system and a new primary health care system in rural areas. Border malaria was addressed in Yunnan by strengthening the surveillance system down to the lowest level, cross-border collaboration with neighbouring countries and non-governmental organizations, and the involvement of other sectors. CONCLUSIONS: Seven decades of work to eliminate malaria in Yunnan have shown the importance of political commitment, technically sound strategies with high quality implementation, a robust surveillance and response system at all levels, community participation and effective management of border malaria. The experiences and lessons learned from elimination remain important for prevention re-establishment of malaria transmission in the Province.

Genomic Epidemiology of Antimalarial Drug Resistance in Plasmodium falciparum in Southern China.

Emerging artemisinin resistance in Southeast Asia poses a significant risk to malaria control and eradication goals, including China's plan to eliminate malaria nationwide by 2020. Plasmodium falciparum was endemic in China, especially in Southern China. Parasites from this region have shown decreased susceptibility to artemisinin and delayed parasite clearance after artemisinin treatment. Understanding the genetic basis of artemisinin resistance and identifying specific genetic loci associated with this phenotype is crucial for surveillance and containment of resistance. In this study, parasites were collected from clinical patients from Yunnan province and Hainan island. The parasites were genotyped using a P. falciparum-specific single nucleotide polymorphism (SNP) microarray. The SNP profiles examined included a total of 27 validated and candidate molecular markers of drug resistance. The structure of the parasite population was evaluated by principal component analysis by using the EIGENSOFT program, and ADMIXTURE was used to calculate maximum likelihood estimates for the substructure analysis. Parasites showed a high prevalence of resistance haplotypes of pfdhfr and pfdhps and moderate prevalence of pfcrt. There was no mutation identified on pfmdr1. Candidate SNPs on chromosomes 10, 13, and 14 that were associated with delayed parasite clearance showed a low prevalence of mutants. Parasites from Southern China were clustered and separated from those from Southeast Asia. Parasites from Yunnan province were substructured from parasites from Hainan island. This study provides evidence for a genomic population with drug resistance in Southern China and also illustrates the utility of SNP microarrays for large-scale parasite molecular epidemiology.

Prevalence of Clinical and Subclinical Plasmodium falciparum and Plasmodium vivax Malaria in Two Remote Rural Communities on the Myanmar-China Border.

Malaria infections may be symptomatic, leading to treatment, or "asymptomatic," typically detected through active surveillance, and not leading to treatment. Malaria elimination may require purging both types of infection. Using detection methods with different sensitivities, we conducted a cross-sectional study in two rural communities located along the border between China's Yunnan Province and Myanmar's Shan and Kachin States, to estimate the prevalence of asymptomatic and symptomatic malaria. In Mong Pawk, all infections detected were asymptomatic, and the prevalence of Plasmodium falciparum was 0.3%, 4.3%, 4.0%, and 7.8% by light microscopy, rapid diagnostic test (RDT), conventional polymerase chain reaction (cPCR), and multiplexed real-time PCR (RT-PCR), respectively, and Plasmodium vivax prevalence was 0% by all detection methods. In Laiza, of 385 asymptomatic participants, 2.3%, 4.4%, and 12.2% were positive for P. vivax by microscopy, cPCR, and RT-PCR, respectively, and 2.3% were P. falciparum-positive only by RT-PCR. Of 34 symptomatic participants in Laiza, 32.4% were P. vivax-positive by all detection methods. Factors associated with infection included gender (males higher than females, P = 0.014), and young age group (5-17 age group compared with others, P = 0.0024). Although the sensitivity of microscopy was adequate to detect symptomatic infections, it missed the vast majority (86.5%) of asymptomatic infections. Although molecular detection methods had no advantage over standard microscopy or RDT diagnosis for clinically apparent infections, malaria elimination along the Myanmar-China border will likely require highly sensitive surveillance tools to identify asymptomatic infections and guide targeted screen-and-treat interventions.

Malaria control along China-Myanmar Border during 2007-2013: an integrated impact evaluation.

