Safety and efficacy assessment of allogeneic human dental pulp stem cells to treat patients with severe COVID-19: structured summary of a study protocol for a randomized controlled trial (Phase I / II)

Abstract: OBJECTIVES: To assess the safety and therapeutic effects of allogeneic human dental pulp stem cells (DPSCs) in treating severe pneumonia caused by COVID-19. TRIAL DESIGN: This is a single centre, two arm ratio 1:1, triple blinded, randomized, placebo-controlled, parallel group, clinical trial. PARTICIPANTS: Twenty serious COVID-19 cases will be enrolled in the trial from April 6th to December 31st 2020. INCLUSION CRITERIA: hospitalised patients at Renmin Hospital of Wuhan University satisfy all criteria as below: 1)Adults aged 18-65 years;2)Voluntarily participate in this clinical trial and sign the "informed consent form" or have consent from a legal representative.3)Diagnosed with severe pneumonia of COVID-19: nucleic acid test SARS-CoV-2 positive; respiratory distress (respiratory rate > 30 times / min); hypoxia (resting oxygen saturation < 93% or arterial partial pressure of oxygen / oxygen concentration < 300 mmHg).4)COVID-19 featured lung lesions in chest X-ray image. EXCLUSION CRITERIA: Patients will be excluded from the study if they meet any of the following criteria. 1.Patients have received other experimental treatment for COVID-19 within the last 30 days;2.Patients have severe liver condition (e.g., Child Pugh score >=C or AST> 5 times of the upper limit);3.Patients with severe renal insufficiency (estimated glomerular filtration rate <=30mL / min/1.73 m2) or patients receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis;4.Patients who are co-infected with HIV, hepatitis B, tuberculosis, influenza virus, adenovirus or other respiratory infection viruses;5.Female patients who have no sexual protection in the last 30 days prior to the screening assessment;6.Pregnant or lactating women or women using estrogen contraception;7.Patients who are planning to become pregnant during the study period or within 6 months after the end of the study period;8.Other conditions that the researchers consider not suitable for participating in this clinical trial. INTERVENTION AND COMPARATOR: There will be two study groups: experimental and control. Both will receive all necessary routine treatment for COVID-19. The experimental group will receive an intravenous injection of dental pulp stem cells suspension (3.0x107 human DPSCs in 30ml saline solution) on day 1, 4 and 7; The control group will receive an equal amount of saline (placebo) on the same days. Clinical and laboratory observations will be performed for analysis during a period of 28 days for each case since the commencement of the study. MAIN OUTCOMES: 1. Primary outcome The primary outcome is Time To Clinical Improvement (TTCI). By definition, TTCI is the time (days) it takes to downgrade two levels from the following six ordered grades [(grade 1) discharge to (grade 6) death] in the clinical state of admission to the start of study treatments (hDPSCs or placebo). Six grades of ordered variables: GradeDescriptionGrade 1:Discharged of patient;Grade 2:Hospitalized without oxygen supplement;Grade 3:Hospitalized, oxygen supplement is required, but NIV / HFNC is not required;Grade 4:Hospitalized in intensive care unit, and NIV / HFNC treatment is required;Grade 5:Hospitalized in intensive care unit, requiring ECMO and/or IMV;Grade 6:Death. ABBREVIATIONS: NIV, non-invasive mechanical ventilation; HFNC, high-flow nasal catheter; IMV, invasive mechanical ventilation. 2. Secondary outcomes 2.1 vital signs: heart rate, blood pressure (systolic blood pressure, diastolic blood pressure). During the screening period, hospitalization every day (additional time points of D1, D4, D7 30min before injection, 2h ± 30min, 24h ± 30min after the injection) and follow-up period D90 ± 3 days. 2.2 Laboratory examinations: during the screening period, 30 minutes before D1, D4, D7 infusion, 2h ± 30min, 24h ± 30min after the end of infusion, D10, D14, D28 during hospitalization or discharge day and follow-up period D90 ± 3 days. 2.3 Blood routine: white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, neutrophils, lymphocytes, monocytes, eosinophils Acidic granulocyte count, basophil count, red blood cell, hemoglobin, hematocrit, average volume of red blood cells, average red blood cell Hb content, average red blood cell Hb concentration, RDW standard deviation, RDW coefficient of variation, platelet count, platelet specific platelet average Volume, platelet distribution width,% of large platelets; 2.4 Liver and kidney function tests: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, Î³-glutamyl transferase, prealbumin, total protein, albumin, globulin, white / globule ratio , Total bilirubin, direct bilirubin, cholinesterase, urea, creatinine, total carbon dioxide, uric acid glucose, potassium, sodium, chlorine, calcium, corrected calcium, magnesium, phosphorus, calcium and phosphorus product, anion gap, penetration Pressure, total cholesterol, triacylglycerol, high density lipoprotein cholesterol, Low density lipoprotein cholesterol, lipoprotein a, creatine kinase, lactate dehydrogenase, estimated glomerular filtration rate. 2.5 Inflammation indicators: hypersensitive C-reactive protein, serum amyloid (SAA); 2.6 Infectious disease testing: Hepatitis B (HBsAg, HBsAb, HBeAg, HBeAb, HBcAb), Hepatitis C (Anti-HCV), AIDS (HIVcombin), syphilis (Anti-TP), cytomegalovirus CMV-IgM, cytomegalovirus CMV-IgG; only during the screening period and follow-up period D90 ± 3. 2.7 Immunological testing: Collect peripheral blood to detect the phenotype of T lymphocyte, B lymphocyte, natural killer cell, Macrophage and neutrophil by using flow cytometry. Collect peripheral blood to detect the gene profile of mononuclear cells by using single-cell analyses. Collect peripheral blood serum to detect various immunoglobulin changes: IgA, IgG, IgM, total IgE; Collect peripheral blood serum to explore the changes of cytokines, Th1 cytokines (IL-1 ß, IL-2, TNF-a, ITN-Î³), Th2 cytokines (IL-4, IL-6, IL -10). 2.8 Pregnancy test: blood ß-HCG, female subjects before menopause are examined during the screening period and follow-up period D90 ± 3. 2.9 Urine routine: color, clarity, urine sugar, bilirubin, ketone bodies, specific gravity, pH, urobilinogen, nitrite, protein, occult blood, leukocyte enzymes, red blood cells, white blood cells, epithelial cells, non-squamous epithelial cells , Transparent cast, pathological cast, crystal, fungus; 2.10 Stool Routine: color, traits, white blood cells, red blood cells, fat globules, eggs of parasites, fungi, occult blood (chemical method), occult blood (immune method), transferrin (2h ± 30min after the injection and not detected after discharge). RANDOMIZATION: Block randomization method will be applied by computer to allocate the participants into experimental and control groups. The random ratio is 1:1. BLINDING (MASKING): Participants, outcomes assessors and investigators (including personnel in laboratory and imaging department who issue the sample report or image observations) will be blinded. Injections of cell suspension and saline will be coded in accordance with the patient's randomisation group. The blind strategy is kept by an investigator who does not deliver the medical care or assess primary outcome results. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Twenty participants will be randomized to the experimental and control groups (10 per group). TRIAL STATUS: Protocol version number, hDPSC-CoVID-2019-02-2020 Version 2.0, March 13, 2020. Patients screening commenced on 16th April and an estimated date of the recruitment of the final participants will be around end of July. . TRIAL REGISTRATION: Registration: World Health Organization Trial Registry: ChiCTR2000031319; March 27,2020. ClinicalTrials.gov Identifier: NCT04336254; April 7, 2020 Other Study ID Numbers: hDPSC-CoVID-2019-02-2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Core Outcome Set for Clinical Trials on Coronavirus Disease 2019 (COS-COVID)

Abstract: Since its outbreak in December 2019, a series of clinical trials on Coronavirus Disease 2019 (COVID-19) have been registered or carried out. However, the significant heterogeneity and less critical outcomes of such trials may be leading to a waste of research resources. This study aimed to develop a core outcome set (COS) for clinical trials on COVID-19 in order to tackle the outcome issues. The study was conducted according to the Core Outcome Measures in Effectiveness Trials (COMET) handbook (version 1.0), a guideline for COS development. A research group was set up that included experts in respiratory and critical medicine, traditional Chinese medicine, evidence-based medicine, clinical pharmacology, and statistics, in addition to medical journal editors. Clinical trial registry websites (chictr.org.cn and clinicaltrials.gov) were searched to retrieve clinical trial protocols and outcomes in order to form an outcome pool. A total of 78 clinical trial protocols on COVID-19 were included and 259 outcomes were collected. After standardization, 132 outcomes were identified within seven different categories, of which 58 were selected to develop a preliminary outcome list for further consensus. After two rounds of Delphi survey and one consensus meeting, the most important outcomes for the different clinical classifications of COVID-19 were identified and determined to constitute the COS for clinical trials on COVID-19 (COS-COVID). The COS-COVID includes one outcome for the mild type (time to 2019-nCoV reverse transcription-polymerase chain reaction (RT-PCR) negativity), four outcomes for the ordinary type (length of hospital stay, composite events, score of clinical symptoms, and time to 2019-nCoV RT-PCR negativity), five outcomes for the severe type (composite events, length of hospital stay, arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2), duration of mechanical ventilation, and time to 2019-nCoV RT-PCR negativity), one outcome for critical type (all-cause mortality), and one outcome for rehabilitation period (pulmonary function). The COS-COVID is currently the most valuable and practical clinical outcome set for the evaluation of intervention effect, and is useful for evidence assessment and decision-making. With a deepening understanding of COVID-19 and application feedback, the COS-COVID should be continuously updated.


