Are we prepared? Lessons from Covid-19 and OMAG position paper on epidemic preparedness.

Covid-19 has once again brought into focus our limited preparedness to deal with epidemics. Most nations, across the globe, have responded with a resolve to come stronger out of this crisis and leaderships across the world have shown great commitment to protecting its people from Covid-19. Covid-19 has also taught us a few things for the future. One such learning has been that a strong shift in focus towards non-communicable diseases driving health infrastructure across the globe for the last few decades has come at neglect of communicable diseases. In that sense, therefore, the current pandemic has been a wake-up call. Organised Medicine Academic Guild (OMAG), an umbrella organization of professional associations gathered a group of health experts to develop a policy document on epidemic preparedness to limit the influence of epidemics like Covid-19.

Insights from COVID-19 cluster containment in Bhilwara District, Rajasthan.

BACKGROUND: In March 2020, a healthcare professional from a renowned private hospital, in the textile city of Bhilwara, Rajasthan, reported clustering of cases of pneumonia amongst doctors and paramedical staff suspected to be due to COVID-19. The basis of suspicion was clinico-eco-epidemiologic-radiological findings as, by that time, about 20 COVID19 cases were reported from the state of Rajasthan including a big Italian group of tourists who travelled extensively in Rajasthan, including Udaipur city. OBJECTIVES: The current study presents the field experience of the Central and the State Rapid Response Teams (RRTs) in the cluster containment at Bhilwara. Methods: The information regarding the sociodemographic profile of the cases was provided by the Senior Medical Officer In-charge. The containment strategy was modeled under 6 pillars. Google Maps was used for preparing spot map. RESULTS: Immediate public health actions of cluster containment including contact tracing, quarantine, and isolation were initiated using epidemiological approach of mapping the cluster and taking care of reservoir of infection by the District Public Health Team supported by Multidisciplinary Rapid Response Team. This was supplemented by strict enforcement of lock down in the District taking care of daily need of the community by the leadership of administration with very strong intersectoral co-ordination (locally called "ruthless containment"). CONCLUSION: The forthcoming challenge resides in re-establishment of inter-district and inter-state travel, which can become a risk of re-entry of the new cases, which needs to be taken care of, with the help of stringent administrative measures and screening at all points of entry. The team in Bhilwara needs to remain vigilant to pick up any imported cases early before local transmission establishes.

Dengue virus is an under-recognised causative agent of acute encephalitis syndrome (AES): Results from a four year AES surveillance study of Japanese encephalitis in selected states of India.

BACKGROUND: Acute encephalitis syndrome (AES) surveillance in India has indicated that Japanese encephalitis virus (JEV) accounts for 5-35% of AES cases annually; the etiology remains unknown in the remaining cases. We implemented comprehensive AES surveillance to identify other etiological agents of AES, with emphasis on dengue virus. METHODS: Serum and cerebrospinal fluid (CSF) specimens were collected from patients enrolled prospectively in AES surveillance from 2014-2017 at selected sites of three high burden states of India. All samples were initially tested for JEV IgM. Specimens negative for JEV by serology were tested for IgM to scrub typhus, dengue virus (DEN), and West Nile virus; all JEV IgM-negative CSF samples were tested by PCR for S. pneumoniae, N. meningitidis, H. influenzae, herpes simplex virus type 1, enteroviruses and DEN. RESULTS: Of 10,107 AES patients, an etiology could be established in 49.2% of patients including JEV (16%), scrub typhus (16%) and DEN (5.2%) as the top three agents. Amongst the DEN positive cases (359/6892), seven (2%) were positive only for dengue virus RNA: one in serum and six in CSF. CONCLUSION: Amongst the pathogens identified, dengue accounted for 5% of all AES cases and was one of the three common etiological agents. These results underscore the importance of including dengue virus in routine testing of AES cases.

Visceral leishmaniasis cyclical trends in Bihar, India - implications for the elimination programme.

