Case Report: Scrub Typhus manifesting as Acute Respiratory Distress Syndrome (ARDS) with corresponding radiological findings

Background Scrub typhus is a life-threatening infectious disease endemic in the Asia-Pacific region. It typically presents with nonspecific symptoms such as fever, headache, and myalgia, making early diagnosis challenging. Acute Respiratory Distress Syndrome (ARDS) is a severe pulmonary condition characterized by acute-onset hypoxemia, bilateral lung infiltrates on radiology, and increased pulmonary capillary permeability. Case Presentation An 18-year-old female student in central India presented with a seven-day history of recurrent fever, chills, dry cough, and severe shortness of breath, escalating to Modified Medical Research Council dyspnea grade III-IV. After unsuccessful local clinic treatment, a chest radiograph revealed bilateral pneumonia. On admission, she displayed tachycardia, tachypnea, hypotension, and hypoxia requiring non-invasive ventilation (NIV). Computed tomography confirmed scrub typhus-associated pneumonia, and serological testing was positive for scrub typhus. She was diagnosed with moderate ARDS and began treatment. Symptomatic improvement was seen in the ICU, and she was discharged on day 10 with radiological and clinical resolution. Management and Outcomes She received intravenous doxycycline and oral azithromycin for scrub typhus and any potential concurrent lung infection. In the ICU, she required continuous NIV and supplemental oxygen, with significant symptomatic improvement, evidenced by reduced tachypnoea and oxygen requirements after 72 hours. She was weaned off NIV and monitored for an additional four days. After satisfactory oxygen saturation on room air, she was discharged on the tenth day. High-resolution CT scan demonstrated resolution of ground glass opacities and consolidation. Sequential chest radiographs exhibited gradual reduction in bilateral alveolar infiltrates over time, in parallel with clinical improvement. Laboratory findings, including reduced CRP and D-dimer values, and a normal hemogram on discharge indicated a resolution of leukopenia. Conclusion This case underscores the importance of early recognition and intervention in scrub typhus-associated ARDS and highlights the utility of timely diagnostic imaging in monitoring the progress of the disease.

typhus and any potential concurrent lung infection.In the ICU, she required continuous NIV and supplemental oxygen, with significant symptomatic improvement, evidenced by reduced tachypnoea and oxygen requirements after 72 hours.She was weaned off NIV and monitored for an additional four days.After satisfactory oxygen saturation on room air, she was discharged on the tenth day.Highresolution CT scan demonstrated resolution of ground glass opacities and consolidation.Sequential chest radiographs exhibited gradual reduction in bilateral alveolar infiltrates over time, in parallel with clinical improvement.Laboratory findings, including reduced CRP and D-dimer values, and a normal hemogram on discharge indicated a resolution of leukopenia.

