Chest radiographic manifestations of scrub typhus.

BACKGROUND AND RATIONALE: Respiratory system involvement in scrub typhus is seen in 20-72% of patients. In endemic areas, good understanding and familiarity with the various radiologic findings of scrub typhus are essential in identifying pulmonary complications.
MATERIALS AND METHODS: Patients admitted to a tertiary care center with scrub typhus between October 2012 and September 2013 and had a chest X ray done were included in the analysis. Details and radiographic findings were noted and factors associated with abnormal X-rays were analyzed.
RESULTS: The study cohort contained 398 patients. Common presenting complaints included fever (100%), generalized myalgia (83%), headache (65%), dyspnea (54%), cough (24.3%), and altered sensorium (14%). Almost half of the patients (49.4%) had normal chest radiographs. Common radiological pulmonary abnormalities included pleural effusion (14.6%), acute respiratory distress syndrome (14%), airspace opacity (10.5%), reticulonodular opacities (10.3%), peribronchial thickening (5.8%), and pulmonary edema (2%). Cardiomegaly was noted in 3.5% of patients. Breathlessness, presence of an eschar, platelet counts of <20,000 cells/cumm, and total serum bilirubin >2 mg/dL had the highest odds of having an abnormal chest radiograph. Patients with an abnormal chest X-ray had a higher requirement of noninvasive ventilation (odds ratio [OR]: 13.98; 95% confidence interval CI: 5.89-33.16), invasive ventilation (OR: 18.07; 95% CI: 6.42-50.88), inotropes (OR: 8.76; 95% CI: 4.35-17.62), higher involvement of other organ systems, longer duration of hospital stay (3.18 ± 3 vs. 7.27 ± 5.58 days; P< 0.001), and higher mortality (OR: 4.63; 95% CI: 1.54-13.85).
CONCLUSION: Almost half of the patients with scrub typhus have abnormal chest radiographs. Chest radiography should be included as part of basic evaluation at presentation in patients with scrub typhus, especially in those with breathlessness, eschar, jaundice, and severe thrombocytopenia.

Background and Rationale

Scrub typhus is an acute bacterial febrile illness caused by Orientia tsutsugamushi.[12] It has now reached endemic proportions and is the predominant pathogen causing acute undifferentiated febrile illness in many parts of India.[123] The basic pathogenesis is vasculitis and perivasculitis of the small blood vessels, resulting in multiple organ involvements.[45] Respiratory system (RS) involvement is quite common and may vary in severity from mild bronchitis to severe acute respiratory distress syndrome (ARDS) warranting mechanical ventilation. Abnormal chest radiography has been described in 42–72% of patients.[367] Common radiological abnormalities include parenchymal fine to coarse reticular infiltrates, nodular infiltrates, consolidation, pulmonary edema, and rarely pleural effusion. However, literature on chest radiographs seen in scrub typhus is scant and described in small cohorts. Familiarity with the various radiologic findings of scrub typhus is important in identifying and initiating prompt treatment, thus helping to reduce morbidity. The aim of this study is to describe the various findings of plain chest radiograph in a large cohort of patients with scrub typhus and to correlate them with clinical features and outcome. To our knowledge, this is the largest cohort of radiological description of pulmonary involvement due to scrub typhus.

Materials and Methods

The study is an analysis of a large, prospective observational study conducted in the emergency department (ED) and the Department of Radio-diagnosis at Christian Medical College, Vellore, which is a 2700-bedded tertiary care teaching hospital in South India. All consecutive adult patients (age >16 years) who presented to the ED and the outpatient department of general medicine between October 2012 and September 2013 and confirmed to have scrub typhus were screened. All patients who had chest X-ray done were included in the study. Diagnosis of ST was confirmed by IgM ELISA positivity (InBios International, Inc., Seattle, USA) and/or presence of a pathognomonic eschar. Chest X rays of these patients were obtained from the computerized hospital information processing system (CHIPS). All chest radiographs were interpreted and reported by two radiologists who were unaware of the final diagnosis. They reviewed the chest radiographs independently and reached a decision on the final interpretation by consensus. The abnormal chest radiographs were reviewed for the presence of radiographic findings such as reticulonodular opacities, airspace opacity, peribronchial thickening, pleural effusion, pulmonary edema, ARDS, and cardiomegaly. Among those who required intensive care or mechanical ventilation, only the abnormalities on X-rays done in the first 48 h of admission were considered as directly caused by scrub typhus. The patients were divided into two groups based on the chest radiographs: A normal chest radiographic group and an abnormal chest radiographic group. These groups were compared for factors associated with abnormal X-rays and the clinical outcome.

