Approach towards surveillance-based diagnosis of acute respiratory illness in India: Expert recommendations.

BACKGROUND: Emerging infectious diseases, often zoonotic, demand a collaborative "One-Health" surveillance approach due to human activities. The need for standardized diagnostic and surveillance algorithms is emphasized to address the difficulty in clinical differentiation and curb antimicrobial resistance. OBJECTIVE: The present recommendations are comprehensive diagnostic and surveillance algorithm for ARIs, developed by the Indian Council of Medical Research (ICMR), which aims to enhance early detection and treatment with improved surveillance. This algorithm shall be serving as a blueprint for respiratory infections landscape in the country and early detection of surge of respiratory infections in the country. CONTENT: The ICMR has risen up to the threat of emerging and re-emerging infections. Here, we seek to recommend a structured approach for diagnosing respiratory illnesses. The recommendations emphasize the significance of prioritizing respiratory pathogens based on factors such as the frequency of occurrence (seasonal or geographical), disease severity, ease of diagnosis and public health importance. The proposed surveillance-based diagnostic algorithm for ARI relies on a combination of gold-standard conventional methods, innovative serological and molecular techniques, as well as radiological approaches, which collectively contribute to the detection of various causative agents. The diagnostic part of the integrated algorithm can be dealt at the local microbiology laboratory of the healthcare facility with the few positive and negative specimens shipped to linked viral disease research laboratories (VRDLs) and other ICMR designated laboratories for genome characterisation, cluster identification and identification of novel agents.

An outbreak of Burkholderia cepacia bloodstream infections in a tertiary-care facility in northern India detected by a healthcare-associated infection surveillance network.

OBJECTIVE: The burden of healthcare-associated infections (HAIs) is higher in low- and middle-income countries, but HAIs are often missed because surveillance is not conducted. Here, we describe the identification of and response to a cluster of Burkholderia cepacia complex (BCC) bloodstream infections (BSIs) associated with high mortality in a surgical ICU (SICU) that joined an HAI surveillance network. SETTING: A 780-bed, tertiary-level, public teaching hospital in northern India. METHODS: After detecting a cluster of BCC in the SICU, cases were identified by reviewing laboratory registers and automated identification and susceptibility testing outputs. Sociodemographic details, clinical records, and potential exposure histories were collected, and a self-appraisal of infection prevention and control (IPC) practices using assessment tools from the World Health Organization and the US Centers for Disease Control and Prevention was conducted. Training and feedback were provided to hospital staff. Environmental samples were collected from high-touch surfaces, intravenous medications, saline, and mouthwash. RESULTS: Between October 2017 and October 2018, 183 BCC BSI cases were identified. Case records were available for 121 case patients. Of these 121 cases, 91 (75%) were male, the median age was 35 years, and 57 (47%) died. IPC scores were low in the areas of technical guidelines, human resources, and monitoring and evaluation. Of the 30 environmental samples, 4 grew BCC. A single source of the outbreak was not identified. CONCLUSIONS: Implementing standardized HAI surveillance in a low-resource setting detected an ongoing Burkholderia cepacia outbreak. The outbreak investigation and use of a multimodal approach reduced incident cases and informed changes in IPC practices.

Litchi consumption and missed meals continue to be associated with acute encephalopathy syndrome among children: an investigation of the 2019 outbreak in Muzaffarpur district, Bihar, India.

BACKGROUND: Muzaffarpur district in Bihar State of India recorded a resurgence of acute encephalopathy syndrome (AES) cases in the summer of 2019 after no reported outbreak in 3 y. Earlier studies generated evidence that litchi consumption and missing the previous evening's meal were associated with AES. We investigated the recent outbreak to understand the risk factors associated with AES. METHODS: We conducted a matched case-control study by comparing AES cases with healthy controls from case-households and the neighborhood community for risk factors like missing evening meal and litchi consumption before onset of AES. RESULTS: We recruited 61 cases and 239 controls. Compared with the community controls, case-patients were five times more likely to have reported eating litchi in the 7 d preceding the onset of illness (adjusted OR [AOR]=5.1; 95% CI 1.3 to 19) and skipping the previous evening's meal (AOR=5.2; 95% CI 1.4 to 20). Compared with household controls, case-patients were five times more likely to be children aged <5 y (AOR=5.3; 95% CI 1.3 to 22) and seven times more likely to have skipped the previous evening's meal (AOR=7.4; 95% CI 1.7 to 34). CONCLUSIONS: Skipping the previous evening's meal and litchi consumption were significantly associated with AES among children in Muzaffarpur and adjoining districts of Bihar.