Conclusion
This case underscores the importance of early recognition and intervention in scrub typhus-associated ARDS and highlights the utility of timely diagnostic imaging in monitoring the progress of the disease.
This article is included in the Emerging Diseases and Outbreaks gateway.This article is included in the Datta Meghe Institute of Higher Education and Research collection.
Introduction Scrub typhus, an infectious ailment brought on by the rickettsial microbe Orientia tsutsugamushi, presents a significant challenge to public health across the Asia-Pacific region.It's notably prominent within the expansive domain referred to as the "tsutsugamushi triangle." 1,2Notably, a recent study on the burden of scrub typhus in India, situated within this geographical region, unveiled its substantial impact, contributing to at least 25.3% of acute undifferentiated febrile illness (AUFI) cases.This disease typically exhibits clinical symptoms following an incubation period of 6-21 days, characterized by fever, headaches, myalgia, and various gastrointestinal issues. 3e pathophysiology of O. tsutsugamushi involves the infection of endothelial cells, leading to vasculitis, followed by the infiltration of T cells and monocytes/macrophages around blood vessels.This sets off a complex cascade of inflammatory responses, where various cytokines are produced by both endothelial and non-endothelial cells.These responses, while serving antimicrobial purposes, can also harm the host's tissues.This dual nature of the immune response can give rise to severe complications, including hepatitis, renal failure, meningoencephalitis, acute respiratory distress syndrome (ARDS), respiratory failure, and occasionally myocarditis. 1 Typical clinical presentations of scrub typhus encompass fever, generalized lymph node enlargement, cough, shortness of breath, muscle pain, headaches, skin rashes, eschar formation, loss of appetite, vomiting, and abdominal discomfort.Unusual complications, although infrequent, may include meningoencephalitis, glomerulonephritis, acute renal failure (ARF), interstitial pneumonia, acute respiratory distress syndrome (ARDS), acute hepatic failure, myocarditis, pericarditis, gastrointestinal bleeding, septic shock, acute hearing loss, acute cholecystitis, and intracranial haemorrhage. 4rub typhus manifesting as Acute Respiratory Distress Syndrome (ARDS) is unique in medical literature due to the convergence of a tropical infectious disease, caused by Orientia tsutsugamushi, with a severe respiratory condition.This combination is distinctive because it involves a broad spectrum of clinical complications, which can include lifethreatening ARDS, not commonly associated with tropical infections.The rarity of this manifestation and the complex interplay between vasculitis, immune responses, and tissue damage make it a subject of special interest in the medical community.Understanding this unique presentation is crucial for early diagnosis and effective management, given the potential for severe morbidity and mortality associated with scrub typhus-induced ARDS. 5 Case report A 18-year-old student hailing from Wardha, India, with recent travel history to Amravati, was urgently brought to Acharya Vinoba Bhave Hospital.She presented with a triad of fever accompanied by chills and rigors 3 to 4 episodes, recurring over the past week.In addition to her febrile episodes, she reported a persistent dry cough for three days and experienced a notable exacerbation of shortness of breath over the previous two days, reaching a severity classified as grade III-IV on the modified Medical Research Council (mMRC) dyspnea scale.Despite seeking initial treatment at a local clinic for two days, her symptoms showed no improvement.Subsequently, a chest radiograph revealed bilateral pneumonia, prompting her referral to the hospital for comprehensive evaluation and management.
During her initial hospitalization, the patient continued to suffer from fever, chills, and acute shortness of breath.She experienced orthopnoea (breathlessness when lying down), and her dry cough exacerbated when supine.On admission, her vital signs included a high pulse rate of 127 beats per minute regular rhytm, a rapid respiratory rate of 36 breaths per minute, blood pressure at 100/70 mmHg, peripheral oxygen saturation of 82% on room air and a body temperature of 98.7°F.A respiratory examination revealed diminished breath sounds bilaterally and scattered crepitations in both lung fields.No evident abnormalities were observed in her central nervous, cardiovascular, or gastrointestinal systems.
Arterial blood gas analysis (ABG) confirmed type I respiratory failure with severe hypoxia on room air PaO 2 of 47 mmHg (normal 80 -100 mmHg), pH of 7.39, pCO 2 of 41 mmHg (normal 40-45 mmHg), HCO 3 of 23 mEq/l necessitating noninvasive positive pressure ventilation.The patient's PF ratio of 153 mmHg suggested moderate ARDS as per Berlin's definition.A chest CT upon admission revealed diffuse ground glass opacities with patchy consolidations in both lungs,

REVISED Amendments from Version 1
Important corrections and a few details have been added to this version which will help with the better understanding of the case.
Any further responses from the reviewers can be found at the end of the article indicative of interstitial pneumonia, along with bilateral mild pleural effusion and a CT Severity index of 21/25, illustrating disease progression.
A complete blood count demonstrated leukopenia with a white blood cell count of 3200 cells/mm 3 , and smears and antigen testing for malarial parasites were negative.Blood samples were forwarded for further analysis, and the initial treatment regimen included intravenous piperacillin and tazobactam (4.5 grams three times a day) alongside azithromycin (500 mg once daily).The patient also received nebulized bronchodilators and inhaled corticosteroids.
The diagnostic workup, focusing on the patient's fever pattern, confirmed a positive serological test for scrub typhus while testing negative for Widal, leptospira, and dengue.Blood and sputum samples, despite being sent for culturing, showed no growth.Elevated levels of C-reactive protein and D-dimer, notably CRP 108 mg/dl (< 5 mg/dl is normal) and D-dimer 2350 ng/dl (< 500 ng/dl is normal), led to the initiation of low molecular weight heparin therapy.A diagnosis of scrub typhus with moderate ARDS was established, prompting the initiation of intravenous doxycycline (100 mg twice daily) and oral azithromycin (500 mg once daily) to manage any concomitant lung infection.
In the ICU, the patient required noninvasive ventilation (NIV) for the initial four days continuously with FiO 2 of 60% PEEP of 5 cm of H 2 O and IPAP of 14 cm of H 2 O, supplemented with 8-10 L of oxygen via a face mask during meals.She exhibited symptomatic improvement after 72 hours, with a gradual reduction in tachypnea and a decreased need for oxygen.Consequently, she was successfully weaned off NIV and transferred to the general ward, where she was monitored for an additional four days.Her ability to maintain oxygen saturation on room air improved, eliminating the need for external oxygen support, and she was discharged on day 10 of her hospital stay.
In Figure 1, upon admission, the high-resolution computed tomography (HRCT) of the thorax reveals bilateral extensive diffuse areas of ground glass opacification, accompanied by superimposed patchy consolidation.The CT severity score for these findings is notably high, with a recorded score of 21 out of 25.These radiological characteristics align with the typical imaging manifestations of scrub typhus-associated acute respiratory distress syndrome (ARDS).High-resolution chest CT scan conducted before discharge illustrated the satisfactory resolution of ground glass opacities and consolidations, affirming her clinical improvement (Figure 2).Sequential chest radiographs, as shown in Figures 3, 4, and 5 displayed a gradual reduction in bilateral alveolar infiltrates over time, further correlating radiological resolution with symptomatic improvement.These positive outcomes were reinforced by significant changes in diagnostic markers during her follow-up, where CRP and D-dimer values markedly reduced and her hemogram returned to normal, demonstrating the resolution of leukopenia.CRP decreased from 108 to 21, D-dimer decreased from 2350 to 430, hemoglobin slightly decreased from 11.5 to 11.2, white blood cell count increased from 3200 to 4900, and platelet count improved from 245,000 to 345,000.This comprehensive case presentation underscores the patient's challenging journey from illness to recovery, emphasizing the vital role of early diagnosis and effective management in scrub typhus-associated ARDS.

