Updated: February 6, 2023

MICROBIOLOGY

• Coronaviruses
  • Positive sense, single-stranded enveloped RNA virus belongs to the family Coronaviridae.
  • Coronavirus name is derived from the Latin corona, meaning crown. The viral envelope under electron microscopy appears crown-like due to small bulbar projections formed by the viral spike (S) peplomers. Neutralizing antibodies against the S-protein are believed to play an important role in protective immunity.
• This topic covers the novel coronavirus 2019, SARS-CoV-2.
• For discussion of other coronaviruses, see individual highlighted modules:
  • Coronavirus for common human respiratory coronavirus infections.
  • SARS for SARS-CoV-1 virus has not been known to circulate since 2002–2003.
  • MERS for the MERS-CoV virus, causing sporadic infections, mainly in the Arabian peninsula since 2012.
  • Coronaviruses also commonly infect birds and mammals, causing gastroenteritis and respiratory diseases.
• SARS-CoV-2 uncertainty exists regarding whether its emergence into human populations appears to be a zoonotic infection or related to release from a laboratory studying the virus.
  • Origin is uncertain, although bats are implicated as this virus is most closely related by genetic analysis to bat SARS-like coronavirus (genus Betacoronavirus, subgenus Sarbecovirus). Circulating viruses similar to the Wuhan (ancestor strain) of SARS-CoV-2 have not yet been demonstrated in an animal reservoir.

CLINICAL

• COVID-19 (novel COronaVirus Disease-2019) is the disease, SARS-CoV-2 is the virus.

Epidemiology

• COVID-19 cases
  • Ongoing pandemic, declared by the WHO. It is unlikely this virus will disappear, and it will likely become part of the repertoire of respiratory viruses that infect humans regularly.
  • Real-time global reports are available through Coronavirus COVID-19 Global Cases Dashboard by Johns Hopkins CSSE.
    
    • Despite global vaccination efforts and mitigation strategies, including facial masks and social distancing, vaccination, and therapies, millions of cases may be occurring worldwide, many now not documented, including among immunized populations, which allows for continued opportunities for the emergence of variants with immune evasiveness features.
      • Omicron appears at least more transmissible than Delta and the Delta variant and is 50-70% more transmissible than earlier variants, including Alpha.
        • Circulating Omicron sublineages in the US may be tracked by this CDC genomic variant surveillance.
          • Includes NOWCAST projection and modeling of what may be happening in real-time since data lags by 2-3+ weeks.
      • Severe infections remain more prevalent in the unimmunized with multiple risk factors and people with poor vaccine responses.
• Risk groups
  • Older age, especially > 65 yrs, and people with comorbidities appear more likely to develop an infection with severe symptoms and be at risk for death.
    • Age gradient, with > 85 years highest; 81% of U.S. deaths are age > 65 years with 80x greater mortality risk than 18- to 29-year-olds.
    • CDC reports that 95% of COVID-19-related deaths have at least one comorbidity.
    • FDA and CDC have age ≥
  • Risks (per CDC): as determined by types of studies
    • Comorbidities (alphabetical order): age ≥ 50 years, cancer, chronic kidney disease, COPD, chronic lung disease, dementia or other neurological conditions, diabetes (types 1 and 2), Down syndrome, HIV, immunocompromised people, mental health conditions (depression, schizophrenia), BMI ≥ 25 (so overweight or obesity), pregnancy, sickle cell or thalassemia, smoking (current or former), solid organ or blood stem cell transplant, stroke/CVA, substance use disorders, active TB.
      • Multiple comorbidities are additive in risk.
    • Children/Teens: generally at less risk for severe illness; however, underlying medical problems, if present, elevate risk.
      • Younger adults are also hospitalized in the U.S., reflecting increasing percentages in many states. These cases in the later phases of the pandemic account for an increasing percentage of cases.
      • Children < 1 yr at high risk for severe illness
      • Children 1–10 yrs: low risk of disease and transmission
      • Children 10–18 yrs: higher risk of disease compared to the 1–10 yr group; however, some studies show a higher risk of transmission than adults.
    • People in congregate settings with disabilities or chronic health problems have worse outcomes and face barriers to care.

