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Table of Contents
RESEARCH ARTICLE
Year : 2019  |  Volume : 56  |  Issue : 4  |  Page : 367-372

Clinical outcome and predictors of severity in scrub typhus patients at a tertiary care hospital in Chandigarh, India


1 Department of General Medicine, Government Medical College and Hospital, Chandigarh, India
2 Department of Microbiology, Government Medical College and Hospital, Chandigarh, India

Date of Submission31-Jan-2018
Date of Acceptance01-Mar-2019
Date of Web Publication30-Nov-2020

Correspondence Address:
Dr. M Gupta
Professor, Level-4, D-Block, Department of General Medicine, Government Medical College & Hospital, Chandigarh—160030
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-9062.302041

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  Abstract 

Background & objectives: Scrub typhus is an under-reported rickettsial illness caused by Orientia tsutsugamushi which is transmitted by trombiculid mites. Serious complications are not uncommon and multiorgan dysfunction may develop leading to death. Paucity of data on the clinical spectrum and determinants of aftermath may be contributing to higher mortality in the region. A prospective study was done to describe the spectrum of organ dysfunction in serologically confirmed cases of scrub typhus and document predictors of adverse outcomes.
Methods: This prospective study was carried out in patients diagnosed to have scrub typhus by IgM ELISA. The clinical features, investigations and complications among survivors were statistically compared to those in the deceased. Fisher’s exact test, t-test and logistic regression have been applied where appropriate.
Results: The study population comprised of 123 patients. Majority of patients (62%) had one or more organ dysfunction. Ten patients (8.1%) did not survive. Complications documented were acute kidney injury (AKI) in 35%, hepatitis in 29.2%, acute respiratory distress syndrome (ARDS) in 26%, shock in 13%, meningitis in 5.7%, disseminated intravascular coagulation (DIC) in 2.6%, pancreatitis in 2.6% and myocarditis in 1.6%. Certain clinical features, biochemical parameters and complications had statistically significant correlation with the outcome. The mean SOFA score was considerably higher in those who did not survive.
Interpretation &conclusion: Patients developing hepatic dysfunction, acute kidney injury and respiratory distress should be identified early and intensively monitored. The SOFA score can be utilized to assess the severity at admission and rapidly triage the sicker patients.

Keywords: Complications; mortality; organ dysfunction; Scrub typhus


How to cite this article:
Gaba S, Gupta M, Singla N, Singh R. Clinical outcome and predictors of severity in scrub typhus patients at a tertiary care hospital in Chandigarh, India. J Vector Borne Dis 2019;56:367-72

How to cite this URL:
Gaba S, Gupta M, Singla N, Singh R. Clinical outcome and predictors of severity in scrub typhus patients at a tertiary care hospital in Chandigarh, India. J Vector Borne Dis [serial online] 2019 [cited 2021 Jan 21];56:367-72. Available from: https://www.jvbd.org/text.asp?2019/56/4/367/302041


  Introduction Top


Scrub typhus usually presents as an undifferentiated acute febrile illness (AFI). Data from a recent large retrospective study involving 1564 AFI patients across six states, shows the main etiologies as malaria 17%, dengue 16%, bacteraemia 8%, scrub typhus 10%, leptospirosis 7%, and chikungunya 6%[1]. In endemic areas, it is responsible for nearly a quarter of all AFI, escalating to 50% in some regions[2]. More importantly, scrub typhus is an under-recognized cause of multiorgan dysfunction syndrome (MODS)[2]. World Health Organization (WHO) has stated, “Scrub typhus is probably one of the most under-diagnosed and under-reported febrile illness requiring hospitalization in the region”[3]. Although this life threatening disease is endemic in our country, it is grossly mis-diagnosed or underdiagnosed owing to its covert nature, non-specific clinical presentation, lack of access to specific diagnostic facilities in most areas and a low index of suspicion by clinicians[4]. Mortality in severe cases[5] or with delayed treatment may be as high as 30%. Many patients have multiorgan involvement predominantly in the form of acute kidney injury (AKI), hepatitis and acute respiratory distress syndrome (ARDS)[6]. Loomba et al[6] observed at least one organ dysfunction in 50% patients, MODS in 30.7% and mortality in 4.9%. Oberoi and Varghese[7] observed more than one organ complication in 31.6%. Himalayan region has shown predominantly hepatic dysfunction in 21–70%, renal dysfunction in 20–42%, and ARDS in 16–18%[8],[9]. South Indian data showed hepatic dysfunction ranging from 19–34 to 86%[10],[11]. Gupta et al from New Delhi, India found AKI in 18%, encephalitis in 21 %, ARDS in 18% and hepatic dysfunction in 54% patients[12]. Authors from Jaipur, India found liver dysfunction, AKI, ARDS and MODS in 96, 60, 9.5, and 16.6% respectively[13].


