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By Christian Hoffmann &
Bernd S. Kamps
22 May
Voice: Google Cloud Text-to-Speech / US
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Summary
First, design natural sunlight representing a clear day at sea level during summer solstice at 40oN latitude and determine the time needed to inactivate 90% percentage of infectious virus; investigate the potential of UVB radiation from sunlight as a potential virucide; and re-challenge 9 rhesus macaques 35 days after initial infection with SARS-CoV-2.
Afterwards, find out that a positive RT-qPCR result may not necessarily mean the person is still infectious or that they still have any meaningful disease; compare daily incidence in 8 Iowa counties bordering Illinois with those in the 7 Illinois counties bordering Iowa; and evaluate the expression of ACE in nasal epithelial samples in children 4 to 9 years old and discuss the implications.
Finally, discuss with your colleagues why the 4.65% prevalence of SARS-CoV-2-specific antibodies found in Los Angeles may be biased; discuss with your patients why hydroxychloroquine doses tolerable for humans are too low to have any effect on SARS-CoV-2 in vivo; and examine lungs from 7 deceased COVID-19 patients with lungs from 7 patients who died from ARDS secondary to influenza A and 10 age-matched, uninfected control lungs. What will you discover?
Epidemiology
Lyu W, Wehby GL. Comparison of Estimated Rates of Coronavirus Disease 2019 (COVID-19) in Border Counties in Iowa Without a Stay-at-Home Order and Border Counties in Illinois With a Stay-at-Home Order. JAMA Netw Open. 2020 May 1;3(5):e2011102. PubMed: https://pubmed.gov/32413112. Full-text: https://doi.org/10.1001/jamanetworkopen.2020.11102
Is it necessary to stay home during the epidemic’s peak? Probably, yes. This well-conducted study focused on the effects of a general stay-at-home-order. On March 21, Illinois did so while Iowa didn’t. Authors compared daily incidence in 8 Iowa counties bordering Illinois with those in the 7 Illinois counties bordering Iowa. Within a month after the stay-at-home order, the curves started to diverge considerably. Cases increased more quickly in Iowa and more slowly in Illinois, leading to an excess of about 30 % in Iowa counties. Sensitivity analyses addressing differences in timing of closing schools and nonessential businesses and differences in population density and poverty rates between the two states supported these findings.
Sood N, Simon P, Ebner P, et al. Seroprevalence of SARS-CoV-2–Specific Antibodies Among Adults in Los Angeles County, California, on April 10-11, 2020. JAMA. Published online May 18, 2020. Full-text: https://doi.org/10.1001/jama.2020.8279
No herd immunity in LA. Participants were offered testing at 6 study sites or at home in mid-April. Among 865 cases, the prevalence of antibodies was 4.65%. However, even this low number may be biased due to nonresponse or due to the fact that symptomatic persons may have been more likely to participate.
Virology
Chandrashekar A, Liu J, Martinot AJ, et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science. 2020 May 20:eabc4776. PubMed: https://pubmed.gov/32434946. Full-text: https://doi.org/10.1126/science.abc4776
No re-infection in macaques. Following initial viral clearance and on day 35 following initial viral infection, 9 rhesus macaques were re-challenged with the same doses of virus that were utilized for the primary infection. Very limited viral RNA was observed in bronchoalveolar lavage on day 1, with no viral RNA detected at subsequent timepoints. These data show that SARS-CoV-2 infection induced protective immunity against re-exposure in non-human primates.
Transmission
Guasp M, Laredo C, Urra X. Higher solar irradiance is associated with a lower incidence of COVID-19. Clin Infect Dis. 2020 May 19:ciaa575. PubMed: https://pubmed.gov/32426805. Full-text: https://doi.org/10.1093/cid/ciaa575
Increasing sunlight exposure in the upcoming weeks may help flatten the curve! UVB radiation from sunlight (the primary source of UV radiation) is the principal environmentally effective virucide, probably much more relevant than temperature and humidity. Authors studied the relationship between the incidence of COVID-19, demographic, and climatologic measurements in different regions across the world. They show a significant association of the incidence of COVID-19 and both reduced solar irradiance and increased population density, highlighting the sterilizing properties of UV radiation.