[Analysis on clinical study protocols of traditional Chinese medicine for coronavirus disease 2019]

Abstract: To analyze the registered clinical trial protocols of traditional Chinese medicine(TCM) for the prevention and treatment of coronavirus disease 2019(COVID-19), in order to provide information for improving the quality of research design. The website of the Chinese Clinical Trial Registry(www.chictr.org.cn) and the American Clinical Trial Registry(clinicaltrials.gov) were searched to collect protocols of TCM for COVID-19. Documents were screened following the inclusion criteria, and data were extracted in regard to registration date, study objective, type of design, sponsor, patient, sample size, intervention, and evaluation index. Descriptive analysis was conducted. A total of 49 clinical trial protocols of TCM for COVID-19 were included. Primary sponsors were mainly hospitals or universities in places like Hubei, Beijing, Zhejiang and other regions. The implementation units are mainly in Hubei, Guangdong, Zhejiang, Henan and other regional hospitals. The types of study design were mainly experimental studies(40), including 30 randomized parallel controlled trials, 7 non-randomized controlled trials, 2 single arm trials and 1 consecutively recruited trial; besides, there were also 6 observational studies, 2 health service studies and 1 preventive study. The sample size reached a total of 30 562 cases, with a maximum of 20 000 for a single study and a minimum of 30. The 49 trials subjects included healthy people(3), isolation and observation cases(1), suspected cases(10),confirmed COVID-19 patients(31) and COVID-19 recovery patients(4). Of the 31 trials planned to include confirmed COVID-19 patients, 16 protocols no definite disease classification, 3 with a clear exclusion of severe subjects, 4 with common subjects, 2 with light, common or severe subjects, 1 with light and common subjects, 1 with common or severe subjects, 3 with severe subjects, and 1 with severe or critical subjects. The experimental interventions included Chinese patent medicine(Lianhua Qingwen Capsules/Granules, Huoxiang Zhengqi Dropping Pills/Oral Liquid, Babao Dan, Gubiao Jiedu Ling, Jinhao Jiere Granules, Compound Yu-xingcao Mixture, Jinye Baidu Granules, Shufeng Jiedu Capsuless, Shuanghuanglian Oral Liquid, Tanreqing Injection, Xuebijing Injection, Reduning Injection, Xiyanping Injection), Chinese medicinal decoction and taichi. The primary evaluation outcomes mainly included antipyretic time, clinical symptom relief, novel coronavirus nucleic acid turning to negative, conversion rate of severe cases and chest CT. There was a quick response of clinical research on the prevention and treatment of COVID-19 with TCM, with the current registered protocols covers the whole process of disease prevention, treatment and rehabilitation. However, issues need to be concerned, including unclear definition of patient's condition, unclear research objectives, unclear intervention process and inappropriate outcomes, etc. In addition, researchers should consider the actual difficulties and workload of doctors in epidemic response environment, and make effort to optimize the process and improve the operability of research protocols under the principle of medical ethics.


ChemoPROphyLaxIs with hydroxychloroquine For covId-19 infeCtious disease (PROLIFIC) to prevent covid-19 infection in frontline healthcare workers: A structured summary of a study protocol for a randomised controlled trial

Abstract: OBJECTIVES: PRIMARY OBJECTIVE: To determine whether chemoprophylaxis with hydroxychloroquine versus placebo increases time to contracting coronavirus disease 2019 (COVID-19) in frontline healthcare workers. SECONDARY OBJECTIVES: 1) To determine whether chemoprophylaxis with daily versus weekly dosing of hydroxychloroquine increases time to contracting COVID-19 disease in frontline healthcare workers. 2) To compare the number of COVID-19 cases between each trial arm on the basis of positive tests (as per current clinical testing methods and/or serology) 3) To compare the percentage of COVID-19 positive individuals with current testing methods versus serologically-proven COVID-19 in each trial arm 4) To compare COVID-19 disease severity in each trial arm 5) To compare recovery time from COVID-19 infection in each trial arm EXPLORATORY OBJECTIVES: 1) To determine compliance (as measured by trough pharmacokinetic hydroxychloroquine levels) on COVID-19 positive tests 2) To determine if genetic factors determine susceptibility to COVID-19 disease or response to treatment 3) To determine if blood group determines susceptibility to COVID-19 disease 4) To compare serum biomarkers of COVID-19 disease in each arm TRIAL DESIGN: Double-blind, multi-centre, 2-arm (3:3:2 ratio) randomised placebo-controlled trial PARTICIPANTS: National Health Service (NHS) workers who have direct patient contact delivering care to patients with COVID-19. Participants in the trial will be recruited from a number of NHS hospitals directly caring for patients with COVID-19. INCLUSION CRITERIA: To be included in the trial the participant MUST: 1) Have given written informed consent to participate 2) Be aged 18 years to 70 years 3) Not previously have been diagnosed with COVID-19 4) Work in a high-risk secondary or tertiary healthcare setting (hospitals accepting COVID-19 patients) with direct patient-facing care EXCLUSION CRITERIA: The presence of any of the following will mean participants are ineligible: 1) Known COVID-19 positive test at baseline (if available) 2) Symptomatic for possible COVID-19 at baseline 3) Known hypersensitivity reaction to hydroxychloroquine, chloroquine or 4-aminoquinolines 4) Known retinal disease 5) Known porphyria 6) Known chronic kidney disease (CKD; eGFR<30ml/min) 7) Known epilepsy 8) Known heart failure or conduction problems 9) Known significant liver disease (Gilbert's syndrome is permitted) 10) Known glucose-6-phosphate dehydrogenase (G6PD) deficiency 11) Currently taking any of the following contraindicated medications: Digoxin, Chloroquine, Halofantrine, Amiodarone, Moxifloxacin, Cyclosporin, Mefloquine, Praziquantel, Ciprofloxacin, Clarithromycin, Prochlorperazine, Fluconazole 12) Currently taking hydroxychloroquine or having a clinical indication for taking hydroxychloroquine 13) Currently breastfeeding 14) Unable to be followed-up during the trial 15) Current or future involvement in the active treatment phase of other interventional research studies (excluding observational/non-interventional studies) before study follow-up visit 16) Not able to use or have access to a modern phone device/web-based technology 17) Any other clinical reason which may preclude entry in the opinion of the investigator INTERVENTION AND COMPARATOR: Interventions being evaluated are: A) Daily hydroxychloroquine or B) Weekly hydroxychloroquine or C) Placebo The maximum treatment period is approximately 13 weeks per participant. Hydroxychloroquine-identical matched placebo tablets will ensure that all participants are taking the same number and dosing regimen of tablets across the three trial arms. There is no variation in the dose of hydroxychloroquine by weight. The dosing regimen for the three arms of the study (A, B, C) are described in further detail below. Arm A: Active Hydroxychloroquine (- daily dosing and placebo-matched hydroxychloroquine - weekly dosing). Form: Tablets Route: Oral. Dose and Frequency: Active hydroxychloroquine: Days 1-2: Loading phase - 400mg (2 x 200mg tablets) taken twice a day for 2 days Days 3 onwards: Maintenance Phase - 200mg (1 x 200mg tablet) taken once daily, every day for 90 days (~3 months) Matched Placebo hydroxychloroquine: Days 3 onwards: Maintenance Phase - 2 tablets taken once a week on the same day each week (every 7th day) for 90 days (~3 months) Arm B: Active Hydroxychloroquine (- weekly dosing and placebo matched hydroxychloroquine - daily dosing.) Form: Tablets Route: Oral. Dose and Frequency: Active hydroxychloroquine: Days 1-2: Loading Phase - 400mg (2 x 200mg tablets) taken twice daily for 2 days Days 3 onwards: Maintenance Phase - 400mg (2 x 200mg tablets) taken once a week on the same day each week (every 7th day) for 90 days (~3 months) Matched Placebo hydroxychloroquine: Days 3 onwards: Maintenance Phase - 1 tablet taken once daily for 90 days (~3 months) Arm C: Matched placebo Hydroxychloroquine (- daily dosing and matched placebo hydroxychloroquine - weekly dosing.) Form: Table. Route: Oral. Frequency: Matched placebo hydroxychloroquine - daily dosing: Days 1-2: Loading Phase - 2 tablets taken twice daily for 2 days Days 3 onwards: Maintenance Phase - 1 tablet taken once daily for 90 days (~3 months) Matched placebo hydroxychloroquine - weekly dosing: Days 3 onwards: Maintenance Phase - 2 tablets taken once a week on the same day each week (every 7th day) for 90 days (~3 months) A schematic of the dosing schedule can be found in the full study protocol (Additional File 1). MAIN OUTCOMES: Time to diagnosis of positive COVID-19 disease (defined by record of date of symptoms onset and confirmed by laboratory test) RANDOMISATION: Participants will be randomised to either hydroxychloroquine dosed daily with weekly placebo, HCQ dosed weekly with daily placebo, or placebo dosed daily and weekly. Randomisation will be in a 3:3:2 ratio [hydroxychloroquine-(daily), hydroxychloroquine-(weekly), placebo], using stratified block randomisation. Random block sizes will be used, and stratification will be by study site. BLINDING (MASKING): Participants and trial investigators consenting participants, delivering trial assessments and procedures will be blinded to intervention. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A sufficient number of participants will be enrolled so that approximately 1000 participants in total will have data suitable for the primary statistical analysis. It is anticipated that approximately 1,200 participants will need to be enrolled in total, to allow for a 20% dropout over the period of the trial. This would result in approximately 450:450:300 participants randomised to hydroxychloroquine daily, hydroxychloroquine weekly+daily matched placebo or matched-placebo daily and weekly. TRIAL STATUS: V 1.0, 7th April 2020 EU Clinical Trials Register EudraCT Number: 2020-001331-26 Date of registration: 14th April 2020 Trial registered before first participant enrolment. Trial site is Cambridge University Hospitals NHS Foundation Trust. Recruitment started on 11th May 2020. It is anticipated that the trial will run for 12 months. The recruitment end date cannot yet be accurately predicted. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Is there any supportive evidence for low dose radiotherapy for COVID-19 pneumonia?