  Material & Methods Top


Study design and setting

A prospective study was conducted in the Department of General Medicine and Microbiology at Government Medical College and Hospital (GMCH), Chandigarh, India.

Sample size

The samples consisted of all consecutive confirmed cases of scrub typhus presenting to the medicine emergency and out-patient department. Of the 1758 patients presenting with AFI, 194 patients tested positive for scrub typhus, however, 123 were included for analysis after appropriate exclusions.

Inclusion criteria

Patients >12 yr of age, with the diagnosis of scrub typhus confirmed by IgM antibody ELISA in their acute or convalescent serum.

Exclusion criteria

Patients with pre-existing co-morbid diseases, having other co-infectious diseases and who did not follow up or refused consent.

Methodology

Detailed demographic data and history were recorded. Complete physical examination was carried out and other likely diagnoses were excluded by an initial battery of investigations including peripheral blood smear/rapid test for malaria, IgM ELISA for leptospira, dengue NS1Ag and IgM antibody test. Chest radiography, abdominal ultrasonography, electrocardiogram and echocardiogram, coagulogram, arterial blood gases and other specialized investigations (like cerebrospinal fluid analysis, CT scan) were done wherever necessary.

Processing of samples for serology

Serum samples (preserved at –20 °C when required) were tested for specific IgM antibodies against Orientia tsutsugamushi using a commercial enzyme-linked immunosorbent Assay (ELISA) kit (InBiOS International Inc. Scrub typhus Detect™ IgM ELISA system). The kit uses O. tsutsugamushi derived recombinant antigen mix. The epidemiological cut off for IgM antibodies for scrub typhus was 0.5, so any OD value higher than this was taken as positive and diagnostic of scrub typhus.

Treatment protocol

Patients were treated with oral doxycycline (intravenous doxycycline when not able to take orally) 100 mg twice a day for 7–10 days. Azithromycin was administered in pregnant patients. All other supportive measures such as haemodialysis, ventilator support, transfusion of blood components, inotropic support were given whenever indicated.

Assessment of severity

Patients with organ dysfunction were assessed for severity by using the sepsis-related organ failure assessment (SOFA) score at admission[14]. Patients were monitored for complications or death during hospitalization, and outcomes evaluated at discharge or death and 2 weeks after discharge. The main outcome was in-hospital mortality, others included need for specialised supportive therapy and duration of hospital stay. The following definitions were used for diagnosis of complications—

Acute kidney injury (AKI): The Kidney disease: Improving global outcomes (KDIGO) criteria of rise of serum creatinine by at least 0.3 mg/dl or 50% of the baseline within a 48 h period or a reduction in urine output to < 0.5 ml/kg/hr for more than 6 h[15];

Hepatitis: Elevation of serum transaminases to >6 times the normal upper limit[16];

Acute respiratory distress syndrome (ARDS): The Berlin criteria which defines ARDS as non-cardiogenic pulmonary oedema with onset within seven days of clinical insult or worsening of new or pre-existing respiratory symptoms, appearance of bilateral chest infiltrates and PaO2/FIO2 of ≤300 mmHg with positive end expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) ≥ 5 cm water. In mild ARDS, PaO2/FIO2> 200, in moderate ARDS it is< 200 but >100 and in severe ARDS[17], it is <100;

Disseminated intravascular coagulation (DIC): Prolongation of PT and/or aPTT; platelet count <100×109/l, or a rapid decline in platelet count over 24 h; the presence of schistocytes (fragmented red cells) in blood smear, and elevated levels of fibrin degradation products (FDPs)[16];

Pancreatitis: Any two of the following—acute onset of clinical symptoms such as abdominal pain, vomiting, guarding and tenderness, elevation of serum amylase/lipase >3 times upper limit of normal and radiological evidence of pancreatitis[18];

Myocarditis: Inflammation of heart muscle leading to chest pain, palpitations and heart failure, accompanied with ECG changes, elevated inflammatory markers and markers of cardiac damage (troponin or creatine kinase cardiac isoenzymes)[19];

Shock: Systolic blood pressure of <90 mmHg for at least 1 h despite adequate fluid resuscitation and evidence of tissue hypoperfusion[18];

Meningoencephalitis: Altered sensorium and signs of meningeal irritation associated with elevated protein and lymphocytic/neutrophilic cytology with normal or low sugar on CSF analysis[16].

