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PLoS Negl Trop Dis. 2022 Nov; 16(11): e0010952.
Published online 2022 Nov 28. doi: 10.1371/journal.pntd.0010952
PMCID: PMC9731453
PMID: 36441812

Neurological manifestations of scrub typhus infection: A systematic review and meta-analysis of clinical features and case fatality

Ali M. Alam, Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing,corresponding author 1 , 2 ,* Conor S. Gillespie, Formal analysis, Methodology, Validation, Writing – review & editing, 3 Jack Goodall, Conceptualization, Supervision, Validation, Writing – original draft, Writing – review & editing, 4 Tina Damodar, Supervision, Writing – original draft, Writing – review & editing, 5 Lance Turtle, Supervision, Writing – review & editing, 4 , 6 , 7 Ravi Vasanthapuram, Supervision, Writing – review & editing, 5 Tom Solomon, Supervision, Writing – review & editing, 6 , 7 and Benedict D. Michael, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing 1 , 7 , 8
Joseph Raymond Zunt, Editor
Author information Article notes Copyright and License information PMC Disclaimer

Associated Data

Supplementary Materials
Data Availability Statement

Abstract

Background

Scrub typhus has become a leading cause of central nervous system (CNS) infection in endemic regions. As a treatable condition, prompt recognition is vital. However, few studies have focused on describing the symptomology and outcomes of neurological scrub typhus infection. We conducted a systematic review and meta-analysis to report the clinical features and case fatality ratio (CFR) in patients with CNS scrub typhus infection.

Methods

A search and analysis plan was published in PROSPERO [ID 328732]. A systematic search of PubMed and Scopus was performed and studies describing patients with CNS manifestations of proven scrub typhus infection were included. The outcomes studied were weighted pooled prevalence (WPP) of clinical features during illness and weighted CFR.

Results

Nineteen studies with 1,221 (656 adults and 565 paediatric) patients were included. The most common clinical features in CNS scrub typhus were those consistent with non-specific acute encephalitis syndromes (AES), such as fever (WPP 100.0% [99.5%-100.0%, I2 = 47.8%]), altered sensorium (67.4% [54.9–78.8%, I2 = 93.3%]), headache (65.0% [51.5–77.6%, I2 = 95.1%]) and neck stiffness 56.6% (29.4–80.4%, I2 = 96.3%). Classical features of scrub typhus were infrequently identified; an eschar was found in only 20.8% (9.8%-34.3%, I2 = 95.4%) and lymphadenopathy in 24.1% (95% CI 11.8% - 38.9%, I2 = 87.8%). The pooled CFR (95% CI) was 3.6% (1.5%– 6.4%, I2 = 67.3%). Paediatric cohorts had a CFR of 6.1% (1.9–12.1%, I2 = 77%) whilst adult cohorts reported 2.6% (0.7–5.3%, I2 = 43%).

Conclusion

Our meta-analyses illustrate that 3.6% of patients with CNS manifestations of scrub typhus die. Clinicians should have a high index of suspicion for scrub typhus in patients presenting with AES in endemic regions and consider starting empiric treatment whilst awaiting results of investigations, even in the absence of classical signs such as an eschar or lymphadenopathy.

Author summary

Scrub typhus is a leading cause of acute encephalitis syndrome in endemic regions, but its clinical features and case fatality rate are not yet fully described. We conducted a systemic review and meta-analysis and found that adults with neurological scrub typhus commonly present with headache and neck stiffness, whilst children present with altered sensorium and seizure activity. Signs classically associated with scrub typhus such as eschar and lymphadenopathy were not commonly reported. Just under 4% of patients with neurological manifestations of scrub typhus die in hospital, and the case fatality rate may be higher in children. Clinicians should have a low threshold to start empiric treatment for scrub typhus when patients present with neurological infections in endemic regions.

Introduction

Scrub typhus is a zoonotic rickettsial illness caused by the bacteria Orientia tsutsugamushi. It is transmitted through larvae (chiggers) of Leptotrombidium mites and is endemic to a region termed the tsutsugamushi triangle, which spans from south-eastern Asia to the pacific [1]. Chigger bites may result in the pathognomonic eschar forming on the skin [2], and other early symptoms of scrub typhus can range from an acute febrile illness to fulminant multi-organ failure [3].

