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US - NIH: COVID-19 Treatment Guidelines - April 21, 2020

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  • US - NIH: COVID-19 Treatment Guidelines - April 21, 2020


    Introduction


    These Treatment Guidelines have been developed to inform clinicians how to care for patients with COVID-19. Because clinical information about the optimal management of COVID-19 is evolving quickly, these Guidelines will be updated frequently as published data and other authoritative information becomes available.

    The recommendations in these Guidelines are based on scientific evidence and expert opinion. Each recommendation includes two ratings: a letter (A, B, or C) that indicates the strength of the recommendation and a Roman numeral (I, II, or III) that indicates the quality of the evidence that supports the recommendation (see Table 1).

    Panel Composition


    Members of the COVID-19 Treatment Guidelines Panel (the Panel) were appointed by the Panel co-chairs and chosen based on their clinical experience and expertise in patient management, translational and clinical science, and/or development of treatment Guidelines. Panel members include representatives from federal agencies, health care and academic organizations, and professional societies. Federal agencies and professional societies represented on the Panel include:
    • American College of Chest Physicians
    • American College of Emergency Physicians
    • American Thoracic Society
    • Biomedical Advanced Research and Development Authority
    • Centers for Disease Control and Prevention
    • Department of Defense
    • Department of Veterans Affairs
    • Food and Drug Administration
    • Infectious Diseases Society of America
    • National Institutes of Health
    • Pediatric Infectious Diseases Society
    • Society of Critical Care Medicine
    • Society of Infectious Diseases Pharmacists.

    The inclusion of representatives from professional societies does not imply that their societies have endorsed all elements of this document.

    The names, affiliations, and conflict of interest disclosures of the Panel members, ex-officio members, and support staff are provided in the Panel Roster and Financial Disclosures.

    Development of the Guidelines


    Each section of the Guidelines was developed by a working group of Panel members with expertise in the section’s area of interest. Each working group was responsible for identifying relevant information and published scientific literature, and conducting a systematic, comprehensive review of that information and literature. The working groups will propose updates to the Guidelines based on the latest published research findings and evolving clinical information.

    Each guideline section has been reviewed, modified as necessary, and voted on by the entire Panel. A majority vote was required for a recommendation to be included in the posted Guidelines. Panel members are required to keep all Panel deliberations and unpublished data considered during the development of the guidelines confidential.

    Method of Synthesizing Data and Formulating Recommendations


    The working groups critically review and synthesize the available data to develop recommendations. Aspects of the data that are considered include, but are not limited to, the type of study (e.g., case series, prospective cohort, randomized controlled trial), the quality and suitability of the methods, the number of participants, and the effect sizes observed. Each recommendation is assigned two ratings according to the scheme presented in Table 1.

    Table 1. Recommendation Rating Scheme
    A: Strong recommendation for the statement

    B: Moderate recommendation for the statement

    C: Optional recommendation for the statement
    I: One or more randomized trials with clinical outcomes and/or validated laboratory endpoints

    II: One or more well-designed, nonrandomized trials or observational cohort studies

    III: Expert opinion
    It is important to note that at present, to develop the recommendations in these Guidelines, the Panel relied heavily on experience with other diseases, supplemented with evolving personal clinical experience with COVID-19, and incorporated the rapidly growing published scientific literature on COVID-19. When information existed in other published Guidelines that the Panel felt important to include in these Guidelines, the information was included with permission from the original sources.

    Evolving Knowledge on Treatment for COVID-19


    Currently there are no Food and Drug Administration (FDA)-approved drugs for COVID-19. However, an array of drugs approved for other indications, as well as multiple investigational agents, are being studied for the treatment of COVID-19 in several hundred clinical trials around the globe. These trials can be accessed at ClinicalTrials.gov. In addition, providers can access and prescribe investigational drugs or agents approved or licensed for other indichttps://www.covid19treatmentguidelin.../introduction/ations through various mechanisms, including Emergency Use Authorizations (EUA), Emergency Investigational New Drug (EIND) applications, compassionate use or expanded access programs with drug manufacturers, and/or off-label use.

    For this reason, whenever possible, the Panel recommends that promising, unapproved or unlicensed treatments for COVID-19 be studied in well-designed controlled clinical trials. This includes drugs that have been approved or licensed for other indications. The Panel recognizes the critical importance of clinical research in generating evidence to address unanswered questions regarding the safety and efficacy of potential treatments for COVID-19. However, the Panel also realizes that many patients and providers who cannot access such trials are still seeking guidance about whether to use these agents.

    Finally, it is important to stress that the rated treatment recommendations in these Guidelines should not be considered mandates. The choice of what to do or not to do for an individual patient is ultimately decided by the patient together with their provider.


    https://www.covid19treatmentguidelin.../introduction/

  • #2

    Overview and Spectrum of COVID-19
    • The COVID-19 Treatment Guidelines Panel (the Panel) does not recommend the use of any agents for pre-exposure prophylaxis (PrEP) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outside of the setting of a clinical trial (AIII).
    • The Panel does not recommend the use of any agents for post-exposure prophylaxis (PEP) against SARS-CoV-2 infection outside of the setting of a clinical trial (AIII).
    • The Panel recommends no additional laboratory testing and no specific treatment for persons with suspected or confirmed asymptomatic or presymptomatic SARS-CoV-2 infection (AIII).
    • At present, no drug has been proven to be safe and effective for treating COVID-19. There are insufficient data to recommend either for or against the use of any antiviral or immunomodulatory therapy in patients with COVID-19 who have mild, moderate, severe, or critical illness (AIII).
    Epidemiology


    The COVID-19 pandemic has exploded since cases were first reported in China in January 2020. As of April 19, 2020, more than 2.4 million cases of COVID-19—caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection—have been reported globally, including >165,000 deaths. Cases have been reported in more than 180 countries, including all 50 states of the United States.1, 2

    Individuals of all ages are at risk for infection and severe disease. However, the probability of fatal disease is highest in people aged ≥65 years and those living in a nursing home or long-term care facility.

    Others at highest risk for COVID-19 are people of any age with certain underlying conditions, especially when not well-controlled, including:3-7
    • Hypertension
    • Cardiovascular disease
    • Diabetes
    • Chronic respiratory disease
    • Cancer
    • Renal disease, and
    • Obesity.
    Clinical Presentation


    The estimated incubation period for COVID-19 is up to 14 days from the time of exposure, with a median incubation period of 4 to 5 days.4,8,9 The spectrum of illness can range from asymptomatic infection to severe pneumonia with acute respiratory distress syndrome (ARDS) and death. In a summary of 72,314 persons with COVID-19 in China, 81% of cases were reported to be mild, 14% were severe, and 5% were critical.10 In a report of 1,482 hospitalized patients with confirmed COVID-19 in the United States, the most common presenting symptoms were cough (86%), fever or chills (85%), and shortness of breath (80%), diarrhea (27%), and nausea (24%).7 Other reported symptoms have included, but are not limited to, sputum production, headache, dizziness, rhinorrhea, anosmia, dysgeusia, sore throat, abdominal pain, anorexia and vomiting.

    Common laboratory findings of COVID-19 include leukopenia and lymphopenia. Other laboratory abnormalities have included elevations in aminotransferase levels, C-reactive protein, D-dimer, ferritin, and lactate dehydrogenase.

    Abnormalities in chest X-ray vary, but typically reveal bilateral multi-focal opacities. Abnormalities seen in computed tomography (CT) of the chest also vary, but typically reveal bilateral peripheral ground-glass opacities with the development of areas of consolidation later in the clinical course.11 Imaging may be normal early in infection and can be abnormal in the absence of symptoms.11
    Diagnosis of SARS-CoV-2 Infection


    Ideally, diagnostic testing would be conducted for all patients with a syndrome consistent with COVID-19, people with known high-risk exposures, and people likely to be at repeated risk of exposure, such as health care workers and first responders. For more information, see the Centers for Disease Control and Prevention (CDC) COVID-19 website.

    CDC recommends that nasopharynx samples be used to detect SARS-CoV-2. Nasal swabs or oropharyngeal swabs may be acceptable alternatives.12 Lower respiratory tract samples have a higher yield than upper tract samples, but often they are not obtained because of concerns about aerosolization of virus during sample collection procedures.

    While initial diagnostic tests for SARS-CoV-2 infection have relied on reverse transcriptase polymerase chain reaction platforms, more recent tests have included a variety of additional platforms. More than 20 diagnostic tests for SARS-CoV-2 infection have received Emergency Use Authorization by the Food and Drug Administration.13 Formal comparisons of these tests are in progress.

    CDC has established a priority system for diagnostic testing for SARS-CoV-2 infection based on the availability of tests;14 the CDC testing guidance is updated periodically.
    • Priority 1: Hospitalized patients and symptomatic health care workers (to reduce the risk of nosocomial infections and maintain the health care system).
    • Priority 2: Individuals with symptoms who live in long-term care facilities, who are aged ≥65 years, or who have underlying conditions, and symptomatic first responders (to ensure those at highest risk of complications of infection are rapidly identified and triaged).
    • Priority 3: In communities experiencing high COVID-19 hospitalizations, critical infrastructure workers and other individuals with symptoms, health care workers and first responders, and individuals with mild symptoms (to decrease community spread and ensure the health of essential workers).

    Of note, false-negative test results can occur. In people with a high likelihood of infection based on exposure history and/or clinical presentation, a single negative test does not completely exclude SARS-CoV-2 infection, and testing should be repeated.
    Routes of SARS-CoV-2 Transmission and Standard Means of Prevention


    The onset and duration of viral shedding and period of infectiousness are not completely defined. Asymptomatic or pre-symptomatic individuals infected with SARS-CoV-2 may have viral RNA detected in upper respiratory specimens before the onset of symptoms.15 Transmission of SARS-CoV-2 from asymptomatic individuals has been described.16-18 The extent to which this occurs remains unknown.
    References
    1. World Health Organization. Coronavirus disease (COVID-2019) situation reports. 2020. Available at: https://www.who.int/emergencies/dise...ation-reports/. Accessed April 9, 2020.
    2. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): cases in U.S. 2020. Available at: https://www.cdc.gov/coronavirus/2019...ses-in-us.html. Accessed April 9, 2020.
    3. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32167524.
    4. Guan WJ, Ni ZY, Hu Y, et al. Characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32109013.
    5. Cai Q, Chen F, Luo F, et al. Obesity and COVID-19 severity in a designated hospital in Shenzhen, China. Preprints with the Lancet. 2020;[Preprint]. Available at:https://papers.ssrn.com/sol3/papers....act_id=3556658
    6. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): People who are at higher risk for severe illness. 2020. Available at: https://www.cdc.gov/coronavirus/2019...gher-risk.html. Accessed April 8, 2020.
    7. Garg S, Kim L, Whitaker M, et al. Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 - COVID-NET, 14 states, March 1-30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(15):458-464. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32298251.
    8. Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020;382(13):1199-1207. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31995857.
    9. Lauer SA, Grantz KH, Bi Q, et al. The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: Estimation and application. Ann Intern Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32150748.
    10. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32091533.
    11. Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 2020;20(4):425-434. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32105637.
    12. Centers for Disease Control and Prevention. Interim guidelines for collecting, handling, and testing clinical specimens from persons for coronavirus disease 2019 (COVID-19). 2020. Available at: https://www.cdc.gov/coronavirus/2019...specimens.html. Accessed April 8, 2020.
    13. Food and Drug Administration. Coronavirus disease 2019 (COVID-19) emergency use authorizations for medical devices. 2020. Available at: https://www.fda.gov/medical-devices/...ons#covid19ivd. Accessed April 8, 2020.
    14. Centers for Disease Control and Prevention. Evaluating and testing persons for coronavirus disease 2019 (COVID-19). 2020. Available at: https://www.cdc.gov/coronavirus/2019...-criteria.html. Accessed April 8, 2020.
    15. Pan Y, Zhang D, Yang P, Poon LLM, Wang Q. Viral load of SARS-CoV-2 in clinical samples. Lancet Infect Dis. 2020;20(4):411-412. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32105638.
    16. Rothe C, Schunk M, Sothmann P, et al. Transmission of 2019-nCoV infection from an asymptomatic contact in Germany. N Engl J Med. 2020;382(10):970-971. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32003551.
    17. Yu P, Zhu J, Zhang Z, Han Y, Huang L. A familial cluster of infection associated with the 2019 novel coronavirus indicating potential person-to-person transmission during the incubation period. J Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32067043.
    18. Bai Y, Yao L, Wei T, et al. Presumed asymptomatic carrier transmission of COVID-19. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32083643.

    https://www.covid19treatmentguidelin....gov/overview/

    Comment


    • #3

      Persons at Risk for Infection with SARS-CoV-2

      Pre-Exposure Prophylaxis


      The COVID-19 Treatment Guidelines Panel (the Panel) does not recommend the use of any agents for SARS-CoV-2 pre-exposure prophylaxis (PrEP) outside the setting of a clinical trial (AIII).

