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Coronavirus March 30 Update

Commentary
3/30/2020 Matthew E Levison, MD, Adjunct Professor of Medicine, Drexel University College of Medicine

 COVID-19 Resources Home Page

Updated case counts can be found at several online sites:

Worldometer

World Health Organization

Johns Hopkins Coronavirus Resource Center

Cruise ships (Moriarty LF, Plucinski MM, Marston BJ, et al. Public health responses to COVID-19 outbreaks on cruise ships -- Worldwide, February-March 2020. MMWR Morb Mortal Wkly Rep. ePub: 23 Mar 2020. doi: http://dx.doi.org/10.15585/mmwr.mm6912e3):

Cruise ships are often settings for outbreaks of infectious diseases because of their closed environment, frequent contact between travelers from many countries and crew who transfer between ships, and high-risk populations (those 65 years of age or older and those with co-morbidities). More than 800 cases of COVID-19 cases occurred during outbreaks on cruise ship voyages, with secondary community-acquired cases linked to returned cruise passengers. Transmission occurred across multiple voyages of several ships.

- On the Diamond Princess, 17.9% of infected individuals had asymptomatic infection, which could partially explain the high attack rate among cruise ship passengers and crew.

- Viral RNA was found up to 17 days after cabins were vacated but before disinfection after disembarkation, on a variety of surfaces in cabins of both symptomatic and asymptomatic infected passengers, although it is unclear whether the RNA came from live or dead virus; if live, the viral particles are theoretically able to be transmitted. Studies on transmissibility of the virus identified on a variety of surfaces are needed to identify them as possible sources of transmission.                                                             

- On the Grand Princess, crew members, who transferred between ships, were likely infected on one ship and then transmitted SARS-CoV-2 to passengers and crew on another ship.

- CDC recommended all cruise travel be deferred worldwide and cruise lines announced a voluntary temporary suspension of operations during the COVID-19 pandemic.

Drugs:

There are no US FDA-approved drugs, antibodies, or vaccines specifically for the treatment of patients with COVID-19. Management of cases is supportive, including supplementary oxygen and mechanical ventilatory support when indicated. Several drugs approved for other indications, as well as several investigational drugs, are being studied in many clinical trials that are underway worldwide (https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html).

            - Remdesivir (RDV) is an investigational broad-spectrum IV antiviral drug. RDV is a nucleoside analog that inhibits inhibits RNA polymerase and viral replication. It has in-vitro activity against SARS-CoV-2 and in-vitro and in-vivo activity against related coronaviruses. RDV has been used compassionately (https://www.nejm.org/doi/full/10.1056/NEJMoa2001191) based on the case patient’s worsening clinical status. RDV is reportedly undergoing randomized controlled trials worldwide to determine the safety and efficacy and also is being used on an uncontrolled, compassionate use basis in some patients (https://rdvcu.gilead.com/).

            - Favipiravir, another broad-spectrum RNA polymerase inhibitor approved for use in Japan for the treatment of influenza, is currently undergoing clinical studies to test efficacy and safety in the treatment of COVID-19 in China (https://www.jstage.jst.go.jp/article/ddt/14/1/14_2020.01012/_pdf/-char/en).

