Loneliness: “the unpleasant experience that occurs when a person’s network of social relations is deficient in some important way, either quantitatively or qualitatively” (Perlman & Peplau, 1984). All of us experienced moments of loneliness, but what we don’t expect about it is that it may considerably vary, depending on quality, quantity and multidimensionality.

80% of people under 18 experienced loneliness occasionally in their life (Galanki & Vasilopoulou, 2007). This percentage varies in a U-curve pattern over the lifetime (Pinquart & Sorensen, 2001), but 15-30% of the individuals experience chronic loneliness instead (Heinrich & Gullone, 2006). What’s this variability due to? Is it possible for it to be linked to the social network extension alone?

Hawkley & Cacioppo (2010) wrote in their review: “Loneliness is synonymous with perceived social isolation, not with objective social isolation. People can live relatively solitary lives and not feel lonely, and conversely, they can live an ostensibly rich social life and feel lonely nevertheless”. When talking about perceptions, the factors to be considered become numerous, individual and subjective: personality, ethnicity, age, health status, they’re just some examples of things which can influence loneliness experience.

Loneliness and health

Dottoressa - Solitudine
Photo by Francisco Venâncio

This multidimensionality becomes even more important when the enormous risks connected to chronic and intense loneliness are taken into consideration. It is enough to think that a premature death risk is incremented by 29% by social isolation and by 26% by perceived loneliness. This risk augmentation is even more surprising because it is comparable to the one experienced by subjects with pathological conditions, as grade 2 or 3 obesity (Holt-Lunstad, Smith, Baker, Harris & Stephenson, 2015).

This happens because, in front of a loneliness experience (be it real or subjective), numerous direct and indirect factors  can compromise aspects related to physical health, sleep, physiological functioning, genic expression and immunitary system, to quote some of them (for a review: Hawkley & Cacioppo, 2010). Starting from the current conditions, the loneliness problem could become epidemic by the year 2030 (Linehan et al., 2014), although its influence is already becoming more serious in relation to the COVID-19 emergency. 

Based on these premises, it is evident how important and urgent it is to define the specific factors that play an individualized role in the temporal and causal determination of experiencing loneliness. A better comprehension of the phenomenon can promote preventive and therapeutic approaches appositely tailored for the “treatment” of loneliness. 

This is the direction taken in Fransenn, Stijnen, Hamers & Schneider’s study (2020): the analysis conducted on the dutch population highlighted how three different age groups (young adults, early middle-aged adults and late middle-aged adults) had different correlations between loneliness perception and the presence of various factors. For example: young adults are particularly sensitive to the frequency of contacts with their friends; early middle-aged adults perceive more loneliness if they’re unemployed; late middle-aged adults’ loneliness perception is linked to their physical health status. 

The clinical implications derived from this study are crucial and consistent with the points previously illustrated:  “Factors associated with loneliness across the adult life span may be understood from an age-normative life-stage perspective. Accordingly, there is no one-size-fits-all approach to reduce loneliness among adults, suggesting that a variety of interventions or an indirect approach may be necessary” (Franssen, Stijnen, Hamers & Schneider, 2020). The study results, besides enriching the theoretic framework, give a contextual frame for the tailoring of personalized interventions, be them therapeutic or preventive, for the management of the loneliness phenomenon.

We interviewed the authors of the aforementioned study, who answered ScientifiCult’s questions.

The interview

Acting on loneliness

Uomo solo in un parcheggio - Solitudine
Photo by Harut Movsisyan

As described by Perlman & Peplau’s loneliness definition you indicated in the introduction of your research, loneliness isn’t exclusively connected to quantitative factors, but also to qualitative ones. This is also reflected in some aspects took into consideration during your study, such as ethnicity, financial status, education and psychological stress. Talking about the qualitative factors that make a network effective against loneliness (e.g.: strength, constancy, positivity, etc.), which ones do you think  would be potential candidates in countering loneliness? And, according to your hypothesis, how would they be related to age?

