Scrub typhus in rural Rajasthan and a review of other Indian studies Rupesh Masand, Ritesh Yadav, Alok Purohit, Balvir Singh Tomar Department of Paediatrics, National Institute of Medical Sciences, Jaipur, Rajasthan, India Abstract Background: Scrub typhus is an acute febrile illness which has been reported from various parts of India with Rajasthan recently joining the list of affected states. Aim: To report a series of paediatric scrub typhus cases from rural Rajasthan. Study design: Retrospective review of children with scrub typhus admitted to the wards and paediatric intensive care unit (PICU) of a tertiary-care hospital. Methods: The study was undertaken over an 8-month period from May to December 2013. All patients with a clinical presentation and/or serological confirmation of scrub typhus who tested negative for malaria, enteric fever, dengue, leptospirosis and urinary tract infection (UTI) were included. A range of investigations were undertaken including IgM-ELISA for scrub typhus, followed by appropriate medical management. Results: Thirty patients satisfied the inclusion criteria. The mean (SD, range) age of the patients was 8?56 (3?43, 3–16) years. The most common clinical features were fever (n530, 100%), headache (n520, 66%), myalgia (n515, 50%), hepatosplenomegaly (n518, 60%) and pallor (n55, 16%). Typical features such as eschar and rash were observed in only one (3?3%) and three (10%) patients, respectively; none had generalised lymphadenopathy or conjunctival congestion. IgM-ELISA for scrub typhus was positive in 28 patients (93?3%) and 27 responded to doxycycline within 24–72 hours. One of the three patients who required PICU support responded to intravenous chloramphenicol and, of the other two (6?6%), one died of acute respiratory distress syndrome and the other owing to acute renal failure. Conclusion: A high index of suspicion is essential for early diagnosis and prevention of complications in scrub typhus together with prompt referral from rural areas to a higher centre. Awareness of the disease manifestations may further help to prevent excessive investigations in patients presenting with non-specific febrile illness and reduce the economic burden to the family and society in resource-constrained settings. Keywords: Scrub typhus, Children, Rural, India

Introduction Scrub typhus is caused by Orientia tsutsugamushi (Japanese word: ‘tsutsuga’ meaning dangerous and ‘mushi’ meaning bug), an obligate intracellular bacterium of the Rickettsiaceae family which is transmitted to humans by the bite of the larva (chiggers) of the trombiculid mite.1 Infected chiggers are found particularly in areas of heavy ‘scrub’ vegetation during the rainy season when the mites lay eggs.2 In recent times, scrub typhus has emerged as one of the leading public health problems. It may present either as a non-specific febrile illness consisting of fever, rash, myalgia and headache, or with serious complications such as acute renal failure, acute respiratory distress syndrome (ARDS), encephalitis, hepatitis, circulatory collapse with haemorrhage,3–4 or even death if diagnosis or appropriate therapy is

Correspondence to: R Masand, Sector 4/467, Malviyanagar, Jaipur, Rajasthan 302017, India, email [email protected]

ß W. S. Maney & Son Ltd 2015

DOI 10.1179/2046905515Y.0000000004

delayed. It is widely endemic in a geographically confined area of the Asia-Pacific region, the so-called ‘tsutsugamushi triangle’ which is Japan, Taiwan, China, South Korea,5 Nepal, Northern Pakistan, Papua New Guinea and the Australian states of Queensland and Northern New South Wales.3 In the past, epidemics and several sporadic cases have been documented from various parts of India.6–22 There have been few reports of scrub typhus in Rajasthan, north-west India.23–25 It was first reported from the Alwar district in 2011. In 2013, an outbreak was officially reported from the rural areas of Alwar and adjoining Jaipur districts during the monsoon and post-monsoon months, i.e. July to October. Its occurrence in a state with an extremely dry climate and the fact that no studies of scrub typhus in children in this population have been published stimulated us to record the clinical and laboratory profile of patients admitted with scrub typhus from rural parts of the Alwar and Jaipur districts in Rajasthan.

