urlscan.io logo urlscan.io
SecurityTrails logo

www.cureus.com Open in urlscan Pro
2606:4700:10::ac43:805  Public Scan

Back to summary
Submitted URL: http://criticalcare.news/sendy/l/KUMLZhmTwelO892Kf1LaaMaQ/ipcds2sTc16BX9A6vAgEIA/bQaPj7CaoClu763hNLtCSOoQ
Effective URL: https://www.cureus.com/articles/78251-high-dose-dexamethasone-versus-tocilizumab-in-moderate-to-severe-covid-19-pneumon...
Submission: On February 05 via api from US — Scanned from DE

Form analysis 5 forms found in the DOM

GET /articles

<form action="/articles" accept-charset="UTF-8" method="get" data-hs-cf-bound="true"><input name="utf8" type="hidden" value="✓">
  <i class="fa fa-search"></i>
  <input type="hidden" name="searched" id="searched" value="true">
  <input type="text" name="q" id="q" value="" placeholder="Search Cureus and PubMed Central">
  <div class="x-close">
    <div class="x"></div>
  </div>
</form>

<form accept-charset="UTF-8" data-hs-cf-bound="true">
  <div class="not-logged-in">Please <a>sign in</a> or <a>sign up</a> to comment.</div>
</form>

POST /publish/articles/78251-high-dose-dexamethasone-versus-tocilizumab-in-moderate-to-severe-covid-19-pneumonia-a-randomized-controlled-trial/send_sign_up_email?source=PDFDownload

<form id="pdf-email-form" action="/publish/articles/78251-high-dose-dexamethasone-versus-tocilizumab-in-moderate-to-severe-covid-19-pneumonia-a-randomized-controlled-trial/send_sign_up_email?source=PDFDownload" accept-charset="UTF-8" method="post"
  data-hs-cf-bound="true"><input name="utf8" type="hidden" value="✓"><input type="hidden" name="authenticity_token" value="o2MIEDoH0wPYhFPGNs3XFZT8jaDMHn9DaaszQV+77oheWOfKpd2/Dqej44jsfIAjLr32lTeuOyWt7PXbBiLMVQ==">
  <div class="large-8 large-offset-1 medium-8 medium-offset-1 columns">
    <input type="email" name="email" id="email" required="required">
  </div>
  <div class="large-1 medium-1 columns end">
    <input type="submit" name="commit" value="send" class="button special" id="pdf-download-button" data-disable-with="send">
  </div>
</form>

POST /users/sign_in?id=78251&open_comments=true&return_to=%2Farticles%2F78251-high-dose-dexamethasone-versus-tocilizumab-in-moderate-to-severe-covid-19-pneumonia-a-randomized-controlled-trial

<form class="new_user" id="new_user" action="/users/sign_in?id=78251&amp;open_comments=true&amp;return_to=%2Farticles%2F78251-high-dose-dexamethasone-versus-tocilizumab-in-moderate-to-severe-covid-19-pneumonia-a-randomized-controlled-trial"
  accept-charset="UTF-8" method="post" data-hs-cf-bound="true"><input name="utf8" type="hidden" value="✓"><input type="hidden" name="authenticity_token" value="o2MIEDoH0wPYhFPGNs3XFZT8jaDMHn9DaaszQV+77oheWOfKpd2/Dqej44jsfIAjLr32lTeuOyWt7PXbBiLMVQ==">
  <div class="form-label-input-wrap no-label">
    <div class="text-wrap">
      <label>Sign in with your email address:</label>
    </div>
  </div>
  <div class="form-label-input-wrap">
    <label for="user_email">Email</label>
    <div class="input-wrap">
      <input required="required" autofocus="autofocus" type="email" name="user[email]" id="user_email">
    </div>
  </div>
  <div class="form-label-input-wrap">
    <label for="user_password">Password</label>
    <div class="input-wrap">
      <input required="required" type="password" name="user[password]" id="user_password">
    </div>
  </div>
  <input value="true" type="hidden" name="user[remember_me]" id="user_remember_me">
  <div class="form-label-input-wrap no-label">
    <div class="devise-submit-wrap">
      <input type="submit" name="commit" value="Sign in" class="button primary large input-wrap" data-disable-with="Sign in">
    </div>
  </div>
</form>

POST /registrations?article_id=78251&return_to=%2Farticles%2F78251-high-dose-dexamethasone-versus-tocilizumab-in-moderate-to-severe-covid-19-pneumonia-a-randomized-controlled-trial&user_type=comment

<form class="new_user" id="continue_registration" data-parsley-validate="true"
  action="/registrations?article_id=78251&amp;return_to=%2Farticles%2F78251-high-dose-dexamethasone-versus-tocilizumab-in-moderate-to-severe-covid-19-pneumonia-a-randomized-controlled-trial&amp;user_type=comment" accept-charset="UTF-8" method="post"
  data-hs-cf-bound="true"><input name="utf8" type="hidden" value="✓"><input type="hidden" name="authenticity_token" value="o2MIEDoH0wPYhFPGNs3XFZT8jaDMHn9DaaszQV+77oheWOfKpd2/Dqej44jsfIAjLr32lTeuOyWt7PXbBiLMVQ==">
  <div class="form-label-input-wrap">
    <label for="user_first_name">First name</label>
    <div class="input-wrap">
      <input autofocus="autofocus" required="required" tabindex="1" type="text" name="user[first_name]" id="user_first_name">
    </div>
  </div>
  <div class="form-label-input-wrap">
    <label for="user_last_name">Last name</label>
    <div class="input-wrap">
      <input autofocus="autofocus" required="required" tabindex="2" type="text" name="user[last_name]" id="user_last_name">
    </div>
  </div>
  <div class="form-label-input-wrap">
    <label for="user_email">Email</label>
    <div class="input-wrap">
      <input required="required" autofocus="autofocus" tabindex="3" type="email" name="user[email]" id="user_email">
    </div>
  </div>
  <div class="form-label-input-wrap">
    <label for="user_password">Password</label>
    <div class="input-wrap">
      <input required="required" tabindex="4" type="password" name="user[password]" id="user_password">
    </div>
  </div>
  <div class="form-label-input-wrap">
    <label class="text control-label" for="user_specialty_id">Specialty</label>
    <div class="input-wrap">
      <select required="required" name="user[specialty_id]" id="user_specialty_id">
        <option value="">Please choose</option>
        <option selected="selected" value="361">I'm not a medical professional.</option>
        <option value="2">Allergy and Immunology</option>
        <option value="357">Anatomy</option>
        <option value="3">Anesthesiology</option>
        <option value="237">Cardiac/Thoracic/Vascular Surgery</option>
        <option value="249">Cardiology</option>
        <option value="360">Dentistry</option>
        <option value="10">Dermatology</option>
        <option value="13">Emergency Medicine</option>
        <option value="246">Epidemiology and Public Health</option>
        <option value="21">Family Medicine</option>
        <option value="363">Forensic Medicine</option>
        <option value="371">General Practice</option>
        <option value="47">Genetics</option>
        <option value="368">Health Policy</option>
        <option selected="selected" value="361">I'm not a medical professional.</option>
        <option value="353">Integrative/Complementary Medicine</option>
        <option value="27">Internal Medicine</option>
        <option value="362">Internal Medicine-Pediatrics</option>
        <option value="283">Internal Medicine: Critical Care</option>
        <option value="284">Internal Medicine: Diabetes and Endocrinology</option>
        <option value="285">Internal Medicine: Gastroenterology</option>
        <option value="352">Internal Medicine: Geriatrics</option>
        <option value="369">Internal Medicine: Hematology</option>
        <option value="281">Internal Medicine: HIV/AIDS</option>
        <option value="282">Internal Medicine: Hospital-based Medicine</option>
        <option value="286">Internal Medicine: Infectious Disease</option>
        <option value="287">Internal Medicine: Nephrology</option>
        <option value="288">Internal Medicine: Pulmonology</option>
        <option value="289">Internal Medicine: Rheumatology</option>
        <option value="314">Medical Education and Simulation</option>
        <option value="219">Medical Physics</option>
        <option value="370">Medical Student</option>
        <option value="59">Neurological Surgery</option>
        <option value="177">Neurology</option>
        <option value="60">Nuclear Medicine</option>
        <option value="364">Nutrition</option>
        <option value="61">Obstetrics and Gynecology</option>
        <option value="367">Occupational Health</option>
        <option value="267">Oncology</option>
        <option value="69">Ophthalmology</option>
        <option value="359">Oral Medicine</option>
        <option value="70">Orthopaedics</option>
        <option value="358">Osteopathic Medicine</option>
        <option value="73">Otolaryngology</option>
        <option value="354">Pain Management</option>
        <option value="355">Palliative Care</option>
        <option value="78">Pathology</option>
        <option value="114">Pediatrics</option>
        <option value="291">Pediatric Surgery</option>
        <option value="135">Physical Medicine and Rehabilitation</option>
        <option value="143">Plastic Surgery</option>
        <option value="351">Podiatry</option>
        <option value="146">Preventive Medicine</option>
        <option value="162">Psychiatry</option>
        <option value="244">Psychology</option>
        <option value="213">Radiation Oncology</option>
        <option value="207">Radiology</option>
        <option value="366">Substance Use and Addiction</option>
        <option value="225">Surgery</option>
        <option value="365">Therapeutics</option>
        <option value="356">Trauma</option>
        <option value="239">Urology</option>
        <option value="150">Miscellaneous</option>
      </select>
    </div>
  </div>
  <div class="row">
    <div class="large-12 columns">
      <h4 class="reg">Email Communication and Personal Data</h4>
    </div>
  </div>
  <div class="row">
    <div class="large-1 medium-1 small-1 columns">
      <input name="user[email_preference][gdpr_verify]" type="hidden" value="0"><input required="required" name="user[email_preference][gdpr_verify]" type="checkbox" value="1" id="user_gdpr_verify">
    </div>
    <div class="large-11 medium-11 small-11 columns">
      <label for="user_gdpr_verify">Cureus personal data will never be sold to third parties and will only be used to enrich the user experience and contact you in direct relation to the application. I agree to opt in to this communication.</label>
    </div>
  </div>
  <div class="form-label-input-wrap recaptcha-centered modal">
    <script src="https://www.recaptcha.net/recaptcha/api.js" async="" defer=""></script>
    <div data-sitekey="6LdWUksUAAAAADUnX2rBGTOHw17gZ-8NmKyvEDzG" class="g-recaptcha ">
      <div style="width: 304px; height: 78px;">
        <div><iframe title="reCAPTCHA"
            src="https://www.recaptcha.net/recaptcha/api2/anchor?ar=1&amp;k=6LdWUksUAAAAADUnX2rBGTOHw17gZ-8NmKyvEDzG&amp;co=aHR0cHM6Ly93d3cuY3VyZXVzLmNvbTo0NDM.&amp;hl=de&amp;v=1p3YWy80wlZ7Q8QFR1gjazwU&amp;size=normal&amp;cb=897s4a5z8fkq" width="304"
            height="78" role="presentation" name="a-n5e601w7lp1u" frameborder="0" scrolling="no" sandbox="allow-forms allow-popups allow-same-origin allow-scripts allow-top-navigation allow-modals allow-popups-to-escape-sandbox"></iframe></div>
        <textarea id="g-recaptcha-response" name="g-recaptcha-response" class="g-recaptcha-response" style="width: 250px; height: 40px; border: 1px solid rgb(193, 193, 193); margin: 10px 25px; padding: 0px; resize: none; display: none;"></textarea>
      </div><iframe style="display: none;"></iframe>
    </div>
    <noscript>
      <div>
        <div style="width: 302px; height: 422px; position: relative;">
          <div style="width: 302px; height: 422px; position: absolute;">
            <iframe src="https://www.recaptcha.net/recaptcha/api/fallback?k=6LdWUksUAAAAADUnX2rBGTOHw17gZ-8NmKyvEDzG" name="ReCAPTCHA" style="width: 302px; height: 422px; border-style: none; border: 0; overflow: hidden;">
            </iframe>
          </div>
        </div>
        <div style="width: 300px; height: 60px; border-style: none;
                bottom: 12px; left: 25px; margin: 0px; padding: 0px; right: 25px;
                background: #f9f9f9; border: 1px solid #c1c1c1; border-radius: 3px;">
          <textarea id="g-recaptcha-response" name="g-recaptcha-response" class="g-recaptcha-response" style="width: 250px; height: 40px; border: 1px solid #c1c1c1;
                  margin: 10px 25px; padding: 0px; resize: none;">                </textarea>
        </div>
      </div>
    </noscript>
  </div>
  <div class="form-label-input-wrap no-label-new modal">
    <p class="text-wrap submit-text-wrap modal"> By joining Cureus, you agree to our <a href="/privacy">Privacy Policy</a> and <a href="/terms">Terms of Use</a>. </p>
  </div>
  <div class="form-label-input-wrap no-label modal">
    <div class="devise-submit-wrap modal">
      <input type="submit" name="commit" value="Sign up" class="button primary large input-wrap modal" data-disable-with="Sign up">
    </div>
  </div>
</form>

Text Content

 * Home
 * Journal
    * Back
    * Journal
    * Articles
    * People
    * Posters
    * Specialties
       * Back
       * Specialties
       * Allergy/Immunology
       * Anatomy
       * Anesthesiology
       * Cardiac/Thoracic/Vascular Surgery
       * Cardiology
       * Dentistry
       * Dermatology
       * Emergency Medicine
       * Endocrinology/Diabetes/Metabolism
       * Environmental Health
       * Epidemiology/Public Health
       * Family/General Practice
       * Forensic Medicine
       * Gastroenterology
       * General Surgery
       * Genetics
       * Healthcare Technology
       * Health Policy
       * Hematology
       * HIV/AIDS
       * Infectious Disease
       * Integrative/Complementary Medicine
       * Internal Medicine
       * Medical Education
       * Medical Physics
       * Medical Simulation
       * Miscellaneous
       * Nephrology
       * Neurology
       * Neurosurgery
       * Nuclear Medicine
       * Nutrition
       * Obstetrics/Gynecology
       * Occupational Health
       * Oncology
       * Ophthalmology
       * Oral Medicine
       * Orthopedics
       * Osteopathic Medicine
       * Otolaryngology
       * Pain Management
       * Palliative Care
       * Pathology
       * Pediatrics
       * Pediatric Surgery
       * Physical Medicine & Rehabilitation
       * Plastic Surgery
       * Podiatry
       * Preventive Medicine
       * Psychiatry
       * Psychology
       * Public Health
       * Pulmonology
       * Quality Improvement
       * Radiation Oncology
       * Radiology
       * Rheumatology
       * Substance Use and Addiction
       * Therapeutics
       * Transplantation
       * Trauma
       * Urology

