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J Family Med Prim Care
J Family Med Prim Care
JFMPC
J Family Med Prim Care
Journal of Family Medicine and Primary Care
2249-4863
2278-7135
Wolters Kluwer - Medknow India

JFMPC-13-3388
10.4103/jfmpc.jfmpc_1965_23
Original Article
Predictors of mortality in scrub typhus: A hospital-based study
Goyal Chandan
Ahmad Sohaib
Chauhan Rishabh
Tewatia Pavit
Department of General Medicine, Himalayan Institute of Medical Sciences, Jolly Grant, Dehradun, Uttarakhand, India
Address for correspondence: Dr. Sohaib Ahmad, Department of General Medicine, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Jolly Grant, Dehradun - 248 016, Uttarakhand, India. E-mail: sohadia@hotmail.com
8 2024
26 7 2024
13 8 33883392
16 12 2023
22 4 2024
29 4 2024
Copyright: © 2024 Journal of Family Medicine and Primary Care
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
ABSTRACT

Purpose:

Scrub typhus is a potentially life-threatening febrile illness associated with serious complications viz. pneumonia, acute respiratory distress syndrome, hepatic failure, acute kidney injury, encephalitis, and shock often culminating in mortality. We aimed to identify the predictors of mortality in scrub typhus.

Methods:

This prospective observational study was conducted in a tertiary referral hospital of the north Indian state of Uttarakhand on in-patients of scrub typhus hospitalized over 1 year

Results:

Of the 109 cases studied (54.1% males), 44% were aged <40 years. Fever (95.4%), loss of appetite (55.9%), myalgia (47.7%), pallor (40.3%), hepatomegaly (27.5%), eschar (17.4%), and splenomegaly (13.7%) were the main clinical features. Hepatic transaminitis (69.7%), renal insufficiency (44.0%), respiratory failure (37.6%), shock (33.9%), central nervous system (CNS) involvement (21.1%), and severe anemia (7.3%) were the major complications at presentations. Intensive care and mechanical ventilation were utilized in 33.9% and 15.5% of cases, respectively. Multivariate logistic regression suggested renal insufficiency, CNS involvement, shock, severe anemia, and mechanical ventilation independently associated with death.

Conclusion:

Respiratory failure, renal insufficiency and neurological involvement, mechanical ventilation, shock, and severe anemia at presentation predict mortality in scrub typhus.

Mortality
renal failure
respiratory distress
scrub meningoencephalitis
scrub typhus,
==== Body
pmcIntroduction

Scrub typhus is a re-emerging potentially life-threatening febrile illness caused by Orientia tsutsugamushi, an obligate intra-cytosolic gram-negative bacterium transmitted by the bite of a trombiculid mite.[1] The endemic “tsutsugamushi triangle” encompasses densely populated regions of Southeast Asia, Northern Australia, and the Asian Pacific Rim with huge human population at risk[2]; one million people are infected annually in South Asia alone.[3] Scrub typhus constitutes 23% of all hospitalizations due to febrile illnesses in some areas of Southeast Asia across all ages. Preterm delivery, small-for-gestational age infants, and increased number of fetal losses are reported when pregnant females are infected. Median mortality rate in the untreated is 6%; mortality decreases to 1.4% in those treated appropriately.[4]

Following the bacterial invasion of endothelial cells, there is disseminated vasculitis and perivascular inflammation resulting in significant vascular leakage and end organ injury. After an incubation period of 6–21 days, patient presents with non-specific symptoms, such as fever, myalgia, hepatosplenomegaly, lymphadenopathy, and thrombocytopenia. A primary papular lesion, which later crusts to form a flat black eschar, may be present. Serious complications in untreated cases, such as pneumonia, acute respiratory distress syndrome, myocarditis, hepatic failure, gastrointestinal bleeding, acute kidney injury, encephalitis, and shock, may occur and are responsible for mortality.[5] Laboratory investigation generally shows thrombocytopenia, leucopenia, proteinuria, deranged renal and hepatic function, and reticulonodular infiltrates on chest radiographs. Due to the potential for fatal complications, presumptive diagnosis and early treatment should be started pending confirmation by serologic tests.

