Currently updated through Nov 18th, 2020

As we are in the midst of a pandemic, we hope to bring you an easy-to-read biweekly summary of COVID-19. Every 2 weeks, we will update the summary with the latest discoveries and knowledge that has been published about the virus, but will keep the basics about the coronavirus both as a refresher and to help put the new onslaught of information that is coming at us into context and the bigger picture. Changes will be highlighted in bold each week. 

Since literature is changing fast, we are not COVID-19 experts, and we are writing this on top of already busy schedules, so if you notice any inaccuracies, please let us know through the comments. We want to hear from you. Let us know if you like the summaries, if you want something different, or if you have any other suggestions!

Virology

SARS-CoV-2 = a novel highly pathogenic coronavirus 
COVID-19 = the disease caused by SARS-CoV-2 

SARS-CoV-2 is a novel coronavirus (in a family of 7 human coronaviruses) that is now causing a growing pandemic across the world. There are currently 7 known coronaviruses that infect humans:

1. Coronavirus #1 229E
2. Coronavirus #2 NL63
3. Coronavirus #3 OC43
4. Coronavirus #4 HKU1
5. SARS-CoV-1 – shares 70-80% of its genome with SARS-CoV-2
6. MERS-CoV
7. SARS-CoV-2 (COVID-19)

The first four have low pathogenicity and typically cause common cold symptoms. The last three are much more pathogenic and have higher mortality rates.  

These viruses are enveloped, single stranded RNA viruses. Little is known about the SARS-CoV-2 virus itself. A study showed that the virus can survive in aerosol up to 3 hours and on surfaces up to 3 days, however it is important to note that the authors generated aerosols using a special chamber designed to maintain aerosol in a lab setting and this doesn’t necessarily translate the same in real world settings. On surfaces, because of the nature of the virus (having an envelope) it can be easily killed with appropriate disinfection of surfaces (and washing your hands!). 

The last three coronaviruses (SARS-CoV-1, MERS-CoV, and SARS-CoV-2) all emerged in the last two decades as zoonotic (animal-to-human transmission) infections. Certain mutations in the viral genome allowed it to spread from human to human, leading to the pandemic that we have today. Currently, the virus is thought to have originated in bats who passed it on to pangolins (intermediate host), and then spread to humans. There is also evidence that the virus mutated as it spread across the world (Tang et al., Gudbjartsson et al.), creating 4 superspreader clusters (SS1-4) with various geographic spread, potentially explaining the differences in transmission and mortality rates between nations and time.

Pathophysiology

SARS-CoV-2 (as well as SARS-CoV-1) uses its spike (S) protein to attach to the ACE-2 receptor found on human epithelial cells in the nasopharynx. The TMPRSS2 enzyme cleaves ACE2R, activating the S protein, and allows the virus to enter the cell. Once inside the cell, the RNA fuses with the vesicle membrane and releases its RNA. The cell then replicates the RNA and releases more virus into the extracellular environment. Type II pneumocytes are preferentially infected and begin producing more virions. From there, it initiates an innate immune response leading to inflammation, which produces the symptoms of pneumonia. T lymphocytes are also infected and the inflammatory response leads to decreased lymphopoiesis and increased apoptosis, resulting in lymphopenia. Damage to the pulmonary epithelial cells leads to edema and recruitment of monocytes and neutrophils, resulting in the development of interstitial mononuclear inflammatory infiltrates that show up as ground-glass opacities on CT imaging. In some individuals, apoptosis of cells predominates leading to increased number of cell death, loss of alveolar integrity and diffuse alveolar damage, accumulation of cellular debris, and development of fibrin rich hyaline membranes. This exacerbation of the initial inflammatory response results in an ARDS (acute respiratory distress syndrome)-like clinical presentation. A strong immune response is required to stop this sequence of events and allow for epithelial regeneration. In some however, the illness progresses to a cytokine storm mediated by a surge of proinflammatory cytokines such as IL-1, IL-6, and the complement pathway, leading to a COVID-19 hyperinflammatory syndrome (CHIS) with multi-organ damage and death (Schett et al). The accentuated inflammation also leads to the activation of coagulation and consumption of clotting factors, resulting in disseminated intravascular coagulation. This drives the development of thrombotic complications such as pulmonary embolism, myocardial infarction, and ischemic strokes. (Wiersinga et al.)

In the elderly, the decreased mucociliary clearance increases the risk of virus particles migrating down to the lower respiratory tract and the decreased ability to mount an adequate immune response and regenerate epithelia lead to their higher mortality rate. (Mason et al.)

Since ACE-2 receptors are also present on arterial and venous endothelial cells and arterial smooth muscle cells throughout the body, hypotheses of virus-directed effects on other organs besides the lungs have been postulated (Puelle et al. demonstrated presence of SARS-CoV-2 RNA in the kidneys, liver, heart, brain, and blood tissue; Chung et al. in nasal mucosa). Specifically, the concomitant inflammatory response to infection along with the direct viral effect on endothelial cells could cause prothrombotic clinical sequelae, prompting the questions of whether anticoagulation would improve clinical outcomes. Bryce and Grimes et al. reported evidence of microthrombi in arteries and capillaries in 21 out of 23 evaluated cases. They also demonstrated endothelial cell damage in the brain, with the authors postulating that the resulting neuronal hypoxia is a contributory mechanism of neuropsychiatric clinical symptoms seen in some of the patients. The authors go on to further hypothesize that the vasoconstriction and hypoxia resulting from endothelial damage promotes platelet aggregation along vessel walls that leads to intravascular coagulopathy and multisystem organ failure.

Sharif-Askari et al. reports lower expression of viral, ACE2, and TMPRSS2 receptors in children and higher expression in smokers and patients with COPD, suggesting that level of receptor expression may be associated with acquisition risk.

Viral loads tend to peak at the time of onset of symptoms (meaning virus is shedding and an individual is infectious PRIOR to the onset of symptoms) and decline slowly over the next 2-4 weeks (with more severe cases having a more prolonged viral shedding period). Recent study in Nature demonstrates that the virus can also replicate in the throat, which may explain the olfactory/taste loss symptoms many patients experience with the infection. Individuals who recover from COVID-19 tend to develop IgM antibodies by 1-2 weeks post disease onset and IgG by 2-4 weeks (Guo et al.). Wu et al. showed that ~70% developed neutralizing antibodies by 14 days post-disease onset. It remains unclear if immunity is long-lasting.

Epidemiology

In December 2019, 14 patients were reported to have been hospitalized with a pneumonia illness of unknown cause in Wuhan, China. A novel coronarvirus was identified, now known as SARS-CoV-2. The virus was linked to the Huanan Seafood Wholesale Market. From there, it spread worldwide. The spread of the virus was aided by the fact that it has a reproductive number (R0) of around 2.3 (number of secondary cases generated by a primary case). This website estimates the current estimated R0 across U.S. States. As of November 18th, 2020, the United States, India, Brazil, France, and Russia have the highest number of cases worldwide. The U.S has surpassed all other countries in the number of deaths due to COVID-19. The U.S. is followed by Brazil, India, Mexico, and the United Kingdom. However, these numbers are constantly changing so please refer to JHU Coronavirus MapTracker for the most up to date case numbers.

For case and mortality trends: New York Times Coronavirus Map

For seroprevalence estimates by country: SeroTracker
O’Driscoll et al. estimates a 5% seroprevalence rate across 45 countries.