BACKGROUND: Implementing effective interventions remain a lot of difficulties along all border regions. The emergence of artemisinin resistance of Plasmodium falciparum strains in the Greater Mekong Subregion is a matter of great concern. China has effectively controlled cross-border transmission of malaria and artemisinin resistance of P. falciparum along the China-Myanmar border. METHODS: A combined quantitative and qualitative study was used to collect data, and then an integrated impact evaluation was conducted to malaria control along the China-Myanmar border during 2007-2013. RESULTS: The parasite prevalence rate (PPR) in the five special regions of Myanmar was decreased from 13.6 % in March 2008 to 1.5 % in November 2013. Compared with the baseline (PPR in March 2008), the risk ratio was only 0.11 [95 % confidence interval (CI), 0.09-0. 14) in November 2013, which is equal to an 89 % reduction in the malaria burden. Annual parasite incidence (API) across 19 Chinese border counties was reduced from 19.6 per 10 000 person-years in 2006 to 0.9 per 10 000 person-years in 2013. Compared with the baseline (API in 2006), the API rate ratio was only 0.05(95 % CI, 0.04-0.05) in 2013, which equates to a reduction of the malaria burden by 95.0 %. Meanwhile, the health service system was strengthened and health inequity of marginalized populations reduced along the international border. CONCLUSION: The effective collaboration between China, Myanmar and the international non-governmental organization promptly carried out the core interventions through simplified processes. The integrated approaches dramatically decreased malaria burden of Chinese-Myanmar border.

Investigation and control of a Plasmodium falciparum malaria outbreak in Shan Special Region II of Myanmar along the China-Myanmar Border from June to December 2014.

BACKGROUND: From 2007 to 2013, intensive control measures reduced malaria burden by 90 % along the China-Myanmar border. However, despite these measures a P. falciparum malaria outbreak was reported in the Shan Special Region II of Myanmar in June of 2014. METHODS: Epidemiological, parasitological and entomological investigations were performed. Dihydroartemisinin piperaquine (DAPQ) was immediately administered to treat parasite positive individuals. Long lasting insecticidal nets (LLIN), indoor residual spraying (IRS) with insecticides and behavior change communication (BCC) were also provided for outbreak control. An embedded efficacy study was conducted evaluating DP. Molecular genotyping via polymerase chain reaction (PCR) was performed on the Kelch gene on chromosome 13. RESULTS: All infections were identified as Plasmodium falciparum by RDT and microscopy. Two fatalities resulted from the outbreak. The attack rate was 72.8 % (67/92) and the incidence density rate was 14.2 per 100 person-weeks. The positive rate of rapid diagnostic test (RDT) was 72.2 % (65/90) and microscopically-determine parasite rate 42.2 % (38/90). Adjusted odds ratio (OR) of multivariate logistic regression analysis for aged <15 years, 15-45 years, inappropriate treatment from a private healer and lack of bed nets were 13.51 (95 % confidence interval, 2.21-105.89), 7.75 (1.48-44.97), 3.78 (1.30-46.18) and 3.21(1.21-15.19) respectively. In the six surrounding communities of the outbreak site, positive RDT rate was 1.2 % (4/328) and microscopically-determine parasite rate 0.6 % (2/328). Two light traps collected a total of 110 anopheline mosquitoes including local vectors, An. minimus, An. sinensis and An. maculates. After intensive control, the detection of malaria attacks, parasites and antigen were reduced to zero between July 1 and December 1, 2014. The cure rate of P. falciparum patients at day 42 was 94.3 % (95 % CI, 80.8-99.3 %). The PCR did not detect K13-propeller mutations. CONCLUSION: Imported P. falciparum caused the outbreak. Age, seeking inappropriate treatment and lack of bed nets were risk factors for infection during the outbreak. P. falciparum was sensitive to treatment with DAPQ. The integrated measures controlled the outbreak and prevented the spread of P. falciparum effectively. The results of this study indicate that malaria control on the China-Myanmar border, especially among special populations, needs further collaboration between China, Myanmar and international societies.

In vivo monitoring of dihydroartemisinin-piperaquine sensitivity in Plasmodium falciparum along the China-Myanmar border of Yunnan Province, China from 2007 to 2013.

BACKGROUND: Artemisinin-based combination therapy (ACT) is the recommended first-line treatment of falciparum malaria in all endemic countries. Artemisinin resistance in Plasmodium falciparum has been confirmed in the Greater Mekong subregion (GMS). Dihydroartemisinin-piperaquine (DAPQ) is the most commonly used ACT in China. To understand the DAPQ sensitivity of P. falciparum, DAPQ resistance was monitored in vivo along the China-Myanmar border from 2007 to 2013. METHODS: Eligible patients with mono-infections of P. falciparum were recruited to this study after obtaining full informed consent. DAPQ tablets for different categories of kg body weight ranges were given once a day for three days. Patients were followed up for 42 days. Polymerase chain reaction (PCR) was conducted to distinguish between re-infection and recrudescence, to confirm the Plasmodium species. The data were entered and analysed by the Kaplan-Meier method. Treatment outcome was assessed according to the WHO recommended standards. RESULTS: 243 patients were completed valid follow-up. The fever clearance time (FCT) and asexual parasite clearance times (APCT) were, respectively, 36.5 ± 10.9 and 43.5 ± 11.8 hours, and there was an increasing trend of both FCT (F = 268.41, P < 0.0001) and APCT (F = 88.6, P < 0.0001) from 2007 to 2013. Eight (3.3%, 95% confidence interval, 1.4-6.4%) patients present parasitaemia on day three after medication; however they were spontaneous cure on day four. 241 (99.2%; 95% CI, 97.1-99.9%) of the patients were adequate clinical and parasitological response (ACPR) and the proportions of ACPR had not changed significantly from 2007 to 2013 (X(2) = 2.81, P = 0.7288). CONCLUSION: In terms of efficacy, DAPQ is still an effective treatment for falciparum malaria. DAPQ sensitivity in P. falciparum had not significantly changed along the China-Myanmar border of Yunnan Province, China. However more attentions should be given to becoming slower fever and parasite clearance.