            - Chloroquine is an oral drug used for malaria treatment and chemoprophylaxis, and hydroxychloroquine is used for treatment of rheumatoid arthritis, systemic lupus erythematosus, and porphyria cutanea tarda. Because these drugs increase the pH of the intracellular phagolysome and allow doxycycline to have bactericidal activity against Coxiella burnetii, the cause of Q fever, hydroxychloroquine is used in combination with doxycycline in the treatment of Q fever endocarditis. Both chloroquine and hydroxychloroquine have in-vitro activity against SARS-CoV, SARS-CoV-2, and other coronaviruses, with hydroxychloroquine having relatively higher potency against SARS-CoV-2 (https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html). A study in China reported that chloroquine treatment of COVID-19 patients was clinically and virologically efficacious versus a comparison group, and chloroquine was added as a recommended antiviral for treatment of COVID-19 in China (https://www.unboundmedicine.com/medline/citation/32074550/full_citation). One small study in France reported that hydroxychloroquine alone or in combination with azithromycin reduced detection of SARS-CoV-2 RNA in upper respiratory tract specimens compared with a non-randomized control group but did not assess clinical benefit (https://www.sciencedirect.com/science/article/pii/S0924857920300996?via%3Dihub). Both chloroquine and hydroxychloroquine have been reportedly well-tolerated in COVID-19 patients, although both can prolong the QT interval. Based upon limited in-vitro and anecdotal clinical data, chloroquine or hydroxychloroquine are currently recommended for treatment of hospitalized COVID-19 patients in several countries. In the United States, several clinical trials of hydroxychloroquine for prophylaxis or treatment of SARS-CoV-2 infection are planned.  More information on trials can be found at https://clinicaltrials.gov. In the meantime, several US states have issued restrictions on prescribing these drugs because physicians are said to be prescribing these drugs for themselves or family members.

            - In a clinical trial in China, the HIV drug lopinavir-ritonavir (Kaletra) did not show promise for treatment of hospitalized COVID-19 patients with pneumonia (https://www.nejm.org/doi/full/10.1056/NEJMoa2001282). This trial was underpowered, and lopinavir-ritonavir is reportedly under investigation in a World Health Organization study.

Immunotherapy: Passive immunotherapy with sera from convalescent patients have been used in epidemic SARS, MERS, and COVID-19, and anecdotal reports suggest convalescent sera may confer protection and reduced viral load (https://www.jci.org/articles/view/138003). According to the governor, New York State will begin treating infected individuals with plasma from recovered patients ( https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-emergency-inds). However, the efficacy of convalescent plasma studied in prior outbreaks of viral respiratory infections is unclear, as adequate control groups were lacking and other factors may have played a role, such a severity of disease and presence of co-morbidities, when convalescent plasma was administered during the course of the disease, titer of neutralizing antibody administered, and effect of other concomitant treatments.

Interleukin-6 may play a role in driving an overactive inflammatory response (“cytokine storm”) in the lungs of patients with COVID-19 who develop acute respiratory distress syndrome. Sarilumab, a fully human monoclonal antibody that inhibits the IL-6 pathway by binding and blocking the IL-6 receptor, will undergo a clinical trial for patients hospitalized with severe COVID-19 infection. Tocilizumab, another IL-6 inhibitor, which has been used in China to treat 21 patients with severe COVID-19 infection with improvement in oxygenation and other clinical outcomes, will also undergo a double-blind, randomized clinical trial in patients with severe COVID-19 pneumonia (https://www.onclive.com/web-exclusives/fda-oks-launch-of-phase-iii--tocilizumab-trial-for-covid19-pneumonia).

Angiotensin converting enzyme (ACE) inhibitors and receptor blocking drugs: The human pathogenic coronaviruses SARS-CoV and SARS-CoV-2 both bind to a receptor, angiotensin-converting enzyme 2 (ACE2), which is expressed by epithelial cells in the lungs and intestine and vascular endothelial cells (https://onlinelibrary.wiley.com/doi/full/10.1002/path.1570). The expression of ACE2 is increased in patients with type 1 or type 2 diabetes or hypertension who are treated with ACE inhibitors (eg, ramipril, captopril, enalapril, lisinopril) or angiotensin II type-I receptor blockers (ARBs—eg, candesartan, valsartan, losartan; https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)11306-8/fulltext). ACE2 is also reportedly increased by thiazolidinediones and ibuprofen. These data suggest that treatment with ACE inhibitors or ARBs, and even ibuprofen, which increase ACE2 expression, could facilitate infection with COVID-19 and increase the risk of developing severe COVID-19. Because of the frequency that these drugs are used in the management of diabetes and hypertensive, confirmation of these observations is critical. 

