book1.pdf

COVID-19 Treatment Guidelines Coronavirus Disease 2019 (COVID-19) Treatment Guidelines Credit NIAID-RML Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/202...

COVID-19 Treatment Guidelines Coronavirus Disease 2019 (COVID-19) Treatment Guidelines Credit NIAID-RML Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 Visit https://www.covid19treatmentguidelines.nih.gov/ to access the most up-to-date guideline. How to Cite the COVID-19 Treatment Guidelines: COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed [insert date]. The COVID-19 Treatment Guidelines Panel regularly updates the recommendations in these guidelines as new information on the management of COVID-19 becomes available. The most recent version of the guidelines can be found on the COVID-19 Treatment Guidelines website (https://www.covid19treatmentguidelines.nih.gov/). Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 Table of Contents What’s New in the Guidelines................................................................................................... 5 Guidelines Development........................................................................................................... 6 Overview Overview of COVID-19.......................................................................................................... 9 Testing for SARS-CoV-2 Infection....................................................................................... 14 Prevention of SARS-CoV-2 Infection.................................................................................. 18 Clinical Spectrum of SARS-CoV-2 Infection....................................................................... 22 Prioritization of Anti-SARS-CoV-2 Therapies for the Treatment of COVID-19 in Nonhospitalized Patients When There Are Logistical Constraints...................................... 32 Clinical Management of Adults Clinical Management of Adults Summary........................................................................... 35 General Management of Nonhospitalized Adults With Acute COVID-19........................... 39 Therapeutic Management of Nonhospitalized Adults With COVID-19............................... 46 Therapeutic Management of Hospitalized Adults With COVID-19..................................... 57 Clinical Management of Children Clinical Management of Children Summary....................................................................... 72 Special Considerations in Children..................................................................................... 79 Therapeutic Management of Nonhospitalized Children With COVID-19............................ 92 Therapeutic Management of Hospitalized Children With COVID-19................................ 102 Therapeutic Management of Hospitalized Children With MIS-C, Plus a Discussion on MIS-A........................................................................................................ 113 Critical Care for Adults Care of Critically Ill Adults With COVID-19 (Summary Recommendations)...................... 125 Introduction to Critical Care Management of Adults With COVID-19............................... 127 Hemodynamics for Adults................................................................................................ 134 Oxygenation and Ventilation for Adults............................................................................. 138 Pharmacologic Interventions for Critically Ill Patients....................................................... 147 Extracorporeal Membrane Oxygenation for Adults.......................................................... 149 Critical Care for Children Introduction to Critical Care Management of Children With COVID-19............................ 151 Hemodynamic Considerations for Children...................................................................... 155 Oxygenation and Ventilation for Children......................................................................... 160 Extracorporeal Membrane Oxygenation for Children....................................................... 170 Antiviral Agents, Including Antibody Products Antiviral Agents, Including Antibody Products (Summary Recommendations)................ 173 COVID-19 Treatment Guidelines 2 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024  Remdesivir........................................................................................................................ 175 Table 4a. Remdesivir: Selected Clinical Trial Data....................................................... 178 Ritonavir-Boosted Nirmatrelvir (Paxlovid)......................................................................... 186 Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant Medications.................................................................................... 193 Molnupiravir...................................................................................................................... 200 Anti-SARS-CoV-2 Monoclonal Antibodies........................................................................ 205 Table 4b. Anti-SARS-CoV-2 Monoclonal Antibodies: Selected Clinical Trial Data...... 207 COVID-19 Convalescent Plasma...................................................................................... 211 Table 4c. COVID-19 Convalescent Plasma: Selected Clinical Trial Data.................... 218 Interferons......................................................................................................................... 228 Table 4d. Interferons: Selected Clinical Trial Data...................................................... 231 Table 4e. Characteristics of Antiviral Agents, Including Antibody Products..................... 238 Immunomodulators Immunomodulators (Summary Recommendations)......................................................... 243 Systemic Corticosteroids.................................................................................................. 244 Table 5a. Systemic Corticosteroids: Selected Clinical Trial Data................................ 250 Inhaled Corticosteroids..................................................................................................... 260 Table 5b. Inhaled Corticosteroids: Selected Clinical Trial Data................................... 263 Interleukin-6 Inhibitors...................................................................................................... 270 Table 5c. Interleukin-6 Inhibitors: Selected Clinical Trial Data..................................... 275 Janus Kinase Inhibitors..................................................................................................... 283 Table 5d: Janus Kinase Inhibitors: Selected Clinical Trial Data................................... 286 Abatacept.......................................................................................................................... 293 Inflixamab.......................................................................................................................... 296 Interleukin-1 Inhibitors...................................................................................................... 299 Vilobelimab....................................................................................................................... 308 Table 5e. Characteristics of Immunomodulators.............................................................. 311 Antithrombotic Therapy in Patients With COVID-19............................................................ 321 Table 6a. Anticoagulant Therapy: Selected Clinical Trial Data.......................................... 336 Table 6b. Antiplatelet Therapy: Selected Clinical Trial Data.............................................. 351 Miscellaneous Drugs Miscellaneous Drugs (Summary Recommendations)....................................................... 356 Fluvoxamine...................................................................................................................... 357 Table 7a. Fluvoxamine: Selected Clinical Trial Data.................................................... 360 Intravenous Immunoglobin............................................................................................... 368 Ivermectin......................................................................................................................... 371 Table 7b. Ivermectin: Selected Clinical Trial Data........................................................ 374 Metformin.......................................................................................................................... 389 COVID-19 Treatment Guidelines 3 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024  Table 7c. Metformin: Selected Clinical Trial Data........................................................ 392 Table 7d. Characteristics of Miscellaneous Drugs............................................................ 395 Supplements Supplements (Summary Recommendations)................................................................... 397 Vitamin C........................................................................................................................... 398 Vitamin D........................................................................................................................... 401 Zinc................................................................................................................................... 404 Considerations for Using Concomitant Medications in Patients With COVID-19.............. 407 Special Populations Special Considerations in People Who Are Immunocompromised.................................. 409 Special Considerations in Adults and Children With Cancer............................................ 427 Special Considerations in Solid Organ Transplant, Hematopoietic Cell Transplant, and Cellular Immunotherapy Candidates, Donors, and Recipients.................................. 435 Special Considerations During Pregnancy and After Delivery.......................................... 444 Pregnancy, Lactation, and COVID-19 Therapeutics.................................................... 452 Influenza and COVID-19................................................................................................... 460 Special Considerations in People With HIV...................................................................... 466 Appendix A, Table 1. COVID-19 Treatment Guidelines Panel Roster................................. 474 Appendix A, Table 2. Panel on COVID-19 Treatment Guidelines Financial Disclosure for Companies Related to COVID-19 Treatment or Diagnostics......................................... 