The central nervous system (CNS) can often be affected in scrub typhus, with neurological manifestations being present in roughly 20% of cases, either in the form of acute encephalitis, meningitis, or as meningoencephalitis [4]. An estimated one million cases of scrub typhus occur annually in the tsutsugamushi triangle [5]. As a result, recent epidemiological studies have suggested that scrub typhus is now a leading cause of CNS infections in endemic regions [6–8]. As changing ecology may increase the prevalence of arthropod-borne CNS infections populations globally [9], neurological manifestations of scrub typhus may become an emerging public health beyond current endemic regions.

Globally, few studies have reported the case fatality rate of scrub typhus infection, and even fewer describe the proportions of patients with specific neurological symptoms of the disease. A systematic review on untreated scrub typhus infection suggests a mortality of 6%[5]. However, given that the administration of easily accessible antibiotics leads to considerably improved outcomes, overall mortality rates have the potential to be considerably lower [4]. Delayed treatment can, on the other hand, contribute to significant neurological sequela or even death [10]. Prompt antibiotic therapy relies on early recognition of scrub typhus. Though small, single-site studies from a select few geographical regions have reported the clinical features CNS scrub typhus [8,11–29], these have not been systematically analysed to help understand when clinicians should consider a diagnosis of scrub typhus CNS disease.

We aimed to evaluate the clinical features and case fatality ratio (CFR) of scrub typhus with neurological manifestations through a meta-analysis of published studies. Our objective was to elucidate clinical features that should increase suspicion and therefore prompt empiric treatment of scrub typhus in patients presenting with syndromes of CNS infection.

Methods

Search strategy and selection criteria

We conducted a systematic review and meta-analysis of studies investigating neurological manifestations of scrub typhus. We undertook a literature search of PubMed (MEDLINE) and Scopus for English language peer-reviewed primary research articles published between 1st January 2000 and 22nd April 2022. We chose these dates as they both reflect modern scrub typhus management and ease of access to serological tests [30]. Key search terms included scrub typhus, Orientia tsutsugamushi, central nervous system, meningitis, encephalitis, and meningoencephalitis (the full search strategy is supplied in S1 Table).

We included studies reporting the hospital mortality of patients with neurological manifestations of scrub typhus. Patients of any age were included if they had either meningitis, encephalitis, encephalopathy, or meningoencephalitis. We excluded studies which were case reports, case series, review articles, conference abstracts and letters. Studies with case numbers below 10 and those not reporting demographic features of their cohorts were excluded to reduce sampling bias (S2 Table).

Titles and abstracts from each database search were imported into EndNote X8 (Clarivate Analytics, Philadelphia, USA) and duplicates were removed. The remaining studies were uploaded to Rayyan (Qatar Computing Research Institute, Doha, Qatar) for screening. Screening of titles and abstracts and subsequent full-texts manuscripts were undertaken in parallel by two authors (AMA and CSG) and conflicts were resolved through consensus. Data were then extracted by the two authors (AMA and CSG). We collected study cohort characteristics and outcomes (a full list of collected data are supplied in S3 Table). Authors of screened articles were contacted to provide additional information when otherwise absent from the publication.

Diagnosis

Scrub typhus infection was defined as cases confirmed by indirect serology (which included IgM enzyme-linked immunosorbent assay [ELISA], immunofluorescence assay [IFA], immunochromatographic test [ICT] and the Weil–Felix test) or direct diagnosis through polymerase chain reaction [PCR]. Patients with co-infections were excluded. Whilst IFA is considered the gold standard for serological diagnosis, IgM ELISA is more commonly used as it requires no sophisticated instrument facilities, whilst still being a robust diagnostic tool in scrub typhus [31]. In comparison, the Weil Felix test have been reported to show lower specificity and should only be considered significant at higher serum titres [32]. Despite this, the Weil-Felix test is still used in smaller laboratories for screening of scrub typhus in rural areas and can be a useful diagnostic tool in the correct context [33,34]. We conducted sensitivity analysis to explore if the meta-analyses were sensitive to the exclusion of papers using the Weil-Felix test for diagnosis of scrub typhus.

Outcomes

The primary aim of our meta-analyses was to study the prevalence of the clinical features seen in patients with neurological manifestation of scrub typhus. Secondly, we estimate a weighted CFR by dividing the number of deaths by the number of patients with proven CNS scrub typhus infections.

Quality assessment

Quality assessment of individual studies was completed by two authors (AMA and CSG) using a point scale based on the CASP tool for cohort studies [35]. We scored studies on five main aspects: study design and methodology (0–2 points), quality of adjustment for confounding factors (0–2 points), definition of outcome (0–2 points), and quality of data (0–3 points). A maximum of 10 points represented the lowest risk of bias and high methodological quality, whilst a score over 6 was deemed to have low risk of bias, a score of 4–6 as moderate and less than 4 as high risk (S4 Table).

