COVID-19 SUMMARY

image designed by Sarah Marraffino

Currently updated through June 10, 2020

As we are in the midst of a pandemic, we hope to bring you an easy-to-read weekly summary of COVID-19. Each week, 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, passed it on to passed it on to pangolins (intermediate host), and then spread to humans (read here for further reading). Recent (not yet peer reviewed) study suggests the virus can also replicate in cats and ferrets! 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 found in the nasopharynx. 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. 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 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).

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). As of June 17, 2020, the United States, Brazil, Russia, India, and United Kingdom have the highest number of cases worldwide. The U.S has over 2 million infections. The U.S. has surpassed all other countries in the number of deaths due to COVID-19 and at the end of May 2020 surpassed 100,000 deaths. The U.S. is followed by Brazil, United Kingdom, Italy, and France. 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

The first surveillance data on hospitalized COVID-19 cases (N=1,482 across 14 states) in the U.S. in March 2020 showed that: 

  • 74.5% were aged ≥50 years
  • 54.4% were male (although males accounted for 49% of the population)
    *Higher prevalence in men was also seen in a population-based study from Iceland 
  • 89.3% had one or more underlying conditions; hypertension (49.7%), obesity (48.3%), chronic lung disease (34.6%), diabetes mellitus (28.3%), and cardiovascular disease (27.8%) (N=178)
  • Among patients with race/ethnicity data (N=580) 
    • 261 (45.0%) were non-Hispanic white (although they accounted for 59% of the population)
    • 192 (33.1%) were non-Hispanic black (although they accounted for 18% of the population)
    • 47 (8.1%) were Hispanic (although they accounted for 14% of the population)
    • 32 (5.5%) were Asian
    • 2 (0.3%) were American Indian/Alaskan Native
    • 46 (7.9%) were of other or unknown race
  • 3 were pregnant 

These results suggest the virus disproportionately affects men and the non-Hispanic black population

MMWR study of COVID-19 patients from Georgia also demonstrated a disproportionate number of non-Hispanic Blacks (83% of the cohort) hospitalized with COVID-19.
Among individuals who have been discharged, case fatality rates ranged from 3.4% in (18-49 year age group) vs. 9.8% (50-64 years) to 35.6% (65 years or older).

Case Fatality Rate (CFR) = # of deaths from infection/# of individuals infected

A publication in The Lancet used mathematical modeling to estimate CFR in COVID-19. In China, the authors estimated the CFR at 1.38% (95% CI 1.23-1.53) while the Infection Fatality Rate (IFR) was estimated to be 0.66%. The same study showed that age is a significant predictor of mortality. Please see Kai Kupferschmidt’s Twitter thread here.

*Important to note that CFR depends on multiple factors (virus characteristics, number of people tested for the virus, and healthcare resources) and cannot be truly assessed unless we know the number of individuals infected with the virus (especially the asymptomatic ones). Therefore, CFR is difficult to estimate during an outbreak. 

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
  2. No vaccine. It will take at least 18 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)
  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. However, another study by Sajadi et al. reports that a majority of the areas with substantial community spread of the virus were among a similar latitude, suggesting SARS-CoV-2 is a seasonal respiratory virus.

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

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: In this study of hospitalized patients with COVID-19, 36.4% had neurological manifestations that included both CNS, PNS and skeletal muscle injury. CNS manifestations included acute cerebrovascular disease (ischemic stroke and cerebral hemorrhage in 2.8% of patients. 
    Toscana et al. documented Guillan-Barre Syndrome in 5 patients with COVID-19 in Italy
    (Ahmad et al. identified 18 published cases of Guillan-Barre Syndrome in COVID-19 so far)
    Wang et al. published a meta-analysis documenting the various neurological manifestations as well as CSF, EEG, and MRI findings of patients presenting with COVID-19.
  • Ocular manifestations: In this study 1.4% had vision impairment 
  • Nose/throat manifestations: In this study 5.6% and 5.1% had abnormal taste and smell, respectively, and 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: 

Sensitivity97%
Specificity25%
Positive Predictive Value65% 
Negative Predictive Value83%

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: 

Predictive factors for mortality: 