476 COVID-19 Treatment Guidelines 4 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 What’s New in the Guidelines Last Updated: February 29, 2024 In response to the rapidly evolving COVID-19 pandemic, the National Institutes of Health assembled a panel of experts to provide practical recommendations for health care providers and issued the first version of the Coronavirus Disease 2019 (COVID-19) Treatment Guidelines on April 21, 2020. For close to 4 years, the COVID-19 Treatment Guidelines Panel (the Panel) has critically reviewed the growing body of research data on COVID-19 and used that information to develop and revise their recommendations for treating patients with this disease. The Panel has released a total of 72 versions of the Guidelines. The federal COVID-19 Public Health Emergency ended in May 2023, and several professional societies currently provide COVID-19 treatment guidelines for their medical specialties or subspecialties. Accordingly, this will be the final update of the COVID-19 Treatment Guidelines. The Panel members hope these Guidelines have been of value to health care providers, and they appreciate the support and input they have received over the past 4 years. The COVID-19 Treatment Guidelines website will remain available until August 16, 2024, and will provide a downloadable PDF of the final version of the Guidelines. February 29, 2024 In preparation for this final version of the Guidelines, the Panel reviewed all the sections that were not updated on December 20, 2023. The information in these sections is current as of February 2024. The Viral Rebound and Symptom Recurrence subsections in Therapeutic Management of Nonhospitalized Adults With COVID-19 and Ritonavir-Boosted Nirmatrelvir (Paxlovid) have been updated with new references. The Panel noted that concerns about the recurrence of symptoms or viral rebound should not be a reason to avoid using antiviral therapy when indicated. The Panel updated the discussion on the role of remdesivir in adults with COVID-19 who require mechanical ventilation or extracorporeal membrane oxygenation in Therapeutic Management of Hospitalized Adults With COVID-19. In Therapeutic Management of Nonhospitalized Children With COVID-19, the vaccination status categories that determine a child’s risk level for progression to severe disease have been changed from “Unvaccinated,” “Primary Series,” and “Up to Date” to “Not Up to Date” and “Up to Date.” Chronic kidney disease and pregnancy were added to the list of risk factors that are associated with progression to severe COVID-19. Other sections that were reviewed for this final version of the Guidelines can be found in: Clinical Management of Adults Clinical Management of Children Critical Care for Adults Critical Care for Children Antivirals, Including Antibody Products Immunomodulators Special Populations COVID-19 Treatment Guidelines 5 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 Guidelines Development Last Updated: February 29, 2024 The COVID-19 Treatment Guidelines were developed in response to the COVID-19 Public Health Emergency declared by the U.S. Department of Health and Human Services in late January 2020. The goal of the Guidelines was to provide clinicians with guidance on caring for patients with COVID-19. Because clinical information about the optimal management of COVID-19 evolved quickly, a multidisciplinary panel of experts frequently updated the Guidelines based on their assessments of the emerging evidence on treatments for this disease. Panel Composition The COVID-19 Treatment Guidelines Panel (the Panel) co-chairs appointed Panel members with clinical experience and expertise in adult or pediatric patient management, translational and clinical science, or the development of treatment guidelines. Panel members included representatives from federal agencies, health care organizations, academic institutions, professional societies, and the community. Federal agencies and professional societies represented on the Panel include: American Association for Respiratory Care American Association of Critical-Care Nurses American College of Chest Physicians American College of Emergency Physicians American College of Obstetricians and Gynecologists American Society of Hematology 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 these societies endorsed all elements of the Guidelines. Appendix A, Table 1, provides the names and affiliations of the Panel members, ex officio members, consultants, and support team members on the Panel roster as of the final update of the Guidelines. Financial disclosures for the Panel members can be found in Appendix A, Table 2. COVID-19 Treatment Guidelines 6 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 Development of the Guidelines Each section of the Guidelines was developed by a working group of Panel members who had expertise in the area addressed in that section. Each working group was responsible for identifying relevant information and published scientific literature and for conducting a systematic, comprehensive review of that information and literature. The working groups proposed updates to the Guidelines based on the latest published research findings and clinical information. Voting members of the Panel reviewed and voted on new Guidelines sections and recommendations. A majority of voting members endorsed each recommendation statement before it was included in the Guidelines. This requirement applied to recommendations for and against treatments and in cases when there was insufficient evidence to recommend either for or against treatments. Section updates that did not affect rated recommendations were approved by the Panel co-chairs without a Panel vote. During the development of the Guidelines, Panel members were required to keep all Panel deliberations and evaluations of unpublished data confidential. Method of Synthesizing Data and Formulating Recommendations The working groups critically reviewed and synthesized the available data to develop recommendations. During this process, the Panel evaluated the data, including the source of the data, the type of study (e.g., randomized controlled trial, prospective or retrospective cohort study, case series, in vitro study), the quality and suitability of the methods, the number of participants, and the effect sizes observed. In addition to evaluating data and reviewing clinical research on COVID-19, Panel members used clinical experiences with COVID-19 and other diseases to develop recommendations. The recommendations in these Guidelines are based on scientific evidence and expert opinion. Each recommendation includes 2 ratings: an uppercase letter (A, B, or C) that indicates the strength of the recommendation and a Roman numeral with or without a lowercase letter (I, IIa, IIb, or III) that indicates the quality of the evidence that supports the recommendation (see Table 1). The ratings for the quality of the evidence reflect both the likelihood of bias in the treatment effect estimate and the precision of the estimate. A rating of I corresponds to a low likelihood of bias and a high precision, a rating of IIa (for randomized trials) or IIb (for observational studies) corresponds to a moderate likelihood of bias and a moderate or high precision, and a rating of III corresponds to a high likelihood of bias (for any type of study). Table 1. Recommendation Rating Scheme Strength of Recommendation Evidence for Recommendation A: Strong recommendation for the statement I:  High quality of evidence: 1 or more randomized trials B: Moderate recommendation for the statement without major limitations,a well-powered subgroup analyses of such trials, or meta-analyses without major C: Weak recommendation for the statement limitations IIa: Moderate quality of evidence: Randomized trials and subgroup analyses of randomized trials that do not meet the criteria for a I rating IIb: Moderate quality of evidence: Observational studies without major limitationsb III: Expert opinion a The rating may be lower than I in cases where trials have produced conflicting results. b This category also includes meta-analyses of observational studies. COVID-19 Treatment Guidelines 7 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 In general, the recommendations in these Guidelines fall into the following categories: The Panel recommends using [blank] for the treatment of COVID-19 (rating). Recommendations in this category are based on evidence that the potential benefits of using the intervention outweigh the potential risks. There is insufficient evidence for the Panel to recommend either for or against the use of [blank] for the treatment of COVID-19 (no rating). This statement is used when data are not sufficient to support a recommendation or when the available data are conflicting. The Panel recommends against the use of [blank] for the treatment of COVID-19, except in a clinical trial (rating). This recommendation is used in cases when the available data have shown no benefit from using the intervention for the treatment of COVID-19, or the intervention has demonstrated safety concerns. More results from clinical trials are needed to further define the role of the intervention in treating COVID-19. The Panel recommends against the use of [blank] for the treatment of COVID-19 (rating). This recommendation is used in cases when the available data show no benefit from using the intervention to treat COVID-19, or the safety concerns for the intervention outweigh any potential benefits. Evolving Knowledge on Treatments for COVID-19 The Food and Drug Administration approved several agents (e.g., baricitinib, ritonavir-boosted nirmatrelvir [Paxlovid], remdesivir, tocilizumab) for the treatment of COVID-19, and a number of other agents have received Emergency Use Authorizations. An array of drugs approved for other indications and multiple investigational agents are being studied for the treatment of COVID-19 in clinical trials around the globe. Information about these trials can be found at ClinicalTrials.gov. Whenever possible, the Panel recommends that unapproved or unlicensed treatments for COVID-19 be studied in well-designed, controlled clinical trials. This recommendation also applies to drugs that have been approved or licensed for indications other than the treatment of COVID-19. Clinical research is critically important to generating evidence that can be used to answer questions about the safety and efficacy of potential treatments for COVID-19. Finally, it is important to stress that the rated treatment recommendations in these Guidelines should not be considered mandates. Ultimately, patients and their health care providers should use a shared decision-making process when considering treatments for COVID-19. COVID-19 Treatment Guidelines 8 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 Overview of COVID-19 Last Updated: December 20, 2023 Epidemiology Individuals of all ages are at risk of SARS-CoV-2 infection. However, the probability of severe COVID-19 is higher in people aged ≥65 years, those living in nursing homes or long-term care facilities, those who are not vaccinated against COVID-19 or who have poor responses to COVID-19 vaccines, and those with certain chronic medical conditions. Data on comorbid health conditions among patients with COVID-19 indicate that patients with cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, diabetes with complications, neurocognitive disorders, and obesity are at increased risk of severe COVID-19. The risk appears to be higher in patients with multiple comorbid conditions. Other conditions that may lead to a high risk of severe COVID-19 include cancer, cystic fibrosis, immunocompromising conditions, liver disease (especially in patients with cirrhosis), pregnancy, and sickle cell disease. Transplant recipients and people who are taking immunosuppressive medications are also at high risk of severe COVID-19.1 See Clinical Spectrum of SARS-CoV-2 Infection for a description of the clinical manifestations of SARS-CoV-2 infection and a discussion of the spectrum of disease. Although COVID-19 vaccination does not eliminate the risk of SARS-CoV-2 infection, vaccination does significantly reduce the risk of COVID-19–related morbidity and mortality, particularly in individuals who are at high risk of progressing to severe disease.2,3 Racial and Ethnic Minorities and Other Marginalized Groups