 * Publishing
    * Back
    * Publishing
    * About Publishing
    * Article Promotion Guide
    * Article Social Boost
    * Author & Reviewer Guides
    * Preferred Editing Service
    * SIQ™ (Scholarly Impact Quotient™)

 * Channels
    * Back
    * Channels
    * Academic Departments
       * Back
       * Academic Departments
       * Alabama College of Osteopathic ...
       * Annals of Simulation
       * Aurora Breast Health Proceedings
       * Baylor Scott & White Medical Ce ...
       * California Institute of Behavio ...
       * Contemporary Reviews in Neurolo ...
       * Dalhousie Emergency Medicine
       * FLAGSHIP: Medical Scholarly Pro ...
       * Houston Methodist Neurosurgery
       * Liberty Medicine Research Channel
       * Marcus Neuroscience Institute
       * Medicine-Pediatrics Academic Ch ...
       * Military Medical Simulation
       * Modern Medical Educator
       * NB Social Pediatrics Research
       * NEMA Research Group
       * Paolo Procacci Foundation
       * Penn State Neurosurgery
       * Research Update Organization
       * Sinai Chicago Research
       * Stanford Neurosurgery
       * The Florida Medical Student Res ...
       * UCSF Neurological Surgery
       * UCSF Surgical Neuroanatomy Coll ...
       * University of Florida-Jacksonvi ...
       * University of Louisville Neuros ...
       * University of Munich Neurology
   
    * Professional Societies
       * Back
       * Professional Societies
       * ACOS Cardiothoracic and Vascula ...
       * ACOS General Surgery
       * ACOS Neurological Surgery
       * ACOS Plastic and Reconstructive ...
       * ACOS Urological Surgery
       * American Red Cross Scientific A ...
       * Canadian Association of Radiati ...
       * International Liaison Committee ...
       * International Pediatric Simulat ...
       * Japan Radiosurgery Society
       * Medical Society of Delaware Aca ...
       * The Radiosurgery Society
   
    * About Channels

 * Competitions
    * Back
    * Competitions
    * Current
       * Back
       * Current
       * Surgically Targeted Radiation Th...
   
    * Archived
       * Back
       * Archived
       * Automated Whole Brain Tractography
       * Clinical and Economic Benefits o...
       * Clinical Applications and Benefi...
       * Defining Health in the Era of Va...
       * Exceptional Responders in Breast...
       * Exceptional Responders in Oncology
       * Frameless Stereotactic Radiosurgery
       * Intraoperative Fluorescence Rese...
       * Investigational Cardiac Radiosur...
       * MR-Guided Radiation Therapy: Cli...
       * Multiple Brain Metastases: Excep...
       * Negative Pressure Wound Therapy ...
       * NPWT with Instillation and Dwell...
       * Optimization Strategies for Orga...
       * Proton Therapy: Advanced Applica...
       * Radiation Therapy as a Modality ...
       * Strategies to Promote Long-Term ...
   
    * About Competitions

 * Newsroom
    * Back
    * Newsroom
    * All Posts
    * News
    * Cureus U
    * Newsletters

 * Blog
 * About
    * Back
    * About
    * Editorial Board
    * Associate Editors
    * Academic Council
    * About Cureus
    * Cureus Honors
    * Careers
    * Advertising & Sponsorship

 * COVID-19
 * ISSN #2168-8184

 * 
 *  
 * Sign In
 * Create an Account

> "Never doubt that a small group of thoughtful, committed citizens can change
> the world. Indeed, it is the only thing that ever has."
> 
> Margaret Mead


SUBMIT RESEARCH
 * Journal
   Articles
   People
   Posters
   Specialties
    * Allergy/Immunology
    * Anatomy
    * Anesthesiology
    * Cardiac/Thoracic/
      Vascular Surgery
    * Cardiology
    * Dentistry
    * Dermatology
    * Emergency Medicine
    * Endocrinology/Diabetes/
      Metabolism
    * Environmental Health
    * Epidemiology/Public Health
    * Family/General Practice
    * Forensic Medicine
    * Gastroenterology
    * General Surgery
    * Genetics
    * Healthcare Technology
    * Health Policy
    * Hematology
    * HIV/AIDS
    * Infectious Disease
    * Integrative/Complementary Medicine
    * Internal Medicine
    * Medical Education
    * Medical Physics
    * Medical Simulation
    * Miscellaneous
    * Nephrology
    * Neurology
    * Neurosurgery
   
    * Nuclear Medicine
    * Nutrition
    * Obstetrics/Gynecology
    * Occupational Health
    * Oncology
    * Ophthalmology
    * Oral Medicine
    * Orthopedics
    * Osteopathic Medicine
    * Otolaryngology
    * Pain Management
    * Palliative Care
    * Pathology
    * Pediatrics
    * Pediatric Surgery
    * Physical Medicine & Rehabilitation
    * Plastic Surgery
    * Podiatry
    * Preventive Medicine
    * Psychiatry
    * Psychology
    * Public Health
    * Pulmonology
    * Quality Improvement
    * Radiation Oncology
    * Radiology
    * Rheumatology
    * Substance Use and Addiction
    * Therapeutics
    * Transplantation
    * Trauma
    * Urology
   
   RECENT TOP ARTICLES
   
   --------------------------------------------------------------------------------
   
   Frontal Fibrosing Alopecia Mimicking Alopecia Syphilitica
   Multiple Indolent Asymptomatic Yellow-Orange Patches and Plaques
   Association of the PECAM-1 (Leu125Val) and P-Selectin (Thr715Pro) Gene
   Polymorphisms With Unexpla...
 * Publishing
    * About Publishing
    * Article Promotion Guide
    * Article Social Boost
    * Author & Reviewer Guides
    * Preferred Editing Service
    * SIQ™ - Scholarly Impact Quotient™

 * Channels
   About Channels
   Academic
    * Alabama College of Osteopathic Medicine Research
    * Annals of Simulation
    * Aurora Breast Health Proceedings
    * Baylor Scott & White Medical Center Department of Neurosurgery
    * California Institute of Behavioral Neurosciences & Psychology
    * Contemporary Reviews in Neurology and Neurosurgery
    * Dalhousie Emergency Medicine
    * FLAGSHIP: Medical Scholarly Proceedings
    * Houston Methodist Neurosurgery
    * Liberty Medicine Research Channel
    * Marcus Neuroscience Institute
    * Medicine-Pediatrics Academic Channel
    * Military Medical Simulation
    * Modern Medical Educator
    * NB Social Pediatrics Research
    * NEMA Research Group
    * Paolo Procacci Foundation
    * Penn State Neurosurgery
    * Research Update Organization
    * Sinai Chicago Research
    * Stanford Neurosurgery
    * The Florida Medical Student Research Publications
    * UCSF Neurological Surgery
    * UCSF Surgical Neuroanatomy Collection
    * University of Florida-Jacksonville Neurosurgery
    * University of Louisville Neurosurgery
    * University of Munich Neurology
   
   Professional Societies
    * ACOS Cardiothoracic and Vascular Surgery
    * ACOS General Surgery
    * ACOS Neurological Surgery
    * ACOS Plastic and Reconstructive Surgery
    * ACOS Urological Surgery
    * American Red Cross Scientific Advisory Council
    * Canadian Association of Radiation Oncology
    * International Liaison Committee on Resuscitation
    * International Pediatric Simulation Society
    * Japan Radiosurgery Society
    * Medical Society of Delaware Academic Channel
    * The Radiosurgery Society

 * Competitions
   About Competitions
   
   CURRENT
   
    * Surgically Targeted Radiation Therapy for Brain Tumors: Clinical Case
      Review
   
   PAST
   
    * Dermatology
       * Clinical and Economic Benefits of Autologous Epidermal Grafting
   
    * Cardiology
       * Investigational Cardiac Radiosurgery
   
    * General
       * Defining Health in the Era of Value-Based Care
       * Intraoperative Fluorescence Research
       * Optimization Strategies for Organ Donation and Utilization
   
    * Neurosurgery
       * Automated Whole Brain Tractography
       * Frameless Stereotactic Radiosurgery
   
    * Oncology
       * Exceptional Responders in Breast Cancer
       * Exceptional Responders in Oncology
   
    * Radiation Oncology
       * MR-Guided Radiation Therapy: Clinical Applications & Experiences
       * Multiple Brain Metastases: Exceptional Outcomes from Stereotactic
         Radiosurgery
       * Proton Therapy: Advanced Applications for the Most Challenging Cases
       * Radiation Therapy as a Modality to Create Abscopal Effects: Current and
         Future Practices
   
    * Surgery
       * Clinical Applications and Benefits Using Closed-Incision Negative
         Pressure Therapy for Incision and Surrounding Soft Tissue Management
       * Negative Pressure Wound Therapy with Instillation
       * NPWT with Instillation and Dwell: Clinical Results in Cleansing and
         Removal of Infectious Material with Novel Dressings

 * Newsroom
    * All Posts
    * News
    * Cureus U
    * Newsletters

 * Blog
 * About
    * Editorial Board
    * Associate Editors
    * Academic Council
    * ISSN #2168-8184
   
    * About Cureus
    * Cureus Honors
    * Careers
    * Advertising & Sponsorship
   
   Cureus is on a mission to change the long-standing paradigm of medical
   publishing, where submitting research can be costly, complex and
   time-consuming.
   
   John R. Adler, MD, Founder
 * COVID-19
 * 
   SUBMIT RESEARCH
   SIGN IN
   Join Now


On May 25, 2018, the GDPR (General Data Protection Regulation) went into effect
and changed how organizations deal with personal data of customers located in
the EU. Though GDPR was built to protect Europeans, it will affect organizations
around the world doing business in the EU. Because of this we are asking our
users located in the EU to opt in to the data we collect in order to bring a
better web experience. Opt-In
ADVERTISEMENT

6.6


RATED BY 5 READERS

6.6

CLARITY OF BACKGROUND AND RATIONALE



6.6

CLINICAL IMPORTANCE



6.2

STUDY DESIGN AND METHODS



7.0

DATA ANALYSIS



7.0

NOVELTY OF CONCLUSIONS



6.2

QUALITY OF PRESENTATION


CONTRIBUTE RATING
Learn more about SIQ™
6.6
Rate article
What's this?

Article
 * Abstract
 * Introduction
 * Materials & Methods
 * Results
 * Discussion
 * Conclusions
 * Appendices
 * References


Disclosures & Acknowledgements

Community discussion

Categories
 * Emergency Medicine
 * Internal Medicine
 * Infectious Disease

Keywords

covid-19, acute respiratory distress syndrome (ards), high-dose dexamethasone,
fungal infection, secondary infection, pulse dose steroids, tocilizumab,
cytokine storms

ADVERTISEMENT

High-Dose Dexamethasone Versus Tocilizumab in Moderate to Severe COVID-19
Pneumonia: A Randomized Controlled Trial
Naveen B. Naik, Goverdhan D. Puri, Kamal Kajal, Varun Mahajan, Ashish Bhalla,
Sandeep Kataria, Karan Singla, Pritam Panigrahi, Ajay Singh, Michelle Lazar,
Anjuman Chander, Venkata Ganesh, Amarjyoti Hazarika, Vikas Suri, Manoj K. Goyal,
Vijayant Kumar Pandey, Narender Kaloria, Tanvir Samra, Kulbhushan Saini, Shiv L.
Soni

PDF
Comment
PDF

 * Article
 * Authors etc.

 * Metrics
 * Comments

 * Figures etc.





Original article
peer-reviewed



HIGH-DOSE DEXAMETHASONE VERSUS TOCILIZUMAB IN MODERATE TO SEVERE COVID-19
PNEUMONIA: A RANDOMIZED CONTROLLED TRIAL

Naveen B. Naik, Goverdhan D. Puri, Kamal Kajal, Varun Mahajan, Ashish Bhalla,
Sandeep Kataria, Karan Singla, Pritam Panigrahi, Ajay Singh, Michelle Lazar,
Anjuman Chander, Venkata Ganesh , Amarjyoti Hazarika, Vikas Suri, Manoj K.
Goyal, Vijayant Kumar Pandey, Narender Kaloria, Tanvir Samra, Kulbhushan Saini,
Shiv L. Soni

--------------------------------------------------------------------------------

Published: December 11, 2021 (see history)

DOI: 10.7759/cureus.20353

Cite this article as: Naik N B, Puri G D, Kajal K, et al. (December 11, 2021)
High-Dose Dexamethasone Versus Tocilizumab in Moderate to Severe COVID-19
Pneumonia: A Randomized Controlled Trial. Cureus 13(12): e20353.
doi:10.7759/cureus.20353

--------------------------------------------------------------------------------


ABSTRACT

BACKGROUND AND OBJECTIVES

Recent randomized controlled trials (RCTs) have indicated potential therapeutic
benefits with high-dose dexamethasone (HDD) or tocilizumab (TCZ) plus standard
care in moderate to severe coronavirus disease 2019 (COVID-19) with acute
respiratory distress syndrome (ARDS). No study has compared these two against
each other. We aimed to compare the efficacy and safety of HDD against TCZ in
moderate to severe COVID-ARDS.

METHODS

Patients admitted with moderate to severe COVID-19 ARDS with clinical worsening
within 48 hours of standard care were randomly assigned to receive either HDD or
TCZ plus standard care. The primary outcome was ventilator-free days (VFDs) at
28 days. The main secondary outcomes were 28-day all-cause mortality and the
incidence of adverse events. Our initial plan was to perform an interim analysis
of the first 42 patients.

RESULTS

VFDs were significantly lower in the HDD arm (median difference: 28 days; 95%
confidence interval (CI): 19.35-36.65; Cohen’s d = 1.14; p < 0.001). We stopped
the trial at the first interim analysis due to high 28-day mortality in the HDD
arm (relative risk (RR) of death: 6.5; p = 0.007; NNT (harm) = 1.91). The
incidence of secondary infections was also significantly high in the HDD arm
(RR: 5.5; p = 0.015; NNT (harm) = 2.33).