We believe there is not one single qualitative factor that may reduce or prevent loneliness. On the contrary, all qualitative social network factors should be taken into account. We showed in our study that a broad set of factors was associated with loneliness. However, the importance of these factors may differ between individuals according to, for example age. We found that frequency of contact with friends was more strongly associated with loneliness among young adults compared to older adults. This may reflect the differences in relationships that are important to a person across the different life phases. For example, a broad social network may be important for young adults, while a smaller network with more close ties may be important for older adults.

Given the correlational nature of your study, it would not therefore be possible to determine a directionality between perceived loneliness and the factors you explored. Therefore, do you believe that interventions aimed at reducing the perceived loneliness could – at the same time – enhance the perceived quality of life and the factors you investigated? If so, which factors do you think would be better improved, in your opinion?

Individuals who feel lonely may perceive a lower quality of life. Therefore, interventions aiming to reduce loneliness may be effective in improving quality of life as well. Furthermore, interventions targeting the factors associated with loneliness may have the same effect: positively influencing the factors associated with loneliness and thereby reducing loneliness. For example, group-based physical activity interventions may not online improve health but may also reduce loneliness. On top of that, if feelings of loneliness are reduced and health is improved, this may contribute to a better quality of life as well.

In your paper, it is explained that ethnicity plays a role in the perception of loneliness. What kind of approach do you think would be more efficient to counter loneliness, when considering this factor? Would you suggest an approach based on cultural integration or one based on the formation of ethnical groups that work as a support network?

In our research paper we suggest that intervention should be developed for specific age groups. In line with this, interventions based on cultural integration may be effective for young adults, while for older adults the ethnical groups may be effective to prevent/reduce loneliness. As mentioned before, frequency of contact with friends is an important factor in relation to loneliness. Therefore, interventions based on cultural integration may help broaden and diversify the social network of young adults. In contrast to this, older migrants miss their country of origin, especially their family, more compared to younger migrants (Ciabuna, Fokkema & Nedelcu, 2016). In our study we also showed that the association between frequency of family contact and loneliness was stronger among older adults compared to young adults. Therefore, formation of ethnical groups could be effective for older adults as it provides opportunities to share memories about the country of origin.

On the basis of your results in the present study, which ones do you think could be the potential implications for loneliness management in the clinical-therapeutic practice? More specifically, how could it be adapted to the different age groups? And what kind of possible social and political interventions could be derived from these results?

We suggest, based on the results of our study, that interventions to counter loneliness should be adapted to the factors that are relevant for a specific age group. There is no one-size-fits- all approach. Awareness of these age-specific factors is a first starting point in choosing any approach to counter loneliness. This should be followed by an assessment of factors at individual level or among specific age groups, preferably by means of one-on-one conversations, to find out which factors are most relevant. This information can then be used to tailor the intervention to these factors and/or to choose appropriate implementation strategies.

Research and methodology

Photo by Steve Buissinne

A common problem in cross-sectional studies is the difference between the life experiences for the compared age groups. For example, the educational environment in which young adults get their education today is quite different from the one where elder people got their own. How important do you think these differences between life experiences in the three age groups are in influencing your research results? And in which ways was this influence shown?

In our study we did not investigate period or cohort effects on loneliness. Therefore, it is hard to say whether differences between life experiences have influenced our results. However, societal changes may influence feelings of loneliness, but every age cohort has its own difficulties. For example, young adults today experience social pressure (i.e., by social media) and stress as they pursue personal (e.g., having many friends), educational, or career goals. While 20th-century young adults had to deal with the pressure to find a partner and start a family. These differences in life experiences may mediate the factors associated with loneliness across age groups.

In your paper, a trend that negatively correlates age and psychological distress (e.g. the risk of depression) to the loneliness perception is shown. The more people get old, the less the psychological distress makes them feel lonely. How would you explain these results?