Abstract: Since early April 2020, there has been intense debate over proposed clinical use of ionizing radiation to treat life-threatening pneumonia in Coronavirus Disease 2019 (COVID-19) patients. At least twelve relevant papers appeared by 20 May 2020. The radiation dose proposed for clinical trials are a single dose (0.1-1 Gy) or two doses (a few mGy followed by 0.1-0.25 Gy involving a putative adaptive response, or 1-1.5 Gy in two fractions 2-3 days apart). The scientific rationale for such proposed so-called low dose radiotherapy (LDRT) is twofold (note that only doses below 0.1 Gy are considered as low doses in the field of radiation protection, but here we follow the term as conventionally used in the field of radiation oncology). Firstly, the potentially positive observations in human case series and biological studies in rodent models on viral or bacterial pneumonia that were conducted in the pre-antibiotic era. Secondly, the potential anti-inflammatory properties of LDRT, which have been seen when LDRT is applied locally to subacute degenerative joint diseases, mainly in Germany. However, the human and animal studies cited as supportive evidence have significant limitations, and whether LDRT produces anti-inflammatory effects in the inflamed lung or exacerbates ongoing COVID-19 damage remains unclear. Therefore, we conclude that the available scientific evidence does not justify clinical trials of LDRT for COVID-19 pneumonia, with unknown benefit and known mortality risks from radiogenic cancer and circulatory disease. Despite the significant uncertainties in these proposals, some clinical trials are ongoing and planned. This paper gives an overview of current situations surrounding LDRT for COVID-19 pneumonia.


Efficient adaptive designs for clinical trials of interventions for COVID-19

Abstract: The COVID-19 pandemic has led to an unprecedented response in terms of clinical research activity. An important part of this research has been focused on randomized controlled clinical trials to evaluate potential therapies for COVID-19. The results from this research need to be obtained as rapidly as possible. This presents a number of challenges associated with considerable uncertainty over the natural history of the disease and the number and characteristics of patients affected, and the emergence of new potential therapies. These challenges make adaptive designs for clinical trials a particularly attractive option. Such designs allow a trial to be modified on the basis of interim analysis data or stopped as soon as sufficiently strong evidence has been observed to answer the research question, without compromising the trial's scientific validity or integrity. In this paper we describe some of the adaptive design approaches that are available and discuss particular issues and challenges associated with their use in the pandemic setting. Our discussion is illustrated by details of four ongoing COVID-19 trials that have used adaptive designs.


Evaluating the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in severely ill adults with COVID-19: A structured summary of a study protocol for a randomized controlled trial

Abstract: OBJECTIVES: The aim of this study is to evaluate the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in hospitalized adults with severe SARS-CoV-2 infection. TRIAL DESIGN: This is a prospective, single-center, phase 2, randomized, controlled trial that is blinded to participants and clinical outcome assessor. PARTICIPANTS: Eligible participants include adults (≥ 18 years) with evidence of SARS-CoV-2 infection by PCR test of nasopharyngeal or oropharyngeal swab within 14 days of randomization, evidence of infiltrates on chest radiography, peripheral capillary oxygen saturation (SpO2) ≤ 94% on room air, and/or need for supplemental oxygen, non-invasive mechanical ventilation, or invasive mechanical ventilation, who are willing and able to provide written informed consent prior to performing study procedures or who have a legally authorized representative available to do so. Exclusion criteria include participation in another clinical trial of anti-viral agent(s)* for coronavirus disease-2019 (COVID-19), receipt of any anti-viral agent(s)* with possible activity against SARS-CoV-2 <24 hours prior to plasma infusion, mechanical ventilation (including extracorporeal membrane oxygenation [ECMO]) for ≥ 5 days, severe multi-organ failure, history of allergic reactions to transfused blood products per NHSN/CDC criteria, known IgA deficiency, and pregnancy. Included participants will be hospitalized at the time of randomization and plasma infusion. *Use of remdesivir as treatment for COVID-19 is permitted. The study will be undertaken at Columbia University Irving Medical Center in New York, USA. INTERVENTION AND COMPARATOR: The investigational treatment is anti-SARS-CoV-2 human convalescent plasma. To procure the investigational treatment, volunteers who recovered from COVID-19 will undergo testing to confirm the presence of anti-SARS-CoV-2 antibody to the spike trimer at a 1:400 dilution. Donors will also be screened for transfusion-transmitted infections (e.g. HIV, HBV, HCV, WNV, HTLV-I/II, T. cruzi, ZIKV). If donors have experienced COVID-19 symptoms within 28 days, they will be screened with a nasopharyngeal swab to confirm they are SARS-CoV-2 PCR-negative. Plasma will be collected using standard apheresis technology by the New York Blood Center. Study participants will be randomized in a 2:1 ratio to receive one unit (200 - 250 mL) of anti-SARS-CoV-2 plasma versus one unit (200 - 250 mL) of the earliest available control plasma. The control plasma cannot be tested for presence of anti-SARS-CoV-2 antibody prior to the transfusion, but will be tested for anti- SARS-CoV-2 antibody after the transfusion to allow for a retrospective per-protocol analysis. MAIN OUTCOMES: The primary endpoint is time to clinical improvement. This is defined as time from randomization to either discharge from the hospital or improvement by one point on the following seven-point ordinal scale, whichever occurs first. 1. Not hospitalized with resumption of normal activities 2. Not hospitalized, but unable to resume normal activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, requiring high-flow oxygen therapy or non-invasive mechanical ventilation 6. Hospitalized, requiring ECMO, invasive mechanical ventilation, or both 7. Death This scale, designed to assess clinical status over time, was based on that recommended by the World Health Organization for use in determining efficacy end-points in clinical trials in hospitalized patients with COVID-19. A recent clinical trial evaluating the efficacy and safety of lopinavir- ritonavir for patients hospitalized with severe COVID-19 used a similar ordinal scale, as have recent clinical trials of novel therapeutics for severe influenza, including a post-hoc analysis of a trial evaluating immune plasma. The primary safety endpoints are cumulative incidence of grade 3 and 4 adverse events and cumulative incidence of serious adverse events during the study period. RANDOMIZATION: Study participants will be randomized in a 2:1 ratio to receive anti-SARS-CoV-2 plasma versus control plasma using a web-based randomization platform. Treatment assignments will be generated using randomly permuted blocks of different sizes to minimize imbalance while also minimizing predictability. BLINDING (MASKING): The study participants and the clinicians who will evaluate post-treatment outcomes will be blinded to group assignment. The blood bank and the clinical research team will not be blinded to group assignment. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): We plan to enroll 129 participants, with 86 in the anti-SARS-CoV-2 arm, and 43 in the control arm. Among the participants, we expect ~70% or n = 72 will achieve clinical improvement. This will yield an 80% power for a one-sided Wald test at 0.15 level of significance under the proportional hazards model with a hazard ratio of 1.5. TRIAL STATUS: Protocol AAAS9924, Version 17APR2020, 4/17/2020 Start of recruitment: April 20, 2020 Recruitment is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04359810 Date of trial registration: April 24, 2020 Retrospectively registered FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Reducing mortality and morbidity in patients with severe COVID-19 disease by advancing ongoing trials of Mesenchymal Stromal (stem) Cell (MSC) therapy - Achieving global consensus and visibility for cellular host-directed therapies

Abstract: As of May 17th 2020, the novel coronavirus disease 2019 (COVID-19) pandemic has caused 307,395 deaths worldwide, out of 3,917,366 cases reported to the World Health Organization. No specific treatments for reducing mortality or morbidity are yet available. Deaths from COVID-19 will continue to rise globally until effective and appropriate treatments and/or vaccines are found. In search of effective treatments, the global medical, scientific, pharma and funding communities have rapidly initiated over 500 COVID-19 clinical trials on a range of antiviral drug regimens and repurposed drugs in various combinations. A paradigm shift is underway from the current focus of drug development targeting the pathogen, to advancing cellular Host-Directed Therapies (HDTs) for tackling the aberrant host immune and inflammatory responses which underlie the pathogenesis of SARS-CoV-2 and high COVID-19 mortality rates. We focus this editorial specifically on the background to, and the rationale for, the use and evaluation of mesenchymal stromal (Stem) cells (MSCs) in treatment trials of patients with severe COVID-19 disease. Currently, the ClinicalTrials.gov and the WHO Clinical Trials Registry Platform (WHO ICTRP) report a combined 28 trials exploring the potential of MSCs or their products for treatment of COVID-19. MSCs should also be trialed for treatment of other circulating WHO priority Blueprint pathogens such as MERS-CoV which causes upto 34% mortality rates. It's about time funding agencies invested more into development MSCs per se, and also for a range of other HDTs, in combination with other therapeutic interventions. MSC therapy could turn out to be an important contribution to bringing an end to the high COVID-19 death rates and preventing long-term functional disability in those who survive disease.


Azithromycin added to hydroxychloroquine for patients admitted to intensive care due to coronavirus disease 2019 (COVID-19)-protocol of randomised controlled trial AZIQUINE-ICU

Abstract: BACKGROUND: Novel coronavirus SARS-CoV-2 is known to be susceptible in vitro to exposure to hydroxychloroquine and its effect has been found to be potentiated by azithromycin. We hypothesise that early administration of hydroxychloroquine alone or in combination with azithromycin can prevent respiratory deterioration in patients admitted to intensive care due to rapidly progressive COVID-19 infection. METHODS: Design: Prospective, multi-centre, double-blind, randomised, controlled trial (RCT). PARTICIPANTS: Adult (> 18 years) within 24 h of admission to the intensive care unit with proven or suspected COVID-19 infection, whether or not mechanically ventilated. Exclusion criteria include duration symptoms of febrile disease for ≥ 1 week, treatment limitations in place or moribund patients, allergy or intolerance of any study treatment, and pregnancy. INTERVENTIONS: Patients will be randomised in 1:1:1 ratio to receive Hydroxychloroquine 800 mg orally in two doses followed by 400 mg daily in two doses and azithromycin 500 mg orally in one dose followed by 250 mg in one dose for a total of 5 days (HC-A group) or hydroxychloroquine + placebo (HC group) or placebo + placebo (C-group) in addition to the best standard of care, which may evolve during the trial period but will not differ between groups. Primary outcome is the composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14. SECONDARY OUTCOMES: The percentage of patients who were prevented from needing intubation until day 14, ICU length of stay, and mortality (in hospital) at day 28 and 90. DISCUSSION: Although both investigational drugs are often administered off label to patients with severe COVID-19, at present, there is no data from RCTs on their safety and efficacy. In vitro and observational trial suggests their potential to limit viral replication and the damage to lungs as the most common reason for ICU admission. Therefore, patients most likely to benefit from the treatment are those with severe but early disease. This trial is designed and powered to investigate whether the treatment in this cohort of patients leads to improved clinical patient-centred outcomes, such as mechanical ventilation-free survival. TRIAL REGISTRATION: Clinical trials.gov: NCT04339816 (Registered on 9 April 2020, amended on 22 June 2020); Eudra CT number: 2020-001456-18 (Registered on 29 March 2020).