Characteristics of COVID-19 cases in the United States (1,320,488 cases, Jan 22-May 30th) (Stokes et al. MMWR, Jun 19, 2020)

• Mediate age: 48 years
• Similar incidence between males and females
• Highest Incidence: persons aged ≥80 years
  Lowest incidence: persons aged ≤9 years
• 36% were non-Hispanic white
  33% were Hispanic
  22% were black
  4% non-Hispanic Asian
  ~6% other/AI/AN/NH/PI
• Most common comorbidities were:
  1) Cardiovascular disease (32%)
  2) Diabetes (30%)
  3) Chronic lung disease (18%)
• Hospitalized: 14%
  ICU admission: 2%
  Died: 5%
• Hospitalizations were 6 times higher and deaths 12 times higher among patients with underlying comorbidities compared to those without underlying comorbidities

Risks for hospitalization due to COVID-19 (Killerby et al. MMWR Jun 26, 2020)

• Age ≥65 years (aOR=3.4)
• Black race (aOR=3.2)
• Diabetes mellitus (aOR=3.1)
• Lack of insurance (aOR=2.8)
• Male sex (aOR=2.4)
• Smoking (aOR=2.3)
• Obesity (aOR=1.9)

COVID-19 mortality (Wortham et al. MMWR Jul 10, 2020)

• Mediate age was 71 years among Hispanics vs. 72 years among nonwhite non Hispanics vs. 81 years among whites
• 35% were whites
  24.9% were blacks
  24.4% were Hispanics
  6.3% were Asian
  ~10% were unknown/AI/AN/NHPI/multiracial/other 
• 60.9% had cardiovascular disease
  39.5% had diabetes mellitus
  20.8% had chronic kidney disease
  19.2% had chronic lung disease

Risk factors for death from COVID-19 (Williamson et al. Nature July 8, 2020)
An EMR-based registry of 17,278,392 adults in the UK

• Male – HR 1.59 (95% CI 1.53-1.65) 
• Older age 
• Diabetes mellitus 
• Severe asthma 
• Black race – 1.48 (95% CI 1.30-1.69)
• South Asian ethnicity – 1.44 (95% CI 1.32-1.58)

Case Fatality Rate (CFR) = # of deaths from infection/# of individuals infected
Sudharsanan et al. reports a CFR ranging from 0.7% (in Germany) to 9.3% (in Italy).  Standardized for age, Italy’s CFR decreases to 3.9% and Germany’s rises to 1.3%. Age-standardized median CFR is 1.9%. Around 66% of the variation can be explained by the age demographics of each country. O’Driscoll et al. show an IFR of 0.001% (lowest) for ages 5-9 and then steadily increasing in 5-year increments, reaching 8.29% at ages 80+. IFRs remained steady across all 45 included countries.

Why is there so much concern over this virus? 

I’ve heard a lot of people say (both personally and on social media) that they don’t understand why everyone is so worried about this virus. If the case fatality rate is projected to be <1%, why are we grinding our economy to a halt when we won’t be able to stop the virus from spreading anyways? Especially when we do not do this for seasonal influenza!

Well, let’s take a look at what we know: 

1. No effective therapy options at this time (although remdesivir and dexamethasone show some benefit, they do not provide a cure to all who are infected)
2. No vaccine. It will take at least 12 months to have a safe effective vaccine for widespread use.
3. The R0 is around 2.3-2.5, higher than that of influenza (1.1-1.5) (although be aware that R0 fluctuates based on public health policies, behavior, as well as the virus itself)
4. 15% of those with COVID-19 developed severe illness requiring hospitalization, and around 5% are reported to be critically ill

Taking all the above into account, we are looking at a respiratory virus with the ability to infect a large portion of a non-immune population, with no known effective therapies in our arsenal, and no effective vaccine on the horizon. This is leading to a surge in hospitalizations of patients with severe respiratory illness and sepsis, threatening to overwhelm an already strained healthcare system during an ongoing flu season.

An MMWR report from the NYC Department of Health announced that there has been 24,172 excess deaths in NYC from March 11-May 2, 2020 than what is usually seen during this time period in previous years.

Well, then what’s the point of fighting a losing battle if so many are going to get infected? Actually, if the healthcare system has the capacity to care for these patients, then hospitals will  have a chance to:

1. Provide good optimal care
2. Have enough ventilators on standby for those who will require it
3. Have enough of a healthy healthcare workforce to care of the patients

This is where social distancing comes in as a public health intervention. The point of it is to mitigate the spread (we past containment in many regions inflicted so far in the US). Social distancing, in addition to other public health measures ranging from contact tracing to city lockdowns, can help spread the number of people infected over time. This leads to a ‘flattening’ in the curve so to say, avoiding a ‘peak’ in the number of cases. By flattening the curve, the healthcare system is more likely to be able to care better for the patients requiring hospitalization. A study out of China and more recently Pan et al. demonstrated that social distancing measures helped avert hundreds of thousands of cases. Du et al. reported that a 1-day delay in implementing social distancing measures resulted in a 2.4 day prolongation of the outbreak.

The Imperial College COVID-19 Response Team predicted in a report that if a long term mitigation or suppression policy is not feasible (due to economical and social impacts), a short-term 3-month population wide mitigation strategy may cut the predicted death rate by half. Unfortunately, without a vaccine for another 12-18 months, relaxation of mitigation measures may lead to a resurgence in cases. Therefore, these efforts may have to be repeated over an 18-month period, with periods of relaxation intermittently.

And a new study in Lancet Global Health suggests that warmer temperatures may not slow the spread of the virus, as West Africa and other areas of the southern hemisphere see an expansion of cases.

Kissler et al. wrote in Science that pandemic transmission dynamics will depend on factors including the degree of seasonal variation in transmission, the duration of immunity, and the degree of cross-immunity between SARS-CoV-2 and other coronaviruses, as well as the intensity and timing of control measures. The study warns that if immunity to the virus is not permanent, it will likely enter into regular circulation. Furthermore, it shows how intermittent social distancing measures may be necessary to slow down the spread of the virus in the upcoming year. Lasry et al. demonstrated that mitigation efforts are associated with slower rate of growth in new cases. Matrajt and Leung also demonstrate the effectiveness of social distancing measures on limiting COVID-19 spread.

Clinical Presentation

Incubation: average 4-5 days (range: 2-14 days)

Clinical symptoms: symptoms are progressive and develop over the course of weeks. They include: fevers, dry cough, fatigue, shortness of breath, sore throat, rhinorrhea, myalgias, diarrhea
*nausea, vomiting, diarrhea, and/or loss of smell or taste may precede other symptoms
Morris et al. also presented a case series of adults who developed multisystem inflammatory syndrome (MIS), majority with positive SARS-CoV-2 PCR at time of hospitalization.

Clinical signs: hypoxia, leukopenia, lymphopenia, thrombocytopenia, elevated D-dimer, elevated ferritin, elevated CRP, CXR with interstitial opacities, CT chest with ground glass opacities (predominantly peripheral).