This study followed the guidelines published by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)[36]. We registered our study protocol prospectively on PROSPERO (ID 328732).

Statistical analysis

All statistical analyses including meta-analysis was completed using R version 4.0 (R Foundation for Statistical Computing, Vienna, Austria). We used the DerSimonian-Laird random-effects model to report prevalence of clinical variables and weighted pooled CFR. A Freeman-Tukey double arcsine transformation was applied to our data. We conducted sub-group analyses in paediatric (defined as studies solely recruiting patients aged <16 years or from paediatric hospitals) and adult cohorts (defined as studies recruiting patients from general hospitals). Forest plots were generated with natural scales, and heterogeneity was assessed using Cochran’s Q test and I2, whilst Egger’s test was used to test for publication bias.

Results

Our search strategy identified 714 records, of which 206 were duplicates. We screened 508 abstracts for inclusion, and of these 148 proceeded to full-text screening. We excluded 129 studies, resulting in 19 eligible studies for meta-analyses (Fig 1).

Included studies and risk of bias assessment

The 19 included studies were published from 2013 to 2020, reflecting 1,221 patients. The studies were from 3 countries, with 15 from India of 1,124 (92.1%) patients, 1 from Laos of 31 (2.5%) patients, 2 from South Korea of 38 (3.1%) patients and 1 from an unspecified country of 28 (2.3%) patients. Most studies recruited patients in tertiary hospitals (12/19, 63.1%), with 4 (21.1%) recruiting their cohorts from teaching hospitals. There was 1 (5.3%) multicentre study, and 2 (10.5%) studies recruited patients from unspecified units. Of the 19 studies, 11 (57.8%) studies were prospective cohorts, 7 (36.8%) were retrospective cohorts and 2 (10.5%) were cross-sectional studies. Over half of the studies (10/19, 52.9%) included patients with a diagnosis of meningoencephalitis, 6 (31.6%) included those with a diagnosis of meningitis and 3 (15.8%) included patients with encephalitis. Only 12 (63.2%) studies specified the treatment provided to their cohorts. Most studies (12/19, 63.2%) were conducted on an adult cohort whilst the remainder (7/19, 36.8%) specifically recruited in paediatric settings. The mean [SD] study enrolment period was 34.8 [27.8] months.

When conducting quality assessment of the studies, 3 studies had an overall high risk of bias, 11 had moderate risk and 5 had low risk (Fig 2 and S3 Table).

An external file that holds a picture, illustration, etc. Object name is pntd.0010952.g002.jpg
Quality assessment for the risk of bias in the 19 included studies for meta-analyses.

Demographics of included cases

Overall, 1,221 patients with neurological manifestations of scrub typhus were included in the analysis (Table 1). Of these, 656 (53.7%) were adults and 565 (46.3%) were paediatric patients. The mean (SD) age was 29.1 (19.0) and 573 (46.9%) were female. Patients presented to hospital after a median (IQR) duration of symptoms of 7.9 (7.0–9.2) days and had a median (IQR) Glasgow coma scale (GCS) score of 11/15 (9–15). Complete treatment data were available for 859 cases of whom 389 (45.3%) were treated with doxycycline monotherapy and 379 (44.1%) with azithromycin only. Combination therapy of more than one antibiotic was given to 82 (9.5%) patients. A handful received chloramphenicol or rifampicin (four and five respectively).