The data were analyzed using Statistical Package for Social Sciences software for Windows (SPSS Inc., Released 2007, version 16.0, Chicago, USA). For comparison between the groups, the continuous variables are presented as mean (standard deviation [SD]) or as median (range) depending upon the distribution of the data. Categorical and nominal variables are presented as percentages. Chi-square test or Fisher exact test was used to compare dichotomous variables, and t-test or Mann–Whitney test was used for continuous variables as appropriate. The differences between the two groups were analyzed by univariate analysis and multivariate logistic regression analysis, and their 95% confidence intervals (CI) were calculated. For all tests, a two-sided P < 0.05 was considered statistically significant.

This study was approved by the Institutional Review Board and Ethics Committee of Christian Medical College, Vellore (IRB Min. No. 8007 dated 19/09/2012), and patient confidentiality was maintained using unique identifiers.

Results

During the study period, 452 patients were confirmed to have scrub typhus. Chest X-ray was not done in 54 patients as they did not have any respiratory symptom and were treated on an outpatient basis. The study cohort contained 398 cases of scrub typhus who had chest radiographs done in the first 48 h of presentation.

The mean age of the patients was 43 ± 14.9 years, and there was a slight female predominance (57%). The mean duration of fever prior to presentation was 8.20 ± 3.2 days. A pathognomonic eschar was present in 58.8% (234/398) with common sites being the groin, genitalia, axilla, neck, and breast folds. Common presenting complaints included fever (100%), generalized myalgia (83%), headache (65%), breathlessness (54%), cough (24.3%), and altered sensorium (14%).

Almost half of the patients (49.4%) had normal chest radiographs. Common radiological pulmonary abnormalities included pleural effusion (14.6%), features of ARDS (14%), airspace opacity (10.5%), reticulonodular opacities (10.3%), peribronchial thickening (5.8%), and pulmonary edema (2%) [Table 1].

Table 1

Chest radiographic findings in scrub typhus (n=398)

Finding	Number	Percentage
Normal	197	49.4
Pleural effusion	58	14.6
Acute respiratory distress syndrome*	56	14
Airspace opacity	42	10.5
Reticulonodular opacity	41	10.3
Peribronchial thickening	23	5.8
Cardiomegaly	14	3.5
Pulmonary edema	8	2
Others	8	2

Others: Postinflammatory changes, granulomas, fibrosis, emphysema. *Bilateral near symmetric pulmonary infiltrates involving one-third or more of each lung field

Comparisons of related clinical and laboratory data between chest radiographic examinations with normal and abnormal findings are shown in Table 2. We found the symptom of breathlessness, presence of an eschar, platelet counts of <20,000 cells/cumm, total serum bilirubin >2 mg/dL to have the highest odds of having an abnormal chest X-ray. Multiple logistic regression analysis showed breathlessness (odds ratio [OR]: 3.02; 95% CI: 1.71–5.31; P < 0.001) and a sequential organ failure assessment score >6 (OR: 3.66; 95% CI: 1.87–7.18; P < 0.001) to be independent predictors of an abnormal chest X-ray.

