|Ahead of print publication
Emergence of “urban scrub typhus” during Monsoon season in an urban pocket and biodiversity hotspot of New Delhi, India
Inam Danish Khan1, Pradeep Bahal2, Bhagwat Singh3, Pallawi Priya4, Rahul Pandey5, Anuradha Makkar6, Ashok Kumar Jindal7
1 Department of Clinical Microbiology and Infectious Diseases, Army College of Medical Sciences and Base Hospital, New Delhi, India
2 Department of Internal Medicine and Geriatric Medicine, Army College of Medical Sciences and Base Hospital, New Delhi, India
3 Army College of Medical Sciences, New Delhi, India
4 Calcutta Medical Research Institute and Belle Vue Clinic, Kolkata, West Bengal, India
5 Department of General Surgery, Army College of Medical Sciences and Base Hospital, New Delhi, India
6 Department of Microbiology, Army College of Medical Sciences and Base Hospital, Delhi, India
7 Commandant, army Hospital Research and Referral, New Delhi, India
|Date of Submission||30-Jun-2021|
|Date of Decision||30-Aug-2021|
|Date of Acceptance||04-Oct-2021|
|Date of Web Publication||01-Apr-2022|
Inam Danish Khan,
Command Hospital (Northern Command), Udhampur, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
Introduction: Scrub typhus is an endemic disease transmitted within the “epidemiological tetrad” of rains, rodents, chigger mites, and scrub vegetation prevalent in “Tsutsugamushi Asia-Pacific triangle,” predisposing one billion population at risk and annual incidence of one million. Scrub typhus is difficult to differentiate clinically from coendemic vector-borne acute undifferentiated febrile illness (AUFI). Untreated scrub typhus may cause disseminated vasculitis, serositis, and hemophagocytic syndrome. Outbreaks of scrub typhus have been reported from Thailand, China, Korea, and rural India. Transmission of scrub typhus in urban areas is relatively rare. Three consequent outbreaks in a urban pocket in New Delhi, India, highlight emergence of urban scrub typhus. Materials and Methods: A cross-sectional, clinicoepidemiological, ambispective outcome surveillance study was conducted among all clinicodemographically homogenous patients presenting with AUFI during 2016–2018. Clinically suspected or intuitively investigated scrub typhus was screened by IgM/IgG immunochromatography and confirmed through IgM enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Spatial, temporal, and vector surveillance through epidemiological mapping, line listing, and mite surveillance was done. Results: Scrub typhus outbreaks affected 161 patients during 2016–2018. Mean age was 31.77 ± 17 years. Most common clinical presentation was fever with headache. Eschar was present in 46.88% patients commonly on abdomen, chest, perineum, and extremities. Coinfections and comorbidities were seen in 3.75% and 14.37% patients, respectively. Seventy percent and 14.8% patients were managed in acute care and intensive care. Mean hospital stay was 8.96 ± 3.86 days. Doxycycline and doxycycline-azithromycin combination were given in 92.5% and 7.5% patients, respectively. All-cause mortality was 6.25%. 126/160 (78.75%) patients were geospatially distributed from urban landscape depicted in epidemiological maps. Temporal-seasonal distribution revealed bell-shaped curve from May to November. Mite carriage was seen in 16% rodents. Conclusion: Urban scrub typhus is emerging in microhabitats fulfilling the epidemiological tetrad and chigger mites undergoing transovarian transmission. Geospatial and temporal mapping are required in urban neighborhoods for risk stratification, outbreak management, vector control, and community education. A high index of suspicion in AUFI and early initiation of doxycycline therapy are required.
Keywords: 56 kDa, chigger, eschar, Orientia tsutsugamushi, outbreak, rodent, scrub typhus
|How to cite this URL:|
Khan ID, Bahal P, Singh B, Priya P, Pandey R, Makkar A, Jindal AK. Emergence of “urban scrub typhus” during Monsoon season in an urban pocket and biodiversity hotspot of New Delhi, India. J Mar Med Soc [Epub ahead of print] [cited 2022 Jul 7]. Available from: https://www.marinemedicalsociety.in/preprintarticle.asp?id=342370
| Introduction|| |
Scrub typhus/bush typhus/tsutsugamushi disease is a neglected endemic zoonoses of public health importance transmitted within the “epidemiological tetrad” of rodents, chigger mites, Orientia tsutsugamushi, and scrub vegetation prevalent in subtropical and tropical regions of the 13 million km2 “Tsutsugamushi Asia-Pacific triangle” comprising of Indian subcontinent, East-Asia, South-East Asia, and Northern-Australia, predisposing one billion population at risk.
