Updated — April 5, 2020

(I’ve added information and links for new pandemic modeling, viral myocarditis, analytical sensitivity of PCR and serology, universal masking for HCWs, and new and emerging treatment options.)

The Virus

Single-strand, enveloped RNA virus. Corona, from Latin, meaning crown (viral envelope has crown-like projections).

This post is about novel coronavirus 2019 (nCoV-19), aka SARS-CoV-2. Disease caused by this virus is termed COVID-19.

SARS-CoV-2 likely originated from bats (or may be pangolins)

Epidemiology

For the latest numbers on COVID-19 cases, see dashboard by Johns Hopkins.

Our World in Data COVID-19 page is another great resource.

Most of you have seen the Imperial College of London’s COVID-19 outbreak modeling that predicted millions of COVID-19 related deaths in US (if no lockdown is enforced) and other countries and that report has informed decision making by governments across the world. However, now according to a new model by a team from Oxford’s Evolutionary Ecology of Infectious Disease lab, half of the population of the UK may have already been infected with the coronavirus. If this modeling is confirmed in follow-up serologic studies, that would mean that <0.01% of those infected require hospital treatment, with a majority showing very minor symptoms, or none at all.

Transmission:

Transmission is mostly by respiratory droplets. These are larger particles that are released with coughing or sneezing and usually fall to ground or other surfaces within 6 feet of the source person.

Airborne transmission can happen, especially with aerosol-generating procedures such as intubation, airway suctioning, sputum induction, etc. So physicians, nurses, and respiratory therapist with close contact with COVID-19 patients should use N-95 masks, if available.

Virus can survive on surfaces for hours and therefore contact precautions are of utmost importance.

One infected person can spread infection to 3 to 4 individuals. However, in crowded conditions, this number can be much higher.

Most of the infection spread is likely from asymptomatic or pre-symptomatic individuals (30% to 50%).

Viral shedding may continue to occur after patient has recovered from clinical illness. However, it is unclear how much role this plays in transmission.

Pathogenesis

SARS-CoV-2 enters cells via ACE-2 receptors which are expressed by epithelial cells of the lung, intestine, kidney, and blood vessels. Initial cellular injury is causes by direct viral Cytopathic effect (anti-viral therapy is likely to help at this stage). Subsequently, additional damage is caused by cytokine storm (Immunomodulation therapy, such as IL-6 blockers, are likely to help at this stage). To learn more, read this chapter on Advances in Virus Research.

Symptoms

Most patients develop symptoms within 4 to 6 days of virus transmission (range 2 to 12). Late symptoms, up to 24 days later, reported in some cases. (Unclear if infection was acquired at initial known exposure or perhaps subsequent, known or unknown, exposure)

Fever, cough, fatigue, and shortness of breath are the most frequent symptoms. G.I. symptoms have been reported but are less fequent. Anosmia and purulent conjunctivitis have also been reported. Recently a case of acute hemorrhagic necrotizing encephalopathy was reported as well.

Myocarditis is an infrequent but serious complication of COVID-19. Patients with myocarditis present with regional wall motion abnormalities, ECG findings of diffuse ST-segment elevation, and late gadolinium enhancement on cardiac MRI. There can be assocaited pericardial effusion. Patients with myocarditis are at increased risk of death due to cardiac arrhythmias.

Symptoms alone are not sufficient to distinguish COVID-19 from other respiratory viral infections such as influenza or RSV.

Most patients (81%) have mild illlness. However, 14% may requires hospitalization and 5% ICU care.

Mortality

Depends on patient’s age and co-morbid conditions.

Patients’ age 60 years or higher are at increased risk of death compared to younger, healthier adults.

However, there are several reports that young, healthy adults can also develop severe illness, requiring ICU care and dying from COVID-19. This is uncommon but well described now.

Patients with underlying cardiovascular diseases, diabetes, chronic respiratory disease (COPD, asthma, etc), and malignancy are at increased risk of death.

Lab Diagnosis

General labs: Common laboratory findings include lymphopenia (63%), leukopenia (9– 25%), leukocytosis (24–30%), elevated liver enzymes (37%), elevated inflammatory markers (ESR and CRP), D- dimers, ferritin and sometimes IL-6. Procalcitonin tends to be normal.