An algorithmic approach to identifying the aetiology of acute encephalitis syndrome in India: results of a 4-year enhanced surveillance study.

BACKGROUND: Annual outbreaks of acute encephalitis syndrome pose a major health burden in India. Although Japanese encephalitis virus (JEV) accounts for around 15% of reported cases, the aetiology of most cases remains unknown. We aimed to establish an enhanced surveillance network and to use a standardised diagnostic algorithm to conduct a systematic evaluation of acute encephalitis syndrome in India. METHODS: In this large-scale, systematic surveillance study in India, patients presenting with acute encephalitis syndrome (ie, acute onset of fever with altered mental status, seizure, or both) to any of the 18 participating hospitals across Uttar Pradesh, West Bengal, and Assam were evaluated for JEV (serum and cerebrospinal fluid [CSF] IgM ELISA) per standard of care. In enhanced surveillance, JEV IgM-negative specimens were additionally evaluated for scrub typhus, dengue virus, and West Nile virus by serum IgM ELISA, and for Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, dengue virus, herpes simplex virus, and enterovirus by CSF PCR across five referral laboratories. In 2017, chikungunya and Leptospira serum IgM by ELISA and Zika virus serum and CSF by PCR were also tested. FINDINGS: Of 10 107 patients with acute encephalitis syndrome enrolled in enhanced surveillance between Jan 1, 2014, and Dec 31, 2017, 5734 (57·8%) of 9917 participants with available data were male and 6179 (62·7%) of 9856 were children aged 15 years and younger. Among patients who provided a sample of either CSF or serum in enhanced surveillance, an aetiology was identified in 1921 (33·2%) of 5786 patients enrolled between 2014 and 2016 and in 1484 (34·3%) of 4321 patients enrolled in 2017. The most commonly identified aetiologies were JEV (1023 [17·7%] of 5786 patients), scrub typhus (645 [18·5%] of 3489), and dengue virus (161 [5·2%] of 3124). Among participants who provided both CSF and serum specimens, an aetiology was identified in 1446 (38·3%) of 3774 patients enrolled between 2014 and 2016 and in 936 (40·3%) of 2324 enrolled in 2017, representing a 3·1-times increase in the number of patients with acute encephalitis syndrome with an identified aetiology compared with standard care alone (299 [12·9%]; p<0·0001). INTERPRETATION: Implementation of a systematic diagnostic algorithm in an enhanced surveillance platform resulted in a 3·1-times increase in identification of the aetiology of acute encephalitis syndrome, besides JEV alone, and highlighted the importance of scrub typhus and dengue virus as important infectious aetiologies in India. These findings have prompted revision of the national testing guidelines for this syndrome across India. FUNDING: US Centers for Disease Control and Prevention.

Shellfish poisoning outbreaks in Cuddalore District, Tamil Nadu, India.

BACKGROUND: Two suspected shellfish poisoning events were reported in Cuddalore District in Tamil Nadu, India, between January and April 2015. OBJECTIVES: The study was conducted to confirm the outbreaks and to identify the source and risk factors. METHODS: For both outbreaks, a case was defined as a person with nausea, vomiting, or dizziness. Sociodemographic details and symptoms were noted down. Data were also collected in a standard 3-day food frequency questionnaire, along with a collection of clam samples. A case-control study was initiated in the April outbreak. Stool samples were collected from cases, and clam vendors were interviewed. RESULTS: In an outbreak that happened in January, all the twenty people reported to be consumed clams were diagnosed as cases (100% attack rate, 100% exposure rate). In the April outbreak, we identified 199 cases (95% attack rate). In both outbreaks, the clams were identified as genus Meretrix meretrix. The most common reported symptoms were dizziness and vomiting. The clams heated and consumed within 30-60 min. No heavy metals or chemicals were detected in the clams, but assays for testing shellfish toxins were unavailable. All 64 selected cases reported clam consumption (100% exposure rate) as did 11 controls (17% exposure rate). Illness was associated with a history of eating of clams (odds ratio = 314, 95% confidence interval = 39-512). Of the six stool samples tested, all were culture negative for Salmonella, Shigella, and Vibrio cholerae. The water at both sites was contaminated with garbage and sewage. CONCLUSION: Coordinated and timely efforts by a multidisciplinary team of epidemiologists, marine biologists, and food safety officers led to the outbreaks' containment.

Outbreak investigation of foodborne illness among political rally attendees, Cuddalore, Tamil Nadu, India.