Table 2

Univariate analysis of the variables among normal and abnormal chest X-ray findings

Variables	n, SD		OR (95% CI)	P
	Patients with normal CXR (n=189)	Patients with abnormal CXR (n=210)
Mean age (years)	40.35 (14.98)	46.43 (14.37)	1.03 (1.01-1.04)	<0.001
Age >60 years	21 (11.11)	37 (17.62)	1.71 (0.96-3.04)	0.068
Male sex	93 (49.21)	79 (37.62)	0.62 (0.42-0.93)	0.020
Duration of fever	8.4 (3.4)	8.1 (3.1)	0.97 (0.91-1.03)	0.337
Breathlessness	52 (27.51)	157 (74.76)	7.8 (5-12.19)	<0.001
Cough	34 (17.99)	56 (26.67)	1.66 (1.02-2.68)	0.039
Diabetes mellitus	27 (14.29)	34 (16.19)	1.16 (0.67-2.01)	0.598
Respiratory rate (/min)	23.53 (6.20)	31.93 (8.80)	1.17 (1.13-1.21)	<0.001
SpO2 <90%	16 (8.47)	80 (38.28)	6.71 (3.74-12.01)	<0.001
Eschar	92 (48.68)	143 (68.10)	2.25 (1.5-3.38)	<0.001
SOFA score	3.01 (2.79)	7.59 (4.50)	1.45 (1.34-1.58)	<0.001
Total WBC count (cells/mL)	9202.70 (4536.57)	11,066.19 (5265.81)	1.00 (1.00-1.00)	<0.001
Creatinine (mg/dL)	1.33 (1.14)	1.78 (1.43)	1.43 (1.15-1.79)	0.002
Bilirubin >2 (mg/dL)	28 (14.81)	82 (39.61)	3.77 (2.31-6.15)	<0.001
Albumin (mg/dL)	3.29 (0.62)	2.66 (0.56)	0.17 (0.11-0.26)	<0.001
SGOT (U/L)	136.88 (157.14)	152.95 (126.74)	1.001 (0.999-1.002)	0.266
SGPT (U/L)	88.68 (83.54)	80.43 (66.35)	0.999 (0.996-1.001)	0.278

SOFA: Sequential organ failure assessment, SGOT: Serum glutamic oxaloacetic transaminase, SGPT: Serum glutamic pyruvate transaminase, OR: Odds ratio, CI: Confidence interval, CXR: Chest X-ray, SD: Standard deviation

The comparison of clinical course and outcome between normal and abnormal chest radiographic groups is shown in Table 3. Patients with an abnormal chest X-ray had a higher requirement of oxygen therapy, noninvasive ventilation, invasive ventilation, inotropes, and higher involvement of other organ systems and had a longer duration of hospital stay.

Table 3

Comparison of clinical course and outcome in scrub typhus patients between normal and abnormal chest radiographic groups

Variables	n, SD		OR (95% CI)	P
	Patients with normal CXR (n=189)	Patients with abnormal CXR (n=210)
Noninvasive ventilation	6 (3.17)	66 (31.43)	13.98 (5.89-33.16)	<0.001
Invasive ventilation	4 (2.12)	59 (28.10)	18.07 (6.42-50.88)	<0.001
Oxygen requirement	30 (15.87)	144 (68.57)	11.56 (7.11-18.82)	<0.001
Inotropes requirement	10 (5.29)	69 (32.86)	8.76 (4.35-17.62)	<0.001
Duration of hospital stay	3.18 (3)	7.27 (5.58)	1.33 (1.23-1.43)	<0.001
CVS involvement	16 (8.47)	94 (44.76)	8.76 (4.91-15.65)	<0.001
Hematological involvement	110 (59.14)	176 (83.81)	3.58 (2.24-5.72)	<0.001
CNS involvement	24 (12.70)	66 (31.43)	3.15 (1.88-5.29)	<0.001
Hepatic involvement	90 (47.62)	161 (76.67)	3.61 (2.35-5.55)	<0.001
Renal involvement	46 (24.34)	86 (40.95)	2.16 (1.4-3.32)	<0.001
Outcome (mortality)	3 (2.12)	18 (9.09)	4.63 (1.54-13.85)	<0.001