Imaging: Chest X-ray is abnormal in only half of the patients. CT chest is more sensitive and typically shows bilateral, multifocal, ground-glass opacification. Areas of consolidation may also be observed.

None of these imaging findings are specific for COVID-19 and can be seen in other viral pneumonias.

Microbiologic diagnosis:

Whom to test? Apple and CDC, together with FEMA, have a new website and app with a COVID-19 screening tool that is really helpful to determine who should be tested.

Nasopharyngeal swab for SARS-CoV-2 PCR seems to be the most appropriate diagnostic test at this time. Also check for Influenza A & B and RSV (symptoms are non-specific).

Watch this video by NEJM to learn how to obtain nasopharyngeal swab.

Analytical sensitivity of a single NP swab PCR is approx. 70% (higher for BAL PCR ~ 95%). Therefore, a negative PCR test does NOT necessarily rule out infection if clinical suspicion is high. This may be the case during early phase of illness. Therefore, may consider repeating if clinical suspicion remains high.

Serology: A subject of intense interest. Not very helpful for the diagnosis of acute SARS-CoV-2 infection but will be helpful for public health purposes to accurately estimate prevalence of disease (plus herd immunity) and to calculate mortality rates, identify individuals who are immune to disease and therefore can return to work, and convalescent plasma therapy.

Almost all immunocompetent adults become seropositive by day 14. Based on preliminary data [personal communication], IgM has low sensitivty and is not reliable. IgG, however, seems to have analytical sensitivity and sepecificity >95%.

Combination of serology and PCR is also being evaluated. In one study, IgM ELISA detected more cases than PCR on day 5.5 of illness. The combination of IgM ELISA + PCR detected 98.6% of cases versus 51.9% with a single PCR. During the first 5.5 days, PCR had higher positivity rate than IgM; the reverse was true after day 5.5.

Does positive serology mean long-term protection to COVID-19? This is yet unknown. In patients with SARS, antibodies remained detectable for 5 to 6 years after illness. However, it’s unclear if these were in sufficient quantities to provide ongoing protection from infection. In general, most experts believe that immunity to COVID-19 will, at least, last for this season.

Batch all blood and imaging tests, if possible, to minimize expsoure to phlebotomists, transport, and radiology staff.

Management

Outpatient: Patients who are stable and breathing comfortably on room air, send them home. Advise them to self-isolate (stay in separate room, wear mask when around others, frequently wipe high-touch surfaces, don’t share household items with others), use Acetaminophen for fever and myalgia, and keep themselves hydrated. Give them a phone number to call if their condition deteriorates.

Inpatient: Patients with moderate to severe symptoms should be hospitalized for observation and treament.

Isolation: All patients with suspected or confirmed COVID-19 should be placed in Modified droplet PLUS Contact precautions which include gown, gloves, mask, and eye shield. Airborne precautions (that include use of N-95 masks or PAPR) or are recommended with aerosol generating procedures such as airway suctioning, intubation, sputum induction, endoscopy, etc.

Contact your institutional infection control department for further guidance as details may vary based on available resources.

Supportive care: Cornerstone of therapy at this time. This may include oxygen, mechanical ventilation, ECMO, electrolyte management, etc. Lots of helpful infomation at Internet Book of Critical Care.

Anti-viral medications:

For now, use of anti-viral medications may be reserved for patients requiring hospitalziation.

Chloroquine: Safe and cheap. Both chloroquine and hydroxychloroquine are effective in limiting the replication of SARS-CoV-2 in-vitro. Proposed mechanisms include alternation in the ACE-2 receptor configuration on cell surface (blocking viral entry in cells), interference with acidification in phagolysosome (blocking viral replication), and immunomodulation by interfering with Toll-like receptor (blocking cytokine storm).

Some early promising data showing that chloroquine use improves lung imaging, shortens time to viral clearance, and shortens disease course.

In another open-label study (n=36), use of hydroxychloroquine (200 mg t.i.d. x 10 days) was associated with a higher rate of undetectable SARS-CoV-2 RNA on nasopharyngeal specimens at day 6 compared with standard of care (70 versus 12.5 percent). It this study, it was combined with azithromycin to prevent/treat superimposed bacterial pneumonia.

See this systematic review for more information.

