Individual heterogeneity and airborne infection: Effect of non-uniform air distribution

The classical Wells–Riley equation assumes homogeneity of susceptible individuals and environments to airborne exposure. However, individual susceptibility to infection is mostly heterogeneous, and exposure variability could arise from differences in inhalation rate, spatiotemporal non-uniformity of infectious aerosol concentrations, and the exposure trajectory and time. Non-uniform air distribution results in spatial non-uniformity of infectious aerosol concentrations. The non-uniformity effect is essentially a problem of individual infection probability. Here, we derived a general dose-response equation and a heterogeneous Wells–Riley equation accounting for individual variability in infection probability. The heterogeneous Wells-Riley equation shows the potential of the zone air distribution effectiveness to consider spatial non-uniformity under steady-state conditions. An existing quanta generation rate formula was theoretically justified. The new equation was then applied to a restaurant reporting an outbreak of coronavirus disease 2019, with spatial and/or temporal heterogeneity of infectious aerosol concentrations. Our results show the need to include spatial non-uniformity in outbreak investigations. A hypothetical two-zone setup was used to demonstrate how the inter-zonal distribution of clean air and the inter-zonal exchange flow affect airborne infections. An infector in a poorly diluted zone with the greatest number of susceptible individuals would result in the most secondary infections, whereas an infector in a well-ventilated zone with few susceptible individuals would result in the least secondary infections.

Exposure and respiratory infection risk via the short-range airborne route.

Leading health authorities have suggested short-range airborne transmission as a major route of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, there is no simple method to assess the short-range airborne infection risk or identify its governing parameters. We proposed a short-range airborne infection risk assessment model based on the continuum model and two-stage jet model. The effects of ventilation, physical distance and activity intensity on the short-range airborne exposure were studied systematically. The results suggested that increasing physical distance and ventilation reduced short-range airborne exposure and infection risk. However, a diminishing return phenomenon was observed when the ventilation rate or physical distance was beyond a certain threshold. When the infectious quantum concentration was less than 1 quantum/L at the mouth, our newly defined threshold distance and threshold ventilation rate were independent of quantum concentration. We estimated threshold distances of 0.59, 1.1, 1.7 and 2.6 m for sedentary/passive, light, moderate and intense activities, respectively. At these distances, the threshold ventilation was estimated to be 8, 20, 43, and 83 L/s per person, respectively. The findings show that both physical distancing and adequate ventilation are essential for minimising infection risk, especially in high-intensity activity or densely populated spaces.

Hypertension Exacerbates Severity and Outcomes of COVID-19 in Elderly Patients: A Retrospective Observational Study.

OBJECTIVE: To evaluate the impact of hypertension on the clinical outcome of COVID-19 patients aged 60 years old and older. METHODS: This single-center retrospective cohort study enrolled consecutive COVID-19 patients aged 60 years old and older, who were admitted to Liyuan Hospital from January 1, 2020 to April 25, 2020. All included patients were divided into two groups: hypertension and nonhypertension group. The baseline demographic characteristics, laboratory test results, chest computed tomography (CT) images and clinical outcomes were collected and analyzed. The prognostic value of hypertension was determined using binary logistic regression. RESULTS: Among the 232 patients included in the analysis, 105 (45.3%) patients had comorbid hypertension. Compared to the nonhypertension group, patients in the hypertension group had higher neutrophil-to-lymphocyte ratios, red cell distribution widths, lactate dehydrogenase, high-sensitivity C-reactive protein, D-dimer and severity of lung lesion, and lower lymphocyte counts (all P<0.05). Furthermore, the hypertension group had a higher proportion of intensive care unit admissions [24 (22.9%) vs. 14 (11.0%), P=0.02) and deaths [16 (15.2%) vs. 3 (2.4%), P<0.001] and a significantly lower probability of survival (P<0.001) than the nonhypertension group. Hypertension (OR: 4.540, 95% CI: 1.203-17.129, P=0.026) was independently correlated with all-cause in-hospital death in elderly patients with COVID-19. CONCLUSION: The elderly COVID-19 patients with hypertension tend to have worse conditions at baseline than those without hypertension. Hypertension may be an independent prognostic factor of poor clinical outcome in elderly COVID-19 patients.