[A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19]

Abstract: OBJECTIVE: To evaluate the efficacy and safety of hydroxychloroquine (HCQ) in the treatment of patients with moderate coronavirus disease 2019 (COVID-19). METHODS: We prospectively enrolled 30 treatment-naïve patients with confirmed COVID-19 after informed consent at Shanghai Public Health Clinical Center. The patients were randomized 1ï¼1 to HCQ group and the control group. Patients in HCQ group were given HCQ 400 mg per day for 5 days plus conventional treatments, while those in the control group were given conventional treatment only. The primary endpoint was negative conversion rate of SARS-CoV-2 nucleic acid in respiratory pharyngeal swab on days 7 after randomization. This study has been approved by the Ethics Committee of Shanghai Public Health Clinical Center and registered online (NCT04261517). RESULTS: One patient in HCQ group developed to severe during the treatment. On day 7, nucleic acid of throat swabs was negative in 13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (P>0.05). The median duration from hospitalization to virus nucleic acid negative conservation was 4 (1,9) days in HCQ group, which is comparable to that in the control group [2 (1,4) days, Z=1.27, P>0.05]. The median time for body temperature normalization in HCQ group was 1 (0,2) day after hospitalization, which was also comparable to that in the control group [1 (0,3) day]. Radiological progression was shown on CT images in 5 cases (33.3%) of the HCQ group and 7 cases (46.7%) of the control group, and all patients showed improvement in follow-up examinations. Four cases (26.7%) of the HCQ group and 3 cases (20%) of the control group had transient diarrhea and abnormal liver function (P>0.05). CONCLUSIONS: The prognosis of COVID-19 moderate patients is good. Larger sample size study are needed to investigate the effects of HCQ in the treatment of COVID-19. Subsequent research should determine better endpoint and fully consider the feasibility of experiments such as sample size.


Imaging features and mechanisms of novel coronavirus pneumonia (COVID-19): Study Protocol Clinical Trial (SPIRIT Compliant)

Abstract: INTRODUCTION: A novel coronavirus, tentatively designated as 2019 Novel Coronavirus (2019-nCoV), now called severe acute respiratory syndrome coronavirus 2, emerged in Wuhan, China, at the end of 2019 and which continues to expand. On February 11, 2020, the World Health Organization (WHO) named the disease coronavirus disease 2019 (COVID-19). On February 28, WHO increased our assessment of the risk of spread and the risk of impact of COVID-19 to very high at a global level. The COVID-19 poses significant threats to international health.Computed tomography (CT) has been an important imaging modality in assisting in the diagnosis and management of patients withCOVID-19. Some retrospective imaging studies have reported chest CT findings of COVID-19 in the past 2 months, suggesting that several CT findings may be characteristic. To our knowledge, there has been no prospective multicentre imaging study of COVID-19 to date.We proposed a hypothesis: There are some specific CT features on Chest CT of COVID-19 patients. And the mechanism of these CT features is explicable based on pathological findings. OBJECTIVE: To investigate the specific CT features of COVID-19 and the formation mechanism of these CT features. METHOD: This study is a prospective multicenter observational study. We will recruit 100 patients with COVID-19 at 55 hospitals. All patients undergo chest CT examination with the same scan protocol. The distribution and morphology of lesions on chest CT, clinical data will be recorded. A number of patients will be pathologically examined after permission is granted. The data of these three aspects will be analyzed synthetically. DISCUSSION: This study will help us to identify the chest CT features of COVID-19 and its mechanism. ETHICS AND DISSEMINATION: This retrospective study was approved by the Biomedical Research Ethics Committee of West China Hospital of Sichuan University (No. 2020-140). Written informed consent will be obtained from all study participants prior to enrollment in the study. To protect privacy of participants, all private information were kept anonymous. The results will be published in a peer-reviewed journal and will be disseminated electronically and in print regardless of results.


Clinical trials during COVID-19

Abstract: As this ever-evolving pandemic lays itself, more of its impact is being understood. Until recently, most guidelines were reported to aid in managing and treating suspected or confirmed cases. Research institutions around the world are responding with a sense of confusion. Some are continuing routinely, especially those who are overseeing clinical trials that could offer life-saving therapies, particularly against the novel coronavirus. Since research must continue even in the face of a shutdown, we aim to collate the currently available recommendations from various organizations and provide guidance to head and neck researchers across the world during these trying times.


A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Abstract: BACKGROUND: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. METHODS: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. RESULTS: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. CONCLUSIONS: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).


Controlled, double-blind, randomized trial to assess the efficacy and safety of hydroxychloroquine chemoprophylaxis in SARS CoV2 infection in healthcare personnel in the hospital setting: A structured summary of a study protocol for a randomised controlled trial

Abstract: BACKGROUND: SARS-CoV-2 infection presents a high transmission in the group of health professionals in Spain (12-15% infected). Currently there is no accepted chemoprophylaxis but hydroxychloroquine (HDQ) is known to inhibit the coronavirus in vitro. Our hypothesis is that oral administration of hydroxychloroquine to healthcare professionals can reduce the incidence and prevalence of infection as well as its severity in this group. METHODS: Design: Prospective, single center, double blind, randomised, controlled trial (RCT). PARTICIPANTS: Adult health-care professionals (18-65 years) working in areas of high exposure and high risk of transmission of SARS-COV-2 (COVID areas, Intensive Care Unit -ICUs-, Emergency, Anesthesia and all those performing aerosol-generating procedures) will be included. Exclusion criteria include previous infection with SARS CoV2 (positive SARS-CoV-2 PCR or IgG serology), pregnancy or lactation, any contraindication to hydroxychloroquine or evidence of unstable or clinically significant systemic disease. INTERVENTIONS: Patients will be randomized (1:1) to receive once-daily oral Hydroxychloroquine 200mg for two months (HC group) or placebo (P group) in addition to the protective measures appropriate to the level of exposure established by the hospital. A serological evaluation will be carried out every 15 days with PCR in case of seroconversion, symptoms or risk exposure. Primary outcome is the percentage of subjects presenting infection (seroconversion and/or PCR +ve) by the SARS-Cov-2 virus during the observation period. Additionally, both the percentage of subjects in each group presenting Pneumonia with severity criteria (Curb 65 ≥2) and that of subjects requiring admission to ICU will be determined. DISCUSSION: While awaiting a vaccine, hygiene measures, social distancing and personal protective equipment are the only primary prophylaxis measures against SARS-CoV-2, but they have not been sufficient to protect our healthcare professionals. Some evidence of the in vitro efficacy of hydroxychloroquine against this virus is known, along with some clinical data that would support the study of this drug in the chemoprophylaxis of infection. However, there are still no data from controlled clinical trials in this regard. If our hypothesis is confirmed, hydroxychloroquine can help professionals fight this infection with more guarantees. PARTICIPANTS: This is a single-center study that will be carried out at the Marqués de Valdecilla University Hospital. 450 health professionals working at the Hospital Universitario Marqués de Valdecilla in areas of high exposure and high risk of transmission of SARS COV2 (COVID hospital areas, Intensive Care Unit, Emergency, Anesthesia and all those performing aerosol-generating procedures) will be included. INCLUSION CRITERIA: 1) Health professionals aged between 18 and 65 years (inclusive) at the time of the first screening visit; 2) They must provide signed written informed consent and agree to comply with the study protocol; 3) Active work in high exposure areas during the last two weeks and during the following weeks. EXCLUSION CRITERIA: 1) Previous infection with SARS CoV2 (positive coronavirus PCR or positive serology with SARS Cov2 negative PCR and absence of symptoms); 2) Current treatment with hydroxychloroquine or chloroquine; 3) Hypersensitivity, allergy or any contraindication for taking hydroxychloroquine, in the technical sheet; 4) Previous or current treatment with tamoxifen or raloxifene; 5) Previous eye disease, especially maculopathy; 6) Known heart failure (Grade III to IV of the New York Heart Association classification) or prolonged QTc; 7) Any type of cancer (except basal cell) in the last 5 years; 6) Refusal to give informed consent; 8) Evidence of any other unstable or clinically significant untreated immune, endocrine, hematological, gastrointestinal, neurological, neoplastic or psychiatric illness; 9) Antibodies positive for the human immunodeficiency virus; 10) Significant kidney or liver disease; 11) Pregnancy or lactation. INTERVENTION AND COMPARATOR: Two groups will be analyzed with a 1: 1 randomization rate. 1)Intervention: (n = 225): One 200 mg hydroxychloroquine sulfate coated tablet once daily for two months.2)Comparator (control group) (n = 225): One hydroxychloroquine placebo tablet (identical to that of the drug) once daily for two months MAIN OUTCOMES: The primary outcome of this study will be to evaluate: number and percentage of healthcare personnel presenting symptomatic and asymptomatic infection (see "Diagnosis of SARS CoV2 infection" below) by the SARS-Cov2 virus during the study observation period (8 weeks) in both treatment arms;number and percentage of healthcare personnel in each group presenting with Pneumonia with severity criteria (Curb 65 ≥2) and number and percentage of healthcare personnel requiring admission to the Intensive Care Unit (ICU) in both treatment arms. DIAGNOSIS OF SARS COV2 INFECTION: Determination of IgA, IgM and IgG type antibodies against SARS-CoV-2 using the Anti-SARS-CoV-2 ELISA kit (EUROIMMUN Medizinische Labordiagnostika AG, Germany) every two weeks. In cases of seroconversion, a SARS-CoV-2 PCR will be performed to rule out / confirm an active infection (RT-PCR in One Step: RT performed with mastermix (Takara) and IDT probes, following protocol published and validated by the CDC Evaluation of COVID-19 in case of SARS-CoV-2 infection RANDOMISATION: Participants will be allocated to intervention and comparator groups according to a balanced randomization scheme (1: 1). The assignment will be made through a computer-generated numeric sequence for all participants BLINDING (MASKING): Both participants and investigators responsible for recruiting and monitoring participants will be blind to the assigned arm. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Taking into account the current high prevalence of infection in healthcare personnel in Spain (up to 15%), to detect a difference equal to or greater than 8% in the percentage estimates through a two-tailed 95% CI, with a statistical power of 80% and a dropout rate of 5%, a total of 450 participants will need to be included (250 in each arm). TRIAL STATUS: The protocol approved by the health authorities in Spain (Spanish Agency for Medicines and Health Products "AEMPS") and the Ethics and Research Committee of Cantabria (CEIm Cantabria) corresponds to version 1.1 of April 2, 2020. Currently, recruitment has not yet started, with the start scheduled for the second week of May 2020. TRIAL REGISTRATION: Eudra CT number: 2020-001704-42 (Registered on 29 March 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


