• Asploro Journal of Biomedical and Clinical Case Reports
• ISSN: 2582-0370
• Article Type: Original Article
• DOI: 10.36502/2020/ASJBCCR.6219
• Asp Biomed Clin Case Rep. 2020 Dec 22;3(3):241-56

Consensus Statement for Pharmacological Management of Coronavirus Disease 2019 (COVID-19): A Pragmatic Approach

Jain R¹, Javeri Y², Nasa P^3*, Kashyap R⁴, Khanna AK⁵, Tayar AA⁶, Bhaskar B⁷, Jagiasi BG⁸, Juneja D⁹, Lipman J^10,11, Ng J¹², Portilla JLP¹³, Zirpe K¹⁴, Popugaev KA¹⁵, Hashmi M¹⁶, Malbrain MLNG^17,18, Kirkman MA¹⁹, Chan MTV²⁰, Turkoglu M²¹, Mer M²², Singer M²³, Harriss M²⁴, Rangappa P²⁵, Piacevoli Q^{26,27,28,29,30}, Mani RK³¹, Mishra RC³², Garg R³³, Yadav R³⁴, Bagdia S³⁵, Donovan S³⁶, Reza ST³⁷, Yeh TY^38,39,40,41, Videtta W^42
1Consultant Critical Care, Nayati Healthcare, Mathura, Uttar Pradesh, India
²Head CCM and Emergency Medicine, Regency Super Specialty Hospital, Lucknow, India
³Specialist and Head Critical Care Medicine, Head -Prevention and Control of Infection, NMC Specialty Hospital, Al Nahda 2, Dubai, UAE
⁴Assistant Professor of Anesthesiology, Department Of Anesthesia and Critical Care Medicine, Mayo Clinic, USA
⁵Associate Professor, Section Head for Research, Department of Anesthesiology, Wake Forest University School of Medicine, Cleveland, OH, USA
⁶Consultant, Head of ICU at Security Forces Hospital, Dammam, Saudi Arabia
⁷Director of the Intensive Care Services, Chair Intensive Care Committee, American Hospital Dubai, UAE
⁸Head of Critical Care Department, Reliance Hospital, Navi Mumbai, India
⁹Associate Director, Institute of Critical Care Medicine, Max Super Specialty Hospital, Saket New Delhi, India
¹⁰The University of Queensland, Australia
¹¹Scientific Consultant, Nimes University Hospital, University of Montpellier, France
¹²Department of Anaesthesiology, Intensive Care and Pain Medicine, Tan Tock Seng Hospital, Singapore
¹³Medicina Intensiva, Coordinador Neuro UCIN, Jefe del Servicio de Cuidados Intermedios, Hospital Nacional Almanzor Aguinaga Asenjo, EsSalud, Perú
¹⁴Prof and Head of Department Neuro Intensive Care Unit, Ruby Hall Clinic, Grant medical Foundation, Pune, India
¹⁵Deputy Director, Head of Regional Vascular Centre, Sklifosovsky Research Institute of Emergency Medicine, Bolshaya Sukharevskaya Square, Russia
¹⁶Professor and Head of Department, Critical Care Medicine, Ziauddin University, Karachi, Pakistan
¹⁷Department Intensive Care Medicine, University Hospital Brussel (UZB), Brussels, Belgium
¹⁸Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium
¹⁹Atkinson Morley Regional Neurosciences Centre, St George’s Hospital, London, UK
²⁰Professor, Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
²¹Associate Professor, Department of Internal Medicine, Medical İntensive Care Unit, Gazi University Faculty of Medicine, Turkey
²²Clinical Head Adult Multidisciplinary Intensive Care Unit, Department of Medicine, Divisions of Critical Care and Pulmonology, University of the Witwatersrand, Johannesburg, South Africa
²³Professor of Intensive Care Medicine, Director, Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
²⁴Pulmonologist, Medcare Hospital Sharjah and Dubai London Clinic and Hospital, Dubai, UAE
²⁵Consultant Intensive Care Physician, Columbia Asia Hospitals, Bangalore, India
²⁶Professor and Head Department of Anaesthesia and Intensive Care, Rome, Italy
²⁷Member of the Board of the FEDERATION EUROPEEN des MEDICINE, Brussels, Belgium
²⁸P. Member of the World Commission on Safety and Quality WFSA, WHO
²⁹Visiting Professor, Ss. Cyril and Methodius University in Skopje, Republic of North Macedonia, Greece
³⁰Visiting Professor, Campus Bio Medico University, Rome, Italy
³¹Director, Strategy and COVID-19 Management, Yashoda Super Specialty Hospital, Kaushambi, Ghaziabad, UP, India
³²Honorary Consultant Intensivist & Internist, Ahmedabad, India
³³Additional Professor of Anaesthesiology, Critical Care, Pain and Palliative Medicine, All India Institute of Medical Sciences, New Delhi, India
³⁴Senior Consultant Critical Care Medicine, Nayati Healthcare, Mathura, UP, India
³⁵Pulmonologist, NMC Royal Hospital DIP, Dubai, UAE
³⁶Clinical Professor of Medicine, UCLA School of Medicine, USA
³⁷Assistant Professor, Critical Care Medicine, Dhaka Medical College Hospital, Dhaka, Bangladesh
³⁸Clinical Associate Professor, Attending Anesthesiologist and Intensivist, Department of Anesthesiology, National Taiwan University Hospital (NTUH), Taiwan
³⁹Chair, Scientific Committee, Taiwan Society of Emergency & Critical Care Medicine (TSECCM), Taiwan
⁴⁰Vice-Chair, Research Committee and International Affairs, TSECCM, Taiwan
⁴¹Secretary General, Taiwan Society of Critical Care Medicine (TSCCM), Taiwan
⁴²Hospital Posadas, Buenos Aires, Argentina