  • Leukocytosis
  • Elevated LDH

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, however when it does present in the severe form, it tends to affect younger infants as reported in this epidemiological study (details below)
    – here is a systematic review by Mehta et al. that summarizes what we know about COVID-19 illness in the pediatric population as of May 11, 2020.
    • In a retrospective case series of  48 pediatric PICU patients in the US/Canada:
      • Median age: 13 years old
      • 83% had comorbidities prior to PICU admission
      • Respiratory and other organ system failure were common; 23% of children had 2+ organ system failure
      • 38% of the cohort  required intubation/tracheostomy ventilation, and 25% required vasoactive support
      • At study end, 4% of patients were reported to have died
      • This highlights that children with severe COVID-19 disease have a high prevalence of co-morbidities
    • In a retrospective cohort of neonates born to COVID-19 positive mothers at Wuhan Children’s hospital from 1/20-2/20:
      • All born via c-section
      • 3/33 neonates tested positive (2 were full term, 1 preterm)
      • Both full term neonates developed fever & lethargy with CXR positive for pneumonia. 
      • Preterm neonate had concomitant bacterial sepsis and respiratory failure
      • All recovered/survived with no therapy
    • Epidemiological study of COVID-19 pediatric cases in the U.S. from CDC MMWR from 2/12-4/2: 
      • Among 149,082 reported cases, 2,572 (1.7%) were in children 
      • Median age: 11 years old 
      • 91% had exposure to a household/community member infected with COVID-19
      • 73% of children reported fevers/chills, cough, or SOB (compared with 93% adults 18-64yrs old)
      • 5.7% of children were hospitalized (compared with 10% of adults 18-64yrs old)
      • Children <1 yrs old had higher % of hospitalizations compared to older children
      • 23% children had comorbidities (chronic lung disease > cardiovascular disease > immunosuppression)
      • *Lots of missing data
    • Castagnoli et al. published systematic review of pediatric COVID-19 literature in JAMA Pediatrics
      • 1065 pediatric patients from China and Singapore
      • 42% were <10yo age, 52% were 10-19yo age
      • Predominant symptoms were fever and cough, followed by mild respiratory symptoms and vomiting
      • Except for 1 patient, none required assisted oxygen
      • Radiographic findings ranged from bronchial thickening, ground glass opacities, and inflammatory lung lesions
    • Largest epidemiological study of pediatric COVID patients:
      • 2143 pediatric patients from China. 
      • 34.1 % patients were identified as laboratory-confirmed cases, remainder were suspected cases. 
      • Median age: 7 years old. 
      • 94% asymptomatic/mild/moderate. 
      • Median time from infection to symptom onset: 2 days. 
      • Proportion severe and critical cases by age group:
        • <1yr: 10.6 %
        • 1-5yr: 7.3%
        • 6-10yr: 4.2%
        • 11-15yr: 4.1%
        • >16yr: 3.0%. 1 death (14 years old). 
      • Limitations: Lack of more granular information like clinical characteristics, co-morbidities, labs, radiology ect.​
    • In a study of 171 children (0-15yrs of age) from China 
      • Fever was present only in 42% of participants
      • Asymptomatic: 16% 
      • URI symptoms: 19%
      • Pneumonia: 65% 
      • 3 patients were critically ill and required invasive ventilation (all 3 had coexisting conditions) 
    • In a cohort report from the pediatric emergency department study in Italy, 100 pediatric patients with confirmed SARS-COV-2 who presented between 3rd of March-27th of March in 17 pediatric ERs revealed:
      • Median age of the children was 3.3 years (Table 1 characteristics)
      • 21% of patients asymptomatic, 58% mild disease, 19% moderate disease, 1% severe disease, and 1% in critical condition.
      • No deaths were reported
      • 6/9 of patients who required respiratory support had coexisting conditions
      • 45% of children were exposed to COVID-19 from a family cluster, which was lower in this cohort compared to other pediatric cohorts and may be secondary to the late lockdown in Italy
    • 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
      Riphagen et al. published a case series in Lancet describing the increased numbers of  hyperinflammatory shock cases in the pediatric population in UK. Although all children were initially SARS-CoV-2 negative, two tested positive post discharge and others had close contact with COVID-19 positive relatives.
      – 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 
    • AsymptomaticWang 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
      Case report demonstrating asymptomatic spread within a family cluster
      – See recent article in Nature for further reading on asymptomatic spread
      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.
    • 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 years3.6%3.5%
70-79 years8.0%12.5%
>80 years 14.8%19.7-22.7%
  • Immunocompromised
    • In a systematic review of COVID-19 Immunocompromised patients, 16 articles were identified with 110 immunocompromised patients (12 children)
      • Most immunocompromised patients were cancer patients (98 patients, 1 of which was a child with leukemia)
      • The remaining patients had immunodeficiency (5 patients) and transplant recipients (3 pediatric liver transplants, 2 adult heart transplants, 2 adult kidney transplants)
      • 72 patients (65.5%) recovered (defined as discharged or just required inpatient stay), 6 patients (5.5%) needed ICU/intubation, 9 patients (8.2%) reached composite outcome of death OR ICU admission and 23 patients (20.9%) died
      • The author group’s conclusions is that existing data show that immunosuppressed hosts may not present a greater risk of an increased severity of disease, compared to the general population