Communities that have been historically marginalized or made socially vulnerable due to a lack of access to health care or an inability to socially isolate are at increased risk of SARS-CoV-2 acquisition, COVID-19–related hospitalization, and death. These communities include racial and ethnic minorities, essential non-health care workers, and some people with disabilities. Key Considerations The COVID-19 Treatment Guidelines Panel recommends that health care providers, health care systems, and payers ensure equitable access to high-quality care and treatment for all patients, regardless of race, ethnic identity, or other minoritized identity or social status (AIII). “Minoritized” refers to social groups that have been deprived of power and status by the dominant culture in society and encompasses not just racial identities but other identities as well, including gender identity and sexual orientation.4 Promoting equitable care for these groups must include considering the full range of medical, demographic, and social factors that may negatively impact health outcomes. Clinicians should be aware that pulse oximeters may not accurately detect hypoxemia in people with darker skin pigmentation.5,6 This may delay treatment and lead to worse clinical outcomes in patients with COVID-19.7 See Clinical Spectrum of SARS-CoV-2 Infection for more information. Supporting equitable access to high-quality care and treatment for all patients is now an imperative for all health care organizations accredited by the Joint Commission, as well as a priority for the Centers for Disease Control and Prevention (CDC) and other public health agencies. COVID-19 Treatment Guidelines 9 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 COVID-19–Related Health Outcomes Historical structural inequities significantly contribute to the health disparities experienced by racial and ethnic minority groups (e.g., Black/African American people, Hispanic people, American Indian/ Alaska Native people).8 Some data have highlighted that select racial and ethnic minority groups experience higher rates of COVID-19, subsequent hospitalization, and death in relation to their share of the total U.S. population. Black/African American people, Hispanic people, and American Indian/Alaska Native people also experience rates of hospitalization that are more than 2 times higher and rates of COVID-19–related death that are approximately 2 times higher than those experienced by White people. The largest disparities were observed among American Indian/Alaska Native people, who experienced a rate of hospitalization almost 3 times higher and a rate of death 2.1 times higher than White people.9 The increased risk of severe COVID-19 among racial and ethnic minority groups may be partly attributed to higher rates of comorbid conditions in these populations (e.g., cardiovascular disease, diabetes, chronic kidney disease, hypertension, obesity, pulmonary disease).9 Disparities in Access to Care Members of racial and ethnic minority groups have an increased risk of exposure to COVID-19 and decreased access to care. Large-scale mobility data reveals that people living in lower-income communities were less able to physically isolate during COVID-19 emergency declarations,10 as members of these communities were frequently unable to work from home.11 A 2020 study evaluating access to health care resources in New York City found that in areas of the city where the majority of the population was Black/African American and Hispanic, there were higher COVID-19 positivity rates and fewer licensed hospital beds and intensive care unit beds than in areas where the majority of the population was White.12 Disparities in Access to COVID-19 Treatments Data from 41 U.S. health care systems reveal racial and ethnic disparities in the use of anti-SARS-CoV-2 monoclonal antibodies (mAbs) for the treatment of COVID-19.13 Black/African American patients, Asian patients, and patients of other races were, respectively, 22.4%, 48.3%, and 46.5% less likely to receive anti-SARS-CoV-2 mAbs for the treatment of COVID-19 than White patients.13,14 Disparities have also been observed in the dispensing rates for ritonavir-boosted nirmatrelvir (Paxlovid) and molnupiravir. One study reported that between April and July 2022, Black/African American patients were prescribed ritonavir-boosted nirmatrelvir 35.8% less often than White patients, and Hispanic patients were prescribed this drug 29.9% less often than White patients.15 Despite a greater number of dispensing sites in neighborhoods with a higher social vulnerability, oral antivirals were prescribed at a lower rate for patients with COVID-19 who were living in these areas than in those with a lesser degree of social vulnerability.16 These disparities are not limited to outpatient settings. One retrospective cohort study of veterans hospitalized with COVID-19 reported that Black veterans had lower odds of receiving COVID-19–specific treatments, including systemic steroids, remdesivir, and immunomodulators, than White veterans.17 Other Marginalized Groups Other marginalized groups also experience worse outcomes for COVID-19. Hospitalization rates for COVID-19 among Medicare beneficiaries who were eligible for disability were approximately 50% higher than those among people who were eligible for Medicare based on age alone, and this discrepancy disproportionately affected Black/African American people, Hispanic people, and American Indian/Alaska Native people.18 COVID-19 Treatment Guidelines 10 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 Migrants, refugees, and essential non-health care workers (e.g., food supply, food service, public transportation, and agricultural workers) also have disproportionately high rates of COVID-19 cases and deaths. These high rates can be attributed to overcrowding, an inability to physically isolate, and inadequate access to health care.19-21 Given the pervasiveness of disparities in access to care and provision of treatment, it is imperative for clinicians, working with others on the patient care team, to assess the social factors that contribute to access and quality gaps and to strive to provide equitable treatment to all patients. These issues have been identified as a strategic priority by the Joint Commission and the CDC. SARS-CoV-2 Variants Like other RNA viruses, SARS-CoV-2 is constantly evolving through random mutations. New mutations can potentially increase or decrease infectiousness and virulence. In addition, mutations can increase the virus’ ability to evade adaptive immune responses from previous SARS-CoV-2 infections or vaccination. This viral evolution may increase the risk of reinfection or decrease the efficacy of vaccines.22 There is evidence that some SARS-CoV-2 variants have reduced susceptibility to plasma from people who were previously infected or immunized, as well as to anti-SARS-CoV-2 mAbs.23-25 Since December 2020, the World Health Organization has assigned Greek letter designations to several identified variants. A SARS-CoV-2 variant designated as a variant of concern displays certain characteristics, such as increased transmissibility or virulence. In addition, vaccines and therapeutics may have decreased effectiveness against variants of concern, and the mutations found in these variants may interfere with the targets of diagnostic tests. The variant of interest designation has been used for important variants that are not fully characterized; however, organizations do not use the same variant designations, and they may define their variant designations differently.26,27 In September 2021, the CDC added a new designation for variants: variants being monitored. The data on these variants indicate a potential or clear impact on approved or authorized medical countermeasures, or these variants are associated with cases of more severe disease or increased transmission rates. However, these variants are either no longer detected or are circulating at very low levels in the United States; therefore, they do not pose a significant and imminent risk to public health in the United States. The Omicron variant was designated as a variant of concern in November 2021 and rapidly became the dominant variant across the globe. The Omicron subvariants BA.1, BA.1.1, and BA.2 emerged in early to mid-2022, followed by the subvariants BA.4, BA.5, BQ.1, BQ.1.1, XBB, EG.5, HV.1, and FL.1.5.1. The newer Omicron subvariants are generally more transmissible than previous variants and are not susceptible to any of the anti-SARS-CoV-2 mAbs that were previously authorized for the treatment and prevention of COVID-19.24,25,28,29 Data on the emergence, transmission, and clinical relevance of these new variants are rapidly evolving; this is especially true for research on how variants might affect transmission rates, disease progression, vaccine development, and the efficacy of current therapeutics. Because the research on variants is moving quickly and the classification of the different variants may change over time, websites such as the CDC’s COVID Data Tracker, CoVariants.org, and the World Health Organization’s Tracking SARS-CoV-2 Variants provide regular updates on data for SARS-CoV-2 variants. References 1. Centers for Disease Control and Prevention. Underlying medical conditions associated with higher risk for severe COVID-19: information for healthcare professionals. 2023. Available at: https://www.cdc.gov/ COVID-19 Treatment Guidelines 11 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024  coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html. Accessed November 13, 2023. 2. Link-Gelles R, Weber ZA, Reese SE, et al. Estimates of bivalent mRNA vaccine durability in preventing COVID-19-associated hospitalization and critical illness among adults with and without immunocompromising conditions—VISION Network, September 2022–April 2023. MMWR Morb Mortal Wkly Rep. 2023;72(21):579-588. Available at: https://www.ncbi.nlm.nih.gov/pubmed/37227984. 3. Our World in Data. United States: COVID-19 weekly death rate by vaccination status. 2022. Available at: https://ourworldindata.org/grapher/united-states-rates-of-covid-19-deaths-by-vaccination-status-by- vaccine?country=12-17~12~12. Accessed November 13, 2023. 4. American Medical Association. Advancing health equity: a guide to language, narrative and concepts. 2021. Available at: https://ama-assn.org/equity-guide. 5. Valbuena VSM, Seelye S, Sjoding MW, et al. Racial bias and reproducibility in pulse oximetry among medical and surgical inpatients in general care in the Veterans Health Administration 2013–19: multicenter, retrospective cohort study. BMJ. 2022;378:e069775. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35793817. 6. Chesley CF, Lane-Fall MB, Panchanadam V, et al. Racial disparities in occult hypoxemia and clinically based mitigation strategies to apply in advance of technological advancements. Respir Care. 2022;67(12):1499- 1507. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35679133. 7. Fawzy A, Wu TD, Wang K, et al. Racial and ethnic discrepancy in pulse oximetry and delayed identification of treatment eligibility among patients with COVID-19. JAMA Intern Med. 2022;182(7):730-738. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35639368. 8. National Academies of Sciences, Engineering, and Medicine. Communities in Action: Pathways to Health Equity. 2017. National Academies Press; 2017. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28418632. 