We mention that psychological distress is a factor associated with loneliness across all three age groups, because the magnitude of the association was nearly similar across the age groups.

COVID-19 and loneliness

Tablet lockdown - Solitudine loneliness
Photo by Elena Mozhvilo

Is there any plan to continue these studies by including a longitudinal analysis? If so, which variables and questions do you think it would be particularly interesting to examine, for such a development?

At the moment there is no plan to continue this study with longitudinal analysis. However, we are exploring if there is a possibility to perform a study to investigate the impact of the current COVID-19 pandemic on feelings of loneliness.

In the light of the recent developments related to the COVID-19 lockdown, how important do you think that the “new technologies and the ability to use them” factor has been in determining the loneliness perception for the different age groups? In which ways? Do you think this has been true even before the lockdown? Could it be true for the future as well?

What we have learned as a community from the COVID-19 lockdown is how important new technologies and the ability to use them are in staying in touch with friends, family, colleagues, etc. when face-to-face contact is impossible. We think that the young adults were more familiar with these new technologies before the lockdown than the older age groups and therefore were more inclined to use them. On the other hand, not being able to socialize with friends may have impacted young adults more than the older age groups, despite the use of technologies. Thus, new technologies and the ability to use them may certainly impact the loneliness perception although research is needed to study the exact impact.


  • Franssen, T., Stijnen, M., Hamers, F., & Schneider, F. (2020). Age differences in demographic, social and health-related factors associated with loneliness across the adult life span (19–65 years): a cross-sectional study in the Netherlands. BMC Public Health, 20(1). doi: 10.1186/s12889-020-09208-0
  • Galanaki, E., & Vassilopoulou, H. (2007). Teachers and children’s loneliness: A review of the literature and educational implications. European Journal of Psychology of Education, 22(4), 455-475. Retrieved November 3, 2020, from
  • Hawkley, L., & Cacioppo, J. (2010). Loneliness Matters: A Theoretical and Empirical Review of Consequences and Mechanisms. Annals Of Behavioral Medicine, 40(2), 218-227. doi: 10.1007/s12160-010-9210-8
  • Heinrich, L., & Gullone, E. (2006). The clinical significance of loneliness: A literature review. Clinical Psychology Review, 26(6), 695-718. doi: 10.1016/j.cpr.2006.04.002
  • Holt-Lunstad, J., Smith, T., Baker, M., Harris, T., & Stephenson, D. (2015). Loneliness and Social Isolation as Risk Factors for Mortality. Perspectives On Psychological Science, 10(2), 227-237. doi: 10.1177/1745691614568352
  • Linehan, T., Bottery, S., Kaye, A., Millar, L., Sinclair, D., & Watson, J. (2014). 2030 vision: The best and worst futures for older people in the UK. London, England: Independent Age and International Longevity Centre-UK.
  • Pinquart, M., & Sorensen, S. (2001). Influences on Loneliness in Older Adults: A Meta-Analysis. Basic And Applied Social Psychology, 23(4), 245-266. doi: 10.1207/s15324834basp2304_2

Traffic density, wind and air stratification influence concentrations of air pollutant NO2

Leipzig researchers use a calculation method to remove weather influences from air pollution data

traffic air pollutant nitrogen dioxide COVID-19
Traffic density, wind and air stratification influence the pollution with the air pollutant nitrogen dioxide, according to the conclusion of a TROPOS study commissioned by the LfULG. Credits: Burkhard Lehmann, LfULG

Leipzig/Dresden. In connection with the effects of the COVID-19 pandemic, satellite measurements made headlines showing how much the air pollutant nitrogen dioxide (NO2) had decreased in China and northern Italy.  In Germany, traffic density is the most important factor. However, weather also has an influence on NO2 concentrations, according to a study by the Leibniz Institute for Tropospheric Research (TROPOS), which evaluated the influence of weather conditions on nitrogen dioxide concentrations in Saxony 2015 to 2018 on behalf of the Saxon State Office for Environment, Agriculture and Geology (LfULG). It was shown that wind speed and the height of the lowest air layer are the most important factors that determine how much pollutants can accumulate locally.