Hematological involvement: Thrombocytopenia (platelet count <100,000/cells cumm), leukopenia (WBC count <2500/cells cumm), leukocytosis (WBC count >11,000/cells cumm) or evidence of coagulopathy, Renal involvement: Serum creatinine >1.4 mg/dL or need for dialysis, CVS involvement: Hypotension or need for inotropic or vasopressor support, CNS involvement: Alteration in the level of consciousness or aseptic meningitis, Hepatic involvement: Serum bilirubin >2 mg/dl or three-fold elevation of SGOT/SGPT or elevated alkaline phosphatase. SGOT: Serum glutamic oxaloacetic transaminase, SGPT: Serum glutamic pyruvate transaminase, OR: Odds ratio, CI: Confidence interval, CXR: Chest X-ray, SD: Standard deviation, WBC: White blood count, CNS: Central nervous system, CVS: Cardiovascular system

All the patients were treated with oral doxycycline (100 mg twice daily for 7 days) with or without intravenous azithromycin (500 mg once daily for 5 days). Seventy-four percent of patients required admission with 20.3% (81/398) requiring intensive care monitoring. The overall mortality rate was 5.1% (21/398) with patients with an abnormal X ray having a higher mortality (OR: 4.63; 95 % CI: 1.54-13.85).

Discussion

Scrub typhus results in significant morbidity and mortality in the Asia-Pacific region where it even accounts for up to 50% of undifferentiated febrile illness in some areas.[3] The mean duration of fever of 8.1 (SD: 3.2) days is comparable to the usual mean duration of presentation in most studies.[389] Our rate of finding an eschar in 58.8% of patients is similar to that reported from other studies that have been performed close to this geographic area.[10] However, the eschar pick-up rate is very varied and ranges from 9.5% to 90%.[811] In our institution, the pick-up rate for an eschar has improved from 45.5% in 2008 to 58.8% in our study.[3] This shows greater awareness and increases vigilance in searching for probably the most important diagnostic clue in patients with scrub typhus.[12]

As seen in our study, RS dysfunction due to scrub typhus is seen in a significant number of patients (46.4%). Varghese et al. described pulmonary dysfunction as the most common complication with majority of the patients eventually requiring invasive or noninvasive ventilatory support.[9] Respiratory symptoms have been reported to range from 20% to 72% among patients with scrub typhus.[3713] The common respiratory symptoms in our study were dyspnea (54%) and cough (22.6%). ARDS, which is probably the most serious pulmonary complication, has been reported in 8–34% of patients with severe scrub typhus.[38914]

In our study, almost half of the patients (49.4%) had normal chest radiographs. This is comparable with reports from Taiwan where 45.2% of the chest radiographs were normal.[15] Common radiological pulmonary abnormalities in our study included pleural effusion, ARDS, airspace opacity, reticulonodular opacities, peribronchial thickening, and pulmonary edema. Previous studies showed reticulonodular opacities, septal lines, pleural effusion, and hilar enlargement to be frequent chest radiographic abnormalities.[81216] In a study by Choi et al. (sample size: 75), the most frequent pulmonary abnormality was bilateral reticulonodular opacities (40%) while Wu et al. (sample size: 136) described pleural effusion as the most frequent abnormality in patients with scrub typhus. We found pleural effusion to be associated in 14.6% of our patients, a rate consistent with other studies (10.8–23.4%).[715] Chest radiographic features suggestive of ARDS were seen in 14% of our patients. In other studies, features of ARDS on chest radiography ranged from 6% to 25%.[315] Only 3.5% of our patients had cardiomegaly although it was reported in up to 28.5% of patients in some studies. Our study had a much larger sample size (452) and included both inpatients and outpatients whereas the other studies included only inpatients.[716]

A limitation of our study was that it was conducted at a single medical center, and hence, the patient population may be biased by patient selection and referral pattern. Nonetheless, the study provides relatively rare information about chest radiographic findings of adult scrub typhus patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.