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This observational, case series study was performed retrospectively to record the clinical and laboratory profile of scrub typhus patients admitted to the paediatric wards and PICU of NIMS Medical College and Hospital, Jaipur during May to December 2013. This tertiary health-care facility is in a rural area of Jaipur district, close to rural parts of the Alwar district in Rajasthan. Thirty patients with a clinical presentation and/or serological confirmation (positive IgM-ELISA) of scrub typhus who tested negative for malaria, enteric fever, dengue, leptospirosis and urinary tract infection were included. All clinical and laboratory data in the subjects’ medical records were entered into a structured proforma. Those with obvious symptoms and signs highly suggestive or diagnostic of a particular febrile illness (other than scrub typhus) and with chronic or recurrent febrile illness were excluded. A range of investigations in all patients included complete blood count, peripheral blood smear for malaria parasites, serum electrolytes, liver function tests, blood culture, IgM-ELISA for scrub typhus, malaria antigen, Widal test, dengue and leptospirosis serology, coagulation screen, urine culture, CSF examination and radiological studies (chest X-ray, abdominal ultrasonography), as per the requirements of each patient. Seven days after onset of symptoms, IgM-ELISA was performed on all study subjects using a commercial test kit (Bios International Inc., Seattle, WA, USA). The following criteria were used to diagnose ARDS, acute renal failure and acute hepatitis, respectively, which were complications in the study subjects: (i) ARDS: acute onset of non-cardiogenic pulmonary oedema manifesting with bilateral alveolar or interstitial infiltrates on chest radiograph and PaO2/FiO2 v200 mmHg on arterial blood gas analysis; (ii) acute renal failure: urine output v0?3 ml/kg/hour for 24 hours or anuria for the past 12 hours even after adequate rehydration; (iii) acute hepatitis: raised serum bilirubin w34?2 mmol/L and/or raised serum transaminases more than three times the upper limit of normal. The response to treatment, i.e. hours to defervescence of symptoms and other relevant data, were recorded in the proforma. Appropriate statistical analysis in the form of calculation of mean and standard deviation was performed wherever indicated. The study was approved by the Ethics Committee of NIMS Medical College.

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5 4

2 1

1 0

0 0 May

June

July

August September October November December Months

Figure 1 Monthly distribution of scrub typhus cases

Table 1 Clinical presentation of 30 patients diagnosed with scrub typhus Clinical features

Total cases n530 (%)

Age, y, mean (SD) [range] M:F ratio Symptoms: Fever Duration, days v7 7–10 10–14 Mean (SD) Headache Myalgia Abdominal pain Tachypnoea Vomiting Anuria Altered sensorium Diarrhoea Signs: Hepatosplenomegaly Pallor Pedal oedema Rash Eschar Anasarca Icterus

8?56 (3?4) [3–16] 2?3:1 30 (100) 5 (16) 14 (46) 11 (36) 9?3 (2?4) 20 (66) 15 (50) 5 (16) 4 (13) 3 (10) 1 (3) 1 (3) 0 18 (60) 5 (16) 3 (10) 3 (10) 1 (3) 1 (3) 1 (3)

No patient had conjunctival congestion or generalised lymphadenopathy

had generalised or localised lymphadenopathy. A comparative analysis of several studies from various parts of India6–22 and one from Thailand26 was undertaken (Table 2). The Indian reports were from central,17 south,18 north19 and east India.20 Laboratory investigations (Table 3) demonstrated anaemia (n518, 60%), leucocytosis (n512,40%) and thrombocytopenia (n58, 26%). Hypo-albuminaemia and hyponatraemia were observed exclusively in the three patients admitted to the PICU. All blood and urine cultures were sterile. IgM-ELISA for scrub typhus was positive in 28 cases (93?3%). A strong clinical suspicion in the remaining two cases prompted initiation of empirical doxycycline therapy. All patients presenting with non-specific febrile illness (n527) suggestive of scrub typhus were admitted to the paediatric wards and given

The mean (SD, range) of the 30 patients was 8?56 (3?43, 3–16) years and the M: F ratio was 2?3:1. Twenty-eight (93?1%) patients presented during July to October which is the monsoon and post-monsoon season in Rajasthan (Fig. 1) The clinical symptoms and signs are shown in Table 1. None of the patients

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Table 2 Comparative analysis of clinical presentation, complications and outcome with previous studies in India

Author Sample size Place of study Age range Mean age, y (SD) Clinical features, %: Fever Headache Hepatomegaly Splenomegaly Myalgia Pain abdomen Vomiting Altered sensorium z seizures Pallor Icterus Rash Eschar Lymphadenopathy Pedal oedema Anasarca Ascites Conjunctival congestion Complications