The disease is grossly under-diagnosed in low- as well as middle-income countries because of limited awareness and lack of diagnostic facilities. This leads to delay in specific treatment and increase in preventable morbidity and mortality.[6] Scrub typhus was acknowledged as a major cause of fever in the Garhwal division of Uttarakhand in 2010 and an important cause of mortality.[78] The aim of this study was to identify the predictors of mortality in scrub typhus.

Methods

Study duration–1 year (January–December 2022).

Study design—Observational study.

Sample size—109.

Data collection

All consecutive patients of scrub typhus were recruited for the single-center study after obtaining the institutional ethics committee approval and patients’ written informed consent. Included were adult patients with febrile illness diagnosed with scrub typhus on the basis of positive IgM by enzyme-linked immunosorbent assay (ELISA). Those with serological or culture-based evidence of other infections were excluded. Demographic data, including duration of fever, relevant clinical details, and investigations, were recorded.

Data interpretation

The outcomes of the patients were categorized as favorable (improved and discharged) or unfavorable (expired or leaving against medical advice due to non-improvement). Parameters of morbidity viz. blood and blood product transfusion, and need for intensive care and dialysis were recorded. Renal impairment (renal failure) was defined as oliguria (<400 ml/24 hours) along with the rise in serum creatinine (>3 mg/dl) and no improvement with rehydration. Respiratory failure was defined as tachypnea (>20/min) requiring non-invasive ventilation along with a fall in saturation of oxygen to <90%. Central nervous system (CNS) involvement was considered if there was failure to localize or respond appropriately to noxious stimuli or if coma persisted for >30 min after generalized convulsions. Hemoglobin <7 gm/dl and platelet counts <20,000/cumm were labeled as severe anemia and severe thrombocytopenia, respectively. Variable combinations of parameters of morbidity were compared between the two outcome groups.

Data analysis

Data were analyzed by statistical software SPSS version 22. Quantitative variables were expressed as mean and standard deviation. Categorical variables were expressed as frequency and percentage. The Chi-square/Fisher’s exact test was used to assess the association between risk factors and outcome. Logistic regression analysis was conducted to estimate univariate odds ratio (95%CI) for adverse outcome, that is, mortality. P value < 0.05 was taken as significant.

Results

Of the 109 cases, there was a slightly male preponderance as compared to female with the mean age of 43.9 years. Nearly half of our patients were aged below 40 years. Major presenting symptoms observed among patients were fever, loss of appetite, and myalgia. Fever was seen in almost all patients, while loss of appetite and myalgia were seen in half of the patients. Major signs were pallor noted in half; however, hepatomegaly, eschar, and splenomegaly were observed in one-third of subjects. Pallor was observed in half of the patients, while other signs were seen in one-third of the patients. Nearly one-third of the patients had thrombocytopenia and anemia as the main hematological abnormalities. Oxygen supplementation via nasal prongs was required in half of the patients who had respiratory involvement; furthermore, one-third of these patients ultimately needed mechanical ventilatory support.

Shock at the time of presentation was significantly associated with respiratory failure, intensive care, non-invasive and mechanical ventilation, kidney injury, and mortality with a P value of < 0.05. Similarly, there was a significant association observed among various organs alike CNS involvement and respiratory failure as well as with intensive care, oxygen requirement, and/or mechanical ventilation and mortality with a significant P value of < 0.05; liver injury was significantly associated with packed cell transfusions, intensive care, and non-invasive oxygen administration. However, there was no significant association seen in patients with other organ dysfunctions. Among hematological abnormalities, severe anemia was significantly associated with liver injury, respiratory failure, and intensive care.

About 14.6% of patients succumbed despite treatment. These patients had a significantly reduced serum albumin and platelet counts, while INR, blood urea nitrogen, creatinine, and blood glucose levels were significantly elevated in those who succumbed as compared to the survivors [Table 1].