9. Mackey K, Ayers CK, Kondo KK, et al. Racial and ethnic disparities in COVID-19-related infections, hospitalizations, and deaths: a systematic review. Ann Intern Med. 2021;174(3):362-373. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33253040. 10. Weill JA, Stigler M, Deschenes O, Springborn MR. Social distancing responses to COVID-19 emergency declarations strongly differentiated by income. Proc Natl Acad Sci U S A. 2020;117(33):19658-19660. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32727905. 11. Economic Policy Institute. Not everybody can work from home: Black and Hispanic workers are much less likely to be able to telework. 2020. Available at: https://www.epi.org/blog/black-and-hispanic-workers-are- much-less-likely-to-be-able-to-work-from-home. Accessed November 13, 2023. 12. Douglas JA, Subica AM. COVID-19 treatment resource disparities and social disadvantage in New York City. Prev Med. 2020;141:106282. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33035550. 13. Wiltz JL, Feehan AK, Molinari NM, et al. Racial and ethnic disparities in receipt of medications for treatment of COVID-19—United States, March 2020–August 2021. MMWR Morb Mortal Wkly Rep. 2022;71(3):96- 102. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35051133. 14. Wu EL, Kumar RN, Moore WJ, et al. Disparities in COVID-19 monoclonal antibody delivery: a retrospective cohort study. J Gen Intern Med. 2022;37(10):2505-2513. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35469360. 15. Boehmer TK, Koumans EH, Skillen EL, et al. Racial and ethnic disparities in outpatient treatment of COVID-19—United States, January–July 2022. MMWR Morb Mortal Wkly Rep. 2022;71(43):1359-1365. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36301738. 16. Gold JAW, Kelleher J, Magid J, et al. Dispensing of oral antiviral drugs for treatment of COVID-19 by ZIP code-level social vulnerability—United States, December 23, 2021–May 21, 2022. MMWR Morb Mortal Wkly Rep. 2022;71(25):825-829. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35737571. 17. Castro AD, Mayr FB, Talisa VB, et al. Variation in clinical treatment and outcomes by race among US veterans hospitalized with COVID-19. JAMA Netw Open. 2022;5(10):e2238507. Available at: https://www. COVID-19 Treatment Guidelines 12 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024  ncbi.nlm.nih.gov/pubmed/36282499. 18. Yuan Y, Thierry JM, Bull-Otterson L, et al. COVID-19 cases and hospitalizations among Medicare beneficiaries with and without disabilities—United States, January 1, 2020–November 20, 2021. MMWR Morb Mortal Wkly Rep. 2022;71(24):791-796. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35709015. 19. Hayward SE, Deal A, Cheng C, et al. Clinical outcomes and risk factors for COVID-19 among migrant populations in high-income countries: a systematic review. J Migr Health. 2021;3:100041. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33903857. 20. Lewnard JA, Mora AM, Nkwocha O, et al. Prevalence and clinical profile of severe acute respiratory syndrome coronavirus 2 infection among farmworkers, California, USA, June–November 2020. Emerg Infect Dis. 2021;27(5):1330-1342. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33657340. 21. Heinzerling A, Vergara XP, Gebreegziabher E, et al. COVID-19 outbreaks and mortality among public transportation workers—California, January 2020–May 2022. MMWR Morb Mortal Wkly Rep. 2022;71(33):1052-1056. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35980867. 22. Walensky RP, Walke HT, Fauci AS. SARS-CoV-2 variants of concern in the United States—challenges and opportunities. JAMA. 2021;325(11):1037-1038. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33595644. 23. Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature. 2021;593(7857):130-135. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33684923. 24. Cameroni E, Bowen JE, Rosen LE, et al. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift. Nature. 2022;602(7898):664-670. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35016195. 25. Liu L, Iketani S, Guo Y, et al. Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2. Nature. 2022;602(7898):676-681. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35016198. 26. World Health Organization. Tracking SARS-CoV-2 variants. 2023. Available at: https://www.who.int/en/activities/tracking-SARS-CoV-2-variants. Accessed November 13, 2023. 27. Centers for Disease Control and Prevention. SARS-CoV-2 variant classifications and definitions. 2023. Available at: https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html. Accessed November 13, 2023. 28. Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization for Evusheld (tixagevimab co-packaged with cilgavimab). 2023. Available at: https://www.fda.gov/media/154701/download. 29. Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization for bebtelovimab. 2022. Available at: https://www.fda.gov/media/156152/download. COVID-19 Treatment Guidelines 13 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 Testing for SARS-CoV-2 Infection Last Updated: December 20, 2023 Summary of Testing for SARS-CoV-2 Infection The COVID-19 Treatment Guidelines Panel (the Panel) defers to the Centers for Disease Control and Prevention (CDC) for recommendations on diagnostic testing for SARS-CoV-2 infection. The Panel also defers to the CDC for recommendations on the use of testing for screening purposes, such as for screening among people who are asymptomatic but have had recent known or suspected exposure to SARS-CoV-2. Some key CDC recommendations include: For diagnosing current SARS-CoV-2 infection, the CDC recommends using either a nucleic acid amplification test (NAAT) or an antigen test and using a specimen from the upper respiratory tract (e.g., nasal, nasopharyngeal). There may be a window period of up to 5 days after exposure before viral antigens or nucleic acids can be detected. NAATs are the most sensitive tests for detecting current SARS-CoV-2 infection. Because antigen tests are less sensitive than NAATs, the Food and Drug Administration recommends repeating antigen tests that produce negative results in certain circumstances, such as when clinical suspicion of COVID-19 is high in people who are symptomatic or when people who are asymptomatic have had known or suspected exposure to SARS-CoV-2. Antibody tests should not be used to diagnose current SARS-CoV-2 infection. Currently, antibody tests are not recommended for assessing SARS-CoV-2 immunity following COVID-19 vaccination or for assessing the need for vaccination in a person who is unvaccinated. Diagnostic Testing for SARS-CoV-2 Infection For diagnosing current SARS-CoV-2 infection, the Centers for Disease Control and Prevention (CDC) recommends using either a nucleic acid amplification test (NAAT) or an antigen test.1 Testing may also be used for screening and to determine the length of a patient’s isolation period.2 There may be a window period of up to 5 days after exposure before viral antigens or nucleic acids can be detected. A number of diagnostic tests for SARS-CoV-2 infection (e.g., NAATs, antigen tests) have received Food and Drug Administration (FDA) Emergency Use Authorizations (EUAs) for use in laboratories and points of care (e.g., physician offices, pharmacies, long-term care facilities, school clinics) and for self-administered testing.3 An influenza and SARS-CoV-2 multiplex NAAT that can simultaneously detect and differentiate between influenza A, influenza B, and SARS-CoV-2 also received an EUA from the FDA.4 The FDA also granted authorization to market the first over-the-counter, at-home, molecular NAAT (i.e., Cue COVID-19) and antigen test (i.e., Flowflex COVID-19) for use in people with symptomatic COVID-19. For diagnosing current SARS-CoV-2 infection, the CDC recommends using a specimen from the upper respiratory tract (e.g., nasal, nasopharyngeal).5 Testing lower respiratory tract specimens is also an option in certain circumstances (e.g., in those receiving mechanical ventilation). For details about collecting and handling specimens for COVID-19 testing, please refer to the CDC’s recommendations. Antigen Testing for SARS-CoV-2 Infection Antigen-based diagnostic tests are widely used at home, at the point of care, and in the laboratory because of their low cost, rapid turnaround time, and availability. Antigen tests and laboratory-based NAATs have similar high specificity. False positive test results can occur with antigen tests, although they are unlikely when the tests are used correctly.6 The likelihood of a false positive antigen test result is higher when the expected probability of SARS-CoV-2 infection is low. Because antigen tests are less sensitive than NAATs, the FDA recommends repeating antigen tests that produce negative results in certain COVID-19 Treatment Guidelines 14 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 circumstances, such as when clinical suspicion of COVID-19 is high in people who are symptomatic or when people who are asymptomatic have had known or suspected exposure to SARS-CoV-2. Nucleic Acid Amplification Testing for SARS-CoV-2 Infection NAATs, such as reverse transcription polymerase chain reaction–based diagnostic tests, which detect viral nucleic acids,7 are the most sensitive tests for detecting current SARS-CoV-2 infection. Diagnostically, some NAATs may produce false negative results if a mutation occurs in the part of the virus’s genome that is assessed by that test.8 The FDA monitors the potential effects of SARS-CoV-2 genetic variations on NAAT results and issues updates when specific variations could affect the performance of NAATs that have received EUAs.9 A single negative test result does not exclude the possibility of SARS-CoV-2 infection in people who have a high likelihood of infection based on their exposure history or clinical presentation.10 Reinfection Reinfection has been reported in people after an initial diagnosis of SARS-CoV-2 infection. Because reinfection can be difficult to distinguish from persistent shedding (i.e., positive NAAT results persisting for weeks or months), the CDC recommends using an antigen test instead of a NAAT in patients who have symptoms compatible with SARS-CoV-2 infection who are within 90 days of recovering from a previous SARS-CoV-2 infection. Because intermittent detection of viral RNA can occur, a negative result on an initial NAAT followed by a positive result on a subsequent test does not necessarily mean a person has been reinfected.11 When the results for an initial and subsequent test are positive, comparative viral sequence data from both tests are needed to distinguish between the persistent presence of viral fragments and reinfection. In the absence of viral sequence data, the cycle threshold (Ct) value from a positive NAAT result may provide information about whether a newly detected infection is related to the persistence of viral fragments or to reinfection. The Ct value is the number of PCR cycles at which the nucleic acid target in the sample becomes detectable. In general, the Ct value is inversely related to the SARS-CoV-2 viral load. Because the clinical utility of Ct values is unclear, an expert should be consulted if these values are used to guide clinical decisions. Serologic or Antibody Testing for Diagnosis of SARS-CoV-2 Infection Unlike NAATs and antigen tests, which detect the presence of SARS-CoV-2, serologic or antibody tests can detect recent or prior SARS-CoV-2 infection or vaccination. The CDC recommends that antibody tests should not be used to diagnose current SARS-CoV-2 infection.12 It may take 21 days or longer after symptom