Transmission

• Through respiratory droplets, aerosolization is possible (especially indoors/prolonged exposure, areas with poor ventilation). Acquisition from fomites is likely uncommon. Virus are found in respiratory secretions and saliva.
  • Spread from a fomite; the risk is considered very low.
• Viral shedding by asymptomatic people may represent a subset of total infections, though some uncertainty remains regarding how much they contribute to totals.
  • Viral shedding may antedate symptoms, usually two days.
  • Viral titers are highest in the earliest phases of infection, 1-2 days before the onset of symptoms, and then in the first 4-6 days of illness in patients without immunosuppression.
• SARS-CoV-2 continues to evolve rapidly due to the inherent infidelity of RNA viruses that generate random mutations and millions of daily infections.
  
  • Asymptomatically infected people who shed and spread are part of the explanation.
    • Not-ill people will not as carefully take measures to avoid transmission.
      • Some are super-spreaders, which may be due to inherent characteristics (e.g., their speech generates aerosol, loud speaking, etc.).
    • Mass gatherings enhance transmission, especially indoors in smaller spaces or with poor ventilation.
    • This is essentially the rationale behind universal mask use indoors when community rates are high.
  • Aerosol spread may contribute, especially in some settings.
    • The amount of airborne transmission frequency is debated, and evidence of viral RNA beyond the expected droplet range, especially indoors, if poor ventilation exists.
      • 6-ft distancing remains a routine social distancing recommendation but has largely not been followed in many settings where mitigation strategies are no long advocated; uncovered face/sneezes may generate partial aerosolization with some activities for greater distances.
  • Whether droplet or aerosol, concern for spreading by those ill or not ill but infected is the rationale for the universal wearing of masks while in public or if one cannot maintain social distancing, at least six feet.
  • Stool shedding is also described later in the disease, but uncertain what role, if any, that plays in transmission.
    • It appears to be a tool that can predict outbreaks and changes in viral contours within communities.

Incubation period and viral shedding, isolation, quarantine or airborne isolation

1. Mean incubation with Omicron is 4.3 days, median 3-4d, range 2–14d.
2. Quarantine and Isolation: some local health departments and institutions may vary from CDC guidance.
   1. 1. Isolation: a term used if SARS-CoV-2 is infected with or without symptoms.
         1. If tested positive (antigen or PCR) regardless of vaccine status: isolate at home and from others x 5d after onset of symptoms.
         2. End isolation after 5 full days if fever-free and not using antipyretics and symptoms improve.
            1. Per CDC, HCW now 7d or two negative serial antigen tests if < 10d.
         3. If severely ill or immunocompromised: isolate x 10d and consult your clinician before ending isolation.
         4. Wear a mask for 10 days inside your home and in public.
            1. Note by author: growing evidence that with the latest Omicron sublineage variants (BA.5), some people with immunity may yield infectious virus through days 10-14, longer if severely immunosuppressed.
         5. Avoid being around people who are at high risk.
      2. Quarantine: a term if potentially exposed.
         1. Quarantine is no longer advised by CDC (Aug 2022) if entirely up to date on immunization.
         2. If exposed (close contact defined as < 6ft from infected person x 15 minutes cumulatively over 24 h) and either unimmunized or not up-to-date (including recommended boosters):
            1. stay home x 5d [the quarantine], wear a well-fitted mask if you cannot be away from others, do not travel, and get tested at least 5d after close contact.
            2. Watch for symptoms x 10d and avoid travel
            3. If you develop symptoms, isolate and get tested
            4. Wear a mask for a full 10 days.
            5. Avoid being around people at high risk
         3. No travel, regardless of immunized status, is recommended x 10 days.
         4. Watch for COVID-19 symptoms x 10 days.
   2. Healthcare worker recommendations:
      1. The CDC updated guidance for HCW (9/22/22), reflecting longer carriage in many infectious virus beyond five days.
         1. Quarantine: in most circumstances, regardless of vaccination status, asymptomatic workers and those who test negative do not need restrictions.
         2. Isolation
            1. HCW with mild to moderate disease (and not immunocompromised) may return to work if:
               • At least 7 days have passed since symptoms first appeared if a negative viral test* is obtained within 48 hours before returning to work (or 10 days if testing is not performed or if a positive test at day 5-7), and
               • At least 24 hours have passed since the last fever without the use of fever-reducing medications, and
               • Symptoms (e.g., cough, shortness of breath) have improved.
            2. HCW with severe/critical infection who are not immunocompromised may return to work if:
               • At least 10 days and up to 20 days have passed since symptoms first appeared, and
               • At least 24 hours have passed since last fever without the use of fever-reducing medications, and
               • Symptoms (e.g., cough, shortness of breath) have improved.
               • The test-based strategy, as described below for moderately to severely immunocompromised HCP, can inform the duration of work restriction.
3. Viral shedding as an infectious risk
   • Occurs following recovery but does not appear to play a role in transmission in relatively healthy people >10d following the onset of infection (though some variants may be infectious longer, viral RNA may be detected long after for many weeks; hence, why repeated routine testing for negative SARS-CoV-2 RT-PCR not recommended).
   • It may not be so short for ill hospitalized patients or those with health problems, but 20-28d is a conservative stance used by some hospitals to remove airborne precautions rather than the two negative nucleic acid amplification tests (NAAT) rule.
     • Rare reports of cultivatable virus > 60 days, especially in severely immunocompromised patients.:
       • A low cycle threshold (CT), e.g., < 30 and usually < 25, may indicate an infectious virus is present.
         • However, difficult to compare results when different testing platforms are used.
4. Some accumulating data suggest that high viral inoculum may lead to an increased risk for disease severity.

