Acute respiratory distress syndrome in Scrub typhus – An under recognized complication!

ABSTRACT

Scrub typhus is an acute febrile illness caused by the bacterium Orientia tsutsugamushi. It usually presents with high-grade fever, body aches, and skin rash. We report the case of a woman who presented with acute febrile illness, bilateral pneumonia, and severe hypoxemia. The presence of a typical eschar on the abdomen, made us suspect scrub typhus. Anti-O. tsutsugamushi Immunoglobulin M (IgM) antibody in the serum was detected in significant titers. She was treated with intravenous doxycycline and supplemental oxygen. Thus, scrub typhus should be considered in the differential diagnosis of febrile illness with acute respiratory distress syndrome.

Introduction

Scrub typhus is caused by bacteria Orientia tsutsugamushi (family Rickettsiaceae) and transmitted by the larvae of Leptotrombidium mites (chiggers).[1] The disease occurs when infected mite larvae bite human beings. Annually, over one million new infections are detected worldwide.[2] In India, it is a re-emerging disease but is largely an overlooked problem. We are reporting this case to highlight the significance of thorough history taking and clinical examination, and to raise awareness of its complications like acute respiratory distress syndrome (ARDS), which could be the presenting feature as in our case.

Case History

A woman in her mid-twenties was admitted to our hospital with high-grade fever, headache, body aches, and generalized weakness for 10 days for which she had taken symptomatic treatment elsewhere. On the eighth day of fever, she developed breathlessness which rapidly progressed, and she was dyspneic even at rest. She did not have a history of any significant medical ailment in the past. She did not have addictions and hailed from an urban area.

On examination, she was febrile, well oriented to time, person, and place, had a pulse rate of 124/min, blood pressure of 110/60 mm Hg, and respiratory rate of 32/min with accessory muscles of respiration working. She did not have jaundice, clubbing, generalized lymphadenopathy, or cyanosis. She had mild pallor and two enlarged, discrete lymph nodes in the right inguinal region. There was no skin rash. She had an area of blackish ulcer (“eschar”) on her right lower anterior abdominal wall as depicted in Figure 1a. Chest examination revealed crepitations bilaterally in the infrascapular area. Her oxygen saturation (SaO₂) was 76% while breathing ambient air. The rest of the systemic examination was within normal limits.

Figure 1.

(a) Eschar on the lower anterior abdominal wall and (b) showing chest radiograph with bilateral mid and lower zone opacities

Her various laboratory parameters were summarized in Table 1. Her peripheral blood smear was negative for the malarial parasite. Card tests for dengue fever and chikungunya were negative. Viral markers like hepatitis B and human immunodeficiency virus (HIV) I and II were non-reactive. Her chest radiograph showed bilateral lower and mid-zone pneumonia as shown in Figure 1b. Her blood gas analysis on room air revealed arterial pH of 7.4 with the partial pressure of carbon dioxide of 32 mm Hg and partial pressure of oxygen (PaO₂) of 41 mm Hg and SaO₂ of 78%. Her PaO₂/FiO₂ (fraction of inspired oxygen) ratio was <195.2 suggestive of moderate ARDS. Though the differential diagnosis for febrile illness is exhaustive and includes malaria, dengue fever, leptospirosis, enteric fever, and brucellosis, the presence of eschar is pathognomonic and boils it down to the rickettsial infection as the most likely cause of fever.

Table 1.

Laboratory investigations of the patient on the day of admission

Parameters	On admission	Normal range
Hemoglobin (gm/dL)	9.2	11.5-16.5
TLC (cells per mm3)	15,900	4,000-11,000
MCV (fL)	92.6	80-100
Platelet count (cells per mm3)	88,000	150,000-450,000
Reticulocyte count (%)	1.1	0.5-1.5
Serum LDH (U/L)	533.7	140-280
Total serum protein (gm/dL)	6.6	6.6-8.3
Serum albumin (gm/dL)	2.97	3.5-5.2
Serum globulin (gm/dL)	3.63	2.5-3.5
Serum creatinine (mg/dL)	0.98	0.5-1.5
Total bilirubin (mg/dL)	0.95	0.2-1
Direct bilirubin (mg/dL)	0.7	0.1-0.5
ALT (U/L)	87.1 U/L	5-40
AST (U/L)	144.8 U/L	5-45
ALP (U/L)	140.8 U/L	35-125
PT (seconds)	11.32	11-16
C-Reactive Protein (CRP) (mg/dL)	16.9	0.5-1.5