onset for seroconversion to occur (i.e., the development of detectable immunoglobulin M or immunoglobulin G antibodies to SARS-CoV-2).13-18 No serologic tests for SARS-CoV-2 have been approved by the FDA. Some, but not all, commercially available serologic tests for SARS-CoV-2 have received EUAs from the FDA.19 Several professional societies and federal agencies, including the Infectious Diseases Society of America, the CDC, and the FDA, provide guidance on the use of serologic testing for SARS-CoV-2. Serologic Testing and Immunity to SARS-CoV-2 Infection Currently, antibody tests are not recommended for assessing SARS-CoV-2 immunity following COVID-19 vaccination or for assessing the need for vaccination in a person who is unvaccinated. The FDA has issued EUAs for more than 80 SARS-CoV-2 serologic tests since the beginning of the pandemic. However, these tests are not currently authorized for routine use in making individual medical decisions.19 SARS-CoV-2 serologic tests are authorized for detecting antibodies, but their COVID-19 Treatment Guidelines 15 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 ability to predict protective immunity has not been validated. Most of these tests are not standardized. Furthermore, as SARS-CoV-2 is not a well-conserved virus, mutations in the receptor binding domain of the virus could lead to decreased binding affinity between antibodies and SARS-CoV-2–specific antigens. If a serologic test is performed, the result should be interpreted with caution. First, it remains unclear how long SARS-CoV-2 antibodies persist following infection or vaccination. A negative serologic test result also does not preclude prior SARS-CoV-2 infection or vaccination against COVID-19. Second, some people who are infected with SARS-CoV-2 or who are vaccinated against COVID-19 (e.g., those who are immunocompromised) may not develop measurable levels of antibodies. It is presumed that those who do not have measurable antibodies after vaccination are at higher risk of SARS-CoV-2 infection than those who have measurable antibodies. Third, because nucleocapsid proteins are not a constituent of the vaccines that are currently approved by the FDA, available through EUAs, or in late-stage clinical trials, serologic tests that detect antibodies by recognizing nucleocapsid proteins should be used to distinguish between antibody responses to natural infection and vaccine-induced antibody responses to the SARS-CoV-2 spike protein antigen. Assuming that the test is reliable, serologic tests that identify recent or prior SARS-CoV-2 infection may be used to determine who may be eligible to donate COVID-19 convalescent plasma and may aid in diagnosing multisystem inflammatory syndrome in children (MIS-C) and multisystem inflammatory syndrome in adults (MIS-A). References 1. Centers for Disease Control and Prevention. Overview of testing for SARS-CoV-2, the virus that causes COVID-19. 2023. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.html. Accessed December 7, 2023. 2. Centers for Disease Control and Prevention. Isolation and precautions for people with COVID-19. 2023. Available at: https://www.cdc.gov/coronavirus/2019-ncov/your-health/isolation.html. Accessed December 5, 2023. 3. Food and Drug Administration. In vitro diagnostics EUAs. 2023. Available at: https://www.fda.gov/medical- devices/covid-19-emergency-use-authorizations-medical-devices/in-vitro-diagnostics-euas. Accessed December 4, 2023. 4. Centers for Disease Control and Prevention. CDC’s influenza SARS-CoV-2 multiplex assay. 2022. Available at: https://www.cdc.gov/coronavirus/2019-ncov/lab/multiplex.html. Accessed December 12, 2023. 5. Centers for Disease Control and Prevention. Interim guidelines for collecting and handling of clinical specimens for COVID-19 testing. 2023. Available at: https://www.cdc.gov/coronavirus/2019-ncov/lab/ guidelines-clinical-specimens.html. Accessed December 7, 2023. 6. Centers for Disease Control and Prevention. Considerations for SARS-CoV-2 antigen testing for healthcare providers testing individuals in the community. 2023. Available at: https://www.cdc.gov/coronavirus/2019- ncov/lab/resources/antigen-tests-guidelines.html. Accessed December 11, 2023. 7. Centers for Disease Control and Prevention. Nucleic acid amplification tests (NAATs). 2023. Available at: https://www.cdc.gov/coronavirus/2019-ncov/lab/naats.html. Accessed December 11, 2023. 8. Food and Drug Administration. Genetic variants of SARS-CoV-2 may lead to false negative results with molecular tests for detection of SARS-CoV-2—letter to clinical laboratory staff and health care providers. 2021. Available at: https://www.fda.gov/medical-devices/letters-health-care-providers/genetic-variants-sars- cov-2-may-lead-false-negative-results-molecular-tests-detection-sars-cov-2. Accessed December 7, 2023. 9. Food and Drug Administration. SARS-CoV-2 viral mutations: impact on COVID-19 tests. 2023. Available at: https://www.fda.gov/medical-devices/coronavirus-covid-19-and-medical-devices/sars-cov-2-viral-mutations- COVID-19 Treatment Guidelines 16 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024  impact-covid-19-tests. Accessed December 7, 2023. 10. Kucirka LM, Lauer SA, Laeyendecker O, Boon D, Lessler J. Variation in false-negative rate of reverse transcriptase polymerase chain reaction-based SARS-CoV-2 tests by time since exposure. Ann Intern Med. 2020;173(4):262-267. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32422057. 11. Xiao AT, Tong YX, Zhang S. Profile of RT-PCR for SARS-CoV-2: a preliminary study from 56 COVID-19 patients. Clin Infect Dis. 2020;71(16):2249-2251. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32306036. 12. Centers for Disease Control and Prevention. Interim guidelines for COVID-19 antibody testing. 2022. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing/antibody-tests-guidelines.html. Accessed December 7, 2023. 13. Guo L, Ren L, Yang S, et al. Profiling early humoral response to diagnose novel coronavirus disease (COVID-19). Clin Infect Dis. 2020;71(15):778-785. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32198501. 14. Haveri A, Smura T, Kuivanen S, et al. Serological and molecular findings during SARS-CoV-2 infection: the first case study in Finland, January to February 2020. Euro Surveill. 2020;25(11):2000266. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32209163. 15. Long QX, Liu BZ, Deng HJ, et al. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med. 2020;26(6):845-848. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32350462. 16. Okba NMA, Müller MA, Li W, et al. Severe acute respiratory syndrome coronavirus 2–specific antibody responses in coronavirus disease patients. Emerg Infect Dis. 2020;26(7):1478-1488. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32267220. 17. Xiang F, Wang X, He X, et al. Antibody detection and dynamic characteristics in patients with coronavirus disease 2019. Clin Infect Dis. 2020;71(8):1930-1934. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32306047. 18. Zhao J, Yuan Q, Wang H, et al. Antibody responses to SARS-CoV-2 in patients with novel coronavirus disease 2019. Clin Infect Dis. 2020;71(16):2027-2034. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32221519. 19. Food and Drug Administration. EUA authorized serology test performance. 2022. Available at: https://www. fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/ eua-authorized-serology-test-performance. Accessed December 7, 2023. COVID-19 Treatment Guidelines 17 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 Prevention of SARS-CoV-2 Infection Last Updated: December 20, 2023 Summary Recommendation The COVID-19 Treatment Guidelines Panel (the Panel) recommends COVID-19 vaccination for everyone who is eligible according to the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (AI). Each recommendation in the Guidelines receives a rating for the strength of the recommendation (A, B, or C) and a rating for the evidence that supports it (I, IIa, IIb, or III). See Guidelines Development for more information. General Prevention Measures Transmission of SARS-CoV-2 occurs primarily through exposure to respiratory droplets.1 Exposure can occur when individuals inhale droplets or particles that contain the virus or touch mucous membranes with hands that have been contaminated with the virus. Exhaled droplets or particles can also deposit the virus onto exposed mucous membranes. The risk of SARS-CoV-2 transmission can be reduced by covering coughs and sneezes, wearing a well-fitted mask around others, and isolating when experiencing symptoms. Frequent handwashing also effectively reduces the risk of infection.2 Health care providers should follow the Centers for Disease Control and Prevention (CDC) recommendations for infection control and the appropriate use of personal protective equipment.3 COVID-19 Vaccines Recommendation The Panel recommends COVID-19 vaccination for everyone who is eligible according to the CDC’s Advisory Committee on Immunization Practices (AI). Rationale Vaccination is the most effective way to prevent COVID-19. Two 2023–2024 mRNA vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), and the 2023–2024 recombinant spike protein with adjuvant vaccine NVX-CoV2373 (Novavax)4 are currently available in the United States. The adenovirus vector vaccine Ad26.COV2.S (Johnson & Johnson/Janssen) is no longer available in the United States. COVID-19 vaccination is recommended for everyone aged ≥6 months in the United States. The Food and Drug Administration (FDA) Emergency Use Authorization fact sheet and the product label for each vaccine provide detailed information on the vaccination schedule and the doses that are approved or authorized for that vaccine. The type and dose of vaccine and the timing of the doses depend on the recipient’s age and underlying medical conditions. The CDC regularly updates the clinical considerations for the COVID-19 vaccines currently approved by the FDA or authorized for use in the United States.5 Adverse Events COVID-19 vaccines are safe and effective. Local and systemic adverse events are relatively common with these vaccines. Most of the adverse events that occurred during vaccine trials were mild or COVID-19 Treatment Guidelines 18 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 moderate in severity (i.e., they did not prevent vaccinated people from engaging in daily activities) and resolved after 1 or 2 days. There have been a few reports of severe allergic reactions following COVID-19 vaccination, including rare reports of patients who experienced anaphylaxis after receiving an mRNA vaccine.6,7 Thrombosis with thrombocytopenia syndrome is a serious condition characterized by blood clots in large blood vessels and low platelet levels. The prevalence of the syndrome was approximately 4 per million among people who received the Johnson & Johnson/Janssen vaccine.8,9 That vaccine is no longer available in the United States. If a patient experiences thrombosis and thrombocytopenia syndrome after receiving a COVID-19 vaccine outside of the United States, a hematologist should be consulted about evaluation and management. Myocarditis and pericarditis after COVID-19 vaccination are rare, and most of the reported cases were very mild and self-limiting.10 These conditions have occurred most often in male adolescents, young adults, and people who have received mRNA vaccines. The results of recent studies suggest that adults aged ≥18 years who received the Johnson & Johnson/ Janssen vaccine have an increased risk of