This page discusses the Coronavirus pandemic that has been spreading rapidly around the world. In the short time that it has existed, we have learned a great deal about it, but our knowledge is still evolving. Vaccinations, more efficient testing and therapy are under investigation. We have learned that public health measures such as wearing a mask in public, social distancing and sanitizing our hands will help enormously to keep us safe. Kidney disease, especially when accompanied by diabetes or heart disease, puts people at higher risk for hospitalization. Also, acute kidney injury is a common problem in ill COVID-19 patients. Kidney Associates is very interested in this disease and in trying to mitigate its course.
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In mid-November, 2017 a visitor to the Huanan Seafood Market in Wuhan City in the Hubei province in China became ill and transmitted an unusual type of pneumonia to others. The outbreak grew slowly, and by December 15 there were 27 cases. By the end of December, the World Health Organization (WHO) was notified of 44 cases. China isolated the new virus, a coronavirus similar to the SARS virus of 2003, by January 7 and within the week the genetic code was shared internationally. Named SARS-CoV-2, the virus caused a new and all too often lethal disease, COVID-19. It was felt to have originated in bats, and although the route of transmission was uncertain, began to spread rapidly around the world. There is yet no definitive cure or vaccine for COVID-19, and in most cases, symptoms such as fever and cough are mild. It was shown to spread while completely asymptomatic and to be highly contagious, spreading through air droplets from one’s breath.
WHAT IS A VIRUS?
We are made up of trillions of cells. Bacteria are made up of one cell. Viruses aren’t even cells; they are smaller than bacteria and are parasites on other cells. They are made up of genetic material that is surrounded by an outer protein coat. They hijack our cells and reassemble replicating their RNA or DNA and repackaging it to make baby viruses that can spread. Viral infections are not new and have been the source of plagues and pandemics all throughout recorded history. The word “corona” comes from the Latin for garland or crown. Coronaviruses are a large family of viruses – with spikes like a crown.
SARS-CoV-2 is a newly discovered coronavirus that spreads through droplets and contact. It came from bats and is thought to have originated from a market in Wuhan City in the Hubei province in China. By the end of December 2019, there were 44 cases in China, 11 of whom were severely ill. By January 3 there were 41 confirmed COVID-19 cases admitted to Wuhan hospitals. 32% had diabetes, hypertension, or cardiovascular disease. The median age was 49, and 27 had been exposed in the Huanan Seafood Market. Fever was present in 98% of cases and cough 76%. 55% developed shortness of breath within 8 days and 63% had lymphopenia. All had abnormal chest CT findings. Complications included acute respiratory distress syndrome (29%), and acute cardiac injury (12%). 6 (15%) of the patients died.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.
Within a few days, there had been 4,593 cases in several countries including Australia, North America, and Europe. On January 9 the mysterious disease was announced by WHO. By January 20 there were 6 deaths (see above) and the next day WHO acknowledged that the disease spread person to person. As the disease was spreading throughout China the Centers for Disease Control and Prevention (CDC) announced that US airports would screen for the disease. The first case appeared in the United States on January 21 in Washington state, a recent traveler from Wuhan City. Contact tracing was then deployed in Washington state. Wuhan went into quarantine – the city and region strictly locked down 18 million people.
A global health emergency was declared by WHO on January 31, 2020, as the disease was spreading in the United States, Germany, and Asia. In 2019 14,000 persons traveled to the United States from China each day, but with 10,000 confirmed cases in China global air travel to the United States from China had to be suspended. On January 31, the United States declared the disease a national public health emergency. In another week deaths from the disease, now officially named COVID-19 would surpass those of SARs from 2003. COVID-19 was declared a pandemic on March 11 and a national emergency on March 13. Between March 13 and March 20, a survey of attitudes and awareness was conducted in Chicago hospitals. The survey showed that 24.6% of patients were worried about getting the coronavirus. 65.9% thought they would possibly get sick but 24.6% felt it was not at all likely. 71.1% correctly identified three symptoms and 58/6% significantly changed their lifestyles. The mean age of the group was 62.1 years of age. 23.4% had heart disease and 24.6% diabetes. 54.4% were diabetic, 75.2% hypertension, and 20% were organ transplant recipients.
Wolf, Michael S, Serper Marina, Opsasnick, Lauren et al. Awareness, Attitudes and Actions Related to COVID-19 Among Adults with Chronic Conditions at the Onset of the US Outbreak. Ann Intern Med 2020;173:100-109.