Table 1

General characteristics of included studies for meta-analyses; * = specification of treatment strategy required reporting of what antibiotics (if any) were given to enrolled patients; PCR = polymerase chain reaction; ELISA = enzyme-linked immunosorbent assay, IFA = immunofluorescence assay, ICT = immunochromatographic test, PCR = polymerase chain reaction, WFT = Weil–Felix test.
StudyCountryStudy designStudy settingStudy cohort populationStudy enrolment periodNumber of patientsMedian or mean age (SD) [IQR]Number of females (%)Number of deaths (%)Diagnostic testSpecified treatment strategy*
Kim 2013 [20]South KoreaRetrospective cohortTertiary hospitalMixed2004–20082270.2 (Not specified)14 (62.6%)0 (0.0%)PCRYes
Viswanathan 2013 [29]IndiaRetrospective cohortUnspecifiedMixed2011–20121741.8 (17.7)7 (41.2%)0 (0.0%)IgM ELISA or WFTYes
Misra 2014 [21]IndiaCross sectionalTertiary hospitalMixed2012–20133737.7 [3 – 71]19 (51.4%)0 (0.0%)ICT or WFTYes
Dittrich 2015 [17]LaosProspective studyTertiary hospitalMixed2003–20113116.0 [8.0–30.0]9 (29.0%)3 (1.0%)IFANo
Abhilash 2015 [11]IndiaRetrospective cohortTertiary hospitalMixed2005–201118941.0 (6.3)81 (42.9%)11 (5.8%)IgM ELISAYes
Sharma 2015 [26]IndiaProspective studyTertiary hospitalMixed2009–20112339.5 [Not specified]10 (43.5%)0 (0.0%)WFTYes
Jamil 2015 [19]IndiaProspective studyTertiary hospitalMixed2013–20141334.8 (16.2)5 (38.5%)2 (6.5%)ICT or WFTYes
Bhat 2016 [14]IndiaProspective studyTeaching hospitalPaediatricUnspecified279.4 (5.2)11 (40.7%)2 (7.4%)IgM ELISANo
Rana 2016 [24]IndiaProspective studyTeaching hospitalMixed2013–20143748.1 [22 – 80]30 (81.1%)0 (0.0%)IgM ELISAYes
Lee 2017 [8]South KoreaRetrospective cohortTertiary hospitalMixed2009–20141635.5 [Not specified]10 (62.5%)0 (0.0%)IFAYes
Rose 2017 [25]IndiaRetrospective cohortTertiary hospitalPaediatric2010–2015638.9 (4.1)39 (61.9%)0 (0.0%)IgM ELISA or WFTYes
Gangwar 2020 [23]IndiaRetrospective cohortTertiary hospitalPaediatric20181467.0 [4.0–11.0]68 (46.6%)13 (8.9%)IgM ELISAYes
Thakur 2020 [27]IndiaCross sectionalMulticentreMixed2013–201821029.8 (16.6)90 (42.9%)14 (6.7%)IgM ELISANo
Valappil 2017 [28]UnspecifiedProspective studyUnspecifiedMixedUnspecified2840.2 (17.6)14 (50.0%)0 (0.0%)IgM ELISANo
Bhat 2017 [15]IndiaProspective studyTeaching hospitalPaediatricUnspecified197.8 (4.9)5 (26.3%)1 (5.2%)IgM ELISANo
Mittal 2018 [22]IndiaRetrospective cohortTertiary hospitalPaediatric20162305.0 [3.0–10.0]116 (50.4%)35 (15.2%)IgM ELISAYes
Dinesh Kumar 2018 [16]IndiaProspective studyTertiary hospitalPaediatricUnspecified146.9 (2.7)7 (50.0%)0 (0.0%)IgM ELISANo
Alam 2020 [12]IndiaProspective studyTeaching hospitalPaediatric2016–2018665.0 (3.8)20 (30.3%)7 (10.6%)IgM ELISAYes
Arora 2021 [13]IndiaProspective studyTertiary hospitalMixed2014–20163346.5 (17.2)18 (54.5%)2 ((6.1%)IgM ELISANo

Clinical features of neurological manifestations of scrub typhus

The most common clinical features reported were fevers (weighted pooled prevalence [WPP] 100.0%, [95% CI 99.5–100.0%], I2 = 47.8%), altered sensorium (WPP 67.4% [54.9–77.8%], I2 = 93.3%), headache (WPP 65.0%, [51.5–77.6%], I2 = 95.1%) and neck stiffness (WPP 55.6%, [29.4–80.4%], I2 = 96.3%) (Table 2). We found a WPP of seizures of 43.8% ([25.1–63.4%], I2 = 96.8%). Identification of an eschar was found in only 20.8% ([9.8–34.3%], I2 = 95.4%) of the pooled patients. Lymphadenopathy was present in only 24.1% ([11.8–38.9%], I2 = 87.8%). Dyspnoea and cough were present in approximately a quarter of patients (25.2% [10.3–43.6%], I2 = 94.1% and 26.2% [12.6–42.3%], I2 = 88.7% respectively).