Scrub typhus has classically been described as a geographically sequestered disease associated with outdoor activities in mite islands of rural countryside where vector-borne transmission of O. tsutsugamushi by trombiculid chigger mites results in annual incidence of one million patients. Scrub typhus has been a disease of military importance. The WHO reports it as the world's most under diagnosed, underrated, and under reported disease.,,
Scrub typhus is difficult to differentiate clinically from coendemic vector-borne acute undifferentiated febrile illness (AUFI) due to overlapping prodrome of abrupt high fever with chills, headache, maculopapular rash, myalgia, and lymphadenopathy. Scrub typhus causes disseminated vasculitis starting with eschar and progressing to vascular injury involving liver, brain, heart, kidney, pancreas, adrenals, thyroid, and lungs. Untreated scrub typhus may lead to disseminated intravascular coagulation causing vascular leak, serositis, hemophagocytic syndrome, and rapid deterioration.
Indian reports exhibit terrain diversity from deserts of Rajasthan; to plateaus, hills, and mountains in rural Maharashtra, Tamil Nadu, Karnataka, Pondicherry, Andhra Pradesh, Jammu, Himachal, Uttarakhand, Manipur, Assam, Sikkim; to plains of Bihar, West Bengal, and Kerala., Indian studies targeting rural populations have found high seroprevalence of reactive antibodies. Scrub typhus has also been reported from Thailand, China, and Korea.,, Transmission of scrub typhus in urban areas is relatively rare in world literature. In a first of its kind, this study characterizes the emergence of urban scrub typhus through three consequent outbreaks among residents of a urban pocket in New Delhi, India.
| Materials and Methods|| |
A cross-sectional, clinicoepidemiological, ambispective outcome surveillance study targeting clinical, laboratory, and outbreak surveillance/control for urban scrub typhus was conducted among all clinicodemographically homogenous patients presenting with AUFI excluding fevers of viral and protozoal etiology during the monsoon period of 3 consecutive years, 2016–2018, after approval from Institutional Ethics, Scientific and Biosafety Committee. All personal identifiers were anonymized for confidentiality of data.
Surveillance included clinicodemographic parameters, history of travel, occupation, socioeconomic status, clinical presentation, laboratory diagnostics, treatment, clinical outcome, and spatiotemporal and geographical epidemiological surveillance. Clinically, scrub typhus was considered in a patient having one or more clinical features comprising (a) fever, regional lymphadenopathy, maculopapular skin rash, myalgia, dry cough, headache, and abdominal discomfort; (b) primary punched out ulcer or eschar; (c) AUFI excluded for other etiology in which defervescence occurred within 48 h of tetracycline administration. Clinically suspected or intuitively investigated scrub typhus was screened by a single cut-off IgM and IgG antibody titer of ≥1:160 against a mixture of O. tsutsugamushi antigens Gilliam, Karp, Kato, and Boryong through rapid lateral flow immunochromatography simultaneously targeting IgM, IgG, and IgA of SD Bioline Tsutsugamushi (18FK10, 18Fk11) kit (Standard Diagnostics, South Korea) followed by confirmation by >0.5 optical density IgM enzyme-linked immunosorbent assay (ELISA) using recombinant p56 kDa type specific antigens (Inbios International, USA) and real-time polymerase chain reaction (qPCR) targeting type specific gene encoding major 56 kDa (Genome Diagnostics Pvt. Ltd, India). Immunochromatography and ELISA with preevaluated respective sensitivity and specificity of 66.7%, 98.4%, 82%, 98% were combined to achieve better diagnostic outcome for patient care. All guidelines for good clinical and clinical and laboratory practices were followed through the preanalytical, analytical, and postanalytical processes.
Clinical outcome was defined in terms of recovery or complication or mortality corroborated through timeline of onset, clinical features at presentation, comorbidities, postanalytical interpretations of diagnostic tests, hospital attendance, outpatient treatment/hospitalization, and follow-up. Altered mental state, seizure, intracranial hemorrhage, and/or infarct and acute encephalitis were defined as central nervous system complications. Lung infiltration with arterial PaO2/FiO2 ≤250, respiratory rate ≥30/min, acute respiratory distress, or requirement for mechanical ventilation was considered respiratory complications. Cardiac complications included arrhythmia, ischemic heart disease or myocarditis, as evident from abnormal serum troponin, creatine phosphokinase, electrocardiogram, or echocardiogram. Renal complications included serum creatinine ≥2 mg/dL or renal deterioration requiring renal replacement therapy. Septic shock was defined as requirement of parenteral vasopressor to maintain systolic blood pressure above 90 mmHg for more than 1 h. Preexisting comorbidities such as diabetes mellitus (DM), hypertension, cerebrovascular disease, chronic liver disease, coronary artery disease, chronic kidney disease (CKD), blood dyscrasias, bronchial asthma, and chronic obstructive lung disease were taken into account. Patients were treated by either twice daily doxycycline monotherapy (2.2 mg/kg body weight, maximum 200 mg/day for 7–15 days), or in combination with azithromycin 10 mg/kg body weight in appropriate dosage.