Discussion
Scrub typhus is a prevalent infectious disease in India, with a higher susceptibility among individuals residing in rural areas, particularly agricultural workers and military personnel. 6,7The clinical spectrum of scrub typhus varies from constitutional symptoms commonly seen in acute febrile illnesses, such as fever, headache, cough, and the presence of an eschar, to severe and potentially life-threatening complications, including pneumonitis, encephalopathy, shock, and septicemia. 8The characteristic necrotic eschar associated with scrub typhus is typically observed at the site of the wound.Fatality rates are influenced by delayed presentation, diagnostic challenges, and drug resistance. 8Importantly, scrub typhus has the potential to progress into acute respiratory distress syndrome (ARDS), displaying a spectrum of lungrelated symptoms ranging from bronchitis and interstitial pneumonitis to the eventual onset of ARDS. 9 In a comprehensive study by Wang CC et al., which focused on ARDS among individuals afflicted with scrub typhus, a mortality rate    of approximately 25% was reported.However, it's noteworthy that this figure could be mitigated through the prompt application of appropriate interventions, such as doxycycline or chloramphenicol. 10 the presented case, the absence of a pathognomonic eschar posed a diagnostic challenge, necessitating the diagnosis of scrub typhus primarily based on ELISA results.Notably, this diagnostic approach underscores the significance of considering scrub typhus as a potential etiology for ARDS, especially in endemic regions.
The identification of diffuse bilateral ground-glass opacities with a peripheral and subpleural distribution, consolidations, and mediastinal lymphadenopathy on CT scans can contribute to the diagnosis of scrub typhus-associated pneumonia.In this case, timely recognition and the initiation of appropriate antibiotic therapy were critical for enhancing patient outcomes.
The strengths of our approach lie in the prompt recognition of scrub typhus as a potential cause of ARDS, even in the absence of a characteristic eschar.The utilization of diagnostic imaging, such as CT scans, played a pivotal role in reaching an accurate diagnosis.Additionally, the adherence to evidence-based treatment protocols, including the use of appropriate antibiotics and non-invasive positive pressure ventilation, demonstrated positive outcomes for the patient.
However, there are some limitations to consider.The delayed presentation of the patient to the healthcare facility highlights the need for increased awareness and early diagnostic strategies for scrub typhus.This case emphasizes the significance of early diagnosis, as delays can lead to severe complications.Additionally, despite the positive outcome in this case, it is essential to acknowledge that scrub typhus-associated ARDS can be associated with high mortality, making early intervention and accurate diagnosis crucial.
The follow-up diagnostic information in this case, including the significant reduction in CRP and D-dimer values and the return to normal hemogram, indicates the resolution of leukopenia and demonstrates the effectiveness of the treatment.The patient's perspective on the use of Bipap is noteworthy, as it reflects the importance of patient compliance and adaptation to treatment measures.The motivation and growing confidence of the patient with noticeable symptomatic improvement and reduced respiratory effort underscore the collaborative role of both clinicians and patients in achieving positive outcomes.

Conclusion
In conclusion, this case highlights the multifaceted challenges and successes in the diagnosis and management of scrub typhus-associated ARDS.It underscores the importance of early recognition, diagnostic imaging, and timely intervention in endemic regions, and the potential for positive outcomes when evidence-based treatment protocols are adhered to.Patient outcomes, as demonstrated in this case, underscore the significance of patient cooperation and adaptation to treatment measures, contributing to improved recovery and overall success in managing scrub typhus-associated ARDS.