Lessons from malaria control to elimination: case study in Hainan and Yunnan provinces.

Reduction patterns of Plasmodium falciparum and P. vivax malaria transmission and the role of an integrated strategy of case management and vector control are compared between different ecological zones. The epidemiology of malaria in Hainan and Yunnan provinces was disparate, even though distinct malaria control strategies have been adapted to different situations based on risk group, vector behaviours, local health infrastructure, and environmental conditions. The island Hainan appears to be victorious in eliminating malaria. However, there is still a long way to go to prevent the reintroduction of malaria in Hainan province and eliminating malaria in the border areas of Yunnan province. This review of the experiences and challenges from malaria control to elimination in Hainan and Yunnan provinces of southern China will provide a basis for the future elimination of malaria in the whole country.

Monitoring Plasmodium vivax chloroquine sensitivity along China-Myanmar border of Yunnan Province, China during 2008-2013.

BACKGROUND: Plasmodium vivax is the most widespread of the malaria parasites infecting human hosts. In malaria-eliminating settings, both imported and local malaria predominantly occurs in border areas, and most of them are P. vivax. Chloroquine (CQ) is the first-line drug for P. vivax treatment in China. To understand CQ sensitivity in P. vivax, in vivo monitoring of CQ resistance was conducted along the China-Myanmar border from 2008 to 2013. METHODS: Eligible patients with mono-infections of P. vivax were recruited to this study after obtaining full informed consent. CQ tablets for different categories of kg body weight ranges were given once a day for three days. Patients were followed up for 28 days. PCR was conducted to distinguish between re-infection and recrudescence, to confirm the Plasmodium species. The data were entered and analysed by the Kaplan-Meier method. Treatment outcome and sensitivity were classified according to the WHO recommended standards. RESULTS: 603 patients were completed valid follow-up. The fever clearance time and asexual parasite clearance times were, respectively, 22.2 ± 10.2 and 38.1 ± 12.6 hours. 594 (98.5%) patients were adequate clinical and parasitological response (ACPR), and nine (1.5%) patients, who were late clinical failure (LCF) or resistant response level I (RI), were imported from the neighbouring districts of Myanmar. CONCLUSION: In terms of efficacy, CQ is still effective for vivax malaria treatment. Plasmodium vivax CQ sensitivity had not significantly changed along the China-Myanmar border of Yunnan Province, China.

Artemisinin-naphthoquine combination versus chloroquine-primaquine to treat vivax malaria: an open-label randomized and non-inferiority trial in Yunnan Province, China.

BACKGROUND: Plasmodium vivax is the main malaria parasite in China, and China is now making efforts to eliminate malaria by 2020. Radical cure of vivax malaria is one of challenges for malaria elimination. The purpose is to evaluate the efficacy and safety of artemisinin-naphthoquine (ANQ) versus chloroquine-primaquine (CQ-PQ) in treatment of vivax malaria in Yunnan Province, China. METHODS: An open-label randomized and non-inferiority design, eligible patients with monoinfections of P. vivax were randomly assigned to receive either a total target dose of ANQ 24.5 mg/kg (naphthoquine 7 mg/kg and artemisinin 17.5 mg/kg), once a day for three days, or a total CQ dose of 24 mg base/kg, once a day for three days plus a PQ dose of 0.45 mg base/kg/day, once a day for eight days. Patients were followed up for one year. The difference in efficacy between ANQ and CQ-PQ was compared via Wilson's test. RESULTS: By day 42, the number of patients free of recurrence was 125 (98.4%; 95% Confidence interval, 94.4-99.8%) for ANQ arm and 123 (96.1%; 95%CI, 91.1-98.7%) for CQ-PQ, and non-significant (P = 0.4496). By day 365, the number was 101 (79.5%; 95%CI, 71.8-85.9%) for ANQ and 106 (82.8%; 95%CI, 75.1-88.9%) for CQ-PQ, and non-significant (P = 0.610). So the proportions of patients free of recurrence had no significant difference between ANQ and CQ-PQ groups by day 28, 42 and 365; compared with CQ-PQ, the side effect of ANQ was mild. CONCLUSION: ANQ is non-inferior to CQ-PQ in terms of patients free of recurrence, and safer than CQ-PQ.