Extrapulmonary manifestations:

• Neurological manifestations: dizziness/headache (Mao et al.), generalized encephalopathy with delirium/psychosis without CSF or MRI abnormalities (Paterson et al., Varatharaj et al.), inflammatory CNS syndromes (Paterson et al., Wang et al.), Guillain-Barre syndrome (Paterson et al., Toscano et al.), and ischemic strokes (Mao et al., Paterson et al., Varatharaj et al.). One case report of meningitis. Pilotto et al. reported on the characteristics of 25 cases with encephalitis thought to be related to recent COVID-19 infections. Frontera et al. published a multicenter prospective cohort trial, demonstrating a 14% prevalence of neurological disorders accompanying a diagnosis of COVID-19. The most common was toxic/metabolic encephalopathy (6.8%), stroke (1.9%), seizure (1.6%), and hypoxic/ischemic injury (1.4%). All CSF specimens collected (N=18) were negative for SARS-CoV-2 RNA. Neurological injury was associated with mortality.
• Ocular manifestations: In this study 1.4% had vision impairment. Rokohl et al. report 69% prevalence of ocular manifestations (burning sensation, epiphora, redness).
• Nose/throat manifestations: 21%-77% report loss of taste or smell (Borsetto et al., Hannum et al., Foster et al.). Another study suggests hearing impairment via damage to the cochlear hair cells.
• Cardiac manifestations: arrhythmias, myocardial injury, myocarditis heart failure (Driggin et al., Kunutsor and Laukkanen)
• Hematologic manifestations: coagulopathy, disseminated intravascular coagulation (DIC), deep venous thrombosis (DVT), presence of antiphospholipid antibodies
  – Klok et al. showed that 31% of patients with COVID-19 in the ICU had thrombotic complications (with the most common being PE in 81% of the participants).
• Gastrointestinal/Hepatic/Biliary manifestations: Nausea, vomiting, and/or diarrhea occur in roughly ¼ of hospitalized COVID-19 patients 
• Musculoskeletal manifestations: 10.7% of patients in this study had skeletal muscle injury. 
• Dermatologic manifestations: Recalcati et al found 20% (18 patients) had skin findings, with most presenting as a non-pruritic erythematous rash. Manalo et al. reports a case presenting with transient livedo reticularis. Casa et al. noted that in 375 cases in Spain with dermatologic findings, 47% had maculopapular eruptions, 19% had acral areas of erythema with vesicles/pustules (pseudo-chilblain aka COVID-toes), 19% had urticarial lesions, 9% had other vesicular eruptions, and 6% had livedo or necrosis. 
• Endocrine manifestations: there have been anecdotal reports of patients presenting with diabetic ketoacidosis

Radiologic (CT) findings: In a study of 1014 cases in Wuhan, China, 66% had ground-glass opacities, 50% had consolidations, and >90% had bilateral findings. 
– CT findings can precede the detection of RNA on PCR test
Performance of CT chest findings for COVID-19 infection: 

Sensitivity	97%
Specificity	25%
Positive Predictive Value	65%
Negative Predictive Value	83%

From Radiological Society of North America Expert Consensus Statement on Reporting Chest CT Findings Related to COVID-19, typical CT chest imaging findings include: 

• Peripheral, bilateral, GGO with or without consolidation or visible intralobular lines (“crazy-paving”)
• Multifocal GGO of rounded morphology with or without consolidation or visible intralobular lines (“crazy-paving”)
• Reverse halo sign or other findings of organizing pneumonia (seen later in the disease)

@ChestImaging has compiled examples of Chest X-rays of COVID-19 positive patients

Disease course:
A paper by Siddiqui et al. proposes a standardized nomenclature for the various stages of the disease
1. Incubation period: 2-14 days (average 5 days)
2. Stage 1 Early (mild) infection: 5-10 days — Flu-like/upper respiratory symptoms
3. Stage II (moderate) infection: a few days — development of pneumonia symptoms (hypoxia, dyspnea)
Stage IIa: without hypoxia
Stage IIb: with hypoxia
4. Stage III (severe) infection: 1-2 weeks –ARDS with acute-onset and progressive respiratory failure +/- cytokine storm
– characterized by a systemic hyperinflammatory response 
– Median LOS in ICU ~ 14 days and hospital ~17 days in critically ill patients
– correlated with very high IL-6 levels (Chen et al.)
– this is the stage where immunomodulatory medications (such as IL-6 inhibitors) would potentially be beneficial
*At any stage of the disease course, some patients improve and do not progress to the next stage 

Independent risk factors for in-hospital death: 

• Older age
• Higher SOFA score 
• D-dimer >1mcg/mL 

Lighter et al. also demonstrated obesity in individuals <60 years of age is a risk factor for hospital admission for COVID-19 infection.

Predictive factors for ICU admission: 

• Leukocytosis
• Elevated ALT and AST 
• Elevated LDH (also predicted ARDS development)
• Elevated procalcitonin 
• N/L ratio >3.13 in pts >50yrs of age 

Predictive factors for mortality: 

• Leukocytosis
• Elevated LDH
• CRP>150mg/L or ferritin >1500microg/L

Online risk calculator to risk stratify individuals who will develop critical illness due to COVID-19 was designed by Liang et al. It incorporates the patient’s age, comorbidities, history of cancer, symptoms, labs (N/L ratio, LDH, direct bilirubin) and presence of radiographic findings.

• Pediatrics – COVID-19 appears to be a mild disease in the majority of children. Clinical presentation, laboratory and radiologic findings appear to be similar to adults. 
  • Age distribution
    <1 year – 15%
    1-4 years – 11%
    5-9 years – 15%
    10-14 years – 27%
    15-17 years – 32% 
  • Hospitalization – 2.5-4.1%
    ICU admission – <1% 
  • Asymptomatic: ~15-41% (Lu et al., Ding et al., Zheng et al.)
    Poline et al. conducted a multicenter prospective cohort study in France and showed that testing based on symptoms would have failed to identify 10 out of 22 children that tested positive for COVID-19. This suggests a high prevalence of asymptomatic infection in children.
    Sola et al. published a study demonstrating that asymptomatic prevalence of COVID-19 among children reflected the prevalence in the community.
  • Most common symptoms were fever, cough, headache, myalgias, and diarrhea
  • Risk factors for severe disease
    • Medical comorbidities
    • Congenital heart disease
    • Neurologic, genetic, or metabolic conditions
  • American Academy of Pediatrics has released guidelines on management of a newborn born to a mother with confirmed or suspected COVID-19 infection
  • There have been reports in the mainstream media of an increase in Kawasaki-like presentation in children during the pandemic, suspicious of a post-infectious phenomena. England’s National Health Service recently issued an advisory due to the increase in cases. In the first reported case in the literature, authors report the case of a 6 month old who developed classic features of KD
  • Among 570 children who met MIS definition as defined by CDC, Godfred-Cato et al. published:
    • Median age: 8 years old
    • Obesity was the most common comorbidity
    • ⅔ were previously healthy
    • Most commonly involved organ systems were: GI, CV, and dermatologic
    • 64% were admitted to the ICU
    • 26% tested positive for SARS-CoV-2 PCR; 46% tested positive for serology
    • Mortality: 1.8%
  • Among 186 children who were hospitalized with multisystem inflammatory syndrome (MIS), Feldstein et al. reported that:
    • Median age was 8.3 years
    • 73 tested positive for PCR, 58 for antibodies, and 55 for neither but had epidemiological link to COVID-19
    • 73% were previously healthy
    • Most commonly involved organ systems were: GI, CV, hematologic, mucocutaneous, and respiratory
    • 80% required ICU care, 20% mechanical ventilation, 8% ECMO, 2% died
    • 40% demonstrated Kawasaki-like features
  • More studies have come out documenting the multisystem hyperinflammatory syndrome seen in children post-COVID-19 (Toubiana et al., Verdoni et al.) Majority tested positive for SARS-CoV-2 IgG antibodies.
• Adults 
  • Asymptomatic – Wang et al. demonstrates that among contacts of individuals diagnosed with COVID-19, 23% (63 out of 279) of cases remained asymptomatic. 46% of them had abnormal CT chest findings. Mean age was 39.3 years and 87.3% had no comorbidities. 14.3% transmitted the virus to others. Only 6.3% had leukocytosis and leukopenia and 12.7% had lymphopenia. None had elevated inflammatory markers.
    – Diamond Princess ship: ⅓ of positive cases were asymptomatic at time of testing
    – Sutton et al. screened all expectant mothers presenting for delivery for COVID-19 in a NYC hospital and found that 87% of positive cases were detected in asymptomatic women.
    – Baggett et al. screened everyone in a Boston homeless shelter and found that out of 147 who tested positive, 88% of them were asymptomatic.
    – Pan et al. describes 26 persistently asymptomatic SARS-CoV-2 carriers and reports no major lab abnormalities but that 77% had abnormal CT chest imaging.
    – Byambasuran et al. performed a meta-analysis and estimated the proportion of asymptomatic cases to be around 15%, with a range of 4-41%.   
    – Torres et al. describes that 40% of children and 18% of school staff with positive COVID-19 antibodies reported no symptoms.
  • Based off the largest case series from China (N=72,314): 
    • No/mild pneumonia (+/- symptoms of pneumonia, hospitalized, no hypoxia) – 81% 
    • Severe pneumonia (O2 sat <93%, worsening lung infiltrates, SOB) – 14%
    • Critical pneumonia (respiratory failure, septic shock, multiorgan failure) – 5%
      – CFR was 49% among those with critical pneumonia 