A tripronged spatiotemporal epidemiological surveillance was targeted at spatial, temporal, and vector surveillance. Epidemiological maps (line listing) were created on Map Marker version 2.13.3_278 (Package name: com.exlyo.mapmarker Version code: 289 Developer: theandroidseb) based on open-source Google map platform, exported as KML/KMZ files to Microsoft Word; accessed through https://www.mapmarker.app (Androidseb, France). Outbreak control measures included cutting of wild scrub vegetation in urban pockets during the peri-monsoon period, door-to-door surveillance, rodent control through Sherman traps or bromadialone poison cakes or zinc-phosphide and barium-carbonate baits or lithographic varnish, and increasing awareness on scrub typhus. Mite surveillance was done in 25 rodents. All patients were followed up for 6-month postrecovery. Clinicodemographic, surveillance, clinical, management, and outcome profile were correlated for descriptive statistics, including frequency, percentages, and 95% confidence intervals (95% CI).
| Results|| |
Scrub typhus outbreaks affected 21, 69, and 71 patients in 2016, 2017, and 2018, respectively. Age range was 1–72 years with mean age 31.77 ± 17 (95% CI: 29.1–34.4) years. Maximum patients were in the 26–40-year age group. Male:female ratio was 1.63:1 (2016), 2.9:1 (2017), and 2.58:1 (2018) with a total of 112/161 (69.57%, 95% CI: 61.75–76.44%) males and 49/161 (30.43%, 95% CI: 23.56–38.25%) females [Table 1]. All of them were urban residents residing within a vicinity radius of 10 km from the hospital. 12/161 (7.45%, 95% CI: 4.08–12.95%) belonged to high-income group whereas 149/161 (92.55%, 95% CI: 87.05–95.92%) belonged to middle-income group. 7/161 were preschool children, 38/161 were students, 32/161 were homemakers, 5/161 were retirees staying at home, and 79/161 were involved in urban occupations not involving exposure to mite islands. There was no history of travel to regions of high endemicity.
|Table 1: Clinicodemographic profile in three consecutive outbreaks of scrub typhus in New Delhi, India, from 2016 to 2018|
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Mean duration of clinical prodrome before hospital attendance was 6 ± 5.3 (95% CI: 5.18–6.82) days. Most common clinical presentation was fever (160/161) with headache (137/161). Eschar was present in 76/161, 47.20% (95% CI: 39.34–55.19%) patients [Figure 1]. Most common sites of eschar were abdomen, arms, chest, perineal region, and lower extremities. Eschar was also seen in axilla, mammary folds, and scrotum [Table 2]. Scrub typhus IgM was positive in all patients, both IgM and IgG in 53 patients and qPCR in all tested patients.
|Figure 1: Characterization of eschar in three consecutive outbreaks of scrub typhus in New Delhi, India, from 2016 to 2018|
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|Table 2: Clinical presentation in three consecutive outbreaks of scrub typhus in New Delhi, India, from 2016 to 2018|
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Coinfections in AUFI such as dengue (2), typhoid (4), and malaria (1) were seen in 6 (3.75%) patients. Comorbidities of hypertension, DM, CKD, chronic obstructive pulmonary disease, and neurological disorders were seen in 23 (14.37%) patients. Sixteen/161 (9.94%, 95% CI: 5.97%–15.9%) were seen as outpatients, 112/161 (69.57%, 95% CI: 61.75%–76.44%) were seen as acute care in-patients and 23/161 (14.29%, 95% CI: 9.46%–20.88%) under intensive care. Mean duration of hospital stay was 8.96 ± 3.86 (95% CI: 8.36–9.56) days. Good prognosis with uneventful outcome was seen in 33.33%, 71.01%, and 88.73% patients in 2016, 2017, and 2018, respectively [Figure 2]. 148/161 (91.93%, 95% CI: 86.31%–95.46%) were treated by doxycycline monotherapy while 12/161, 7.45% were treated with doxycycline plus azithromycin. Patients developing complications such as gastrointestinal hemorrhage (1), diffuse alveolar hemorrhage (1), acute renal failure (2), acute respiratory distress (2), acute liver damage (1), and myocarditis (1) were managed under intensive care with intravenous doxycycline. Both antimicrobials were well tolerated. All-cause mortality was 10/161 (6.21%, 95% CI: 3.19%–11.44%) during 2016–2018. No further complications or reinfections were found in treated patients during the 6-month follow-up period.