Based on in-vitro data and pharmacokinetics, a loading dose of 400 mg b.i.d. of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg b.i.d. x 5 days has been recommended (chloroquine phosphate dose is 500-mg b.i.d. x 10 days)

Check G6PD level before chloroquine use (not needed for hydroxychloroquine, even though package insert recommends it)

Can it be used as prophylaxis? See below in Prevention section.

Hydroxychloroquine PLUS azithromycin combination: An open-label non randomized clinical trial of 36 patients showed that hydroxychloroquine was associated with significantl viral load reduction/disappearance in COVID-19 patients and its effect was reinforced by azithromycin.

Remdesivir: A broad-spectrum antiviral drug. The MOA of remdesivir is not substantially different from other nucleoside analogues, which are structural mimics of natural nucleosides that can be triphosphorylated by cellular enzymes and incorporated into the viral RNA/DNA strands by the viral polymerases. Remdesivir was initially developed to treat Ebola but has activity against mutiple RNA viruses such as RSV and the coronaviruses (including MERS and SARS viruses). It was initially available for compassionate use but is now only available through clinical trials. Seems to be the most promising anti-viral therapy at present based on initial observations.

Tocilizumab: A humanized monoclonal antibody against the interleukin-6 receptor. Tocilizumab is currently used for various auto-immune diseases including RA and cytokine release syndrome, a side effect of CAR-T cell therapies. It is expected to reduce lung and vascular injury that is caused by cytokine storm (resulting in hypoxemia, septic shock, ARDS,and multi-organ failure) by blocking IL-6. Dose is 4 to 8 mg/kg (max 800-mg/dose), up to 2 doses given 12 hours apart.

Lopinavir–Ritonavir: In a randomized, controlled, open-label trial involving hospitalized adults with confirmed COVID-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care. (However, study drug was started late in severely ill patients when cytokine storm is probably the main driver of mortality. Perhaps early use could have improved the outcomes)

Favipiravir: Broad-spectrum anti-viral drug that woks by selective inhibition of viral RNA-dependent RNA polymerase. Approved in 2014 in Japan for stockpiling against influenza pandemics. An open-label control study in China comparing Favipiravir against lopinavir/ritonavir showed shorter viral clearance time and improvement in chest imaging compared to LPV/RTV. (Not available in US)

Sarilumab: A humanized monoclonal antibody against the interleukin-6 receptor. A randomized clinical trial is evaluating the efficacy and safety of Sarilumab in hospitalized patients With COVID-19.

Convalescent plasma: Patients who recover from COVID-19 have neutralizing antibodies against the virus. So, in theory, pooled IVIG from patients who recover from illness should help. It seems to work for SARS. So it might work for SARS-CoV-2 too.

On Friday, April 3, FDA announced the Expanded Access Program for Convalescent Plasma led by Mayo Clinic. This program will provide access to convalescent plasma for patients in acute care facilities infected with SARS-CoV-2 who have severe or life-threatening COVID-19; or who are at high risk of progression to severe or life-threatening disease.

Ivermectin: Anti-parasitic drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. A single treatment able to effect ∼5000-fold reduction in virus at 48h in cell culture. However, no clinical data yet.

Steroids: May prolong viral replication (observed in MERS-CoV). Therefore do NOT use steroids to treat COVID-19 related pneumonitis.

Other agents: A number of anti-retrovirals such as Ribaviran, and Nitazoxanide (1g po b.i.d. x 5days) are curently either being used or studied.

Nearly 70 drugs and experimental compounds may be effective in treating the coronavirus. So stay tuned for a lot of in-vitro and human studies in coming months.

When to use which anti-viral drug?

From the list of easily available anti-virals, I would consdier Chloroquine or Hydroxychloroquine as first-line, followed by Protease inhibitors PLUS Ribaviran combination (2nd line), followed by Nitazoxanide (3rd line).

Remdesivir is probably the most promising anti-viral agent for COVID-19. If you can get it (via clinical trials or otherwise), you should use it. Tocilizumab use should be limited to severe cases with elevated IL-6 levels.

Prevention

Mitigation strategies such as social distancing, isolation of known cases at home or in healthcare setting, and other measures to stop the spread the infection can slow the epidemic, termed as “Flattening the curve”, easing the burden on healthcare system and giving more time for preparation.