• Predictors of death in adults as reported in this retrospective review of 201 patients in China with confirmed COVID-19
  • • Median age of 51
    • 42% developed ARDS => 22% Death
    • Risk factors (for development of ARDS leading to death):
      • Older age (>65)
      • Neutrophilia
      • Organ dysfunction
      • Coagulation dysfunction
    • Methylprednisolone appeared to be protective against death (HR 0.38, CI 0.2-0.72, p=0.003)
  • According to this MMWR from the CDC: 40% of patients in the US with confirmed COVID-19 have underlying conditions
  • In largest series of critically ill of 1591 patients with laboratory-confirmed COVID-19 in 72 hospitals in Lombardy ICU network between 2/20-3/18:
    • Median age was 63, 82% were male
    • From the available data of 1043, 68% had at least 1 comorbidity & 49% had hypertension 
    • From the available data of 1300, 99% needed respiratory support, 88% received mechanical ventilation and 11% received non-mechanical ventilation 
    • Median PEEP= 14 (not different between younger patients aged <63 and older patients >64
    • FIO2 greater than 50% in 89% and median FIO2 was lower in younger patients
    • The median PAO2/FIO2 was 160 with median higher in younger patients
    • Among 1581 patient with disposition data available, 58% were still in ICU, and 26% were discharged and 26% died in ICU
    • Older patients had higher mortality than younger patients (36% vs 15% different in <63 Vs >64)
  • Letter to the Editor in NEJM describes 393 cases in New York City, and found similar characteristics compared to the studies in China. One noted difference was the increased prevalence of gastrointestinal symptoms (diarrhea, nausea, vomiting) that occurred in almost one-fourth of the NYC cohort. Of those that required mechanical ventilation (N=130), 30% did not require supplemental oxygen on arrival to the ED.
  • This study by the COVIDSurg Collaborative reported a 23.8% 30d post-operative mortality rate (compared to the standard 3%) in patients who underwent surgery and tested positive for SARS-CoV-2 either 7 days prior or 30 days post-surgery.

• Elderly (age 60 and above) – the population most affected by COVID-19.
  Case Fatality Rate based on age:

Age range	China (N=72,314)	Italy (N=22,512)
60-69 years	3.6%	3.5%
70-79 years	8.0%	12.5%
>80 years	14.8%	19.7-22.7%

• Immunocompromised – Outcomes data on immunocompromised patients is mixed. While some studies report no increased risk of adverse effects (Ren et al., D’Antiga et al.), other studies suggest worse outcomes in this population (Pereira et al., Liang et al., Fernandez-Ruiz et al.)
  • Haberman et al. describes 86 patients who were on biologics and other immunomodulatory therapies and reports no association with worse COVID-19 outcomes.
  • Kates et al. in a retrospective study of 482 solid-organ transplant patients, age and comorbidities were the factors associated with COVID-19 mortality rather than degree of immunosuppression.
  • HIV patients: Multiple studies have demonstrated that persons living with HIV present similarly to those without HIV and so far, no major differences in outcomes (Vizcarra et al., Blanco et al., Harter et al., Gervasconi et al.)
    – Dandachi et al. published a prospective, multicenter study showing that among 286 individuals living with HIV, CD4<200, older age, chronic lung disease, and hypertension were associated with worse outcomes (need for hospitalization, ICU admission, intubation, and death).

• Pregnant 
  • American Academy of Pediatrics has released guidelines on management of a newborn born to a mother with confirmed or suspected COVID-19 infection
  • Pregnant women do not appear to be at increased risk for severe illness (read more here) although MMWR published a large study that included 409,462 COVID-19-symptomatic women (age 15-44yrs) and showed that risk of ICU admission (1.05% vs. 0.39%, need for mechanical ventilation (0.29% vs. 0.11%) and ECMO (0.07% vs. 0.03%), and death (0.15% vs. 0.12%) was higher among pregnant women.
  • Small case series of 9 women show the following pregnancy outcomes: 
    • 4/10 newborns had full term births 
    • 6/10 newborns were premature
    • 2/10 were small for gestational age, 1/10 was large for gestational age 
    • Majority of the newborns showed symptoms of an illness, although all tested negative for COVID-19
    • 9/10 newborns survived
  • Retrospective case control did not show any difference in birth outcomes 
  • Knight et al. published a cohort study of pregnant women in the UK, reporting that the majority (81%) of pregnant women hospitalized with COVID-19 were in the third trimester. Case fatality rate was 1.2%. At the end of the study, 42% of women had not yet given birth. Out of the 58% who did, 97% had live births, with 26% (N=244) of newborns receiving NICU care. Twelve (4.9%) newborns tested positive for SARS-CoV-2.
  • Systematic review of 108 pregnant women who developed COVID-19 reported 3 ICU admissions, no maternal deaths, 1 newborn death, and 1 intrauterine death. Although 22 presented earlier than 3rd trimester, article had no information on eventual birth outcomes. (similar outcomes seen in another systematic review by Yang et al.).
  • Baud et al. reports on a second trimester miscarriage possibly related to COVID-19 infection
  • Smith et al. published in the Lancet a systematic review of pregnancy outcomes from 9 articles:

• Only 67.4% were symptomatic at admission
• 0% maternal mortality rate (1 required ICU admission)
• 63.8% had preterm births 
• 61.1% (11/18) had fetal distress 
• 80.0% had a Caesarean section 
• 76.9% required NICU admission 
• 42.8% newborns had low birth weight
  • Huntley et al. publishes another systematic review of 538 pregnancies and 435 deliveries (from 99 articles) and demonstrates:
    • 75.3% were symptomatic at time of testing
    • 0% maternal mortality rate (3% required ICU admission)
    • 20.1% had preterm births
    • 84.7% had Caesarean section
    • 0% vertical transmission rate
    • 0.3% neonatal deaths
  • Flaherman et al. published a prospective trial of 263 newborns born to mothers with confirmed or suspected COVID-19 and found that newborns born to mothers with COVID-19 diagnosis within 2 weeks of delivery had earlier deliveries (37.5wk vs. 39wk gestation, p=0.0009) and increased prevalence of NICU admission (26% vs. 12.2%, p=0.04). Only 1.1% of newborns tested positive for SARS-CoV-2 and none had a lower respiratory tract infection at 6-8 weeks out from birth.
  • Woodworth et al. reports 12.9% rate of preterm births (<37weeks) in mothers with active COVID-19 infection compared to 10.2% among the general population.