On March 13 a travel ban from Europe went into effect. Between March 19 and April 3 states went into lockdown, as each created stay at home rules curtailing nonessential activities. We saw travel between nations and even between cities and states come to a halt and an entire nation sheltered in place, avoiding social gatherings and working from home. Restaurants, schools, and shops closed. Elective surgery halted.
Telemedicine was used by physicians to care for patients unable to come to the clinic and was approved by the Center for Medicare and Medicaid Services (CMS). Kidney Associates was an early adapter of telemedicine, and patients can see us from home to avoid possible exposure. As patients now can see their doctors through telemedicine portals, Zoom, Facetime and WebEx have become standard methods of communication. Binging television series became a national pastime. Major meetings, travel plans, and even the Tokyo summer Olympics were canceled or postponed. The White House developed social distancing guidelines through April 30. Sheltering in place worked. The National Bureau of Economic Statistics determined that as a result of the executive order in California to avoid nonessential activities, the case rate dropped by 125.5 cases/100,000 between March 19 and April 20. The economic study also estimated that 400 jobs were lost for each life saved.
Friedson AI, McNichols D, Sabia JJ, Dave D. Did California’s Shelter in Place Order Work? 2020. Available from: NBER
On March 27 the CARES Act was signed into law to help offset the impact isolation would have on the economy. The disease continued to escalate and surpassed one million by April 4. By April 11 the death rates in the United States exceeded those of all other nations. Mathematical models were showing that a shutdown would delay disease spread, and proved right. As states reopened and gatherings took place, the disease surged. The shutdown that lasted approximately two months saw states starting to lift restrictions by May 20.
Sheltering in place became lax as the nation fatigued of it. National protests of COVID-19 restrictions put pressure on public officials to relax controls over working conditions. Demonstrations to fight police injustice against African Americans were sparked by the May 25, 2020, choking death of George Floyd during an arrest in Minneapolis. As a video taken by a bystander emerged, protests erupted in Minneapolis and other large cities starting that Tuesday and grew in intensity. During this period social distancing was all but forgotten. The large protests did not create a population spike in COVID-19 cases and deaths because during the periods of unrest, mainly because of nonparticipant behavior. But, as people celebrated holidays and gatherings, the disease surged. Meanwhile, grave economic impact forced political divisions in the United States as heated discussions and controversies grew around wearking a mask v personal freedom, opening restaurants, bars, and places of congregation to avoid financial ruin for many proprietors, and when to reopen schools. By June 30, the NIAID chief, Anthony Fauci, predicted that COVID-19 cases could escalate from 40,000 cases to 100,000 new cases per day.
Cases resurged since late June. During July serious debate took place between medical experts and sports associations, local and national leadership. The conflict was the same – how to balance safety with a halt in our lifestyles and economy. In the South records for the number of cases and the number of deaths was shattered. In mid-July, the disease claimed over 140,000 lives with Florida announcing 10,000 new cases per day. As a flood of misinformation hit social media, doubt and fear were coupled with economic devastation and sickness. On July 19 Miami Beach, Florida imposed a curfew.
In the middle of July Arizona surged to the extent that the city of Tuscon was down to 17 free ICU beds. When the state escaped a large outbreak in April and May, bars and restaurants reopened, testing efforts grew lax and the state leaders and citizens assumed the danger had passed. But by the middle of July, nearly 27% of the tests taken over the past week returned positive. The surge was coupled with anger and blame, and a flow of mixed messages. As the surge worsened the state shut down public gathering places like restaurants, bars, and gyms.
Most restaurants and other gathering places have not fully reopened. Zoom conferencing and working from home are commonplace. World and local travel have significantly decreased with many summer vacations cancelled. Political events such as the Democratic and Republican National Conventions took different approaches to gathering and social distancing. The RNC was lax with less masking and distancing. The DNC was for the most part virtual. By the end of the summer the number of cases in five counties was over 100,000 each. These included Harris County (107,490 cases; CFR 2208 deaths; CFR 0.02) Cook County (126,992 cases; 5065 deaths; CFR 0.03988), Maricopa County (134,004 cases; 2,976 deaths; CFR 0.022), Miami-Dade (159,059 cases; 2,537 deaths; CFR 0.0159) and Los Angeles County (242,521 cases; 5,829 deaths; 0.024). The highest number of deaths in the nation was in Queens, 5,992 deaths. The USA leads the world in deaths, 185,744 but has had 6,114,406 cases, and has a CFR of 0.0326 which is 9th worldwide. The USA has 56.4 deaths per 100,000.