CONCLUSIONS

In our study population, HDD was associated with a very high rate of mortality
and adverse events. We would not recommend HDD to mitigate the cytokine storm in
moderate to severe COVID-19 ARDS. TCZ appears to be a much better and safer
alternative.


INTRODUCTION

Coronavirus disease 2019 (COVID-19) has been associated with high mortality in
moderate and severe acute respiratory distress syndrome (ARDS). The
hyper-inflammatory response triggered by SARS-CoV-2 is characterized by the
overproduction of pro-inflammatory cytokines, leading to organ dysfunction
[1,2]. Intervening timely with immunomodulatory therapies might mitigate the
severity. Based on this assumption, researchers have been focusing on several
interventions, including IL-6 inhibitors and corticosteroids [3-10]. The largest
trial of tocilizumab (TCZ) to date has shown significant survival benefits with
TCZ plus standard care [11]. However, the dose of corticosteroids in COVID-19
has remained controversial. Although the results of two recent randomized
controlled trials (RCTs) have shown potential therapeutic benefits with
dexamethasone, the practice remains variable [12,13].

The COVID-19 pandemic has exhausted the resources of low- and middle-income
countries. The scenario was remarkably grim in India, amidst the second wave,
with insufficient TCZ supply [14]. Affordable and widely available effective
alternate immunomodulatory therapies besides TCZ were urgently needed. We
hypothesized that timely treatment with high-dose dexamethasone (HDD) may
downregulate the integrated pathways of
inflammation-coagulation-fibroproliferation and potentially improve patient
outcomes. To the best of our understanding, this is the first RCT to compare the
efficacy of HDD against TCZ in patients with moderate to severe COVID-19 ARDS.


MATERIALS & METHODS

STUDY DESIGN

This study was conducted between May 6 and June 28, 2021, at a tertiary care
hospital in India. Our objective was to investigate the efficacy and safety of
early rescue therapy with HDD versus TCZ in COVID-19 unresponsive to standard
care. The study protocol, statistical analysis proposal, and criteria for
premature study termination were planned a priori (Figure 4 and Figure 5 in the
Appendices). The trial was approved by the Institutional Ethics Committee
(reference number: NK/7349/Study/939) and registered in the clinical trial
registry of India (CTRI/2021/04/033263 (April 30, 2021)). Prior to enrolment and
randomization, written informed consent was taken from the participants or their
legal representatives.

PARTICIPANTS

Participants aged 18 years and older, with confirmed SARS-CoV-2 infection by
reverse-transcriptase polymerase chain reaction (RT-PCR) assay, were recruited.
Patients with a partial pressure of arterial oxygen to fraction of inspired
oxygen (PaO2/FiO2) ratio of less than 200 on admission and receiving standard
care were screened for eligibility. Among these patients, those with clinical
worsening in less than 48 hours of the initiation of standard care were
randomized. Clinical worsening was defined as follows: (1) decrease in PaO2/FiO2
by more than 50 of the baseline admission value, (2) oxygenation/ventilation
device is upgraded, and (3) static or rising levels of C-reactive protein (CRP >
50 mg/L).

The exclusion criteria included patients with prior history of immunosuppression
and use of immunosuppressive drugs, raised septic biomarkers suggestive of
invasive bacterial or fungal infection, AST/ALT ≥ five times the upper limit of
normal, leukocytes < 2 × 103/μL, thrombocytes < 50 × 103/μL, and acute or
chronic diverticulitis.

RANDOMIZATION

Block randomization was done using an online random number generator with
varying block sizes with the unique subject or patient code generated against
the block sequence number [15]. This is an open-label study, and after
randomization, there was no masking. The investigators, treating clinical teams,
and participants were not blinded, whereas the research personnel compiling and
analyzing the outcome data were blinded to the group allotment.

PROCEDURE

Patients with COVID-19 who were admitted to our hospital with PaO2/FiO2 < 200
received standard care as per the hospital treatment protocol. Standard care
included (a) oxygen supplementation; (b) intravenous (i.v.) remdesivir loading
dose of 200 mg on day 1, followed by 100 mg for the next four days; (c) i.v.
dexamethasone 6 mg for 10 days; (d) therapeutic low-molecular-weight heparin 1.5
mg/kg/day; and (e) proning.

Within 48 hours of the initiation of standard care, if a patient showed clinical
worsening, they were randomized to one of the intervention arms, HDD or TCZ.
Patients in the HDD arm received i.v. dexamethasone 20 mg once daily for three
days plus standard care until day 10. HDD dose of 20 mg was selected on the
basis of a recent RCT [13]. Patients in the TCZ arm received a single i.v.
infusion of TCZ 6 mg/kg plus standard care of 6 mg dexamethasone for 10 days. An
additional dose of TCZ (6 mg/kg) will be administered if the patient shows no
clinical improvement within 24 hours. The low dosing of TCZ was based on a
previous study and due to supply considerations [14,16].

OUTCOMES

The primary outcome was ventilator-free days (VFDs) within 28 days since
randomization. The secondary endpoints were all-cause mortality, the incidence
of adverse events (i.e., secondary infections, insulin requirement for
hyperglycemia, and vasopressor requirement), variation in the Sequential Organ
Failure Assessment (SOFA) score and WHO Clinical Progression Scale (WHO-CPS),
duration of ICU stay, CRP variation, time to negative result on RT-PCR, and time
to discharge.

STATISTICAL ANALYSIS

The study was designed to compare the means of VFDs across the two groups to
demonstrate an effect size of 0.8 (Cohen’s d) with a power of 80% and α at 0.05.
A sample size of 42 across two groups (21 per group) was estimated using G power
3.1.9.4. A priori, when this sample size had been reached, we planned for an
interim analysis to decide whether to proceed with recruitment to our secondary
sample size or to stop the trial based on preset criteria (Figure 5 in the
Appendices). Normality was assessed using skewness indicators and/or Q-Q plots.
Categorical data have been expressed as count (%) and were analyzed using the
Chi-squared/Fisher’s exact test. Time to event analysis has been done using the
Kaplan-Meier (K-M) survival estimates, competing risks regression, and Cox
proportional hazards, where assumptions have been met and the model fit was
significantly better than the null. Missing data was less than 5%, so no
imputation methods were used. The analysis has been done using SPSS version 25.0
for Windows (SPSS Inc., Chicago, IL, USA), Stata 15 (StataCorp. 2017. Stata
Statistical Software: Release 15. College Station, TX: StataCorp LLC), and R
studio 1.4.1130.0.


RESULTS

A total of 87 patients with COVID-19 ARDS on admission were screened for
inclusion, of whom 42 were randomized (Figure 1). The demography, clinical
characteristics, and biomarkers of the patients at baseline and intervention are
presented in Table 1.

FIGURE 1: CONSOLIDATED STANDARDS OF REPORTING TRIALS (CONSORT) FLOW DIAGRAM OF
THE STUDY.




  High-dose dexamethasone arm (n = 21) Tocilizumab arm (n = 21) p-value Age,
median (IQR), years 51 (45–58) 50 (44–65) 0.920a BMI, median (IQR), kg/m2 30.20
(26.4–35.6) 27.45 (25.90–30.61) 0.232a Sex, number (%) Male 12 (57.14%) 12
(57.14%) 1.000b Female 9 (42.86%) 9 (42.86%) Coexisting conditions, number (%)
Diabetes mellitus 7 (33.33%) 8 (38.10%) 0.747b Hypertension 11 (52.38%) 13
(61.90%) 0.533b Chronic kidney disease 0 (0%) 0 (0%) - Coronary artery disease 0
(0%) 1 (4.76%) 1.000b Chronic liver disease 0 (0%) 0 (0%) - Chronic obstructive
pulmonary disease 0 (0%) 2 (9.52%) 1.000b Asthma 0 (0%) 1 (4.76%) 1.000b
Hypothyroid 2 (9.52%) 1 (4.76%) 1.000b Pregnancy 1 (4.76%) 2 (9.52%) 0.698b Days
from symptom onset, median (IQR), days On admission 6 (6–7) 7 (6–7) 0.039a On
the first dose of intervention (high-dose dexamethasone or tocilizumab) 7 (7–8)
8 (7–9) 0.011*a PaO2/FiO2, median (IQR), mmHg On admission 125.14
(110.29–138.67) 134.5 (117–181) 0.07a On the first dose of intervention
(high-dose dexamethasone or tocilizumab) 81.07 (68.22–91.60) 80.93 (62.20–113)
0.920a Respiratory support at admission, number (%) Invasive mechanical
ventilation 0 (0%) 0 (0%) 0.617b Noninvasive ventilation 2 (9.52%) 1 (4.76%)
High-flow nasal cannula 1 (4.76%) 2 (9.52%) Non-rebreather mask 15 (71.43%) 12
(57.14%) Face mask/nasal prongs 3 (14.29%) 6 (28.57%) Respiratory support at
intervention, number (%) Invasive mechanical ventilation 1 (4.76%) 1 (4.76%)
0.597b Noninvasive ventilation 8 (38.10%) 5 (23.81%) High-flow nasal cannula 12
(57.14%) 15 (71.43%) Non-rebreather mask 0 (0%) 0 (0%) Face mask/nasal prongs 0
(0%) 0 (0%) Hours in prone position during hospital stay, median (IQR) 96
(0–128) 48 (0–80) 0.063a Laboratory variables at admission, median (IQR)
C-Reactive protein, median (IQR), mg/dL 54.2 (33.4–75.1) 75 (47–90) 0.218a White
blood cell count, median (IQR), × 103/μL 8.4 (7.6–10.7) 8.1 (7.30–9.70) 0.413a
Neutrophil/lymphocyte ratio 15.62 (12.21–20.75) 16.40 (10.33–21.40) 0.811a
Platelet count, × 103/μL 246 (189–316.5) 221 (168–276 ) 0.083a Ferritin, ng/mL
702.5 (503.2–989) 522 (321.8–969) 0.252a D-Dimer, ng/mL 1568 (694–3455) 853
(512–2388) 0.204a Laboratory variables at intervention, median (IQR) C-Reactive
protein, median (IQR), mg/dL 89.2 (72–135.70) 111 (74.30–151.40) 0.443a White
blood cell count, median (IQR), × 103/μL 11.2 (9.3–13.20) 10.6 (9.1–11.70)
0.227a Neutrophil/lymphocyte ratio 17 (10.94–21.78) 13 (9.73–19.10) 0.489a
Platelet count, median (IQR), × 103/μL 233 (196–347.5) 258 (172–357) 0.597a
Ferritin, median (IQR), ng/mL 607 (428.45–1410) 631.9 (256.65–992.77) 0.170a
D-Dimer, median (IQR), ng/mL 1118 (541.65–3513.1) 649 (389.38–1734.75) 0.930a

TABLE 1: DEMOGRAPHY, CLINICAL CHARACTERISTICS, AND BIOMARKERS OF PATIENTS AT
BASELINE AND INTERVENTION.

*p-value < 0.05 was considered significant; a: Mann–Whitney U-test; b:
Chi-squared/Fisher’s exact test.

IQR: interquartile range; PaO2/FiO2: partial pressure of arterial oxygen to
fraction of inspired oxygen.



UNIVARIATE ANALYSIS

Primary Outcome

VFDs were significantly lower in the HDD group (9.76 ± 12.94 (95% CI:
3.87-25.65) versus 22.86 ± 9.75 (95% CI: 18.42-27.30); Cohen’s d = 1.14; p <
0.001) at a calculated power of 99.99% (Figure 2a). The median difference was 28
days (95% CI: 19.35-36.65) (Table 2).

FIGURE 2: OUTCOMES. (A) VIOLIN PLOT OF VENTILATOR-FREE DAYS. (B) BAR DIAGRAM
SHOWING MORTALITY DISTRIBUTED AMONG THE TREATMENT GROUP AND POSTTREATMENT
INTUBATION STATUS. ONE PATIENT WAS INTUBATED ON THE DAY OF THERAPY IN THE
TOCILIZUMAB ARM AND WAS SUCCESSFULLY EXTUBATED AS WELL. (C) KAPLAN–MEIER
ESTIMATES OF CUMULATIVE HOSPITAL DISCHARGE RATES AND (D) IMPROVEMENT IN WHO
CLINICAL PROGRESSION SCALE.




Outcomes HDD arm (n = 21) TCZ arm (n = 21) p-value Primary outcome
Ventilator-free days Mean ± SD (95% CI) 9.76 ± 12.94 (3.87–25.65) 22.86 ± 9.75
(18.42–27.30)   Median (IQR) 0 (0–25) 28 (24–28) 0.001*a Secondary outcome
28-Day results All-cause mortality, number (%) 13 (61.90%) 2 (9.52%) <0.001*b
Intubation rates posttreatment, number (%) 13 (61.90%) 2 (9.52%) <0.001*b ICU
free, median (IQR), days 1 (1–5) 4 (3.5–5.5) 0.017*a MV duration, median (IQR),
days 12 (2.5–15.5) 0 (0–3) <0.001*a Discharged from the hospital within 28 days,
number (%) 8 (38.10%) 19 (90.48%) 0.030*b SOFA score, median, (IQR) On treatment
day 5 (4–8) 5 (4–6) 0.353a 48 hours later 4 (4–8) 4 (4–5) 0.303a 7 days after
intervention 5 (2–7) 2 (2–2) 0.002*a WHO-CPS score, median, (IQR) On treatment
day 6 (6–6) 6 (6–6) 0.573a 7 days after intervention 6 (5–8) 5 (3–5) <0.001*a
Mean time (days) to improvement in WHO-CPS score by 1 (i.e., a decrease by 1)
17.90 (underestimated) 6.48 (underestimated) 0.002*c Renal replacement therapy,
number (%) 2 (9.52%) 0 (0%) 0.488b Vasopressor use, number (%) 13 (61.90%) 3
(14.29%) 0.001*b Time to RT-PCR negative status (days), median (IQR) 19 (17–19)
17 (16–17) 0.026*a Hospital stay, median (IQR), days 17 (13–17) 12 (11–12)
0.003*a

TABLE 2: OUTCOMES.

*p-value < 0.05 was considered significant; a: Mann–Whitney U-test; b:
Chi-squared/Fisher's exact test; c: log-rank test from Kaplan–Meier survival
estimates (see text and Appendices for further details).