Corresponding Author: Prashant Nasa, MD ^{ORCID ID}
Address: Specialist and Head Critical Care Medicine, Head -Prevention and Control of Infection, NMC Specialty Hospital, Al Nahda 2, Dubai, UAE.
Received date: 19 November 2020; Accepted date: 14 December 2020; Published date: 22 December 2020

Citation: Jain R, Javeri Y, Nasa P, Kashyap R, Khanna AK, Tayar AA, Bhaskar B, Jagiasi BG, Juneja D, Lipman J, Ng J, Portilla JLP, Zirpe K, Popugaev KA, Hashmi M, Malbrain MLNG, Kirkman MA, Chan MTV, Turkoglu M, Mer M, Singer M, Harriss M, Rangappa P, Piacevoli Q, Mani RK, Mishra RC, Garg R, Yadav R, Bagdia S, Donovan S, Reza ST, Yeh TY, Videtta W. Consensus Statement for Pharmacological Management of Coronavirus Disease 2019 (COVID-19): A Pragmatic Approach. Asp Biomed Clin Case Rep. 2020 Dec 22;3(3):241-56.

Copyright © 2020 Jain R, Javeri Y, Nasa P, Kashyap R, Khanna AK, Tayar AA, Bhaskar B, Jagiasi BG, Juneja D, Lipman J, Ng J, Portilla JLP, Zirpe K, Popugaev KA, Hashmi M, Malbrain MLNG, Kirkman MA, Chan MTV, Turkoglu M, Mer M, Singer M, Harriss M, Rangappa P, Piacevoli Q, Mani RK, Mishra RC, Garg R, Yadav R, Bagdia S, Donovan S, Reza ST, Yeh TY, Videtta W. This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium provided the original work is properly cited.