|Figure 2: Morbidity and mortality in three consecutive outbreaks of scrub typhus in New Delhi, India, from 2016 to 2018|
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126/161 (78.26%) patients were geospatially distributed from the urban landscape around the hospital, depicted in epidemiological maps [Figure 3]. Temporal and seasonal distribution was similar to bell-shaped curve from late May to early November with maximum patients during August, September, and October, corroborating with the monsoon season of 2016–2018 [Figure 4]. Mite surveillance conducted among 25 rodents revealed carriage of mites in 16% rodents in an area of 1.3 km × 1.8 km in the vicinity of the hospital.
|Figure 3: Geospatial mapping in two consecutive outbreaks of scrub typhus in New Delhi, India, from 2017 to 2018|
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|Figure 4: Temporal and seasonal distribution in three consecutive outbreaks of scrub typhus in New Delhi, India, from 2016 to 2018|
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| Discussion|| |
Outbreaks of urban scrub typhus have not yet been described in Indian scenario. While rural outbreaks of scrub typhus have been reported, these consecutive urban outbreaks highlight transgression of geospatial barriers and invasion of vector into urban landscape, depicting an epidemiological shift. Proximity of high-density urban populace in urban slums and unauthorized settlements, to green neighborhoods, wood piles, cattle sheds, rodent-infested dwellings, urban parks, and ridge reserve forests exemplifies higher outbreak potential which may remain under reported, undiagnosed and untreated. Activities such as gardening, resting or drying clothes on open grass, and open defecation increase transmission. The study population is completely urban with no contributory history of occupational or travel-related exposures, highlighting exposure from urban microhabitats in peri-monsoon season. Higher incidence in males aged 26–40 depicts higher professional/recreational activity. Urbanization of scrub typhus with similar clinical features described in this study has been reported in industrialized and developed metropolitan cities such as Seoul, Guangzhou, southern and eastern China, and northern and central Vietnam.,
Incubation period of scrub typhus is 6–21 days, which was reflected in patient attendance after mean 6 days of clinical prodrome. 15%–50% of AUFI may be attributable to scrub typhus in tropical regions. Despite an established simple and inexpensive treatment for scrub typhus, 30% patients suffer from high morbidity and consequent adverse prognosis due to systemic complications or preexisting comorbidities or coinfections or combinations. While complications are attributable to delay in presentation or diagnosis or treatment, coinfections and comorbidities rapidly desaturate patients with low physiological reserves. Urban scrub typhus is diagnosed early as observed in this study due to better healthcare accessibility and diagnostic intrepidity compared to rural scrub typhus which can present with complications. Median case fatality rate for untreated and treated patients is 6% and 1.4%. Early diagnosis and treatment aided by institutional SOP of mandatory screening of scrub typhus in all AUFI, improved prognosis from 2016 to 2018., Cotransmission of other tropical vector borne diseases with overlapping clinical presentation of fever, hemorrhagic, and neurological complications such as dengue, chikungunya, malaria, varicella, leptospirosis, severe fever with thrombocytopenia syndrome and typhoid mandates early diagnosis, treatment, environmental and policy intervention.,,
Diagnostic guidelines mention high fever with chills, rigors, and bodyaches with a history of rural outdoor activity as clinically suspected case to be presumptively treated with doxycycline for 5–7 days or azithromycin for 3–5 days. Cephalosporins and quinolones are contraindicated. Chemoprophylaxis can be achieved by doxycycline 200 mg single dose. Clinical correlates of eschar, centripetally distributed centrifugally spreading (5–10 days) maculopapular rash over upper trunk and forelimbs, and regional lymphadenopathy expedite clinical suspicion, early diagnosis, and empirical therapy. Eschar is considered as a pathognomonic painless necrotic ulcer observed where skin surfaces meet providing irritation and humid temperature inciting mite bite, demarcating the feeding site of chiggers and multiplication site of Orientia. Nevertheless, eschar can be confused with lesions in burns, gangrene, ulcer, fungal infection, spotted fever, spider bite wound, and anthrax. Eschars on axillary and mammary folds, back, scrotum, and perineal region may be unknown to patients and warrant thorough clinical examination in AUFI. Eschar and rash have not been found pathognomonic of urban scrub typhus despite the disease being the third most frequently notifiable disease in South Korea, which was observed in this study as well. Low prevalence of eschar has been reported from most Indian studies.