Statistical analysis

Statistical analysis was done using the SPSS software package. Descriptive statistics were obtained for all the study variables. All the data were expressed as mean (± SD). All the categorical variables were compared using Fisher’s exact test. Continuous data were analysed using t-test and p <0.05 was considered statistically significant. Logistic regression analysis of complications was performed to find predictors of mortality.

Ethical statement: Ethical approval was obtained from Institutional Ethics Committee, GMCH, Chandigarh (No. 2015/0042) on 20 January 2016. Written informed consent was taken from all study participants/next of kin.


  Results Top


The study population comprised of 123 patients of which 113 survived and 10 died. The mean age (± SD) of participants was 31.44 ± 13.41 yrs.

Clinical features

Symptoms that had a significant bearing on the outcome of the illness included vomiting, dyspnoea, decreased urine output, seizures and altered sensorium [Table 1]. The clinical parameters which were statistically significant among those who did not survive were systolic blood pressure (BP) < 90 mmHg, hepatomegaly, splenomegaly, rhonchi and crepitations, pleural effusion, conjunctival congestion, peripheral oedema and altered sensorium [Table 1].
Table 1: Frequency of symptoms and signs reaching statistical significance

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Haematological parameters

Although the mean haemoglobin and platelets were much lower in those who did not survive, these parameters did not reach statistical significance. The total leucocyte count (TLC) of the patients who died was statistically higher as compared to the survivors (p <0.05).

Electrolyte and renal functions

Only elevated urea was found to have statistical significance. Serum sodium was lower in those who died but not statistically significant. Serum potassium and creatinine did not have any predictive value.

Liver function tests

The variables that statistically correlated with mortality were bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and alkaline phosphatase (ALP) [Table 2]. On using multivariate logistic regression model for independent variables affecting outcome, odds ratio >1 was seen with haemoglobin, platelets, TLC, sodium, potassium, SGOT, SGPT and creatinine. Odds ratio of <1 was seen with albumin, ALP, urea and bilirubin. The p-value was significant for all these variables.
Table 2: Significant laboratory parameters

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Complications

[Table 3] shows that 62% patients had one or more organ dysfunction and 35% had AKI, which was oliguric in 60.4%. In all, 11.6% required haemodialysis and two mortalities were noted. Hepatitis was present in 29.2% and 26% patients developed ARDS; 8.1% patients had mild, 12.2% had moderate and 5.7% had severe ARDS; Meningoencephalitis was seen in 5.7%, with 1 death, while survivors recovered completely. Using multivariate logistic regression model for the above complications, outcome of 97.56% cases could be correctly predicted and the area under ROC curve was 0.991 [Figure 1]. The variables that were independently associated with mortality were showing presence of AKI, severe hepatitis, DIC, myocarditis and shock [Table 3].
Figure 1: ROC curve depicting the complications in scrub typhus patients.

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Table 3: Various complications observed in scrub typhus patients

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For more than one simultaneous complication, statistical significance was observable in those with AKI with hepatitis, AKI with ARDS, AKI with shock, hepatitis with ARDS, hepatitis with shock and ARDS with shock as shown in [Table 4].
Table 4: Outcomes associated with more than one simultaneous complication

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Severity assessment using SOFA score and outcome

Higher SOFA score was associated with worse outcome. The mean SOFA score in the survivors was 4.93 ± 2.78 and that of in the deceased was 12.2 ± 2.82. Apart from the total SOFA score, each of the sub-scores except that for platelet count was statistically significant [Table 5].
Table 5: Analysis of the SOFA score of participants

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Interventions required in the participants

Certain interventions were required during the course of illness as shown in [Table 6]. The need for mechanical ventilation and inotropes was associated with high mortality with statistical significance.
Table 6: Interventions required in the participants