Probable cross-corridor transmission of SARS-CoV-2 due to cross airflows and its control.

A COVID-19 outbreak occurred in May 2020 in a public housing building in Hong Kong - Luk Chuen House, located in Lek Yuen Estate. The horizontal cluster linked to the index case' flat (flat 812) remains to be explained. Computational fluid dynamics simulations were conducted to obtain the wind-pressure coefficients of each external opening on the eighth floor of the building. The data were then used in a multi-zone airflow model to estimate the airflow rate and aerosol concentration in the flats and corridors on that floor. Apart from flat 812 and corridors, the virus-laden aerosol concentrations in flats 811, 813, 815, 817 and 819 (opposite to flat 812, across the corridor) were the highest on the eighth floor. When the doors of flats 813 and 817 were opened by 20%, the hourly-averaged aerosol concentrations in these two flats were at least four times as high as those in flats 811, 815 and 819 during the index case's home hours or the suspected exposure period of secondary cases. Thus, the flats across the corridor that were immediately downstream from flat 812 were at the highest exposure risk under a prevailing easterly wind, especially when their doors or windows that connected to the corridor were open. Given that the floorplan and dimension of Luk Chuen House are similar to those of many hotels, our findings provide a probable explanation for COVID-19 outbreaks in quarantine hotels. Positive pressure and sufficient ventilation in the corridor would help to minimise such cross-corridor infections.

Spread of SARS-CoV-2 aerosols via two connected drainage stacks in a high-rise housing outbreak of COVID-19.

Vertical transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) along a vertical column of flats has been documented in several outbreaks of coronavirus disease 2019 (COVID-19) in Guangdong and Hong Kong. We describe an outbreak in Luk Chuen House, involving two vertical columns of flats associated with an unusually connected two-stack drainage system, in which nine individuals from seven households were infected. The index case resided in Flat 812 (8th floor, Unit 12), two flats (813, 817) on its opposite side reported one case each (i.e., a horizontal sub-cluster). All other flats with infected residents were vertically associated, forming a vertical sub-cluster. We injected tracer gas (SF6) into drainage stacks via toilet or balcony of Flat 812, monitored gas concentrations in roof vent, toilet, façade, and living room in four of the seven flats with infected residents and four flats with no infected residents. The measured gas concentration distributions agreed with the observed distribution of affected flats. Aerosols leaking into drainage stacks may generate the vertical sub-cluster, whereas airflow across the corridor probably caused the horizontal sub-cluster. Sequencing and phylogenetic analyses also revealed a common point-source. The findings provided additional evidence of probable roles of drainage systems in SARS-CoV-2 transmission.

Predominant airborne transmission and insignificant fomite transmission of SARS-CoV-2 in a two-bus COVID-19 outbreak originating from the same pre-symptomatic index case.

The number of people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to increase worldwide, but despite extensive research, there remains significant uncertainty about the predominant routes of SARS-CoV-2 transmission. We conducted a mechanistic modeling and calculated the exposure dose and infection risk of each passenger in a two-bus COVID-19 outbreak in Hunan province, China. This outbreak originated from a single pre-symptomatic index case. Some human behavioral data related to exposure including boarding and alighting time of some passengers and seating position and mask wearing of all passengers were obtained from the available closed-circuit television images/clips and/or questionnaire survey. Least-squares fitting was performed to explore the effect of effective viral load on transmission risk, and the most likely quanta generation rate was also estimated. This study reveals the leading role of airborne SARS-CoV-2 transmission and negligible role of fomite transmission in a poorly ventilated indoor environment, highlighting the need for more targeted interventions in such environments. The quanta generation rate of the index case differed by a factor of 1.8 on the two buses and transmission occurred in the afternoon of the same day, indicating a time-varying effective viral load within a short period of five hours.

Poor ventilation worsens short-range airborne transmission of respiratory infection.

