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COVID-19 Rebound: No Increased Risk with Antiviral Use


COVID-19 Rebound occurs between 2 – 8 days after the initial illness recovery and is described by the CDC as a recurrence of COVID-19 symptoms or a new positive viral test after having tested negative. High profile cases of COVID-19 rebound following the use of antiviral medications has led to growing concern that the use of these agents may prolong illness or paradoxically worsen outcomes. Two recent studies, one comparing symptomatic and viral rebound in untreated outpatients, and another examining differences in rebound rates of hospitalized patients, have shown reassuring results, with no increased risk of rebound due to antiviral use, and no increased morbidity or mortality associated with COVID-19 rebound.


Annals of Internal Medicine

  • Outpatients with COVID-19
    • Retrospective analysis of previous RCT
    • 563 patients in the placebo arm were followed for symptom and viral (laboratory) rebound
    • 13 different symptoms recorded daily during the study
    • Patients underwent RNA testing on days 0 to 14, and then again on days 21 and 28
    • Median onset of symptom rebound was on day 11 and occurred in 26% of participants
    • Viral rebound occurred in 31% of participants
    • Only 3% of participants had BOTH viral and symptom rebound
    • Most rebounds were transient

The Lancet Infectious Diseases

  • Hospitalized patients with COVID-19 during the omicron wave in Hong Kong  
    • Retrospective study | Viral rebound and composite outcomes were assessed
    • 4,592 patients who did not initially require supplemental oxygen
    • 563 received Molnupiravir (Lagevrio)| 242 received Nirmatrelvir–Ritonavir (Paxlovid) | 3787 did not receive any oral antiviral treatment (control group)
    • Viral burden rebound was observed in 4 to 7% of hospitalized patients and there was no statistically significant difference between each group
    • Viral rebound was more common in certain groups: Younger adults (age 18–65 years) | Fully Vaccinated | Prior poor health | Immunocompromised | Patients on corticosteroids
    • Viral rebound was not associated with increased adverse clinical outcomes
    • Researchers in conclusion suspect that COVID-19 rebound may be due to the natural biphasic course of the disease or that the course of antiviral medications may not be adequate for certain patient populations (e.g., the immunocompromised)

Learn More – Primary Sources

ACP: COVID-19 rebound occurs with or without antivirals, doesn’t affect outcomes, studies find

Annals of Internal Medicine: Symptom and Viral Rebound in Untreated SARS-CoV-2 Infection

The Lancet ID: Viral burden rebound in hospitalised patients with COVID-19 receiving oral antivirals in Hong Kong: a population-wide retrospective cohort study

EMAS Position Statement: Use of Vitamin D Among Postmenopausal Women


EMAS, an international society that promotes health in women and men at midlife and beyond, has produced a position statement targeting the use of vitamin D in postmenopausal women. The literature suggests “an association between vitamin D deficiency and adverse health outcomes in postmenopausal women, although they cannot establish causality.” The document includes an extensive literature review.

‘Vitamin D’ Overview

What is it?

  • Group of lipophilic hormones
  • Regulates calcium homeostasis via kidney, gastrointestinal tract, skeleton and parathyroid
  • Critical for skeletal health but impacts multiple tissues
  • Two major forms
    • Vitamin D2 (ergocalciferol)
    • Vitamin D3 (cholecalciferol)
      • Major source through cutaneous synthesis through exposure to sunlight
      • Small amount from animal diet (fatty fish, eggs and milk)


  • Vitamin D status: Measure serum 25-hydroxyvitamin D levels
    • <20 ng/ml (<50 nmol/l): Vitamin D deficiency
    • <10 ng/ml (<25 nmol/l): Severe Vitamin D deficiency

Vitamin D Deficiency and Associated Health Outcomes

  • Skeletal
    • Increased fracture risk
  • Menopausal Symptomatology  
    • Evidence is inconsistent
    • Some studies have demonstrated increased risk
      • Hot flashes | Depression | Sexual dysfunction | Sleep disturbances
  • Cardiac
    • Increased prevalence for CVD risk factors
      • Metabolic syndrome | Type 2 diabetes | Atherogenic dyslipidemia
    • Increased incidence for CVD events
  • Cancer
    • Increased risk for cancers: Colorectal | Lung | Breast
    • Overall and cancer-specific mortality rates are increased in postmenopausal women
    • No evidence for ovarian or other gyn cancers
  • Infections and Inflammation
    • Increased risk for respiratory infection
    • Increased risk for autoimmune disorders