Three American professional cardiology societies (American Heart Association (AHA), American College of Cardiology (ACC), and Heart Failure Society of America (HFSA) as well as the European Society of Cardiology (ESC), the European Society of Hypertension, Canadian Cardiovascular Society, and the International Society of Hypertension, have issued statements urging continuation of renin–angiotensin–aldosterone system (RAAS) antagonists in patients, despite theoretical concerns that their use might worsen outcomes in the event of COVID-19 infection.

SARS-CoV-2 can bind to ACE2 receptors on endothelial cells and may cause damage to the blood vessel in the microcirculation, which leads to disseminated intravascular coagulopathy (DIC) and high D-dimer levels (https://www.practiceupdate.com/content/abnormal-coagulation-parameters-and-poor-prognosis-in-patients-with-covid-19/97218).

Diagnostic testing:

Diagnostic testing for the presence of viral RNA is critical for tracking COVID-19’s spread, informing case management, and controlling transmission. Although the extent that asymptomatic infection contributes to transmission is unclear, the Chinese were said to release data that document as high as one-third of those who tested positive for the virus showed no or delayed symptoms (https://www.dw.com/en/up-to-30-of-coronavirus-cases-asymptomatic/a-52900988). Similarly, among the Japanese patients evacuated from Wuhan, 30.8% were asymptomatic (https://www.ijidonline.com/article/S1201-9712(20)30139-9/pdf). China does not count asymptomatic carriers as confirmed cases, but they nevertheless place them in isolation. South Korea, instead of a nationwide lockdown, extensively tests for the presence of the SARS-CoV-2, classifies those who test positive as confirmed cases regardless of whether they experience any symptoms, and isolates all people who test positive. In the USA, only people with symptoms are tested. In the absence of extensive testing in the US, anyone in communities where there is extensive person-to-person spread is presumed to be contagious, whether symptomatic or not, and encouraged to shelter-in-place at home, except for those engaged in essential services, and when outdoors to maintain safe distances (6 feet) from one another.

US regulators in recent weeks have approved PCR (polymerase chain reaction) tests developed by hospitals and commercial laboratories. Patient samples must then sent to an often geographically distant testing facility where these tests are run in batches over a period of hours with test results available several days later. A point-of-service test has been approved that can run several patient samples at a time on devices already in use at many healthcare settings and return results in just 45 minutes (https://www.statnews.com/2020/03/21/coronavirus-test-returns-results-in-45-minutes/). Drive-thru testing sites, as in South Korea, have been increasingly set up over the US. An appointment with a physician’s orders for testing, photo ID, and insurance card are required, and test results are available in about a week.

A finger-prick test that detects the presence of antibodies in human blood within 10 to 15 minutes is being evaluated in the UK; it can detect infection at some time in the past, but it does not tell whether SARS-CoV-2 is currently present (https://www.theguardian.com/world/2020/mar/25/uk-coronavirus-mass-home-testing-to-be-made-available-within-days). Large-scale seroprevalence studies done in a systematic way are required to understand the extent of asymptomatic infection in the population.

Shortage of hospital beds and equipment:

An estimated 15% of COVID-19 infected patients will require hospitalization, and another 5% will have critical illness that requires admission to an ICU and likely require mechanical ventilation. Unless the epidemic curve of infected individuals is flattened over a very extended period of time, there will likely be shortages of hospital beds, ICU beds, ventilators, and other supplies, as well as shortages in the medical workforce, including respiratory therapists and critical care nurses, who will become ill or quarantined. Rural and smaller hospitals that have much less space, supplies, and staff will be disproportionally affected. Diagnostic, therapeutic, and preventive interventions will also be scarce. Public health measures known to reduce viral transmission, such as sheltering-in-place, social distancing, cough etiquette, and hand hygiene, may make resource shortages less severe by narrowing the gap between medical need and the available supply. 

 COVID-19 Resources Home Page
Matthew Levison, MD

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