Keywords: Consensus Statement, COVID-19, Modified Delphi Method, Pharmacologic Management

Abstract

Introduction: In the absence of high-quality evidence for Coronavirus disease-2019 (COVID-19), supportive care is advocated during this pandemic. We aim to develop a consensus statement from global experts for pharmacological management, based on the pathophysiology of COVID-19.
Material and Methods: We used a modified Delphi methodology in three steps: 1) Formulation of the steering committee and questionnaire; 2) Delphi methodology and selection of experts; 3) Final meeting of the steering committee and analysis, discussion, preparation, and presentation of captured data.
Results: 34 (73·9%) experts accepted the invitation for the study. We conducted two rounds of Delphi and consensus (>70% votes) was achieved on 11 out of 24 statements after the end of round two.
Conclusion: This global consensus suggests that “Anti-viral therapy should be administered in the early infection phase of COVID-19 followed by low dose steroid therapy in pulmonary phase. Prophylactic dose anticoagulation should be used in hospitalized, mild to moderate COVID-19 patients. We make no suggestions for the use of immune modulation therapy”.

Introduction

Coronavirus disease 2019 (COVID-19) has taken the world by storm with more than 45 million cases and 1.2 million deaths (as of November 1, 2020) globally. Hospitalization and intensive care unit (ICU) admission rates vary widely, ranging from 15-30% and 4-12% respectively. Critically ill COVID-19 patients have unusually high mortality rates, leaving the clinician with a short window of opportunity to act [1,2]. Despite desperate efforts in search of effective pharmacotherapeutic agents, with over 3600 listed clinical trials underway according to ClinicalTrials.gov (last accessed October 15, 2020), the ongoing lack of concrete evidence has impelled authorities and professional bodies to predominantly recommend supportive care [3-5]. There is a paucity on a global consensus for a pragmatic pharmacological management protocol. We brought together global experts and developed a consensus view that would act as an interim guide for managing COVID-19 patients until ongoing research studies provide more definitive evidence.

Methodology

A modified Delphi methodology was used to generate a consensus statement involving a three-step approach.

Step-1: Formation of the steering committee, literature review, and preparation of focused questionnaire:

Seven critical care physicians who are currently managing of COVID-19 formed a steering committee.

Literature Search Strategy:

We searched various electronic databases including Google Scholar, PubMed, and Embase for literature published since the start of the pandemic and July 10, 2020, using keywords, such as “COVID-19”, “pharmacological management”, “consensus statement”, “modified Delphi methodology” “epidemiology”, “pathophysiology”, “anti-viral”, “anticoagulation”, “immune modulation” and “adjunctive therapies”. Non-English articles, animal studies, and articles for pharmacological management in the pediatric population were excluded from this search. Major contemporary guidelines by the World Health Organization (WHO), US Centers for disease control and prevention (CDC), European Society of Intensive Care Medicine (ESICM), Indian Council for Medical Research (ICMR), Society of Critical Care Medicine (SCCM) were also reviewed. A final pool of 209 relevant articles related to COVID-19, were created and stored in an online cloud forum to facilitate the generation of a focused questionnaire for the first round.

After discussions among the steering committee, a set of cornerstone therapies and their timing in relation to disease pathophysiology, and various biomarkers for starting and monitoring treatment response were identified. On review of the literature, the pathophysiological model of the disease includes three different phases of illness [6]. Each stage lasts for approximately five days and has a particular presentation related to virus and host interaction. Targeting these phases differently may lead to successful management of COVID-19 disease.

Based on these inputs, five sections of experimental therapies including anti-viral agents, anticoagulation, steroids, immunomodulators, antibiotics, and adjuvant therapies were identified a preliminary questionnaire for the Delphi survey was framed, discussed among the steering committee, and validated.

Step-2: Delphi methodology and selection of experts:

Delphi Methodology:

The Delphi methodology was selected for this project as it is a reliable instrument for developing consensus especially when evidence is lacking or limited [7]. The modified Delphi was used to involve experts within the field of intensive care and using their “collective intelligence” to develop a consensus pharmacological management. There are different rounds of iterative discussion among experts to achieve consensus. COVID-19 pandemic is an appropriate problem because of the lack of available effective treatment options. The statement which reached desired consensus during the first round were removed and the left-over statement circulated during the second round. We planned to have two to three rounds of the survey (Fig-1).