In July 2015, we investigated a foodborne illness outbreak in Sithalikuppam and Verupachi villages, Cuddalore district, Tamil Nadu, among the political rally attendees to determine the risk factors for illness. We conducted a retrospective cohort study, calculated risk ratio for the food exposures, and cultured stool specimens. Of 55 rally attendees, we identified 36 (65%) case patients; 32 (89%) had diarrhea and 20 (56%) had vomiting. Median incubation period was 14 h. Eighty-nine percent (32/36) of those who ate lemon rice at dinner had illness compared to 21% (4/19) of those who did not (RR 4.2). Of the six nonattendees who ate leftovers on July 25, all ate only lemon rice and became ill. Stool cultures were negative for Salmonella, Shigella, and Vibrio species. Lemon rice was probably contaminated with enterotoxins such as from Bacillus cereus. Our findings highlighted need for community food safety education and importance of thorough outbreak investigations.

Evaluation of a hospital-based surveillance system for birth defects in Chennai, India.

The Birth Defects Registry of India-Chennai (BDRI-C) was created in 2001 to monitor birth defects and provide timely referrals. Using established guidelines to evaluate surveillance systems, we examined the following attributes of BDRI-C to help strengthen the registry: simplicity, flexibility, data quality, representativeness, acceptability, timeliness, and stability. We reviewed BDRI-C documents, including reporting forms; interviewed key informants; and calculated data completeness, coverage, and reporting time. BDRI-C captured 14% of the births in Chennai April 2013 - March 2014. About 7% of institutions in Chennai registered in BDRI-C, and of those registered, 37% provided data in 2013. Median reporting time was 44 days after birth in 2013. BDRI-C is a useful, simple, flexible, and timely passive birth defects surveillance system; however, improvements can be made to ensure BDRI-C is representative of Chennai, data processing and quality checks are on-going, and the system is acceptable for member institutions and stable.

Multiple importations and transmission of colistin-resistant Klebsiella pneumoniae in a hospital in northern India.

OBJECTIVE: Resistance to colistin, a last resort antibiotic, has emerged in India. We investigated colistin-resistant Klebsiella pneumoniae(ColR-KP) in a hospital in India to describe infections, characterize resistance of isolates, compare concordance of detection methods, and identify transmission events. DESIGN: Retrospective observational study. METHODS: Case-patients were defined as individuals from whom ColR-KP was isolated from a clinical specimen between January 2016 and October 2017. Isolates resistant to colistin by Vitek 2 were confirmed by broth microdilution (BMD). Isolates underwent colistin susceptibility testing by disk diffusion and whole-genome sequencing. Medical records were reviewed. RESULTS: Of 846 K. pneumoniae isolates, 34 (4%) were colistin resistant. In total, 22 case-patients were identified. Most (90%) were male; their median age was 33 years. Half were transferred from another hospital; 45% died. Case-patients were admitted for a median of 14 days before detection of ColR-KP. Also, 7 case-patients (32%) received colistin before detection of ColR-KP. All isolates were resistant to carbapenems and susceptible to tigecycline. Isolates resistant to colistin by Vitek 2 were also resistant by BMD; 2 ColR-KP isolates were resistant by disk diffusion. Moreover, 8 multilocus sequence types were identified. Isolates were negative for mobile colistin resistance (mcr) genes. Based on sequencing analysis, in-hospital transmission may have occurred with 8 case-patients (38%). CONCLUSIONS: Multiple infections caused by highly resistant, mcr-negative ColR-KP with substantial mortality were identified. Disk diffusion correlated poorly with Vitek 2 and BMD for detection of ColR-KP. Sequencing indicated multiple importation and in-hospital transmission events. Enhanced detection for ColR-KP may be warranted in India.

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.

Risk Factors for Acquiring Scrub Typhus among Children in Deoria and Gorakhpur Districts, Uttar Pradesh, India, 2017.

Scrub typhus is associated with outbreaks of acute encephalitis syndrome in Uttar Pradesh, India. A case-control study indicated that children residing, playing, or visiting fields; living with firewood stored indoors; handling cattle fodder; and practicing open defecation were at increased risk for scrub typhus. Communication messages should focus on changing these behaviors.

Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control study.