To explain the observed phenomenon that most SARS-CoV-2 transmission occurs indoors whereas its outdoor transmission is rare, a simple macroscopic aerosol balance model is developed to link short- and long-range airborne transmission. The model considers the involvement of exhaled droplets with initial diameter ≤50 µm in the short-range airborne route, whereas only a fraction of these droplets with an initial diameter within 15 µm or equivalently a final diameter within 5 µm considered in the long-range airborne route. One surprising finding is that the room ventilation rate significantly affects the short-range airborne route, in contrast to traditional belief. When the ventilation rate in a room is insufficient, the airborne infection risks due to both short- and long-range transmission are high. A ventilation rate of 10 L/s per person provides a similar concentration vs distance decay profile to that in outdoor settings, which provides additional justification for the widely adopted ventilation standard of 10 L/s per person. The newly obtained data do not support the basic assumption in the existing ventilation standard ASHRAE 62.1 (2019) that the required people outdoor air rate is constant if the standard is used directly for respiratory infection control. Instead, it is necessary to increase the ventilation rate when the physical distance between people is less than approximately 2 m.

Insufficient ventilation led to a probable long-range airborne transmission of SARS-CoV-2 on two buses.

Uncertainty remains on the threshold of ventilation rate in airborne transmission of SARS-CoV-2. We analyzed a COVID-19 outbreak in January 2020 in Hunan Province, China, involving an infected 24-year-old man, Mr. X, taking two subsequent buses, B1 and B2, in the same afternoon. We investigated the possibility of airborne transmission and the ventilation conditions for its occurrence. The ventilation rates on the buses were measured using a tracer-concentration decay method with the original driver on the original route. We measured and calculated the spread of the exhaled virus-laden droplet tracer from the suspected index case. Ten additional passengers were found to be infected, with seven of them (including one asymptomatic) on B1 and two on B2 when Mr. X was present, and one passenger infected on the subsequent B1 trip. B1 and B2 had time-averaged ventilation rates of approximately 1.7 and 3.2 L/s per person, respectively. The difference in ventilation rates and exposure time could explain why B1 had a higher attack rate than B2. Airborne transmission due to poor ventilation below 3.2 L/s played a role in this two-bus outbreak of COVID-19.

WLAN-Log-Based Superspreader Detection in the COVID-19 Pandemic

Identifying “superspreaders” of disease is a pressing concern for society during pandemics such as COVID-19. Superspreaders represent a group of people who have much more social contacts than others. The widespread deployment of WLAN infrastructure enables non-invasive contact tracing via people’s ubiquitous mobile devices. This technology offers promise for detecting superspreaders. In this paper, we propose a general framework for WLAN-log-based superspreader detection. In our framework, we first use WLAN logs to construct contact graphs by jointly considering human symmetric and asymmetric interactions. Next, we adopt three vertex centrality measurements over the contact graphs to generate three groups of superspreader candidates. Finally, we leverage SEIR simulation to determine groups of superspreaders among these candidates, who are the most critical individuals for the spread of disease based on the simulation results. We have implemented our framework and evaluate it over a WLAN dataset with 41 million log entries from a large-scale university. Our evaluation shows superspreaders exist on university campuses. They change over the first few weeks of a semester, but stabilize throughout the rest of the term. The data also demonstrate that both symmetric and asymmetric contact tracing can discover superspreaders, but the latter performs better with daily contact graphs. Further, the evaluation shows no consistent differences among three vertex centrality measures for long-term (i.e., weekly) contact graphs, which necessitates the inclusion of SEIR simulation in our framework. We believe our proposed framework and these results can provide timely guidance for public health administrators regarding effective testing, intervention, and vaccination policies.

Probable airborne transmission of SARS-CoV-2 in a poorly ventilated restaurant.

