Steroids in severe scrub typhus infection: a retrospective cohort study

1 Introduction

Scrub typhus is a zoonotic rickettsial infection that is highly prevalent in the Tsutsugamushi triangle (1, 2) with a global pooled seroprevalence of 10.73% among healthy individuals and 22.58% among febrile patients (3). The incidence of infection with scrub typhus in southern India is reported as 6.0 per 1000 person years, out of which 21.6% required hospitalization (4). It is associated with significant mortality and morbidity (5). Severe disease leads to multi-organ dysfunction requiring intensive care unit (ICU) admission and is characterized by respiratory failure due to pneumonitis and acute respiratory distress syndrome (ARDS), circulatory shock, acute kidney injury, thrombocytopenia, neurological dysfunction (aseptic meningitis), and transaminitis (6, 7). The mortality of scrub typhus patients needing ICU admission is high (20–29%) (5, 8–10).

Steroids have been shown to improve outcomes in severe community acquired pneumonia (11), coronavirus disease 2019 (COVID-19)- related acute hypoxemic respiratory failure (12) and ARDS of varied etiology (13). Steroids are likely to be beneficial in adult septic shock (14). Given the high mortality of severe scrub typhus infection, particularly in patients with ARDS and circulatory shock, it is important to explore the role of steroids in severe scrub typhus infection (5, 15). Furthermore, the vasculitic pathogenesis of scrub typhus with endothelial activation (16–18) and transient expression of anti-nuclear antibody during the acute phase of illness (19) provide a biological rationale for ascertaining any immunomodulatory role that steroids might have.

Studies on the role of steroids in severe scrub typhus infection are limited. This retrospective cohort study was conducted to evaluate the association between corticosteroid therapy and outcomes among critically ill patients with scrub typhus infection and includes patients with severe shock requiring vasopressor therapy as well as those with respiratory failure due to pneumonitis and ARDS.

2 Methods

2.1 Study design and setting

A retrospective study spanning 3 years (January 2022– December 2024) was carried out in a 24-bed medical ICU in a 2,800-bed university-affiliated teaching hospital in India. All consecutive patients meeting the case definition and admitted to the ICU during the study period were included; no sampling was performed and no a priori sample-size calculation was undertaken, as the study was a retrospective analysis of all available eligible patients. Patients were identified retrospectively from the ICU database using the search terms “scrub”, “typhus”, “rickettsial” and “undifferentiated febrile illness” within the pre-specified study period. The charts were reviewed for inclusion in the study based on clinical details and immunoglobulin-M Enzyme-Linked Immunosorbent Assay (IgM ELISA) test results for scrub typhus.

2.2 Participants

Patients who presented with an acute undifferentiated febrile illness (AUFI) with a positive IgM ELISA test for scrub typhus were identified as cases. Patients with an AUFI suggestive of scrub typhus infection who had the characteristic eschar of scrub typhus were also included even if they had a negative test. Only critically ill patients with organ dysfunction, and requiring respiratory, hemodynamic or renal support, who fulfilled the case definition of scrub typhus infection and admitted to the ICU were included.

2.3 Steroid exposure

The role of steroids in severe scrub typhus infection was evaluated by assessing if steroids (in any form or dose) were associated with a reduction in mortality and organ-support-free days. Steroids were prescribed at the discretion of the attending intensivist. Although there was no pre-prescribed protocol, the most common indications were refractory vasopressor-dependent shock and/or severe pneumonitis or ARDS. The formulation, daily dose of steroids administered, and the total duration of treatment were abstracted from records.

2.4 Outcomes

The primary outcome was 28-day all-cause mortality, ascertained from hospital records and by telephonic follow-up if patients were discharged earlier. Secondary outcomes included ventilator-free days (VFD) at 28-days, vasopressor-free days at 28-days, ICU length of stay, hospital length of stay, use and duration of non-invasive (NIV) and invasive mechanical ventilation (IMV), use and duration of vasopressor support. Ventilator-free and vasopressor-free days were calculated using the Schoenfeld convention (20), in which patients dying by day-28 were assigned 0 days and surviving patients received 28 minus the days of support.

2.5 Data collection

Baseline demographic data, clinical variables and outcomes were collected from retrospective chart review. All data was available as digitally archived discharge summaries, laboratory investigations reports and scanned copies of handwritten inpatient charts. Illness severity was assessed using the Acute Physiology and Chronic Health evaluation (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores (21, 22).