      At present, no agent given before an exposure (i.e., as PrEP) is known to be effective in preventing SARS-CoV-2 infection. Clinical trials using hydroxychloroquine, chloroquine, or HIV protease inhibitors as PrEP are in development or underway.
      Post-Exposure Prophylaxis


      The Panel does not recommend the use of any agents for SARS-CoV-2 post-exposure prophylaxis (PEP) outside the setting of a clinical trial (AIII).

      At present, no agent is known to be effective for preventing SARS-CoV-2 infection after an exposure (i.e., as PEP). Potential options for PEP currently under investigation in clinical trials include hydroxychloroquine, chloroquine, or lopinavir/ritonavir.


      https://www.covid19treatmentguidelin...w/prophylaxis/

      Comment


      • #4

        Management of Persons with COVID-19


        Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can experience a range of clinical manifestations, from no symptoms to critical illness. This section discusses the clinical management of patients according to the severity of their illness. Currently, no Food and Drug Administration (FDA)-approved drugs exist to specifically treat patients with COVID-19. Chloroquine and hydroxychloroquine, which are not FDA approved for COVID-19, are available from the Strategic National Stockpile for hospitalized adults and adolescents (weighing >50 kg) under an Emergency Use Authorization. An array of drugs approved for other indications, as well as multiple investigational agents, are being studied for the treatment of COVID-19 in several hundred clinical trials around the globe. Some drugs can be accessed through expanded access or compassionate use mechanisms. Available clinical data for these drugs under investigation are discussed in Therapeutic Options for COVID-19 Currently Under Investigation. As noted in that section, no drug has been proven to be safe and effective for the treatment of COVID-19.

        In general, patients with COVID-19 can be grouped into the following illness categories:
        • Asymptomatic or Presymptomatic Infection: Individuals who test positive for SARS-CoV-2 but have no symptoms
        • Mild Illness: Individuals who have any of various signs and symptoms (e.g., fever, cough, sore throat, malaise, headache, muscle pain) without shortness of breath, dyspnea, or abnormal imaging
        • Moderate Illness: Individuals who have evidence of lower respiratory disease by clinical assessment or imaging and a saturation of oxygen (SaO2) >93% on room air at sea level.
        • Severe Illness: Individuals who have respiratory frequency >30 breaths per minute, SaO2 ≤93% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300, or lung infiltrates >50%
        • Critical Illness: Individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction
        Asymptomatic or Presymptomatic Infection


        Asymptomatic infection can occur, although the percentage of patients who remain truly asymptomatic for the course of their infection is unknown. It is unclear at present what percentage of individuals who present with asymptomatic infection may progress to clinical disease. Some asymptomatic individuals have been reported to have objective radiographic findings consistent with COVID-19 pneumonia. Eventually, the availability of widespread testing for SARS-CoV-2 and the development of serologic assays for antibodies to the virus will help determine the true prevalence of asymptomatic and presymptomatic infections.1

        Persons who test positive for SARS-CoV-2 and who are asymptomatic should self-isolate. If they remain asymptomatic, they can discontinue isolation 7 days after the date of their first positive SARS-CoV-2 test.2 Individuals who become symptomatic should contact their health care provider for further guidance. Health care workers who test positive and are asymptomatic may obtain additional guidance from their occupational health service. See the Centers for Disease Control and Prevention COVID-19 website for detailed information.

        The Panel recommends no additional laboratory testing and no specific treatment for persons with suspected or confirmed asymptomatic or presymptomatic SARS-CoV-2 infection (AIII).
        Mild Illness


        Patients may have mild illness defined by any of various signs and symptoms (e.g., fever, cough, sore throat, malaise, headache, muscle pain) without shortness of breath or dyspnea or abnormal imaging. Most mildly ill patients can be managed in an ambulatory setting or at home through telemedicine or remote visits.

        All patients with symptomatic COVID-19 and risk factors for severe disease should be closely monitored. In some patients the clinical course may rapidly progress.3, 4

        No specific laboratory evaluations are indicated in otherwise healthy patients with mild COVID-19 disease.

        There are insufficient data to recommend either for or against any antiviral or immunomodulatory therapy in patients with COVID-19 with mild illness (AIII).
        Moderate Illness


        Moderate COVID-19 illness is defined as evidence of lower respiratory disease by clinical assessment or imaging with SpO2 >93% on room air at sea level. Given that pulmonary disease can rapidly progress in patients with COVID-19, patients with moderate COVID-19 should be admitted to a health care facility for close observation. If bacterial pneumonia or sepsis is strongly suspected, administer empiric antibiotic treatment for community-acquired pneumonia, re-evaluate daily, and if there is no evidence of bacterial infection, de-escalate or stop antibiotics.

        Most patients with moderate to severe illness will require hospitalization. Hospital infection prevention and control measures include use of personal protective equipment (PPE) for droplet and contact precautions (e.g., masks, face shields, gloves, gowns), including eye protection (e.g., face shields or goggles) and single-patient dedicated medical equipment (e.g., stethoscopes, blood pressure cuffs, thermometers).5,6 The number of individuals and providers entering the room of a patient with COVID-19 should be limited. If necessary, confirmed COVID-19 patients may be cohorted in the same room. If available, airborne infection isolation rooms (AIIRs) should be used for patients who will be undergoing any aerosol-generating procedures. During these procedures, all staff should wear N95 respirators or powered, air-purifying respirators (PAPRs) rather than a surgical mask.7

        The optimal pulmonary imaging technique for people with COVID-19 is yet to be defined. Initial evaluation may include chest x-ray, ultrasound, or if indicated, CT. Electrocardiogram (ECG) should be performed if indicated. Laboratory testing includes a complete blood count (CBC) with differential and a metabolic profile, including liver and renal function tests. Measurements of inflammatory markers such as C-reactive protein (CRP), D-dimer, and ferritin, while not part of standard care, may have prognostic value.

        There are insufficient data for the Panel to recommend either for or against any antiviral or immunomodulatory therapy in patients with COVID-19 with moderate illness (AIII).

        Clinicians can refer to the Therapeutic Options for COVID-19 Currently Under Investigation section and Tables 2a and 3a of these guidelines to review the available clinical data regarding investigational drugs being evaluated for treatment of this disease.
        Severe Illness


        Patients with COVID-19 are considered to have severe illness if they have SpO2 ≤93% on room air at sea level, respiratory rate >30, PaO2/FiO2 <300, or lung infiltrates >50%. These patients may experience rapid clinical deterioration and will likely need to undergo aerosol-generating procedures. They should be placed in AIIRs, if available. Administer oxygen therapy immediately using nasal cannula or high-flow oxygen.

        If secondary bacterial pneumonia or sepsis is suspected, administer empiric antibiotics, re-evaluate daily, and if there is no evidence of bacterial infection, de-escalate or stop antibiotics.

        Evaluation should include pulmonary imagining (chest x-ray, ultrasound, or if indicated, CT) and ECG, if indicated. Laboratory evaluation includes CBC with differential and metabolic profile, including liver and renal function tests. Measurements of inflammatory markers such as CRP, D-dimer, and ferritin, while not part of standard care, may have prognostic value.

        There are insufficient data for the Panel to recommend either for or against any antiviral or immunomodulatory therapy in patients with COVID-19 with severe illness (AIII).

        Clinicians can refer to the Therapeutic Options for COVID-19 Currently Under Investigation section and Tables 2a and 3a of these guidelines to review the available clinical data regarding drugs being evaluated for treatment of this disease.
        Critical Illness


        (For additional details, see Care of Critically Ill Patients with COVID-19.)

        COVID-19 is primarily a pulmonary disease. Severe cases may be associated with acute respiratory distress syndrome (ARDS), septic shock that may represent virus-induced distributive shock, cardiac dysfunction, elevations in multiple inflammatory cytokines that provoke a cytokine storm, and/or exacerbation of underlying co-morbidities. In addition to pulmonary disease, patients with COVID-19 may also experience cardiac, hepatic, renal, and central nervous system disease.

        Since patients with critical illness are likely to undergo aerosol-generating procedures, they should be placed in AIIRs when available.

        Most of the recommendations for the management of critically ill patients with COVID-19 are extrapolated from experience with other life-threatening infections.8 Currently, there is limited information to suggest that the critical care management of patients with COVID-19 should differ substantially from the management of other critically ill patients, although special precautions to prevent environmental contamination by SARS-CoV-2 is warranted.

        The Surviving Sepsis Campaign (SSC), an initiative supported by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, issued Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19) in March 2020.8 The Panel relied heavily on the SSC guidelines in making the recommendations in these Treatment Guidelines and gratefully acknowledges the work of the SSC COVID-19 Guidelines Panel.

        As with any patient in the intensive care unit (ICU), successful clinical management of a patient with COVID-19 depends on attention to the primary process leading to the ICU admission, but also to other comorbidities and nosocomial complications.

        There are insufficient data for the Panel to recommend either for or against any antiviral or immunomodulatory therapy in critically ill patients with COVID-19 (AIII).

        Clinicians can refer to the Therapeutic Options for COVID-19 Currently Under Investigation section and Tables 2a and 3a of these guidelines to review the available clinical data regarding drugs being evaluated for treatment of this disease.
        References
        1. Wang Y, Liu Y, Liu L, Wang X, Luo N, Ling L. Clinical outcome of 55 asymptomatic cases at the time of hospital admission infected with SARS-coronavirus-2 in Shenzhen, China. J Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32179910.
        2. Centers for Disease Control and Prevention. Discontinuation of isolation for persons with COVID-19 not in healthcare settings (interim guidance). 2020. Available at: https://www.cdc.gov/coronavirus/2019...-patients.html. Accessed April 8, 2020.
        3. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32109013.
        4. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31986264.
        5. Centers for Disease Control and Prevention. Interim infection prevention and control recommendations for patients with suspected or confirmed coronavirus disease 2019 (COVID-19) in healthcare settings. 2020. Available at: https://www.cdc.gov/coronavirus/2019...endations.html. Accessed April 8, 2020.
        6. Centers for Disease Control and Prevention. Strategies to optimize the supply of PPE and equipment. 2020. Available at: https://www.cdc.gov/coronavirus/2019...egy/index.html. Accessed April 8, 2020.
        7. Centers for Disease Control and Prevention. Approved respirator standards. 2006. Available at: https://www.cdc.gov/niosh/npptl/stan...r/default.html. Accessed April 8, 2020.
        8. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32224769.

        https://www.covid19treatmentguidelin...t-of-covid-19/

        Comment


        • #5

          Special Considerations in Pregnancy and Post-Delivery


          There is current guidance from the Centers for Disease Control and Prevention (CDC), the American College of Obstetricians and Gynecologists (ACOG), and the Society for Maternal Fetal Medicine on the management of pregnant patients with COVID-19.1-4 This section of the Treatment Guidelines complements that guidance and focuses on considerations regarding management of COVID-19 in pregnancy.

          Limited information is available regarding the effect of COVID-19 on obstetric or neonatal outcomes. Initial reports of COVID-19 disease acquired in the third trimester were largely reassuring, but most data are limited to case reports and case series.5,6 In one of the larger series from Wuhan, China, pregnant women did not appear to be at risk for more severe disease.7 Among 147 pregnant women with COVID-19 (64 confirmed cases, 82 suspected cases, and 1 case of asymptomatic infection), 8% had severe disease and 1% had critical disease. In comparison, in the general population of persons with COVID-19, 13.8% had severe disease and 6.1% had critical disease.8 While data are still emerging, the US experience has been similar to date. 9

          ACOG has developed algorithms to evaluate pregnant outpatients with suspected or confirmed COVID-19.10 As with non-pregnant patients, a wide range of clinical manifestations of the disease occur, from mild symptoms that can be managed with supportive care at home to severe disease and respiratory failure requiring intensive care unit admission. As with other patients, in the pregnant patient with symptoms compatible with COVID-19, the illness severity, underlying co-morbidities, and clinical status should all be assessed to determine whether in-person evaluation for potential hospitalization is needed.