• Vertical transmission: small case-series and case-control studies show no evidence of vertical transmission of infection from mother to child. 
  – However this retrospective cohort of neonates showed 3/33 developed symptoms and tested positive COVID-19, indicated that vertical transmission -IS- possible
  – Two case reports suggest the possibility of vertical transmission. In one, the amniotic fluid was positive for SARS-CoV-2 PCR while the cord blood was not. In the other case report, neonate was isolated from COVID-19 positive mother immediately after C-section but nevertheless tested positive on date of birth.
  –Diriba et al. conducted a meta-analysis and reported no cases of vertical maternal-fetal transmission of COVID-19.
  • Breastfeeding: Groß et al. reported detection of SARS-CoV-2 RNA in the breastmilk of a mother who was positive for COVID-19

*It is incredibly important not to anchor on a diagnosis of COVID-19 during the pandemic. Although it is at the forefront of all our minds, patients will continue to develop other respiratory viral illnesses, bacterial pneumonias, and other non-infectious diseases. A delayed diagnosis can harm patients. So while it is important to consider COVID-19 within your differential diagnosis, consider other causes as well and proceed with appropriate workup and management.

Diagnostics

*Respiratory viral panel DOES NOT DETECT SARS-CoV-2 virus. It only detects the first 4 human coronaviruses listed in the beginning of this post. 

Dec. 26, 2019 – First four cases of pneumonia without an unidentified source reported to public health in Wuhan, China 
Jan. 7, 2020 – SARS-CoV-2 identified 
Jan. 12, 2020 – SARS-CoV-2 genome sequence shared
Jan. 13, 2020 – SARS-CoV-2 PCR test developed

1. COVID-19 PCR test – Sensitivity and specificity of the test is not yet fully known. One paper showed a sensitivity of 67%. Sensitivity also ranges based on time of collection (33% 4 days after exposure, 62% on the day of symptom onset, and 80% 3 days after symptom onset (Wiersinga et al.) Another paper showed the difference in positive COVID-19 tests based on type of respiratory specimen, which was confirmed by a subsequent paper.
   1. Bronchoalveolar lavage fluid (BAL): (14/15) 93%
   2. Sputum: 72% (72/104) 
   3. Nasal swabs: 63% (5/8) (McCullogh et al. reported 80% sensitivity of self-collected midnasal swabs compared to clinician-collected nasopharyngeal swabs)
   4. Fibrobronchoscope brush biopsy: 46% (6/13)  
   5. Pharyngeal swabs: 32% (126/398)  
   6. Saliva: 86% (Landry et al.)
   7. Deep throat saliva swabs (self-collected) demonstrated low positivity rate and lower viral loads compared to standard nasopharyngeal swab, suggesting a false negative rate of ~31% (Lai et al.)
   8. Feces: 29% (44/153) 
   9. Blood: 1% (3/307)  
   10. Urine: 0% (0/72)   

– severity of disease influences the likelihood of a positive test (with many tests becoming negative after 15 days of illness in mild cases)
– viral load can potentially be a marker of severity and prognosis of the disease
– median duration of positivity is ~12-15 days, ranging from 4-50 days and is associated with age, severity of disease, lymphopenia, eosinopenia, and CD8+ T cell, IL-6, and IL-10 levels (Lin et al., Sun et al.)
– Results from Penarrubia et al. also suggests mutations in the virus can also affect the sensitivity of the PCR test, as the PCR may not detect the mutated genomic region.
*It remains unknown whether detection of viral RNA by PCR implies ongoing infectiousness and transmissibility of the virus although studies such as Wolfel et al. and Bullard et al. suggest loss of infectivity by day 7-8 after initial positive PCR. Consequently, the U.S. CDC recommends discontinuation of isolation precautions 10 days after the onset of symptoms, except when a patient is immunocompromised. Avanzato et al. published a case report in Cell demonstrating ongoing infectious viral shedding up to 105 days in an immunocompromised asymptomatic patient.
– This paper suggests false negative probability is lowest day 5-9 after onset of symptoms.
– Factors contributing to false negative PCR tests are: adequacy of specimen collection technique, time of exposure, and specimen source (Wiersinga et al.)

2. COVID-19 serology test – IgM appears to develop ~5–14 days and IgG 2–4 weeks after onset of symptoms (read another recent paper here and here)
– sensitivity is ~83–89%, specificity is ~91–99% (at ≥14 days post symptom onset)
– combined use of PCR and IgM appears to increase diagnostic sensitivity  
– will also help ascertain those who have developed immunity to the virus
– The first SARS-CoV-2 IgM/IgG rapid diagnostic serology test is approved by FDA for emergency use
– Center for Health Security compiled a list of all clinically and research-only available serologic tests
– Higher antibody titers seem to be associated with severity of disease (Zhao et al.)
– do not necessarily correlate with clinical improvement (Wolfel et al., To et al.)
– persistence of antibodies and protection from re-infection remains unknown but studies of asymptomatic or those with mild COVID-19 symptoms show loss of neutralizing and IgG antibodies by 8 weeks. In contrast, Gudbjartsson et al. measured antibodies in 30,576 (1237 of whom were PCR+ for COVID-19) individuals in Iceland and reported that antibody titers had not declined 4 months after the initial infection. Orth-Holler et al. noted a decrease (although still detectable) in antibodies by 18 weeks and also suggested that duration of antibody presence may differ based on which type of antibody/assay the study is using.
– Check out the IDSA guidelines on further information on how to use antibody testing

Sethuraman et al. published a fantastic chart in JAMA demonstrating the timeline for diagnostic tests in COVID-19.

If you want to brush up on what sensitivity and specificity of a test really mean, read Dr. Natalie Dean’s tweetorial!

Can patients swab themselves instead of having a healthcare provider do it? 
Tu et al. demonstrates data that patient-collected mid-turbinate swabs are just as sensitive as nasopharyngeal swabs collected by healthcare providers. Callahan et al. reported good observance between nasal swabs and nasopharyngeal swabs, but only in those with viral loads >1000copies/mL.

When to suspect COVID-19:
Anyone with symptoms of pneumonia without an identified cause. 

Since the virus has spread across the globe, travel history no longer is a useful clinical marker to assess risk of exposure to COVID-19

When to test someone for COVID-19:

Given the shortage of tests, refer to your local institution’s guidelines, local public health department, and the CDC evaluation/testing guidelines for whom to test. 

Can a patient be co-infected with more than 1 virus? 

Yes. A paper from Wuhan found co-infection in 5.8% (N=104) of patients. Kim et al. in JAMA reports that coinfection with another respiratory virus occurred in 20.7% of respiratory isolates that tested positive for SARS-CoV-2. Chu et al. from Seattle found co-infection in 16% (4 out of 25). 

Can a patient be re-infected with COVID-19?

Kai-Wang To et al. published a case report of an individual who got reinfected by a different strain of SARS-CoV-2 (distinguished by whole genome sequencing) 142 days after the 1st episode. More research is needed to confirm the possibility of reinfection. Tillett et al. also reported a case where a patient re-presented with symptoms of COVID-19 7 weeks after his first episode. Once again, the strains were genetically different. More research is needed to confirm the possibility of reinfection and better elucidate how common it really is.

