COVID-19 SUMMARY

Currently updated through April 1st, 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, 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).

SARS-CoV-2 (as well as SARS-CoV-1) uses its spike (S) protein to attach to the ACE-2 receptor in alveolar epithelial cells. From there, it is able to cause inflammation in the lungs leading to ARDS and spread through the blood, causing a cytokine storm and other organ damage. 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). Pathogenesis of the viral infection is not fully known.

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 April 1st, 2020, United States, Italy, Spain, China, and Germany have the highest number of cases. 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

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

The most recent 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 peak flu season. We are already seeing this in parts of Italy, Spain, and United States.  Here in the United States, the state of New York is requesting for more ventilators in anticipation of the need for this as more people get infected.

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 are likely 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. 

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.

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).

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%

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
– 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 

Indicators of poor outcomes

  1. Older age (>60 years of age)
  2. Comorbidities 
  3. Abnormal vital signs 
  4. Lymphopenia
  5. Increased levels of inflammatory markers (i.e. CRP, ferritin, D-dimer, IL-6, etc)
  6. Presence of dyspnea 
  • PediatricsCOVID-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)
    • 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
    • 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 case series of 9 infants in China — all recovered
      • 4 had fever 
      • 2 had mild upper respiratory symptoms 
      • 1 asymptomatic 
      • 2 had no information on symptoms 
  • Adults 
    • Asymptomatic – unknown % at this time
      – 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
    • 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)
  • 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 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. 
  • Pregnant 
    • 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 
    • 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

*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 influenza infection, 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

2. COVID-19 serology test IgM appears to develop ~514 days and IgG 24 weeks after onset of symptoms (read another recent paper here)
– sensitivity is ~89%, specificity is ~91% (in this study)
combined use of PCR and IgM appears to increase diagnostic sensitivity  
– will also help ascertain those who have developed immunity to the virus

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

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? 

Theoretically, yes. A case-report from China documents a man who tested positive for both Influenza A and COVID-19. Another paper from Wuhan found co-infection in 5.8% (N=104) of patients.

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
    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
      – currently available through clinical trials. Compassionate use has been halted due to demand, but Gilead is working on opening up an expanded access program. Check in at https://rdvcu.gilead.com/ for updates. 
    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
    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
    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
    5. 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
      2. Sarilumab – monoclonal IL-6 antibody
    6. Lopinavir/ritonavira 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
      – can potentially cause liver toxicity and GI upset
  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
  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.
    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 
  6. 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)

Transmission/Prevention

The SARS-CoV-2 is transmitted by respiratory droplets, and likely by fomites as well (think hand to respiratory tract/mucosal membranes). In addition, both viral RNA and live virus have been isolated in stool samples, raising the possibility of transmission via fecal-oral route as well. 

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. 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.

And what about viability of the virus on different surfaces? The aforementioned report found that SARS-CoV-2 was viable on:
Plastic: up to 72 hours
Stainless steel: up to 48 hours
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. 

Can an asymptomatic individual transmit the virus?
Yes. 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. A news article in Nature has a good discussion on this.

Prevention: 

  1. Respiratory hygiene – cover your cough or sneeze by covering your mouth and nose with your bent elbow
  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, Milana Bogorodskaya, and Jeff Pearson.

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