    • In an article published in BMJ reporting the recommendation of UK’s National institute for health and care excellence (NICE) guidelines, the committee’s consensus is that immunocompromised children do not seem to have increased risk of severe COVID-19
      • Per the guidelines, COVID-19 usually causes mild self-limiting illness even in immunocompromised children
      • The guidelines emphasize that immunocompromised children shouldn’t avoid regular appointments (albeit, telemedicine is still the preferred alternative method) and their usual treatment shouldn’t be discontinued
    • In the largest to date report of solid organ recipients with COVID 19, 90 patients were analysed in the first 3 weeks of the outbreak in NY in 2 centers:
      • Median age 57 years
      • 46 were kidney recipients, 17 lung, 13 liver, 9 heart and 5 dual‐organ transplants.
      • Most common presenting symptoms were fever (70%), cough (59%) and dyspnea (43%)
      • 22 (24%) had mild, 41 (46%) moderate and 27 (30%) severe disease
      • Among the 68 hospitalized patients, 12% required non‐rebreather and 35% required intubation
      • 91% received hydroxychloroquine, 66% azithromycin, 3% remdesivir, 21% tocilizumab and 24% bolus steroids
      • 16 died (18% overall, 24% of hospitalized, 52% of ICU) and 37 (54%) were discharged
      • This report alludes to SOT recipients having more severe outcomes but due to testing limitations, alot of the mild/asymptomatic patients are missed
    • In a retrospective single center study in Wuhan, China following 87 heart transplant recipients between Dec 20, 2019 and Feb 25, 2020 assessed for incidence of COVID-19:
      •  72% were male, average age: 51 years old
      •  95.4% were on immunosuppressants
      • Comorbidities included hypertension in 32.2% of patients, hyperlipidemia in 17.2%, and diabetes in 23%. 
      • 68.6% were in contact with asymptomatic returned travelers and 92% lived together with relatives (anywhere between 1-8 members in the household)
      • 96.6% of patients in the cohort undertook precautionary procedures after Jan 23rd, including 64.4% who self-quarantined at home. 
      • Laboratory assessment was undertaken for 47 patients in the cohort, of whom 21.3% had pre-existing lymphopenia. 
      • Four patients developed URI, 3 of whom tested negative for SARS-COV-2.
      • Despite ‘similar exposures’ to non-heart transplant patients, the cohort exhibited fewer infections than expected.
    • In a letter to the editor reporting preliminary experience from one of the main hospitals of Lombardy looking at pediatric liver transplant recipients. 
      • Hospital hosts one of the largest European centers for pediatric transplantation (700 pediatric liver transplant, 3 recipients in the last 2 months). 
      • From 200 transplant recipients (including 10 current inpatient, 3 who are receiving chemotherapy for hepatoblastoma), none developed clinical pulmonary disease despite 2 testing positive for SARS-COV2. 
      • This number includes recipients who attend outpatient clinics, and were consulted from phone consultation logs. 
      • This seems to suggest that immunocompromised patients are not at an increased risk compared to the general population and there are no reasons to postpone life-saving transplantation or chemotherapy.
    • A retrospective peer reviewed study assessed 2,007 cases of hospitalized COVID-19 cases from 575 hospitals in China including adult malignancy patients. 
      • From that cohort, 18 patients were reported to have a history of cancer, of which the majority was lung cancer (5/18). 
      • Of these patients, 4/18 received chemotherapy in the preceding month, 2/18 had unknown treatment status, and the remaining 12/18 were designated ‘cancer survivors’ not currently receiving maintenance treatment. 
      • The oncology cohort was older, more likely to have a history of smoking, and had more severe CT findings than non-oncology patients. 
      • Most notably, the oncology cohort was observed to have higher risk of severe events (defined as ICU stay, need for mechanical ventilation or death): 7/18 patients vs. 124/1572. 
      • Limitations of study: 
        • Small cohort of oncology patients
        • Heterogeneous cancer status (mixed group of active chemotherapy patients vs cancer survivors)
        • Heterogeneous additional co-morbidities alongside malignancy. 
    • A study of 18 solid-organ transplant patients (kidney [44.4%], liver [33.3%] and heart [22.2%]) in Spain demonstrated similar presentation compared to other studies, with a 27.8% case fatality rate and with 30% of survivors with worsening respiratory status at last date of follow up. 
    • Haberman et al. describes 86 patients who were on biologics and other immunomodulatory therapies and reports no association with worse COVID-19 outcomes.
    • Vizcarra et al. published a prospective cohort study comparing 51 HIV-positive patients with confirmed/suspected COVID-19 vs. 1288 HIV-positive patients without COVID-19 and demonstrated that the risk factors were similar to those seen in the general population (obesity and other comorbidities) as well as the use of tenofovir medication.
      • Median CD4 of patients infected with COVID-19 was 565 with only 12% having CD4<200 at the time of COVID-19 symptoms.
  • 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)
    • 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
  • 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.
    • 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. Recent 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) 
    4. Fibrobronchoscope brush biopsy: 46% (6/13)  
    5. Pharyngeal swabs: 32% (126/398)  
    6. Feces: 29% (44/153) 
    7. Blood: 1% (3/307)  
    8. 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.
– This paper suggests false negative probability is lowest day 5-9 after onset of symptoms.