2.6 Statistical analysis

Data entry was done using a standardized EpiData form and statistical analysis was performed on SPSS version 29. Continuous variables were summarized as mean (standard deviation, SD) or median (interquartile range, IQR) and compared using Student’s t-test or the Mann–Whitney U-test, as appropriate. Categorical variables were expressed as counts (percentages) and compared using the chi-square test or Fisher’s exact test.

In addition to crude outcome analysis, multivariable logistic regression was performed to estimate the independent effect of steroids on 28-day mortality. Although multivariable logistic regression analysis was planned a priori, the model was refined post hoc given the relatively low event rate (mortality) that precluded the use of multiple covariates (23). A decision to use respiratory and cardiovascular SOFA components separately rather than the composite SOFA score in the logistic regression analysis was made because the two contemporary indications for steroids in critical illness — septic shock with vasopressor dependence and severe pulmonary infection or ARDS with respiratory failure — operate through distinct mechanistic pathways that a composite SOFA could obscure. A prespecified sensitivity analysis was also performed excluding patients who died within the first 24-hours of ICU admission, since the pharmacodynamic lag of steroids makes early death an unreliable marker of treatment unresponsiveness. A Firth penalized logistic regression was additionally performed post hoc (24, 25).

Figures were generated in R using the ggplot2 package; generative AI (Claude, Anthropic) assisted in drafting this figure-generation code, which was executed and inspected by the authors (see Acknowledgments).

2.7 Ethical approval

The study was approved by the Institutional Review Board (IRB Min No 2502150 dated 26 February 2025), with a waiver of informed consent given the retrospective nature of the chart review.

3 Results

3.1 Patient characteristics

Patient identification and flow through the study are summarized in Figure 1. A total of 114 critically ill patients with scrub typhus infection, with moderate disease severity (median APACHE II score 13, IQR: 9–18), were admitted during the study period. Of these, 67 received steroids. Patients receiving steroids were significantly older (mean (SD) age 48.2 [14.1] vs 42.0 [15.9] years; p = 0.04) and had significantly higher SOFA scores, specifically in the respiratory and cardiovascular SOFA components (Table 1). There was no difference in the comorbidities and time to initial presentation to the hospital between the two groups (Table 1). Scrub typhus serology was positive in 86.8% of patients; the remaining presented as an AUFI, had an eschar, and had a therapeutic response to doxycycline, consistent with a diagnosis of scrub typhus infection.

Table 1. Baseline characteristics of patients with severe scrub typhus, stratified by steroid use (n = 114).

Values are mean (SD), median (IQR), or n (%) as appropriate. SOFA, Sequential Organ Failure Assessment; APACHE II, Acute Physiology and Chronic Health Evaluation II; IQR, interquartile range; SD, standard deviation; ICU, intensive care unit. Continuous variables were compared using Student’s t-test or the Mann–Whitney U-test; categorical variables using the chi-square or Fisher’s exact test, as appropriate. Comorbidities occurring in ≤ 2 patients (ischaemic heart disease, chronic liver disease, prior systemic steroid use, obesity, seizure disorder) are not shown individually. None of the patients had chronic obstructive pulmonary disease, chronic heart failure, rheumatic heart disease, chronic kidney disease, HIV infection, or were receiving prior immunosuppressant therapy.

3.2 Steroid exposure

Hydrocortisone was the steroid formulation used in all patients (n = 67) at a median dose of 200 mg (IQR: 150–200) per day for a median duration of 3 (IQR: 1–5) days. Duration was computed as the interval in calendar days between first and last administration, consistent with the convention used for ICU and hospital length of stay; eleven patients (16%) received steroids for less than 24 hours. The median (IQR) duration of antimicrobial therapy (doxycycline, or azithromycin, or both) was 5 (4–6) days in both groups. There were no adverse drug reactions recorded in the patient charts that were directly attributable to steroids.