          If hospitalization is indicated, ideally the care should be provided in a facility that has the capability to conduct close maternal and fetal monitoring. The principles of management of COVID-19 in the pregnant patient may include:
          • Fetal and uterine contraction monitoring
          • Individualized delivery planning
          • A team-based approach with multispecialty consultation.

          Other recommendations, as outlined for the non-pregnant patient, will also apply in pregnancy.
          Timing of Delivery:
          • In most cases, the timing of delivery should be dictated by obstetric indications rather than maternal diagnosis of COVID-19. For women with suspected or confirmed COVID-19 early in pregnancy who recover, no alteration to the usual timing of delivery is indicated.
          • For women with suspected or confirmed COVID-19 in the third trimester, it is reasonable to attempt to postpone delivery (if no other medical indications arise) until a negative test result is obtained or quarantine restrictions are lifted in an attempt to avoid virus transmission to the neonate.
          • In general, a diagnosis of COVID-19 in pregnancy is not an indication for early delivery.11
          • Based on limited data on primarily cesarean deliveries, there appears to be no risk of vertical transmission of SARS-CoV-2 via the transplacental route.11
          Management of COVID-19 in the Setting of Pregnancy:
          • There are no Food and Drug Administration-approved medications for the treatment of COVID-19.
          • Most clinical trials to date have excluded pregnant and lactating women.
          • Decisions regarding the use of drugs approved for other indications or investigational agents to treat COVID-19 must be made with shared decision-making, considering the safety of the medication and the risk and seriousness of maternal disease (see Therapeutic Options for COVID-19 Currently Under Investigation and Considerations for Certain Concomitant Medications in Patients with COVID-19).
          • Involvement of a multidisciplinary team in these discussions, including, among others, specialists in obstetrics, maternal-fetal medicine, and pediatrics, is recommended.
          • Enrollment of pregnant and lactating women in clinical trials (if eligible) is encouraged.
          Post-Delivery:
          • Currently, CDC recommends temporarily separating newborn infants from mothers who are persons under investigation (PUI) for SARS-CoV-2 or who have COVID-19 because of concern for transmission of SARS-CoV-2 to the infant via respiratory droplets.
          • ACOG supports breastfeeding for infants. They recommend that, for women who are PUI or confirmed to have SARS-CoV-2 infection, the decision about whether and how to start or continue breastfeeding be made by the mother in coordination with her family and health care practitioners.11
          • CDC has developed interim guidance on breastfeeding, recommending that women who intend to breastfeed and who are temporarily separated from their infants express their breastmilk, ideally from a dedicated pump, practice good hand hygiene before and after pumping, and consider having a healthy person feed the infant.
          • CDC advises that women with COVID-19 who choose to room-in with their infants and feed them at the breast should practice good hand hygiene and wear a facemask to prevent transmission of the virus to the infant via respiratory droplets during breastfeeding.1 SARS-CoV-2 has not been isolated from breast milk.5
          References
          1. Centers for Disease Control and Prevention. Interim considerations for infection prevention and control of coronavirus disease 2019 (COVID-19) in inpatient obstetric healthcare settings. 2020. Available at: https://www.cdc.gov/coronavirus/2019...-guidance.html. Accessed April 2, 2020.
          2. The American College of Obstetricians and Gynecologists. Practice advisory: novel coronavirus 2019 (COVID-19). 2020. Available at: https://www.acog.org/clinical/clinic...ronavirus-2019.
          3. Society for Maternal Fetal Medicine. Coronavirus (COVID-19) and pregnancy: what maternal fetal medicine subspecialists need to know. 2020. Available at: https://www.smfm.org/covid19. Accessed April 8, 2020.
          4. Rasmussen SA, Smulian JC, Lednicky JA, Wen TS, Jamieson DJ. Coronavirus disease 2019 (COVID-19) and pregnancy: what obstetricians need to know. Am J Obstet Gynecol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32105680.
          5. Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet. 2020;395(10226):809-815. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32151335.
          6. Liu Y, Chen H, Tang K, Guo Y. Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy. J Infect. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32145216.
          7. Breslin N, Baptiste C, Miller R, et al. COVID-19 in pregnancy: early lessons. American Journal of Obstetrics & Gynecology MFM. 2020. [In Press]. Available at: https://www.sciencedirect.com/scienc...410?via%3Dihub.
          8. World Health Organization. Report of the WHO-China joint mission on coronavirus disease 2019 (COVID-19). 2020. Available at: https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf. Accessed March 27, 2020.
          9. Breslin N, Baptiste C, Gyamfi-Bannerman C, et al. COVID-19 infection among asymptomatic and symptomatic pregnant women: Two weeks of confirmed presentations to an affiliated pair of New York City hospitals. Am J Obstet Gynecol MFM. 2020:100118. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32292903.
          10. The American College of Obstetricians and Gynecologists. Outpatient assessment and management for pregnant women with suspected or confirmed novel coronavirus (COVID-19). 2020. Available at: https://www.smfm.org/covid19/. Accessed April 2, 2020.
          11. The American College of Obstetricians and Gynecologists. COVID-19 frequently asked questions for obstetricians-gynecologists, obstetrics. 2020. Available at: https://www.acog.org/clinical-information/physician-faqs/covid-19-faqs-for-ob-gyns-obstetrics. Accessed April 2, 2020.

          https://www.covid19treatmentguidelin...post-delivery/


          Comment


          • #6

            Special Considerations in Children


            Data on disease severity and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children are limited. Overall, several large epidemiologic studies suggest that disease manifestations are substantially less severe in children than in adults, although there are reports of children with COVID-19 requiring intensive care unit (ICU)-level care.1-6 Preliminary data from the Centers for Disease Control and Prevention also show that hospitalization rates and ICU admission rates for children are lower than for adults. Severe cases of COVID-19 in children were associated with younger age and underlying conditions, although a significant number of the pediatric cases did not have complete data available at the time of the preliminary report. Without widespread testing, including for mild symptoms, the true incidence of severe disease in children is unclear. Data on perinatal vertical transmission to neonates are limited to small case series with conflicting results; some studies have demonstrated lack of transmission, whereas others have not been able to definitively rule out this possibility.7-9

            No specific data are available establishing risk factors for severe COVID-19 disease in children. Based on adult data and extrapolation from other pediatric respiratory viruses, severely immunocompromised children and those with underlying cardiopulmonary disease may be at higher risk for severe disease. Children with risk factors recognized in adults, including obesity, diabetes, and hypertension, may also be at risk, although there are no published data supporting this association and insufficient data to guide therapy. As data emerge on risk factors for severe disease, it may be possible to provide more directed guidance for specific populations at high risk for COVID-19 and to tailor treatment recommendations accordingly.

            As above, there are insufficient data to recommend for or against the use of specific antivirals or immunomodulatory agents for the treatment of COVID-19 in pediatric patients. Disease classifications outlined in this document primarily focus on COVID-19 in adults. Several different classification schemes have been used to stratify patients with COVID-19 and other respiratory infections based on illness severity and/or primary site of infection. General considerations, such as underlying conditions, disease severity, and potential for drug toxicity or drug interactions, may inform management decisions on a case-by-case basis. Enrollment of children in clinical trials should be prioritized if trials are available. A number of drugs are being investigated for the treatment of COVID-19 in adults; clinicians can refer to Therapeutic Options for COVID-19 Currently Under Investigation to review special considerations for use of these drugs in children and refer toTable 2b for dosing recommendations in children.
            References
            1. Sun D, Li H, Lu XX, et al. Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study. World J Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32193831.
            2. Cui Y, Tian M, Huang D, et al. A 55-day-old female infant infected with COVID 19: presenting with pneumonia, liver injury, and heart damage. J Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32179908.
            3. Cai J, Xu J, Lin D, et al. A Case Series of children with 2019 novel coronavirus infection: clinical and epidemiological features. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32112072.
            4. Kam KQ, Yung CF, Cui L, et al. A well infant with coronavirus disease 2019 (COVID-19) with high viral load. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32112082.
            5. Dong Y, Mo X, Hu Y, et al. Epidemiological characteristics of 2,143 pediatric patients with 2019 coronavirus disease in China. Pediatrics. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32179660.
            6. Centers for Disease Control and Prevention. Coronavirus disease 2019 in children—United States, February 12–April 2, 2020. 2020. Available at: https://www.cdc.gov/mmwr/volumes/69/wr/mm6914e4.htm.
            7. Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet. 2020;395(10226):809-815. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32151335.
            8. Fan C, Lei D, Fang C, et al. Perinatal transmission of COVID-19 associated SARS-CoV-2: should we worry? Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32182347.
            9. Zeng L, Xia S, Yuan W, et al. Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China. JAMA Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32215598.

            https://www.covid19treatmentguidelin...view/children/

            Comment


            • #7

              Care of Critically Ill Patients with COVID-19
              Infection Control:
              • For health care workers who are performing aerosol-generating procedures on patients with COVID-19, the COVID-19 Treatment Guidelines Panel (the Panel) recommends using fit-tested respirators (N-95 respirators) or powered air-purifying respirators rather than surgical masks, in addition to other personal protective equipment (i.e., gloves, gown, and eye protection such as a face shield or safety goggles) (AIII).
              • The Panel recommends that endotracheal intubation for patients with COVID-19 be done by health care providers with extensive airway management experience, if possible (AIII).
              • The Panel recommends that intubation be achieved by video laryngoscopy, if possible (CIII).
              Hemodynamic Support:
              • The Panel recommends norepinephrine as the first-choice vasopressor (AII).
              • The Panel recommends using dobutamine in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and the use of vasopressor agents (BII).
              Ventilatory Support:
              • For adults with COVID-19 and acute hypoxemic respiratory failure despite conventional oxygen therapy, the Panel recommends high-flow nasal cannula (HFNC) oxygen over noninvasive positive pressure ventilation (NIPPV) (BI).
              • In the absence of an indication for endotracheal intubation, the Panel recommends a closely monitored trial of NIPPV for adults with COVID-19 and acute hypoxemic respiratory failure for whom HFNC is not available (BIII).
              • For adults with COVID-19 who are receiving supplemental oxygen, the Panel recommends close monitoring for worsening of respiratory status and recommends early intubation by an experienced practitioner in a controlled setting (AII).
              • For mechanically ventilated adults with COVID-19 and acute respiratory distress syndrome (ARDS), the Panel recommends using low tidal volume (Vt) ventilation (Vt 4–8 mL/kg of predicted body weight) over higher tidal volumes (Vt >8 mL/kg) (AI).
              • For mechanically ventilated adults with COVID-19 and refractory hypoxemia despite optimized ventilation, the Panel recommends prone ventilation for 12 to 16 hours per day over no prone ventilation (BII).
              • For mechanically ventilated adults with COVID-19, severe ARDS, and hypoxemia despite optimized ventilation and other rescue strategies, the Panel recommends a trial of inhaled pulmonary vasodilator as a rescue therapy; if no rapid improvement in oxygenation is observed, the patient should be tapered off treatment (CIII).
              • There are insufficient data to recommend either for or against the routine use of extracorporeal membrane oxygenation for patients with COVID-19 and refractory hypoxemia (BIII).
              Drug Therapy:
              • There are insufficient data for the Panel to recommend either for or against any antiviral or immunomodulatory therapy in patients with severe COVID-19 disease (AIII).
              • In patients with COVID-19 and severe or critical illness, there are insufficient data to recommend empiric broad-spectrum antimicrobial therapy in the absence of another indication (BIII).
              • The Panel recommends against the routine use of systemic corticosteroids for the treatment of mechanically ventilated patients with COVID-19 without ARDS (BIII).
              • In mechanically ventilated adults with COVID-19 and ARDS, there are insufficient data to recommend either for or against corticosteroid therapy in the absence of another indication (CI).
              • In COVID-19 patients with refractory shock, low-dose corticosteroid therapy is preferred over no corticosteroid therapy (BII).

              https://www.covid19treatmentguidelin...critical-care/

              Comment


              • #8

                Laboratory Diagnosis

                Recommendations:
                • For intubated and mechanically ventilated adults who are suspected to have coronavirus disease 2019 (COVID-19) but who do not have a confirmed diagnosis:
                  • The COVID-19 Treatment Guidelines Panel (the Panel) recommends obtaining lower respiratory tract samples to establish a diagnosis of COVID-19 over upper respiratory tract (nasopharyngeal or oropharyngeal) samples (BII).
                  • The Panel recommends obtaining endotracheal aspirates over bronchial wash or bronchoalveolar lavage (BAL) samples when obtaining lower respiratory samples to establish a diagnosis of COVID-19 (BII).
                Rationale


                SARS-CoV-2 poses several diagnostic challenges, including potentially discordant shedding of virus from the upper versus lower respiratory tract. COVID-19 diagnosis is currently based on using a reverse transcriptase polymerase chain reaction (RT-PCR) assay to detect viral RNA in respiratory samples. The high specificity of RT-PCR removes the need for lower respiratory tract samples to diagnose COVID-19 when a nasopharyngeal swab is positive for a patient with recent onset of the disease. Lower respiratory tract specimens are considered by some experts to have higher yield, due to high viral load, consistent with what has been observed for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).1-7 Thus, lower respiratory tract samples should be obtained whenever possible if there is diagnostic uncertainty regarding COVID-19.