Symptoms (in the unimmunized): note symptoms of Omicron infection may be milder, resembling a URTI, in both immunized and unimmunized but still capable of producing a severe infection.

• Most common
  • Fever
  • Cough (dry)
  • Fatigue
• Less common
  • Myalgia
  • Pharyngitis (or other respiratory symptoms)
  • Headache
  • GI including diarrhea
  • Conjunctivitis
  • Loss of taste or smell
  • Rash (chilblains, discoloring on fingers/toes)
• Serious/warning symptoms
  • Shortness of breath
  • Chest pain/pressure
  • Confusion
  • Lethargy
  • Cyanosis

Disease spectrum

• Although severe COVID-19 illness is primarily a lower respiratory tract infection in the earlier phases of the pandemic, early and mild cases may have features of upper respiratory tract viral infection, especially with Omicron and more so in breakthrough infections the immunized.
• The information below represents knowledge before the Omicron variant.
• ~80% of infections are not severe, and patients recuperate without special treatment.
  • Especially true for children and younger adults, although the Omicron variants are prompting greater hospitalizations in younger populations.
• ~20% develop significant infection (higher risk if elderly or comorbidities). Percentages are derived from earlier in the pandemic and appear to be less in the Omicron-subvariant era.
  • ~15% require hospitalization.
  • ~5% require ICU care.
  • Lower percentages for those < 50 yrs, even with comorbidities.
• Overall mortality risk: varies widely between regions and countries, as well as the variant circulating. Omicron has less pathogenicity than Delta or Alpha variants, notably less pneumonia despite increased growth advantage and transmission.
  • Estimates are difficult as the number of asymptomatic infections and unreported infections, if known, would lower rates.
    • Both under- and over-reporting are possible, especially as home antigen testing or undiagnosed URIs are not reported.
    • Rates have changed over time.
    • U.S. COVID fatalities > 1 million, although attributable mortality is estimated to be higher, with more than 3 million deaths.
• For hospitalized patients with pneumonia, the disease course in people hospitalized with risk factors, especially older patients, and those with comorbidities:
  • ~50% develop hypoxemia by day 8 if unimmunized, but this figure is much less in the Omicron era, especially in immunized and boosted.
    • Severe illness and cytokine release syndrome appear to develop primarily within 5–10d after symptom onset in susceptible patients.
    • Markers of a severe infection include regular high fevers (>39°C), RR > 30, worsening oxygen requirements (4–6L nasal cannula), also elevated IL-6 levels (> 40–100), CRP, ferritin, and d-dimer.
    • ARDS develops in 17–29% +/- multiorgan system failure.
  • Patients in the ICU often require mechanical ventilation with prone positions recommended if poor lung compliance; ECMO is used in some centers.
• Greater severity of illness was reported with combined influenza and SARS-CoV-2 infection.

SITES OF INFECTION

• Like many severe viral infections, a growing list of potential associations and complications.
• Progressive illness, including the hyperinflammatory phase, may cause a multi-organ system failure.
• Pulmonary
  • Pneumonia with characteristic ground-glass infiltrates, later with evolution to ARDS.
  • Co-infection with other viruses is described as a superinfection with bacteria and molds (especially Aspergillus).
• GI
  • Some patients have nausea, vomiting, or diarrhea at the onset.
    • May herald more serious disease
  • The virus has been recovered from stool, but the significance is uncertain.
  • Liver: increased LFTs common
• CNS: encephalopathy is not uncommon, but true encephalitis (abnormal CSF and detection of the virus) appears rare.