Oligosymptomatic patients not presenting with eschar and rash may be intuitively screened by immunochromatography. The gold standard for diagnosis of scrub typhus is IgM immunofluorescence assay, though IgM detected by combination of immunochromatography and ELISA becomes highly sensitive and specific. While IgM was positive in all patients, serological assays detecting cross-reactive antibodies in endemic areas may have limited reliability due to polymicrobial exposures by cotransmitted tropical pathogens sharing time, space, reservoirs and modes of transmission. Tropical endemicity can confer co-reactivity and/or cross-reactivity for dengue, malaria, typhoid, scrub typhus, Chlamydophila, and Mycoplasma; emphasizing empiricism of targeted therapies for broad-spectrum cover. Scrub typhus serotypes Gilliam, Karp, Kato, and Boryong may be discerned by genotypic identification and strain typing by nucleic acid amplification from eschar or blood. Many acute encephalitis syndromes, acute kidney injuries, and acute respiratory distress syndromes from India attributed to scrub typhus by seroepidemiological studies report mortality between <1% and 50%.,,
Infectious diseases evolve across complex amalgamation of social, economic, demographic, environmental, and microbiological factors. Sixty-one percent infectious diseases have zoonotic potential. India stands among the top 20 countries in global burden of zoonoses. Scrub typhus has been expanding across geographical barriers in a paradigm shift from its rural and semiurban expanse toward urban areas as witnessed by this study. The classical countryside mite islands associated with scrub typhus seem to get sequestrated in urban pockets and biodiversity hotspots due to destruction of microecosystems erstwhile unaltered by human activity. Chiggers generally thrive by feeding on rats in high relative humidity, low temperature, low sunlight, and a dense susbtrate vegetative canopy. Delhi-NCR (28° 38' 41.2800'' N, 77° 13' 0.1956'' E) has the world's second largest urban agglomeration with estimated population of 29 million in 2018 according to United Nations report 2018. With rapid urbanization, Delhi-NCR is slated to become the world's largest urban agglomeration overtaking Tokyo by 2028 with estimated 37.2 million population. Delhi-NCR is located at an altitude of 225 m/738 ft in a monsoon-influenced humid subtropical climate (Koppen Cwa) bordering a hot semi-arid climate (Koppen BSh) with temperatures between 0°C and 46°C. Urban ridge reserve forests, wild vegetation, and urban parks get inundated during monsoon and attract displaced arthropods, mammals, and avifauna creating concentrated microhabitats evolving into biodiversity hotspots and mite islands accessible to local residents, thereby facilitating occupational, vocational, recreational, and household exposures due to rodent migration, as depicted by mite surveillance in this study. A 100% efficient transovarial transmission helps persistence of Orientia in the unfavorable season. Chigger mites can also acquire Orientia from mammals such as stray animals and unmonitored livestock while co-feeding on the host with infected larva. The endemicity of scrub typhus in urban environments can render evolving epidemiological perspectives in terms of transmission and disease burden.
Scrub typhus is still a neglected tropical disease in India and not notifiable under the National Vector Borne Diseases Control Program, although it is notifiable with Integrated Disease Surveillance Project wherein provisions for diagnostic and treatment audit exists along with promotion of community education. Dynamic and static modeling strategies for delineating pathogen reservoirs, mite activity, pathogenicity of O. tsutsugamushi, clinical presentation in special hosts, rapid and specific diagnosis and treatment, and development of imumunoprophylaxis are required. Urban scrub typhus mandates risk management and targeted intervention to enhance preparedness and resilience capital in communities and affiliated health systems.
| Conclusion|| |
Urban Scrub typhus is emerging in microhabitats fulfilling the epidemiological tetrad and chigger mites undergoing transovarian transmission. Geospatial and temporal mapping is required in urban neighborhoods for risk stratification, outbreak management, vector control and community education. A high index of suspicion in AUFI, early differentiation from tropical vector-borne diseases, and early institution of doxycycline therapy is required to improve outcome.
The authors acknowledge the contributions and support of various clinicians and laboratory staff involved in patient care, diagnosis, and auxiliary support during the study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]