3.3 Unadjusted outcomes

Unadjusted patient outcomes are summarized in Table 2. The 28-day mortality was 14.9% (17/114) and significantly higher among patients who received steroids (23.9% vs 2.1%; p < 0.001). Overall, ventilatory and vasoactive support were each required in 88 patients (77.2%); 71 (62.3%) required both, 17 ventilatory support alone, and 17 vasoactive supports alone. Non-invasive ventilation was used at similar rates in both groups (59.7% vs 55.3%; p = 0.64). Invasive mechanical ventilation, in contrast, was substantially more frequent among steroid recipients (49.3% vs 17.0%; p = 0.001), and ventilator-free days at 28 days were correspondingly lower (median 24 [IQR: 19–26] vs 27 [25–28]; p < 0.001). Vasopressor support was also significantly more common in the steroid group (97.0% vs 48.9%; p < 0.001), with fewer vasopressor-free days (26 [16–27] vs 28 [27–28]; p < 0.001). The pattern of exposure has been shown as a heat map in Figure 2, where cardiovascular SOFA and respiratory SOFA scores have been plotted against each other, and the percentage of patients administered steroids for each combination of SOFA scores captured. The heat map shows a significant concentration of patients who received steroids in the higher SOFA scores categories, especially cardiovascular SOFA.

Table 2. Unadjusted clinical outcomes stratified by steroid use (n = 114).

Values are n (%) or median (IQR), as appropriate. Ventilator-free and vasopressor-free days were calculated using the Schoenfeld convention (patients dying by day 28 assigned 0 days; surviving patients receive 28 minus the days of support). NIV, non-invasive ventilation; IMV, invasive mechanical ventilation; IQR, interquartile range; ICU, intensive care unit. Categorical variables compared using the chi-square or Fisher’s exact test; continuous variables using the Mann–Whitney U-test.

3.4 Multivariable analysis

Given the high degree of confounding with steroid use, a multivariable logistic regression was performed including age, respiratory SOFA, cardiovascular SOFA, and steroid use (Table 3). Older age (OR, 1.08; 95% CI, 1.03–1.15) and higher respiratory SOFA score (OR, 2.02; 95% CI, 1.09–3.74) were independently associated with mortality, while cardiovascular SOFA (OR, 0.82; 95% CI, 0.51–1.32) and steroid use (OR, 9.34; 95% CI, 0.85–102.7) were not. Because only one death occurred among patients who did not receive steroids, a Firth penalized logistic regression was also performed; this yielded a similar, imprecise estimate for steroid use (adjusted OR, 6.12; 95% CI, 1.00–72.11; Table 3). Baseline imbalance between groups remained substantial, with standardized mean differences of 1.42 for cardiovascular SOFA, 0.75 for respiratory SOFA, and 0.41 for age. In the prespecified sensitivity analysis excluding the six patients who died within 24 hours of ICU admission (all in the steroid group), 28-day mortality remained higher among steroid recipients (16.4% vs 2.1%; p = 0.02), with directionally consistent findings for ventilator-free days, vasopressor-free days, and ICU and hospital length of stay.

Table 3. Association between steroid exposure and mortality.

Multivariable model adjusted for age, respiratory SOFA, cardiovascular SOFA, and steroid use. Model fit: Omnibus χ² = 30.21 (df = 4), p < 0.001; Nagelkerke R² = 0.409; –2LL = 65.821. OR, odds ratio; CI, confidence interval; SOFA, Sequential Organ Failure Assessment.

4 Discussion

In this retrospective cohort of patients admitted to the ICU with severe scrub typhus infection, steroids were not independently associated with mortality. On multivariable logistic regression analysis, only older age and higher respiratory SOFA scores were independently associated with mortality. The association with age is consistent with similar findings (aOR for age, 1.063 per year; 95% CI, 1.010-1.118) noted from a Nepalese ICU cohort (8), but previous studies have not demonstrated a significant association with either cardiovascular or respiratory dysfunction on multivariate modeling (8, 9), which is in contrast to the independent effect of respiratory SOFA on mortality (OR, 2.02; 95% CI, 1.09–3.74) in the current study. The higher mortality with steroids observed on bivariate analysis is likely to be due to its use in patients with more organ dysfunction. The principal premise underlying steroid use in severe scrub typhus is that the disease is, at its pathological core, an infectious vasculitis with widespread endothelial involvement (16–18). This mechanism conceptually parallels the vascular and immune-mediated injury seen in severe COVID-19 pneumonia and in ARDS of varied etiology, conditions in which steroids have demonstrated benefit at doses similar to those used in this cohort (13, 14). The transient expression of anti-nuclear antibodies during the acute phase of scrub typhus suggests an additional element of dysregulated adaptive immunity that may be amenable to immune modulation (19). Hydrocortisone was uniformly noted as the steroid formulation administered in this study, possibly related to its prevalent use in vasopressor-dependent septic shock (14, 26) and severe community acquired pneumonia (11, 27). By contrast, the survival benefit of corticosteroids in ARDS (13) and in COVID-19–related respiratory failure (12) was established with dexamethasone, a long-acting glucocorticoid with negligible mineralocorticoid activity and sustained anti-inflammatory coverage. Given the significant inflammatory burden and endothelial activation seen in severe scrub typhus, and the independent effect of respiratory, rather than cardiovascular dysfunction on mortality in the current study, a longer acting agent like dexamethasone may provide better anti-inflammatory potential than hydrocortisone, and warrants further investigation, as planned in an ongoing randomized trial (28).