Background: Visceral leishmaniasis (VL) is a vector-borne disease of public health importance in India, with the highest burden of disease in the states of Bihar, Jharkhand, West Bengal and Uttar Pradesh. The disease is currently targeted for elimination (annual incidence to less than one per 10,000 population) using indoor residual spraying, active case detection and treatment. Historically the disease trend in India has been regarded as cyclical with case resurgence characteristically occurring every 15 years.  Understanding this pattern is essential if the VL elimination gains are to be sustained. To better understand the cyclical trends, annual climatic indicators including rainfall, temperature and humidity over time were compared with annual VL case incidence data.  Methods: Annual climate data (rainfall, average and maximum temperature and specific humidity) from 1956-2004 were used to identify potential factors influencing VL incidence.  Months relevant to the VL life-cycle were identified and defined (Monsoon, Sand-fly Peak, Pre-Sand-fly Peak and Annual) for analysis. The Kruskall-Wallis test was used to determine significant difference between categorical rainfall and VL incidence, whilst univariate negative binomial regression models were used to determine predictors of disease incidence. Results: The negative binomial regression model showed statistically significant associations (p <0.05) for VL incidence and maximum temperature, and average temperature, when considering annual and pre-sand fly peak time periods. No other associations between humidity, rainfall or temperature and VL incidence were detected (all values p >0.05).  Conclusion: The VL programme in Bihar has made significant progress in adopting best practices for improved treatment and vector control, with the aim to achieve VL elimination.  However, open access granular programme data for indoor residual spray activities and case detection is required to fully understand the role of climate in disease transmission and potential resurgence.

Malaria control in a tribal area of central India using existing tools.

Malaria is difficult to control in central India because of geographical terrain, efficient vectors, and perennial transmission of Plasmodium falciparum and socio-cultural practices of ethnic tribes. The objective was to develop a model to prevent and control malaria in hard to reach areas using existing tools. Baigachak (Tribe population 31,900) situated in Dindori district was undertaken for this study. Intervention measures used are indoor residual spray (IRS), long lasting insecticide treated bed nets (LLINs), prompt diagnosis and treatment along with intensive Information, Education and Communication (IEC) involving school children as agent of change. Door to door rapid fever surveys were carried out in the study area from 2009 to 14 and finger prick blood smears were made from all fever cases and examined under microscope. Mosquitoes were assayed for the presence of sporozoites by enzyme-linked immunosorbent assay (ELISA) technique and sibling species by polymerase chain reaction (PCR). There are two highly efficient vectors i.e. Anopheles culicifacies and An. fluviatilis. In monsoon season of 2009, the man hour density for An. culicifacies was 36.2 which declined to 10.9 during monsoon season of 2010-14 (t = 6.52; p < 0.0001). Epidemiological results revealed that malaria positivity was declined from 27% in 2009-3% in 2014 (Trend chi2 = 57.21; p < 0.0001) and P. falciparum declined from 23.6 to 2.4% (Trend chi2 = 48.33; p < 0.0001). Spleen rate was declined from 47% in 2009-5% in 2014 (χ2 for trend = 6.1; p = 0.0135). Baigachak has achieved a remarkable 89% reduction in malaria. This study confirms that the control strategies undertaken in this study are useful and should be extended at multiple sites for further validation.

Clinical and molecular monitoring of Plasmodium falciparum resistance to antimalarial drug (artesunate+sulphadoxine-pyrimethamine) in two highly malarious district of Madhya Pradesh, Central India from 2012-2014.

The spread of P. falciparum resistant strain has led to a significant resurgence of malaria morbidity and mortality. The current cornerstone in malaria treatment in India is Artemisinin based Combination (Artesunate + Sulphadoxine-Pyrimethamine) Therapy (ACT) for treatment of uncomplicated P. falciparum malaria since 2010. In the present study we assessed the therapeutic efficacy of ACT and molecular monitoring of antimalarial resistance. Therapeutic efficacy was determined by in vivo method using 28 days follow-up. Molecular genotyping of dihydrofolate reductase (dhfr), dihydropteroate synthase (dhps) and kelch13 genes were analyzed. msp-1 and msp-2 genotyping were used to differentiate recrudescence. Therapeutic efficacy of ACT was determined in 237 patients over the three year period. Most of the patients showed adequate clinical and parasitological response (99.6%). Molecular study revealed that 72% parasites were of mutant genotype (27.2% single mutants, 43.5% double mutants and 1.3% triple mutants) for pfdhfr while pfdhps showed 78.2% wild type alleles and 21.8% mutants (18.1% single mutants and 3.7% double mutants). Analysis of total 135 samples revealed mutation in k13 gene along with non-synonymous single mutation at codon M579T (1.5%) and double mutations at codon M579T & N657H in 37%. ACT remains effective for the treatment of uncomplicated P. falciparum malaria in Madhya Pradesh, Central India. However, increasing mutation in pfdhfr (particularly triple mutations) and pfdhps may reduce susceptibility to partner drug SP and mutation in k13 propeller gene, highlighting the need for continuous monitoring of the efficacy of ACT.