Vitamin D Supplementation Recommendations for Postmenopausal Women

Skeletal Health

  • No vitamin D deficiency or low fracture risk
    • No evidence to support vitamin D supplementation
  • Vitamin D deficiency with osteoporosis and/or high fracture risk (FRAX model)
    • Vitamin D: 2000 to 4000 IU (4000 to 6000 IU in obese patients)
    • Calcium: 1000 to 1200 mg of calcium (dietary or supplements)
    • Encourage Vitamin D and calcium use for minimum 3 to 5 years
    • Check vitamin D levels 3 to 6 months with target above 20 ng/ml (<50 nmol/l)

Menopausal Symptomatology

  • Vitamin D supplementation is not recommended to improve menopausal symptoms

Cardiovascular Disease

  • No effect of vitamin D supplementation on decreasing CVD risk


  • No effect of vitamin D supplementation on cancer incidence although some studies identified a small reduction in cancer-related mortality

Infections and Inflammation

  • Vitamin D supplementation may ‘modestly’ decrease the risk for acute respiratory tract infections including COVID-19
  • Concerns regarding study design such as “heterogeneity in design, duration, population and vitamin D dosage among studies must be underscored”


  • Typical daily dose of 1000 to 1200 mg of calcium is not associated with increased risk for cardiovascular disease or nephrolithiasis
  • Studies on vitamin D supplementation have significant limitations due to heterogeneity regarding dose, inclusion of calcium and baseline vitamin D status
  • More research needed to
    • Discriminate between vitamin D replacement and supplementation
    • Determine the need for universal vitamin D screening in postmenopausal women

Learn More – Primary Sources:

EMAS position statement: Vitamin D and menopausal health

IDSA 2018 Clinical Practice Guidelines: Seasonal Influenza


Seasonal influenza is a respiratory illness caused by the Influenza A and B viruses. Virus outbreaks typically occur in the winter season, and symptoms can range from mild to life threatening. While most patients recover from uncomplicated influenza, the illness can progress to severe disease and death. Young children, older adults, pregnant and postpartum patients, and those with certain medical conditions such as immunosuppression, are at highest risk of complications. While influenza rates declined markedly during the COVID-19 pandemic, the virus returned aggressively in 2022 with unprecedented rates of infection compared to recent years. The cornerstone of influenza treatment remains prevention with yearly vaccination. The IDSA last released a clinical practice guideline in 2018 to assist with diagnosis, treatment, chemoprophylaxis and outbreak management.


Signs and Symptoms

  • Commonly: Fever | Myalgia | Non-productive cough
  • Also typical: Sore Throat | Rhinorrhea | Headache | Nausea | Weakness
  • Complications: Pneumonia | Respiratory failure | ARDS | Multiorgan failure | Sepsis | Liver inflammation| Rhabdomyolysis | Myocarditis | Encephalitis | AKI
  • Laboratory, physical exam, and imaging findings are not specific for the flu and generally do not clarify diagnosis in the absence of flu testing

Outpatient Testing

  • Clinicians should preform outpatient testing for the flu during an influenza outbreak in patients who:
    • Are high risk (e.g. older age, immunocompromise, pregnant) and present with acute respiratory illness or flu-like symptoms if testing will alter clinical management
    • Develop acute respiratory symptoms, with or without fever, in addition to exacerbation of chronic medical conditions or known complication of the flu (e.g. pneumonia) and testing will alter clinical management
    • Are not high risk but present with flu-like illness, pneumonia or respiratory illness and are likely to be discharged or reduce the use of antibiotics in the setting of a positive flu test, or otherwise alter clinical management
  • Clinicians can consider outpatient testing for the flu in the absence of high local flu activity if a patient presents with acute respiratory symptoms, prioritizing those with immunocompromise or high-risk conditions