                However, BAL and sputum induction are aerosol-generating procedures and should be performed only with careful consideration of the risk to staff of aerosol generation. Endotracheal aspirates appear to carry a lower risk of aerosolization than BAL and are thought by some experts to have comparable sensitivity and specificity to BAL specimens.
                References
                1. Chan PK, To WK, Ng KC, et al. Laboratory diagnosis of SARS. Emerg Infect Dis. 2004;10(5):825-831. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15200815.
                2. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32159775.
                3. Centers for Disease Control and Prevention. Evaluating and Testing Persons for Coronavirus Disease 2019 (COVID-19). 2020; https://www.cdc.gov/coronavirus/2019-nCoV/hcp/clinical-criteria.html. Accessed April 8, 2020.
                4. Hase R, Kurita T, Muranaka E, Sasazawa H, Mito H, Yano Y. A case of imported COVID-19 diagnosed by PCR-positive lower respiratory specimen but with PCR-negative throat swabs. Infect Dis (Lond). 2020:1-4. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32238024.
                5. Tang P, Louie M, Richardson SE, et al. Interpretation of diagnostic laboratory tests for severe acute respiratory syndrome: the Toronto experience. CMAJ. 2004;170(1):47-54. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14707219.
                6. Memish ZA, Al-Tawfiq JA, Makhdoom HQ, et al. Respiratory tract samples, viral load, and genome fraction yield in patients with Middle East respiratory syndrome. J Infect Dis. 2014;210(10):1590-1594. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24837403.
                7. Centers for Disease Control and Prevention. Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons Under Investigation (PUIs) for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) – Version 2.1. 2020; https://www.cdc.gov/coronavirus/mers/guidelines-clinical-specimens.html. Accessed April 8, 2020.

                https://www.covid19treatmentguidelin...ory-diagnosis/


                Comment


                • #9

                  Hemodynamics


                  For the most part, these hemodynamic recommendations are similar to those previously published in the Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Ultimately, COVID-19 patients who require fluid resuscitation or hemodynamic management of shock should be treated and managed identically to those with septic shock.1

                  COVID-19 patients who require fluid resuscitation or hemodynamic management of shock should be treated and managed for septic shock in accordance with other published guidelines, with the following exceptions.
                  Recommendation:
                  • For adults with COVID-19 and shock, the COVID-19 Treatment Guidelines Panel (the Panel) recommends using dynamic parameters, skin temperature, capillary refilling time, and/or lactate over static parameters to assess fluid responsiveness (BII).
                  Rationale


                  No direct evidence addresses the optimal resuscitation strategy for patients with COVID-19 and shock. In a systematic review and meta-analysis of 13 non-COVID-19 randomized clinical trials (n = 1,652),2 dynamic assessment to guide fluid therapy reduced mortality (risk ratio 0.59; 95% confidence interval [CI], 0.42–0.83), intensive care unit (ICU) length of stay (mean duration -1.16 days; 95% CI, -1.97 to -0.36), and duration of mechanical ventilation (weighted mean difference -2.98 hours; 95% CI, -5.08 to -0.89). Dynamic parameters used in these trials included stroke volume variation (SVV), pulse pressure variation (PPV), and stroke volume change with passive leg raise or fluid challenge. Passive leg raising, followed by PPV and SVV, appears to predict fluid responsiveness with the highest accuracy.3 The static parameters included components of early goal-directed therapy (e.g., central venous pressure, mean arterial pressure).

                  Resuscitation of non-COVID-19 patients with shock based on serum lactate levels has been summarized in a systematic review and meta-analysis of seven randomized clinical trials (n = 1,301). Compared with central venous oxygen saturation (ScVO2)-guided therapy, early lactate clearance-directed therapy was associated with a reduction in mortality (relative ratio 0.68; 95% CI, 0.56–0.82), shorter length of ICU stay (mean difference -1.64 days; 95% CI, -3.23 to -0.05), and shorter duration of mechanical ventilation (mean difference -10.22  hours; 95% CI, -15.94 to -4.50).4
                  Recommendation:
                  • For the acute resuscitation of adults with COVID-19 and shock, the Panel recommends using buffered/balanced crystalloids over unbalanced crystalloids (BII).
                  Rationale


                  A pragmatic randomized trial that compared balanced and unbalanced crystalloids in 15,802 critically ill adults found a lower rate of a composite outcome, including death, new renal-replacement therapy, or persistent renal dysfunction (odds ratio [OR] 0.90; 95% CI, 0.82–0.99; P = 0.04).5 The subset of sepsis patients in this trial (n = 1,641) was found to have a lower mortality (adjusted odds ratio 0.74; 95% CI, 0.59–0.93; P = 0.01), as well as fewer days requiring vasopressors and renal replacement therapy.6 A subsequent meta-analysis of 21 randomized controlled trials (n = 20,213) that compared balanced crystalloids to 0.9% saline for resuscitation of critically ill adults and children reported nonsignificant differences in hospital mortality (OR 0.91; 95% CI, 0.83–1.01) and acute kidney injury (OR 0.92; 95% CI, 0.84–1.00).7
                  Recommendation:
                  • For the acute resuscitation of adults with COVID-19 and shock, the Panel recommends against the initial use of albumin for resuscitation (BI).
                  Rationale


                  A meta-analysis of 20 non-COVID-19 randomized controlled trials (n = 13,047) that compared the use of albumin or fresh-frozen plasma to crystalloids in critically ill patients found no difference in all-cause mortality,8 while a meta-analysis of 17 non-COVID-19 randomized controlled trials (n = 1,977) that compared the use of albumin to crystalloids specifically in patients with sepsis observed a reduction in mortality (OR 0.82; 95% CI, 0.67–1.0; P = 0.047).9 Given the higher cost of albumin and the lack of a definitive clinical benefit, the Panel suggests avoiding the use of albumin for initial, routine resuscitation of patients with COVID-19 and shock.
                  Additional Recommendations Based on General Principles of Critical Care:
                  • The Panel recommends against using hydroxyethyl starches for intravascular volume replacement in patients with sepsis or septic shock (AI).
                  • The Panel recommends norepinephrine as the first-choice vasopressor (AII). The Panel recommends adding either vasopressin (up to 0.03 U/min) (BII) or epinephrine (CII) to norepinephrine to raise mean arterial pressure to target, or adding vasopressin (up to 0.03 U/min) (CII) to decrease norepinephrine dosage.
                  • The Panel recommends using dopamine as an alternative vasopressor agent to norepinephrine only in certain patients (e.g., patients with low risk of tachyarrhythmias and absolute or relative bradycardia) (BII).
                  • The Panel recommends against using low-dose dopamine for renal protection (BII).
                  • The Panel recommends using dobutamine in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and the use of vasopressor agents (BII).
                  • The Panel recommends that all patients who require vasopressors have an arterial catheter placed as soon as practical, if resources are available (BIII).
                  • For adults with COVID-19 and refractory shock, the Panel recommends using low-dose corticosteroid therapy (“shock-reversal”) over no corticosteroid (BII).
                    • A typical corticosteroid regimen in septic shock is intravenous hydrocortisone 200 mg per day administered either as an infusion or intermittent doses. The duration of hydrocortisone therapy is usually a clinical decision.
                  References
                  1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486-552. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28098591.
                  2. Bednarczyk JM, Fridfinnson JA, Kumar A, et al. Incorporating dynamic assessment of fluid responsiveness into goal-directed therapy: a systematic review and meta-analysis. Crit Care Med. 2017;45(9):1538-1545. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28817481.
                  3. Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will this hemodynamically unstable patient respond to a bolus of intravenous fluids? JAMA. 2016;316(12):1298-1309. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27673307.
                  4. Pan J, Peng M, Liao C, Hu X, Wang A, Li X. Relative efficacy and safety of early lactate clearance-guided therapy resuscitation in patients with sepsis: a meta-analysis. Medicine (Baltimore). 2019;98(8):e14453. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30813144.
                  5. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378(9):829-839. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29485925.
                  6. Brown RM, Wang L, Coston TD, et al. Balanced crystalloids versus saline in sepsis. a secondary analysis of the SMART clinical trial. Am J Respir Crit Care Med. 2019;200(12):1487-1495. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31454263.
                  7. Antequera Martin AM, Barea Mendoza JA, Muriel A, et al. Buffered solutions versus 0.9% saline for resuscitation in critically ill adults and children. Cochrane Database Syst Rev. 2019;7:CD012247. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31334842.
                  8. Lewis SR, Pritchard MW, Evans DJ, et al. Colloids versus crystalloids for fluid resuscitation in critically ill people. Cochrane Database Syst Rev. 2018;8:CD000567. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30073665.
                  9. AP, Dan A, McCaffrey J, Finfer S. The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis. Crit Care Med. 2011;39(2):386-391. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21248514.

                  https://www.covid19treatmentguidelin.../hemodynamics/


                  Comment


                  • #10

                    Oxygenation and Ventilation


                    For mechanically ventilated patients, the recommendations below emphasize well-described and documented recommendations from the Surviving Sepsis Campaign (SSC) Guidelines for adult sepsis, pediatric sepsis, and COVID-19, which provide more details about management and the data supporting the recommendations.
                    Recommendations:
                    • For adults with COVID-19 who are receiving supplemental oxygen, the COVID-19 Treatment Guidelines Panel (the Panel) recommends close monitoring for worsening respiratory status and recommends early intubation by an experienced practitioner in a controlled setting (AII).
                    • For adults with COVID-19 and acute hypoxemic respiratory failure despite conventional oxygen therapy, the Panel recommends high-flow nasal cannula (HFNC) oxygen over noninvasive positive pressure ventilation (NIPPV) (BI).
                    • In the absence of an indication for endotracheal intubation, the Panel recommends a closely monitored trial of NIPPV for adults with COVID-19 and acute hypoxemic respiratory failure for whom HFNC is not available (BIII).
                    Rationale


                    Hypoxemia is common in hospitalized patients with COVID-19. Criteria for admission to the hospital, intensive care unit (ICU) admission, and mechanical ventilation differ in various countries. In some hospitals in the United States, >25% of hospitalized patients require ICU care, mostly due to acute respiratory failure.1-5

                    In adults with COVID-19 and acute hypoxemic respiratory failure, conventional oxygen therapy may be insufficient to meet the oxygen needs of the patient. Options include HFNC, NIPPV, or intubation and invasive mechanical ventilation.

                    HFNC and NIPPV are preferable to conventional oxygen therapy based on data from non-COVID-19 clinical trials and meta-analyses that showed reductions in the need for therapeutic escalation and the need for intubation.6, 7

                    HFNC is preferred over NIPPV in patients with acute hypoxemic respiratory failure based on data from an unblinded clinical trial that was performed prior to the COVID-19 pandemic. This trial found more ventilator-free days with HFNC than with conventional oxygen therapy or NIPPV (24 days vs. 22 days vs. 19 days, respectively; P = 0.02) and lower 90-day mortality with HFNC than with both conventional oxygen therapy (hazard ratio [HR] 2.01; 95% confidence interval [CI], 1.01–3.99) and NIPPV (HR 2.50; 95% CI, 1.31–4.78).8

                    In the subgroup of more severely hypoxemic patients with PaO2/FiO2 ≤200, HFNC reduced the rate of intubation compared to conventional oxygen therapy or NIPPV (HRs 2.07 and 2.57, respectively). These findings were corroborated in a meta-analysis that showed a lower likelihood of intubation (odds ratio [OR] 0.48; 95% CI, 0.31–0.73) and ICU mortality (OR 0.36; 95% CI, 0.20–0.63) with HFNC than with NIPPV.9 In situations where the options for respiratory support are limited, reducing the need for intubation may be particularly important.