A thorough search of experts involved in the management of severe to critical COVID-19 patients was undertaken by the steering committee members. 46 experts from all affected regions of the world were selected and invited to participate. After receiving confirmation of participation, these members were provided with the first round of the questionnaire. To avoid dominance, conflicts of interest, and group pressures, the expert panel was strictly anonymized throughout the process. Experts could communicate only with the steering committee. Consent for using their opinions for research and publication purposes was obtained concurrently. A panel of 30 experts participated in the first round, and 27 in the second round.

The first-round questionnaire had five sections with 23 questions, 13 of which were multiple choices, and ten with ordinal qualitative responses on a five-point Likert scale. This form was generated on the “Google Forms” platform. A free text space for comments was

provided after each section to incorporate suggestions for the subsequent round questionnaire. Experts were
asked to provide their opinion on these practice points within 72 hours. A brief report on the first-round result was generated, without disclosing the identity of the experts. This feedback report and a modified second-round questionnaire were sent to the experts in round two (Table-1). This questionnaire had 24 questions, 14 had multiple choices and 10 were Likert scale. In this round, identity capturing was mandatory to enable communication with experts. A free text space was provided after each question to explain the extreme position of an expert regarding any particular statement.

Statistics

Captured data from both rounds of questionnaires were analyzed to evaluate the consensus level. For statements with responses on an ordinal Likert scale, consensus was defined when >70% of participants agreed/strongly agreed or disagreed/strongly disagreed with a statement in round two. To calculate the central tendency of response and dispersion along the central value, a median and interquartile range (IQR) descriptor was used. A similar level of agreement has been considered appropriate in previous studies [7]. For multiple-choice type questions, a consensus for a particular option was considered to be generated when it reached >70% of the vote. In the absence of substantial evidence in a particular area, subjective opinions were likely hence unanimous consent was not expected for all recommendations. Therefore, a predefined threshold to mark consensus was established among the steering committee, with good consensus achieved if agreement was >70%, and strong if > 90%. For questions not reaching a consensus level, data is presented in ranking order of votes for each option.

Results

Expert panel selection and preparation of questionnaire:

34 (73·9%) experts accepted the invitation and agreed to participation in the study. Thirty (88·2%) completed the first-round questionnaire: 18(60%) from Asia, 6(20%) from Europe, 2(6%) each from North and South America, and 1(3·3%) each from Africa and Oceania. For the second round, 27 (90%) of the 30 experts completed the survey.

Results of Round 1 and 2:

In the first round, only four of 13 multiple choice questions and only two of ten Likert scale statements received consensus (Table-2). In the second round, a modified questionnaire was prepared based on the responses and comments from the first round. Multiple-choice qualitative questions were now changed to a single best response system. Least responded options from the first round were eliminated. One new question was added after reviewing comments from the first round.

Among the 24 statements in the second round, eleven could reach the pre-determined level of consensus (two multiple-choice type questions, four agreements, and one strong disagreement on Likert scale questions) (Table-1). A strong consensus (>80%) was achieved for two qualitative questions and two strong agreements (Table-1).

Anti-Viral Therapy:

On a question related to specific anti-viral agents, round one had consensus on Remdesivir (73·3% votes) but opinion was divided when experts were asked to rank the best anti-viral agent: Remdesivir (51·9%), no anti-viral therapy (18·5%), Favipiravir (11·1%), and a Hydroxychloroquine (HCQ)-Azithromycin combination (11·1%) (Table-1 and Table-2). The question relating to compassionate use of experimental therapy showed opinion remained widely divided (disagreement: 14·8%, neutral: 29·6%, agreement: 51·5 % [median:4 IQR:1·5]) (Table-1).

Anticoagulation Therapy:

In the first round, two answers reached consensus, namely using D-Dimer levels as the biomarker of choice to guide anticoagulation therapy [26 votes (86·7%)] and low molecular weight heparin (LMWH) as the choice of anticoagulant [27 votes (90%)]. There was strong agreement on need for clinical and laboratory parameter-related guidance for aggressive anticoagulation therapy (100% agreement). In the second round, we were able to reach consensus on one new question, namely the anticoagulation prophylaxis in mild-to-moderate COVID-19 (70·3% agreement; median 4 IQR:2).