Epidemiology of Plasmodium vivax Malaria in India.

Historically, malaria in India was predominantly caused by Plasmodium vivax, accounting for 53% of the estimated cases. After the spread of drug-resistant Plasmodium falciparum in the 1990s, the prevalence of the two species remained equivalent at the national level for a decade. By 2014, the proportion of P. vivax has decreased to 34% nationally, but with high regional variation. In 2014, P. vivax accounted for around 380,000 malaria cases in India; almost a sixth of all P. vivax cases reported globally. Plasmodium vivax has remained resistant to control measures, particularly in urban areas. Urban malaria is predominantly caused by P. vivax and is subject to outbreaks, often associated with increased mortality, and triggered by bursts of migration and construction. The epidemiology of P. vivax varies substantially within India, including multiple relapse phenotypes with varying latencies between primary infection and relapse. Moreover, the hypnozoite reservoir maintains transmission potential and enables reestablishment of the parasite in areas in which it was thought eradicated. The burden of malaria in India is complex because of the highly variable malaria eco-epidemiological profiles, transmission factors, and the presence of multiple Plasmodium species and Anopheles vectors. This review of P. vivax malaria in India describes epidemiological trends with particular attention to four states: Gujarat, Karnataka, Haryana, and Odisha.

Monitoring the efficacy of antimalarial medicines in India via sentinel sites: Outcomes and risk factors for treatment failure.

BACKGROUND & OBJECTIVES: To combat the problem of antimalarial drug resistance, monitoring the changes in drug efficacy over time through periodic surveillance is essential. Since 2009, systematic and continuous monitoring is being done through nationwide sentinel site system. Potential early warning signs like partner drug resistance markers were also monitored in the clinical samples from the study areas. METHODS: A total of 1864 patients with acute uncomplicated malaria were enrolled in therapeutic efficacy studies of artesunate plus sulphadoxine-pyrimethamine (AS+SP) for Plasmodium falciparum; those infected with P. vivax were given chloroquine (CQ). Polymerase chain reaction (PCR) was used to distinguish post-treatment reinfection from treatment failures. Isolates of P. falciparum were also analysed for dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) gene mutations. RESULTS: Overall, 1687 (91.7%) patients completed the follow-up. In most of the falciparum patients the parasitaemia was cleared within 24 h of treatment, except 12 patients who remained parasite positive after 72 h. Presence of dhfr and dhps quintuple mutation was observed predominantly in treatment failure samples. A daily dose of artesunate of < 3 mg/kg of body weight, age of <5 yr, and fever at enrolment were associated with an increased risk of treatment failure. The AS+SP in P. falciparum was effective in > 95% cases in all the sentinel sites except in Northeastern region (NE). Chloroquine remained 100% efficacious in case of P. vivax infections. INTERPRETATION & CONCLUSION: Till 2012, India's national antimalarial drug resistance monitoring system proved highly efficacious and safe towards first-line antimalarials used in the country, except in Northeastern region where a decline in efficacy of AS+SP has been observed. This led to change in first-line treatment for P. falciparum to artemether-lumefantrine in Northeastern region.

Surveillance of artemisinin resistance in Plasmodium falciparum in India using the kelch13 molecular marker.

Malaria treatment in Southeast Asia is threatened with the emergence of artemisinin-resistant Plasmodium falciparum. Genome association studies have strongly linked a locus on P. falciparum chromosome 13 to artemisinin resistance, and recently, mutations in the kelch13 propeller region (Pfk-13) were strongly linked to resistance. To date, this information has not been shown in Indian samples. Pfk-13 mutations were assessed in samples from efficacy studies of artemisinin combination treatments in India. Samples were PCR amplified and sequenced from codon 427 to 727. Out of 384 samples, nonsynonymous mutations in the propeller region were found in four patients from the northeastern states, but their presence did not correlate with ACT treatment failures. This is the first report of Pfk-13 point mutations from India. Further phenotyping and genotyping studies are required to assess the status of artemisinin resistance in this region.