The CDC predicted up to 211,000 deaths by September 26, 2020. In the USA vaccines produced by Astra Zeneca, Moderna and Pfizer were in phase 3 testing, but on September 8, Astra Zeneca halted the clinical trial on one of them because of a serious adverse event (SAE) that needed to be resolved. Rapid testing kits for both antigen and antibody were being deployed. Remdesivir, dexamethasone and convalescent serum all showed promise. School openings across the globe experienced the most feared problem – that the disease would spread on campus as many students partied and ignored health warnings. Debate ensued whether to send infected students back to their homes or contain them in quarantine on campus.
References frequently reviewed:
New York Times
New York Post
nbcmiami.com July 20,2020
Clickorlando.com July 31,2020
Wall Street Journal, July 15,2020
New York City was hit particularly hard and deserves special mention because of how people must move about – elevators and subways. It is no wonder that 5,700 persons were hospitalized there from March 1 through April 4, 2020. The mean age was 63 and many had hypertension, obesity, and diabetes. 14.2% were in the ICU and 12.2% were on assisted ventilation. 3.2% required dialysis. In the end, 2,634 people or 21% of the hospitalized died.
Between March 1 and May 16, 2020, there were 191,392 confirmed COVID-19 cases and 20,141 deaths. While the overall infection fatality risk was 1.45% (CI 1.09-1.87). But, when age was taken into consideration, the infection fatality rate was 17% for those over 75 years old, and the risk was 6.1% for those 65-75 years of age.
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area [published online ahead of print, 2020 Apr 22] [published correction appears in doi: 10.1001/jama.2020.7681]. JAMA. 2020;323(20):2052-2059. doi:10.1001/jama.2020.6775
The first case of COVID-19 in Houston was March 4, 2020, identified as a Fort Bend County man in his 70s who had traveled to Egypt. By March 11 the Houston Livestock Show and Rodeo was cancelled as a result of a 40 year old Montgomery County man developing it from person to person spread, and not through travel abroad. The NRG Park was shut down and the county declared a public health emergency. This case was traced to the February 28 Bar-B-Que cookoff at the Houston Livestock and Rodeo. The contest that day was potentially attended by 73,433 persons. The Rodeo is a major Houston event and was scheduled to run until March 22. Houston had 14 cases on March 11. Two days later the President issued a federal emergency declaration to free up public funds and enable the Federal Emergency Management Association to coordinate the pandemic.
By March 16, County Judge Lina Hidalgo ordered schools closed, restaurants closed for dining, bars closed. Takeout from restaurants was permitted. On March 19 the Texas Governor, Greg Abbott ordered limiting social gatherings to 10 people or less. Schools, bars, and gyms remained closed and restaurants limited to takeout. He also banned visitation at nursing homes. Texas was declared a public health disaster. Hospitals stopped elective surgery. A stay at home order was put into place for Harris County and Houston on March 24. On March 31, churches in Texas were permitted to stay open per Governor Greg Abbott. On April 17 the ban on elective surgery was lifted and state parks were allowed to open. Around that period there were 252 new cases per day in Harris County. 96 people in Houston had died from COVID-19.
On April 27 masks were required in all public places in Harris Country. The stay-at-home order was lifted on May 1 as the state testing was only 14,000 per day. This was felt inadequate by health authorities. The state was now reporting 50 COVID-19 deaths per day. The Harris Country Stay at home order was extended through May 20. Violation in public health orders would not be punished by jail time. The state governor and Harris County/Houston officials clashed on coronavirus restrictions, with Governor Abbott feeling they were too restrictive. By May 18 all stay-at-home orders were lifted by the state, allowing businesses to reopen gradually. The death toll for the state was 58 cases per day. At the of May the percent new cases in Houston were 5.4. There had been 299 deaths thus far.
The May 25 Memorial Day was celebrated with partying, especially with social gatherings at beaches and ignoring the rules of wearing masks. In Minneapolis, however, the brutal murder of Houstonian, George Floyd by a police officer sparked protests around the country. On June 3, 60,000 protested in Houston, but many ignored social distancing and the wearing of masks. Restaurants increased capacity from 25 to 50% capacity by June 3 and Houston traffic increased. Despite rules regarding social distancing and the wearing of masks, many either wore their masks improperly or not at all. With an incubation period of 3-7 days, it was no wonder that over the next week the number of cases in Houston started rising. Despite over 2000 hospitalizations per day throughout the state, by June 12 businesses were operating at 75% capacity. Many stores in Houston required their customers to wear masks.