Steroid Therapy:

In round one, there was no agreement but consensus (74·1% of votes) was achieved on the use of low dose steroids during the pulmonary phase (5-15 days from symptom onset) in round two. Adverse reactions with steroids were hyperglycemia and loss of glycemic control (70·4% votes), secondary infections (40·7% votes), and delayed viral clearance. Experts also agreed that steroid use may lead to oxygenation improvement (70·4%) and recommended inflammatory marker-guided use to enhance patient safety (70·4%). A new question regarding the choice of steroid received split results among Dexamethasone (63%) and Methylprednisolone (25·9%). CRP (33·3%), Ferritin (22·2%), and Procalcitonin (18·5%) were considered the biomarkers that can most help in guiding steroid therapy.

Immuno-Modulation Therapy:

Only CRP to guide immunomodulation therapy reached consensus (72·4%) in the first round. In the second round, none of the three statements could reach consensus (Table-3).

General Care:

This section dealt with antibiotics and adjuvant therapies in critically ill COVID-19. There was disagreement (77·8%) on routine antibiotics use in COVID-19 and strong agreement (92·6% votes) for antibiotics use only in suspected co-infections or secondary infections. No consensus was reached for any specific initial antibiotic therapy, with most of the experts (40·7 %) advocating routine ICU protocol-based antibiotics. With regard to adjuvant therapies, there was no consensus agreement in any round; on request from the experts for an additional choice (“none of the above”) in the second round garnered 51·9% of votes (Table-1 and Table-2).

The study was concluded at round two, as the steering committee felt that opinion on unresolved questions remained too widely divided to generate consensus in the absence of new substantial evidence. The results of these questions are projected as received (Table-1).

Discussion

Consensus Statement:

The global consensus states that “anti-viral therapy should be given in the early infection phase of COVID-19 followed by low-dose steroid therapy in the pulmonary phase. Prophylactic dose anticoagulation should be used in hospitalized, mild-to-moderate COVID-19 patients. Consensus for the use of immune modulation therapy is low, with tocilizumab being the most voted agent.”

COVID-19 is a novel disease stimulating global medical collaboration. Many pathophysiological models and studies have been published but we still lack a specific treatment regimen. The respiratory system is commonly involved but increased thrombotic potential with both systemic and pulmonary thrombi, and multi-organ involvement, affecting predominantly kidneys, heart, and brain, are noted [1,2,6]. Simultaneously, an exaggerated pro-inflammatory response and types of cytokine release syndromes have been described in critically ill patients, especially in those with fatal outcomes [6,8,9]. It is common to observe elevated levels of D-Dimer, inflammatory biomarkers such as C-reactive protein (CRP), Ferritin, interleukin (IL)-6, IL-1and raised Neutrophil-lymphocyte ratio in severe COVID-19 disease [6,10]. Activation of self-perpetuating inflammatory and coagulation pathways, similar to but more virulent than more traditional sepsis phenotypes, likely plays a role in disease progression [6,10].

A Delphi methodology was adopted because of evidence-based on good controlled trials is expected to take time. The experience of experts who are actively involved in the clinical care of COVID-19 and also involved in research was valuable to develop consensus on available treatment options for COVID-19 and will guide the clinicians till evidence emerge from the trials.

Early Anti-Viral Therapy:

Anti-viral therapy should be administered in the early infection phase of COVID-19 (0-5 days of symptoms onset) to defer further progression. There was no consensus however could be achieved on best anti-viral agent. However, in round one experts were favoring Remdesivir. This may reflect the changing evidence during the survey and experts own experience with anti-viral drugs.