Table 2

Weighted pooled prevalence (WPP) of clinical features in patients with neurological manifestations of scrub typhus; * = Defined as general changes in brain function including abnormal Glasgow coma scale score; Ɨ = defined as hepatomegaly, splenomegaly or both Case fatality ratio.
Adult cohortsPaediatric cohortsWeighted pooled prevalence95% CIp Value for Cochran’s QI2Eggers’s test (p value)
Fever (%)648/656 (98.8%)565/565 (100.0%)100.0%99.5% - 100.0%0.01247.8%0.004
Headache (%)424/656 (64.6%)155/565 (27.4%)65.0%51.5% - 77.6%<0.00195.1%0.004
Altered sensorium (%) *325/639 (50.9%)323/436 (74.1%)67.4%54.9% - 78.8%<0.00193.3%0.344
Neck stiffness (%)93/142 (65.5%)71/337 (21.1%)55.6%29.4% - 80.4%<0.00196.3%0.001
Seizures (%)95/407 (23.3%)417/502 (83.1%)43.8%25.1% - 63.4%<0.00196.8%0.115
Dyspnoea (%)148/355 (41.7%)44/175 (25.1%)25.2%10.3% - 43.6%<0.00194.1%0.188
Cough (%)72/286 (25.2%)23/123 (18.7%)26.2%12.6% - 42.3%<0.00188.7%0.503
Diarrhoea (%)21/247 (8.5%)28/439 (6.4%)5.8%3.4% - 8.6%0.18235.9%0.598
Abdominal pain (%)66/301 (21.9%)101/499 (20.2%)24.3%16.5% - 33.0%<0.00182.2%0.124
Vomiting (%)234/543 (43.1%)187/392 (47.7%)46.2%34.1% - 58.5%<0.00191.6%0.740
Jaundice (%)9/60 (15.0%)23/376 (6.1%)8.3%2.9% - 15.5%0.16472.9%0.164
Organomegaly (%) Ɨ111/324 (34.3%)297/565 (52.6%)48.0%38.3% - 57.7%<0.00185.4%0.556
Lymphadenopathy (%)59/307 (19.2%)26/112 (23.3%)24.1%11.8% - 38.9%<0.00187.8%0.257
Eschar (%)147/559 (26.3%)31/546 (5.7%)20.8%9.8% - 34.3%<0.00195.4%0.067
Rash (%)97/353 (27.5%)50/532 (9.4%)20.2%11.1% - 31.1%<0.00191.3%0.149

In sub-group analysis, the most common symptoms identified in paediatric cohorts of 565 patients were fever in 565 (100.0%), seizures in 417 (83.1%), altered sensorium in 323 (74.1%) and organomegaly in 297 (52.6%). In adult cohorts of 656 patients, the common features reported were fever in 648 (98.8%). Headaches were reported in 424 of the 656 patients (64.6%). Neck stiffness was assessed in 142 patients and reported in 93 (65.5%), and altered sensorium was assessed in 639 and reported in 325 (50.9%).

Taken together, adult patients were more likely than children to present with headache, neck stiffness and an eschar. However, even in adult cohorts, an eschar was only identified in one in five cases. Children were more likely to present with altered sensorium, seizures, and organomegaly.

In hospital mortality data were available for 1,221 patients and the number of patients who died with CNS complications of scrub typhus infection was 90 (7.4%). The calculated pooled CFR (95% CI) was 3.6% (1.5–6.4%, I2 = 67.4%). The pooled CFR (95% CI) was 2.4% (0.6–4.9%, I2 = 39.9%) in adult cohorts and higher in the paediatric cohorts with a CFR of 6.1% (1.9–12.1%, I2 = 76.6%) (Fig 3, funnel plots are show in S5 Table).

An external file that holds a picture, illustration, etc. Object name is pntd.0010952.g003.jpg
Forest plot showing case fatality ratio for adult, paediatric and combined cohorts; events are defined as number of in hospital fatalities [8,11–17,19–22,24–26,28,29,37].

Sensitivity analysis

When conducting sensitivity analysis with and without studies utilising the Weil-Felix test, we found no significant difference in both the weighted pooled prevalence of the clinical features of scrub typhus, and the reported case fatality ratio (S5 Table).

Discussion

Scrub typhus is an increasingly prevalent cause of neurological infection in endemic regions [9]. In this systematic review and meta-analyses of 20 studies representing 1,221 patients, we investigated the clinical features and CFR in patients with CNS scrub typhus. Most studies had a moderate to high risk of bias, and there was significant heterogeneity between the included cohorts.

We identified that patients with neurological manifestations of scrub typhus present with non-specific AES features, including fever, headache, altered sensorium, neck stiffness and seizures [38]. The ‘characteristic’ symptoms of scrub typhus were uncommonly reported, with the pathognomonic eschar seen in only 20% of patients and lymphadenopathy being present in 24%. Nevertheless, the eschar may be more common in adults and conversely organomegaly in children. However, as these features are reported in only one in four to five patients with proven CNS scrub typhus, the absence of these signs should not be used to rule out scrub typhus infection. In comparison, approximately 25% of patients reported non-specific respiratory symptoms such as shortness of breath and cough–a finding described in other aetiologies of CNS infections such as Haemophilus influenzae, cryptococcus and Nipah virus [39–41].