TREATMENT

FOLLOW UP

• For the immunized, CDC issued guidance that 5d after onset, if symptoms have resolved or improved, people can leave isolation as long as wearing masks for days 5-10.
  • For healthcare personnel, CDC has revised this to 7 days or two serial negative antigen tests within 48h.
• Case fatality rates are highly variable in regions and different countries. Unclear why, and it may be multifactorial.
• Recovery from COVID-19 produces antibodies, but the response is heterogeneous, significantly lower in asymptomatic infected patients, and measurable responses such as antibody levels may diminish significantly in as little as 2–3 months. The protective immunity duration is unclear. T-cell responses are also likely critical.
• Advice for COVID-19 (+) patients and self-isolation/quarantine: 5d isolation, then mask-wearing for an additional 5d. For further details, see the CDC link for a table with recommendations.

OTHER INFORMATION

• Testing for viral RNA may include asymptomatic in addition to symptomatic patients; however, if not molecular tests, see the CDC algorithm for proper interpretation and follow-up testing (if needed) when using antigen-based tests.
• Severe illness strikes the same populations at high risk for seasonal influenza complications (e.g., elderly, immunosuppressed, obese and those with comorbidities).
• The case fatality rate remains higher than seasonal influenza, especially in advanced elderly and those with multiple comorbidities transplant patients.

Basis for recommendation

1. Bhimraj A, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 [last updated 8/30/22, accessed 12/12/2022]

   Comment: Regularly updated, and generally in concert with the NIH GL. One major area where our guide differs is in convalescent plasma use which we believe has a role for early illness in hospitalized patients (< 3d) or in some severely immunosuppressed patients who cannot generate meaningful antibody responses.
   

2. NIH COVID-19 Treatment Guidelines. https://www.covid19treatmentguidelines.nih.gov/ (last updated 9/30/2022, accessed 1/31/23)

   Comment: Revised regularly with updates. The format includes updated reference tables for some drugs. Informs much of the basis for RDV, dexamethasone, tocilizumab and baricitinib use discussed. Also rates outpatient COVID-19 therapies for early disease. The panel places the only remaining mAb bebtelovimab as a third line (along with molnupiravir) due to limited clinical data to support use while having excellent in vitro activity against Omicron and subvariants.
   

3. Hanson KE. Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19, last updated 12/20/20, [accessed 1/31/2023]. [https://www.idsociety.org/practice-guideline/covid-19-guideline-diagnostic...]

   Comment: Helpful guidance including the suggestion that lower tract specimens (if performed with a validated assay) may be more sensitive than the traditional nasopharyngeal swab, though the evidence is limited. Rapid testing, including antigen and serology also addressed. Also, look at CDC for diagnostic guidance information.
   

References

4. Sullivan DJ, Gebo KA, Shoham S, et al. Early Outpatient Treatment for Covid-19 with Convalescent Plasma. N Engl J Med. 2022.  [PMID:35353960]

   Comment: Though convalescent plasma is now limited by the FDA to patients who are immunosuppressed, this RCT of early administration of high-titer convalescent plasma showed a 54% reduction in hospitalization within 28d of symptom onset.
   

5. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022.  [PMID:35172054]

   Comment: Trial in unimmunized patients with mild-moderate COVID-19 found 87-88% reduction in hospitalization or death compared to placebo. The drug is relatively well-tolerated. Achilles heel is the co-packaging with ritonavir to boost nirmtrelavir levels which is the SARS-CoV-2 specific protease inhibitor. Ritonavir with its suicide inhibitor impact on CYP3A4 knocks out many patients who are on meds such as tacrolimus. Need to check for drug interactions. Patients on statins can have drug held for the 5 day course.
   

6. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022;386(6):509-520.  [PMID:34914868]

   Comment: It was disappointing that the efficacy fell to 30% from the preliminary 50% impact at reducing hospitalization or death in this study of mild-moderate COVID-19 in unimmunized patients. The drug has a clean slide effect profile. Much has been made of genotoxicity concerns, but the impact is not clear from a 5d course. Check for pregnancy in women of childbearing age. Notably, fewer deaths in the molnupiravir arm, but not statistically significant. Probably worthwhile in patients at high risk for disease progression and at least in early 2022 is the easiest to procure and take compared to other outpatient medications for COVID-19.
   

7. Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. N Engl J Med. 2021.  [PMID:33523609]

   Comment: A subset of patients in the expanded access use of COVID-19 convalescent plasma found that high titer recipients who received units before critical illness had a lower risk of death compared to patients who got low titer plasma.
   

8. Libster R, Pérez Marc G, Wappner D, et al. Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med. 2021.  [PMID:33406353]

   Comment: Small but well done double-blind RCT of patients > 65 yrs with mild COVID-18 and less than three days of symptoms. A total of 160 patients found that severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P = 0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed. The study is the best evidence that you need high titer units and early administration to have an effect.
   

9. Gottlieb RL, Nirula A, Chen P, et al. Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2021.  [PMID:33475701]

   Comment: Interim results from the ongoing BLAZE-1 trial showing that combination therapy of these mAbs resulted in decreased viral load and less need for hospitalization.
   

10. Korley FK, Durkalski-Mauldin V, Yeatts SD, et al. Early Convalescent Plasma for High-Risk Outpatients with Covid-19. N Engl J Med. 2021.  [PMID:34407339]

    Comment: The use of high-titer convalescent plasma was not helpful in this trial of 511 patients who received it < 7d from the onset of symptoms. The average duration of symptoms in the active arm was 4 days (median IQR).
    

11. O'Brien MP, Forleo-Neto E, Musser BJ, et al. Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19. N Engl J Med. 2021.  [PMID:34347950]

    Comment: This RCT enrolled 12 yrs and older with close household contact with COVID-19 within 96h of the index person receiving the COVID-19 diagnosis. SQ dosing was x one at 600 mg/600 mg. Symptomatic infection was seen in 11/753 (1.5%) vs. 59/752 (7.8%) on the placebo group. The relative risk reduction [1 minus the relative risk], 81.4%; P< 0.001). This appears to be an effective intervention for those at high risk with exposure (unimmunized) but would also consider in the immunized in the advanced elderly, immunosuppressed especially.
    

12. Salama C, Han J, Yau L, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021;384(1):20-30.  [PMID:33332779]

    Comment: Called a positive trial for tocilizumab, important points are that 1) statistical significance only when the rate of progressing to mechanical ventilation is included (not just mechanical ventilation and death as hard endpoints) and 2) > 80% of patients also received dexamethasone, suggesting that the two drugs need to work together to help patients.
    

13. Parr JB. Time to Reassess Tocilizumab's Role in COVID-19 Pneumonia. JAMA Intern Med. 2021;181(1):12-15.  [PMID:33079980]

    Comment: Helpful data synthesis of major tocilizumab trials. Data overall is mixed, there may be efficacy but nothing like that suggested from observational trials--at least for immunomodulatory monotherapy tocilizumab. The author suggests waiting for more RCT data to determine if the drug is helpful for COVID-19 patients. This paper included EMPACTA; however, not RECOVERY or REMAP-CAP which has defined a difference between dexamethasone + tocilizumab vs. tocilizumab monotherapy.
    

14. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 2020.  [PMID:32876694]

    Comment: 7 randomized trials that included 1703 patients of whom 647 died, 28-day all-cause mortality was lower among patients who received corticosteroids compared with those who received usual care or placebo (summary odds ratio, 0.66). Dexamethasone and hydrocortisone had a similar impact while the single methylprednisolone trial had less effect on mortality.
    

15. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020.  [PMID:32445440]

    Comment: The ACTT1 results that showed improved LOS by 4 days in patients receiving RDV. The average duration of symptoms prior to enrollment was 9d median with a wide range. The key observation from data is that benefit was derived in patients who were started prior to mechanical ventilation, suggesting that the use of the drug earlier in the disease course has efficacy--consistent with its mechanism of action as an antiviral. Final results are now available.
    

16. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569-1578.  [PMID:32423584]

    Comment: Unimpressive trial, but the drug may have been given to late to too ill a population.
    N = 237 patients, halted
    Confirmed infection, 12d or fewer of symptoms, lung involvement
    Remdesivir 200 mg d 1 then 100 mg IV daily vs. placebo
    Findings:
    1. No clinical improvement (subgroup < 10d with trend)
    2. No difference in mortality (subgroup < 10d with trend)
    3. No effect on viral load in upper or lower respiratory tracts
    

17. Chinazzi M, Davis JT, Ajelli M, et al. The effect of travel restrictions on the spread of the 2019 novel coronavirus (COVID-19) outbreak. Science. 2020.  [PMID:32144116]

    Comment: Although extraordinary measures may have slowed or stopped COVID-19 in China, questions remain whether this is durable and at what cost to society? It may buy time but effective drugs or vaccines remain in the far future it seems. Authors suggest "the travel quarantine of Wuhan delayed the overall epidemic progression by only 3 to 5 days in Mainland China, but has a more marked effect at the international scale, where case importations were reduced by nearly 80% until mid-February. Modeling results also indicate that sustained 90% travel restrictions to and from Mainland China only modestly affect the epidemic trajectory unless combined with a 50% or higher reduction of transmission in the community."
    