At present, no trials have showed direct efficacy in terms of mortality with any anti-viral agent. Results from the Adaptive COVID-19 Treatment Trial (ACTT) with more than 1000 patients enrolled, found patients who received Remdesivir had a significantly faster time to recovery (31%) as compared with those who received placebo (P < 0.001) [11]. Remdesivir group had a shorter time to recovery than those in the placebo group (median 11 days vs. 15 days, p<0·001, odds ratio 1·32, 95% confidence interval (CI) 1·12-1·55) however mortality benefit was non-significant in Remdesivir group [11]. The data on compassionate use of Remdesivir for COVID-19 patients reported 62% reduction in the risk of mortality as compared to standard treatment without Remdesivir. There was a significant reduction in mortality rate in patients treated with Remdesivir (7.6% versus 12.5% at day 14) (adjusted OR, 0.38; 95% CI, 0.22-0.68, P = 0.001.) [12]. Recently, the preliminary results from WHO Solidarity trial on antiviral agents reported no overall reduction in mortality duration and initiation of invasive mechanical ventilation [13]. Favipiravir was compared with a Lopinavir/Ritonavir (historical controls) combination in an open label nonrandomized controlled study and found a shorter viral clearance time with Favipiravir (median (IQR) 4 (2·5–9) days versus 11 (8–13) days; p<0·001) but no mortality benefit [14]. Similarly, a Lopinavir/Ritonavir combination used in an RCT also failed to show statistically significant mortality improvements (HR 1·24; 95% CI, 0·90 to 1·72) [15].

A question related to the use of HCQ and Azithromycin gathered split votes. This divergence reflects current practice and the lack of a strong evidence base [16]. Small observational studies reported good viral clearance or improved outcomes, but had methodological and statistical limitations [17]. Larger randomized study (including RECOVERY trial) show no outcome benefit in terms of need for ventilation or mortality [16].

Anticoagulation Therapy:

Diffuse endothelium damage and hypercoagulability is a common finding in severe COVID-19 illness [2,6,9,18].

Study reported that patients requiring anticoagulation were more likely to require invasive mechanical ventilation (29·8% vs. 8·1%, p<0·001) and decreased mortality [19,20]. Experts agreed that anticoagulation prophylaxis has to be considered for mild-moderate COVID-19 disease. The role of higher doses of anticoagulation in selected COVID-19 patients is to be considered and expert agreed that can be guided by clinical and laboratory parameters. D-Dimer received consensus as the biomarker of choice to guide anticoagulation therapy (86·7%) and low molecular weight heparin (LMWH) as the choice of anticoagulant (90%). Similar strategic biomarker-based inclusion has been suggested by the American College of Cardiology [21].

Steroid Therapy:

This section was the most debated section among experts and the steering committee with maximum inconsistency between rounds. A prominent “bandwagon effect” was obvious from second-round responses [7,22].

In the first round, no consensus could be reached for any of the five questions, but as the preliminary results of the Dexamethasone arm of the RECOVERY trial were released [22], a significant shift in opinion was evident. Consensus (74·1%) was achieved on the use of low dose steroids during the pulmonary phase (5-15 days from symptom onset) however this vote occurred before the publication of the pre-print showing benefit only in those starting treatments after seven days of symptom onset.

Preliminary results of the RECOVERY trial suggest that dexamethasone 6 mg once daily for up to ten days reduces death by a third in mechanically ventilated patients and by a fifth in patients on oxygen support alone, but had no effect in patients not receiving any respiratory support [22]. Recently published meta-analysis by the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group suggests that corticosteroid use in Critically sick COVID-19 patients was significantly associated with lower 28-day all-cause mortality [23].

Immunomodulation Therapy:

CRP was the only biomarker target which expert agreed, can guide immunomodulation therapy. There was no support for immunomodulator therapy, albeit a minority view (48·1 %), for IL-6 inhibitor, tocilizumab and its use in either the pulmonary (44·4%) or hyper inflammation (37%) phase. The majority (63%) considered that IL-6 levels, followed by CRP levels (44·4%) would be useful in identifying the hyperinflammatory stage. The recently published studies RCT and largest observational studies had conflicting results on the use of Tocilizumab in COVID-19 [24-27]. This may reflect the overall role of tocilizumab in the management of severe COVID-19 is very doubtful and to be considered only in a very small subgroup of patients [28].