In paediatric cohorts, organomegaly was common and may signify a useful clinical marker. Organomegaly in scrub typhus is not well reported in literature but has often been described in other systemic bacterial infections such as typhoid and tuberculosis [42]; hepatomegaly specifically has been reported to be present in up to one in ten patients with CNS infections [43]. Presence of organomegaly may suggest systemic and disseminated scrub typhus in children, and therefore act as an indicator that the CNS may also be affected. This is of particular importance given some children within our meta-analysis did not present with signs suggestive of AES (such as headaches or altered sensorium), but may have substantial neurological involvement given the majority reported seizures. Seizure activity can be common in AES in children [44] and may be in part due to the increased occurrence of febrile convulsions, rather than neurological inflammation itself [45]. Nevertheless, clinicians should be alert to the potential for acute seizure activity in children with CNS scrub typhus given its potential effect on long-term morbidity [46].

Our meta-analyses suggests that approximately 3.6 per 100 patients with scrub typhus neurological infection die in hospital. This CFR was comparable to a study investigating outcomes of all-cause CNS infections among 725 patients in a tropical region [47]. However, our pooled CFR was not as high as those reported for other aetiologies of CNS infections such as herpes simplex virus (HSV) encephalitis [48,49], meningococcal meningitis [48] and Japanese encephalitis [50]. In the studies included in our analyses, most patients were treated with appropriate antibiotics (such as doxycycline, azithromycin, rifampicin, or chloramphenicol) and our CFR was roughly half of that seen in untreated scrub typhus infection [5]. Tetracyclines, and doxycycline in particular, have good CNS penetration [51] and can lead to an early cure of severe scrub typhus with neurological involvement [52]. Early antibiotic therapy remains integral to ensuring improved outcomes in scrub typhus [53].

We observed that CFR may be higher in paediatric cohorts when compared with adult cohorts. The CFR in paediatric cohorts was 6.1%, which corroborates studies examining outcomes in all-cause CNS infections in paediatric cohorts [54,55]. We considered treatment difference as a cause for the differing CFR–paediatric cohorts were often treated with azithromycin rather than doxycycline, likely due to concerns regarding the side-effects of tetracyclines in children [56]. However, a meta-analysis has illustrated that there is no observable difference between antibiotics for treatment of scrub typhus, with all options producing favourable outcomes [53]. Therefore, an alternate explanation we suggest is that there may be a greater delay in diagnosis in paediatric cohorts. The clinical presentations of all-cause CNS infections in young children can be nonspecific; features suggestive of AES were not common among paediatric patients. A high index of suspicion and syndromic approach is essential as delay in initiation of antibiotics is associated with increased mortality in bacterial infections of the CNS in children [57,58]. Given the propensity of scrub typhus to present with diverse clinical features, identifying behavioural and geographical risk factors to indicate the possibility of chigger bites is important in diagnosis [59]. In children, this may be harder to obtain, further delaying the diagnosis. Furthermore, paediatric cohorts in our study reported higher proportions of seizures which could contribute to mortality, whilst the prevalence of organomegaly in paediatric cohorts could suggest that higher proportions of disseminated scrub typhus infections occur in children [60].

Limitations and future direction

Our study had several limitations. Our analyses were based on estimates derived from cohort studies which often did not report potential confounders for fatality. For example, co-morbidities (especially those causing immunocompromise) have been shown to be associated with worse outcomes in patients with neurological infections [61]. Furthermore, very few studies specified a timescale for their cohorts, and both these factors may bias results for our calculated fatality. We explored heterogeneity using predefined analyses and though the between-study heterogeneity we report may represent true variation in clinical features and CFR, difference in methodology and study quality may confound this measure. We included serological tests given their prevalence in endemic regions, but acknowledge that they are imperfect and their accuracy is highly dependent on the cut-offs used for diagnosis. Finally, though we explored the clinical features present in patients with scrub typhus CNS infections, we did not investigate blood studies, cerebrospinal fluid or imaging findings in these patients. Some studies in our meta-analyses reported these findings, and there is scope to analyse investigation findings in scrub typhus to elucidate characteristics features when compared to other CNS infections.