Patients who received steroids had markedly higher cardiovascular and respiratory SOFA scores at baseline, reflecting the clinical context in which steroids were administered —vasopressor-dependent shock and severe pneumonitis, as reflected in the heat map in Figure 2. All organ-support requirements — invasive ventilation, vasopressor use, ventilator-free days, vasopressor-free days — were significantly worse in the steroid group, consistent with selection of the sickest patients for treatment. The crude unadjusted mortality difference (23.9% vs 2.1%) is more likely a reflection of illness severity rather than a causal effect of steroids. The marked baseline imbalance in severity between groups and the low event rate produced very wide confidence intervals that precluded meaningful interpretation of the effect of steroids on mortality. The finding that respiratory SOFA was independently associated with mortality, while cardiovascular SOFA was not, is consistent with the established importance of pulmonary complications as a major determinant of outcome in severe scrub typhus (8, 9, 15). This confounding by indication is an inherent and unavoidable limitation of all observational studies and is precisely why randomized evidence is required. The ASTEROIDS trial (Adjunctive steroids in severe Scrub typhus pneumonitis), a multicenter randomized placebo-controlled trial of dexamethasone in severe scrub typhus pneumonitis and ARDS (CTRI/2024/12/077709) (28), will provide evidence on the role of steroids in the subset of patients with pneumonitis and ARDS.

The wide confidence intervals around the adjusted OR for steroid use deserve specific comment. With only 17 deaths across 114 patients and four covariates in the multivariable model, the analysis operates below the conventional benchmark of approximately 10 events per predictor variable (24). The estimated association between steroid use and mortality remained imprecise, precluding reliable inference regarding either the magnitude or direction of effect. Although Firth penalization can reduce small-sample bias in the presence of quasi-separation, it cannot account for the substantial confounding by indication inherent in this cohort. The resulting confidence intervals therefore remained too wide to permit reliable inference regarding the effect of steroids on mortality.

4.1 Limitations

Several limitations should be acknowledged. First, the retrospective single-center design is subject to indication bias and unmeasured confounding; the magnitude of baseline severity imbalance suggests that residual confounding by variables not captured in the dataset cannot be excluded. Second, the small number of mortality events (n = 17) fundamentally limits the precision of adjusted estimates. Third, steroid exposure was not standardized. Although hydrocortisone was used with relatively consistent dosing, indications and duration of use were heterogeneous. These significant limitations mandate the conduct of prospective randomized trials in severe scrub typhus infection with homogenous patient populations, such as those with pneumonitis and ARDS with low-dose vasopressor requirement.

5 Conclusions

In this retrospective cohort of patients admitted to the ICU with severe scrub typhus infection, steroids were not independently associated with 28-day mortality after adjusting for age and illness severity. Given the baseline differences between the treatment groups and the limited number of mortality events, the effect of steroids on mortality remains uncertain. Further prospective studies are needed to evaluate the role of steroids in severe scrub typhus, particularly among patients with pneumonitis and ARDS.

Generative AI statement

The author(s) declared that generative AI was used in the creation of this manuscript. During the preparation of this work, the authors used Claude (Anthropic, model Claude Opus 4.8) to assist with drafting figure-generation code (the STROBE figure as Figure 1 and the heat map in Figure 2) in R studio (using the ggplot2 package). The figures were regenerated from the source dataset and visually inspected by the authors for accuracy. The authors reviewed and edited all output and take full responsibility for the content and accuracy of the publication.

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Footnotes

Edited by: Archana Shrestha, Kathmandu University, Nepal

Reviewed by: Raghavendra Huchchannavar, K S Hegde Medical Academy (Nitte DU), India

Hemasri Velmurugan, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), India