General Care:

With regard to adjuvant therapies, there was no consensus agreement in any round. This underlines the view that adjuvant therapies need to prove their worth as guided by the dictum “primum non nocere“.

Strengths:

The Delphi method has well-recognized benefits and pitfalls [7]. It helps find a set of commonly agreed-upon statements without bringing experts physically together. It allowed us to combine quantitative and qualitative approaches and ensure good quality feedback from experts for Delphi rounds. This was imperative in an emerging scenario like the COVID-19 pandemic where the current evidence-based on pathophysiology is limited. The strength of the study is the multinational expert panel. We attempted to include experts from across the globe, especially working in countries actively reeling under the pandemic. The timelines were maintained despite their busy schedule. Anonymity was preserved to avoid dominance, conflict of interest, and group pressures that are potentially inherent biases when using the Delphi methodology. We were thus able to describe qualitative best practice points from the compiled opinions of worldwide experts. This format will help clinician in taking a pragmatic approach towards the management of the COVID-19 pandemic as the treatment can be chosen based on the phase of disease till further evidence is available.

Limitations

This study has several limitations:

1. Identity capture was not compulsory in the first round, so we are unable to report any inconsistency and heterogeneity in individual responses.
2. As the study was time-sensitive it was concluded in two rounds and stability of responses was not compared.
3. In some sections, a “significant bandwagon effect” was seen. For example, the steroid questions in the second-round had many more positive responses than in the first round. A contrast effect cannot be ruled out in the second round as the “immune-modulatory therapies” section was followed by “low dose steroid therapy.”
4. The distribution of experts is skewed to Asia because of the narrow timeframe for participation and completion of survey and inclusion of experts. There was the unavailability of few experts who were invited based on the criteria decided by steering committee because of the unprecedented situation of the COVID-19 pandemic. There were some additional dropouts of experts in round two. We tried to minimize this by actively engaging the experts and minimized the time frame of the process (three weeks). A summary of the results of the first round was included with individualized covering letters in the second round to raise their interest.
5. Other factors that may have affected consensus were the uneven responses of experts, non-availability of specific treatment options in some countries, and variable government health policies.
6. Lastly, this is only a contemporary best qualitative opinion of experts and may change with evolving evidence; it also needs quantitative inputs from well-structured intervention studies.

Conclusions

Global Experts gave consensus on use of anti-viral therapy in the early infection phase of COVID-19 followed by low-dose steroid therapy in the pulmonary phase. Prophylactic dose anticoagulation should be used in mild-to-moderate COVID-19. This document can also be used to generate hypotheses for future trials and protocol based therapy till further evidence evolve.

Contributors

RJ, YJ conceived the idea for this paper. RJ and PN wrote and prepared original draft with figures tables and panel. RJ, YJ, PN, RK prepared Delphi questionnaire, coordinated and conducted Delphi process and critically evaluated the prepared draft, and made substantial editorial contributions to the final document. All the co-authors (experts) participated in Delphi process, reviewed, and made substantial critical comments for preparation of the final draft of the document. All authors approved the final version for submission.

Acknowledgement

We acknowledge the contribution of Dr Gentle Sunder Shrestha, Dr Hemanshu Prabhakar and Dr Swagata Tripathy for their role in the steering group. The study was conducted under the auspices of Indian Sepsis Forum (ISF). The ISF is a regional collaboration established with an aim to reduce the burden of sepsis in Indian subcontinent. This is an academic alliance to share knowledge among allied specialists in Infectious disease, Microbiology, Intensive care medicine and Acute care.

Declaration of Interest

MLNGM is a member of the medical advisory Board of Pulsion Medical Systems (now fully integrated into Getinge, Solna, Sweden) and Serenno Medical (Tel Aviv, Israel), consults for Baxter, Maltron, ConvaTec, Acelity, Spiegelberg, and Holtech Medical.

All other authors declare that they have no competing interests in relation to the content published in this manuscript.

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