HDD: high-dose dexamethasone; TCZ: tocilizumab; CI: confidence interval; IQR:
interquartile range; MV: mechanical ventilation; ICU: intensive care unit; SOFA:
Sequential Organ Failure Assessment score; WHO-CPS: World Health Organization
Clinical Progression Scale; RT-PCR: reverse-transcriptase polymerase chain
reaction.



Secondary Outcomes

All-cause mortality at 28 days was significantly higher at 61.9% (95% CI:
39.06%-80.46%) in the HDD group, compared with 9.52% (95% CI: 2.21%-32.89%) in
the TCZ group, with a p < 0.001, a large effect size of w = 0.72, and calculated
power > 97% (Figure 2b). The relative risk (RR) of death in the HDD group was
6.5 (95% CI: 1.67-25.33; p = 0.007; NNT (harm) = 1.91). The preventable fraction
for mortality in the TCZ group was computed as 0.79 (95% CI: 0.064-0.98) with a
preventable fraction in the population of 0.333. The proportion of patients
discharged at day 28 was significantly higher in the TCZ group at 90.48% (95%
CI: 67.1%-97.79%) versus 38.10% (95% CI: 19.54%-60.93%) in the HDD group (Table
2).

The SOFA and WHO-CPS scores were significantly better in the TCZ group on day 7
after the intervention, paralleling an improvement in the PaO2/FiO2 ratio on day
7 in the TCZ group (median difference: 132.96 (95% CI: 55.15-210.77; p < 0.001))
(Figure 6 in the Appendices). The proportion of patients requiring vasopressors
was 61.90% in the HDD group against 14.29% in the TCZ group (p = 0.001). The
median number of days a patient remained RT-PCR positive for SARS-CoV-2 was
higher in the HDD group. The duration of hospital stay was also high in the HDD
group (Table 2).

The distributions of PaO2/FiO2, total leucocyte count (TLC),
neutrophil/lymphocyte (N/L) ratio, CRP, ferritin, and D-dimer in both groups at
various time points are presented in Figure 3 (also see Table 4, Figure 6, and
Figure 7 in the Appendices). CRP had the best negative correlation with
PaO2/FiO2 (Figure 8 in the Appendices).

FIGURE 3: BOXPLOTS OF BIOMARKERS STRATIFIED BY TREATMENT GROUPS AND OUTCOME
(DISCHARGED/EXPIRED) AT VARIOUS TIME POINTS: (A) PAO2/FIO2 RATIO (PFR), (B)
TOTAL LEUKOCYTE COUNT (TLC), (C) NEUTROPHIL/LYMPHOCYTE RATIO (N/L RATIO OR NLR),
(D) C-REACTIVE PROTEIN (CRP), (E) D-DIMER, AND (F) FERRITIN.




MULTIVARIATE AND SURVIVAL ANALYSIS

The median time to discharge was 20 days (95% CI: 13 to infinity) in the HDD
group against 10 days (95% CI: 9-13) with a log-rank test p-value < 0.001
(Figure 2c). The median time to RT-PCR negative status was 12 days (95% CI:
11-14) in the HDD group and 10 days (95% CI: 9-10) in the TCZ group (log-rank
test p = 0.006). A K-M analysis with a similarly censored time variable and
WHO-CPS improvement as the dependent variable gave a mean time to the
improvement of 17.9 (95% CI: 12.80-23.00) in the HDD group against 6.48 (95% CI:
3.40-9.55) in the TCZ group (Figure 2d and Table 5 in the Appendices).

After assessing for proportionality, the Cox proportional hazards model was fit
on the above and adjusted for the variables PaO2/FiO2 ratio at baseline, days
from symptom onset at intervention, CRP, TLC, and N/L ratio at intervention.
This gave a hazard ratio of 3.69 (95% CI: 1.34-10.15; p = 0.024) for WHO-CPS
improvement in the TCZ group (Figure 2d and Table 6 in the Appendices).

A competing risks regression with days posttreatment as the time variable and
death as competing interest gave an adjusted sub-hazard ratio (SHR) for
discharge of 5.86 (95% CI: 1.49-23.04; p = 0.011) in the TCZ group. Similarly,
with discharge as a competing interest, the TCZ group had an adjusted SHR for
death of 0.085 (95% CI: 0.016-0.44; p = 0.003) (Table 7, Figure 9, and Figure
10 in the Appendices).

ADVERSE EVENT OUTCOMES

The main reason the trial was stopped at the interim analysis stage was the
increased mortality and adverse event rate observed in the HDD arm. This was
chiefly due to new infections in HDD (relative risk: 5.5; 95% CI: 1.38-21.86; p
= 0.015; NNT (harm) = 2.33; 95% CI: 5.53-1.48). Table 3 summarizes the adverse
events per Common Terminology Criteria for Adverse Events (CTCAE) version 5
[17]. The overall adverse event rate per 100 patient days was 61.43 in the HDD
group versus 27.72 in the TCZ group.

  Adverse events, number of patients (%) Number of events Event rate ratio
HDD/TCZ p-value (exact rate ratio test) Total (n = 42) HDD (n = 21) TCZ (n = 21)
HDD (number in 306 patient days) TCZ (number in 220 patient days) Deaths 15
(36.06%) 13 (61.9%) 2 (9.52%) 13 2 4.67 (1.06–42.65) 0.023* Infections 13
(30.95%) 11 (52.38%) 2 (9.52%) 25 2 8.9 (2.24–78.28) <0.001* Grade 3 or worse
adverse events by CTCAE version 5, MedDRA system organ class preferred terms
Cardiac disorders Supraventricular tachycardia 1 (2.38%) 0 (0%) 1 (4.76%) 0 1 0
(0–28.04) 0.41 Sinus bradycardia 1 (2.38%) 0 (0%) 1 (4.76%) 0 1 0 (0–28.04) 0.41
Cardiac arrest 15 (36.06%) 13 (61.9%) 2 (9.52%) 13 2 4.67 (1.06–42.65) 0.023*
Infections or infestations Fungemia 8 (19.04%) 8 (38.09%) 0 (0%) 8 0 Zero
denominator 0.013* Catheter-related infection 7(16%) 6 (28.27%) 1 (4.76%) 6 1
4.31 (0.52–198.42) 0.158 Lung infection 11 (26.19%) 10 (47.61%) 1 (4.76%) 11 1
7.91 (1.15–340.41) 0.016* Respiratory, thoracic, and mediastinal disorders Grade
4 adult respiratory distress syndrome 15 (36.06%) 13 (61.9%) 3 (14.28%) 13 3
3.12 (0.85–17.04) 0.065 Vascular disorders Shock 16 (38.09%) 13 (61.90%) 3
(14.29%) 13 3 3.12 (0.85–17.04) 0.065 Metabolism and nutrition disorders
Hyperglycemiaᴪ 30 (71.43%) 21 (100%) 9 (42.86%) 106 49 1.56 (1.09–2.23) 0.009*
Gastrointestinal disorders Gastric hemorrhage 4 (9.52%) 4 (19.04%) 0 (0%) 18 0
Zero denominator <0.001* Total number of events‡ 188 61 2.22 (1.65–3.01) <0.001*

TABLE 3: ADVERSE EVENTS.

All cardiac arrests were grade 5.

‡Excludes deaths and infections to avoid duplication.

ᴪBlood sugar > 180 mg/dL.

*p-value < 0.05 was considered significant.

HDD: high-dose dexamethasone; TCZ: tocilizumab; CTCAE: Common Terminology
Criteria for Adverse Events.




DISCUSSION

Steroids have been extensively used and evaluated since the beginning of the
pandemic. Several cohort studies described varied findings, either favorable or
unfavorable, promoting confusion especially when it concerns the dose of
steroids [8-10]. The first RCT on the role of steroids in COVID-19 has
recommended that dexamethasone 6 mg once daily for 10 days decreased mortality
[12]. A recent RCT on HDD has shown therapeutic benefit at doses of 20 mg per
day in critically ill patients with COVID-19 [13]. Treatment with HDD was
beneficial in lowering mortality and the period of mechanical ventilation in
critically ill patients with non-COVID-19 ARDS [18]. Despite these promising
results, there is still uncertainty regarding the role of HDD in
COVID-19. Several meta-analyses have claimed TCZ to be a safe and effective drug
in reducing the risk of death [19-21]. In a low- to middle-income country with
scarce TCZ supply amidst the pandemic, we surmised that HDD would be an easily
accessible, low-cost, and potentially effective treatment option. At moderate or
high doses, it has not been linked with detrimental effects [12,13]. Hence, we
sought to compare the therapeutic effectiveness of HDD and TCZ in COVID-19.

VFDs were selected as the principal outcome as it takes into account mortality
and the period of ventilation together in a manner that summarizes the net
effect of an intervention on these parameters [22]. The major difference between
recent RCTs and our study is that patients with clinical worsening within 48
hours of receiving standard care were treated with HDD or TCZ, as a rescue,
second-line therapy [11-13,19-21]. Characteristically, ARDS presents with a
profound pulmonary and systemic inflammatory reaction within 48 hours, giving
rise to aggravated pulmonary inflammation and fibroproliferation [23]. Failed
efforts to halt the self-perpetuating tissue inflammation within a specified
time lead to the subsequent suppression of lung function and increased chances
of mortality. Therefore, we ensured that all the randomized patients
unresponsive to standard care received immediate rescue therapy within 48 hours
of worsening ARDS.

Notably, our findings show that HDD was associated with high 28-day mortality
and was poorly tolerated. There was a significantly higher incidence of adverse
events, especially new infections. This high incidence was beyond the
predetermined limits of futility, fostering a very weak probability of a large
trial. Our findings have unveiled the ineffectiveness and poor safety of HDD
therapy in COVID-19 ARDS with PaO2/FiO2 < 200. Hence, as decided by the
institute clinical management board, the trial was stopped immediately after the
prespecified interim analysis.

Our study results favor the use of TCZ in moderate to severe COVID-19. Several
RCTs examining the role of TCZ in COVID-19 reported conflicting results [24,25].
These trials differed considerably in study design, illness severity of enrolled
patients, and imbalances in the use of steroids between study groups. The
RECOVERY trial reported all-cause mortality of 31% among patients allocated to
the TCZ arm and 35% in the usual care arm (rate ratio: 0.85; 95% CI:
0.76-0.95; p = 0.0028) [11]. Our study had an all-cause mortality rate ratio of
0.21 (95% CI: 0.02-0.93; p = 0.022); however, our study was never powered to
detect this outcome. Nevertheless, IL-6 inhibitors also have the potential to
suppress the host immune response and could hypothetically raise the probability
of acquiring secondary infections. In our trial, we did not witness a greater
risk of infection or adverse events with TCZ use. These findings support
previous RCTs about the safety of TCZ in COVID-19 [11,24,25].

Our study has certain limitations. First, the trial was discontinued after the
first interim analysis, at a limited sample size; hence, the precision of the
treatment effect estimates might be low than anticipated. However, it would be
prudent to note that this interim analysis sample size was calculated to be
valid for demonstrating a large effect size with adequate power when it came to
VFDs as the primary outcome measure. A larger sample size, no doubt, would have
been able to detect the differences in the effects of HDD or TCZ on mortality.
Second, the study lacks a control arm. We did not compare outcomes against a
control group that should have received only the standard care. Third, a
different dose of dexamethasone might have provided a different result;
therefore, the outcomes portrayed in this study should be linked only to the
particular dose administered. Despite the above limitations, our robust study
design and results add necessary evidence to the scientific community. Our
findings await subsequent clarification from ongoing clinical trials on
different doses of dexamethasone [26-28].


CONCLUSIONS

Our study findings discourage the use of high doses of dexamethasone in the
management of moderate to severe COVID-19 ARDS. The routine use of such high
doses to mitigate the inflammatory cytokine storm in these patients might worsen
outcomes possibly due to a high rate of secondary infections and therefore
cannot be recommended.

From this study, we can conclude that tocilizumab is associated with a decreased
mortality, reduced need for invasive mechanical ventilation, and a higher
probability of successful hospital discharge in comparison with high-dose
dexamethasone when used in the context of mitigating the adverse effects of the
cytokine storm.