On June 19 many amusement parks opened at 50% capacity as the state testing rate approached 10%. By June 24 the rate approached 12% as hospitals felt they were reaching crisis levels of admissions. On June 15 there were 3,820 patients in Houston area hospitals were on June 1 there were only 519. The county averages 338 cases per day and Houston sustained 422 deaths. The surge in hospitalizations threatened that Houston would have to close back down. The following day elective surgeries in local hospitals were ordered postponed. Despite the surge in hospitalizations, the Lieutenant Governor stated that the increased number of cases was because of increased testing. Restaurant capacity was again rolled back, but many at home, ordering take out and grocery deliveries. The percent new cases rose from 6.71 on June 15 to 16.89% on July 15. As most people celebrated the Fourth of July in front of the television, Governor Abbott ordered masks to be worn in public throughout the state. On Independence Day, 7,890 persons in the state were in hospital beds with COVID-19, the number of admissions doubling from the week before. Over the month of July, the number of hospitalizations in Harris Country rose. It reached 2,672 on July 15, but by Aug 6 was at 1,559. The number of new cases in Harris county continues to rise, 1685 on August 6. School openings were delayed and many Houston Independent Schools are offering home learning. Houston’s deaths were up to 1866.
Although the Rt for Houston had been less than 1 for several days, by the end of August it was once again greater than 1. By September 2 the number of patients hospitalized in Houston hospitals 717, with 348 patients in Intensive Care. The hospitalization rate for Texas Medical Center was also increased – 114/day. The week prior it was 96/day, but the previous month it was 165 hospitalizations per day. By September 2, there 2,954 deaths in Houston. On September 2, there were 1001 new cases in Harris Country.
UNDERSTANDING THE SCIENCE
Viral infections are not new and have been the source of plagues and pandemics through all of recorded history. A virus is a life form that includes DNA or RNA, molecular chains that can cause amino acids sequencing and manufacture proteins. They can also replicate. A virus is protected by an envelope of proteins and sugars that will allow it to migrate through the environment. The characteristics of the virus determine how it attacks human cells. Since they multiply in great numbers the frequency of mutations may be very high.
We are all too familiar with viruses – smallpox, influenza, measles, polio, rhinovirus, adenovirus, and even other coronaviruses. The coronavirus known as SARS-CoV-2 is unique for it has protein spikes on its envelope. The tip of the spike, known as the receptor binding domain (RBD) has mutated so that it attacks a specific receptor on the cell. This is known as the ACE2 receptor, and is found in many organs, particularly lungs, kidneys, heart, pancreas and blood vessels. When the virus attacks, the body responds through an innate immunity system, recruiting a type of lymphocyte known as a T helper cell to the vicinity. The helper cell then recruits a number of other cells types through the release of cytokines – hormones on a cellular level. The reaction to these hormones plays a key role in what happens next. It is ideal for helpers recruit killer cells that destroy the virus, and regulatory cells that modulate the response so that normal body cells are not injured. Cells that will make antibodies are also recruited, as these antibodies will be necessary to neutralize the virus in there is recurrent exposure. In the elderly and in patients with diabetes, CKD, heart or lung disease, as well as those with any type of immune compromise, the immune system may not react to a virus properly. Either the virus multiplies unchecked or the cytokines are overly destructive, or the body cannot make antibodies that will protect the person another attack. For these reasons people who are vulnerable have a greater odd of becoming critically ill or being overcome by the infection.
AAKP Renalife – Fadem 2020
FROM BATS TO MAN
THE ACE2 BINDING REGION The SARS-CoV-2 virus specifically binds a receptor known as the ACE2 binding region. In the bat, the ACE2 binding region is SCH014 and differs from the human ACE2 binding region. This was demonstrated by combining human ACE2 binding molecules with the retrovirus, HIV, along with cell lines from the Horseshoe bat and civets. An insert region between aa310 and aa518 allowed non-ACE2 binding to human ACE2 receptors showing there is compatibility (1).
Six receptor-binding-domain amino acids are critical for binding to ACE2 receptors. Although the coordinates in the earlier SARS-CoV virus correspond to SARS-CoV-2, five differ. These coordinates still have a high affinity for binding, but it is possible that natural selection to a ideal binding ligand happened in humans. The genetic data demonstrate that SARS-Cov-2 does not come from a previously used virus and developed in the human.