Declining efficacy of artesunate plus sulphadoxine-pyrimethamine in northeastern India.

BACKGROUND: Anti-malarial drug resistance in Plasmodium falciparum in India has historically travelled from northeast India along the Myanmar border. The treatment policy for P. falciparum in the region was, therefore, changed from chloroquine to artesunate (AS) plus sulphadoxine-pyrimethamine (SP) in selected areas in 2005 and in 2008 it became the first-line treatment. Recognizing that resistance to the partner drug can limit the useful life of this combination therapy, routine in vivo and molecular monitoring of anti-malarial drug efficacy through sentinel sites was initiated in 2009. METHODS: Between May and October 2012, 190 subjects with acute uncomplicated falciparum malaria were enrolled in therapeutic efficacy studies in the states of Arunachal Pradesh, Tripura, and Mizoram. Clinical and parasitological assessments were conducted over 42 days of follow-up. Multivariate analysis was used to determine risk factors associated with treatment failure. Genotyping was done to distinguish re-infection from recrudescence as well as to determine the prevalence of molecular markers of antifolate resistance among isolates. RESULTS: A total of 169 patients completed 42 days of follow-up at three sites. The crude and PCR-corrected Kaplan-Meier survival estimates of AS + SP were 60.8% (95% CI: 48.0-71.4) and 76.6% (95% CI: 64.1-85.2) in Gomati, Tripura; 74.6% (95% CI: 62.0-83.6) and 81.7% (95% CI: 69.4-89.5) in Lunglei, Mizoram; and, 59.5% (95% CI: 42.0-73.2) and 82.3% (95% CI: 64.6-91.6) in Changlang, Arunachal Pradesh. Most patients with P. falciparum cleared parasitaemia within 24 hours of treatment, but eight, including three patients who failed treatment, remained parasitaemic on day 3. Risk factors associated with treatment failure included age < five years, fever at the time of enrolment and AS under dosing. No adverse events were reported. Presence of dhfr plus dhps quintuple mutation was observed predominantly in treatment failure samples. CONCLUSION: AS + SP treatment failure was widespread in northeast India and exceeded the threshold for changing drug policy. Based on these results, in January 2013 the expert committee of the National Vector Borne Disease Control Programme formulated the first subnational drug policy for India and selected artemether plus lumefantrine as the new first-line treatment in the northeast. Continued monitoring of anti-malarial drug efficacy is essential for effective malaria control.

Improving malaria treatment and prevention in India by aiding district managers to manage their programmes with local information: a trial assessing the impact of Lot Quality Assurance Sampling on programme outcomes.

OBJECTIVES: This paper reports the first trial of Lot Quality Assurance Sampling (LQAS) assessing associations between access to LQAS data and subsequent improvements in district programming. This trial concerns India's approach to addressing an increase in malaria-attributable deaths by training community health workers to diagnose, treat and prevent malaria, while using LQAS to monitor sub-district performance and make programme improvements. METHODS: The Ministry of Health introduced LQAS into four matched high malaria burden districts (Annual Parasite Incidence >5) (N > 5 million). In each sub-district, we sampled four populations in three 6-monthly surveys: households, children <5 years, people with fever in the last 2 weeks and community health workers. In three districts, trained local staff collected, analysed and used data for programme management; in one control district, non-local staff collected data and did not disseminate results. For eight indicators, we calculated the change in proportion from survey one to three and used a Difference-in-Differences test to compare the relative change between intervention and control districts. RESULTS: Coverage increased from survey one to three for 24 of 32 comparisons. Difference-in-Differences tests revealed that intervention districts exhibited significantly greater change in four of six vertical strategies (insecticide treated bed-nets and indoor residual spraying), one of six treatment-seeking behaviours and four of 12 health worker capacity indicators. The control district displayed greater improvement than two intervention districts for one health worker capacity indicator. One district with poor management did not improve. CONCLUSIONS: In this study, LQAS results appeared to support district managers to increase coverage in underperforming areas, especially for vertical strategies in the presence of diligent managers.