A snapshot of the ongoing clinical research on COVID-19

Abstract: The pandemic of coronavirus disease 2019 (COVID-19) presents an unprecedented challenge to rapidly develop new diagnostic, preventive and therapeutic strategies. Currently, thousands of new COVID-19 patients are quickly enrolled in clinical studies. We aimed to investigate the characteristics of the COVID-19 studies registered in ClinicalTrials.gov and report the extent to which they have incorporated features that are desirable for generating high-quality evidence. On April 28, 2020, a total of 945 studies on COVID-19 have been registered in ClinicalTrials.gov; 586 studies are interventional (62.0%), the most frequent allocation scheme is the parallel group assignment (437; 74.6%), they are open-label and the most common primary purpose is the research on treatment. Too many of the ongoing interventional studies have a small expected sample size and may not generate credible evidence at completion. This might lead to a delayed recognition of effective therapies that are urgently needed, and a waste of time and resources. In the COVID-19 pandemic era, it is crucial that the adoption of new diagnostic, preventive and therapeutic strategies is based upon evidence coming from well-designed, adequately powered and carefully conducted clinical trials.


Effect of hydroxychloroquine on prevention of COVID-19 virus infection among healthcare professionals: a structured summary of a study protocol for a randomised controlled trial

Abstract: OBJECTIVES: Comparison of the effect of hydroxychloroquine with placebo to prevent infection from the COVID -19 virus among healthcare professionals TRIAL DESIGN: Single centre, 2-arm, double-blind randomised (ratio 1:1) placebo-controlled trial PARTICIPANTS: Treatment staff who are in contact with patients and have at least 3 shifts a week in Arash hospital affiliated with Tehran University of Medical Sciences, in Iran and who consent to participate in the study. Exclusion criteria include: History of COVID -19 virus infection, clinical symptoms such as fever, nausea, dyspnea and myalgia in the past two months, history of underlying diseases hypersensitivity to hydroxychloroquine and G6PD enzyme deficiency. INTERVENTION AND COMPARATOR: Intervention group: Hydroxychloroquine 200 mg tablet of Amin Pharmaceutical. CONTROL GROUP: placebo which is completely similar in form and taste to 200 mg hydroxychloroquine tablet and is manufactured by the same factory (Amin Pharmacy). The dosage is two tablets daily, once a week for one to three months (based on the duration of the Coronavirus epidemic in Tehran). MAIN OUTCOMES: Confirmed COVID-19 virus infection using Polymerase chain reaction (PCR) test is the primary outcome. The time period for measuring the primary outcome is any infection within the trial period up to one month after taking the last dose. RANDOMISATION: The randomized block allocation method was developed using Stata version 15 software by an independent researcher, using a block size of six. Allocation to the two treatment groups will be conducted by this researcher using paper labels (random 10-digit codes) in a 1:1 ratio t The labels will be attached to the drug packages in order of randomization. Drug packages will be arranged in a box according to the randomization list. BLINDING (MASKING): Participants and caregivers are blinded to group assignment and the data will be analyzed by an independent statistical expert who is unaware of the treatment allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 282 participants will be randomised with 141 participants the Hydroxychloroquineeach intervention group and 141 participants to the placebo control group TRIAL STATUS: The protocol version number is 99-1-101-47091 and the approval ID is IR.TUMS.VCR.REC.1399.001 and recruitment began April 7, 2020, and is anticipated to be complete by August 7, 2020. TRIAL REGISTRATION: The name of the trial register is Iranian registry of clinical trial (IRCT), registration number is IRCT20120826010664N6, date of trial registration is April 7, 2020, FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Clinical trials for inflammatory bowel disease: a global guidance during COVID-19 pandemic

Abstract: The severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]-causing coronavirus disease [COVID]-19 pandemic poses major challenges for patients with inflammatory bowel disease to be recruited and maintained in clinical trials. However, clinical trials offer patients who have failed multiple drugs access to study medications with alternative mode of action and the potential for relief from inflammation-mediated symptoms. Therefore, the continuation of clinical trials in IBD during the COVID-19 pandemic is important both for participants and the community of IBD patients, due to the dire need of an expanded therapeutic armamentarium. As the safety of patients in clinical trials is the leading principle, we are providing ten specific rules to guide patients and principal investigators safely through the challenging time.


Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial

Abstract: Importance: There is no specific antiviral therapy recommended for coronavirus disease 2019 (COVID-19). In vitro studies indicate that the antiviral effect of chloroquine diphosphate (CQ) requires a high concentration of the drug. Objective: To evaluate the safety and efficacy of 2 CQ dosages in patients with severe COVID-19. Design, Setting, and Participants: This parallel, double-masked, randomized, phase IIb clinical trial with 81 adult patients who were hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was conducted from March 23 to April 5, 2020, at a tertiary care facility in Manaus, Brazilian Amazon. Interventions: Patients were allocated to receive high-dosage CQ (ie, 600 mg CQ twice daily for 10 days) or low-dosage CQ (ie, 450 mg twice daily on day 1 and once daily for 4 days). Main Outcomes and Measures: Primary outcome was reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group. Data presented here refer primarily to safety and lethality outcomes during treatment on day 13. Secondary end points included participant clinical status, laboratory examinations, and electrocardiogram results. Outcomes will be presented to day 28. Viral respiratory secretion RNA detection was performed on days 0 and 4. Results: Out of a predefined sample size of 440 patients, 81 were enrolled (41 [50.6%] to high-dosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively. Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instance of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%). Conclusions and Relevance: The preliminary findings of this study suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir. These findings cannot be extrapolated to patients with nonsevere COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04323527.


Bacteria bound to cloth; glucoprotamin; toluidine blue O; surgical helmets versus filtering masks


Supporting the Health Care Workforce During the COVID-19 Global Epidemic.


The Practice of Wearing Surgical Masks during the COVID-19 Pandemic.


Americans are told to wear cloth masks.


Facemasks for the prevention of infection in healthcare and community settings.

Abstract: Facemasks are recommended for diseases transmitted through droplets and respirators for respiratory aerosols, yet recommendations and terminology vary between guidelines. The concepts of droplet and airborne transmission that are entrenched in clinical practice have recently been shown to be more complex than previously thought. Several randomised clinical trials of facemasks have been conducted in community and healthcare settings, using widely varying interventions, including mixed interventions (such as masks and handwashing), and diverse outcomes. Of the nine trials of facemasks identified in community settings, in all but one, facemasks were used for respiratory protection of well people. They found that facemasks and facemasks plus hand hygiene may prevent infection in community settings, subject to early use and compliance. Two trials in healthcare workers favoured respirators for clinical respiratory illness. The use of reusable cloth masks is widespread globally, particularly in Asia, which is an important region for emerging infections, but there is no clinical research to inform their use and most policies offer no guidance on them. Health economic analyses of facemasks are scarce and the few published cost effectiveness models do not use clinical efficacy data. The lack of research on facemasks and respirators is reflected in varied and sometimes conflicting policies and guidelines. Further research should focus on examining the efficacy of facemasks against specific infectious threats such as influenza and tuberculosis, assessing the efficacy of cloth masks, investigating common practices such as reuse of masks, assessing compliance, filling in policy gaps, and obtaining cost effectiveness data using clinical efficacy estimates.


High-Risk Aerosol-Generating Procedures in COVID-19: Respiratory Protective Equipment Considerations.

Abstract: The correct selection and utilization of respiratory personal protective equipment is of the utmost importance in the current COVID-19 pandemic. This is especially true for health care workers exposed to high-risk aerosol-generating procedures, including otolaryngologists, ophthalmologists, neurosurgeons, maxillofacial surgeons, and laparoscopic surgeons. This communication provides a review of approved forms of respiratory protection and compares their characteristics, including surgical masks, N95 respirator, elastomeric respirators, powered air-purifying respirators, and controlled air-purifying respirators. For standard airborne precautions, N95 respirator are appropriate for respiratory protection. However, high-risk aerosol-generating procedures may create aerosolization of high viral loads that represent increased risk to health care workers. In these situations, enhanced respiratory protection with filters certified as 99, 100, or HEPA (high-efficiency particulate air) may be appropriate.


A randomized clinical trial of three options for N95 respirators and medical masks in health workers.