18. Mizumoto K, Chowell G. Estimating Risk for Death from 2019 Novel Coronavirus Disease, China, January-February 2020. Emerg Infect Dis. 2020;26(6).  [PMID:32168464]

    Comment: An early report and these typically have higher rates of infection due to concentrated, very ill patients than later in epidemics. Authors estimate of the risk for death in Wuhan reached values as high as 12% in the epicenter of the epidemic and ≈1% in other, more mildly affected areas. The elevated death risk estimates are probably associated with a breakdown of the healthcare system.
    

19. Liu W, Zhang Q, Chen J, et al. Detection of Covid-19 in Children in Early January 2020 in Wuhan, China. N Engl J Med. 2020.  [PMID:32163697]

    Comment: A retrospective look at 366 children hospitalized for respiratory illness. SARS-CoV-2 detected only in 6 (1.6) of patients. Only 1 of the COVID children required ICU care. Of the COVID patients, fever and cough were common and four had pneumonia.
    

20. Shen C, Wang Z, Zhao F, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020.  [PMID:32219428]

    Comment: A small study of 5 patients who required mechanical ventilation who appeared to benefit from convalescent plasma containing neutralizing antibodies, though also received methylprednisolone and putative antiviral therapies directed against SARS-CoV-2 infection. Authors suggest that many parameters improved including in the 4 ARDS patients.
    

21. Bourouiba L. Turbulent Gas Clouds and Respiratory Pathogen Emissions: Potential Implications for Reducing Transmission of COVID-19. JAMA. 2020.  [PMID:32215590]

    Comment: Wading into the aerosol v. droplet debate, the suggestion that forceful uncovered sneezes may cause infectious droplets to go beyond the 6 ft range currently advised by the CDC. This concern has prompted universal mask wear for HCWs, but also for the general public. There may be people who are not ill and therefore sneeze or cough, asymptomatic shedding and dispersing virus.
    

22. Jin X, Lian JS, Hu JH, et al. Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms. Gut. 2020.  [PMID:32213556]

    Comment: Paper suggests that some patients presented with GI symptoms as part of COVID-19, 11.4% of 651 in this study from Zheijiang University in Hangzhou. A caveat is their definition of GI included nausea only in addition to diarrhea and vomiting as they only needed one of the three to qualify for GI symptoms. They also suggested that patients who had GI had more severe COVID infection.
    

23. Giacomelli A, Pezzati L, Conti F, et al. Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study. Clin Infect Dis. 2020.  [PMID:32215618]

    Comment: Authors report on patients in earlier phases of COVID-19 infection, 20 (33.9%) reported at least one taste or olfactory disorder and 11 (18.6%) both. This is not unique though as other viral respiratory infections may also cause these symptoms.
    

24. Lescure FX, Bouadma L, Nguyen D, et al. Clinical and virological data of the first cases of COVID-19 in Europe: a case series. Lancet Infect Dis. 2020.  [PMID:32224310]

    Comment: Series of only five patients from France; however, the descriptions of three potential phenotypes may offer insights into different viral- and Immuno-pathogenesis. 1. Paucisymptom patient: nasopharyngeal high viral titer (and virus in feces), 2. Symptoms then decompensation (~day 10, respiratory decompensation): low viral titer compared to earlier in nasopharyngeal samples and 3. Clinical progression/death: high viral titers in upper and lower respiratory samples plus persisting viremia.
    