Treatment

NIH Treatment Guidelines
IDSA Treatment Guidelines

1. Supportive care 
2. ARDS and critical care management 
3. Potential antiviral therapies – NONE of these have been proven to be effective against COVID-19 and discussion of them here does not endorse their use in a clinical setting
   For a more extensive review of potential antiviral therapies, click here
   Guidelines:
   IDSA: Only recommends treatments against COVID-19 in the context of a clinical trial
   CMAJ: Endorse only the use of steroids in severe COVID-19 with ARDS. Do not recommend treatment with convalescent plasma or antivirals. Remdesivir, tocilizumab, and other therapies were not included in the guideline.
   NIH: Recommend use of remdesivir for individuals who have oxygen saturation of 94% or below or who require supplemental oxygen.
   1. Remdesivir – adenosine analogue prodrug that inhibits viral RNA synthesis by binding to RNA polymerase and acting as an RNA-chain terminator
      – has shown to be effective in-vitro
      – specific to RNA polymerase so has low risk of toxicity
      – The NIH COVID-19 treatment guidelines now recommend use of remdesivir for all hospitalized patients who require supplemental oxygen
      – Interim SOLIDARITY trial results showed no effect of remdesivir on 28-d mortality, need for mechanical ventilation, or length of hospital stay compared to placebo.
      – The multicenter, randomized, placebo-controlled ACTT-1 trial published in NEJM (N=1059) showed shorter median recovery time (15d vs. 11d) with remdesivir. Further analyses demonstrated that benefit seemed to be optimized in those who started remdesivir earlier in the illness course (<10d of symptoms) and those who were stable but required oxygen (ordinal score 5). Although difference in 14d mortality (7.1% in remdesivir group vs. 11.9% in placebo group) was not statistically significant, the confidence interval barely passed 1.0 (HR 0.70, 95% CI 0.47, 1.04). There was no difference in adverse effects between the two groups.
      – Wang et al. published in The Lancet the results of a multicenter, placebo-controlled RCT that enrolled 237 individuals with COVID-19, hypoxia, and <12 days from symptom onset to receive remdesivir or placebo for 10 days. Results showed no significant difference in time to clinical improvement at 28 days. Eight (12%) in the remdesivir group had to stop the trial because of adverse effects (including 5 that developed worsening respiratory failure). Authors argue that the study was underpowered to assess a significant benefit from remdesivir.
      – Grein et al. published in NEJM the outcomes of 53 hospitalized patients with COVID-19 illness (mix of severity, but all with hypoxia) who received remdesivir on a compassionate use basis. At 28-day follow up, 13% of patients died and 47% were discharged. Mortality among intubated patients was 18% (lower than most previous accounts reporting 26%,  49% and 67%) and 5% among non-intubated patients.
      – Goldman et al. reports that 5-day course of remdesivir may be non-inferior to a 10-day course. The phase-3 trial randomized 402 patients with hypoxia (but not on mechanical ventilation or organ failure) to one of the two treatment arms. Clinical outcome based on an ordinal scale at 14d showed no difference between the two arms, but the 10d arm had higher rate of adverse effects. Main caveats of the study include that the 10d group was sicker and that only 44% of the 10d group completed the 10d regimen.
      – currently available through clinical trials and under an emergency use authorization (EUA) from the FDA. (based on unpublished interim analysis results from NIH clinical trial (https://clinicaltrials.gov/ct2/show/NCT04280705)
   2. Lopinavir/ritonavir – RECOVERY trial published their findings that lopinavir/ritonavir did not have any effect on mortality, duration of hospitalization, or need for mechanical ventilation compared to standard care at 28d of follow up.
      – Interim SOLIDARITY trial results showed no effect of lopinavir (with or without interferon) on 28-d mortality, need for mechanical ventilation, or length of hospital stay compared to placebo.
4. Monoclonal antibodies (Bamlinivimab) – an antibody directed against the spike protein in SARS-CoV-2 with the effect of preventing the attachment and entry of the virus into human cells.
   – Chen et al. is conducting a phase-II randomized, controlled clinical trial where 452 patients deemed at high risk of hospitalization received either bamlinivimab (one of 3 dosages) or placebo and found that during interim analysis, results of a secondary endpoint showed a decreased risk of hospitalization or ED visit in the treatment arm (1.6%) vs. the control arm (6.3%).
   – received Emergency Use Authorization from the FDA on 11/9/2020 for use in COVID-19 infected individuals who are not hospitalized but are at higher risk of hospitalization and severe disease (age >65yrs, presence of comorbidities)
5. IL-1 inhibitors – IL-1 is a proinflammatory cytokine that induces neutrophilia, fever, and activation of acute phase reactants. Inhibition of IL-1 may help inhibit the hyperinflammatory response in critically-ill COVID-19 patients based on  SARS-CoV-1 research data. 
   – Cavalli et al. published an observational study of 29 COVID-19 patients with hyperinflammation who received anakinra (IL-1 inhibitor) and compared it to a retrospective similar cohort of patients, with results demonstrating improved survival (90% vs. 56%, p=0.009) at 21 days.
6. IL-6 inhibitors – may help inhibit the cytokine storm that is thought to cause critical illness with septic shock and multiorgan failure
   – clinical trials of tocilizumab and sarilumab are ongoing
   1. Tocilizumab
      – Among 21 individuals with critical COVID-19 infection who received tocilizumab, 16 (76%) improved
      – Luo et al. administered tocilizumab to 15 patients (as well as steroids to 8 of the 15) and had 3 deaths (all in patients who received tocilizumab and steroids). Notably, IL-6 > 1000pg/mL was associated with mortality.
      – The CORIMUNO study revealed that tocilizumab was effective at reducing the number of patients who progressed to needing ventilatory support or death at day 14.
      – Martinez-Sanz et al. reported that in their multicenter cohort study, administration of tocilizumab was associated with decreased risk of death (HR 0.34, p=0.005) in those with CRP levels >150mg/L.
      – Knorr et al. published a single-center observational study demonstrating that among 66 patients with severe COVID-19 who received tocilizumab, 49% were eventually discharged and 42% died. (Most also received steroids and hydroxychloroquine).
      – Ip et al. published single-center retrospective study of 547 ICU patients, tocilizumab demonstrated trend towards mortality benefit (aHR, 0.76 [95% CI, 0.57–1.00]).
      – Guaraldi et al. published retrospective study of 544 patients among 3 hospitals in Italy and showed that among individuals with severe COVID-19 pneumonia, tocilizumab was associated with reduced risk of mechanical ventilation need or death,with adjusted HR 0.61, [95% CI 0.42-0.92]. New infection risk was 13% among those receiving tocilizumab compared to 4%.
      – The COVACTA trial, a randomized, placebo-controlled Phase III trial, did not meet the primary clinical end point of improved clinical status at 4 weeks nor secondary endpoint of 4 week mortality. There was a positive trend towards less days to discharge in the treatment group. Full data and paper are not yet published so it’s difficult to interpret the above findings.
      – The EMPACTA trial, another randomized, placebo-controlled Phase III trial, demonstrated that patients who received tocilizumab were less likely to proceed to mechanical ventilation or death by 28 days (12.2% vs 19.3%; OR 0.56, 95% CI 0.32, 0.97). However, there was no difference in mortality nor duration of hospital stay.
      – Stone et al. conducted a randomized, double-blind, placebo-controlled trial of 243 patients who received 1 dose of tocilizumab (8mg/kg) and found that there was no change in mortality or need for mechanical ventilation.
      – Hermine et al. conducted a randomized, controlled trial of tocilizumab among non-critically ill patients and showed no benefit in mortality nor clinical improvement.
   2. Sarilumab – monoclonal IL-6 antibody
      – a recent Phase II trial was stopped early when it was found to not provide benefit to severely ill patients with COVID-19 although the trial continues to enroll critically ill patients
   3. Siltuximab – chimeric monoclonal antibody against IL-6
      – preliminary report from Italy of 21 patients who received siltuximab showed no clear benefit, with 33% improving, 43% remaining stable, and 24% worsening at median follow up of 8 days.
7. Glucocorticoids – NIH COVID-19 Treatment Guidelines recommend the use of dexamethasone with or without remdesivir in patients who are hospitalized AND requiring supplemental oxygen.
   – RECOVERY trial published a pre-peer review manuscript describing a mortality reduction in mechanically ventilated patients (RR=0.65, p=0.0003) and those requiring supplemental oxygen (RR=0.80, p=0.002). Dexamethasone 6mg daily was administered for 10 days or until discharge (median: 6 days). Of note, patients on mechanical ventilation or requiring oxygen had a significantly longer duration of symptoms than those not on oxygen. Mortality reduction was also noted for those with >7 days vs. <7 days of symptom duration.
   – Jeronimo et al. published a double-blind, placebo-controlled, RCT that demonstrated no change in 28-d mortality with 5-day course of methylprednisolone (1mg/kg/day), except in those >60 years old (who also had a higher CRP). 
   – REACT group published a meta-analysis of 7 randomized, controlled trials and demonstrated that treatment with dexamethasone vs. placebo resulted in a lower mortality (OR 0.64, 95% CI 0.5-0.82). Hydrocortisone and methylprednisone did not show a mortality benefit.
8. IVIG/plasma exchange
   1. Convalescent sera from recovered patients – individuals who recover from COVID-19 infection develop antibodies to the virus. These antibodies can then be extracted from the individuals’ blood and administered to patients with active COVID-19 infection to help their immune system fight off the virus.
      – This case-series demonstrated good clinical outcomes in 5 patients who received convalescent sera from recovered patients. The patients were all on mechanical ventilation and received prior antiviral and glucocorticoids prior to administration of plasma. It was administered between day 13-22 of the patients’ hospital stay.
      – Another case-series from Wuhan, China showed improved clinical outcome as well as improved lymphopenia and decreased CRP and SARS-CoV-2 viral load. However, a huge caveat is that all patients received other treatments such as lopinavir/ritonavir, interferon, and glucocorticoids, making it difficult to assess how much of the outcomes are due to the effects of convalescent serum.
      – Zeng et al. compares 6 patients who received convalescent plasma around day 20 to 11 who did not receive it, finding that viral RNA was undetectable by post-treatment day 3 in all 6 patients, but 5 out of 6 died nevertheless. There was no difference in mortality between the two groups. The authors argue CP may be more beneficial in earlier stages of the disease.
      – Rogers et al. demonstrated no difference in mortality or time to hospital discharge with CP administered w/in 10 days of symptom onset, although those >65yrs of age did have a faster time to hospital discharge. Two patients developed transfusion reactions.
      – The first randomized controlled trial of CP showed no difference in time to clinical improvement between those who received CP and those who did not. Limitations of this trial include the prolonged period between symptom onset and initiation of therapy and it was underpowered as it had to be stopped early.
      – Joyner et al. published Mayo Clinic’s multicenter experience with CP, demonstrating a lower 7-d and 30-d mortality when CP had high IgG antibody levels and was given within 3 days of diagnosis.
      – Ibrahim et al. performed a prospective, open-label study of CP administered to severe (administered avg. 12.6d post symptom onset) vs critical (administered avg. 23.1d post symptom onset) patients with COVID-19 and found that hospital mortality decreased from 55% to 13% (p<0.02) with earlier administration of CP.
      – clinical trials are currently underway (great summary by Bloch et al.)
      –13/14 patients had serum neutralizing antibodies which indicates humoral and cellular immunity in COVID-10 convalescent individuals, as there is strong correlation between neutralizing antibody titers and virus specific T cells.
      – currently available through clinical trials and under an emergency use authorization (EUA) from the FDA
   2. IVIG – may work in the future once a certain percentage of the population has become infected and recovered from the virus that antibodies are present in a population sample 
      – small case series of 3 patients demonstrated considerable clinical improvement and decreased CRP levels with administration of IVIG. Findings confounded by concomitant use of antibiotics and antivirals.
      – small retrospective study by Xie et al. showed that among 58 patients with severe COVID-19 pneumonia, those who received IVIg <48 hrs after admission had lower 28d mortality rate and # of days on mechanical ventilation  than those who received it >48 hrs after admission.
9. Mesenchymal stem cells – stem cells obtained from bone marrow (as well as peripheral blood and adipose tissue) are hypothesized to help dampen the hyperinflammatory state triggered by COVID-19 as well as help regenerate lung tissues
   – a small study by Leng et al. of 10 patients who were not improving on standard therapy (7 receiving stem cells, 3 who did not) demonstrated that at 14d followup, all 7 patients improved clinically, while in the 3 who didn’t receive stem cells, 1 died, 1 developed ARDS, and 1 remained clinically stable.
10. Avoiding certain medications (ibuprofen, ACE inhibitors, ARBS) – so far, there is no sufficient data to suggest these medications worsen outcomes. (for further reading, NEJM published a special report on RAAS inhibitors and COVID-19)