Abstract: RATIONALE We compared three policy options for the use of medical masks and N95 respirators in healthcare workers (HCWs). OBJECTIVES A cluster randomized clinical trial of 1,669 hospital-based HCWs in Beijing, China in the winter of 2009-2010. METHODS Participants were randomized to medical masks, N95 respirators, or targeted use of N95 respirators while doing high-risk procedures or barrier nursing. Outcomes included clinical respiratory illness (CRI) and laboratory-confirmed respiratory pathogens in symptomatic subjects. MEASUREMENTS AND MAIN RESULTS The rate of CRI was highest in the medical mask arm (98 of 572; 17%), followed by the targeted N95 arm (61 of 516; 11.8%), and the N95 arm (42 of 581; 7.2%) (P < 0.05). Bacterial respiratory tract colonization in subjects with CRI was highest in the medical mask arm (14.7%; 84 of 572), followed by the targeted N95 arm (10.1%; 52 of 516), and lowest in the N95 arm (6.2%; 36 of 581) (P = 0.02). After adjusting for confounders, only continuous use of N95 remained significant against CRI and bacterial colonization, and for just CRI compared with targeted N95 use. Targeted N95 use was not superior to medical masks. CONCLUSIONS Continuous use of N95 respirators was more efficacious against CRI than intermittent use of N95 or medical masks. Most policies for HCWs recommend use of medical masks alone or targeted N95 respirator use. Continuous use of N95s resulted in significantly lower rates of bacterial colonization, a novel finding that points to more research on the clinical significance of bacterial infection in symptomatic HCWs. This study provides further data to inform occupational policy options for HCWs. Clinical trial registered with Australian New Zealand Clinical Trials Registry http://www.anzctr.org.au (ACTRN 12609000778280).


A quantitative assessment of the efficacy of surgical and N95 masks to filter influenza virus in patients with acute influenza infection.

Abstract: We assessed the in vivo efficacy of surgical and N95 (respirator) masks to filter reverse transcription-polymerase chain reaction (RT-PCR)-detectable virus when worn correctly by patients with laboratory-confirmed acute influenza. Of 26 patients with a clinical diagnosis of influenza, 19 had the diagnosis confirmed by RT-PCR, and 9 went on to complete the study. Surgical and N95 masks were equally effective in preventing the spread of PCR-detectable influenza.


Modifying reusable elastomeric respirators to utilise breathing system filters with 3D printed adapters, a safe alternative to N95 during COVID-19

Abstract: The COVID-19 pandemic has caused a worldwide shortage of personal protective equipment including N95 and FFP3 respirators. Reusable elastomeric respirators are suitable alternatives when used with compatible filters. These filters may be difficult to source and elastomeric respirators are not recommended for surgical use as the exhaled air is not filtered. Breathing system filters are routinely used in anaesthetic circuits to filter virus and bacteria. In this study, we designed 3D printed adapters that allowed elastomeric respirators to utilise breathing system filters and made simple modifications to the respirators to filter exhaled breaths. We then evaluated the performance and safety of our modified elastomeric respirators with quantitative fit tests. We recruited 8 volunteers to perform quantitative fit tests. Fit factors, respiratory rate and end-tidal carbon dioxide were recorded before and after wearing the modified respirators for 1 hour. All 8 volunteers obtained fit factors of 200+, the maximum achievable, for all tests exercises in all fit tests. The mean (range) end-tidal carbon dioxide was 4.5 (3.9-5.5) kPa and 4.6 (range 4.1-5.3) kPa before and after 1 hour of usage. The mean (range) respiratory rate was 16.5 (11-24) min-1 and 17.4 (15-22) min-1 before and after 1 hour of usage. Four (50%) did not experience any subjective discomfort while 2 (25%) reported pressure on the face, 1 (12.5%) reported exhalation resistance and 1 (12.5%) reported transient dizziness with exertion. Breathing system filters combined with properly fitted reusable elastomeric respirators is a safe alternative to N95 during the COVID-19 pandemic.


Commercially available endoscopy facemasks to prevent aerosolizing spread of droplets during COVID-19 outbreak


A Scalable Method of Applying Heat and Humidity for Decontamination of N95 Respirators During the COVID-19 Crisis

Abstract: A lack of N95 respirators during the COVID-19 crisis has placed healthcare workers at risk. It is important for any N95 reuse strategy to determine the effects that proposed protocols would have on the physical functioning of the mask, as well as the practical aspects of implementation. Here we propose and implement a method of heating N95 respirators with moisture (85{degrees}C, 60-85% humidity). We test both mask filtration efficiency and fit to validate this process. Our tests focus on the 3M 1860 and 3M 8210 Plus N95 models. After five cycles of the heating procedure, both respirators pass quantitative fit testing (score of >100) and show no degradation of mask filtration efficiency. We also test the Chen Heng V9501 KN95 and HKYQ N95 finding no degradation of mask filtration efficiency, however even for unheated masks these scored <50 for every fit test. The heating method presented here is scalable from individual masks to over a thousand a day with a single industrial convection oven, making this method practical for local application inside health-care facilities.


Effect of gamma sterilization on filtering efficiency of various respiratory face-masks

Abstract: Three types of respiratory masks viz N95, non-woven fabric and double layer cotton cloth are being used as an essential inhalation protective measure against COVID-19 by suppressing the entry of respiratory droplets. The filtering efficiency of these masks were tested before and after sterilisation using gamma radiation for the two flow rate conditions corresponding normal breath rate (20lpm) and during sneezing/coughing (90lpm).Sterilisation is carried out using a gamma irradiator containing Co-60 source for the two dose exposures viz. 15kGy and 25kGy. The filtering efficiency for surgical (non-woven fabric) and double layer cotton cloth mask is found to vary from 18% to 22% for the cumulative particle of size [≥] 0.3 micron in both un-irradiated and irradiated condition. The filtration efficiency of N95 mask is found to be reduced to 70% for the most penetrating particle size (0.3 micron) with the flow rate of 20lpm and further reduced for particles in the range of 0.1 and 0.2 micron with flow rate of 90 lpm. The reduction in efficiency after gamma sterilization is associated with reduction of electrostatic interaction of filter medium with particles laden in the air stream. Even with reduced filtering efficiency due to gamma sterilisation, the N95 masks are much superior than the surgical and cloth masks. Instead of disposing N95 mask after single use, they can be reused a few times as N70 mask during this pandemic crisis after sterilisation using gamma radiation.


Informing Homemade Emergency Facemask Design: The Ability of Common Fabrics to Filter Ultrafine Particles

Abstract: Objectives: To examine the ability of fabrics which might be used to create homemade face masks to filter out ultrafine (smaller than 1m in diameter) particles. Method: Twenty commonly available fabrics and materials were evaluated for their ability to reduce air concentrations of ultrafine particles. Further assessment was made on the filtration ability of select fabrics while damp and of fabric combinations which might be used to construct homemade masks. Results: Single fabric layers blocked a range of ultrafine particles. When fabrics were layered, significantly more ultrafine particles were filtered. Several fabric combinations were successful in removing similar amounts of ultrafine particles when compared to an N95 mask and surgical mask. Conclusions: The current coronavirus pandemic has left many communities without access to commercial facemasks. Our findings suggest that face masks made from layered common fabric can help filter ultrafine particles and provide some protection for the wearer when commercial facemasks are unavailable.


Characterization of a novel, low-cost, scalable vaporized hydrogen peroxide system for sterilization of N95 respirators and other COVID-19 related personal protective equipment.

Abstract: Due to the virulence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for the respiratory disease termed COVID-19, there has been a significant increase in demand for surgical masks and N95 respirators in medical clinics as well as within communities operating during the COVID-19 epidemic. Thus, community members, business owners, and even medical personnel have resorted to alternative methods for sterilizing face coverings and N95 respirators for reuse. While significant work has shown that vaporized hydrogen peroxide (VHP) can be used to sterilize N95 respirators, the cost and installation time for these sterilization systems limit their accessibility. To this end, we have designed and constructed a novel, cost-effective, and scalable VHP system that can be used to sterilize N95 respirators and other face coverings for clinical and community applications. N95 respirators inoculated with P22 bacteriophage showed a greater than 6-log10 reduction in viral load when sterilized in the VHP system for one 60-minute cycle. Further, N95 respirators treated with 20 cycles in this VHP system showed comparable filtration efficiency to untreated N95 respirators in a 50 to 200 nanometer particulate challenge filtration test. While a 23% average increase in water droplet roll-off time was observed for N95 respirators treated with 5 cycles in the sterilization, no breakdown in fluid resistance was detected. These data suggest that our VHP system is effective in sterilizing N95 respirators and other polypropylene masks for reuse. Relating to the present epidemic, deployment of this system reduces the risk of COVID-19 community transmission while conserving monetary resources otherwise spent on the continuous purchase of disposable N95 respirators and other face coverings. In summary, this novel, scientifically validated sterilization system can be easily built at a low cost and implemented in a wide range of settings.


Hydrogen Peroxide Vapor sterilization of N95 respirators for reuse

Abstract: Abstract Reprocessing of used N95 respirators may ameliorate supply chain constraints during the COVID-19 pandemic and provide a higher filtration crisis alternative. The FDA Medical Countermeasures Initiative previously funded a study of HP vapor decontamination of respirators using a Clarus C system (Bioquell, Horsham, PA) which normally is used to fumigate hospital rooms. The process preserved respirator function, but it is unknown if HP vapor would be virucidal since respirators have porous fabric that may harbor virus. We evaluated the virucidal activity of HP vapor using a BQ-50 system (Bioquell, Horsham, PA) after inoculating 3M 1870 N95 respirators (3M, St. Paul, MN) with 3 aerosolized bacteriophage that are a reasonable proxy for SARS-CoV-2. Inoculation resulted in contamination of the respirator with 9.87e4 plaque forming units (PFU) of phage phi-6, 4.17e7 PFU of phage T7 and 1.35e7 PFU of phage T1. Respirators were reprocessed with BQ-50 with a long aeration phase to reduce HP vapors. Virucidal activity was measured by a standard plaquing assay prior to and after sterilization. A single HP vapor cycle resulted in complete eradication of phage from masks (limit of detection 10 PFU, lower than the infectious dose of the majority of respiratory viral pathogens). After 5 cycles, the respirators appeared similar to new with no deformity. Use of a Bioquell machine can be scaled to permit simultaneous sterilization of a large number of used but otherwise intact respirators. HP vapor reprocessing may ease shortages and provide a higher filtration crisis alternative to non-NIOSH masks.