SARS-CoV-2 is optimized for binding to the human ACE2 receptor, and the S protein has an activation protease enzyme called furin at cleavage sites on the S12/S2 boundary that leads to activation. This protease furin determines infectivity. Furin is not species specific.(2)
That SARS-CoV could be infective was predicted in 2015. An infective virus was created in the laboratory and demonstrated that viral particles could mutate in alveoli. This research was performed by a collaboration of leading investigators from around the world led by the University of North Carolina. (1. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. 2. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. 3. National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas, USA. 4. Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China. 5. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. 6. Cystic Fibrosis Center, Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. 7. Institute for Research in Biomedicine, Bellinzona Institute of Microbiology, Zurich, Switzerland. 8. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. 9. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. Correspondence should be addressed to R.S.B. (firstname.lastname@example.org) or V.D.M. (email@example.com).) (3)
The observation that the virus can mutate in the lung suggests that the bat virus first infected man and underwent a series of mutations while replicating in the lungs of man. This led to the perfect spike domain region to attack the ACE2 receptor.
1. Ren W, Qu X, Li W, Han Z, Yu M, Zhou P, et al. Difference in receptor usage between severe acute respiratory syndrome (SARS) coronavirus and SARS-like coronavirus of bat origin. J Virol. 2008;82(4):1899-907.
3. Menachery VD, Yount BL, Jr., Debbink K, Agnihothram S, Gralinski LE, Plante JA, et al. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nature medicine. 2015;21(12):1508-13.
Remdesivir – Remdesivir inhibits how the viral particle RNA replicates. 10-day courses were tried in compassionate use. Although the mortality in this critically ill group was 18% there was a 68% improvement in oxygenation and a 57% rate of improvement in the patients who were on mechanical ventilators (1).
Further studies have been completed. A meta-analysis of randomized controlled trials with remdesivir does show benefit over placebo (OR=0.61 95% CI 0.45-0.82; P=0.001) https://www.medrxiv.org/content/10.1101/2020.08.21.20179200v2 (2).
The Solidarity Trial is a huge international 405 hospital and 30 country open-label randomized trial of remdesivir, hydroxychloroquine*, lopinavir*, interferon plus lopinavir, interferon only, and no study drug. The mortality of ventilated patients was 39% and Kaplan-Meier (KM) 28-day mortality was 12%. The RR of Remdesivir was (0.95 CI .81-1.11 p=50) and none of the drugs had any benefit with regard to hospital stay or initiation of ventilation. (*dropped) https://www.medrxiv.org/content/10.1101/2020.10.15.20209817v1 (3).
The New Engl J Med study https://www.nejm.org/doi/full/10.1056/NEJMoa2007764 was a double-blind randomized trial – 541 randomized to remdesivir and 521 randomized to placebo. 903 of the patients had severe disease but the benefit was greater when the drug was given earlier. There were 60 trial sites. Recovery time was shortened by 5 days. KM was 6.7% for remdesivir v 11.9% for placebo. Since the NEJM study, had blinded controls and was placebo-based it should be weighted higher than the Solidarity Trial (4).
1. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. The New England journal of medicine. 2020.
2. Sarfraz A, Sarfraz Z, Sanchez-Gonzalez M, Michel J, Michel G, Frontela O, et al. Randomized Controlled Trials of Remdesivir in Hospitalized COVID-19 Patients: A Systematic Review and Meta-Analysis. medRxiv. 2020:2020.08.21.20179200.
3. Pan H, Peto R, Abdool Karim Q, Alejandria M, Henao Restrepo AM, Hernandez Garcia C, et al. Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results. medRxiv. 2020:2020.10.15.20209817.
4. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the Treatment of Covid-19 — Final Report. New England Journal of Medicine. 2020.
Convalescent serum – The plasma of patients who recovered from COVID-19 will contain antibodies that can neutralize the virus in other patients. While this does not stimulate the patient to develop their own antibodies, it is useful for the treatment of critically ill patients. In a recent study, it reversed the respiratory distress, and in 3 out of 5 patients studied allowed the patients to be successfully discharged from the hospital. The remaining 2 patients were upgraded to stable condition and improving at the time the paper was published.(1)
1. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. Jama. 2020;323(16):1582-9.