Several factors may contribute to the possibility of our pooled CFR being an underestimate of the true CFR in CNS scrub typhus. Our studies were centred around six sites, with many studies recruiting patients from the same sites (Fig 4A). Furthermore, all studies included in our meta-analyses recruited from either tertiary or teaching hospitals and the clinicians at sites recruiting patients may be more adept at recognising and managing neurological scrub typhus infections. This reduces the generalisability of our results and fatality may be higher in settings where fewer specialists are available; more studies are needed in other settings in the tsusugamushi triangle, particularly from rural regions where burden of scrub typhus is high [12,62].

An external file that holds a picture, illustration, etc. Object name is pntd.0010952.g004.jpg

A: Map illustrating tsustugamushi triangle and the included studies in our meta-analyses, circles are proportionate to the size of the cohorts. The map was created using public domain image (https://commons.wikimedia.org/wiki/File:BlankMap-World.svg). B: Graph illustrating number of published cases of central nervous system (CNS) scrub typhus described in literature.

Increasing numbers of CNS scrub typhus have been described in the literature (Fig 4B). However, only one included study in our analyses reported the long term sequalae of neurological scrub typhus infection [23]. With greater access to acyclovir, there has been drastic improvement in mortality in patients with HSV encephalitis. However, with this improved mortality, more patients have been found to suffer from prolonged neurological deficits [63]. Similarly, given scrub typhus’s excellent response to antibiotics, there is the possibility that many patients suffer from long-term neurological morbidity. Further research is required to quantify the burden of morbidity. Additionally, there is little known about the specific cause of death in those with neurological manifestations of scrub typhus. Some studies report that meningoencephalitis is a predictor of poorer outcome in patients [64], but few detail why this may be. With seizures being common in our analyses, the possible implication of subsequent neurological complications such as status epilepticus on fatality should be investigated. Identifying and intervening in treatable causes of death may have substantial effects on the long-term prognosis and survival of this population.

Conclusion

In this study of neurological manifestations of scrub typhus, we found an overall CFR of 3.8%, which may be highest in children. Adults were more likely to present with headache and neck stiffness, whereas children were more likely to present with altered sensorium and seizures. Nevertheless, clinical features were often non-specific; the pathognomonic eschar was only present in a minority, especially in children, and should not be used to rule out scrub typhus infection. In endemic areas clinicians should have a low threshold for empirical antibiotic therapy in patients presenting with AES, whilst undertaking investigations for alternative aetiologies. Further high-quality evidence which focuses on long-term morbidity in patients with neurological manifestations of scrub typhus are required.

Supporting information

S1 Table

Search strategy.

(DOCX)

S2 Table

Inclusion criteria.

(DOCX)

S3 Table

Data collected.

(DOCX)

S4 Table

Bias assessment.

(DOCX)

S5 Table

Sensitivity analysis (excluding studies which used Weil-Felix test in diagnosis).

(DOCX)

S1 Fig

Funnel plots.

(DOCX)

Funding Statement

BDM is supported by the UKRI/MRC (MR/V03605X/1), the MRC/UKRI (MR/V007181//1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). The funders did not play any role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Data Availability

All data are available in the manuscript and the Supporting Information files.

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2022 Nov; 16(11): e0010952.
Published online 2022 Nov 28. doi: 10.1371/journal.pntd.0010952.r001

Decision Letter 0

Joseph M. Vinetz, Section Editor and Joseph Raymond Zunt, Academic Editor
Copyright and License information PMC Disclaimer

14 Oct 2022

Dear Dr Alam,

Thank you very much for submitting your manuscript "Neurological manifestations of scrub typhus infection: a systematic review and meta-analysis of clinical features and case fatality" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Joseph Raymond Zunt

Academic Editor

PLOS Neglected Tropical Diseases

Joseph Vinetz

Section Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: -Are the objectives of the study clearly articulated with a clear testable hypothesis stated? Yes

-Is the study design appropriate to address the stated objectives? No

-Is the population clearly described and appropriate for the hypothesis being tested? No (some queries need to be addressed)

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested? Yes

-Were correct statistical analysis used to support conclusions? Yes

-Are there concerns about ethical or regulatory requirements being met? Yes

Reviewer #2: This is a well-planned meta-analysis with clear aims stated. The authors ensured the inclusion of the most appropriate studies using a robust criteria. The analyses were described and suitable for the aims stated.

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: -Does the analysis presented match the analysis plan? Yes

-Are the results clearly and completely presented? Yes

-Are the figures (Tables, Images) of sufficient quality for clarity? Yes

Reviewer #2: The results are presented in a clear manner and supplemented by the figures included.