2. COVID-19 serology test – IgM appears to develop ~514 days and IgG 24 weeks after onset of symptoms (read another recent paper here and here)
– sensitivity is ~8389%, specificity is ~9199%
– 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.)
– durability of antibodies and protection from re-infection remains unknown

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). 

Treatment

  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
      – 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. Chloroquine – an antimalarial drug that disrupts the ability of the virus to fuse with the host cell
      – has shown to be effective in-vitro
      – can potentially cause QTc prolongation, liver toxicity, and/or retinopathy
      clinical trials are ongoing in China
      Huang et al. demonstrated that out of 10 people who received chloroquine compared to 12 that received lopinavir/ritonavir, the chloroquine group had faster time to viral clearance and hospital discharge by day 14. Although notably lopinavir/ritonavir group started treatment on average 4 days later than the chloroquine group.
      Borba et al. reported that 25% of participants receiving higher dose chloroquine (1200mg daily) plus azithromycin (as part of CAP therapy) developed QTc prolongation. Study enrollment into the higher dose chloroquine arm had to be stopped early due to the findings.
      – FDA revoked the emergency authorization use of chloroquine for COVID-19 treatment
    3. Hydroxychloroquine – has the same mechanism of action as chloroquine but is better tolerated
      – has shown to be effective in-vitro with more potency than chloroquine against SARS-CoV-2
      new small RCT of 62 patients (Feb 4-Feb 28) with mild (no hypoxia) COVID-19 illness from Wuhan, China where 31 were randomized to receive hydroxychloroquine for 5 days with standard of care vs standard of care (which included oxygen, antiviral therapy, antibiotics, and +/- steroids). Results showed faster resolution of cough, fever, and CT chest infiltrates in the hydroxychloroquine group. All 4 individuals who progressed to severe illness were in the control group.
      Mahevas et al. showed no difference in outcomes between patients who received HCQ (N=84) and those who did not (N=97); 9.5% in the HCQ group developed ECG changes that required discontinuation of HCQ
      Tang et al. published an open-label RCT demonstrating that there was no difference in 28-day negative conversion rate between HCQ and standard of care group. However, in adjusted analyses, HCQ was associated with improved clinical symptoms and more improvement in CRP and lymphopenia.
      Magagnoli et al. performed a retrospective study at VA and found that the group using HCQ had higher mortality rate of 27.8% compared to 22.1% with HCQ+azithromycin and 11.4% in the no treatment group.
      Geleris et al. reported an observational study in NYC that used propensity based matching between the HCQ and non-HCQ groups and found no difference in outcome (intubation or death) at median 22.5d of follow up.
      Giacomelli et al. performed a retrospective study that showed there was no difference in 30-day mortality between patients who received HCQ + Lopinavir/ritonavir early in the course (<5 days from onset of symptoms) vs. later in the course (>5 days from onset of symptoms)
      Boulware et al. demonstrates HCQ has no efficacy as post-exposure prophylaxis for COVID-19
      – FDA revoked the emergency authorization use of hydroxychloroquine for COVID-19 treatment
    4. Hydroxychloroquine + azithromycin – a combination treatment that was shown to be associated with more rapid microbiological eradication of the virus in an incredibly small open-label, non-randomized trial
      – although shown to be associated with quicker eradication, the different treatment groups were not randomized and not equal, leading to significant biases that could have influenced the results. Furthermore, it is unclear whether microbiological eradication leads to better clinical outcomes.
      – for further evaluation of this study, read Dr. Pogue’s tweetorial
      new prospective study from France looked at 11 individuals with moderate/severe COVID-19 illness who received hydroxychloroquine + azithromycin. Within 5 days, 1 patient died, 2 were transferred to the ICU, and 1 had discontinuation of the treatment due to QTc prolongation. Results showed that 8/10 continued to have positive PCR after the 5 day treatment course.