Dexamethasone A large United Kingdom Study published in the New England Journal of Medicine a randomized controlled trial of 2,104 hospitalized patients assigned to receive dexamethasone (DXM) and 4,321 patients assigned to receive usual care – the usual care group (UCG). The mortality within 28 days in the DXM group was 482 patients (22.9%) contrasted with 1110 patients in the UCG (25.7%). The age adjusted rate ratio was 0.83 (95%CI 0.75-0.93;P<0.001). The death rate was also lower in the DXM group than the UCG in patients requiring assisted mechanical ventilation (29.3% vs 41.4% RR 0.64, 95%CI 0.51-0.81). DXM results were not different among those who dod not require respiratory support at randomization.(1)
1. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. New England Journal of Medicine. 2020.
Monoclonal Antibodies – Taking it a step beyond serum, specific antibodies that are produced by memory B cells are specific for the receptor binding domain of the SARS-CoV-2 virus can neutralize the virus. This is a promising new therapy but more research must be done before it is ready for human use.(1)
1. Ye L, Chen X, Li R, Pan Z, Qian C, Yang Y, et al. Human monoclonal antibodies block the binding of SARS-CoV-2 spike protein to angiotensin converting enzyme 2 receptor. medRxiv. 2020:2020.04.06.20055475.
The Hydroxychloroquine Story – Hydroxychloroquine is a malaria drug that is in use today for the treatment of lupus. It is generally safe when used by physicians, but it can prolong the QT portion of the heart rhythm and may potentiate a fatal arrhythmia. The drug was found in vitro to inhibit viral activity. Recommendations to use the drug as therapy before clinical trials were completed in the management of COVID-19 were premature and led to high expectations that were never met. On March 20 Raoult’s team published 20 cases of COVID-19 in a case control open observational study. This observation revealed viral load reduction in the nasal carriage at day 6, particularly when azithromycin was added. The study was not randomized, was underpowered, and did not provide a long follow up period. (1) Around that time other clinical trials were in progress. The University of Minnesota launched a multi-center randomized, double blind, placebo-controlled clinical trial to determine if hydroxychloroquine could prevent patient who were exposed to COVID-19 from getting symptomatic. On March 30, the FDA granted emergency use authorization for hydroxychloroquine in patients with COVID-19. However evidence was emerging that Hydroxychloroquine was not meeting expectations. But political pressure and false hopes publicly challenged scientific research, and on June 4, Lancet retracted a previously published paper that demonstrated the drug was not effective in ill COVID-19 patients. This was followed by a retraction in the New England Journal of Medicine. On June 18 WHO ended its study of hydroxychloroquine after it was shown not to reduce mortality. The NIH also halted its study on June 20 citing it was ineffective.(2,3)
The ORCHID Trial NCT04332991 had started enrolling on April 2. It was sponsored by Massachusetts General Hospital. This multicenter, blinded randomized trial of hydroxychloroquine v placebo was designed to study the treatment of hospitalized COVID-19 patients. On June 20 the Data Safety Monitoring Board halted the ORCHID trial because there had been no demonstrated benefit.(4)
The RECOVERY Trial enrolled 11,000 patients from 175 National Health Service Hospitals in the United Kingdom. This is a large randomized trial to assess therapy, including hydroxychloroquine. However, the Data Monitoring Committee halted this trial on June 8 when it was determined that there was no benefit. In this trial 3,132 patients were randomized to the usual care group (UCG) and 1,542 to hydroxychloroquine (HCQ). All patients were hospitalized. With respect to HCQ, the mortality rate was not different – 25.7% for the HCQ and 23.5% for the UCG (HR 1.11 95%CI .98-1.260p=0.10.(5)
The French open label multi-center adaptive randomized DiSCoVeRy Trial began March 24. It halted its hydroxychloroquine arm on May 24. It was designed to evaluate therapy in patients with low pulmonary saturation or respiratory failure secondary to COVID-19.(6) Thus far several well designed randomized controlled trials have failed to show benefit.
CLINICAL TRIAL NCT04326725 (7) is currently ongoing in Istanbul and is using a very low dose of hydroxychloroquine (200 mg every three weeks) given along with zinc. It should end soon and the results released. It is a prospective, case control study that is not blinded and not randomized. Also the people it is being given to are health care workers who are asymptomatic but have no known direct exposure to COVID-19. Zinc was given along with hydroxychloroquine, so we won’t be able to determine whether it is the zinc or the hydroxychloroquine or nothing that helped. If the results are negative then it confirms that hydroxychloroquine is not of value in the early clinical management of patients with COVID-19. The incidence of COVID-19 among health care workers in our institutions who wear masks and social distance has dropped and is very low. Since the Istanbul trial has only 80 subjects, it will be difficult to show any effect when compared with the current low rates today, and it may only demonstrate that hydroxychloroquine is not necessary if patients or health care workers wear a mask and distance when possible.