Guillain-Barré syndrome.11 In contrast, people who received mRNA vaccines do not have an increased risk of Guillain-Barré syndrome.12 The CDC monitors severe adverse events, such as strokes, and provides regular updates on selected adverse events of COVID-19 vaccines. Vaccination in Pregnant and Lactating People Pregnant and lactating individuals were not included in the initial COVID-19 vaccine trials. However, the CDC and the American College of Obstetricians and Gynecologists recommend vaccination for pregnant and lactating people. This recommendation is based on the accumulated safety and efficacy data on the use of these vaccines in pregnant people, as well on as the increased risk of severe disease in pregnant individuals with COVID-19.13-17 These organizations also recommend vaccination for people who are trying to become pregnant or who may become pregnant in the future. The American College of Obstetricians and Gynecologists provides guidance for clinicians on counseling pregnant patients about COVID-19 vaccination.18 Pre-Exposure Prophylaxis As of January 2024, no biomedical intervention other than vaccines prevents COVID-19 disease. Previously, the FDA authorized the use of the anti-SARS-CoV-2 monoclonal antibodies tixagevimab plus cilgavimab (Evusheld) as pre-exposure prophylaxis (PrEP) of COVID-19 in people who were not expected to mount an adequate immune response to COVID-19 vaccination and in people with COVID-19 vaccine contraindications.19 Due to the increased prevalence of Omicron subvariants that are not susceptible to tixagevimab plus cilgavimab, this combination is not currently authorized by the FDA for use as PrEP of COVID-19.20 It remains critical that these individuals: Keep up to date with COVID-19 vaccination unless a contraindication exists. Take precautions to avoid infection. The CDC provides information on the prevention of COVID-19 in people who are immunocompromised. Be tested for SARS-CoV-2 infection if they experience signs and symptoms consistent with COVID-19 and, if infected, promptly seek medical attention. COVID-19 Treatment Guidelines 19 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 Post-Exposure Prophylaxis As of January 2024, no biomedical intervention other than vaccines prevents disease after exposure to SARS-CoV-2. Previously, the FDA authorized the use of the anti-SARS-CoV-2 monoclonal antibody products bamlanivimab plus etesevimab and casirivimab plus imdevimab as post-exposure prophylaxis (PEP) in certain people at high risk of progression to severe COVID-19. However, the Omicron subvariants are not susceptible to these products; therefore, their use as SARS-CoV-2 PEP is not recommended. References 1. Centers for Disease Control and Prevention. COVID-19 overview and infection prevention and control priorities in non-U.S. healthcare settings. 2023. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/ non-us-settings/overview/index.html. Accessed December 1, 2023. 2. Centers for Disease Control and Prevention. How to protect yourself and others. 2023. Available at: https:// www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Accessed December 1, 2023. 3. Centers for Disease Control and Prevention. Interim infection prevention and control recommendations for healthcare personnel during the coronavirus disease 2019 (COVID-19) pandemic. 2023. Available at: https:// www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-recommendations.html. Accessed December 1, 2023. 4. Food and Drug Administration. FDA authorizes updated Novavax COVID-19 vaccine formulated to better protect against currently circulating variants. 2023. Available at: https://www.fda.gov/news-events/ press-announcements/fda-authorizes-updated-novavax-covid-19-vaccine-formulated-better-protect-against- currently. Accessed December 1, 2023. 5. Centers for Disease Control and Prevention. Use of COVID-19 vaccines in the United States. 2023. Available at: https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html. Accessed December 1, 2023. 6. Centers for Disease Control and Prevention. Interim considerations: preparing for the potential management of anaphylaxis after COVID-19 vaccination. 2022. Available at: https://www.cdc.gov/vaccines/covid-19/clinical- considerations/managing-anaphylaxis.html. Accessed December 1, 2023. 7. Food and Drug Administration. Fact sheet for healthcare providers administering vaccine (vaccination providers): Emergency Use Authorization (EUA) of the Janssen COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19). 2022. Available at: https://www.fda.gov/media/146304/download. 8. See I, Su JR, Lale A, et al. US case reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, March 2 to April 21, 2021. JAMA. 2021;325(24):2448-2456. Available at: https://pubmed.ncbi.nlm.nih.gov/33929487. 9. See I, Lale A, Marquez P, et al. Case series of thrombosis with thrombocytopenia syndrome after COVID-19 vaccination—United States, December 2020 to August 2021. Ann Intern Med. 2022;175(4):513-522. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35038274. 10. Centers for Disease Control and Prevention. Selected adverse events reported after COVID-19 vaccination. 2023. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/adverse-events.html. Accessed December 1, 2023. 11. Hanson KE, Goddard K, Lewis N, et al. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Netw Open. 2022;5(4):e228879. Available at: https://pubmed.ncbi.nlm.nih.gov/35471572. 12. Abara WE, Gee J, Marquez P, et al. Reports of Guillain-Barré syndrome after COVID-19 vaccination in the United States. JAMA Netw Open. 2023;6(2):e2253845. Available at: https://pubmed.ncbi.nlm.nih. gov/36723942. 13. Centers for Disease Control and Prevention. COVID-19 vaccines while pregnant or breastfeeding. 2023. COVID-19 Treatment Guidelines 20 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024  Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/pregnancy.html. Accessed December 1, 2023. 14. Shimabukuro TT, Kim SY, Myers TR, et al. Preliminary findings of mRNA COVID-19 vaccine safety in pregnant persons. N Engl J Med. 2021;384(24):2273-2282. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33882218. 15. Zauche LH, Wallace B, Smoots AN, et al. Receipt of mRNA COVID-19 vaccines and risk of spontaneous abortion. N Engl J Med. 2021;385(16):1533-1535. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34496196. 16. Goldshtein I, Nevo D, Steinberg DM, et al. Association between BNT162b2 vaccination and incidence of SARS-CoV-2 infection in pregnant women. JAMA. 2021;326(8):728-735. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34251417. 17. Collier AY, McMahan K, Yu J, et al. Immunogenicity of COVID-19 mRNA vaccines in pregnant and lactating women. JAMA. 2021;325(23):2370-2380. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33983379. 18. American College of Obstetricians and Gynecologists. COVID-19 vaccination considerations for obstetric- gynecologic care. 2023. Available at: https://www.acog.org/clinical/clinical-guidance/practice-advisory/ articles/2020/12/covid-19-vaccination-considerations-for-obstetric-gynecologic-care. Accessed December 1, 2023. 19. Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization for Evusheld (tixagevimab co-packaged with cilgavimab). 2023. Available at: https://www.fda.gov/media/154701/download. 20. Food and Drug Administration. FDA announces Evusheld is not currently authorized for emergency use in the U.S. 2023. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-announces-evusheld-not- currently-authorized-emergency-use-us. Accessed December 1, 2023. COVID-19 Treatment Guidelines 21 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 Clinical Spectrum of SARS-CoV-2 Infection Last Updated: February 29, 2024 Patients with SARS-CoV-2 infection can experience a range of clinical manifestations, from no symptoms to critical illness. In general, adults with SARS-CoV-2 infection can be grouped into the following severity of illness categories; however, the criteria for each category may overlap or vary across clinical guidelines and clinical trials, and a patient’s clinical status may change over time. Asymptomatic or presymptomatic infection: Individuals who test positive for SARS-CoV-2 using a virologic test (i.e., a nucleic acid amplification test [NAAT] or an antigen test) but have no symptoms consistent with COVID-19. Mild illness: Individuals who have any of the various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell) but do not have shortness of breath, dyspnea, or abnormal chest imaging. Moderate illness: Individuals who show evidence of lower respiratory disease during clinical assessment or imaging and who have an oxygen saturation measured by pulse oximetry (SpO2) ≥94% on room air at sea level. Severe illness: Individuals who have an SpO2 50%. Critical illness: Individuals who have respiratory failure, septic shock, or multiple organ dysfunction. SpO2 is a key parameter for defining the illness categories listed above. However, pulse oximetry has important limitations (discussed in more detail below). Clinicians who use SpO2 when assessing a patient must be aware of those limitations and conduct the assessment in the context of that patient’s clinical status. The risk of progressing to severe disease increases with age and the number of underlying conditions. Patients aged ≥50 years, especially those aged ≥65 years, and patients who are immunosuppressed, unvaccinated, or not up to date with COVID-19 vaccinations are at a higher risk of progressing to severe COVID-19.1,2 Certain underlying conditions are also associated with a higher risk of severe COVID-19, including cancer, cardiovascular disease, chronic kidney disease, chronic liver disease, chronic lung disease, diabetes, advanced or untreated HIV infection, obesity, pregnancy, cigarette smoking, and being a recipient of immunosuppressive therapy or a transplant.3 Health care providers should closely monitor patients who have COVID-19 and any of these conditions until clinical recovery is achieved. The initial evaluation for patients may include chest imaging (e.g., X-ray, ultrasound or computed tomography scan) and an electrocardiogram, if indicated. Laboratory testing should include a complete blood count with differential and a metabolic profile, including liver and renal function tests. Although inflammatory markers such as C-reactive protein (CRP), D-dimer, and ferritin are not routinely measured as part of standard care, results from such measurements may have prognostic value.4-7 The definitions for the severity of illness categories also apply to pregnant patients. However, the threshold for certain interventions is different for pregnant and nonpregnant patients. For example, oxygen supplementation for pregnant patients is generally used when SpO2 falls below 95% on room air at sea level to accommodate the physiologic changes in oxygen demand during pregnancy and to ensure COVID-19 Treatment Guidelines 22 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 adequate oxygen delivery to the fetus.8 If laboratory parameters are used for monitoring pregnant patients and making decisions about interventions, clinicians should be aware that normal physiologic changes during pregnancy can alter several laboratory values. In general, leukocyte cell count increases throughout gestation and delivery and peaks during the immediate postpartum period. This increase is mainly due to neutrophilia.9 D-dimer and CRP levels also increase during pregnancy and are often higher in pregnant patients than in