--------------------------------------------------------------------------------


REFERENCES

 1.  Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ:
     COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet.
     2020, 395:1033-4. 10.1016/S0140-6736(20)30628-0
 2.  Henderson LA, Canna SW, Schulert GS, et al.: On the alert for cytokine
     storm: immunopathology in COVID-19. Arthritis Rheumatol. 2020, 72:1059-63.
     10.1002/art.41285
 3.  Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB: Pharmacologic treatments
     for coronavirus disease 2019 (COVID-19): a review. JAMA. 2020, 323:1824-36.
     10.1001/jama.2020.6019
 4.  Alijotas-Reig J, Esteve-Valverde E, Belizna C, et al.: Immunomodulatory
     therapy for the management of severe COVID-19. Beyond the anti-viral
     therapy: a comprehensive review. Autoimmun Rev. 2020, 19:102569.
     10.1016/j.autrev.2020.102569
 5.  Hermine O, Mariette X, Tharaux PL, Resche-Rigon M, Porcher R, Ravaud P:
     Effect of tocilizumab vs usual care in adults hospitalized with COVID-19
     and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern
     Med. 2021, 181:32-40. 10.1001/jamainternmed.2020.6820
 6.  Salvarani C, Dolci G, Massari M, et al.: Effect of tocilizumab vs standard
     care on clinical worsening in patients hospitalized with COVID-19
     pneumonia: a randomized clinical trial. JAMA Intern Med. 2021, 181:24-31.
     10.1001/jamainternmed.2020.6615
 7.  Zhang C, Wu Z, Li JW, Zhao H, Wang GQ: Cytokine release syndrome in severe
     COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to
     reduce mortality. Int J Antimicrob Agents. 2020, 55:105954.
     10.1016/j.ijantimicag.2020.105954
 8.  Russell CD, Millar JE, Baillie JK: Clinical evidence does not support
     corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020,
     395:473-5. 10.1016/S0140-6736(20)30317-2
 9.  Yang Z, Liu J, Zhou Y, Zhao X, Zhao Q, Liu J: The effect of corticosteroid
     treatment on patients with coronavirus infection: a systematic review and
     meta-analysis. J Infect. 2020, 81:e13-20. 10.1016/j.jinf.2020.03.062
 10. Sterne JA, Murthy S, Diaz JV, et al.: Association between administration of
     systemic corticosteroids and mortality among critically ill patients with
     COVID-19: a meta-analysis. JAMA. 2020, 324:1330-41. 10.1001/jama.2020.17023
 11. RECOVERY Collaborative Group: Tocilizumab in patients admitted to hospital
     with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform
     trial. Lancet. 2021, 397:1637-45. 10.1016/S0140-6736(21)00676-0
 12. Horby P, Lim WS, Emberson JR, et al.: Dexamethasone in hospitalized
     patients with Covid-19. N Engl J Med. 2021, 384:693-704.
     10.1056/NEJMoa2021436
 13. Tomazini BM, Maia IS, Cavalcanti AB, et al.: Effect of dexamethasone on
     days alive and ventilator-free in patients with moderate or severe acute
     respiratory distress syndrome and COVID-19: the CoDEX randomized clinical
     trial. JAMA. 2020, 324:1307-16. 10.1001/jama.2020.17021
 14. National Herald: India stares at shortage of COVID-19 drug tocilizumab as
     importer Cipla runs out of stock. (2021). Accessed: November 17, 2021:
     https://www.nationalheraldindia.com/india/india-stares-at-shortage-of-covid-19-drug-tocilizumab-as-importer-cipla-run....
 15. Sealed Envelope: Create a randomisation list. (2021). Accessed: November
     17, 2021: https://www.sealedenvelope.com/simple-randomiser/v1/lists.
 16. De Rossi N, Scarpazza C, Filippini C, et al.: Early use of low dose
     tocilizumab in patients with COVID-19: a retrospective cohort study with a
     complete follow-up. EClinicalMedicine. 2020, 25:100459.
     10.1016/j.eclinm.2020.100459
 17. Protocol Development: Common Terminology Criteria for Adverse Events
     (CTCAE). (2021). Accessed: November 17, 2021:
     https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm.
 18. Villar J, Ferrando C, Martínez D, et al.: Dexamethasone treatment for the
     acute respiratory distress syndrome: a multicentre, randomised controlled
     trial. Lancet Respir Med. 2020, 8:267-76. 10.1016/S2213-2600(19)30417-5
 19. Aziz M, Haghbin H, Abu Sitta E, et al.: Efficacy of tocilizumab in
     COVID-19: a systematic review and meta-analysis. J Med Virol. 2021,
     93:1620-30. 10.1002/jmv.26509
 20. Zhao J, Cui W, Tian BP: Efficacy of tocilizumab treatment in severely ill
     COVID-19 patients. Crit Care. 2020, 24:524. 10.1186/s13054-020-03224-7
 21. Chen CX, Hu F, Wei J, Yuan LT, Wen TM, Gale RP, Liang Y: Systematic review
     and meta-analysis of tocilizumab in persons with coronavirus disease-2019
     (COVID-19). Leukemia. 2021, 35:1661-70. 10.1038/s41375-021-01264-8
 22. Yehya N, Harhay MO, Curley MA, Schoenfeld DA, Reeder RW: Reappraisal of
     ventilator-free days in critical care research. Am J Respir Crit Care Med.
     2019, 200:828-36. 10.1164/rccm.201810-2050CP
 23. Burnham EL, Janssen WJ, Riches DW, Moss M, Downey GP: The
     fibroproliferative response in acute respiratory distress syndrome:
     mechanisms and clinical significance. Eur Respir J. 2014, 43:276-85.
     10.1183/09031936.00196412
 24. Tleyjeh IM, Kashour Z, Damlaj M, et al.: Efficacy and safety of tocilizumab
     in COVID-19 patients: a living systematic review and meta-analysis. Clin
     Microbiol Infect. 2021, 27:215-27. 10.1016/j.cmi.2020.10.036
 25. Rosas IO, Bräu N, Waters M, et al.: Tocilizumab in hospitalized patients
     with severe Covid-19 pneumonia. N Engl J Med. 2021, 384:1503-16.
     10.1056/NEJMoa2028700
 26. Munch MW, Granholm A, Myatra SN, et al.: Higher vs lower doses of
     dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID
     2) trial: protocol and statistical analysis plan. Acta Anaesthesiol Scand.
     2021, 65:834-45. 10.1111/aas.13795
 27. Maskin LP, Olarte GL, Palizas F Jr, et al.: High dose dexamethasone
     treatment for acute respiratory distress syndrome secondary to COVID-19: a
     structured summary of a study protocol for a randomised controlled trial.
     Trials. 2020, 21:743. 10.1186/s13063-020-04646-y
 28. University of Oxford: Randomised Evaluation of COVID-19 Therapy (RECOVERY).
     (2021). https://clinicaltrials.gov/ct2/show/NCT04381936.

--------------------------------------------------------------------------------


APPENDICES

The study protocol that was initially proposed has been represented in the
following flowchart (Figure 4), and the a priori statistical analysis plan is
depicted in Figure 5.

FIGURE 4: THE PROPOSED STUDY PROTOCOL.

PaO2/FiO2: partial pressure of arterial oxygen to fraction of inspired oxygen;
f/b: followed by; MPS: methylprednisolone; TLC: total leucocyte count; AST:
aspartate aminotransferase; ALT: alanine aminotransferase; CRP: C-reactive
protein; WHO-CPS: World Health Organization Clinical Progression Scale; NRBM:
non-rebreather mask; HFNC: high-flow nasal cannula; NIV: noninvasive
ventilation; IPPV: invasive positive pressure ventilation.



FIGURE 5: STATISTICAL ANALYSIS/INTERIM ANALYSIS PLAN.




The course of biomarkers is shown in Table 4 as the median difference between
various time points. The relationship between the biomarkers and PaO2/FiO2 ratio
is shown in Figure 6. Figure 7 depicts the median and interquartile range of the
various biomarkers between groups as violin plots, and Figure 8 illustrates the
correlation scatterplot between the markers and PaO2/FiO2 ratio, which shows the
Spearman rank correlation coefficients. CRP appears to have the best negative
correlation with the PaO2/FiO2 ratio.

Outcomes High-dose dexamethasone (n = 21) Tocilizumab (n = 21) p-value** CRP
(mg/dL), median difference between time points (95% CI) Baseline to treatment
day 35 (-10.88 to 80.88) 36 (-5.03 to 77.03) 0.93 Treatment day to 24 hours
-16.4 (-61.11 to 28.31) -53.5 (-96.21 to -10.71) 0.116 Treatment day to 48 hours
-32.9 (-75.83 to 10.03) -73.5 (-111.16 to -35.84) 0.038* Treatment day to day 3
- 48.49 (-93.62 to -3.36) -95.33 (-126.86 to -63.79) 0.014* Treatment day to day
4 - 51.51 (-104.05 to 1.04) -102.88 (-131.55 to -74.20) 0.004* Treatment day to
day 7 -51 (-111.99 to 9.99) -108.54 (-136.85 to - 80.22) 0.001* Treatment day to
day 10 - 54.42 (-108.03 to -0.80) -109.91 (-145.52 to -74.30) 0.002* Treatment
day to outcome day - 57.1 (-111.02 to -3.18) -110.36 (-137.23 to -83.48) 0.008*
Ferritin (ng/mL), median difference between time points (95% CI) Baseline to
treatment day -53.8 (-539.43 to 431.84) 151 (-276.89 to 578.89) 0.428 Treatment
day to 24 hours -62 (-575.75 to 451.75) -72.1 (-543.9 to 399.7) 0.327 Treatment
day to 48 hours -59.7 (-539.28 to 419.88) -159 (-545.61 to 227.611) 0.333
Treatment day to day 3 - 141.7 (-651.60 to 368.20) -179 (-547.59 to 189.59)
0.428 Treatment day to day 4 - 166.7 (-671.02 to 337.62) -114 (-1394.34 to
1166.34) 0.428 Treatment day to day 7 -150 (-693.09 to 393.09) -333 (-705.78 to
39.78) 0.274 Treatment day to day 10 - 111.7 (-638.47 to 415.07) -361 (-778.4 to
56.4) 0.122 Treatment day to outcome day - 269.4 (-936.06 to 397.27) -461
(-790.71 to -131.29) 0.333 D-Dimer (ng/mL), median difference between time
points (95% CI) Baseline to treatment day -514.8 (-2205.57 to 1175.97) 47
(-2053.98 to 2147.98) 0.064 Treatment day to 24 hours -474.06 (-2062.58 to
1114.46) 772 (-809.9 to 2353.9) 0.011* Treatment day to 48 hours 75.8 (-1513.10
to 1664.70) 771 (-901.35 to -2443.35) 0.554 Treatment day to day 3 71.8
(-1180.89 to 1324.49) 152 (-1278.13 to 1582.13) 0.155 Treatment day to day 4
214.58 (-1398.48 to 1827.64) -114 (-1394.34 to 1166.34) 0.285 Treatment day to
day 7 -68.2 (-1182.07 to 1045.67) -357 (-1559.94 to 845.94) 0.148 Treatment day
to day 10 - 307.7 (-1585.92 to 970.52) -440 (-1979.02 to 1099.02) 0.094
Treatment day to outcome day - 288.2 (-1639.72 to 1063.32) -675 (-1838.18 to
488.18) 0.213

TABLE 4: COURSE OF BIOMARKERS IN OUR STUDY POPULATION.

*p < 0.05 was considered significant; **Mann–Whitney U-test for comparing change
from baseline to treatment day and from treatment day to indicated time point
between treatment groups (the negative sign indicates a decrease from each
earlier mentioned time point). Median differences and 95% CIs have been derived
from quantile regression.

CRP: C-reactive protein.



FIGURE 6: TREND OF PAO2/FIO2 (P/F) RATIO WITH BIOMARKERS IN EACH GROUP (MEDIAN
VALUES AND STANDARD ERRORS HAVE BEEN PLOTTED).




FIGURE 7: PANEL OF VIOLIN PLOTS SHOWING PROGRESSION OVER TIME OF CRP (A AND D),
FERRITIN (B AND E), AND D-DIMER (C AND F): A, B, AND C FOR THE HIGH-DOSE
DEXAMETHASONE (HDD) GROUP, AND D, E, AND F FOR THE TOCILIZUMAB (TCZ) GROUP.
PAIRWISE COMPARISONS ARE WITH THE WILCOXON SIGNED-RANK TEST.

CRP: C-reactive protein.



FIGURE 8: SCATTERGRAPH SHOWING CORRELATIONS BETWEEN PAO2/FIO2 RATIO, CRP,
FERRITIN, AND D-DIMER IN ALL CASES AND BY GROUPS.

HDD: high-dose dexamethasone; TCZ: tocilizumab; CRP: C-reactive protein;
non-axial numbers (maroon): Spearman rank correlation coefficients; *: p-value <
0.05.



 Table 5, Table 6, and Table 7, and Figure 9 and Figure 10 show the results of
the survival analysis and competing risks regression.

Dependent variable Time variable Measured result Values 95% CI Statistical test
Extended mean Discharge Days posttreatment Mean time HDD 17.80 (underestimated)
15.19–20.41 Log rank p value < 0.0001 24.33 Mean time TCZ 10.85 9.72–11.93 10.85
Median time HDD 20 13–infinity   Median time TCZ 10 9–13 Expiry Days
posttreatment Mean time HDD 16.87 15.10–18.63 Log rank p value = 0.839 16.87
Mean time TCZ 15.05 (underestimated) 13.83–16.26 69.99 Median time HDD 17 15–19
  Median time TCZ Not computed 13–infinity RT-PCR negative status Days
posttreatment censored at 28 days if expired Median time HDD 12 11–14 Log-rank
p-value = 0.0059   Median time TCZ 10 9–10 WPS improvement by a score of 1 Days
posttreatment censored at 28 days if expired Mean time HDD 17.90
(underestimated) 12.80–23 Log-rank p-value = 0.0024 46.50 Mean time TCZ 6.48
(underestimated) 3.40–9.55 7.61 Median time HDD Not computed 3–infinity   Median
time TCZ 4 3–6

TABLE 5: SURVIVAL ANALYSIS OUTCOMES (KAPLAN–MEIER ESTIMATES).

p < 0.05 was considered significant; N.B., where median survival time could not
be computed in any one group, the restricted means and extended means have been
provided for careful interpretation, if necessary.

HDD: high-dose dexamethasone; RT-PCR: real-time polymerase chain reaction; TCZ:
tocilizumab; WPS: WHO Clinical Progression Scale.



Dependent variable Time variable Measured result Values 95% CI p-value LR
Chi-squared compared to null Prob>Chi-squared compared to null phtest Schonfeld
residuals prob>Chi-squared (p-value) Discharge Days posttreatment HR TCZ 5.153
2.090–12.702 0.001 14.93 <0.001 0.5614 Adjusted# HR TCZ 5.106 1.628–16.009 0.005
18.38 0.053 0.5185 Expired Days posttreatment HR TCZ 0.843 0.159–4.471 0.841
0.04 0.839 0.5501 Adjusted# HR TCZ 0.315 0.034–2.899 0.308 9.57 0.144 0.678 WPS
improvement by a score of 1 Days posttreatment censored at 28 days if expired HR
TCZ 3.18 1.39–7.27 0.006 14.64 0.0001 0.5038 Adjusted# HR TCZ 3.69 1.34–10.15
0.024 18.71 0.032 0.5203

TABLE 6: COX PROPORTIONAL HAZARDS MODEL ESTIMATES.

p < 0.05 was considered significant; #adjusting for the variables PaO2/FiO2
ratio at baseline, days from symptom onset at intervention, C-reactive protein
(CRP), total leukocyte count (TLC), and neutrophil/lymphocyte (N/L) ratio at
intervention.

HR: hazard ratio; TCZ: tocilizumab; WPS: WHO Clinical Progression Scale.



Dependent variable Competing interest Time variable Measured result Values 95%
CI p-value Wald Chi-squared compared to null Prob>Chi-squared compared to null
Discharge Expiry Days posttreatment Sub-HR TCZ 4.269 1.906–9.565 <0.001 12.44
0.0004 Adjusted# sub-HR TCZ 5.856 1.488–23.037 0.011 26.49 0.0002 Expiry
Discharge Days posttreatment Sub-HR TCZ 0.119 0.024–0.584 0.009 6.89 0.0087
Adjusted# sub-HR TCZ 0.085 0.016–0.435 0.003 21.83 0.0013

TABLE 7: COMPETING RISKS REGRESSION.

p < 0.05 was considered significant.

HR: hazard ratio; TCZ: tocilizumab.