Inpatient Testing

  • Clinicians should preform inpatient testing for the flu during an influenza outbreak in patients who:
    • Are being admitted with acute respiratory illness, with or without fever
    • Are being admitted for acute worsening of chronic cardiopulmonary disease (e.g. asthma, CHF, COPD)
    • Are being admitted with respiratory symptoms, with or without fever, in the setting of immunocompromise or high-risk comorbidities
    • Develop respiratory symptoms while hospitalized in the absence of a clear alternative diagnosis
  • Clinicians should test for the flu during low local influenza activity if the patient is being admitted for acute respiratory illness and has: Known exposure to the flu | Exposure to a respiratory illness outbreak of uncertain cause | Traveled from an area with high flu activity
  • Clinicians can consider testing for influenza in patients who present with acute febrile respiratory illness and are at high risk of complications, if testing will alter management

Modes of Testing

  • Clinicians should obtain upper respiratory specimens for testing as soon as symptoms develop, and preferably within 4 days to improve yield and accuracy
  • Nasopharyngeal specimens are preferred
    • Endotracheal aspirate or BAL specimens can be used for inpatients on mechanical ventilation        
  • Outpatient testing:
    • Rapid molecular assays (e.g. nucleic acid amplification tests) are preferred over rapid diagnostic tests
  • Inpatient testing:
    • Reverse-transcription polymerase chain reaction (RT-PCR) or other molecular assays are preferred
    • RT-PCR targeting multiple respiratory pathogens should be used in immunocompromised patients or in immunocompetent patient’s if it will influence care
  • Consider resistance testing for:
    • Patients who develop influenza infection while on chemoprophylaxisImmunosuppressed patients or patients with severe disease with evidence of ongoing disease after 7 to 10 days
    • Patient who received subtherapeutic doses of NAI therapy


  • Start antiviral therapy as soon as possible in all patients with positive flu testing who meet the following criteria:
    • Inpatients hospitalized for influenza infection, regardless of duration
    • Outpatients with severe or progressive illness, regardless of duration
    • Outpatients at high risk for complications
    • Children < 2 years old and adults ≥ 65 years old
    • Pregnant patients and those within 2 weeks postpartum
  • Consider antiviral therapy in all patients not at risk for complications who the meet the following criteria:
    • Outpatients who present within 48 hours of symptom onset
    • Outpatients with symptoms who are household contacts of those at high risk of complications
    • Outpatient symptomatic healthcare workers who care for patients
      who are at high risk of developing complications if infected with influenza
  • Antiviral therapy is with: Oral oseltamivir | Inhaled Zanamivir | Single dose of intravenous Peramivir
  • Oral and inhaled therapies should be given for 5 days, but course may be extended for immunosuppressed and hospitalized patients
  • Further work up for alternative causes and antibiotics for bacterial coinfection should be added for patients who: Present with severe disease | Improve but then deteriorate | Fail to improve after 3 to 5 days of antiviral therapy


  • Oral and inhaled NAIs are the preferred drugs for chemoprophylaxis
  • Post exposure prophylaxis should be given with 48 hours of exposure and last for 7 days since last contact with known exposure
  • If a patient on chemoprophylaxis tests positive for the flu they should be switched to antiviral treatment dosing

Preexposure Chemoprophylaxis

  • Preexposure chemoprophylaxis for the length of flu season may be considered for:
    • Patients at high risk of flu complications who are unable to be vaccinated (e.g., the severely immunosuppressed) or unlikely to respond to vaccines (e.g., recent stem cell transplant patients)
  • Short term preexposure chemoprophylaxis and administration of inactivated flu vaccine may be considered for:
    • Patients at high risk for flu complications in whom the vaccine is expected to be effective during times of high flu activity 

Postexposure Chemoprophylaxis

  • Consider giving postexposure chemoprophylaxis to Asymptomatic high-risk patients who are unable to be adequately vaccinated with a household exposure
  • Consider giving postexposure chemoprophylaxis and the inactivated influenza vaccine to unvaccinated patients with household members at high risk for complications

Institutional Outbreak Control:

  • Outbreak control measures include: Chemoprophylaxis for residents/patients for 14 days and at least 7 days after last symptom onset of last identified case| Surveillance testing | Testing for all patients who develop respiratory symptoms | Empiric treatment dose antiviral therapy for patients who develop symptoms prior to test results

Primary Sources – Learn More:

Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa

CDC Flu Information for Health Professionals

Annals of Internal Medicine: Influenza