nonpregnant patients.10 Detailed information on treating COVID-19 in pregnant patients can be found in Special Considerations During Pregnancy and After Delivery and in the pregnancy considerations subsections in the Guidelines. In children with COVID-19, radiographic abnormalities are common and, for the most part, should not be the only criteria used to determine the severity of illness. The normal values for respiratory rate also vary with age in children. Therefore, hypoxemia should be the primary criterion used to define severe COVID-19, especially in younger children. In a small subset of children and young adults, SARS-CoV-2 infection may be followed by the severe inflammatory condition multisystem inflammatory syndrome in children (MIS-C).11,12 This syndrome is discussed in detail in Special Considerations in Children. Clinical Considerations for the Use of Pulse Oximetry During the COVID-19 pandemic, the use of pulse oximetry to assess and monitor patients’ oxygenation status increased in hospital, outpatient health care facility, and home settings. Although pulse oximetry is useful for estimating blood oxygen levels, pulse oximeters may not accurately detect hypoxemia under certain circumstances. To avoid delays in recognizing hypoxemia, clinicians who use pulse oximetry to assist with clinical decisions should keep these limitations in mind. Pulse oximetry results can be affected by skin pigmentation, thickness, or temperature. Poor blood circulation or the use of tobacco or fingernail polish also may affect results. The Food and Drug Administration (FDA) advises clinicians to refer to the label or manufacturer website of a pulse oximeter or sensor to ascertain its accuracy.13 The FDA also advises using pulse oximetry only as an estimate of blood oxygen saturation, because an SpO2 reading represents a range of arterial oxygen saturation (SaO2). For example, an SpO2 reading of 90% may represent a range of SaO2 from 86% to 94%. Studies that compared SpO2 and SaO2 levels measured before the pandemic found that pulse oximeters overestimated oxygen saturation in people who were classified as having darker skin pigmentation and in people whose race or ethnic origin was reported as non-Hispanic Black, Black, or African American.14,15 Several published reports have compared SpO2 and SaO2 measurements in patients with COVID-19, including children.14,16-18 The studies demonstrated that occult hypoxemia (defined as an SaO2 92%) was more common in patients with darker skin pigmentation, which may result in adverse consequences. The likelihood of error was greater in the lower ranges of SpO2. In 1 of these studies, occult hypoxemia was associated with more organ dysfunction and hospital mortality.17 These studies did not specify the specific devices used to assess SpO2 levels. The FDA has recognized the need for better real-world evidence to address ongoing concerns about the accuracy of pulse oximeters when they are used to measure oxygen saturation in people with darker skin pigmentation.19 A 5-hospital registry study of patients evaluated in the emergency department or hospitalized for COVID-19 found that 24% were not identified as eligible for treatment due to overestimation of SaO2.20 The majority of patients (55%) who were not identified as eligible were Black. The study also examined the amount of time delay patients experienced before being identified as eligible for treatment. The median delay for patients who were Black was 1 hour longer than the delay for patients who were White. COVID-19 Treatment Guidelines 23 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 In pulse oximetry, skin tone is an important variable, but accurately measuring oxygen saturation is a complex process. One observational study in adults was unable to identify a consistently predictable difference between SaO2 and SpO2 over time for individual patients.16 Factors other than skin pigmentation (e.g., peripheral perfusion, pulse oximeter sensor placement) are likely involved. Despite the limitations of pulse oximetry, an FDA-cleared pulse oximeter for home use can contribute to an assessment of a patient’s overall clinical status. Practitioners should advise patients to follow the manufacturer’s instructions for use, place the oximeter on the index or ring finger, and ensure the hand is warm, relaxed, and held below the level of the heart. Fingernail polish should be removed before testing. Patients should be at rest, indoors, and breathing quietly without talking for several minutes before testing. Rather than accepting the first reading, patients or caretakers should observe the readings on the pulse oximeter for ≥30 seconds until a steady number is displayed and inform their health care provider if the reading is repeatedly below a previously specified value (generally 95% on room air at sea level).13,21 Pulse oximetry has been widely adopted as a remote patient monitoring tool, but when the use of pulse oximeters is compared with close monitoring of clinical progress via video consultation, telephone calls, text messaging, or home visits, there is insufficient evidence that it improves clinical outcomes.22,23 Not all commercially available pulse oximeters have been cleared by the FDA. SpO2 readings obtained through devices not cleared by the FDA, such as over-the-counter sports oximeters or mobile phone applications, lack sufficient accuracy for clinical use. Abnormal readings on these devices should be confirmed with an FDA-cleared device or an arterial blood gas analysis.24,25 Regardless of the setting, SpO2 should always be interpreted within the context of a patient’s entire clinical presentation. Regardless of a pulse oximeter reading, a patient’s signs and symptoms (e.g., dyspnea, tachypnea, chest pain, changes in cognition or attentional state, cyanosis) should be evaluated. Asymptomatic or Presymptomatic Infection Asymptomatic SARS-CoV-2 infection can occur, although the percentage of patients who remain truly asymptomatic throughout the course of infection is variable and incompletely defined. The percentage of individuals who present with asymptomatic infection and progress to clinical disease is unclear. Some asymptomatic individuals have been reported to have objective radiographic findings consistent with COVID-19 pneumonia.26,27 Mild Illness Patients with mild illness may exhibit a variety of signs and symptoms (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell). They do not have shortness of breath, dyspnea on exertion, or abnormal imaging. Most patients who are mildly ill can be managed in an ambulatory setting or at home. No imaging or specific laboratory evaluations are routinely indicated in otherwise healthy patients with mild COVID-19. Patients aged ≥50 years, especially those aged ≥65 years, patients with certain underlying comorbidities, and patients who are immunosuppressed, unvaccinated, or not up to date with COVID-19 vaccinations are at higher risk of disease progression and are candidates for antiviral therapy.1,2 See Therapeutic Management of Nonhospitalized Adults With COVID-19 for recommendations regarding anti-SARS-CoV-2 therapies. Moderate Illness Moderate illness is defined as evidence of lower respiratory disease during clinical assessment or imaging, with an SpO2 ≥94% on room air at sea level. Given that pulmonary disease can progress rapidly in patients with COVID-19, patients with moderate disease should be closely monitored. See Therapeutic Management of Nonhospitalized Adults With COVID-19 for recommendations regarding COVID-19 Treatment Guidelines 24 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 anti-SARS-CoV-2 therapies in patients at high risk of progression to severe disease. Severe Illness Patients with COVID-19 are considered to have severe illness if they have an SpO2 50%. These patients may experience rapid clinical deterioration and should be given oxygen therapy and hospitalized. See Therapeutic Management of Hospitalized Adults With COVID-19 for treatment recommendations. Critical Illness SARS-CoV-2 infection can cause acute respiratory distress syndrome, virus-induced distributive (septic) shock, cardiac shock, an exaggerated inflammatory response, thrombotic disease, and exacerbation of underlying comorbidities. The clinical management of patients with COVID-19 who are in the intensive care unit should include treatment with immunomodulators and, in some cases, the addition of remdesivir. These patients should also receive treatment for any comorbid conditions and nosocomial complications. For more information, see Critical Care for Adults and Therapeutic Management of Hospitalized Adults With COVID-19. Infectious Complications in Patients With COVID-19 Some patients with COVID-19 may have additional infections when they present for care or that develop during the course of treatment. These coinfections may complicate treatment and recovery. Older patients or those with certain comorbidities or immunocompromising conditions may be at higher risk for these infections. The use of immunomodulators such as dexamethasone, Janus kinase inhibitors (e.g., baricitinib, tofacitinib), interleukin-6 inhibitors (e.g., tocilizumab, sarilumab), tumor necrosis factor inhibitors (e.g., infliximab), or abatacept to treat COVID-19 may also increase the risk of infectious complications. However, when these therapies are used appropriately, the benefits outweigh the risks. Infectious complications in patients with COVID-19 can be categorized as follows: Coinfections at presentation: Although most individuals present with only SARS-CoV-2 infection, concomitant viral infections, including influenza and other respiratory viruses, have been reported.28-30 Community-acquired bacterial pneumonia has also been reported, but it is uncommon.28,31,32 Antibacterial therapy is generally not recommended unless additional evidence for bacterial pneumonia is present (e.g., leukocytosis, the presence of a focal infiltrate on imaging). Reactivation of latent infections: There are case reports of underlying chronic hepatitis B virus and latent tuberculosis infections reactivating in patients with COVID-19 who receive immunomodulators as treatment, although the data are currently limited.33-35 Reactivation of herpes simplex virus and varicella zoster virus infections have also been reported.36 Cases of severe and disseminated strongyloidiasis have been reported in patients with COVID-19 during treatment with tocilizumab and corticosteroids.37,38 Many clinicians would initiate empiric treatment (e.g., with the antiparasitic drug ivermectin), with or without serologic testing, in patients who require immunomodulators for the treatment of COVID-19 and have come from areas where Strongyloides is endemic (i.e., tropical, subtropical, or warm temperate areas).39,40 Nosocomial infections: Hospitalized patients with COVID-19 may acquire common nosocomial infections, such as hospital-acquired pneumonia (including ventilator-associated pneumonia), line- COVID-19 Treatment Guidelines 25 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024  related bacteremia or fungemia, catheter-associated urinary tract infection, and diarrhea associated with Clostridioides difficile.41,42 Early diagnosis and treatment of these infections are important for improving outcomes in these patients. Opportunistic fungal infections: Invasive fungal infections, including aspergillosis and mucormycosis, have been reported in hospitalized patients with COVID-19.43-46 Although these infections are relatively rare, they can