FIGURE 9: COMPETING RISKS REGRESSION CURVES FOR THE OUTCOME OF DISCHARGE.




FIGURE 10: COMPETING RISKS REGRESSION CURVES FOR THE OUTCOME OF DEATH.





Original article
peer-reviewed


HIGH-DOSE DEXAMETHASONE VERSUS TOCILIZUMAB IN MODERATE TO SEVERE COVID-19
PNEUMONIA: A RANDOMIZED CONTROLLED TRIAL

Naveen B. Naik, Goverdhan D. Puri, Kamal Kajal, Varun Mahajan, Ashish
Bhalla, Sandeep Kataria, Karan Singla, Pritam Panigrahi, Ajay
Singh, Michelle Lazar, Anjuman Chander, Venkata Ganesh, Amarjyoti
Hazarika, Vikas Suri, Manoj K. Goyal, Vijayant Kumar Pandey, Narender
Kaloria, Tanvir Samra, Kulbhushan Saini, Shiv L. Soni

--------------------------------------------------------------------------------


AUTHOR INFORMATION

NAVEEN B. NAIK

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

GOVERDHAN D. PURI

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

KAMAL KAJAL

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

VARUN MAHAJAN

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

ASHISH BHALLA

Internal Medicine, Postgraduate Institute of Medical Education and Research,
Chandigarh, IND

SANDEEP KATARIA

Anesthesia, BronxCare Health System, New York, USA

KARAN SINGLA

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

PRITAM PANIGRAHI

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

AJAY SINGH

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

MICHELLE LAZAR

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

ANJUMAN CHANDER

Anesthesia, Postgraduate Institute of Medical Education and Research,
Chandigarh, IND

VENKATA GANESH CORRESPONDING AUTHOR

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

AMARJYOTI HAZARIKA

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

VIKAS SURI

Internal Medicine, Postgraduate Institute of Medical Education and Research,
Chandigarh, IND

MANOJ K. GOYAL

Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh,
IND

VIJAYANT KUMAR PANDEY

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

NARENDER KALORIA

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

TANVIR SAMRA

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

KULBHUSHAN SAINI

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

SHIV L. SONI

Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and
Research, Chandigarh, IND

--------------------------------------------------------------------------------

ETHICS STATEMENT AND CONFLICT OF INTEREST DISCLOSURES

Human subjects: Consent was obtained or waived by all participants in this
study. Institutional Ethics Committee issued approval INT/IEC/2021/SPL-697.
Animal subjects: All authors have confirmed that this study did not involve
animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE
uniform disclosure form, all authors declare the following: Payment/services
info: All authors have declared that no financial support was received from any
organization for the submitted work. Financial relationships: All authors have
declared that they have no financial relationships at present or within the
previous three years with any organizations that might have an interest in the
submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the
submitted work.

ACKNOWLEDGEMENTS

We would like to thank all the patients and their families who participated and
contributed to this study.

--------------------------------------------------------------------------------


ARTICLE INFORMATION

DOI

10.7759/cureus.20353

CITE THIS ARTICLE AS:

Naik N B, Puri G D, Kajal K, et al. (December 11, 2021) High-Dose Dexamethasone
Versus Tocilizumab in Moderate to Severe COVID-19 Pneumonia: A Randomized
Controlled Trial. Cureus 13(12): e20353. doi:10.7759/cureus.20353

PUBLICATION HISTORY

Peer review began: November 26, 2021
Peer review concluded: December 10, 2021
Published: December 11, 2021

COPYRIGHT

© Copyright 2021
Naik et al. This is an open access article distributed under the terms of the
Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and
source are credited.

LICENSE

This is an open access article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original author and source are
credited.



Original article
peer-reviewed


HIGH-DOSE DEXAMETHASONE VERSUS TOCILIZUMAB IN MODERATE TO SEVERE COVID-19
PNEUMONIA: A RANDOMIZED CONTROLLED TRIAL

Naveen B. Naik, Goverdhan D. Puri, Kamal Kajal, Varun Mahajan, Ashish
Bhalla, Sandeep Kataria, Karan Singla, Pritam Panigrahi, Ajay
Singh, Michelle Lazar, Anjuman Chander, Venkata Ganesh, Amarjyoti
Hazarika, Vikas Suri, Manoj K. Goyal, Vijayant Kumar Pandey, Narender
Kaloria, Tanvir Samra, Kulbhushan Saini, Shiv L. Soni

--------------------------------------------------------------------------------


FIGURES ETC.

FIGURE 1: CONSOLIDATED STANDARDS OF REPORTING TRIALS (CONSORT) FLOW DIAGRAM OF
THE STUDY.


  Download full-size


FIGURE 2: OUTCOMES. (A) VIOLIN PLOT OF VENTILATOR-FREE DAYS. (B) BAR DIAGRAM
SHOWING MORTALITY DISTRIBUTED AMONG THE TREATMENT GROUP AND POSTTREATMENT
INTUBATION STATUS. ONE PATIENT WAS INTUBATED ON THE DAY OF THERAPY IN THE
TOCILIZUMAB ARM AND WAS SUCCESSFULLY EXTUBATED AS WELL. (C) KAPLAN–MEIER
ESTIMATES OF CUMULATIVE HOSPITAL DISCHARGE RATES AND (D) IMPROVEMENT IN WHO
CLINICAL PROGRESSION SCALE.


  Download full-size


FIGURE 3: BOXPLOTS OF BIOMARKERS STRATIFIED BY TREATMENT GROUPS AND OUTCOME
(DISCHARGED/EXPIRED) AT VARIOUS TIME POINTS: (A) PAO2/FIO2 RATIO (PFR), (B)
TOTAL LEUKOCYTE COUNT (TLC), (C) NEUTROPHIL/LYMPHOCYTE RATIO (N/L RATIO OR NLR),
(D) C-REACTIVE PROTEIN (CRP), (E) D-DIMER, AND (F) FERRITIN.


  Download full-size


FIGURE 4: THE PROPOSED STUDY PROTOCOL.

PaO2/FiO2: partial pressure of arterial oxygen to fraction of inspired oxygen;
f/b: followed by; MPS: methylprednisolone; TLC: total leucocyte count; AST:
aspartate aminotransferase; ALT: alanine aminotransferase; CRP: C-reactive
protein; WHO-CPS: World Health Organization Clinical Progression Scale; NRBM:
non-rebreather mask; HFNC: high-flow nasal cannula; NIV: noninvasive
ventilation; IPPV: invasive positive pressure ventilation.

  Download full-size


FIGURE 5: STATISTICAL ANALYSIS/INTERIM ANALYSIS PLAN.


  Download full-size


FIGURE 6: TREND OF PAO2/FIO2 (P/F) RATIO WITH BIOMARKERS IN EACH GROUP (MEDIAN
VALUES AND STANDARD ERRORS HAVE BEEN PLOTTED).


  Download full-size


FIGURE 7: PANEL OF VIOLIN PLOTS SHOWING PROGRESSION OVER TIME OF CRP (A AND D),
FERRITIN (B AND E), AND D-DIMER (C AND F): A, B, AND C FOR THE HIGH-DOSE
DEXAMETHASONE (HDD) GROUP, AND D, E, AND F FOR THE TOCILIZUMAB (TCZ) GROUP.
PAIRWISE COMPARISONS ARE WITH THE WILCOXON SIGNED-RANK TEST.

CRP: C-reactive protein.

  Download full-size


FIGURE 8: SCATTERGRAPH SHOWING CORRELATIONS BETWEEN PAO2/FIO2 RATIO, CRP,
FERRITIN, AND D-DIMER IN ALL CASES AND BY GROUPS.

HDD: high-dose dexamethasone; TCZ: tocilizumab; CRP: C-reactive protein;
non-axial numbers (maroon): Spearman rank correlation coefficients; *: p-value <
0.05.

  Download full-size


FIGURE 9: COMPETING RISKS REGRESSION CURVES FOR THE OUTCOME OF DISCHARGE.


  Download full-size


FIGURE 10: COMPETING RISKS REGRESSION CURVES FOR THE OUTCOME OF DEATH.


  Download full-size


  High-dose dexamethasone arm (n = 21) Tocilizumab arm (n = 21) p-value Age,
median (IQR), years 51 (45–58) 50 (44–65) 0.920a BMI, median (IQR), kg/m2 30.20
(26.4–35.6) 27.45 (25.90–30.61) 0.232a Sex, number (%) Male 12 (57.14%) 12
(57.14%) 1.000b Female 9 (42.86%) 9 (42.86%) Coexisting conditions, number (%)
Diabetes mellitus 7 (33.33%) 8 (38.10%) 0.747b Hypertension 11 (52.38%) 13
(61.90%) 0.533b Chronic kidney disease 0 (0%) 0 (0%) - Coronary artery disease 0
(0%) 1 (4.76%) 1.000b Chronic liver disease 0 (0%) 0 (0%) - Chronic obstructive
pulmonary disease 0 (0%) 2 (9.52%) 1.000b Asthma 0 (0%) 1 (4.76%) 1.000b
Hypothyroid 2 (9.52%) 1 (4.76%) 1.000b Pregnancy 1 (4.76%) 2 (9.52%) 0.698b Days
from symptom onset, median (IQR), days On admission 6 (6–7) 7 (6–7) 0.039a On
the first dose of intervention (high-dose dexamethasone or tocilizumab) 7 (7–8)
8 (7–9) 0.011*a PaO2/FiO2, median (IQR), mmHg On admission 125.14
(110.29–138.67) 134.5 (117–181) 0.07a On the first dose of intervention
(high-dose dexamethasone or tocilizumab) 81.07 (68.22–91.60) 80.93 (62.20–113)
0.920a Respiratory support at admission, number (%) Invasive mechanical
ventilation 0 (0%) 0 (0%) 0.617b Noninvasive ventilation 2 (9.52%) 1 (4.76%)
High-flow nasal cannula 1 (4.76%) 2 (9.52%) Non-rebreather mask 15 (71.43%) 12
(57.14%) Face mask/nasal prongs 3 (14.29%) 6 (28.57%) Respiratory support at
intervention, number (%) Invasive mechanical ventilation 1 (4.76%) 1 (4.76%)
0.597b Noninvasive ventilation 8 (38.10%) 5 (23.81%) High-flow nasal cannula 12
(57.14%) 15 (71.43%) Non-rebreather mask 0 (0%) 0 (0%) Face mask/nasal prongs 0
(0%) 0 (0%) Hours in prone position during hospital stay, median (IQR) 96
(0–128) 48 (0–80) 0.063a Laboratory variables at admission, median (IQR)
C-Reactive protein, median (IQR), mg/dL 54.2 (33.4–75.1) 75 (47–90) 0.218a White
blood cell count, median (IQR), × 103/μL 8.4 (7.6–10.7) 8.1 (7.30–9.70) 0.413a
Neutrophil/lymphocyte ratio 15.62 (12.21–20.75) 16.40 (10.33–21.40) 0.811a
Platelet count, × 103/μL 246 (189–316.5) 221 (168–276 ) 0.083a Ferritin, ng/mL
702.5 (503.2–989) 522 (321.8–969) 0.252a D-Dimer, ng/mL 1568 (694–3455) 853
(512–2388) 0.204a Laboratory variables at intervention, median (IQR) C-Reactive
protein, median (IQR), mg/dL 89.2 (72–135.70) 111 (74.30–151.40) 0.443a White
blood cell count, median (IQR), × 103/μL 11.2 (9.3–13.20) 10.6 (9.1–11.70)
0.227a Neutrophil/lymphocyte ratio 17 (10.94–21.78) 13 (9.73–19.10) 0.489a
Platelet count, median (IQR), × 103/μL 233 (196–347.5) 258 (172–357) 0.597a
Ferritin, median (IQR), ng/mL 607 (428.45–1410) 631.9 (256.65–992.77) 0.170a
D-Dimer, median (IQR), ng/mL 1118 (541.65–3513.1) 649 (389.38–1734.75) 0.930a

TABLE 1: DEMOGRAPHY, CLINICAL CHARACTERISTICS, AND BIOMARKERS OF PATIENTS AT
BASELINE AND INTERVENTION.

*p-value < 0.05 was considered significant; a: Mann–Whitney U-test; b:
Chi-squared/Fisher’s exact test.

IQR: interquartile range; PaO2/FiO2: partial pressure of arterial oxygen to
fraction of inspired oxygen.