      – Raoult et al. further released the abstract of their 1061 person cohort who received HCQ and azithromycin with good clinical outcomes. Demonstrates it’s safe to use but difficult to interpret efficacy of treatment without a comparison group and reading the full manuscript.
      – In a retrospective propensity-matched study by Rosenberg et al., there was no difference in in-hospital mortality between patients who received HCQ, HCQ+azithromycin, azithromycin alone, or neither of the two drugs.
      – the concern of using this combination of medication is the increased risk of QTc prolongation. Chorin et al. demonstrated that 30% of patients receiving the drug combination had an increase of >40ms of their QTc and 11% had a QTc>500ms.
    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.
      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. Lopinavir/ritonavir – a protease inhibitor that was used in old anti-HIV regimens
      – has not been shown to be effective in a clinical randomized-controlled trial
      – the major critique of the trial was the late onset of therapy (13 days) and whether initiation earlier in the course would have led to better outcomes in treatment group
      Giacomelli et al. performed a retrospective study that showed there was no difference in 30-day mortality between patients who received HCQ + Lopinavir/ritonavir early in the course (<5 days from onset of symptoms) vs. later in the course (>5 days from onset of symptoms)
      – can potentially cause liver toxicity and GI upset
    8. Lopinavir/ritonavir + Interferon-beta 1b + Ribavirin – all three drugs have some in vitro activity against SARS-CoV-2. Would combining all 3 have a clinical effect on the infection?
      Hung et al. conducted a Phase 2, open-label, 2:1 RCT of the above regimen compared to lopinavir/r alone and found a shorter time to negative viral load (7 vs. 12 days, p=0.001), faster resolution of clinical symptoms (4 vs. 8 days, p<0.0001), and shorter hospital stay (9 vs. 14.5 days, p=0.016). Of note, the cohort of patients was not severely ill (only 13% required supplemental oxygen and 5% ICU care). Furthermore, 54% of participants received concomitant antibiotics and 6% received corticosteroids.
  4. Glucocorticoids – controversial; no data to recommend use at this time. The CDC and WHO recommend against use of corticosteroids for COVID-19 based on observational data for SARS, MERS, and influenza that suggested that there may be harm, despite potential benefit shown in one recent study. Recent Surviving Sepsis guidelines for critically ill patients with COVID-19 give a weak recommendation for corticosteroid use in patients with ARDS
    – Meta-analysis by Li et al. of clinical outcomes with steroid use in SARS, MERS, and COVID-19 showed delayed virus clearing, increased use of mechanical ventilation, and prolonged hospitalization time. No difference in mortality was noted.
    RECOVERY trial published a press release stating that dexamethasone reduced mortality in by mechanically ventilated patients (RR=0.65, p=0.0003) and those requiring supplemental oxygen (RR=0.80, p=0.0021). However, study has not yet been published so it is not possible to interpret these data at this time. 
  5. 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.
      – 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.
      – 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.
    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.
  6. 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 few case reports demonstrated favorable outcomes in regards to respiratory status, clinical improvement, and inflammatory markers after administration of mesenchymal stem cells (although they are all written in Chinese so we could not access them).
  7. 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

  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.

The airborne transmission debate: as mentioned in the introduction, 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. 

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. A case report of a family cluster from China demonstrates asymptomatic spread among family members. 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)
  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. 

That’s it for now! Please be aware that information on COVID-19 is constantly changing so make sure to fact-check us if you are reading this more than a day after this page is updated.

This summary is a joint effort of Ahmed Abdul Azim, Fatima Al-Dhaheri, and Milana Bogorodskaya.

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