A Novel Questionnaire to Ergonomically Assess Respirators among Health Care Staff: Development and Validation

Abstract: BACKGROUND: Health care workers are at a high risk of exposure to infectious diseases spread by airborne transmission. N95 respirators are the most common respirators used in the health care system and negligence in using them may cause health problems. Hence, more emphasis should be on ergonomic aspects of this mask. This study aimed to develop a tool for ergonomic evaluation of these respirators. MATERIALS AND METHODS: After reviewing previous studies and employees’ problems in the use of the N95 respirators, 50 questionnaires were designed and their validity was assessed. Then, the questionnaire was completed by 290 staff members of Masih Daneshvari Hospital and its internal consistency and reproducibility were investigated using Cronbach’s alpha coefficient and test-retest method, respectively. Confirmatory factor analysis was used to assess its consistency and internal consistency (construct validity). RESULTS: With the confirmation of the face and content validities, internal consistency (0.89) calculated by the Cronbach’s alpha coefficient and reproducibility of the questionnaire (0.997; p<0.001) assessed by using the ICC Index, were approved. Following examining internal consistency and stability, the questionnaire convergent construct validity was also confirmed using confirmatory factor analysis. CONCLUSION: The questionnaire contained 42 items and it is beneficial to use it in the health care system to evaluate the ergonomic problems of the respirators and to have optimal choice in this respect. Also, it can be used in the promotion of the staffs’ behavior in wearing these respirators when necessary.


[Rational use of respiratory protective equipment: advice for health care professionals in time of COVID-19].

Abstract: The current COVID-19 pandemic has led to a worldwide shortage of respiratory protective equipment. In order to offer maximum protection against infection for all healthcare workers, we need to optimise our use of the available equipment. This article provides practical advice on which type of mask is indicated in what specific situation, what requirements the mask should meet and how to optimise the local workflow, including the re-use of masks after decontamination.


Nasal plugs for preventing respiratory infections.

Abstract: Nasal plugs were made from an N-95 respirator, surgical mask or a cotton ball and inserted into the nares of volunteer healthcare workers for 30 min. Initial and persistent respiratory resistance, choking sensation, and discomfort in the mouth and nose areas were recorded for the three different nasal plugs, the N-95 respirator and a surgical mask. Nasal plugs were more convenient and better tolerated than the masks. The ability of the nasal plug material to prevent infection by droplet transmission was also tested. A piece of each material was placed on a blood agar plate, the volunteer coughed onto the plate and the material was removed. Bacterial colonies only grew in the areas not previously covered by the nasal plug material. The cotton ball nasal plug is probably as effective as the N-95 respirator or surgical masks at preventing infection, and is much cheaper.


FFP3, FFP2, N95, surgical masks and respirators: what should we be wearing for ophthalmic surgery in the COVID-19 pandemic?


Respiratory Protection Considerations for Healthcare Workers During the COVID-19 Pandemic

Abstract: The COVID-19 pandemic has resulted in a surge of patients that exceeds available human and physical resources in many settings, triggering the implementation of crisis standards of care. High-quality respiratory protection is essential to reduce exposure among healthcare workers, yet dire shortages of personal protective equipment in the United States threaten the health and safety of this essential workforce. In the context of rapidly changing conditions and incomplete data, this article outlines 3 important strategies to improve healthcare workers' respiratory protection. At a minimum, healthcare workers delivering care to patients with confirmed or suspected COVID-19 should wear N95 respirators and full-face shields. Several mechanisms exist to boost and protect the supply of N95 respirators, including rigorous decontamination protocols, invoking the Defense Production Act, expanded use of reusable elastomeric respirators, and repurposing industrial N95 respirators. Finally, homemade facial coverings do not protect healthcare workers and should be avoided. These strategies, coupled with longer-term strategies of investments in protective equipment research, infrastructure, and data systems, provide a framework to protect healthcare workers immediately and enhance preparedness efforts for future pandemics.


Update to device-related pressure ulcers: SECURE prevention. COVID-19, face masks and skin damage

Abstract: The 2019 novel coronavirus disease (COVID-19) pandemic has brought the effects of device-related pressure ulcers (DRPU) into sharp focus. With the increased use of personal protective equipment (PPE), including face masks, continuous positive airway pressure (CAPP) masks and other devices, the incidence of DRPUs among health professionals and patients alike has risen starkly. As such, the Journal of Wound Care (JWC) consensus document, Device-related pressure ulcers: SECURE prevention, published in February 2020, is more relevant than ever. To help support patients and frontline health professionals, JWC is republishing the consensus in a digital format, along with a new introductory article outlining the DRPU risks posed by PPE and other medical devices used by patients and health professionals during the pandemic, and how the skin damage can be avoided. The aim is to provide frontline staff with a clear, simple strategy on how to prevent the risk of personal skin damage and/or DRPU during the pandemic, as well as point them in the direction of more indepth guidance on long-term strategies for prevention, for both themselves and patients.


Reuse of N95 Masks


Recomendaciones de la Sociedad de Gastroenterología del Perú para evitar la propagación del SARS-CoV-2 a través de procedimientos de endoscopía digestiva./ [Recommendations of the Society of Gastroenterology of Peru to avoid the spread of SARS-CoV-2 through digestive endoscopy procedures]

Abstract: The SARS-CoV-2 coronavirus produces the disease called COVID-19, currently spreading in a rapidly evolving pandemic. It can be transmitted by contact, drops and aerosols, and has been isolated from gastrointestinal secretions and faeces. During digestive endoscopy, transmission by any of these mechanisms could occur. It is recommended to limit digestive endoscopy to cases of digestive bleeding, severe dysphagia, foreign body in the digestive tract, biliary obstruction with intractable pain or cholangitis, pseudocyst or complicated encapsulated pancreatic necrosis, gastrointestinal obstruction, and cases at risk of deterioration over time. It is recommended to screen patients based on temperature, symptoms, and epidemiological factors to classify them according to their risk of infection. For procedures in low risk patients, personnel must wear a disposable gown, gloves, eye or face shield, standard surgical mask, disposable hat, disposable shoe covers. In cases of intermediate or high risk, or confirmed COVID-19, protection should be increased using disposable waterproof gown, N95 respirator or similar, and double glove. In case of shortage it may be necessary to reuse N95 respirators for up to 5 uses, following CDC recommendations for donning, removing and storing to prevent secondary contact contamination. Likewise, all protective equipment should be put on and removed according to CDC recommendations. The presence of personnel in endoscopy should be limited to the bare minimum. Said personnel must have daily temperature control and if it is above 37.3ºC, the corresponding evaluation must be carried out. After each procedure, the stretcher and room surfaces should be properly disinfected. High-level disinfection of endoscopes eliminates SARS-CoV-2.


Coronavirus disease 2019 (COVID-19) pandemic: International variation of personal protective equipment (PPE) and infection prevention and control (IPC) guidelines


Use of Face Masks in COVID-19


Physical distancing, face masks, and eye protection for prevention of COVID-19


High-Risk Aerosol-Generating Procedures in COVID-19: Respiratory Protective Equipment Considerations


Why not use the Easybreath snorkeling mask to prevent COVID-19 transmission during endoscopy procedures when FFP2 are lacking?


Medical mask with plasma sterilizing layer

Abstract: In this brief report we propose a new design of a medical mask with a plasma layer, which provides both additional air filtration from microdrops, bacteria and viruses due to the electrostatic effect and self-disinfecting of surfaces by a pulsed barrier discharge. The key features of the mask are the mutual arrangement of the layers, the direction of air flows and the synchronization of the discharge with respiration, which ensures the safe wearing of the mask and high degree of protection against pathogenic microorganisms.


Evaluation of the rationale for concurrent use of N95 filtering facepiece respirators with loose-fitting powered air-purifying respirators during aerosol-generating medical procedures

Abstract: The concurrent use of N95 filtering facepiece respirators with powered air-purifying respirators during aerosol-generating medical procedures in patients with severe respiratory pathogens has been promoted as offering additional protection against infectious agents. The purpose of this article is to examine the impact of this additional respiratory equipment upon protection and personal performance. The presumed additive protective effect of an N95 filtering facepiece respirator used concurrently with a powered air-purifying respirator has not been subjected to rigorous scientific investigation. The burden imposed by additional respiratory protective equipment should not be discounted, and the potentially minor contribution to protection may be offset by the negative impact on personal performance. Novel uses of protective equipment occasionally are spawned during crisis situations, but their generalized applicability to healthcare workers should ultimately be evidence-based.


Dispersal of Respiratory Droplets With Open vs Closed Oxygen Delivery Masks Implications for the Transmission of Severe Acute Respiratory Syndrome

Abstract: Nosocomial transmission of droplet-borne respiratory infections such as severe acute respiratory syndrome (SARS) may be influenced by the choice of oxygen face mask. A subject inhaled saline mist and exhaled through three oxygen masks to illustrate the pattern of dispersal of pulmonary gas. In two commonly used masks, exhaled gas formed a plume emanating from the side vents, while a third mask with a valved manifold, which was modified by adding a respiratory filter, retained the droplets. Maintaining respiratory isolation during the administration of oxygen may reduce the risk of the nosocomial transmission of respiratory infections such as SARS.