Table 1 Comparison of complications in scrub typhus in relation to the outcomes

Parameters of morbidity	Expired (n=16)	Improved (n=93)	P	
Liver involvement (n=76)	10 (62.5)	66 (70.9)	0.559	
Renal insufficiency (n=48)	13 (81.2)	35 (37.6)	0.001	
Respiratory failure (n=41)	14 (87.5)	27 (29.0)	<0.001	
Shock (n=37)	11 (68.7)	26 (27.9)	0.003	
ICU admission (n=37)	14 (87.5)	23 (24.7)	0.001	
Renal insufficiency + liver involvement (n=30)	9 (56.2)	21 (22.5)	0.012	
Liver involvement + shock (n=27)	6 (37.5)	21 (22.5)	0.219	
Respiratory failure + renal insufficiency (n=26)	12 (75.0)	14 (15)	<0.001	
Respiratory failure + liver involvement (n=25)	9 (56.2)	16 (17.2)	0.002	
CNS involvement (n=23)	9 (56.2)	14 (15.0)	0.001	
Respiratory failure + shock (n=23)	10 (43.5)	13 (13.9)	<0.001	
Renal insufficiency + shock (n=22)	8 (50)	14 (15.0)	0.004	
Mechanical ventilation (n=17)	11 (68.7)	6 (6.4)	0.001	
Respiratory failure + renal insufficiency + liver involvement (n=17)	8 (50.0)	9 (9.6)	<0.001	
Respiratory failure + renal insufficiency + shock (n=17)	8 (50.0)	8 (8.6)	<0.001	
Renal insufficiency + liver involvement + shock (n=16)	5 (31.2)	11 (11.8)	0.058	
Liver + CNS involvement (n=15)	6 (37.5)	9 (9.6)	0.009	
Packed RBC transfused (n=14)	5 (31.2)	9 (9.6)	0.017	
CNS involvement + respiratory failure (n=13)	8 (50.0)	5 (5.3)	<0.001	
CNS involvement + renal insufficiency (n=12)	7 (43.7)	5 (5.3)	<0.001	
CNS + respiratory failure + liver involvement (n=11)	7 (43.7)	4 (4.3)	<0.001	
CNS + respiratory failure + renal involvement (n=10)	7 (43.7)	3 (3.2)	<0.001	
Respiratory failure + renal insufficiency + liver involvement + shock (n=9)	4 (25.0)	5 (5.3)	0.25	
CNS + respiratory failure + renal + liver involvement (n=9)	6 (37.5)	3 (3.2)	<0.001	
Severe anemia (n=8)	3 (18.7)	5 (5.3)	0.092	
CNS involvement + shock (n=7)	3 (18.7)	4 (4.3)	0.063	
CNS + respiratory failure + shock (n=6)	4 (25.0)	2 (2.1)	0.004	
Hemodialysis (n=5)	3 (18.7)	2 (2.1)	0.022	
Severe anemia + shock (n=5)	3 (18.7)	2 (2.1)	0.022	
CNS + respiratory failure + renal involvement + shock (n=4)	3 (18.7)	1 (1.0)	0.010	
CNS + respiratory failure + renal + liver involvement + shock (n=4)	3 (18.7)	1 (1.0)	0.010	
Severe thrombocytopenia (n=4)	2 (12.5)	2 (2.1)	0.102	
Shock + thrombocytopenia (n=3)	1 (6.2)	2 (2.1)	0.394	
Respiratory failure + renal insufficiency + severe anemia (n=3)	2 (12.5)	1 (1.0)	0.056	
Respiratory failure + renal insufficiency + thrombocytopenia (n=1)	1 (6.2))	0 (0.0)	0.147	
CNS + respiratory failure + severe anemia (n=1)	1 (6.2)	0 (0)	0.147	
CNS + respiratory failure + thrombocytopenia (n=1)	1 (6.2)	0 (0)	0.147	
CNS + respiratory failure + renal involvement + severe anemia (n=1)	1 (6.2)	0 (0)	0.147	
CNS + respiratory failure + renal involvement + thrombocytopenia (n=1)	1 (6.2)	0 (0)	0.147	
Figures in parentheses reflect the percentage of the column

It was observed that the presence of respiratory failure (odds ratio = 16.8, P < 0.001), intensive care unit (ICU) admission (odds ratio = 22.1, P < 0.001), oxygen therapy (odds ratio = 16.8, P < 0.001), mechanical ventilation (odds ratio = 38.8, P < 0.001), hemodialysis (odds ratio = 10.8, P = 0.015), transfusion of packed red blood counts (RBCs) (odds ratio = 4.1, P = 0.026), CNS involvement (odds ratio = 7.1, P = 0.001), renal insufficiency (odds ratio = 8.5, P = 0.015), and shock (odds ratio = 5.5, P = 0.003) were significantly associated with in-hospital death due to scrub typhus infection. In univariate analysis, severe anemia did not show significant association with death (odds ratio = 4.1, P = 0.07). Multivariable logistic regression using statistically significant risk factors suggested renal insufficiency, CNS involvement, shock, severe anemia, and mechanical ventilation independently associated with death. However, the confidence interval (CI) was very wide because of small number of events (mortality).