Read the original CDC paper here.

I have outlined preventive measures for general public in this blog post including social distancing, frequent hand washing (with soap and water), covering cough and sneezes, and staying home when sick.

For healthcare workers, follow your institutional and CDC guidelines. Some additional ideas are:

~ Creating a command center to coordinate all COVID-19 planning and communications. If possible, designate a geographic area in the hospital that is well equipped to handle COVID-19 patients. Restrict visitors.

~ Update the FIT testing for all hospital staff taking care of COVID-19 patients. Limit number of healthcare providers who see a COVID-19 patient. Utilize available telemedicine tools to reduce exposure while delivering affective care.

Chloroquine or hydroxychloroquine for COVID-19 prophylaxis

This is a subject of pure speculation at this time. However, since a lot of people are asking about it or considering it, here are some preliminary thoughts:

Could it work? Possibly. See mechanism of action described above in Anti-viral medications section.

Who should be taking it? No one on their own. Physicians may consider it for their heavily immunocompromised patients such as lung transplant recipients, BMT, etc. who are either exposed to a COVID-19 patient or at significant risk of exposure.

Should healthcare workers taking care of COVID-19 patients use it? No data to guide. Your hospital should make a policy about it. I personally think it might be worth considering in healthcare providers taking care of confirmed COIVD-19 cases.

Dose and duration is unknown but two ongoing clinical trials, one for primary prophylaxis and other for secondary (post-exposure) prophylaxis in healthcare setting are investigating it. See trial design for dosing and schedule.

Outside the clinical trials, once weekly dosing may be appropriate. (e.g. Chloroquine 500 mg once weekly) as the drug has very long half-life (over 3 weeks) — personal opinion.

Should general public take it for prevention? No.

Universal masking

Considering that 30 to 50% of the patients are asymptomatic (no fever or respiratory symptoms) and that the sensitivity of a single NP swab PCR is approx. 70% even for symptomatic patients, universal masking for HCW seems necessary. (Note: cloth masks are NOT sufficient for HCWs)

(Michael Klompas,writing for NEJM: Universal masking alone is not a panacea. A mask will not protect providers caring for a patient with active Covid-19 if it’s not accompanied by meticulous hand hygiene, eye protection, gloves, and a gown. A mask alone will not prevent health care workers with early Covid-19 from contaminating their hands and spreading the virus to patients and colleagues. Focusing on universal masking alone may, paradoxically, lead to more transmission of Covid-19 if it diverts attention from implementing more fundamental infection-control measures)

Related Notes

Pregnancy and COVID-19: Little is known. But there are 2 published papers that included a total of 18 pregnant women with suspected or confirmed COVID-19 pneumonia, there was no lab or clinical evidence of transmission to the neonate. However, a new report published in JAMA on March 26 described one possible case of vertical transission of 2019-nCoV.

COVID-19 and ACE inhibitors: SARS-CoV-2 bind to their target cells through ACE-2, which is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels. The expression of ACE-2 is substantially increased in patients with diabetes and hypertension, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs). This has led to hypothesis that treatment with ACE-2-stimulating drugs increases the risk of developing severe and fatal COVID-19. However, it remains a theoretical construct at this time. Current recommendation is to continue ACE inhibitors if a patient is already on them but not start in new patients.

Counterpoint: Some investigatiors have hypothesized that ACE2 may potentially be beneficial rather than harmful during lung injury and suggest that RAAS-inhibitor withdrawal may be harmful in some high-risk patients with known or suspected Covid-19.

COVID-19 and Ibuprofen: ACE-2 expression can also be increased by ibuprofen. Consequently, the increased expression of ACE-2 may facilitate infection with COVID-19. Data is conflicting. For now, consider using Acetaminophen (Tylenol, Panadol) instead of ibuprofen.

COVID-19 is an emerging, rapidly evolving situation. Follow links below for most up to date information.

For the latest research, visit NIH and NEJM sites.

~ For general public, see Mayo Clinic and my blog post for FAQ and the podcast below.

And finally my favorite Coronavirus video:

Disclaimer: Views expressed here are my own and do NOT represent official guidelines from Mayo Clinic.

~ Rizwan Sohail
Dr. Sohail is a Professor of Medicine at Mayo Clinic. You can follow him on Twitter.