Although airborne transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been recognized, the condition of ventilation for its occurrence is still being debated. We analyzed a coronavirus disease 2019 (COVID-19) outbreak involving three families in a restaurant in Guangzhou, China, assessed the possibility of airborne transmission, and characterized the associated environmental conditions. We collected epidemiological data, obtained a full video recording and seating records from the restaurant, and measured the dispersion of a warm tracer gas as a surrogate for exhaled droplets from the index case. Computer simulations were performed to simulate the spread of fine exhaled droplets. We compared the in-room location of subsequently infected cases and spread of the simulated virus-laden aerosol tracer. The ventilation rate was measured using the tracer gas concentration decay method. This outbreak involved ten infected persons in three families (A, B, C). All ten persons ate lunch at three neighboring tables at the same restaurant on January 24, 2020. None of the restaurant staff or the 68 patrons at the other 15 tables became infected. During this occasion, the measured ventilation rate was 0.9 L/s per person. No close contact or fomite contact was identified, aside from back-to-back sitting in some cases. Analysis of the airflow dynamics indicates that the infection distribution is consistent with a spread pattern representative of long-range transmission of exhaled virus-laden aerosols. Airborne transmission of the SARS-CoV-2 virus is possible in crowded space with a ventilation rate of 1 L/s per person.

Impact of intervention methods on COVID-19 transmission in Shenzhen.

By March 31, 2020, COVID-19 had spread to more than 200 countries. Over 750,000 confirmed cases were reported, leading to more than 36,000 deaths. In this study, we analysed the efficiency of various intervention strategies to prevent infection by the virus, SARS-CoV-2, using an agent-based SEIIR model, in the fully urbanised city of Shenzhen, Guangdong Province, China. Shortening the duration from symptom onset to hospital admission, quarantining recent arrivals from Hubei Province, and letting symptomatic individuals stay at home were found to be the three most important interventions to reduce the risk of infection in Shenzhen. The ideal time window for a mandatory quarantine of arrivals from Hubei Province was between 10 January and January 17, 2020, while the ideal time window for local intervention strategies was between 15 and 22 January. The risk of infection could have been reduced by 50% if all symptomatic individuals had immediately gone to hospital for isolation, and by 35% if a 14-day quarantine for arrivals from Hubei Province had been introduced one week earlier. Intervention strategies implemented in Shenzhen were effective, and the spread of infection would be controlled even if the initial basic reproduction number had doubled. Our results may be useful for other cities when choosing their intervention strategies to prevent outbreaks of COVID-19.

The discovery of potential natural products for targeting SARS-CoV-2 spike protein by virtual screening (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters into the cells through its spike proteins binding to human angiotensin-converting enzyme 2 (ACE2) protein and causes virus infection in host cells. Until now, there are no available antiviral drugs have been reported that can effectively block virus infection. The study aimed to discover the potential compounds to prevent viral spike proteins to bind to the human ACE2 proteins from Taiwan Database of Extracts and Compounds (TDEC) by structure-based virtual screening. In this study, to rapidly discover potential inhibitors against SARS-CoV-2 spike proteins, the molecular docking calculation was performed by AutoDock Vina program. Herein, we found that 39 potential compounds may have good binding affinities and can respectively bind to the viral receptor-binding domain (RBD) of spike protein in the prefusion conformation and spike-ACE2 complex protein in silico. Among those compounds, especially natural products thioflexibilolide A and candidine that were respectively isolated from the soft corals Sinularia flexibilis and Phaius mishmensis may have better binding affinity than others. This study provided the predictions that these compounds may have the potential to prevent SARS-CoV-2 spike protein from entry into cells.

Identification of Candidate COVID-19 Therapeutics using hPSC-derived Lung Organoids (preprint)

Summary ParagraphThe SARS-CoV-2 virus has caused already over 3.5 million COVID-19 cases and 250,000 deaths globally. There is an urgent need to create novel models to study SARS-CoV-2 using human disease-relevant cells to understand key features of virus biology and facilitate drug screening. As primary SARS-CoV-2 infection is respiratory-based, we developed a lung organoid model using human pluripotent stem cells (hPSCs) that could be adapted for drug screens. The lung organoids, particularly aveolar type II cells, express ACE2 and are permissive to SARS-CoV-2 infection. Transcriptomic analysis following SARS-CoV-2 infection revealed a robust induction of chemokines and cytokines with little type I/III interferon signaling, similar to that observed amongst human COVID-19 pulmonary infections. We performed a high throughput screen using hPSC-derived lung organoids and identified FDA-approved drug candidates, including imatinib and mycophenolic acid, as inhibitors of SARS-CoV-2 entry. Pre- or post-treatment with these drugs at physiologically relevant levels decreased SARS-CoV-2 infection of hPSC-derived lung organoids. Together, these data demonstrate that hPSC-derived lung cells infected by SARS-CoV-2 can model human COVID-19 disease and provide a valuable resource to screen for FDA-approved drugs that might be repurposed and should be considered for COVID-19 clinical trials.