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Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: -Are the conclusions supported by the data presented? No

-Are the limitations of analysis clearly described? No

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study? Yes

-Is public health relevance addressed? Yes

Reviewer #2: The conclusions match the results found with clear limitations conveyed.

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: (No Response)

Reviewer #2: Nil

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Summary and General Comments

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Reviewer #1: The authors have conducted a systematic review and meta analysis to report the clinical features and case fatality ratio in scrub typhus patients. They have conducted the review according to their hypothesis. I have a few queries:

1. Is lymphadenopathy a pathognomonic feature of scrub typhus? Please give references for this.

2. In para 4 of Introduction, authors mention inclusion of case series in their review but in para 2 of methods, they have mentioned excluding case series. This needs clarification.

3. Methodology: Scrub typhus diagnosed by IFA, Weil-Felix and ELISA have been included in these study for review. The specificity of Weil-Felix is poor and should ideally not be included in review such as these. The authors should take a look at their data after removing patients diagnosed solely by Weil-Felix test.

4. Results: Dyspnoea was present in 25.1% of patients. Was this ARDS? If yes, then it would be difficult to delineate in which patients mortality was due to CNS disease versus ARDS. The authors have not mentioned anything related to this.

5. Results: In Table 1 and figure 3, the studies mentioned as Kumar 2018, Jamil 2019 and Arora 2020 are missing from the reference list.

Reviewer #2: Scrub typhus is an important but neglected infectious disease and this meta-analysis on the neurological manifestations of scrub typhus is extremely welcomed. The authors have included studies based on a robust criteria and although the included studies exhibited heterogeneity and risk of bias, some conclusions could be drawn from the analysed data. I have some comments to add:

- The serological assays used (please correct in the text - indirect immunofluorescence assay, Weil-Felix test and IgM ELISA) are imperfect and accuracy highly dependent on the cut-offs used for diagnosis (if based on an acute sample only rather than paired acute and convalescent samples). The Weil-Felix test is no longer widely utilised due to lack of sensitivity and specificity. In India, where most of the included studies were from, the InBios Scrub Typhus IgM ELISA is widely used and there have been debate around an appropriate OD cut-off if based on a single acute sample.

It would be helpful to allude to the imperfections of serological testing in the manuscript. Also, did some studies include molecular assays or culture? If so, was there concordance with the serological results?

- Historically, sensori-neural hearing loss was described in patients with scrub typhus. Were there any descriptions of this in the included studies?

- In the included studies, was testing of CSF samples performed? If so, it could be clinically helpful to include the cell count pattern, protein and glucose levels in scrub typhus patients with CNS involvement, even if molecular testing for Orientia tsutsugamushi is unavailable.

- With regards to treatment, it is important to clarify route of antibiotic administration as drug absorption through the gastrointestinal route may be impaired in critically unwell patients with organ dysfunction. There is also a discrepancy in the availability of parenteral antibiotics between regions - e.g. IV doxycycline is widely available in India but often not elsewhere. Did the included studies clarify this?

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Reviewer #1: No

Reviewer #2: No

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2022 Nov; 16(11): e0010952.
Published online 2022 Nov 28. doi: 10.1371/journal.pntd.0010952.r002

Author response to Decision Letter 0

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31 Oct 2022

Attachment

Submitted filename: Response to reviewers.pdf

2022 Nov; 16(11): e0010952.
Published online 2022 Nov 28. doi: 10.1371/journal.pntd.0010952.r003

Decision Letter 1

Joseph M. Vinetz, Section Editor and Joseph Raymond Zunt, Academic Editor
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7 Nov 2022

Dear Dr Alam,

We are pleased to inform you that your manuscript 'Neurological manifestations of scrub typhus infection: a systematic review and meta-analysis of clinical features and case fatality' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

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Joseph Vinetz

Section Editor

PLOS Neglected Tropical Diseases

***********************************************************

2022 Nov; 16(11): e0010952.
Published online 2022 Nov 28. doi: 10.1371/journal.pntd.0010952.r004

Acceptance letter

Joseph M. Vinetz, Section Editor and Joseph Raymond Zunt, Academic Editor
Copyright and License information PMC Disclaimer

24 Nov 2022

Dear Dr Alam,

We are delighted to inform you that your manuscript, "Neurological manifestations of scrub typhus infection: a systematic review and meta-analysis of clinical features and case fatality," has been formally accepted for publication in PLOS Neglected Tropical Diseases.

We have now passed your article onto the PLOS Production Department who will complete the rest of the publication process. All authors will receive a confirmation email upon publication.

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