A blinded, randomized controlled trial was published in the New England Journal of Medicine on June 4. In this study patients exposed to COVID-19 who were without symptoms were randomized to a group treated with large doses of HCQ and a control group treated with a placebo. The incidence was 11.8% in the treated and 14.3% in placebo group; this was not significant.This study was confirmed July 26 by a large study from Spain that randomized 2,314 healthy contacts of COVID-19 patients to hydroxychloroquine or usual care. There was no benefit of treatment with HCQ (6.2% usual care vs. 5.7% HCQ; RR 0.89 [ CI 0.54-1.46]), nor was there evidence that HCQ could prevent SARS-CoV-2 transmission. (17.8% usual care vs. 18.7% HCQ). Adverse events were 5.9% in the usual care and 51.6% in the HCQ group; there were no deaths or hospitalizations in either group.(8,9)
On July 4, 2020 the SOLIDARITY Trial Steering Committee discontinued its arms on hydroxychloroquine (HCQ) and lopinavir/ritonavir in light of evidence presented at a HCQ WHO summit on July 2. The SOLIDARITY Trial is sponsored by WHO.(10)
1. Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. 2020;56(1):105949.
2. Mehra MR, Desai SS, Ruschitzka F, Patel AN. RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020.
3. Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Retraction: Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2007621. New England Journal of Medicine. 2020.
4. A href=”https://clinicaltrials.gov/ct2/show/NCT04332991″> Clinical Trial NCT04332991 (ORCHID TRIAL)
Vitamin C – Vitamin C is an antioxidant that removes the free radicals that can damage other cells. It thus has antiinflammatory properties and can stimulate the immune system. It may protect the blood vessel walls from damage. Since patients who have a severe illness like COVID-19 may require increased vitamin D, it is being studied and data from large trials should be available soon. there are 15 clinical trials that are pending for both critically ill and asymptomatic patients. There are thus far no trials that either recommend using or not using vitamin C in asymptomatic patients.
Vitamin D – Vitamin D deficiency is very common in the United States, particularly among the elderly and persons with darker complexion. Vitamin D supplements may modulate T cell regulatory activity and protect against respiratory tract infection. The effects of vitamin D in patients with COVID-19 are not known but 8 clinical trials are ongoing.
Zinc– Zinc has been shown to be able to enter cells and intervere with viral replication. While there is not data to recommend either for or against its use in the treatment of COVID-19, there are ongoing clinical trials investigating this. However, zinc use above the recommendated dose can cause copper deficiency, may cause hematological abnormalities and can cause irreversible neurological disorders.So, at this time it is not recommended that persons not enrolled in a clinical trial exceed the recommended dose of zinc.
Carr AC. A new clinical trial to test high-dose vitamin C in patients with COVID-19. Critical care (London, England).
Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, et al. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients. 2020;12(4).
https://www.thelancet.com/retrieve/pii/S2213858720301832 – great article on vitamin D
Carr AC. A new clinical trial to test high-dose vitamin C in patients with COVID-19. Critical care (London, England).
Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, et al. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients. 2020;12(4).
https://www.thelancet.com/retrieve/pii/S2213858720301832 – great article on vitamin D
Zabetakis I, Lordan R, Norton C, Tsoupras A. COVID-19: The Inflammation Link and the Role of Nutrition in Potential Mitigation. Nutrients. 2020;12(5).
TOPICS FOR DISCUSSION
Herd immunity occurs when a percentage of the population has become immune to the virus, having either been vaccinated or acquiring the disease and developed neutralizing antibodies or cellular immunity to the virus. At the point of immunity the transmission rate is no longer exponential, and this is represented mathematically. It is the point at which the disease ceases to be an epidemic, but will not be 100% of the population for SARS-CoV-2. Once herd immunity is reached, it is unlikely that those patients who were not candidates for a vaccination will acquire the disease. We are not yet at the point where herd immunity can be achieved, and until then the focus should be on protecting the vulnerable from exposure.