25. Guo L, Ren L, Yang S, et al. Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19). Clin Infect Dis. 2020.  [PMID:32198501]

    Comment: Authors used a nucleocapsid-based antibody for the detection of antibodies against SARS-CoV-2. IgM and IgA antibodies were found 5 days (IQR 3-6) after symptom onset, while IgG was detected on 14 days (IQR 10-18). Positive responses overall were seen as IgM 85.4%, IgA 92.7% and IgG 77.9% respectively. Considering both confirmed and probable cases, the positive rates of IgM antibodies were 75.6% and 93.1%, respectively. The detection efficiency by IgM ELISA is higher than that of qPCR method after 5.5 days of symptom onset. The positive detection rate is significantly increased (98.6%) when combined IgM ELISA assay with PCR for each patient compare with a single qPCR test (51.9%).
    

26. Long QX, Tang XJ, Shi QL, et al. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. 2020.  [PMID:32555424]

    Comment: 37 asymptomatic individuals displayed longer viral shedding, less cytokine generation and less serological responsiveness.
    Asymptomatic 93.3% (28/30) and 81.1% (30/37) had less IgG and neutralizing Abs
    ‒In comparison , 96.8% (30/31) and 62.2% (23/37) of symptomatic patients.
    -40% asymptomatic seronegative vs. 12.9% of the symptomatic group during convalescence
    §Protective immunity may not be long-lived
    

27. Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020.  [PMID:32492293]

    Comment: HCQ did not appear to prevent illness consistent with COVID-19 in patients with moderate or high-risk exposure to the virus when started within four days of the exposure.
    

28. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020.  [PMID:32678530]

    Comment: Pragmatic trial and also important to note the extraordinarily high background mortality in the U.K at the time (~40%). 28-day mortality in the usual care group was highest in those patients receiving IMV (40.7%), intermediate in those receiving oxygen only (25.0%), and lowest among those who were not receiving respiratory support at randomization (13.2%). The greatest absolute reductions in 28-day mortality were seen in the sickest patients, and subgroup analysis suggests in those > 7d of symptoms which would correlate with the inflammatory phase. Dexamethasone improves 28d mortality compared to placebo in patients requiring IMV (NNT = 8.5) and those patients requiring oxygen therapy (NNT = 29). There was no benefit to patients not requiring oxygenation support and even a signal for harm.
    

29. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020.  [PMID:31978945]

    Comment: An early report includes electron microscopy photomicrographs as well as sequence analysis of what is now termed COVID-19 disease and SARS-2-CoV virus.
    

30. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020.  [PMID:32015507]

    Comment: Authors have sequenced what is now termed SARS-2-CoV. Its genome 79.5% sequence identify to SARS-CoV. Furthermore, it was found that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus.
    

31. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020.  [PMID:32031570]

    Comment: One of the initial major reports of the Wuhan COVID-19 epidemic. In this series, the median age was 56 and slightly more men (54%) affected. Predominant symptoms include fever, fatigue and dry cough. Leukopenia was seen in ~70%. Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]).
    

32. Ai T, Yang Z, Hou H, et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020.  [PMID:32101510]

    Comment: Chest CT shows early ground-glass infiltrates which may offer speedier "diagnosis" than PCR studies in an epidemic setting as a first finding if molecular assays not readily available.
    

33. Kam KQ, Yung CF, Cui L, et al. A Well Infant with Coronavirus Disease 2019 (COVID-19) with High Viral Load. Clin Infect Dis. 2020.  [PMID:32112082]

    Comment: No surprise, here an infant sheds high levels of the virus but is without symptoms. Children are well known "vectors" of viral infection often without significant disease is well known for regular coronavirus infections, influenza and others.
    

34. Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19. N Engl J Med. 2020.  [PMID:33332778]

    Comment: Interim analysis of the mAb product studied among 275 outpatients with mild-moderate COVID-19. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody–negative at baseline, the corresponding percentages were 15% and 6% (difference, −9 percentage points; 95% CI, −29 to 11). No differences were seen in the active arm compared to placebo for adverse reactions.
    

35. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2020.  [PMID:32821939]

    Comment: Though the open-label trial cited as a reason to use 5-day instead of 10-d RDV for severe COVID-19, the fact that the 10-d course did worse without notably more side effects is concerning that the 5d data perhaps not as solid. Also, the FDA cites this trial as a reason (along with ACTT-1) to expand RDV use to those hospitalized but not needing oxygen; however, NNT =~100 and limited patients not requiring oxygen at randomization included.
    

36. Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020.  [PMID:32235945]

    Comment: A small but well-conducted study looking at 9 cases with most patients on day 1 having mild or prodromal symptoms. Key findings include finding virus in upper respiratory tissues with no difference between nasopharyngeal and oropharyngeal speeding which was very high during the first week of illness, but not in stool. Viral RNA remained in sputum beyond the resolution of symptoms. Seroconversion occurred by day 7 in 50% of patients but by day 14 in 100%. Despite the knowledge gained about viral kinetics, this paper offers proof that illness may also present as a routine upper respiratory tract infection without pneumonia or lower tract symptoms.
    

37. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020.  [PMID:32275812]

    Comment: Early experience with this antiviral in severe COVID-19 illness, found that there was an improvement in 36 of 53 patients (68%). Seven patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. The lack of a control arm makes this number difficult to understand whether the drug is helpful. As authors indicate, there is a need to await RCT data.
    

38. Kim D, Quinn J, Pinsky B, et al. Rates of Co-infection Between SARS-CoV-2 and Other Respiratory Pathogens. JAMA. 2020.  [PMID:32293646]

    Comment: Series of 1217 specimens analyzed for respiratory viruses, found 116/1217 specimens (9.5%) were positive for SARS-CoV-2 and 318 (26.1%) were positive for 1 or more non–SARS-CoV-2 pathogens. WIthin the SARS-CoV-2 positive specimens, 24 (20.7%) were positive for 1 or more additional pathogens. The most commonly detected co-infections were rhinovirus/enterovirus (6.9%), respiratory syncytial virus (5.2%), and non–SARS-CoV-2 Coronaviridae (4.3%). This report yielded higher viral co-pathogen rates than earlier COVID-19 studies, but similar to the co-infection rates seen with many standard respiratory viral illnesses. Importantly, this means that finding a virus other than the SARS-CoV-2 should not be grounds for concluding that COVID-19 is not present.
    

39. Chow EJ, Schwartz NG, Tobolowsky FA, et al. Symptom Screening at Illness Onset of Health Care Personnel With SARS-CoV-2 Infection in King County, Washington. JAMA. 2020.  [PMID:32301962]

    Comment: Syndromic screening that used fever and respiratory symptoms failed to detect SARS-CoV-2 infection (often at high titer) in 17% of HCWs presenting for assessment. While limited testing has forced decisions to screen people at a higher likelihood of infection, the wide range of potential COVID-19 infection means that some may unknowingly work and spread the virus. This no doubt is one reason the virus has spread so rapidly.
    

40. Grasselli G, Zangrillo A, Zanella A, et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020.  [PMID:32250385]

    Comment: A large critical care experience derived from Northern Italy had 1591 patients who 68% had 1 comorbidity and 82% were male. Mortality as of the 3/25/20 writing date was 26%.
    

41. Liu Y, Ning Z, Chen Y, et al. Aerodynamic analysis of SARS-CoV-2 in two Wuhan hospitals. Nature. 2020.  [PMID:32340022]

    Comment: An entry into the PRO potential for routine aerosolization of SARS-CoV-2. Viral RNA (unclear if infectious) found in toilet areas but not in ventilated isolation words. Levels also seen in areas prone to crowing including medical staff areas.
    

42. Borba MGS, Val FFA, Sampaio VS, et al. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw Open. 2020;3(4):e208857.  [PMID:32339248]

    Comment: High dose CQ suggested to contribute to mortality. 440 patients, 81 were enrolled (41 [50.6%] to a high-dosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively. Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instances of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%).
    

43. Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091.  [PMID:32217556]

    Comment: Patients in this Chinese retrospective study were older (median 68 yrs), male (73%) and had cardiovascular disease, including hypertension. While ARDS was common, acute cardiac injury and heart failure were also felt to contribute to high mortality.
    

44. Cheng Y, Wong R, Soo YO, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44-6.  [PMID:15616839]

    Comment: SARS paper that may inform COVID-19 infection. Benefit from convalescent plasma for treatment suggested by earlier discharge.
    

45. Barnette, GK et al. Oral Sabizabulin for High-Risk, Hospitalized Adults with Covid-19: Interim Analysis. NEJM July 2022

    Comment:
    Interim analysis of this multinational trial of a colchicine-like drug that binds to alpha and beta microtubules that may interfere with both viral assembly and inflammatory drivers was halted early by the DSMB because of mortality benefit. The drug was part of 150 randomized patients that yielded a 24.9% absolute reduction or 55.2% relative reduction in deaths compared to the standard of care, which mainly was dexamethasone, with about one-third receiving RDV and about half immunized. Conducted during Delta and early Omicron waves. The company has applied for a EUA.
    
    
    

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