Mortality

Mahajan et al.20 n55 Himachal Pradesh 3 – 15 y 8?2 (4?6)

Gupta et al.21 n55

Sirisanthana et al.26 n530

This study n530

Karnataka 5 m – 12 y 5?6

Dingra et al.19 n520 Jammu & Kashmir 5 – 18 y –

Sikkim 5 – 12 y 8?2 (3?1)

Thailand 1?25 – 13 y 6?8

Rajasthan 3 – 16 y 8?56 (3?4)

100 Present 97?0 0 Present 0 0 28?0

100 5?5 69?4 50 16?6 5?5 19?4 2?7

100 0 76?0 76?0 0 23?8 0 19?0

100 40?0 40?0 40?0 40?0 20 100 40?0

100 40?0 60?0 60?0 0 0 0 20?0

100 0 73?0 23 0 0 10?0 3?0

100 66?0 60?0 60?0 50?0 16?0 10?0 0

0 0 43?0 22?0 78?0 87?0 74?0 74?0 52?0 Enceph. Pneumon. Gangrene ARFzother 13?0

50?1 2?7 55?5 55?0 8?3 38?8 27?7 16?6 2?7 Enceph. Gangrene Hepatitis

0 0 100 100 61?9 51?1 0 0 46?0 Enceph. GI bleed

20?0 0 0 0 40?0 40?0 0 0 0 Enceph.

100 0 20?0 20?0 0 80?0 20?0 20?0 20?0 ARDS

0 0 30 68?0 93?0 0 0 0 33?0 Pneumon. Meningitis

16?0 3?0 10?0 3?0 0 10?0 3?0 3?0 0 ARDS (2) ARF (1) Hepatitis (1)

0

0

Rathi et al.17 n523 Madhya Pradesh 8 m – 20 y 8?0

Ratageri et al.18 n536

0

0

0

6?6

Enceph, encephalitis; Pneumon, pneumonitis; ARDS, acute respiratory distress syndrome; ARF, acute renal failure; 0, not present; m, months; y, years; SD, standard deviation

Table 3 Laboratory profile of 30 patients Investigations Haemoglobin, g/dl Anaemia, g/dl (j9?0) Total leucocyte count |109/L Leucocytosis* Platelet count |109/L Thrombocytopenia (v100|109/L) C-reactive protein, mg/L Raised CRP (i8 mg/L) Serum albumin, g/L Hypo-albuminaemia (v30 g/L) S. alanine aminotransferase, U/L Raised alanine aminotransferase (i100 U/L) S. bilirubin, mmol/L S. bilirubin w34?2 mmol/L S. sodium, mmol/L Hyponatraemia (j130 mmol/L) S. creatinine, mmol/L Raised serum creatinine (w100 mmol/L) Positive IgM ELISA test

Normal range

Mean (range)

12–14 – 6?0–17?5 – 150–400 – 0?4–7?9 – 39–53 – 15–45 – 10?0–17?1 – 138–146 – 27–88 – –

9?6 (5?2–14?0) – 14?3 (4?6–24?1) – 120 (40–460) – 28?3 (5–80) – 35 (21–51) – 101?5 (30–457) – 15?9 (10–53) – 133?5 (122–141) – 104?4 (27–230) – –

n (%) 18 (60) 12 (40) 8 (26) 16 (53) 3 (10) 18 (60) – 1 (3?3) 3 (10) 1 (3?3) 28 (93?3)

CRP, C-reactive protein; *age-specific criteria are: 3 yrs w17?5|109/L, 4–7 yrs w15?5|109/L, 8–13 yrs w13?5|109/L, w13–16 yrs w11?0|109/L

doxycycline, 4 mg/kg/day orally divided into 12hourly doses (maximum 200 mg/day) for 10 days. Response to therapy in 27 patients (90%) including the two IgM ELISA-negative cases within 24–72 hours (mean 43) in the form of rapid defervescence of fever and improvement in their general condition strengthened the diagnosis. Three patients

with complications were admitted directly to the PICU and given i.v. chloramphenicol, 50– 100 mg/kg/day, divided into 6-hourly doses (maximum 4 g/24 hrs). Azithromycin, 10 mg/kg/day, once daily (maximum 500 mg/day) by nasogastric tube was added in two patients who had not responded to chloramphenicol alone after 48 hours of