She was treated with doxycycline 100 mg intravenously twice daily, along with other supportive treatment and supplemental oxygen at the rate of 10 L/min using a non-rebreathing face mask to maintain SaO₂ of more than 94%. Within 48 h of starting specific antibiotic treatment, her SaO₂ started improving. In the meantime, her Weil–Felix agglutination test showed antibody titers of 1:640 to Proteus OX-K antigen. Finally, the confirmatory test for O. tsutsugamushi Immunoglobulin M (IgM) antibody was too positive in 1:160 titers. The blood and sputum cultures were sterile. Subsequently over the next 5 days, she became afebrile and did not require supplemental oxygen any further. She was treated with antibiotics for 14 days and was discharged in stable condition.

In view of febrile illness with an eschar, positive Weil–Felix reaction and IgM O. tsutsugamushi antibody and dramatic response to doxycycline within 48 h, a final diagnosis of scrub typhus with its complication of ARDS was made.

Discussion

Scrub typhus, one of the commonest rickettsial infections, is endemic to “tsutsugamushi triangle” and has been reported from the various parts of the Indian subcontinent.[3,4] Incubation period varies from 5 to 14 days after being bitten by infected chiggers. It starts as an acute febrile illness with a sore throat, cough, myalgia, headache, skin rash, and an eschar at the site of inoculation. Devasagayam et al.[4] reported symptoms of confirmed cases in the descending order—fever (34.7%), eschar (22.1%), headache (18.2%), nausea/vomiting (17.1%), abdominal pain (10.5%), breathlessness (10.4%), cough (10.4%), jaundice (5.6%), and seizure (2.7%).

The presence of eschar in the setting of unexplained febrile illness is pathognomonic of scrub typhus though it may be found in other conditions. Our patient was not aware of its presence. It has been reported with variable frequency from 9.5% in North India (Mahajan et al.) to 90% of the cases in a Korean study.[5,6]

Severe scrub typhus is associated with the involvement of various organs. Pulmonary manifestations include bronchitis and interstitial pneumonia which may progress to ARDS. About 11% of scrub typhus patients progressed to ARDS with a mortality rate of 25% in a study by Wang et al.[7] Older age, development of thrombocytopenia, early onset of pneumonia, and delay in diagnosis were identified as risk factors for ARDS by Tsay et al.[8] In their 4 years’ study, 12 out of the 33 (36%) patients of scrub typhus developed pneumonia. Of these 42% progressed to ARDS and 2 (16%) expired. Sinha et al.[9] from north west India reported ARDS in 5 (11.5%) cases, of which 2 needed ventilatory support. It was observed in 20.5% of cases by Devasagayam et al.[4] while 19.1% required mechanical ventilation. Varghese et al.[3] observed respiratory system dysfunction as a part of multiple organ dysfunction syndrome (MODS) in 76.9% of cases. While ARDS was seen in 33.2% of cases, 68.9% needed ventilator support. Their case-fatality rate in those with ARDS was 18%. Pneumonia progressing to ARDS was one of the most common complications observed in more than one-third of hospitalized patients in a recent review by John and Varghese.[10]

The diagnosis was classically established earlier by the Weil–Felix reaction. Serologic tests like indirect immunofluorescence or enzyme-linked immunosorbent assay to detect IgM O. tsutsugamushi antibodies are used nowadays, with molecular tests such as quantitative polymerase chain reaction being restricted to high-resource settings.[3]

The mainstay of treatment of severe scrub typhus is doxycycline 100 mg twice daily for 14 days orally or intravenously. Azithromycin can also be used as an alternative.[11] While the response to treatment is often dramatic, failure of defervescence within 48 h should raise the suspicion of an alternative diagnosis. Treatment should be initiated while awaiting lab confirmation as delay in treatment might prove to be fatal. In our case, timely initiation of specific treatment halted the need for ventilation.

The initial clinical symptoms of scrub typhus are non-specific like other viral illnesses or malaria. There is a good chance of misdiagnosis due to lack of awareness of the disease and non-availability of the specific serological test. The diagnosis may be missed in the absence of rash or a typical eschar, or if the eschar is present in hidden areas of the body, such as the axilla or scrotum.[4]

Key points

1. Scrub typhus is an underdiagnosed cause of acute undifferentiated febrile illness with ARDS.

2. A high degree of suspicion along with a thorough clinical examination is needed to diagnose this disease.

3. One must be aware of its complications and atypical presentations, as a timely diagnosis can reduce the morbidity and mortality associated with this disease.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.