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  Discussion Top


The Tricity region (Chandigarh, Panchkula and Mohali) is unique in that it is located at the foot hills of the Shivalik range of Himalayas. The resurgence of scrub typhus here is pronounced due to the demographic shifts and ecoepidemiological changes. Sharma et al[20] from Chandigarh region have observed hepatitis, AKI, shock, ARDS, DIC and MODS in 32, 61, 27, 32.16 and 20%, respectively. However, similar study from this region inferred that meningoencephalitis (27%), followed by ARDS (11%), AKI (9%) and shock (4%) were the most common complications[21]. There is considerable variation in the incidence of complications observed in various studies which may be partially attributed to different strains of the pathogen. Authors from far east Meghalaya simultaneously reported hepatitis in 16.7%, AKI in 12%, ARDS in 5% and MODS in 14.4%[22]. Kumar et al[8] found the incidence of hepatitis, shock and ARDS to be 71, 22.1 and 18.2%, respectively whereas Gupta et al[8],[12] reported these to be 54.5, 28 and 18.2%, respectively. In a case series of 55 patients of scrub typhus, 31 % had ARDS[23]. Complications reported from an outbreak in Goa were hepatitis in 80%, ARDS in 60%, AKI in 33%, DIC in 26%, shock 46.7% and MODS 33.3%[24]. Myocarditis and pancreatitis have been described in larger studies apart from being reported as isolated case reports[25],[26]. Pancreatitis has been documented in 6.6–13%, while myocarditis in 6.7%[8], [24]. Kumar et al[8] found them in 6.6 and 2.1%, respectively[8]. In our study, 2.4% had pancreatitis and 1.6% had myocarditis. We observed meningoencephalitis in 5.7% patients, which is in agreement with Kumar et al[8] (9%). Abhilash et al[27] recommended that in endemic regions, scrub typhus should be considered in the differential diagnosis of aseptic meningitis. Up to 20% of cases in the seasonal encephalitis outbreaks in Gorakhpur, Uttar Pradesh have been found to be caused by scrub typhus[28].

The mortality in our study was 8.1% while it was 13.6% in a study by Sharma et al[20] and nil in that by Gupta et al[12]. Sharma et al[20] observed that mortality in patients with MODS was 43% while that of in those without MODS was 11%[20]. Many authors have attempted to document the predictors of mortality. Sharma et al[20] found that ARDS requiring mechanical ventilation, AKI requiring dialysis, hypotension requiring inotropic support and central nervous dysfunction were linked with poor survival[20]. In another study, ARDS and AKI were the strongest risk factors for death[9]. A recent study has demonstrated high morbidity and mortality in scrub typhus associated with ARDS, besides highlighting that clinical features like dyspnoea, cough, low blood pressure (MAP <65 mmHg) and laboratory parameters like decreased haemoglobin, haematocrit, serum albumin, and increased serum creatinine, serum total bilirubin, transaminases, lactate dehydrogenase and serum lactate were statistically significant in scrub typhus patients with ARDS[29]. Univariate analysis in another large retrospective study showed that elevated bilirubin and alkaline phosphatase and requirement of inotropes or mechanical ventilation were associated with worse outcome, whereas on multivariate analysis, renal dysfunction, neurological dysfunction and shock were found to be independent predictors of mortality[30].

In our study, patients with AKI, hepatitis and shock were at an increased risk of death and this correlation was statistically significant. Multiorgan dysfunction increased the risk even more. On using logistic regression, ARDS was found to be significant predictor of mortality. Analysis of the SOFA score also yielded a statistically significant correlation with mortality. This may be a very significant finding as the mean SOFA score in those who survived was 4.93 ± 2.78 whereas it was 12.2 ± 2.82 in those who succumbed. Individually also, the subscores for PaO2/FiO2, serum bilirubin, creatinine, Glasgow Coma Scale (GCS) and mean arterial pressure (MAP) were higher in them. In a cohort of scrub typhus patients with multiorgan dysfunction, APACHE-II score and duration of fever independently predicted mortality[31]. In another study, the need for mechanical ventilation could be predicted by acute respiratory failure, SOFA score, APACHE-II score, platelet count, and LDH[32].


  Conclusion Top


Although being a geographically limited rural tropical disease, scrub typhus is now not uncommon to present to tertiary centres such as in Chandigarh. The disease has varied clinical outcomes and can be catastrophic unless it is swiftly diagnosed or treated empirically. We recommend that SOFA score be used at admission so as to classify patients who need intensive monitoring and care.

Conflict of interest: None.

 
  References Top

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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