BACKGROUND: Outbreaks of unexplained illness frequently remain under-investigated. In India, outbreaks of an acute neurological illness with high mortality among children occur annually in Muzaffarpur, the country's largest litchi cultivation region. In 2014, we aimed to investigate the cause and risk factors for this illness. METHODS: In this hospital-based surveillance and nested age-matched case-control study, we did laboratory investigations to assess potential infectious and non-infectious causes of this acute neurological illness. Cases were children aged 15 years or younger who were admitted to two hospitals in Muzaffarpur with new-onset seizures or altered sensorium. Age-matched controls were residents of Muzaffarpur who were admitted to the same two hospitals for a non-neurologic illness within seven days of the date of admission of the case. Clinical specimens (blood, cerebrospinal fluid, and urine) and environmental specimens (litchis) were tested for evidence of infectious pathogens, pesticides, toxic metals, and other non-infectious causes, including presence of hypoglycin A or methylenecyclopropylglycine (MCPG), naturally-occurring fruit-based toxins that cause hypoglycaemia and metabolic derangement. Matched and unmatched (controlling for age) bivariate analyses were done and risk factors for illness were expressed as matched odds ratios and odds ratios (unmatched analyses). FINDINGS: Between May 26, and July 17, 2014, 390 patients meeting the case definition were admitted to the two referral hospitals in Muzaffarpur, of whom 122 (31%) died. On admission, 204 (62%) of 327 had blood glucose concentration of 70 mg/dL or less. 104 cases were compared with 104 age-matched hospital controls. Litchi consumption (matched odds ratio [mOR] 9·6 [95% CI 3·6 - 24]) and absence of an evening meal (2·2 [1·2-4·3]) in the 24 h preceding illness onset were associated with illness. The absence of an evening meal significantly modified the effect of eating litchis on illness (odds ratio [OR] 7·8 [95% CI 3·3-18·8], without evening meal; OR 3·6 [1·1-11·1] with an evening meal). Tests for infectious agents and pesticides were negative. Metabolites of hypoglycin A, MCPG, or both were detected in 48 [66%] of 73 urine specimens from case-patients and none from 15 controls; 72 (90%) of 80 case-patient specimens had abnormal plasma acylcarnitine profiles, consistent with severe disruption of fatty acid metabolism. In 36 litchi arils tested from Muzaffarpur, hypoglycin A concentrations ranged from 12·4 µg/g to 152·0 µg/g and MCPG ranged from 44·9 µg/g to 220·0 µg/g. INTERPRETATION: Our investigation suggests an outbreak of acute encephalopathy in Muzaffarpur associated with both hypoglycin A and MCPG toxicity. To prevent illness and reduce mortality in the region, we recommended minimising litchi consumption, ensuring receipt of an evening meal and implementing rapid glucose correction for suspected illness. A comprehensive investigative approach in Muzaffarpur led to timely public health recommendations, underscoring the importance of using systematic methods in other unexplained illness outbreaks. FUNDING: US Centers for Disease Control and Prevention.

Outbreaks of unexplained neurologic illness - Muzaffarpur, India, 2013-2014.

Outbreaks of an unexplained acute neurologic illness affecting young children and associated with high case-fatality rates have been reported in the Muzaffarpur district of Bihar state in India since 1995. The outbreaks generally peak in June and decline weeks later with the onset of monsoon rains. There have been multiple epidemiologic and laboratory investigations of this syndrome, leading to a wide spectrum of proposed causes for the illness, including infectious encephalitis and exposure to pesticides. An association between illness and litchi fruit has been postulated because Muzaffarpur is a litchi fruit-producing region. To better characterize clinical and epidemiologic features of the illness that might suggest its cause and how it can be prevented, the Indian National Centre for Disease Control (NCDC) and CDC investigated outbreaks in 2013 and 2014. Clinical and laboratory findings in 2013 suggested a noninflammatory encephalopathy, possibly caused by a toxin. A common laboratory finding was low blood glucose (<70 mg/dL) on admission, a finding associated with a poorer outcome; 44% of all cases were fatal. An ongoing 2014 investigation has found no evidence of any infectious etiology and supports the possibility that exposure to a toxin might be the cause. The outbreak period coincides with the month-long litchi harvesting season in Muzaffarpur. Although a specific etiology has not yet been determined, the 2014 investigation has identified the illness as a hypoglycemic encephalopathy and confirmed the importance of ongoing laboratory evaluation of environmental toxins to identify a potential causative agent, including markers for methylenecyclopropylglycine (MCPG), a compound found in litchi seeds known to cause hypoglycemia in animal studies. Current public health recommendations are focused on reducing mortality by urging affected families to seek prompt medical care, and ensuring rapid assessment and correction of hypoglycemia in ill children.