                    It is essential that hypoxemic patients with COVID-19 be monitored closely for signs of respiratory decompensation. To ensure the safety of both the patient and health care workers, intubation should be performed in a controlled setting by an experienced practitioner.

                    Early intubation may be particularly appropriate when patients have additional acute organ dysfunction or chronic comorbidities, or when HFNC and NIPPV are not available. NIPPV has a high failure rate in both patients with non-COVID-19 viral pneumonia10, 11 and patients with acute respiratory distress syndrome (ARDS).12, 13 NIPPV may generate aerosol spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and thus increase nosocomial transmission of the infection.14, 15 It remains uncertain whether HFNC results in less risk of nosocomial SARS-CoV-2 transmission due to aerosol generation.

                    The use of supplemental oxygen in adults with COVID-19 has not been studied, but indirect evidence from other critical illnesses suggests the optimal oxygen target is an SpO2 between 92% and 96%:
                    • A meta-analysis of 25 randomized controlled trials found that a liberal oxygen strategy (median SpO2 96%) was associated with increased hospital mortality (relative risk 1.21; 95% CI, 1.03–1.43).16
                    • The LOCO2 randomized controlled trial compared a conservative oxygen strategy (target SpO2 88% to 92%) to a liberal oxygen strategy (target SpO2 ≥96%).17 The trial was stopped early due to futility. Mortality was increased among those who received the conservative oxygen therapy at Day 28 (risk difference +8%; 95% CI, -5% to +21%) and Day 90 (risk difference +14%; 95% CI, +0.7% to +27%). These differences would be important if they were real, but the study was too small to definitively confirm or exclude an effect.
                    Recommendations:
                    • For mechanically ventilated adults with COVID-19 and ARDS:
                      • The Panel recommends using low tidal volume (Vt) ventilation (Vt 4–8 mL/kg of predicted body weight) over higher tidal volumes (Vt >8 mL/kg) (AI).
                      • The Panel recommends targeting plateau pressures of <30 cm H2O (AII).
                      • The Panel recommends using a conservative fluid strategy over a liberal fluid strategy (BII).
                      • The Panel recommends against the routine use of inhaled nitric oxide (AI).
                    Rationale


                    Currently there is no evidence that ventilator management of patients with ARDS due to COVID-19 should differ from management of patients with viral pneumonia due to influenza or other respiratory viruses.
                    Recommendations:
                    • For mechanically ventilated adults with COVID-19 and moderate-to-severe ARDS:
                      • The Panel recommends using a higher positive end-expiratory pressure (PEEP) strategy over a lower PEEP strategy (BII).
                      • For mechanically ventilated adults with COVID-19 and refractory hypoxemia despite optimizing ventilation, the Panel recommends prone ventilation for 12 to 16 hours per day over no prone ventilation (BII).
                    Rationale


                    Proning is a recommended strategy in non-COVID-19-related ARDS for improving oxygenation and reducing the heterogeneity of lung ventilation. Proning has been used to treat patients with COVID-19, although there is currently not enough clinical experience with this strategy to draw conclusions about its effect on long-term outcomes.18 However, even in centers that are experienced in prone ventilation, proning requires multiple staff members to safely turn the patient and prevent dislodgement of the endotracheal tube, as well as other tubes and catheters. Each staff member should wear the recommended personal protective equipment (PPE). Depending on local resources, especially when PPE may be in short supply, the risk of COVID-19 exposure during the process of proning may outweigh the benefit of proning to the patient.
                    Recommendations:
                    • The Panel recommends using, as needed, intermittent boluses of neuromuscular blocking agents (NMBA), or continuous NMBA infusion, to facilitate protective lung ventilation (BIII).
                      • In the event of persistent ventilator dyssynchrony, which places the patient at risk for ventilator lung injury, the need for ongoing deep sedation, prone ventilation, or persistently high plateau pressures, the Panel recommends using a continuous NMBA infusion for up to 48 hours as long as patient anxiety and pain can be adequately monitored and controlled (BIII).
                    Rationale


                    The recommendation for intermittent boluses of NMBA or continuous infusion of NMBA to facilitate lung protection may require a health care provider to enter the patient’s room more frequently for close clinical monitoring. Thus, in some situations the risks of COVID-19 exposure and the use of PPE for each entry may outweigh the benefit of NMBA treatment.
                    Recommendations:
                    • For mechanically ventilated adults with COVID-19, severe ARDS, and hypoxemia despite optimized ventilation and other rescue strategies:
                      • The Panel recommends using recruitment maneuvers rather than not using recruitment maneuvers (CII).
                      • If recruitment maneuvers are used, the Panel recommends against using staircase (incremental PEEP) recruitment maneuvers (AII).
                      • The Panel recommends a trial of inhaled pulmonary vasodilator as a rescue therapy; if no rapid improvement in oxygenation is observed, the treatment should be tapered off (CIII).
                    References
                    1. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32109013.
                    2. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32091533.
                    3. Arentz M, Yim E, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients With COVID-19 in Washington State. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32191259.
                    4. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32224769.
                    5. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32031570.
                    6. Xu XP, Zhang XC, Hu SL, et al. Noninvasive ventilation in acute hypoxemic nonhypercapnic respiratory failure: a systematic review and meta-analysis. Crit Care Med. 2017;45(7):e727-e733. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28441237.
                    7. Zhao H, Wang H, Sun F, Lyu S, An Y. High-flow nasal cannula oxygen therapy is superior to conventional oxygen therapy but not to noninvasive mechanical ventilation on intubation rate: a systematic review and meta-analysis. Crit Care. 2017;21(1):184. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28701227.
                    8. Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015;372(23):2185-2196. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25981908.
                    9. Ni YN, Luo J, Yu H, Liu D, Liang BM, Liang ZA. The effect of high-flow nasal cannula in reducing the mortality and the rate of endotracheal intubation when used before mechanical ventilation compared with conventional oxygen therapy and noninvasive positive pressure ventilation. A systematic review and meta-analysis. Am J Emerg Med. 2018;36(2):226-233. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28780231.
                    10. Alraddadi BM, Qushmaq I, Al-Hameed FM, et al. Noninvasive ventilation in critically ill patients with the Middle East respiratory syndrome. Influenza Other Respir Viruses. 2019;13(4):382-390. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30884185.
                    11. Esquinas AM, Egbert Pravinkumar S, Scala R, et al. Noninvasive mechanical ventilation in high-risk pulmonary infections: a clinical review. Eur Respir Rev. 2014;23(134):427-438. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25445941.
                    12. He H, Sun B, Liang L, et al. A multicenter RCT of noninvasive ventilation in pneumonia-induced early mild acute respiratory distress syndrome. Crit Care. 2019;23(1):300. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31484582.
                    13. Antonelli M, Conti G, Moro ML, et al. Predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study. Intensive Care Med. 2001;27(11):1718-1728. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11810114.
                    14. Tran K, Cimon K, Severn M, Pessoa-Silva CL, Conly J. Aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review. PLoS One. 2012;7(4):e35797. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22563403.
                    15. Yu IT, Xie ZH, Tsoi KK, et al. Why did outbreaks of severe acute respiratory syndrome occur in some hospital wards but not in others? Clin Infect Dis. 2007;44(8):1017-1025. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17366443.
                    16. Chu DK, Kim LH, Young PJ, et al. Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis. Lancet. 2018;391(10131):1693-1705. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29726345.
                    17. Barrot L, Asfar P, Mauny F, et al. Liberal or conservative oxygen therapy for acute respiratory distress syndrome. N Engl J Med. 2020;382(11):999-1008. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32160661.
                    18. Pan C, Chen L, Lu C, et al. Lung recruitability in SARS-CoV-2 associated acute respiratory distress syndrome: a single-center, observational study. Am J Respir Crit Care Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32200645.

                    https://www.covid19treatmentguidelin...d-ventilation/


                    Comment


                    • #11

                      Pharmacologic Interventions

                      Recommendations:
                      • There are insufficient data for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against any antiviral or immunomodulatory therapy in COVID-19 patients with severe disease (AIII).
                      • There are insufficient data for the Panel to recommend either for or against the use of interleukin 6 (IL-6) antagonists (e.g., sarilumab, siltuximab, tocilizumab) for the treatment of COVID-19 (AIII).
                      Rationale


                      IL-6 is a pleiotropic, pro-inflammatory cytokine produced by a variety of cell types, including lymphocytes, monocytes, and fibroblasts. Infection by the related SARS-CoV induces a dose-dependent production of IL-6 from bronchial epithelial cells.1

                      Elevations in IL-6 levels may be an important mediator when severe systemic inflammatory responses occur in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. COVID-19-associated systemic inflammation and hypoxic respiratory failure is associated with heightened cytokine release as indicated by elevated blood levels of IL-6 and C-reactive protein, but typically not procalcitonin.

                      There are no data from randomized clinical trials or large observational cohort studies describing the efficacy of tocilizumab among patients with COVID-19. There are anecdotal reports of improved oxygenation in patients with COVID-19, systemic inflammation, and hypoxic respiratory failure.

                      The primary laboratory abnormalities reported with tocilizumab treatment are elevated levels of liver enzymes that appear to be dose dependent. Neutropenia or thrombocytopenia are uncommon. Additional adverse events, such as risk for serious infections (e.g., tuberculosis, other bacterial pathogens), have been reported only in the context of continuous dosing of tocilizumab.2-7

                      Clinicians have used tocilizumab for desperately ill patients. The results of ongoing trials will enable clinicians to make evidence-based decisions about whether to use this drug and how to best use it.
                      Recommendations:
                      • The Panel recommends against the routine use of systemic corticosteroids for the treatment of mechanically ventilated patients with COVID-19 without acute respiratory distress syndrome (ARDS) (BIII).
                      • In mechanically ventilated adults with COVID-19 and ARDS, there are insufficient data to recommend either for or against corticosteroid therapy in the absence of another indication (CI).
                      Rationale


                      No randomized clinical trials of corticosteroid use in patients with COVID-19, including those with severe disease, have been performed.

                      Cytokine elevations have been described in patients with severe COVID-19 pneumonia; thus, clinicians have used corticosteroids to treat severe COVID-19.8, 9 In addition, the anti-inflammatory properties of corticosteroids may help suppress the inflammatory and cytokine-related lung injury that is characteristic of ARDS.

                      Prior experience with influenza and other coronaviruses may be relevant. A recent Cochrane analysis of influenza pneumonia demonstrated increased mortality and increased incidence of hospital-acquired pneumonia (HAP) in patients who were administered corticosteroids.10 The analysis was confounded by study heterogeneity, including different dosage regimens and different durations of therapy for corticosteroid interventions.

                      For Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), and influenza, some studies have demonstrated an association between corticosteroid use and delayed viral clearance.11-13

                      Limited data have been published from uncontrolled studies that used varying doses and durations of corticosteroid therapy for COVID-19. A recent retrospective series of patients with COVID-19 and associated ARDS observed, in an unadjusted analysis, a decrease in mortality (hazard ratio 0.38; 95% confidence interval, 0.20–0.72) with methylprednisolone, but there were confounding factors in this analysis.14

                      In the absence of ARDS, the routine use of corticosteroids is not recommended, although patients with COVID-19 may have other indications to receive corticosteroids, including refractory shock or myocarditis.10,15

                      Clinicians have used corticosteroids in severe and critical COVID-19.14 The results of ongoing trials will enable clinicians to make evidence-based decisions about whether to use this drug and will help define the optimal timing, dose, and duration of corticosteroid therapy in patients with COVID-19, including those with ARDS (a list of these clinical trials is available on ClinicalTrials.gov).
                      Recommendations:
                      • In patients with COVID-19 and severe or critical illness, there are insufficient data to recommend empiric broad-spectrum antimicrobial therapy in the absence of another indication (BIII).
                      • If antimicrobials are initiated, the Panel recommends that their use should be reassessed daily in order to minimize the adverse consequences of unnecessary antimicrobial therapy (AIII).
                      Rationale


                      There are no reliable estimates of the incidence or prevalence of co-pathogens with COVID-19 at this time.