Identification of Drugs Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colonic Organoids (preprint)

Summary ParagraphThe current COVID-19 pandemic is caused by SARS-coronavirus 2 (SARS-CoV-2). There are currently no therapeutic options for mitigating this disease due to lack of a vaccine and limited knowledge of SARS-CoV-2 biology. As a result, there is an urgent need to create new disease models to study SARS-CoV-2 biology and to screen for therapeutics using human disease-relevant tissues. COVID-19 patients typically present with respiratory symptoms including cough, dyspnea, and respiratory distress, but nearly 25% of patients have gastrointestinal indications including anorexia, diarrhea, vomiting, and abdominal pain. Moreover, these symptoms are associated with worse COVID-19 outcomes1. Here, we report using human pluripotent stem cell-derived colonic organoids (hPSC-COs) to explore the permissiveness of colonic cell types to SARS-CoV-2 infection. Single cell RNA-seq and immunostaining showed that the putative viral entry receptor ACE2 is expressed in multiple hESC-derived colonic cell types, but highly enriched in enterocytes. Multiple cell types in the COs can be infected by a SARS-CoV-2 pseudo-entry virus, which was further validated in vivo using a humanized mouse model. We used hPSC-derived COs in a high throughput platform to screen 1280 FDA-approved drugs against viral infection. Mycophenolic acid and quinacrine dihydrochloride were found to block the infection of SARS-CoV-2 pseudo-entry virus in COs both in vitro and in vivo, and confirmed to block infection of SARS-CoV-2 virus. This study established both in vitro and in vivo organoid models to investigate infection of SARS-CoV-2 disease-relevant human colonic cell types and identified drugs that blocks SARS-CoV-2 infection, suitable for rapid clinical testing.

Identification of Drugs Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colonic Organoids (preprint)

The current COVID-19 pandemic is caused by SARS-coronavirus 2 (SARS-CoV-2). There are currently no therapeutic options for mitigating this disease due to lack of a vaccine and limited knowledge of SARS-CoV-2 biology. As a result, there is an urgent need to create new disease models to study SARS-CoV-2 biology and to screen for therapeutics using human disease-relevant tissues. COVID-19 patients typically present with respiratory symptoms including cough, dyspnea, and respiratory distress, but nearly 25% of patients have gastrointestinal indications including anorexia, diarrhea, vomiting, and abdominal pain. Moreover, these symptoms are associated with worse COVID-19 outcomes1. Here, we report using human pluripotent stem cell-derived colonic organoids (hPSC-COs) to explore the permissiveness of colonic cell types to SARS-CoV-2 infection. Single cell RNA-seq and immunostaining showed that the putative viral entry receptor ACE2 is expressed in multiple hESC-derived colonic cell types, but highly enriched in enterocytes. Multiple cell types in the COs can be infected by a SARS-CoV-2 pseudo- entry virus, which was further validated in vivo using a humanized mouse model. We used hPSC-derived COs in a high throughput platform to screen 1280 FDA-approved drugs against viral infection. Mycophenolic acid and quinacrine dihydrochloride were found to block the infection of SARS-CoV-2 pseudo-entry virus in COs both in vitro and in vivo, and confirmed to block infection of SARS-CoV-2 virus. This study established both in vitro and in vivo organoid models to investigate infection of SARS-CoV-2 disease-relevant human colonic cell types and identified drugs that blocks SARS-CoV-2 infection, suitable for rapid clinical testing.