We also compiled the combinations of the various parameters of morbidity and compared them in survivors and those with an adverse outcome [see Table 1]. As mentioned above, the low numbers of those who succumbed prevented us from formulating a nomogram and assigning the relative contribution of these parameters to the mortality.

Discussion

Mortality in scrub typhus infection was seen to be significantly associated with shock, severe anemia, and renal and/or neurological involvement along with respiratory failure necessitating the need for mechanical ventilation at the time of presentation. Multi-organ dysfunction with or without shock was also significantly associated with mortality.

Clinical presentation

The disease mainly affected young adults with a slight male preponderance concordant to the study conducted by Abhilash et al.[9] who reported 56.8% of cases. The reason for negligible gender preference lies in the fact that both the genders are almost equally involved in the agricultural activities and are exposed to bites of larval mites. Fever was the most common clinical manifestation similar to the observations noted by Vikrant et al.,[10] Singh,[11] Thipmontree,[12] and Mahajan et al.[13] Patients with scrub typhus frequently have multisystem involvement, the main target cells of O. tsutsugamushi are endothelial cells and monocytes, and the illness is associated with endothelial dysfunction and vasculitis. Involvement of the lungs and brain is the major cause of a fatal outcome[8] concordant to our observations.

Multisystem involvement

In our study, acute liver injury, renal insufficiency, respiratory failure, and neurological involvement were the main organ dysfunctions associated with scrub typhus and are also associated with mortality specifically when occurring simultaneously. Our observations of respiratory failure and acute respiratory distress syndrome (ARDS) in those who succumbed (75%) versus survivors (40.8%; P = 0.03) are corroborated by Verghese et al.[14] Likewise, renal failure was evident in 41.7% of those who died as compared to 10.6% of the survivors (P = 0.005).[14]

Similar conclusions were put forth by Bhargava et al.[8] for ARDS (16.2%) and its impact on the mortality (68.9% vs 7.12%; P < 0.001). Henceforth, Sharma et al.[15] found a significant association between ARDS (25%; P < 0.001), renal failure (32%; P < 0.001), and mortality. Another study conducted by Verghese et al.[16] found that mortality was statistically significantly associated with mechanical ventilatory support (83.3%), hepatic failure (61%), and cerebral dysfunction (7%) with a P value < 0.05.

Multisystem involvement with complications

Those who succumbed had multi-organ dysfunctions with/out shock suggesting either a highly virulent strain or a compromised host. Moreover, CNS tropism may be responsible for an adverse outcome as suggested by CNS involvement as an independent predictor of mortality even in the absence of other organ dysfunctions. The point is validated by the association of neurological involvement with respiratory failure necessitating intensive care and ventilation.

Outcome

The fact that the patients in the outcome categories had no significant difference in their mean age and comorbidities suggests that the hosts may be compromised by the organism itself following the infection. Among the organ dysfunctions studied, liver injury seems to be merely transaminitis significantly associated with anemia; albeit, there is apparently no association with other organ dysfunction, prolongation of hospitalization, and mortality.

The strength of the study was the protocol-based evaluation and comparison of various clinical features, hematological, biochemical parameters, and organ dysfunction which were conducted for the outcome-based categories. The study was conducted at a single-center catering to a population at risk for contracting the disease, and hence, it provides an insight into the relevance of clinical presentation and its impact on the outcome of the disease. This may have ramifications in assessing the prognosis of patients despite optimum treatment in those with organ dysfunction at presentation for a potentially fatal disease that is endemic to the region.

Limitation

The limitation of our study was owing to the small numbers especially in those with adverse outcome limited the statistical conviction for the studied predictors of mortality especially for the community at risk.

Ethics approval

“This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Swami Rama Himalayan University, Dehradun, India (Date 14.09.2022/No SRHU/HIMS/ETHICS 2022/280).”

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.
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