be fatal, and they may be seen more commonly in patients who are immunocompromised or receiving mechanical ventilation. The majority of mucormycosis cases have been reported in India and are associated with diabetes mellitus or the use of corticosteroids.47,48 The approach for managing these fungal infections should be the same as the approach for managing invasive fungal infections in other settings. SARS-CoV-2 Reinfection and Breakthrough Infection As seen with other respiratory viral infections, reinfection after recovery from prior infection has been reported for SARS-CoV-2.49 Reinfection may occur as initial immune responses to the primary infection wane over time. Data regarding the prevalence, risk factors, timing, and severity of reinfection are evolving and vary depending on the circulating variants. Breakthrough SARS-CoV-2 infections (i.e., infection in people who are up to date with COVID-19 vaccinations) also occur.50 When compared with infection in people who are unvaccinated, breakthrough infections in vaccinated individuals appear less likely to lead to severe illness or symptoms that persist ≥28 days.50-53 The time to breakthrough infection has been reported to be shorter for patients with immunocompromising conditions (i.e., solid organ or bone marrow transplant recipients or people with HIV) than for those with no immunocompromising conditions.50 Although data are limited, no evidence suggests that the treatment of suspected or documented SARS-CoV-2 reinfection or breakthrough infection should be different from the treatment used during the initial infection, as outlined in Therapeutic Management of Nonhospitalized Adults With COVID-19 and Therapeutic Management of Hospitalized Adults With COVID-19. Prolonged Viral Shedding, Persistent Symptoms, and Other Conditions After SARS-CoV-2 Infection Symptomatic SARS-CoV-2 infection is typically associated with a decline in viral shedding and resolution of COVID-19 symptoms over days to weeks. However, in some cases, reduced viral shedding and symptom resolution are followed by viral or symptom rebound. People who are immunocompromised may experience viral shedding for many weeks. Some people experience symptoms that develop or persist for more than 4 weeks after the initial COVID-19 diagnosis. Viral or Symptom Rebound Soon After COVID-19 Observational studies and results from clinical trials of therapeutic agents have described SARS-CoV-2 viral or COVID-19 symptom rebound in patients who have completed treatment for COVID-19.54-56 Viral and symptom rebounds have also occurred when anti-SARS-CoV-2 therapies were not used.56,57 Typically, this phenomenon has not been associated with progression to severe COVID-19. Prolonged Viral Shedding in Patients Who Are Immunocompromised Patients who are immunocompromised may experience prolonged shedding of SARS-CoV-2 with or without COVID-19 symptoms.58,59 Prolonged viral shedding may affect SARS-CoV-2 testing strategies and isolation duration for these patients. In some cases, the prolonged shedding may be associated with persistent COVID-19 symptoms. See Special Considerations in People Who Are Immunocompromised for more information on the clinical management of people who are immunocompromised. COVID-19 Treatment Guidelines 26 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 Persistent, New, or Recurrent Symptoms More Than 4 Weeks After SARS-CoV-2 Infection Some patients report persistent, new, or recurrent symptoms and conditions (e.g., cardiopulmonary injury, neurocognitive impairment, new-onset diabetes, gastrointestinal and dermatologic manifestations) more than 4 weeks after the initial COVID-19 diagnosis.60 The nomenclature for this phenomenon is evolving; no clinical terminology has been established. The terminology used includes long COVID, post-COVID condition, post–COVID-19 syndrome, and post-acute sequelae of SARS-CoV-2. Patients who have these symptoms or conditions have been called “long haulers.” Data on the incidence, natural history, and etiology of these symptoms are emerging. However, reports on these syndromes have several limitations, such as differing case definitions, a lack of comparator groups, and overlap between the reported symptoms and the symptoms of post-intensive care syndrome that have been described in patients without COVID-19. In addition, many reports only included patients who attended post-COVID clinics. Details on the pathogenesis, clinical presentation, and treatment for these conditions are beyond the scope of these Guidelines. The Centers for Disease Control and Prevention provides information about the timeframes, presentation of symptoms, and management strategies for post-COVID conditions. Research on the prevalence, characteristics, and pathophysiology of persistent symptoms and conditions after COVID-19 is ongoing, including research through the National Institutes of Health’s RECOVER Initiative, which aims to inform potential therapeutic strategies. MIS-C and multisystem inflammatory syndrome in adults (MIS-A) are serious postinfectious complications of SARS-CoV-2 infection. For more information on these syndromes, see Therapeutic Management of Hospitalized Children With MIS-C, Plus a Discussion on MIS-A. References 1. Skarbinski J, Wood MS, Chervo TC, et al. Risk of severe clinical outcomes among persons with SARS-CoV-2 infection with differing levels of vaccination during widespread Omicron (B.1.1.529) and Delta (B.1.617.2) variant circulation in Northern California: a retrospective cohort study. Lancet Reg Health Am. 2022;12:100297. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35756977. 2. Taylor CA, Patel K, Patton ME, et al. COVID-19–associated hospitalizations among U.S. adults aged ≥65 Years—COVID-NET, 13 states, January–August 2023. MMWR Morb Mortal Wkly Rep. 2023;72(40):1089- 1094. Available at: https://www.ncbi.nlm.nih.gov/pubmed/37796744. 3. Centers for Disease Control and Prevention. Underlying medical conditions associated with higher risk for severe COVID-19: information for healthcare professionals. 2023. Available at: https://www.cdc.gov/ coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html. Accessed January 10, 2024. 4. Tan C, Huang Y, Shi F, et al. C-reactive protein correlates with computed tomographic findings and predicts severe COVID-19 early. J Med Virol. 2020;92(7):856-862. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32281668. 5. Berger JS, Kunichoff D, Adhikari S, et al. Prevalence and outcomes of D-dimer elevation in hospitalized patients with COVID-19. Arterioscler Thromb Vasc Biol. 2020;40(10):2539-2547. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32840379. 6. Casas-Rojo JM, Antón-Santos JM, Millán-Núñez-Cortés J, et al. Clinical characteristics of patients hospitalized with COVID-19 in Spain: results from the SEMI-COVID-19 registry. Rev Clin Esp (Barc). 2020;220(8):480-494. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32762922. 7. Smilowitz NR, Kunichoff D, Garshick M, et al. C-reactive protein and clinical outcomes in patients with COVID-19. Eur Heart J. 2021;42(23):2270-2279. Available at: https://www.ncbi.nlm.nih.gov/ pubmed/33448289. 8. Society for Maternal-Fetal Medicine. Management considerations for pregnant patients with COVID-19. 2021. Available at: https://s3.amazonaws.com/cdn.smfm.org/media/2734/SMFM_COVID_Management_of_ COVID-19 Treatment Guidelines 27 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024  COVID_pos_preg_patients_2-2-21_(final).pdf. 9. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009;114(6):1326-1331. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19935037. 10. Anderson BL, Mendez-Figueroa H, Dahlke JD, et al. Pregnancy-induced changes in immune protection of the genital tract: defining normal. Am J Obstet Gynecol. 2013;208(4):321.e1-321.e9. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23313311. 11. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395(10237):1607-1608. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32386565. 12. Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395(10239):1771-1778. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32410760. 13. Food and Drug Administration. Pulse oximeter accuracy and limitations: FDA safety communication. 2023. Available at: https://www.fda.gov/medical-devices/safety-communications/pulse-oximeter-accuracy-and- limitations-fda-safety-communication. Accessed January 10, 2024. 14. Valbuena VSM, Seelye S, Sjoding MW, et al. Racial bias and reproducibility in pulse oximetry among medical and surgical inpatients in general care in the Veterans Health Administration 2013–19: multicenter, retrospective cohort study. BMJ. 2022;378:e069775. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35793817. 15. Shi C, Goodall M, Dumville J, et al. The accuracy of pulse oximetry in measuring oxygen saturation by levels of skin pigmentation: a systematic review and meta-analysis. BMC Med. 2022;20(1):267. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35971142. 16. Chesley CF, Lane-Fall MB, Panchanadam V, et al. Racial disparities in occult hypoxemia and clinically based mitigation strategies to apply in advance of technological advancements. Respir Care. 2022;67(12):1499- 1507. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35679133. 17. Wong AI, Charpignon M, Kim H, et al. Analysis of discrepancies between pulse oximetry and arterial oxygen saturation measurements by race and ethnicity and association with organ dysfunction and mortality. JAMA Netw Open. 2021;4(11):e2131674. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34730820. 18. Savorgnan F, Hassan A, Borges N, Acosta S. Pulse oximetry and arterial saturation difference in pediatric COVID-19 patients: retrospective analysis by race. Pediatr Crit Care Med. 2023;24(6):458-462. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36825900. 19. Food and Drug Administration. Approach for improving the performance evaluation of pulse oximeter devices taking into consideration skin pigmentation, race and ethnicity. 2023. Available at: https://www.fda.gov/media/173905/download. 20. Fawzy A, Wu TD, Wang K, et al. Racial and ethnic discrepancy in pulse oximetry and delayed identification of treatment eligibility among patients with COVID-19. JAMA Intern Med. 2022;182(7):730-738. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35639368. 21. Luks AM, Swenson ER. Pulse oximetry for monitoring patients with COVID-19 at home. Potential pitfalls and practical guidance. Ann Am Thorac Soc. 2020;17(9):1040-1046. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32521167. 22. Alboksmaty A, Beaney T, Elkin S, et al. Effectiveness and safety of pulse oximetry in remote patient monitoring of patients with COVID-19: a systematic review. Lancet Digit Health. 2022;4(4):e279-e289. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35337644. 23. Lee KC, Morgan AU, Chaiyachati KH, et al. Pulse oximetry for monitoring patients with COVID-19 at home—a pragmatic, randomized trial. N Engl J Med. 2022;386(19):1857-1859. Available at: https://www. ncbi.nlm.nih.gov/pubmed/35385625. COVID-19 Treatment Guidelines 28 Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 4/30/2024 24. Harskamp RE, Bekker L, Himmelreich JCL, et al. Performance of popular pulse oximeters compared with simultaneous arterial oxygen saturation or clinical-grade pulse oximetry: a cross-sectional validation study in intensive care patients. BMJ Open Respir Res. 2021;8(1):e000939. Available at: https://www.ncbi.nlm.nih. gov/pubmed/34489238. 25. Lipnick MS, Feiner JR, Au P,