                      For patients with COVID-19, some experts routinely administer broad-spectrum antibiotics to all patients with moderate or severe hypoxemia. Other experts administer antibiotics only for specific situations, such as the presence of a lobar infiltrate on chest x-ray, leukocytosis, an elevated serum lactate, microbiologic data, or shock.

                      Gram stain and cultures or testing of respiratory specimens are often not available due to concern about aerosolization of virus during diagnostic procedures or when processing specimens.

                      There are no clinical trials that have evaluated the use of empiric antimicrobial agents in patients with COVID-19 or other severe coronavirus infections.

                      With influenza, empiric antibacterial treatment is strongly recommended for patients with initial severe disease (i.e., those with extensive pneumonia, respiratory failure, hypotension, and fever) and those who deteriorate after initial improvement.16 These recommendations are based on observations that bacterial superinfections, especially those due to Staphylococcus aureus and Streptococcus pneumonia, are not uncommon and have dire consequences if not treated promptly.

                      Whether moderate or severe COVID-19 disease should be approached like severe influenza will remain uncertain until more microbiologic and clinical data become available.
                      References
                      1. Yoshikawa T, Hill T, Li K, Peters CJ, Tseng CT. Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells. J Virol. 2009;83(7):3039-3048. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19004938.
                      2. Brunner HI, Ruperto N, Zuber Z, et al. Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial. Ann Rheum Dis. 2015;74(6):1110-1117. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24834925.
                      3. Genovese MC, van Adelsberg J, Fan C, et al. Two years of sarilumab in patients with rheumatoid arthritis and an inadequate response to MTX: safety, efficacy and radiographic outcomes. Rheumatology (Oxford). 2018;57(8):1423-1431. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29746672.
                      4. Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008;371(9617):998-1006. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18358927.
                      5. Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23(8):943-947. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29622697.
                      6. Campbell L, Chen C, Bhagat SS, Parker RA, Ostor AJ. Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatology (Oxford). 2011;50(3):552-562. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21078627.
                      7. Geng Z, Yu Y, Hu S, Dong L, Ye C. Tocilizumab and the risk of respiratory adverse events in patients with rheumatoid arthritis: a systematic review and meta-analysis of randomised controlled trials. Clin Exp Rheumatol. 2019;37(2):318-323. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30183597.
                      8. Gao Y, Li T, Han M, et al. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19. J Med Virol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32181911.
                      9. Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020;34(2). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32171193.
                      10. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32222812.
                      11. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med. 2018;197(6):757-767. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29161116.
                      12. Lee N, Allen Chan KC, Hui DS, et al. Effects of early corticosteroid treatment on plasma SARS-associated coronavirus RNA concentrations in adult patients. J Clin Virol. 2004;31(4):304-309. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15494274.
                      13. Lee N, Chan PK, Hui DS, et al. Viral loads and duration of viral shedding in adult patients hospitalized with influenza. J Infect Dis. 2009;200(4):492-500. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19591575.
                      14. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32167524.
                      15. Hu H, Ma F, Wei X, Fang Y. Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin. Eur Heart J. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32176300.
                      16. Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical practice guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza. Clin Infect Dis. 2019;68(6):e1-e47. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30566567.

                      https://www.covid19treatmentguidelin...interventions/

                      Comment


                      • #12

                        Extracorporeal Membrane Oxygenation

                        Recommendation:
                        • There are insufficient data to recommend either for or against the routine use of extracorporeal membrane oxygenation (ECMO) for patients with COVID-19 and refractory hypoxemia (BIII).
                        Rationale


                        While ECMO may serve as an effective short-term rescue therapy in patients with severe acute respiratory distress syndrome and refractory hypoxemia, there is no conclusive evidence that ECMO is responsible for better clinical outcomes in patients who received ECMO than in patients who did not receive ECMO.1-4

                        ECMO is used by some experts, when available, for patients with refractory hypoxemia despite optimization of ventilation strategies and adjunctive therapies. Ideally, clinicians who are interested in using ECMO should either try to enter their patient into clinical trials or clinical registries so that more informative data can be obtained. The following resources provide more information on the use of ECMO in patients with COVID-19:References
                        1. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374(9698):1351-1363. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19762075.
                        2. Pham T, Combes A, Roze H, et al. Extracorporeal membrane oxygenation for pandemic influenza A(H1N1)-induced acute respiratory distress syndrome: a cohort study and propensity-matched analysis. Am J Respir Crit Care Med. 2013;187(3):276-285. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23155145.
                        3. Harrington D, Drazen JM. Learning from a by a and board. N Engl J Med. 2018;378(21):2031-2032. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29791830.
                        4. Munshi L, Walkey A, Goligher E, Pham T, Uleryk EM, Fan E. Venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis. Lancet Respir Med. 2019;7(2):163-172. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30642776.

                        https://www.covid19treatmentguidelin...e-oxygenation/


                        Comment


                        • #13

                          Therapeutic Options for COVID-19 Currently Under Investigation
                          At present, no drug has been proven to be safe and effective for treating COVID-19. There are no Food and Drug Administration (FDA)-approved drugs specifically to treat patients with COVID-19. Although reports have appeared in the medical literature and the lay press claiming successful treatment of patients with COVID-19 with a variety of agents, definitive clinical trial data are needed to identify optimal treatments for this disease. Recommended clinical management of patients with COVID-19 includes infection prevention and control measures and supportive care, including supplemental oxygen and mechanical ventilatory support when indicated. As in the management of any disease, treatment decisions ultimately reside with the patient and their health care provider.
                          Antivirals:
                          • There are insufficient clinical data to recommend either for or against using chloroquine or hydroxychloroquine for the treatment of COVID-19 (AIII).
                            • If chloroquine or hydroxychloroquine is used, clinicians should monitor the patient for adverse effects, especially prolonged QTc interval (AIII).
                          • There are insufficient clinical data to recommend either for or against using the investigational antiviral drug remdesivir for the treatment of COVID-19 (AIII).
                            • Remdesivir as a treatment for COVID-19 is currently being investigated in clinical trials and is also available through expanded access and compassionate use mechanisms for certain patient populations.
                          • Except in the context of a clinical trial, the COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of the following drugs for the treatment of COVID-19:
                            • The combination of hydroxychloroquine plus azithromycin (AIII) because of the potential for toxicities.
                            • Lopinavir/ritonavir (AI) or other HIV protease inhibitors (AIII) because of unfavorable pharmacodynamics and negative clinical trial data.
                          Host Modifiers/Immune-Based Therapy:
                          • There are insufficient clinical data to recommend either for or against the use of convalescent plasma or hyperimmune immunoglobulin for the treatment of COVID-19 (AIII).
                          • There are insufficient clinical data to recommend either for or against the use of the following agents for the treatment of COVID-19 (AIII):
                            • Interleukin-6 inhibitors (e.g., sarilumab, siltuximab, tocilizumab)
                            • Interleukin-1 inhibitors (e.g., anakinra)
                          • Except in the context of a clinical trial, the Panel recommends against the use of other immunomodulators, such as:
                            • Interferons (AIII), because of lack of efficacy in treatment of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) and toxicity.
                            • Janus kinase inhibitors (e.g., baricitinib) (AIII), because of their broad immunosuppressive effect.

                          https://www.covid19treatmentguidelin...investigation/

                          Comment


                          • #14

                            Potential Antiviral Drugs Under Evaluation for the Treatment of COVID-19


                            For more information on the antiviral agents that are under evaluation for COVID-19, see Tables 2a and 2b
                            Chloroquine or Hydroxychloroquine

                            Recommendation:
                            • There are insufficient clinical data to recommend either for or against using chloroquine or hydroxychloroquine for the treatment of COVID-19 (AIII).
                              • When chloroquine or hydroxychloroquine is used, clinicians should monitor the patient for adverse effects (AEs), especially prolonged QTc interval (AIII).
                            Rationale for Recommendation:


                            Chloroquine and hydroxychloroquine have been used in small randomized trials1 and in some case series with conflicting study reports (as described below). Both drugs are available through the Strategic National Stockpile for hospitalized adults and adolescents weighing ≥50 kg who cannot access these drugs through a clinical trial.
                            Background:


                            Chloroquine is an antimalarial drug developed in 1934. Hydroxychloroquine, an analogue of chloroquine, was developed in 1946 and is used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In general, hydroxychloroquine has less toxicity (including less propensity to prolong the QTc interval) and fewer drug-drug interactions than chloroquine.
                            Proposed Mechanism of Action and Rationale for Use in COVID-19:
                            • Both chloroquine and hydroxychloroquine increase the endosomal pH, inhibiting fusion of the SARS-CoV-2 and the host cell membrane.2
                            • Chloroquine inhibits glycosylation of the cellular angiotensin-converting enzyme 2 (ACE2) receptor, which may interfere with binding of SARS-CoV to the cell receptor.3
                            • In vitro, both drugs may block the transport of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from early endosomes to endolysosomes, which may be required for release of the viral genome.4
                            • Several studies have demonstrated in vitro activity of chloroquine against SARS-CoV.3,5
                            • Both drugs have immunomodulatory effects.
                            Clinical Data in COVID-19:


                            The clinical data available to date on the use of chloroquine and hydroxychloroquine to treat COVID-19 have been mostly from use in patients with mild, and in some cases, moderate disease; data on use of the drugs in patients with severe and critical COVID-19 are very limited. The clinical data are summarized below.
                            Chloroquine

                            Study Description:


                            In a small randomized controlled trial in China, 22 hospitalized patients with COVID-19 (none critically ill) were randomized to chloroquine 500 mg orally twice daily or lopinavir 400 mg/ritonavir 100 mg twice daily for 10 days. Patients with a history of heart disease (chronic disease and history of arrhythmia), kidney, liver, or hematologic diseases were excluded from participation. Primary study outcome was SARS-CoV-2 polymerase chain reaction (PCR) negativity at Days 10 and 14. Secondary outcomes included improvement of lung computed tomography (CT) scan at Days 10 and 14, discharge at Day 14, and clinical recovery at Day 10, as well as safety determined by evaluation of study drug-related AEs.
                            Results:
                            • Ten patients received chloroquine and 12 patients received lopinavir/ritonavir. Patients had good peripheral capillary oxygen saturation (SpO2) at baseline (97% to 98%).
                            • Compared to the lopinavir/ritonavir-treated patients, the chloroquine-treated patients had a shorter duration from symptom onset to initiation of treatment (2.5 days vs. 6.5 days, P < 0.001).
                            • Though not statistically significant, patients in the chloroquine arm were younger (median age 41.5 years vs. 53.0 years, P = 0.09). Few patients had co-morbidities.
                            • At Day 10, 90% of the chloroquine-treated patients and 75% of the lopinavir/ritonavir-treated patients had negative SARS-CoV-2 PCR. At Day 14, the percentages for the chloroquine-treated patients and the lopinavir/ritonavir-treated patients were 100% and 91.2%, respectively.
                            • At Day 10, 20% of the chloroquine-treated patients and 8.3% of the lopinavir/ritonavir-treated patients had CT scan improvement. At Day 14, the percentages for the chloroquine-treated patients and lopinavir/ritonavir-treated patients were 100% and 75%, respectively.
                            • At Day 14, 100% of the chloroquine-treated patients and 50% of the lopinavir/ritonavir-treated patients were discharged from the hospital.
                            • The risk ratios of these outcome data cross 1, and the results were not statistically significant.
                            • Both drugs were generally well-tolerated.
                            Limitations:
                            • The trial sample size was very small, and the participants were fairly young.
                            • The chloroquine-treated patients were younger and had fewer symptoms prior to treatment initiation, which are variables that could have affected the study protocol-defined outcomes.
                            • Patients with chronic co-morbidities and critically ill patients were excluded from the study.
                            Hydroxychloroquine

                            Study Description:


                            In a randomized controlled trial in China, 62 hospitalized patients with mild (SaO2/SpO2 ratio >93% or PaO2/FIO2 ratio >300 mm Hg) CT-confirmed COVID-19 pneumonia were randomized to hydroxychloroquine 200 twice daily for 5 days plus standard treatment or to standard treatment only.6 Standard treatment included oxygen therapy, antiviral and antibacterial therapy, and immunoglobin, with or without corticosteroids.
                            Results:
                            • Compared to the control patients, the hydroxychloroquine-treated patients had a 1 day-shorter mean duration of fever (2.2 days vs. 3.2 days) and cough (2.0 days vs. 3.1 days).
                            • 13% of the control patients and none of the hydroxychloroquine-treated patients experienced progression of illness.
                            • 80.6% of hydroxychloroquine-treated patients and 54.8% of control patients experienced either moderate or significant improvement in chest CT scan.
                            • AEs (1 rash, 1 headache) occurred among 2 (6.4%) hydroxychloroquine-treated patients; none occurred among the control patients.
                            Limitations:
                            • The trial had a small sample size and short follow-up.
                            • Standard treatment is complex and not well defined.
                            • The presence and distribution of associated co-morbidities (e.g., hypertension [HTN], diabetes, lung disease) was not reported.
                            • There was no indication that radiologists were blinded to the treatment status of the patients, which could have biased determination of the chest CT outcome.
                            Study Description:


                            A pilot trial in China randomized 30 patients with COVID-19 to hydroxychloroquine 400 mg once a day for 5 days or conventional treatment.
                            Results:
                            • The trial demonstrated no difference in viral clearance of nasopharyngeal (NP) swabs at Day 7 between the hydroxychloroquine arm (86.7%) and the control arm (93.3%).7
                            • One patient in the hydroxychloroquine arm progressed to severe pneumonia. At follow-up, all patients showed clinical improvement.
                            Study Description:


                            In a case series from France, 26 hospitalized adults with SARS-CoV-2 infection categorized as asymptomatic or with upper or lower respiratory tract infection who received hydroxychloroquine 200 mg 3 times daily for 10 days were compared to 16 control individuals (i.e., who refused treatment, did not meet eligibility criteria, or were from a different clinic).8
                            Results:
                            • Six patients in the hydroxychloroquine group were excluded from the analysis for the following reasons:
                              • One died
                              • Three were transferred to the intensive care unit (ICU)
                              • One stopped the study drug due to nausea
                              • One withdrew from the study
                            • Six patients also received azithromycin.
                            • By Day 6, NP PCRs were negative in 14 of 20 (70%) hydroxychloroquine-treated patients and 2 of 16 (12.5%) controls.
                            • Among the hydroxychloroquine patients, 8 of 14 (57.1%) who received only hydroxychloroquine and 6 of 6 (100%) who received hydroxychloroquine and azithromycin had negative NP PCRs by Day 6.
                            • Clinical outcomes for all patients were not reported.
                            Limitations:
                            • There are several methodologic concerns with this case series:
                              • The small sample size of the series.
                              • The criteria for enrollment of cases and controls is unclear.
                              • Asymptomatic individuals were enrolled.
                              • Exclusion of six hydroxychloroquine patients includes one death and three ICU transfers.
                              • No clinical outcomes were reported; thus, the clinical significance of a negative PCR is unknown.
                              • The reason for the addition of azithromycin for some patients is unclear.
                            Adverse Effects:
                            • Chloroquine and hydroxychloroquine have a similar toxicity profile, although hydroxychloroquine is better tolerated and has a lower incidence of toxicity than chloroquine.
                            • Cardiac Adverse Effects:
                              • QTc prolongation, Torsade de Pointes, ventricular arrythmia, and cardiac deaths.
                              • The risk of QTc prolongation is greater for chloroquine than for hydroxychloroquine.
                              • Concomitant medications that pose a moderate to high risk for QTc prolongation (e.g., antiarrhythmics, antipsychotics, antifungals, macrolides [including azithromycin] and fluoroquinolone antibiotics)9 should be used only if necessary. Consider using doxycycline rather than azithromycin as empiric therapy for atypical pneumonia.
                              • Baseline and follow-up electrocardiogram (ECG) are recommended when there are potential drug interactions with concomitant medications (e.g., azithromycin) or underlying cardiac diseases.10
                              • The risk-benefit ratio should be closely assessed for patients with cardiac disease, history of ventricular arrhythmia, bradycardia (<50 beats per minute), or uncorrected hypokalemia and/or hypomagnesemia.
                            • Other Adverse Effects:
                              • Hypoglycemia, rash, and nausea (daily divided doses may reduce nausea).
                              • Retinopathy, bone marrow suppression with long-term use, but not likely with short-term use.
                            • There is no evidence that glucose-6-phosphate dehydrogenase (G6PD) deficiency is relevant for the use of hydroxychloroquine, and G6PD testing is not recommended.
                            • With chloroquine use, there is a greater risk for hemolysis in patients with G6PD deficiency. Conduct G6PD testing before initiation of chloroquine. Consider using hydroxychloroquine until G6PD test results are available. If the test results indicate that the patient is G6PD deficient, hydroxychloroquine should be continued.
                            Drug-Drug Interactions:
                            • Chloroquine and hydroxychloroquine are moderate inhibitors of cytochrome P450 (CYP) 2D6 and are also P-glycoprotein (P-gp) inhibitors. Use caution when co-administering the drugs with concomitant medications metabolized by CYP2D6 (e.g., certain antipsychotics, beta-blockers, selective serotonin reuptake inhibitors, and methadone) or transported by P-gp (e.g., certain direct-acting oral anticoagulants or digoxin).11
                            Considerations in Pregnancy:
                            • Anti-rheumatic doses of chloroquine and hydroxychloroquine have been used safely in pregnant women with SLE.
                            • Hydroxychloroquine has not been associated with adverse pregnancy outcomes in ≥300 human pregnancies with exposure to the drug.
                            • A lower dose of chloroquine (500 mg once a week) is used for malaria prophylaxis in pregnancy.
                            • Dosing/pharmacokinetics/pharmacodynamics: No dosing changes in pregnancy.
                            Considerations in Children:
                            • Chloroquine and hydroxychloroquine have been used routinely in pediatric populations for the treatment and prevention of malaria and for rheumatologic conditions.
                            Drug Availability:
                            • Hydroxychloroquine is Food and Drug Administration (FDA)-approved for the treatment of malaria, lupus erythematosus, and RA and is available commercially. Hydroxychloroquine is not approved for the treatment of COVID-19.
                            • FDA issued an emergency use authorization (EUA) for the use of chloroquine and hydroxychloroquine donated to the Strategic National Stockpile. The EUA authorizes the use of these donated drugs for the treatment of hospitalized adolescent and adult COVID-19 patients who weigh ≥50 kg and for whom a clinical trial is not available, or participation is not feasible.
                            Hydroxychloroquine plus Azithromycin

                            Recommendation:
                            • The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of hydroxychloroquine plus azithromycin for the treatment of COVID-19, except in the context of a clinical trial (AIII).
                            Rationale for Recommendation:


                            Chloroquine and hydroxychloroquine for COVID-19 have been used in small randomized trials and in some case series with conflicting study reports (as described above). The combination of hydroxychloroquine and azithromycin was associated with QTc prolongation in patients with COVID-19.
                            Clinical Data in COVID-19

                            Study Description:


                            In a case series of 80 hospitalized patients with COVID-19 (including six patients from a previous study),8 patients were treated with hydroxychloroquine sulfate 200 mg three times daily for 3 to 10 days plus azithromycin 500 mg for 1 day followed by 250 mg once daily for 4 days. Mean time from symptom onset to treatment was 4.9 ± 3.6 days. Outcomes evaluated included the need for oxygen therapy or ICU transfer after ≥3 days of therapy, NP PCR, SARS-CoV-2 culture, and length of hospitalization.12,13
                            Clinical Results:
                            • One (1.2%) patient died and three (3.8%) patients required ICU transfer, 12 (15%) patients required oxygen therapy.
                            • 65 (81.2%) patients were discharged to home or transferred to other units for continuing treatment; 14 (17.4%) patients remained hospitalized at the time the study results were published.
                            Laboratory Results:
                            • 40 of 60 (66.7%) patients tested on Day 6 had negative NP PCR.
                            • All patients tested had negative PCRs by Days 12 through14.
                            • Culture positivity decreased over time among the small number of patients for whom cultures were obtained.
                            Limitations:
                            • The trial’s lack of a control group, which is particularly important because many people with mild disease improve in the absence of treatment.
                            • The criteria for selection of cases was not reported.
                            • Data for PCR and culture results were missing.
                            • The definition of “discharge” varied and was unclear.
                            • The lack of complete or longer-term follow-up.
                            Study Description:


                            A prospective case series from France of 11 consecutive hospitalized patients with COVID-19 (eight with significant co-morbid conditions: obesity in two; solid cancer in three; hematological cancer in two; HIV-infection in one). Ten of 11 patients were receiving supplemental oxygen upon treatment initiation.13 All patients were treated with hydroxychloroquine 600 mg once daily for 10 days and azithromycin 500 mg for 1 day followed by 250 mg once daily for 4 days.
                            Results:
                            • Within 5 days, the condition of three patients worsened, including one patient who died and two patients who were transferred to the ICU.
                            • AEs: Hydroxychloroquine was discontinued in one patient due to QTc prolongation.
                            • Qualitative NP PCR remained positive at Days 5 and 6 after treatment initiation in 8 of 10 patients (repeat testing not done in the patient who died).
                            Study Description:


                            A case series in the United States reported changes in QTc interval in 84 patients with COVID-19 who received the combination of hydroxychloroquine and azithromycin.14
                            Results:
                            • 84 patients, 74% male, mean age 63 ± 15 years, 65% had HTN, baseline serum creatinine 1.4 mg/dL, 13% required vasopressors, 11% had coronary artery disease.
                            • Concomitant drugs that may prolong QTc interval: 11% on neuropsychiatric drugs and 8% received levofloxacin, lopinavir/ritonavir or tacrolimus.
                            • Four patients died, without arrhythmia.
                            • Mean baseline QTc was 435 ± 24 ms, mean maximum QTc was 463 ± 35 ms.
                            • Mean time to maximum QTc was 3.6 ±1.6 days, ECG follow-up was done for a mean of 4.3 days.
                            • 11% of patients developed QTc >500 ms; the QTc increased by 40 to 60 ms and >60 ms in 18% and 12% of patients, respectively.
                            • Baseline QTc was not a predictor of subsequent QTc increase during therapy.
                            • In multivariate analysis, acute kidney injury (in five patients) was a significant predictor of severe QTc prolongation (odds ratio [OR] 19.45: 95% CI, 2.06–183.88, P = 0.01).
                            Clinical Trials:


                            Clinical trials to test the safety and efficacy of chloroquine or hydroxychloroquine with or without azithromycin in people who have or are at risk for COVID-19 are in development in the United States and internationally. Please check ClinicalTrials.gov for the latest information.
                            Lopinavir/Ritonavir and Other HIV Protease Inhibitors

                            Recommendation:
                            • The Panel recommends against the use of lopinavir/ritonavir (AI) or other HIV protease inhibitors (AIII) for the treatment of COVID-19, except in the context of a clinical trial.
                            Rationale for Recommendation:


                            The pharmacodynamics of HIV protease inhibitors do not support their therapeutic use for COVID-19. Also, lopinavir/ritonavir was studied in a small randomized controlled trial in patients with COVID-19 with negative results (see below).
                            Lopinavir/Ritonavir

                            Proposed Mechanism of Action and Rationale for Use in COVID-19:
                            • Replication of SARS-CoV-2 depends on the cleavage of polyproteins into an RNA-dependent RNA polymerase and a helicase.15 The enzymes responsible for this cleavage are two proteases, 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro).
                            • Lopinavir/ritonavir is an inhibitor of SARS-CoV 3CLpro in vitro, and this protease appears highly conserved in SARS-CoV-2 infection.16,17
                            • Although lopinavir/ritonavir has in vitro activity against SARS-CoV, it is thought to have a poor selectivity index, indicating that higher than tolerable levels of the drug might be required to achieve meaningful inhibition in vivo.18
                            • Lopinavir is excreted in the gastrointestinal (GI) tract, and thus coronavirus-infected enterocytes might be exposed to higher concentrations of the drug.19
                            Clinical Data in COVID-19:

                            Study Description:
                            • In a Chinese cohort of 55 pre-symptomatic patients identified early in the course of the infection (i.e., tested RT-PCR positive after a family member or close contact was found to have COVID-19), all of whom were given lopinavir/ritonavir for 7 days; all recovered and none required ICU admission.20
                            Study Description:


                            In a clinical trial that randomized 199 patients to lopinavir 400 mg/ritonavir 100 mg orally twice daily for 14 days or to standard of care (SOC), patients randomized to the lopinavir/ritonavir arm did not have a shorter time to clinical improvement.21
                            Results:
                            • There was a lower, but not statistically significant, mortality rate (lopinavir/ritonavir 19.2%, on SOC 25.0%) and shorter ICU stay compared to those given SOC (6 days vs. 11 days; difference = -5 days; 95% CI, -9 to 0).
                            • The duration of hospital stays and time to clearance of viral RNA from respiratory tract samples did not differ between the lopinavir/ritonavir and SOC arms.
                            • Nausea, vomiting, and diarrhea were all more frequent in the lopinavir/ritonavir-treated group.
                            • The study was powered only to show a fairly large effect.
                            Study Description:


                            In a trial of 44 hospitalized patients with mild-to-moderate COVID-19, 21 patients were randomized to lopinavir/ritonavir, 16 patients to the broad-spectrum antiviral Arbidol (available in Russia), and seven patients to SOC.22
                            Results:
                            • The time to a negative SARS-CoV-2 nucleic acid pharyngeal swab was not shorter for patients receiving lopinavir/ritonavir (8.5 days [IQR: 3, 13]) than for those receiving SOC (4 days [IQR: 3, 10.5]).
                            • Progression to severe/critical status occurred among eight (38%) patients receiving lopinavir/ritonavir and one patient (14%) on SOC.
                            Study Description:


                            A small randomized study in China compared lopinavir/ritonavir to chloroquine. Please refer to the chloroquine section for the study description.23
                            Clinical Trials:


                            None in the United States
                            Monitoring, Adverse Effects, and Drug-Drug InteractionsConsiderations in Pregnancy:Considerations in Children:
                            • Lopinavir/ritonavir is approved for the treatment of HIV in infants, children, and adolescents.
                            • There are no data on the efficacy of lopinavir/ritonavir used to treat SARS-CoV-2 infection in pediatric patients.
                            Darunavir/Cobicistat or Darunavir/Ritonavir

                            Rationale for Use, Proposed Mechanism of Action for COVID-19:
                            • Inhibition of the 3CLpro enzyme of SARS-CoV-2 and possibly also inhibition of the PLpro enzyme.
                            • Results from an unpublished randomized controlled trial of 30 patients in China showed that darunavir/cobicistat was not effective in the treatment of COVID-19.24
                            Clinical Trials:


                            None in the United States
                            Other HIV Protease Inhibitors, Including Atazanavir:


                            There are no data from clinical trials that support the use of other HIV protease inhibitors to treat COVID-19.
                            Remdesivir

                            Recommendation:
                            • There are insufficient clinical data to recommend either for or against the use of the investigational antiviral agent remdesivir for the treatment of COVID-19 (AIII).
                            Rationale for Recommendation:


                            Remdesivir is an investigational antiviral drug. Clinical trials of remdesivir for treatment of COVID-19 are underway or in development, but trial data is not yet available.
                            Proposed Mechanism of Action and Rationale for Use in COVID-19:


                            Remdesivir is an intravenous investigational nucleotide prodrug of an adenosine analog. It has demonstrated in vitro activity against SARS-CoV-2,2 and in vitro and in vivo activity (based on animal studies) against SARS-CoV and MERS-CoV.25-27 Remdesivir binds to the viral RNA-dependent RNA polymerase, inhibiting viral replication through premature termination of RNA transcription.

                            Preclinical studies show that remdesivir improves disease outcomes and reduces levels of SARS-CoV in mice.25 When given as prophylaxis or therapy, remdesivir also reduces MERS-CoV levels and lung injury in mice. In a rhesus macaque model of MERS-CoV infection, prophylactic remdesivir prevented MERS-CoV clinical disease.27 When given 12 hours after MERS-CoV infection to rhesus macaques, remdesivir reduced viral replication and the severity of lung disease compared to control animals.

                            Remdesivir is administered by intravenous infusion at 200 mg on Day 1 followed by 100 mg/day for up to 10 days; the drug is usually infused over 30 to 60 minutes.
                            Clinical Data to Date:


                            Only anecdotal data are available.
                            Clinical Trials:


                            Multiple clinical trials are currently underway or in development. Please check ClinicalTrials.gov for the latest information.

                            In areas of the United States without access to clinical trials, remdesivir may be available through an expanded access program or compassionate use program for a subset of patients.
                            Monitoring, Adverse Effects, and Drug-Drug Interactions:


                            Remdesivir can cause GI symptoms (e.g., nausea, vomiting), elevated transaminases, and prothrombin time elevation (without change in international normalized ratio [INR]). Remdesivir is a CYP3A4, CYP2C8, and CYP2D6 substrate in vitro. Coadministration of remdesivir with inhibitors of these enzymes is not expected to have a significant impact on remdesivir concentrations. Remdesivir concentration may be affected by strong CYP inducers, but the interaction is not expected to be clinically significant.28

                            Because remdesivir formulation contains renally cleared sulfobutylether-beta-cyclodextrin sodium (SBECD), patients with estimated glomerular filtration rate (eGFR) <50 mL/min are excluded from some clinical trials (some trials have a cutoff of eGFR <30 mL/min).
                            Considerations in Pregnancy:
                            • Remdesivir is available for pregnant women through a compassionate access program.
                            • In a randomized controlled Ebola treatment trial of therapies including remdesivir, among 98 females who received remdesivir, six had a positive pregnancy test; the obstetric and neonatal outcomes were not reported in the study.29
                            Considerations in Children:
                            • Currently, remdesivir is only available for compassionate use for patients aged <18 years.
                            • In the same randomized controlled trial for the treatment of Ebola virus infection, 41 pediatric patients aged <7 days to <18 years received remdesivir.29 The safety and clinical outcomes in children were not reported separately in the published results for the trial.
                            References
                            1. Food and Drug Administration. Emergency Use Authorization—COVID-19 Therapeutics. 2020. Available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#covidtherapeutics. Accessed April 8, 2020.
                            2. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32020029.
                            3. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16115318.
                            4. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32194981.
                            5. Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun. 2004;323(1):264-268. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15351731.
                            6. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020. [Preprint]. Available at: https://www.medrxiv.org/content/10.1....22.20040758v2.
                            7. Chen J, Liu L, Liu P, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). Journal of ZheJiang University (Medical Sciences). 2020;49(1). Available at: http://www.zjujournals.com/med/EN/10...292.2020.03.03.
                            8. Gautret P, Lagier J, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. 2020. [In press]. Available at: https://www.sciencedirect.com/science/article/pii/S0924857920300996.
                            9. CredibleMeds. Combines list of drugs that prolong QT and/or cause torsades de pointes (TDP). 2020. Available at: https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf
                            10. American College of Cardiology. Ventricular arrhythmia risk due to hydroxychloroquine-azithromycin treatment for COVID-19. 2020. Available at: https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19. Accessed April 8, 2020.
                            11. University of Liverpool. COVID-19 drug interactions. 2020. Available at: https://www.covid19-druginteractions.org/.Accessed April 8, 2020.
                            12. Gautret P, Lagier J, Parola P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study. 2020. Available at: https://covid19-evidence.paho.org/handle/20.500.12663/921.
                            13. Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 Infection. Médecine et Maladies Infectieuses. 2020. [In press]. Available at: https://www.sciencedirect.com/scienc...58?via%3Dihub#!
                            14. Chorin E, Dai M, Shulman E, et al. The QT Interval in patients with SARS-CoV-2 infection treated with hydroxychloroquine/azithromycin. medRxiv. 2020. [Preprint]. Available at: https://www.medrxiv.org/content/10.1....02.20047050v1.
                            15. Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses—drug discovery and therapeutic options. Nat Rev Drug Discov. 2016;15(5):327-347. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26868298.
                            16. Tahir ul Qamar M, Alqahtani SM, Alamri MA, Chen L. Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants. Journal of Pharmaceutical Analysis. 2020. [In press]. Available at: https://www.sciencedirect.com/scienc...95177920301271.
                            17. Liu X, Wang X. Potential inhibitors for 2019-nCoV coronavirus M protease from clinically approved medicines. bioRxiv. 2020. [Preprint]. Available at: https://www.biorxiv.org/content/10.1...100v1.full.pdf.
                            18. Chen F, Chan KH, Jiang Y, et al. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol. 2004;31(1):69-75. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15288617.
                            19. Chu CM, Cheng VC, **** IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-256. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14985565.
                            20. Wang Y, Liu Y, Liu L, Wang X, Luo N, Ling L. Clinical outcome of 55 asymptomatic cases at the time of hospital admission infected with SARS-Coronavirus-2 in Shenzhen, China. J Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32179910.
                            21. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32187464.
                            22. Li Y, Xie Z, Lin W, et al. An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). medRxiv. 2020. [Preprint]. Available at: https://www.medrxiv.org/content/10.1....19.20038984v1.
                            23. Huang M, Tang T, Pang P, et al. Treating COVID-19 with chloroquine. J Mol Cell Biol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32236562.
                            24. Johnson & Johnson. Lack of evidence to support use of darunavir-based treatments for SARS-CoV-2. 2020. Available at: https://www.jnj.com/lack-of-evidence...or-coronavirus. Accessed April 8, 2020.
                            25. Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9(396). Available at: https://www.ncbi.nlm.nih.gov/pubmed/28659436.
                            26. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11(1):222. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31924756.
                            27. de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci USA. 2020;117(12):6771-6776. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32054787.
                            28. Gilead Sciences. Remdesivir (GS-5734) Investigator’s Brochure. Edition 5 (dated 21 February 2020).
                            29. Mulangu S, Dodd LE, Davey RT, Jr., et al. A randomized, controlled trial of ebola virus disease therapeutics. N Engl J Med. 2019;381(24):2293-2303. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31774950.

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                            • #15

                              Table 2a. Potential Antiviral Agents Under Evaluation for Treatment of COVID-19: Clinical Data to Date


                              Information presented in this table may include data from pre-print/non-peer reviewed articles. This table will be updated as new information becomes available.
                              Click here to view this table.
                              References
                              1. ZITHROMAX (azithromycin) [package insert]. Food and Drug Administration. 2013. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050710s039,050711s036,050784s023lbl.pdf. Accessed: April 8, 2020.
                              2. Gielen V, Johnston SL, Edwards MR. Azithromycin induces anti-viral responses in bronchial epithelial cells. Eur Respir J. 2010;36(3):646-654. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20150207.
                              3. Culic O, Erakovic V, Cepelak I, et al. Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects. Eur J Pharmacol. 2002;450(3):277-289. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12208321.
                              4. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1):72-73. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32074550.
                              5. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32020029.
                              6. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16115318.
                              7. Huang M, Tang T, Pang P, et al. Treating COVID-19 with chloroquine. J Mol Cell Biol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32236562.
                              8. PLAQUENIL (hydroxychloroquine sulfate) [package insert]. Food and Drug Administration. 2017.Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf. Accessed: April 8, 2020.
                              9. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020;[Preprint]. Available at: https://www.medrxiv.org/content/10.1....22.20040758v2.
                              10. Chen J, Liu L, Liu P, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). Journal of ZheJiang University (Medical Sciences). 2020;49(1). Available at: http://www.zjujournals.com/med/EN/10...292.2020.03.03.
                              11. Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 Infection. Médecine et Maladies Infectieuses. 2020. [In press]. Available at: https://www.sciencedirect.com/scienc...58?via%3Dihub#!
                              12. Chorin E, Dai M, Shulman E, et al. The QT interval in patients with SARS-CoV-2 infection treated with hydroxychloroquine/azithromycin. medRxiv. 2020. [Preprint]. Available at: https://www.medrxiv.org/content/10.1....02.20047050v1.
                              13. Nukoolkarn V, Lee VS, Malaisree M, Aruksakulwong O, Hannongbua S. Molecular dynamic simulations analysis of ritonavir and lopinavir as SARS-CoV 3CL(pro) inhibitors. J Theor Biol. 2008;254(4):861-867. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18706430.
                              14. Li Y, Xie Z, Lin W, et al. An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). medRxiv. 2020. [Preprint]. Available at: https://www.medrxiv.org/content/10.1....19.20038984v1.
                              15. Johnson & Johnson. Lack of evidence to support use of darunavir-based treatments for SARS-CoV-2. 2020. Available at: https://www.jnj.com/lack-of-evidence-to-support-darunavir-based-hiv-treatments-for-coronavirus. Accessed April 8, 2020.
                              16. Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531(7594):381-385. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26934220.
                              17. Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32176772.
                              18. Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382(10):929-936. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32004427.

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