View larger

  High-dose dexamethasone arm (n = 21) Tocilizumab arm (n = 21) p-value Age,
median (IQR), years 51 (45–58) 50 (44–65) 0.920a BMI, median (IQR), kg/m2 30.20
(26.4–35.6) 27.45 (25.90–30.61) 0.232a Sex, number (%) Male 12 (57.14%) 12
(57.14%) 1.000b Female 9 (42.86%) 9 (42.86%) Coexisting conditions, number (%)
Diabetes mellitus 7 (33.33%) 8 (38.10%) 0.747b Hypertension 11 (52.38%) 13
(61.90%) 0.533b Chronic kidney disease 0 (0%) 0 (0%) - Coronary artery disease 0
(0%) 1 (4.76%) 1.000b Chronic liver disease 0 (0%) 0 (0%) - Chronic obstructive
pulmonary disease 0 (0%) 2 (9.52%) 1.000b Asthma 0 (0%) 1 (4.76%) 1.000b
Hypothyroid 2 (9.52%) 1 (4.76%) 1.000b Pregnancy 1 (4.76%) 2 (9.52%) 0.698b Days
from symptom onset, median (IQR), days On admission 6 (6–7) 7 (6–7) 0.039a On
the first dose of intervention (high-dose dexamethasone or tocilizumab) 7 (7–8)
8 (7–9) 0.011*a PaO2/FiO2, median (IQR), mmHg On admission 125.14
(110.29–138.67) 134.5 (117–181) 0.07a On the first dose of intervention
(high-dose dexamethasone or tocilizumab) 81.07 (68.22–91.60) 80.93 (62.20–113)
0.920a Respiratory support at admission, number (%) Invasive mechanical
ventilation 0 (0%) 0 (0%) 0.617b Noninvasive ventilation 2 (9.52%) 1 (4.76%)
High-flow nasal cannula 1 (4.76%) 2 (9.52%) Non-rebreather mask 15 (71.43%) 12
(57.14%) Face mask/nasal prongs 3 (14.29%) 6 (28.57%) Respiratory support at
intervention, number (%) Invasive mechanical ventilation 1 (4.76%) 1 (4.76%)
0.597b Noninvasive ventilation 8 (38.10%) 5 (23.81%) High-flow nasal cannula 12
(57.14%) 15 (71.43%) Non-rebreather mask 0 (0%) 0 (0%) Face mask/nasal prongs 0
(0%) 0 (0%) Hours in prone position during hospital stay, median (IQR) 96
(0–128) 48 (0–80) 0.063a Laboratory variables at admission, median (IQR)
C-Reactive protein, median (IQR), mg/dL 54.2 (33.4–75.1) 75 (47–90) 0.218a White
blood cell count, median (IQR), × 103/μL 8.4 (7.6–10.7) 8.1 (7.30–9.70) 0.413a
Neutrophil/lymphocyte ratio 15.62 (12.21–20.75) 16.40 (10.33–21.40) 0.811a
Platelet count, × 103/μL 246 (189–316.5) 221 (168–276 ) 0.083a Ferritin, ng/mL
702.5 (503.2–989) 522 (321.8–969) 0.252a D-Dimer, ng/mL 1568 (694–3455) 853
(512–2388) 0.204a Laboratory variables at intervention, median (IQR) C-Reactive
protein, median (IQR), mg/dL 89.2 (72–135.70) 111 (74.30–151.40) 0.443a White
blood cell count, median (IQR), × 103/μL 11.2 (9.3–13.20) 10.6 (9.1–11.70)
0.227a Neutrophil/lymphocyte ratio 17 (10.94–21.78) 13 (9.73–19.10) 0.489a
Platelet count, median (IQR), × 103/μL 233 (196–347.5) 258 (172–357) 0.597a
Ferritin, median (IQR), ng/mL 607 (428.45–1410) 631.9 (256.65–992.77) 0.170a
D-Dimer, median (IQR), ng/mL 1118 (541.65–3513.1) 649 (389.38–1734.75) 0.930a




Outcomes HDD arm (n = 21) TCZ arm (n = 21) p-value Primary outcome
Ventilator-free days Mean ± SD (95% CI) 9.76 ± 12.94 (3.87–25.65) 22.86 ± 9.75
(18.42–27.30)   Median (IQR) 0 (0–25) 28 (24–28) 0.001*a Secondary outcome
28-Day results All-cause mortality, number (%) 13 (61.90%) 2 (9.52%) <0.001*b
Intubation rates posttreatment, number (%) 13 (61.90%) 2 (9.52%) <0.001*b ICU
free, median (IQR), days 1 (1–5) 4 (3.5–5.5) 0.017*a MV duration, median (IQR),
days 12 (2.5–15.5) 0 (0–3) <0.001*a Discharged from the hospital within 28 days,
number (%) 8 (38.10%) 19 (90.48%) 0.030*b SOFA score, median, (IQR) On treatment
day 5 (4–8) 5 (4–6) 0.353a 48 hours later 4 (4–8) 4 (4–5) 0.303a 7 days after
intervention 5 (2–7) 2 (2–2) 0.002*a WHO-CPS score, median, (IQR) On treatment
day 6 (6–6) 6 (6–6) 0.573a 7 days after intervention 6 (5–8) 5 (3–5) <0.001*a
Mean time (days) to improvement in WHO-CPS score by 1 (i.e., a decrease by 1)
17.90 (underestimated) 6.48 (underestimated) 0.002*c Renal replacement therapy,
number (%) 2 (9.52%) 0 (0%) 0.488b Vasopressor use, number (%) 13 (61.90%) 3
(14.29%) 0.001*b Time to RT-PCR negative status (days), median (IQR) 19 (17–19)
17 (16–17) 0.026*a Hospital stay, median (IQR), days 17 (13–17) 12 (11–12)
0.003*a

TABLE 2: OUTCOMES.

*p-value < 0.05 was considered significant; a: Mann–Whitney U-test; b:
Chi-squared/Fisher's exact test; c: log-rank test from Kaplan–Meier survival
estimates (see text and Appendices for further details).

HDD: high-dose dexamethasone; TCZ: tocilizumab; CI: confidence interval; IQR:
interquartile range; MV: mechanical ventilation; ICU: intensive care unit; SOFA:
Sequential Organ Failure Assessment score; WHO-CPS: World Health Organization
Clinical Progression Scale; RT-PCR: reverse-transcriptase polymerase chain
reaction.

View larger

Outcomes HDD arm (n = 21) TCZ arm (n = 21) p-value Primary outcome
Ventilator-free days Mean ± SD (95% CI) 9.76 ± 12.94 (3.87–25.65) 22.86 ± 9.75
(18.42–27.30)   Median (IQR) 0 (0–25) 28 (24–28) 0.001*a Secondary outcome
28-Day results All-cause mortality, number (%) 13 (61.90%) 2 (9.52%) <0.001*b
Intubation rates posttreatment, number (%) 13 (61.90%) 2 (9.52%) <0.001*b ICU
free, median (IQR), days 1 (1–5) 4 (3.5–5.5) 0.017*a MV duration, median (IQR),
days 12 (2.5–15.5) 0 (0–3) <0.001*a Discharged from the hospital within 28 days,
number (%) 8 (38.10%) 19 (90.48%) 0.030*b SOFA score, median, (IQR) On treatment
day 5 (4–8) 5 (4–6) 0.353a 48 hours later 4 (4–8) 4 (4–5) 0.303a 7 days after
intervention 5 (2–7) 2 (2–2) 0.002*a WHO-CPS score, median, (IQR) On treatment
day 6 (6–6) 6 (6–6) 0.573a 7 days after intervention 6 (5–8) 5 (3–5) <0.001*a
Mean time (days) to improvement in WHO-CPS score by 1 (i.e., a decrease by 1)
17.90 (underestimated) 6.48 (underestimated) 0.002*c Renal replacement therapy,
number (%) 2 (9.52%) 0 (0%) 0.488b Vasopressor use, number (%) 13 (61.90%) 3
(14.29%) 0.001*b Time to RT-PCR negative status (days), median (IQR) 19 (17–19)
17 (16–17) 0.026*a Hospital stay, median (IQR), days 17 (13–17) 12 (11–12)
0.003*a




  Adverse events, number of patients (%) Number of events Event rate ratio
HDD/TCZ p-value (exact rate ratio test) Total (n = 42) HDD (n = 21) TCZ (n = 21)
HDD (number in 306 patient days) TCZ (number in 220 patient days) Deaths 15
(36.06%) 13 (61.9%) 2 (9.52%) 13 2 4.67 (1.06–42.65) 0.023* Infections 13
(30.95%) 11 (52.38%) 2 (9.52%) 25 2 8.9 (2.24–78.28) <0.001* Grade 3 or worse
adverse events by CTCAE version 5, MedDRA system organ class preferred terms
Cardiac disorders Supraventricular tachycardia 1 (2.38%) 0 (0%) 1 (4.76%) 0 1 0
(0–28.04) 0.41 Sinus bradycardia 1 (2.38%) 0 (0%) 1 (4.76%) 0 1 0 (0–28.04) 0.41
Cardiac arrest 15 (36.06%) 13 (61.9%) 2 (9.52%) 13 2 4.67 (1.06–42.65) 0.023*
Infections or infestations Fungemia 8 (19.04%) 8 (38.09%) 0 (0%) 8 0 Zero
denominator 0.013* Catheter-related infection 7(16%) 6 (28.27%) 1 (4.76%) 6 1
4.31 (0.52–198.42) 0.158 Lung infection 11 (26.19%) 10 (47.61%) 1 (4.76%) 11 1
7.91 (1.15–340.41) 0.016* Respiratory, thoracic, and mediastinal disorders Grade
4 adult respiratory distress syndrome 15 (36.06%) 13 (61.9%) 3 (14.28%) 13 3
3.12 (0.85–17.04) 0.065 Vascular disorders Shock 16 (38.09%) 13 (61.90%) 3
(14.29%) 13 3 3.12 (0.85–17.04) 0.065 Metabolism and nutrition disorders
Hyperglycemiaᴪ 30 (71.43%) 21 (100%) 9 (42.86%) 106 49 1.56 (1.09–2.23) 0.009*
Gastrointestinal disorders Gastric hemorrhage 4 (9.52%) 4 (19.04%) 0 (0%) 18 0
Zero denominator <0.001* Total number of events‡ 188 61 2.22 (1.65–3.01) <0.001*

TABLE 3: ADVERSE EVENTS.

All cardiac arrests were grade 5.

‡Excludes deaths and infections to avoid duplication.

ᴪBlood sugar > 180 mg/dL.

*p-value < 0.05 was considered significant.

HDD: high-dose dexamethasone; TCZ: tocilizumab; CTCAE: Common Terminology
Criteria for Adverse Events.

View larger

  Adverse events, number of patients (%) Number of events Event rate ratio
HDD/TCZ p-value (exact rate ratio test) Total (n = 42) HDD (n = 21) TCZ (n = 21)
HDD (number in 306 patient days) TCZ (number in 220 patient days) Deaths 15
(36.06%) 13 (61.9%) 2 (9.52%) 13 2 4.67 (1.06–42.65) 0.023* Infections 13
(30.95%) 11 (52.38%) 2 (9.52%) 25 2 8.9 (2.24–78.28) <0.001* Grade 3 or worse
adverse events by CTCAE version 5, MedDRA system organ class preferred terms
Cardiac disorders Supraventricular tachycardia 1 (2.38%) 0 (0%) 1 (4.76%) 0 1 0
(0–28.04) 0.41 Sinus bradycardia 1 (2.38%) 0 (0%) 1 (4.76%) 0 1 0 (0–28.04) 0.41
Cardiac arrest 15 (36.06%) 13 (61.9%) 2 (9.52%) 13 2 4.67 (1.06–42.65) 0.023*
Infections or infestations Fungemia 8 (19.04%) 8 (38.09%) 0 (0%) 8 0 Zero
denominator 0.013* Catheter-related infection 7(16%) 6 (28.27%) 1 (4.76%) 6 1
4.31 (0.52–198.42) 0.158 Lung infection 11 (26.19%) 10 (47.61%) 1 (4.76%) 11 1
7.91 (1.15–340.41) 0.016* Respiratory, thoracic, and mediastinal disorders Grade
4 adult respiratory distress syndrome 15 (36.06%) 13 (61.9%) 3 (14.28%) 13 3
3.12 (0.85–17.04) 0.065 Vascular disorders Shock 16 (38.09%) 13 (61.90%) 3
(14.29%) 13 3 3.12 (0.85–17.04) 0.065 Metabolism and nutrition disorders
Hyperglycemiaᴪ 30 (71.43%) 21 (100%) 9 (42.86%) 106 49 1.56 (1.09–2.23) 0.009*
Gastrointestinal disorders Gastric hemorrhage 4 (9.52%) 4 (19.04%) 0 (0%) 18 0
Zero denominator <0.001* Total number of events‡ 188 61 2.22 (1.65–3.01) <0.001*




Outcomes High-dose dexamethasone (n = 21) Tocilizumab (n = 21) p-value** CRP
(mg/dL), median difference between time points (95% CI) Baseline to treatment
day 35 (-10.88 to 80.88) 36 (-5.03 to 77.03) 0.93 Treatment day to 24 hours
-16.4 (-61.11 to 28.31) -53.5 (-96.21 to -10.71) 0.116 Treatment day to 48 hours
-32.9 (-75.83 to 10.03) -73.5 (-111.16 to -35.84) 0.038* Treatment day to day 3
- 48.49 (-93.62 to -3.36) -95.33 (-126.86 to -63.79) 0.014* Treatment day to day
4 - 51.51 (-104.05 to 1.04) -102.88 (-131.55 to -74.20) 0.004* Treatment day to
day 7 -51 (-111.99 to 9.99) -108.54 (-136.85 to - 80.22) 0.001* Treatment day to
day 10 - 54.42 (-108.03 to -0.80) -109.91 (-145.52 to -74.30) 0.002* Treatment
day to outcome day - 57.1 (-111.02 to -3.18) -110.36 (-137.23 to -83.48) 0.008*
Ferritin (ng/mL), median difference between time points (95% CI) Baseline to
treatment day -53.8 (-539.43 to 431.84) 151 (-276.89 to 578.89) 0.428 Treatment
day to 24 hours -62 (-575.75 to 451.75) -72.1 (-543.9 to 399.7) 0.327 Treatment
day to 48 hours -59.7 (-539.28 to 419.88) -159 (-545.61 to 227.611) 0.333
Treatment day to day 3 - 141.7 (-651.60 to 368.20) -179 (-547.59 to 189.59)
0.428 Treatment day to day 4 - 166.7 (-671.02 to 337.62) -114 (-1394.34 to
1166.34) 0.428 Treatment day to day 7 -150 (-693.09 to 393.09) -333 (-705.78 to
39.78) 0.274 Treatment day to day 10 - 111.7 (-638.47 to 415.07) -361 (-778.4 to
56.4) 0.122 Treatment day to outcome day - 269.4 (-936.06 to 397.27) -461
(-790.71 to -131.29) 0.333 D-Dimer (ng/mL), median difference between time
points (95% CI) Baseline to treatment day -514.8 (-2205.57 to 1175.97) 47
(-2053.98 to 2147.98) 0.064 Treatment day to 24 hours -474.06 (-2062.58 to
1114.46) 772 (-809.9 to 2353.9) 0.011* Treatment day to 48 hours 75.8 (-1513.10
to 1664.70) 771 (-901.35 to -2443.35) 0.554 Treatment day to day 3 71.8
(-1180.89 to 1324.49) 152 (-1278.13 to 1582.13) 0.155 Treatment day to day 4
214.58 (-1398.48 to 1827.64) -114 (-1394.34 to 1166.34) 0.285 Treatment day to
day 7 -68.2 (-1182.07 to 1045.67) -357 (-1559.94 to 845.94) 0.148 Treatment day
to day 10 - 307.7 (-1585.92 to 970.52) -440 (-1979.02 to 1099.02) 0.094
Treatment day to outcome day - 288.2 (-1639.72 to 1063.32) -675 (-1838.18 to
488.18) 0.213

TABLE 4: COURSE OF BIOMARKERS IN OUR STUDY POPULATION.

*p < 0.05 was considered significant; **Mann–Whitney U-test for comparing change
from baseline to treatment day and from treatment day to indicated time point
between treatment groups (the negative sign indicates a decrease from each
earlier mentioned time point). Median differences and 95% CIs have been derived
from quantile regression.