Consent
Written informed consent from the patient for the use and publication of patient's data was taken.

4.
Saxena The case report has relevant information on ARDS in scrub typhus.
Regarding the background of the case, no information on prior treatment before the patient came to the current health care setting was mentioned.Specifically history of any antibiotics used outside, as this could reiterate the role of right group of antibiotics in treatment of scrub typhus.Since it is a case of scrub typhus and the supporting evidence clearly here is the serological testing, it will be worthwhile elaborating on the ELISA (IgM/IgG, kit name and the target antigen used).

Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?Yes

Is the case presented with sufficient detail to be useful for other practitioners? Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Zoonoses, Immunodiagnostics of infectious and auto immune conditions

Dear authors/Editor,
There is improvement in this article and I have suggested a few minor changes.I have not included any reservation as these are minor changes that can be made to avoid this cycle of repeating reviews.

Many thanks, Zahid
Is the background of the case's history and progression described in sufficient detail?Yes

Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?Yes

Is the case presented with sufficient detail to be useful for other practitioners? Yes
Competing Interests: No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
Reviewer

Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?Yes

Is the case presented with sufficient detail to be useful for other practitioners? Yes
Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Pediatric Intensive care
We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
Typical clinical presentations of scrub typhus encompass fever, generalized lymph node enlargement, cough, shortness of breath, muscle pain, headaches, skin rashes, eschar formation, loss of appetite, vomiting, and abdominal discomfort.Unusual complications, although infrequent, may include meningoencephalitis, glomerulonephritis, acute renal failure (ARF), interstitial pneumonia, acute respiratory distress syndrome (ARDS), acute hepatic failure, myocarditis, pericarditis, gastrointestinal bleeding, septic shock, acute hearing loss, acute cholecystitis, and intracranial hemorrhage.(Please provide frequency for these complications or clinical features) In the case report section, please avoid providing specific date and time of the presentation to minimize the risk of patient identification.
The vitals need further clarity and I think the temperature presented is wrong.It can not be 98C.Heart rate of 127 ?sinus tachycardia?
Please include reference for the lab results used in the case report.
The patient also received nebulized bronchodilators and inhaled corticosteroids.(Whatwas the reason for this?
Did this patient have any ABG prior to starting on NIV? Please include the results in the case report.
Please consider using arrows to highlight findings or areas of interest in the images.
The case report is well written however needs some changes as highlighted in the report.It provides details about a health problem of significant importance.

Is the background of the case's history and progression described in sufficient detail? Yes
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?Yes Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?Yes

Is the case presented with sufficient detail to be useful for other practitioners? Yes
Competing Interests: No competing interests were disclosed.
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.
The vitals need further clarity and I think the temperature presented is wrong.It can not be 98C.Heart rate of 127 ?sinus tachycardia?-Changes made.
-Tachycardia + Rhythm regular Please include reference for the lab results used in the case report. -added The patient also received nebulized bronchodilators and inhaled corticosteroids.(Whatwas the reason for this?
-patient had episodic wheezing hence bronchodilators and ICS added.No past history of OAD.
Did this patient have any ABG prior to starting on NIV? Please include the results in the case report.
-Yes, Details added O. tsutsugamushi infecte endothelial cells responsible of inflammatory cascade activation, which is involved in unusual manifestations such as hepatitis, meningoencephalitis, myocarditis or ARDS.According to authors, ARDS is a rare complication in case of tropical infectious disease, whereas its frequently observed in case of O. tsutsugamushi infection, due to this inflammatory activation.The different figures offer a useful view of lungs evolution according to time, which is often discuss and debate by clinicians.This manuscript is well written but some additional information are needed. Comments.
The patient presents a bilateral pneumonia, observed in chest radiography and in chest CT.
There was revealed diffuse ground glass opacities with patchy consolidations in both lungs, indicative of interstitial pneumonia.Authors report in the abstract and the description of the case that it is "characteristic imaging manifestations of scrub typhus-associated pneumonia".○ Is the background of the case's history and progression described in sufficient detail?Yes

Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?
Initial antimicrobial therapy was intravenous piperacillin and associated to azithromycin.Is it due to antimicrobial resistance profile of bacteria?Even in case of interstitial pneumonia images, which is due to other bacterias than communityacquired pneumonia?Antibiotic choice as keeping in mind the local resistance pattern and doxycycline was initiated once scrub typhus was confirmed 5.
Why introduction of nebulized bronchodilators and inhaled corticosteroids treatment?There are not recommended of ARDS, may it an interesting treatment in case of O. tsutsugamushi pulmonary infection?Nebulised bronchodilators and ICS were used as patient had occasional wheezing, not a known case of OAD.