• ACEI/ARBS – upregulate ACE-2 protein expression which may lead to increased viral attachment
  – but ACE-2 also counteracts ACE protein and Angiotensin II activity, which have been implicated in lung injury → reduced lung damage
  – associated with less severe disease and lower IL-6 levels in COVID-19 patients (Meng et al.) and with lower mortality (Zhang et al.)
  – 2 NEJM articles published May 1st (Mancia et al., and Reynolds et al.) also reported no significant increase in COVID-19 risk, mortality,  or morbidity in individuals taking ACEI/ARBs. (Similar results demonstrated in Mackey et al.) (Mehra et al. paper was retracted by NEJM).
  – for further reading, NEJM published a special report on RAAS inhibitors and COVID-19
• NSAIDs – based on incredibly limited data, there is a suggestion that NSAIDs induce upregulation of ACE-2 receptors
  – it remains unknown if this is clinically significant
  – Lund et al. reports no difference in 30-day mortality or severity of infection between those who received NSAIDs and those who did not, in the Danish nationwide registry-based study.

SOLIDARITY trial – a multinational, multicenter randomized-controlled trial launched by WHO that will study multiple therapy regimens for COVID-19.
– interim results at which time 11,266 patients were enrolled across 30 countries showed no mortality benefit of any of the 4 treatment arms compared to placebo

1. Remdesivir
2. (Hydroxy)chloroquine – this treatment group has been temporarily suspended due to safety concerns
3. Lopinavir/ritonavir
4. Lopinavir/ritonavir + interferon-beta

Transmission/Prevention

IDSA Guidelines

The SARS-CoV-2 is transmitted by respiratory droplets, and by fomite contact transmission as well (think hand to respiratory tract/mucosal membranes). Whether SARS-CoV-2 is transmitted airborne remains a debate. Similarly, although SARS-CoV-2 has been isolated in stool and blood samples, as well as ocular secretions, the significance of this in regards to transmission potential remains unknown.

Types of transmission:

Respiratory droplet transmission: virus within respiratory droplets is released through respiratory secretions when an infected person coughs, sneezes, talks, or laughs and makes contact with the mucous membranes of a nearby uninfected person (usually within 6 feet) 

Fomite transmission: infected virus present on a surface is transferred to a hand and then the hand comes in contact with mucous membranes (eyes, nose, mouth). A study by Binder et al. and Harvey et al. demonstrates that fomite transmission may not be a common mode of transmission of SARS-CoV-2. 