User acceptance of reusable respirators in health care

Abstract: BACKGROUND: Inclusion of reusable respirators, such as elastomeric half-face respirators (EHFRs) and powered air-purifying respirators (PAPRs), in hospital respiratory protection inventories may represent 1 solution to the problem of N95 respirator shortages experienced during pandemics. User acceptance of these devices is 1 potential barrier to implementing such a strategy in respiratory protection programs. METHODS: To assess user attitudes toward various respirators, health care workers enrolled in respiratory protection programs in a medical system using EHFRs, N95s, and PAPRs and completed an online questionnaire that addressed attitudes, beliefs, and respirator preferences under different risk scenarios. Responses were compared between user groups. RESULTS: Of 1,152 participants, 53% currently used N95s, 24% used EHFRs, and 23% used PAPRs. N95 users rated their respirators more favorably compared with EHFR and PAPR users (P < .001) regarding comfort and communication, however, EHFR users rated their respirators much more highly regarding sense of protection (P < .001). For all user groups, reusable respirators were significantly more likely (odds ratios 2.3-7.7) to be preferred over N95 filtering facepiece respirators in higher risk scenarios compared to “usual circumstance” scenarios. CONCLUSIONS: Despite somewhat less favorable ratings on comfort and communication, experienced EHFR and PAPR users still prefer reusable respirators over N95s in certain higher risk scenarios. This suggests that reusable respirators are an acceptable alternative to N95 respirators in health care and offer 1 viable solution to prevent pandemic-generated respirator shortages.


Novel Coronavirus 2019 (2019-nCoV) Infection: Part I - Preparedness and Management in the Pediatric Intensive Care Unit in Resource-limited Settings

Abstract: First reported in China, the 2019 novel coronavirus has been spreading across the globe. Till 26 March, 2020, 416,686 cases have been diagnosed and 18,589 have died the world over. The coronavirus disease mainly starts with a respiratory illness and about 5-16% require intensive care management for acute respiratory distress syndrome (ARDS) and multi-organ dysfunction. Children account for about 1-2% of the total cases, and 6% of these fall under severe or critical category requiring pediatric intensive care unit (PICU) care. Diagnosis involves a combination of clinical and epidemiological features with laboratory confirmation. Preparedness strategies for managing this pandemic are the need of the hour, and involve setting up cohort ICUs with isolation rooms. Re-allocation of resources in managing this crisis involves careful planning, halting elective surgeries and training of healthcare workers. Strict adherence to infection control like personal protective equipment and disinfection is the key to contain the disease transmission. Although many therapies have been tried in various regions, there is a lack of strong evidence to recommend anti-virals or immunomodulatory drugs.


Evaluation of the user seal check on gross leakage detection of 3 different designs of N95 filtering facepiece respirators

Abstract: BACKGROUND: The use of N95 respirators prevents spread of respiratory infectious agents, but leakage hampers its protection. Manufacturers recommend a user seal check to identify on-site gross leakage. However, no empirical evidence is provided. Therefore, this study aims to examine validity of a user seal check on gross leakage detection in commonly used types of N95 respirators. METHODS: A convenience sample of 638 nursing students was recruited. On the wearing of 3 different designs of N95 respirators, namely 3M-1860s, 3M-1862, and Kimberly-Clark 46827, the standardized user seal check procedure was carried out to identify gross leakage. Repeated testing of leakage was followed by the use of a quantitative fit testing (QNFT) device in performing normal breathing and deep breathing exercises. Sensitivity, specificity, predictive values, and likelihood ratios were calculated accordingly. RESULTS: As indicated by QNFT, prevalence of actual gross leakage was 31.0%-39.2% with the 3M respirators and 65.4%-65.8% with the Kimberly-Clark respirator. Sensitivity and specificity of the user seal check for identifying actual gross leakage were approximately 27.7% and 75.5% for 3M-1860s, 22.1% and 80.5% for 3M-1862, and 26.9% and 80.2% for Kimberly-Clark 46827, respectively. Likelihood ratios were close to 1 (range, 0.89-1.51) for all types of respirators. CONCLUSIONS: The results did not support user seal checks in detecting any actual gross leakage in the donning of N95 respirators. However, such a check might alert health care workers that donning a tight-fitting respirator should be performed carefully.


Novel Coronavirus International Public Health Emergency: Guidance on Radiation Oncology Facility Operation


Calculating an institutional personal protective equipment (PPE) burn rate to project future usage patterns during the 2020 COVID-19 pandemic


Respirators and surgical facemasks for COVID-19: implications for MRI

Abstract: • Respirators used for COVID-19 protection have not been tested for MR safety. • Three of four respirators tested contained ferromagnetic components. • These respirators are ‘MR unsafe’. • Respirators used for COVID-19 protection should be reviewed locally for MR safety. • Surgical masks offer a WHO approved safe alternative for MR staff.


Skin Reactions of N95 masks and Medial Masks among Health Care Personnel: A self‐report questionnaire survey in China


AORN Guidance Statement: Human and Avian Influenza and Severe Acute Respiratory Syndrome


Sensitivity and specificity of the user-seal-check in determining the fit of N95 respirators

Abstract: Summary N95 respirators are recommended by the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) to prevent the inhalation of droplets which may transmit respiratory pathogens. The reliability of N95 respirators in preventing transmission depends on their fit to the wearer. Quantitative fit testing (QNFT) is the gold standard used to determine this fit objectively. The manufacturers of the respirators also recommend performing a self-reported user-seal-check to detect for leakage. This study aims to investigate the capability of the user-seal-check in determining the fit of N95 respirators by investigating the sensitivity and specificity of the user-seal-check compared with QNFT. A prospective and cross-sectional research design was used. A total of 204 local Chinese undergraduate nursing students were recruited to test two commonly used respirator models (3M 1860S and 3M 1862). The results of the user-seal-check were compared with the results of the gold standard QNFT using the Condensation Nucleus Counter Fit Tester System. The sensitivity and specificity of the user-seal-check results obtained with the respirators were calculated. The results indicated low sensitivity, accuracy and predictive value of the user-seal-check in determining the fit of the N95 respirators. The user-seal-check was not found to be reliable as a substitute for QNFT. The results also suggested that the user-seal-check may be unreliable for detecting gross leakage. We recommend that QNFT is used to determine the fit of N95 respirators.


Helmet Modification to PPE with 3D Printing During the COVID-19 Pandemic at Duke University Medical Center: A Novel Technique

Abstract: Abstract Care for patients during COVID-19 poses challenges that require the protection of staff with recommendations that health care workers wear at minimum, an N95 mask or equivalent while performing an aerosol-generating procedure with a face shield. The United States faces shortages of personal protective equipment, and surgeons who use loupes and headlights have difficulty using these in conjunction with face shields. Most arthroplasty surgeons use surgical helmet systems, but in the current pandemic, many hospitals have delayed elective arthroplasty surgeries and the helmet systems are going unused. As a result, the authors have begun retrofitting these arthroplasty helmets to serve as personal protective equipment (PPE). The purpose of this paper is to outline the conception, design, donning technique, and safety testing of these arthroplasty helmets being re-purposed as PPE.


Association between 2019-nCoV transmission and N95 respirator use


SARS-CoV-2/COVID-19: Empfehlungen zu Diagnostik und Therapie

Abstract: COVID-19, a new viral disease affecting primarily the respiratory system and the lung, has caused a pandemic with serious challenges to health systems around the world. In about 20% of patients, severe symptoms occur after a mean incubation period of 5 – 6 days; 5% of patients need intensive care therapy. Morbidity is about 1 – 2%. Protecting health care workers is of paramount importance in order to prevent hospital acquired infections. Therefore, during all procedures associated with aerosol production, a personal safety equipment consisting of a FFP2/FFP3 (N95) respiratory mask, gloves, safety glasses and a waterproof overall should be used. Therapy is based on established recommendations issued for patients with acute lung injury (ARDS). Lung protective ventilation, prone position, restrictive fluid management and an adequate management of organ failures are the mainstays of therapy. In case of fulminant lung failure, veno-venous extracorporeal membrane oxygenation may be used as a rescue in experienced centres. New, experimental therapies evolve with ever increasing frequency; currently, however, there is no evidence based recommendation possible. If off-label and compassionate use of these drugs is considered, an individual benefit-risk assessment is necessary, since serious side effects have been reported.


CORONA-steps for tracheotomy in COVID-19 patients: A staff-safe method for airway management

Abstract: • The recent outbreak of SARS‐CoV‐2 has assumed worldwide proportion. • Tracheostomy in intubated COVID-19 patients requires adjunctive safeguards. • A step-by-step approach named CORONA is proposed in order to recall essential recommendations during the surgical procedure. • The CORONA-method would allow a secure space in which health workers can guarantee their activity, safely.


Simple Respiratory Protection—Evaluation of the Filtration Performance of Cloth Masks and Common Fabric Materials Against 20–1000 nm Size Particles

Abstract: A shortage of disposable filtering facepiece respirators can be expected during a pandemic respiratory infection such as influenza A. Some individuals may want to use common fabric materials for respiratory protection because of shortage or affordability reasons. To address the filtration performance of common fabric materials against nano-size particles including viruses, five major categories of fabric materials including sweatshirts, T-shirts, towels, scarves, and cloth masks were tested for polydisperse and monodisperse aerosols (20–1000 nm) at two different face velocities (5.5 and 16.5 cm s(−1)) and compared with the penetration levels for N95 respirator filter media. The results showed that cloth masks and other fabric materials tested in the study had 40–90% instantaneous penetration levels against polydisperse NaCl aerosols employed in the National Institute for Occupational Safety and Health particulate respirator test protocol at 5.5 cm s(−1). Similarly, varying levels of penetrations (9–98%) were obtained for different size monodisperse NaCl aerosol particles in the 20–1000 nm range. The penetration levels of these fabric materials against both polydisperse and monodisperse aerosols were much higher than the penetrations for the control N95 respirator filter media. At 16.5 cm s(−1) face velocity, monodisperse aerosol penetrations slightly increased, while polydisperse aerosol penetrations showed no significant effect except one fabric mask with an increase. Results obtained in the study show that common fabric materials may provide marginal protection against nanoparticles including those in the size ranges of virus-containing particles in exhaled breath.


The preventive effect of hydrocolloid dressing to prevent facial pressure and facial marks during use of medical protective equipment in Covid-19 pandemic