[Efficacy of compound dihydroartemisinin/piperaquine in treatment of uncomplicated falciparum malaria in Myanmar].

OBJECTIVE: To observe the therapeutic efficacy of compound dihydroartemisinin-piperaquine for treatment of uncomplicated falciparum malaria in Myanmar. METHODS: From 2007 to 2008, patients aged 6 to 60 years with uncomplicated P. falciparum infection and parasite density 500 to 200 000 parasites/microl were enrolled following an informed consent. A three-day course of total 8 tablets compound dihydroartemisinin-piperaquine was administered to an adult (each tablet containing 40 mg of dihydroartemisinin and 320 mg of piperaquine phosphate), dosage for children was based on ages (details in the treatment regimen) . The indices including fever subsiding time, parasite clearance time, asexual parasite clearance time and adverse clinical responses were observed and collected on days 7, 14, 21, and 28 after treatment. RESULTS: A total of 134 patients completed the treatment. The mean fever subsiding time and mean asexual parasite clearance time were (25.5 +/- 2.8) h and (39.5 +/- 7.8) h respectively. Asexual parasite clearance rate was 100% on day 7. Four cases recrudesced on day 28 and 16 cases had slight adverse clinical responses such as uncomfortable gastrointestinal tract, headache, nausea, vomit and diarrhea, which disappeared as soon as drug withdrawal. CONCLUSION: The compound dihydroartemisinin/piperaquine shows a sound efficacy in treating uncomplicated falciparum malaria

Spatio-temporal distribution of malaria in Yunnan Province, China.

The spatio-temporal distribution pattern of malaria in Yunnan Province, China was studied using a geographic information system technique. Both descriptive and temporal scan statistics revealed seasonal fluctuation in malaria incidences in Yunnan Province with only one peak during 1995-2000, and two apparent peaks from 2001 to 2005. Spatial autocorrelation analysis indicated that malaria incidence was not randomly distributed in the province. Further analysis using spatial scan statistics discovered that the high risk areas were mainly clustered at the bordering areas with Myanmar and Laos, and in Yuanjiang River Basin. There were obvious associations between Plasmodium vivax and Plasmodoium falciparum malaria incidences and climatic factors with a clear 1-month lagged effect, especially in cluster areas. All these could provide information on where and when malaria prevention and control measures would be applied. These findings imply that countermeasures should target high risk areas at suitable times, when climatic factors facilitate the transmission of malaria.

[Fluctuation in the resistance of Plasmodium falciparum to chloroquine in China].

OBJECTIVE: To investigate whether chloroquine-resistance of Plasmodium falciparum had changed after stopping or reducing the use of chloroquine as an antimalarial in Hainan and Yunnan provinces. METHODS: WHO standard in vitro microtest and 4-week in vivo test were used, assays were carried out in different time after stopping or reducing the use of chloroquine. RESULTS: In vitro test in Hainan indicated that the rate of chloroquine-resistant P. falciparum was 97.9% in 1981, and dropped to 26.7% in 1997 (P<0.01). The mean concentration of chloroquine for complete inhibition of schizont formation was 10.46 +/- 7.14 pmol/microl blood in 1981, decreased to 1.63 +/- 1.47 pmol/microl blood in 1997 (P<0.01). The proportion of samples taken from malaria cases that required high concentration (>6.4 pmol/microl blood) of chloroquine for complete inhibition of schizont formation was 83.3% in 1981 and only 6.7% in 1997 (P<0.01). In the 4-week in vivo test, the rate of chloroquine-resistant P. falciparum decreased from 84.2% in 1981 to 18.4% in 1997 (P<0.01). RIII cases accounted for 53.1% of the total resistant cases in 1981, and for 14.3% in 1997 (P<0.01). In vitro test in Yunnan revealed that the rate of chloroquine-resistant P. falciparum, the mean concentration of chloroquine for complete inhibition of schizont formation and the proportion of samples taken from malaria cases that required >6.4 pmol/microl blood of chloroquine for complete inhibition of schizont formation were 97.4%, 17.2 +/- 12.6 pmol/microl blood and 58.9% in 1981 respectively, and dropped to 70.4% (P< 0.01), 4.0 +/- 3.3 pmol/microl blood (P<0.01) and 16.6% (P<0.01) in 2002 respectively. CONCLUSION: The resistance of P. falciparum to chloroquine declined progressively after its use had been stopped or reduced in Hainan and Yunnan provinces.