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administration. All three patients required mechanical ventilation and whole blood transfusion, and one required peritoneal dialysis. One of these three who had ARDS and acute hepatitis responded to intravenous chloramphenicol 48 hours after administration and was subsequently discharged after 7 days. Although a combination of chloramphenicol and azithromycin was administered to the other two cases, one died (6?6%) of ARDS and the other of acute renal failure.

the study was conducted in a tertiary care centre delayed hospitalisation. Three cases who presented 10 days after onset of symptoms required PICU support for management of ARDS and acute renal failure. This highlights the need to raise awareness amongst general practitioners and for specific diagnostic tests to be available in rural areas so that patients can be referred as soon as possible. The absence of lymphadenopathy and conjunctival congestion and the presence of eschar and rash in only one and three cases, respectively, was unusual. This is similar to a Thai study which reported an absence of lymphadenopathy, conjunctival hyperaemia and eschar in their cases. The presence of rash was reported in only one of their 15 patients.33 The absence of a rash in a majority of the patients may be owing to its evanescent nature. As is evident in Table 2 the presentation, general course and prognosis of scrub typhus may vary considerably with infection probably by different serotypes of O. tsutsugamushi and the varied antigenic character of the endemic strain.34 None of the patients had a history of mite-bite. A small mite with a painless, non-itchy and hardly noticeable bite might be the explanation.35 The bite lesion usually enlarges, undergoes central necrosis and crusts to form a flat black eschar which is pathognomonic of scrub typhus.3 However, it is rarely seen in SouthEast Asia including the Indian subcontinent.7,9,12 In this series, an eschar was observed in only one patient. Variation in cutaneous immunity has been suggested as the reason for an absence of eschar in certain cases.36 The leucocyte count during early phase of scrub typhus is low or normal, which becomes elevated as the disease course progresses. Laboratory analysis demonstrated leucocytosis in 12 cases (40%) and leucopenia in none. However, previous studies in India and the US have observed leucocytosis in 30?0–89?5% of cases.18,37,38 Thrombocytopenia was observed in 26% of cases (eight) in this series which is similar to other Indian studies.18,38 In contrast, low platelet counts have been reported in 60% cases from the US.39 Hypo-albuminaemia, leucocytosis and hyponatraemia occurred in our three critically sick patients. Hypo-albuminaemia and leucocytosis are thought to be associated with severe scrub typhus,40,41 but this requires validation in a larger study sample. The isolation of O. tsutsugamushi requires mice or chick embryo or inoculation into tissue culture, but this is extremely hazardous26 and therefore cannot be used for diagnostic purposes. The indirect fluorescent assay (IFA), indirect immune-peroxidase (IIP) and PCR-based tests are considered to be the gold standard serological tests, but they require highly trained personnel, and the production of antigens might vary, leading to inconsistencies in interpreting results. Furthermore, owing to

Discussion Scrub typhus is an emerging disease in Rajasthan and was first reported from the Alwar district in 2011. Since then, there have been annual outbreaks during the monsoon and the post-monsoon period (July to October) with the worst affected districts being Alwar, Jaipur, Kota, Baran, Jhalawar and Bundi. Physicians including paediatricians in India do not usually include rickettsia infection in their differential diagnosis.17 This might be because of a lack of awareness, non-specific symptoms and signs or the unavailability of specific diagnostic laboratory tests;14 however, scrub typhus has been reported from different parts of India (Table 2).6–22 There have been few reports of scrub typhus in Rajasthan, and, to the best of our knowledge, this is the first report in children. If not diagnosed and treated promptly, scrub typhus can be fatal.27,28 Age at presentation ranged from 3–16 years with a mean (SD) age of 8?6 (3?4) years and a male preponderance of 2?3:1. Comparison with other Indian studies 17–21 demonstrated the presence of scrub typhus in children of all ages (Table 2). Two studies17,18 reported the disease in infants. Vertical transmission from transplacental infection in acute febrile illness during pregnancy and perinatal bloodborne infection during labour can cause scrub typhus in neonates also.29 Scrub typhus is common in rural areas. All the patients were from the rural areas of the Alwar and Jaipur districts in Rajasthan and defaecated in open fields which made them vulnerable to chigger bite.21 Similar to a Darjeeling study,30 a large number of cases presented during July to October when there is significant rainfall. One Thai study31 reported a large number of field rodents infected by O. tsutsugamushi owing to more chiggers attached to their bodies during the rainy season, thus explaining the clustering of cases. Moreover, there is growth of secondary ‘scrub’ vegetation which is the habitat for trombiculid mites (mite ‘islands’),32 which is why the disease is called ‘scrub typhus ’. Mean (SD) interval between onset of symptoms and hospitalisation was 9?0 (3?74) days. The nonspecific nature of the symptoms and the fact that