CRP: C-reactive protein.

View larger

Outcomes High-dose dexamethasone (n = 21) Tocilizumab (n = 21) p-value** CRP
(mg/dL), median difference between time points (95% CI) Baseline to treatment
day 35 (-10.88 to 80.88) 36 (-5.03 to 77.03) 0.93 Treatment day to 24 hours
-16.4 (-61.11 to 28.31) -53.5 (-96.21 to -10.71) 0.116 Treatment day to 48 hours
-32.9 (-75.83 to 10.03) -73.5 (-111.16 to -35.84) 0.038* Treatment day to day 3
- 48.49 (-93.62 to -3.36) -95.33 (-126.86 to -63.79) 0.014* Treatment day to day
4 - 51.51 (-104.05 to 1.04) -102.88 (-131.55 to -74.20) 0.004* Treatment day to
day 7 -51 (-111.99 to 9.99) -108.54 (-136.85 to - 80.22) 0.001* Treatment day to
day 10 - 54.42 (-108.03 to -0.80) -109.91 (-145.52 to -74.30) 0.002* Treatment
day to outcome day - 57.1 (-111.02 to -3.18) -110.36 (-137.23 to -83.48) 0.008*
Ferritin (ng/mL), median difference between time points (95% CI) Baseline to
treatment day -53.8 (-539.43 to 431.84) 151 (-276.89 to 578.89) 0.428 Treatment
day to 24 hours -62 (-575.75 to 451.75) -72.1 (-543.9 to 399.7) 0.327 Treatment
day to 48 hours -59.7 (-539.28 to 419.88) -159 (-545.61 to 227.611) 0.333
Treatment day to day 3 - 141.7 (-651.60 to 368.20) -179 (-547.59 to 189.59)
0.428 Treatment day to day 4 - 166.7 (-671.02 to 337.62) -114 (-1394.34 to
1166.34) 0.428 Treatment day to day 7 -150 (-693.09 to 393.09) -333 (-705.78 to
39.78) 0.274 Treatment day to day 10 - 111.7 (-638.47 to 415.07) -361 (-778.4 to
56.4) 0.122 Treatment day to outcome day - 269.4 (-936.06 to 397.27) -461
(-790.71 to -131.29) 0.333 D-Dimer (ng/mL), median difference between time
points (95% CI) Baseline to treatment day -514.8 (-2205.57 to 1175.97) 47
(-2053.98 to 2147.98) 0.064 Treatment day to 24 hours -474.06 (-2062.58 to
1114.46) 772 (-809.9 to 2353.9) 0.011* Treatment day to 48 hours 75.8 (-1513.10
to 1664.70) 771 (-901.35 to -2443.35) 0.554 Treatment day to day 3 71.8
(-1180.89 to 1324.49) 152 (-1278.13 to 1582.13) 0.155 Treatment day to day 4
214.58 (-1398.48 to 1827.64) -114 (-1394.34 to 1166.34) 0.285 Treatment day to
day 7 -68.2 (-1182.07 to 1045.67) -357 (-1559.94 to 845.94) 0.148 Treatment day
to day 10 - 307.7 (-1585.92 to 970.52) -440 (-1979.02 to 1099.02) 0.094
Treatment day to outcome day - 288.2 (-1639.72 to 1063.32) -675 (-1838.18 to
488.18) 0.213




Dependent variable Time variable Measured result Values 95% CI Statistical test
Extended mean Discharge Days posttreatment Mean time HDD 17.80 (underestimated)
15.19–20.41 Log rank p value < 0.0001 24.33 Mean time TCZ 10.85 9.72–11.93 10.85
Median time HDD 20 13–infinity   Median time TCZ 10 9–13 Expiry Days
posttreatment Mean time HDD 16.87 15.10–18.63 Log rank p value = 0.839 16.87
Mean time TCZ 15.05 (underestimated) 13.83–16.26 69.99 Median time HDD 17 15–19
  Median time TCZ Not computed 13–infinity RT-PCR negative status Days
posttreatment censored at 28 days if expired Median time HDD 12 11–14 Log-rank
p-value = 0.0059   Median time TCZ 10 9–10 WPS improvement by a score of 1 Days
posttreatment censored at 28 days if expired Mean time HDD 17.90
(underestimated) 12.80–23 Log-rank p-value = 0.0024 46.50 Mean time TCZ 6.48
(underestimated) 3.40–9.55 7.61 Median time HDD Not computed 3–infinity   Median
time TCZ 4 3–6

TABLE 5: SURVIVAL ANALYSIS OUTCOMES (KAPLAN–MEIER ESTIMATES).

p < 0.05 was considered significant; N.B., where median survival time could not
be computed in any one group, the restricted means and extended means have been
provided for careful interpretation, if necessary.

HDD: high-dose dexamethasone; RT-PCR: real-time polymerase chain reaction; TCZ:
tocilizumab; WPS: WHO Clinical Progression Scale.

View larger

Dependent variable Time variable Measured result Values 95% CI Statistical test
Extended mean Discharge Days posttreatment Mean time HDD 17.80 (underestimated)
15.19–20.41 Log rank p value < 0.0001 24.33 Mean time TCZ 10.85 9.72–11.93 10.85
Median time HDD 20 13–infinity   Median time TCZ 10 9–13 Expiry Days
posttreatment Mean time HDD 16.87 15.10–18.63 Log rank p value = 0.839 16.87
Mean time TCZ 15.05 (underestimated) 13.83–16.26 69.99 Median time HDD 17 15–19
  Median time TCZ Not computed 13–infinity RT-PCR negative status Days
posttreatment censored at 28 days if expired Median time HDD 12 11–14 Log-rank
p-value = 0.0059   Median time TCZ 10 9–10 WPS improvement by a score of 1 Days
posttreatment censored at 28 days if expired Mean time HDD 17.90
(underestimated) 12.80–23 Log-rank p-value = 0.0024 46.50 Mean time TCZ 6.48
(underestimated) 3.40–9.55 7.61 Median time HDD Not computed 3–infinity   Median
time TCZ 4 3–6




Dependent variable Time variable Measured result Values 95% CI p-value LR
Chi-squared compared to null Prob>Chi-squared compared to null phtest Schonfeld
residuals prob>Chi-squared (p-value) Discharge Days posttreatment HR TCZ 5.153
2.090–12.702 0.001 14.93 <0.001 0.5614 Adjusted# HR TCZ 5.106 1.628–16.009 0.005
18.38 0.053 0.5185 Expired Days posttreatment HR TCZ 0.843 0.159–4.471 0.841
0.04 0.839 0.5501 Adjusted# HR TCZ 0.315 0.034–2.899 0.308 9.57 0.144 0.678 WPS
improvement by a score of 1 Days posttreatment censored at 28 days if expired HR
TCZ 3.18 1.39–7.27 0.006 14.64 0.0001 0.5038 Adjusted# HR TCZ 3.69 1.34–10.15
0.024 18.71 0.032 0.5203

TABLE 6: COX PROPORTIONAL HAZARDS MODEL ESTIMATES.

p < 0.05 was considered significant; #adjusting for the variables PaO2/FiO2
ratio at baseline, days from symptom onset at intervention, C-reactive protein
(CRP), total leukocyte count (TLC), and neutrophil/lymphocyte (N/L) ratio at
intervention.

HR: hazard ratio; TCZ: tocilizumab; WPS: WHO Clinical Progression Scale.

View larger

Dependent variable Time variable Measured result Values 95% CI p-value LR
Chi-squared compared to null Prob>Chi-squared compared to null phtest Schonfeld
residuals prob>Chi-squared (p-value) Discharge Days posttreatment HR TCZ 5.153
2.090–12.702 0.001 14.93 <0.001 0.5614 Adjusted# HR TCZ 5.106 1.628–16.009 0.005
18.38 0.053 0.5185 Expired Days posttreatment HR TCZ 0.843 0.159–4.471 0.841
0.04 0.839 0.5501 Adjusted# HR TCZ 0.315 0.034–2.899 0.308 9.57 0.144 0.678 WPS
improvement by a score of 1 Days posttreatment censored at 28 days if expired HR
TCZ 3.18 1.39–7.27 0.006 14.64 0.0001 0.5038 Adjusted# HR TCZ 3.69 1.34–10.15
0.024 18.71 0.032 0.5203




Dependent variable Competing interest Time variable Measured result Values 95%
CI p-value Wald Chi-squared compared to null Prob>Chi-squared compared to null
Discharge Expiry Days posttreatment Sub-HR TCZ 4.269 1.906–9.565 <0.001 12.44
0.0004 Adjusted# sub-HR TCZ 5.856 1.488–23.037 0.011 26.49 0.0002 Expiry
Discharge Days posttreatment Sub-HR TCZ 0.119 0.024–0.584 0.009 6.89 0.0087
Adjusted# sub-HR TCZ 0.085 0.016–0.435 0.003 21.83 0.0013

TABLE 7: COMPETING RISKS REGRESSION.

p < 0.05 was considered significant.

HR: hazard ratio; TCZ: tocilizumab.

View larger

Dependent variable Competing interest Time variable Measured result Values 95%
CI p-value Wald Chi-squared compared to null Prob>Chi-squared compared to null
Discharge Expiry Days posttreatment Sub-HR TCZ 4.269 1.906–9.565 <0.001 12.44
0.0004 Adjusted# sub-HR TCZ 5.856 1.488–23.037 0.011 26.49 0.0002 Expiry
Discharge Days posttreatment Sub-HR TCZ 0.119 0.024–0.584 0.009 6.89 0.0087
Adjusted# sub-HR TCZ 0.085 0.016–0.435 0.003 21.83 0.0013



-

HOW LIKELY ARE YOU TO RECOMMEND THIS ARTICLE TO A PEER?

--------------------------------------------------------------------------------


6.6

RATED BY 5 READERS

CONTRIBUTE RATING

Scholarly Impact Quotient™ (SIQ™) is our unique post-publication peer review
rating process. Learn more here.


COMMENTS

Please sign in or sign up to comment.
ADVERTISEMENT


--------------------------------------------------------------------------------


RELATED ARTICLES

Double Whammy: Subacute Stent Thrombosis While Being Adherent to Dual Antipl ...

Salbutamol-Induced QT Interval Prolongation in a Two-Year-Old Patient

Frontal Fibrosing Alopecia Mimicking Alopecia Syphilitica

Undulant Fevers and Bitemporal Headaches: A Clinical Presentation of Human B ...

Clinical Prognosis of Patients With Mild COVID-19 Treated With Casirivimab/I ...

Interstitial Lung Disease and Transverse Myelitis: A Possible Complication o ...



YOU’RE ABOUT TO LEAVE THE CUREUS WEBSITE!

This link will take you to a third party website that is not affiliated with
Cureus, Inc. Please note that Cureus is not responsible for any content or
activities contained within our partner or affiliate websites.

Proceed

Cancel and return to Cureus


WHAT'S SIQ™?

Scholarly Impact Quotient™ (SIQ™) is our unique post-publication peer review
rating process. SIQ™ assesses article importance and quality by embracing the
collective intelligence of the Cureus community-at-large. All registered users
are invited to contribute to the SIQ™ of any published article. (Authors cannot
rate their own articles.)

High ratings should be reserved for work that is truly groundbreaking in its
respective field. Anything above 5 should be considered above average. While all
registered Cureus users can rate any published article, the opinion of domain
experts is weighted appreciably more than that of non-specialists. An article’s
SIQ™ will appear alongside the article after being rated twice and is
recalculated with each additional rating.

Visit our SIQ™ page to find out more.

Close

SCHOLARLY IMPACT QUOTIENT™ (SIQ™)

Scholarly Impact Quotient™ (SIQ™) is our unique post-publication peer review
rating process. SIQ™ assesses article importance and quality by embracing the
collective intelligence of the Cureus community-at-large. All registered users
are invited to contribute to the SIQ™ of any published article. (Authors cannot
rate their own articles.)

Already have an account? Sign in.

Cancel Join Now

ENTER YOUR EMAIL ADDRESS TO RECEIVE YOUR FREE PDF DOWNLOAD.

Please note that by doing so you agree to be added to our monthly email
newsletter distribution list.



New here? Sign up.


SIGN IN TO CUREUS

sign in using LinkedIn
sign in using Google
sign in using Facebook

--------------------------------------------------------------------------------

or
Sign in with your email address:
Email

Password


Don't have an account? Sign Up
Forgot your password?
Resend confirmation instructions


SIGN UP FOR CUREUS

sign up using LinkedIn
sign up using Google
sign up using Facebook

--------------------------------------------------------------------------------

or
First name

Last name

Email

Password

Specialty
Please choose I'm not a medical professional. Allergy and Immunology Anatomy
Anesthesiology Cardiac/Thoracic/Vascular Surgery Cardiology Dentistry
Dermatology Emergency Medicine Epidemiology and Public Health Family Medicine
Forensic Medicine General Practice Genetics Health Policy I'm not a medical
professional. Integrative/Complementary Medicine Internal Medicine Internal
Medicine-Pediatrics Internal Medicine: Critical Care Internal Medicine: Diabetes
and Endocrinology Internal Medicine: Gastroenterology Internal Medicine:
Geriatrics Internal Medicine: Hematology Internal Medicine: HIV/AIDS Internal
Medicine: Hospital-based Medicine Internal Medicine: Infectious Disease Internal
Medicine: Nephrology Internal Medicine: Pulmonology Internal Medicine:
Rheumatology Medical Education and Simulation Medical Physics Medical Student
Neurological Surgery Neurology Nuclear Medicine Nutrition Obstetrics and
Gynecology Occupational Health Oncology Ophthalmology Oral Medicine Orthopaedics
Osteopathic Medicine Otolaryngology Pain Management Palliative Care Pathology
Pediatrics Pediatric Surgery Physical Medicine and Rehabilitation Plastic
Surgery Podiatry Preventive Medicine Psychiatry Psychology Radiation Oncology
Radiology Substance Use and Addiction Surgery Therapeutics Trauma Urology
Miscellaneous

EMAIL COMMUNICATION AND PERSONAL DATA

Cureus personal data will never be sold to third parties and will only be used
to enrich the user experience and contact you in direct relation to the
application. I agree to opt in to this communication.


By joining Cureus, you agree to our Privacy Policy and Terms of Use.