Ratnesar-Shumate S, Williams G, Green B, et al. Simulated Sunlight Rapidly Inactivates SARS-CoV-2 on Surfaces. J Infect Dis. 2020 May 20:jiaa274. PubMed: https://pubmed.gov/32432672. Full-text: https://doi.org/10.1093/infdis/jiaa274
This lab data supports the above observation of inactivation. Store your masks in the sun! Simulated sunlight rapidly inactivated SARS-CoV-2 suspended in either simulated saliva or culture media and dried on stainless steel plates. Ninety percent of infectious virus was inactivated every 6.8 minutes in simulated saliva and every 14.3 minutes in culture media when exposed to simulated sunlight representative of the sun on a clear summer day. No significant decay was observed in darkness over 60 minutes.
Bunyavanich S, Do A, Vicencio A. Nasal Gene Expression of Angiotensin-Converting Enzyme 2 in Children and Adults. JAMA. 2020 May 20. PubMed: https://pubmed.gov/32432657. Full-text: https://doi.org/10.1001/jama.2020.8707
Is this the reason for lower infection rates in children? As the nasal epithelium is one of the first sites of infection, investigators evaluated the expression of ACE in nasal epithelial samples collected 2015-2018 as part of an asthma study. Among a cohort of 305 patients, all age groups had higher expression of ACE2 in the nasal epithelium compared with younger children (4-9 years old). ACE2 expression was age-dependent and higher with each subsequent age group after adjusting for sex and asthma. A good argument for opening a day care center for children.
Diagnostics
Tom MR, Mina MJ. To Interpret the SARS-CoV-2 Test, Consider the Cycle Threshold Value. Clin Infect Dis. 2020 May 21:ciaa619. PubMed: https://pubmed.gov/32435816. Full-text: https://doi.org/10.1093/cid/ciaa619
A positive RT-qPCR result may not necessarily mean the person is still infectious or that they still have any meaningful disease. The RNA could be from nonviable virus and/or the amount of live virus may be too low for transmission. RT-qPCR provides quantification by first reverse transcribing RNA into DNA, and then performing qPCR where a fluorescence signal increases proportionally to the amount of amplified nucleic acid. The test is positive if the fluorescence reaches a specified threshold within a certain number of PCR cycles (Ct value, inversely related to the viral load). Many qPCR assays use a Ct cut-off of 40, allowing detection of very few starting RNA molecules. The authors suggest to use this Ct value or to calculate viral load which can help to refine decision-making (re: shorter isolation etc.).
Severe COVID-19
Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020 May 21. PubMed: https://pubmed.gov/32437596. Full-text: https://doi.org/10.1056/NEJMoa2015432
It’s not influenza. The authors carefully examined lungs from 7 deceased COVID-19 patients with lungs from 7 patients who died from ARDS secondary to influenza A and 10 age-matched, uninfected control lungs. In COVID-19 or influenza, the histologic pattern was diffuse alveolar damage with perivascular T-cell infiltration. However, the COVID-19 lungs showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi and the amount of vessel growth were 9 and almost 3 times as prevalent as in influenza, respectively.
Treatment
Fan J, Zhang X, Liu J, et al. Connecting hydroxychloroquine in vitro antiviral activity to in vivo concentration for prediction of antiviral effect: a critical step in treating COVID-19 patients. Clin Infect Dis. 2020 May 21:ciaa623. PubMed: https://pubmed.gov/32435791. Full-text: https://doi.org/10.1093/cid/ciaa623
The price for the most cryptic abstract of the day goes to this FDA group. “Translation of in vitro antiviral activity to the in vivo setting is crucial to identify potentially effective dosing regimens of hydroxychloroquine. In vitro EC50/EC90 values for hydroxychloroquine should be compared to the in vivo free extracellular tissue concentration, which is similar to the free plasma hydroxychloroquine concentration.” Did they not dare to tell the truth? Their (important, yet cryptic) message was: HCQ doses tolerable for humans are too low to have any antiviral effect.
Parang K, El-Sayed NS, Kazeminy AJ, Tiwari RK. Comparative Antiviral Activity of Remdesivir and Anti-HIV Nucleoside Analogs Against Human Coronavirus 229E (HCoV-229E). Molecules. 2020 May 17;25(10):E2343. PubMed: https://pubmed.gov/32429580. Full-text: https://doi.org/10.3390/molecules25102343.
Most almost-misleading title of the day: Comparative, not comparable. A series of anti-HIV nucleosides were compared with remdesivir for antiviral activity against seasonal HCoV-229E in MRC-5 cells. Remdesivir was found to be potent, with an EC50 value of 0.07 μM. Only emtricitabine (FTC) showed modest activity, with an EC50 value of 82 μM. Other NRTIs did not show comparable activity. But it was comparative, yes.