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exorbitant costs, they are beyond the reach of most patients in India. The Weil–Felix test is the cheapest test available and is used when serological facilities are unavailable. Although not very sensitive, when positive, it is highly specific.14,42 As IFA or IIP are not available in our institution, ELISA for testing IgM antibodies against O. tsutsugamushi was employed for diagnosis. Primary infection produces a rapid rise in IgM antibodies within 8 days, whereas secondary infection is characterised by a sharp rise in IgG levels, with a variable IgM response. The test kit for diagnosis has been shown to be 91% sensitive and 100% specific.43 However, indigenous strains need to be incorporated in these test kits for their adaptation to the various Indian conditions. Complications of scrub typhus develop after the first week of illness and are directly related to the blood load of O. tsutsugamushi.44 In this study, complications were observed in three cases (10%): ARDS in two (6?6%) and acute renal failure and acute hepatitis in one case (3?3%) each. In a Taiwan study,45 11?1% of scrub typhus patients developed ARDS and the mortality rate of those patients was 25%. However, in a Thai study,26 ARDS was not observed as a complication despite the presence of pneumonitis. Before being hospitalised and diagnosed, 27 study subjects received amoxicillin (n518) or cefixime (n59) orally from local practitioners. The remaining three cases were receiving daily parenteral ceftriaxone before referral. After admission in this hospital, specific treatment was initiated and 27 patients responded to doxycycline therapy; these were patients who presented within 10 days of onset of symptoms. Doxycycline can be safely administered to children under 8 years of age as it has not been shown to stain the developing secondary teeth when used in the dose and duration recommended for rickettsia infection.46–48 Three cases presenting with complications were managed in the PICU with intravenous chloramphenicol initially, followed by the addition of azithromycin (n52) and supportive measures including mechanical ventilation. One case with ARDS and acute hepatitis survived and was subsequently discharged. This is similar to other studies,26,33 although cases of scrub typhus resistant to doxycycline and chloramphenicol have been reported recently from Thailand.49 Azithromycin is effective in doxycycline-resistant strains and can be used in children.50,51 One trial has speculated the role of rifampin in treating such poorly responsive cases.52 In a retrospective analysis of Korean children with scrub typhus, roxithromycin was found to be as effective as doxycycline or chloramphenicol, thus suggesting its role as an alternative therapy.53

Scrub typhus in rural Rajasthan

Although the case fatality rate reported for scrub typhus varies from 14% in India54 to 15–30% in Taiwan and 10% in Korea,55 it was observed to be 6?6% (n52) in this study (Table 2) in which patients, having received treatment from local practitioners, presented late with complications. Studies have shown inter-strain variability in virulence,56 and since serotyping and genotyping were not done, it can be speculated that the strain present in this region may be less virulent. The limitations of the study were that it was retrospective rather than prospective. During the outbreak, all the study subjects were examined by several doctors after hospitalisation which might have led to errors in observing and recording clinical data. A high index of suspicion is essential for early diagnosis and prevention of complications of scrub typhus in children and for expediting referral to higher centres. Awareness of the disease manifestations may further help to prevent excessive investigation of patients presenting with non-specific febrile illness and also lower the economic burden on the family and society in resource-constrained settings.

Disclaimer Statements Contributors The authors Contributed equally.

Funding None.

Conflicts of interest None.

Ethics approval Approval to perform this study was provided by the Institutional Ethics Committee of NIMS Medical College, Jaipur, Rajasthan, India after review of the methodology.

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Scrub typhus in rural Rajasthan and a review of other Indian studies.

Scrub typhus is an acute febrile illness which has been reported from various parts of India with Rajasthan recently joining the list of affected stat...
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