There are many questions that surround the development of immunity. For instance does the detection of antibodies mean that immunity is conferred and for how long. Can people who have had been exposed to previous coronaviruses through upper respiratory infections in the past have some sort of immunity? Can people who have undetectable antibodies still have a cellular immunity to the disease, and when exposed have a killer C cell response? As these questions are answered we will have more firm evidence on how we can achieve herd immunity.
The renin angiotensin system is designed to be a protective mechanism from stress. Renin is secreted from the juxtagloerular apparatus in the kidney in response to low sodium, low blood pressure or neurogenic stimuli. It then causes the breakdown of angiotensinogen to the 10 aminoacid peptide, angiotensin 1. Angiotensin I is activated to angiotensin II, an 8 aminoacid peptide by converting enzyme 1, for which their is a receptor – the ACE1 receptor. There is also a receptor for the enzyme’s deflation product, ACE 2. It is the ACE 2 receptor that is the target for SARS-CoV-2. Angiotensin 2 is accountable for vasoconstriction, blood pressure elevation, inflammation and fibrosis. Since it is activated during illnesses involving the kidney, it is associated with progressive kidney disease. The angiotensin II receptor blockers block the receptor for AII, not ACE2. Because angiotensin is a potent stimulator of blood pressure, its blockade is a major treatment for hypertension.
ACE2 receptors are on many cells, particularly the heart, lungs and kidneys. There are most prevalent in the lung. They are actually upregulated with the antihypertensives like converting enzyme inhibitors and angiotensin receptor blockers. Since they have a beneficial effect of blocking the formation of AII, their up regulation is beneficial. When SARS-CoV-2 attacks the receptors, the theory is that does not fully saturate them in patients on medications, and is less dangerous.
A study has shown that older patients taking ACE inhibitors have a lower risk for hospitalization from COVID-19. However current recommendations are to continue ACE and ARB therapy if already on it, but neither drug should be added for the care of COVID-19 patients pending further evidence.
Reference: Khera R, Clark C, Lu Y, Guo Y, Ren S, Truax B, et al. Association of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers with the Risk of Hospitalization and Death in Hypertensive Patients with Coronavirus Disease-19. medRxiv. 2020:2020.05.17.20104943.
MASK AND SOCIAL DISTANCE - WHAT CAN WE DO TO STAY SAFE?
Since the droplets are contained in our breath, we must wear a mask to limit the spread. These are generally procedure masks as are used in surgery. Cloth masks are acceptable in the community so long as they cover the nostrils and mouth. These masks are loosely fitting, comfortable, but do not protect the wearer; they protect those who are nearby. We protect others when we wear a mask.
The virus attacks the body through receptors on targeted cells and can easily enter through our mouth and nasal passages. Viral particles may linger without symptoms for a few days in the throat, and the person may be asymptomatic, but still infected. The receptors for SARS-CoV-2 are known as ACE2 receptors, and are on the heart, lungs and kidney, especially the lungs. If the virus defeats our protective mechanisms, they can drop to the lungs and initiate a power innate immune response. This be be accompanied by powerful cytokines that can destroy lung tissue as well as the virus.
The droplets from SARS-CoV-2 are generally thought to be greater than 5um, and expected to fall onto a surface after traveling 6 feet when a mask is not worn. With a mask they can be contained to less than 8 inches. The problem is if the virus is aerosolized and the droplets are less than 5 um. Then they can travel farther. During bronchoscopies and even nasal testing, the droplets may be aerosolized. Therefore, instead of a procedure mask, health workers should wear a special N95 fitted respirator when working in special circumstances where aerosolization is possible
A virus spreads by a transmission rate that is calculated by how many persons will be infected. The Ro transmission rate for SARS-CoV-2 is between 2.3 to 2.6. We also look at the Rt – or transmission rate in a community. That will fall as persons contain the spread. The disease has an incubation period of 5 days give or take 2. That means that if exposed to the disease, you may become symptomatic in less than 7 days. You will be contagious until you are free of the disease, usually less than two weeks or less.
Yes. A study by the National Bureau of Economic Statistics determined that as the result of the March 19 executive order in California to shelter in place for nonessential activities COVID-19 cases were reduced by 125.5 cases per 100,000 population to 219.7 per 100,000 by April 20. This resulted in 1661 fewer COVID-19 deaths but resulted in 400 jobs lost for each life saved during the month.
Reference: Friedson AI, McNichols D, Sabia JJ, Dave D. Did California’s Shelter in Place Order Work?2020. Available from: https://www.nber.org/papers/w26992.pdf.