6.
Low molecular weight heparin therapy seems to have been introduced according to the existence of a pro-inflammatory status (Elevated levels of C-reactive protein and D-dimer).With a NIV support responsible of a bed rest in a pubescent patient, is it not the standard care?Or is it a specific treatment in case of severe O. tsutsugamushi infection?
This was used as standard care and not specific to scrub typhus 7.
The conclusion could reinforce that Interstitial pneumonia images should make perform an ELISA test to search scrub typhus and introduce appropriate antibiotic treatment early in case of documentation and in such cases the treatment of O. tsutsugamushi is based on doxycycline or chloramphenicol, which are not the standard treatment in case of pneumonia.
Yes I agree, with you a detailed fever profile should be done for patients presenting with interstial pneumonias.

8.
Competing Interests: No competing interests were disclosed.
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Figure 1 .
Figure 1.On admission, HRCT of the thorax shows bilateral extensive diffuse areas of ground glass opacification with superimposed patchy consolidation; with a CT severity score of 21/25.These findings were consistent with the characteristic imaging manifestations of scrub typhus-associated ARDS.

Figure 2 .
Figure 2. On discharge, HRCT Thorax suggestive of good resolution with non-specific scattered ground glass opacities and no evidence of fibrosis.
Report 14 May 2024 https://doi.org/10.5256/f1000research.165517.r270078© 2024 Jouvet P et al.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Philippe JouvetUniversity of Montréal, Montréal, Canada Arnaud Wiedmann 1 Pediatrics, Sainte-Justine Hospital, Montreal, Québec, Canada 2 Pediatrics, CHU Nancy, Nancy, France Bhanushali et al. completed the informations related to the clinical case as best as possible.The case described enriches rare literature on the topic, making it possible to serve as a basis for discussion for similar situations.

Competing Interests:
No competing interests were disclosed.Reviewer Report 22 February 2024 https://doi.org/10.5256/f1000research.155477.r243744© 2024 Jouvet P et al.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Philippe Jouvet University of Montréal, Montréal, Canada Arnaud Wiedmann 1 Pediatrics, Sainte-Justine Hospital, Montreal, Québec, Canada 2 Pediatrics, CHU Nancy, Nancy, France Bhanushali and al. report a case of a 18 year-old indian female, who presented an ARDS due to scrub typhus.Scurub typhus is a frequent cause of unspecific acute undifferentiated febrile illness (fever, headaches, myalgia, and various gastrointestinal issues) in the Asia-Pacific region, due to the rickettsial microbe Orientia tsutsugamushi.
Why non-specific interstitial pneumonia images are characteristic of scrub typhus-associated pneumonia?Can the authors further specify what are the differential diagnosis ?Authors report a "low blood pressure at 100/70 mmHg", and a "body temperature of 98.7°C".A blood pressure at 100/70 mmHg is in the normal range, maybe there was other shock signs such as decrease urinary output?A temperature of 98.7°C is not compatible with life.Did authors mean 38.7°C?The conclusion could reinforce that Interstitial pneumonia images should make perform an ELISA test to search scrub typhus and introduce appropriate antibiotic treatment early in case of documentation and in such cases the treatment of O. tsutsugamushi is based on doxycycline or chloramphenicol, which are not the standard treatment in case of pneumonia.
○ ○The authors report a neutropenia but no neutrophils count is provided (only white blood cells) ○ Authors only report the initial PaO 2 FiO 2 ratio (at 153mmHg).They only notice the initial management with Non-Invasive Ventilation, without information in FiO 2 , or PEEP value, or PEEP evolution compared to chest radiography evolution.Could they had such information may be with a graph?○Initial antimicrobial therapy was intravenous piperacillin and associated to azithromycin.Is it due to antimicrobial resistance profile of bacteria?Even in case of interstitial pneumonia images, which is due to other bacterias than community-acquired pneumonia?○Whyintroduction of nebulized bronchodilators and inhaled corticosteroids treatment?There are not recommended of ARDS, may it an interesting treatment in case of O. tsutsugamushi pulmonary infection?○ Low molecular weight heparin therapy seems to have been introduced according to the existence of a pro-inflammatory status (Elevated levels of C-reactive protein and D-dimer).With a NIV support responsible of a bed rest in a pubescent patient, is it not the standard care?Or is it a specific treatment in case of severe O. tsutsugamushi infection?○