In order to determine the influence of various weather factors on air quality, the team used a statistical method that allows meteorological fluctuations to be mathematically removed from long-term measurements. The air quality fluctuates, in some cases very strongly, due to different emissions and the influence of the weather. Until now, however, it has been difficult to estimate, what share legal measures such as low emission zones or diesel driving bans have and what share the weather influences have in the actual air quality? With the method used, this will be easier in the future.

Nitrogen dioxide (NO2) is an irritant gas which attacks the mucous membrane of the respiratory tract, causes inflammatory reactions as an oxidant and increases the effect of other air pollutants. As a precursor substance, it can also contribute to the formation of particulate matter. Limit values have been set in the EU to protect the population: For nitrogen dioxide, an annual average value of 40 micrograms per cubic metre of air applies (μg/m³). To protect the health of the population, measures must be taken if these limit values are not complied with. In 2018/2019, for example, various measures were taken in Germany, ranging from a reduction in the number of lanes (e.g. in Leipzig) to driving bans for older diesel vehicles (e.g. in Stuttgart).

To evaluate the effectiveness of such measures, it would be helpful to determine the exact influence of weather conditions. The Saxon State Office for Environment, Agriculture and Geology (LfULG) therefore commissioned TROPOS to carry out a study on the influence of weather factors on NO2 concentrations and provided its measurement data from the Saxon air quality measurement network and meteorological data for this purpose. The researchers were thus able to evaluate data from 29 stations in Saxony over a period of four years, which represent a cross-section of air pollution – from stations at traffic centres to urban and rural background stations and stations on the ridge of the Erzgebirge mountains. They also calculated the height of the lowest layer in the atmosphere and incorporated data from traffic counting stations in Leipzig and Dresden into the study. A method from the field of machine learning was used for the statistical modelling, the application of which in the field of air quality was first published by British researchers in 2009.

In this way, the study was able to demonstrate that the traffic density at all traffic stations is most significantly responsible for nitrogen oxide concentrations. However, two weather parameters also have a significant influence on nitrogen dioxide concentrations: wind speed and the height of the so-called mixing layer. The latter is a meteorological parameter that indicates the height to which the lowest layer of air, where the emissions mix, extends. “It was also shown that high humidity can also reduce the concentration of nitrogen dioxide, which could be due to the fact that the pollutants deposit more strongly on moist surfaces. However, the exact causes are still unclear,” says Dominik van Pinxteren.

The statistical analysis has also enabled the researchers to remove the influence of the weather from the time series of pollutant concentrations: Adjusted for the weather, the concentration of nitrogen oxides (NOx) decreased by a total of 10 micrograms per cubic meter between 2015 and 2018 on average over all traffic stations in Saxony. In urban and rural areas and on the ridge of the Erzgebirge, however, NOx concentrations tend to remain at the same level. Even though there have been some improvements in air quality in recent years, there are good scientific arguments for further reducing air pollution.

In a way, this also applies to premature conclusions from the corona crisis: in order to find out how strong the influence of the initial restrictions on air quality actually was, the influence of the weather would have to be statistically removed in a longer series of measurements. To this end, investigations for the Leipzig area are currently underway at TROPOS, as is a Europe-wide study of the EU research infrastructure for short-lived atmospheric constituents such as aerosol, clouds and trace gases (ACTRIS), the German contribution to which is coordinated by TROPOS.


Dominik van Pinxteren, Sebastian Düsing, Alfred Wiedensohler, Hartmut Herrmann (2020): Meteorological influences on nitrogen dioxide: Influence of weather conditions and weathering on nitrogen dioxide concentrations in outdoor air 2015 to 2018. Series of publications of the LfULG, issue 2/2020 (in German only)
This study was commissioned by the State Office for Environment, Agriculture and Geology (LfULG).