Airborne transmission: virus within very small respiratory particles (smaller than droplet) that remain in the air over a longer period of time and can travel farther in distance is released through respiratory secretions of an infected cough. Because the virus within the respiratory particle remains in the air for longer and can travel farther, it can infect a greater amount of people. Fecal-oral route: ingestion of fecal matter with live virus. Live, infectious virus has been isolated from stool samples (Wang et al., Xiao et al.), raising the possibility of transmission via fecal-oral route as well.

The airborne transmission debate

A report published in the New England Journal of Medicine talked about aerosol stability of up to 3 hours in the air. However, it’s important to note that aerosolization of the virus was done under experimental conditions. This may not reflect actual transmission routes in routine conditions. The World Health Organization acknowledged the report; however, for the reasons outlined above, it continues to recommend surgical masks with eye protection + gloves + gown in non aerosol generating conditions. A study by Liu et al. demonstrated that open air, ventilation, and rigorous sanitation can reduce aerosol transmission. On 3/30/2020, Greenhalgh et al. affiliated to the university of Oxford published similar recommendations. 

To add fuel to said debate, Santarpia et al. at University of Nebraska Medical Center shared a preprint in which they report isolating viral RNA and culturable virus in the hallways outside patient rooms who were not actively coughing. This raised concern that even mildly ill patients may expel virus that can be transported by aerosol in a “local environment” even in non-aerosol generating conditions. The WHO and the Controversies in Hospital Infection Prevention both have good summaries explaining the discrepancies and why surgical masks might be appropriate even if the virus can remain in the air for some time. The debate continues: On July 6th, Morawska and Milton published a commentary in CID making a case for airborne transmission. The WHO acknowledges that airborne transmission is a possibility, but argues that most outbreaks could still be explained with droplet and fomite transmission and thus far, no evidence of nosocomial transmission has occurred among healthcare workers wearing surgical masks outside of performing aerosol-generating procedures.

More recently, Binder et al. studied 20 hospitalized patients with COVID-19 and was only able to detect viable SARS-CoV-2 virus in air samples of 3 patients, suggesting that transmission through aerosols is uncommon. Meanwhile, Bahl et al. published an analysis of droplets expelled by singing and demonstrated that they followed the air pattern when without adequate ventilation required for dispersal, arguing for potential aerosol spread of the virus.

And what about viability of the virus on different surfaces? The aforementioned report found that SARS-CoV-2 was viable on:
– Paper: up to 3 hours
– Cloth: up to 48 hours
– Wood: up to 48 hours
– Plastic: up to 72 hours to 7 days
– Stainless steel: up to 48 hours to 7 days
– Cardboard: up to 24 hours
– Copper: 4 hours

This is an evolving topic. A recent MMWR noted that “SARS-CoV-2 RNA was identified on a variety of surfaces in cabins of both symptomatic and asymptomatic infected passengers up to 17 days after cabins were vacated on the Diamond Princess but before disinfection procedures had been conducted”. This does not prove infectiousness, but does raise some concerns. On surfaces, because of the nature of the virus (having an envelope) it can be easily killed with appropriate disinfection of surfaces (and washing your hands!). Ratnesar-Shumate et al. described the effective inactivation of SARS-CoV-2 virus on saliva and cultured media with simulated sunlight.

Heinzerling et al. demonstrated that among 121 healthcare workers that were exposed to a patient with COVID-19, 35% developed symptoms, and 2% (3 people) tested positive for SARS-CoV-2. All 3 wore no PPE when exposed to the patient. And a study from Wong et al. demonstrated that amongst close contacts of a patient who was not known to have COVID-19 for the first 35 hours of his hospital stay, none of the healthcare workers became infected, despite only wearing surgical masks and practicing good hygiene.

In Li et al., among household contacts, secondary transmission from individuals with COVID-19 to other household members was 16.7% overall, 27.8% for spouses, 17.1% for adults overall, and 4% for children. Transmission was 0% when the infected member of the household quarantined themselves from the rest of the household. Absence of fever or cough did not affect the transmission rate.

Can an asymptomatic individual transmit the virus?
Yes, although it remains unclear how likely asymptomatic individuals are likely to transmit the virus. Recent study from Singapore suggests presymptomatic spread 1-3 days before the onset of symptoms. Lee et al. demonstrated similar viral loads between symptomatic and asymptomatic individuals. A study evaluating serial intervals of transmission also suggests transmission from asymptomatic/PREsymptomatic individuals. The CDC MMWR investigation of the King County, Washington outbreak detected SARS-CoV-2 viral RNA in 23 individuals, 56% of whom were asymptomatic at the time of testing. 77% of the asymptomatic individuals went on to have symptoms in the next 7 days, while the others remained asymptomatic. And He et al. estimated that 44% of secondary cases were infected prior to the onset of symptoms in the index case. Furuse et al. similarly estimated that 41% transmitted the virus while asymptomatic.

How long does an individual remain infectious? 

Viral loads tend to peak at the time of onset of symptoms and decline slowly over the next 2-4 weeks (with more severe cases having a more prolonged viral shedding period up to 6 weeks). HOWEVER, whether detection of viral RNA in a specimen indicates ongoing viral replication and shedding REMAINS UNKNOWN. 

Wolfel et al. reported that they were not able to isolate live virus 8 days after onset of symptoms. Cheng et al. in Taiwan reported that of 22 secondary cases that were positive COVID-19, all of them had exposure to the initial positive case within 5 days of symptom onset, suggesting that infectivity may be low after 5-6 days post-symptom onset.

The Korean CDC reports that out of 285 “re-positive” cases (individuals who tested positive for SARS-CoV-2 RNA after discharge from isolation), 3 newly confirmed cases were found, all of whom had other known contacts. This finding provides further evidence that RNA detection does not equal ongoing infectivity.

When to remove isolation precautions for individuals with COVID-19?
Refer to the CDC website page here.

Prevention: 

1. Respiratory hygiene – cover your cough or sneeze by covering your mouth and nose with your bent elbow
   – Leung et al. demonstrated that wearing a mask decreases the transmission of respiratory viruses in exhaled breath
   – Wilson et al. showed that wearing a mask reduced infection risk by 44-99% (short 30s exposures) and by 24-94% (prolonged 20 min. exposures)
   – Hendrix et al. reports a hair salon in Missouri where two hairstylists with symptomatic COVID-19 did not transmit the virus to any of the 139 clients when both stylists and clients were masked. Further evidence of masks’ effectiveness.
   – Verma et al. demonstrated that an uncovered cough can transmit respiratory droplets up to 12 ft away
2. Avoid contact with individuals who have symptoms of a respiratory infection as much as reasonably possible (at the very least, maintain a distance of 6 feet or more)
3. Social distancing – even asymptomatic individuals may transmit the virus
4. Wash your hands frequently with soap and water or hand sanitizer with at least 60% alcohol (to avoid transmitting virus from infected hands to the respiratory tract) 
5. Avoid touching your mouth, nose, and eyes with unwashed hands
6. Disinfect: high touch surfaces (such as door knobs), mobile phones and other objects/surfaces touched with unwashed hands (EPA approved disinfectants)
7. Wear appropriate personal protective equipment when caring for a patient with suspected or confirmed COVID-19 infection 

For practical day to day advice on how to keep yourself and others safe from getting or transmitting SAR-CoV-2, please read this article for more detailed guidance. 

For real-time clinical advice on COVID-19 related matters from ID-trained physicians, call the CDC Clinician Call Center (1-800-CDC-INFO or 1-800-232-4636). More information can be found here.

That’s it for now! Please be aware that information on COVID-19 is constantly changing so make sure to fact-check us.

This summary is updated biweekly by Milana Bogorodskaya.