LfULG-Projekt „Meteorologische Einflüsse auf Stickstoffdioxid“:


Press release on traffic density, wind and air stratification influence concentrations of air pollutant NO2 by Tilo Arnhold from the Leibniz Institute for Tropospheric Research (TROPOS)

Addressing the infodemic around the COVID 19 pandemic, decision-making simulation game wins first ComplexityJam

Addressing the topic of an onslaught of conflicting information and fake news in connection to the coronavirus pandemic, ComplexityJam #survivetheinfodemic challenged participants to represent he complexity of the situation through games and interactive digital narratives, in an online international game jam event coordinated by INDCOR EU COST Action and MOME University, which ended on June 13 with a virtual award ceremony.

The main award went to “Temp in Charge”.

The ComplexityJam international online game developing competition was initiated by the INDCOR COST Action, which stands for Interactive Digital Narratives for Complexity Representations. The INDCOR project was launched on May 29 with almost 80 participants attending from 12 different countries, including the US, the UK, Sweden, The Netherlands, Hungary, and Turkey. 11 entries were developed before the deadline, June 5. The resulting works addressed issues of social distancing, information overload, fake news identification, successful collaboration and the responsible decision-making during the pandemic. The main task was to provide orientation during the pandemic and provide an outlet for playful creativity through the creation of complex representations.
ComplexityJam infodemic pandemic

The winners were selected by a five-member International jury of acclaimed scholars and award-winning professionals: Janet Murray (Professor and Associate Dean for Research and Faculty Affairs, Georgia Institute of Technology, US), Lindsay Grace (Professor and Knight Chair for Interactive Media, University of Miami, US), Szabolcs Józsa (Founder, Nemesys Games, HU), Odile Limpach (ProfessorCologne Game Lab, DE) and Simon Meek (Creative Director, The Secret Experiment, BAFTA winner, UK).

  1. “Temp in Charge” wins the ComplexityJam main award The president contracted pneumonia and you are his temporary stand-in for just one week. You must make decisions about the current pandemic and economic situation. There is no need to panic when you have the EasyGuv 6000 application at hand by which running a government becomes an easy task. Find solutions to your problems with just a few clicks.

Team: Resul Alıcı (Bahcesehir University Game Design graduate and Unico Studio game designer), Burak Karakas (Bahcesehir University).
The jury found this work to offer the most complete experience. It directly addresses the question of difficult decisions based on competing pieces of information. “Temp in Charge” makes us aware of the complexity of political decision-making via a friendly, easy-to use interface.

  1. “Trial Day” wins Runner-up Award for development Trial Day is a game about information overload in the age of a pandemic, of post-truth and fake news. You are an aspiring journalist. Welcome to your new job’s trial day! Your ultimate goal? Play their game as best as you can and identify which news pieces to trust! But be aware: your choices and behavior are being monitored!

Team: Eren Çaylak, Sid Chou, Glenn Curtis, Yiting Liu, Dimitra Mavrogonatou, Kirstin McLellan. (This team was assembled by the ComplexityJam organizers and included participants from New York University, Turkey, Greece, and Glasgow School of Art)
The jury particularly liked the trial aspect and its rapid-fired approach that challenges the interactor to make quick decisions. The simple, yet effective graphic depiction of the trial elements adds considerably to the experience.

  1. “Essential workers” wins Special Award “the most potential for further development” Workers is a cooperative online multiplayer game about a community working together to overcome the COVID-19 pandemic. Players must balance their personal safety against the necessities of the community. If anyone loses, everyone loses.

Team: Aditya Anupam, Jordan Graves, Marian Dominquez Mirazo, Colin Stricklin, Kevin Tang, Michael Vogel (all Georgia Institute of Technology, USA)
The jury was impressed by this entry and how it translates an underlying scientific model into accessible game play. In addition, it raises awareness of “essential workers” – people in important jobs who are too often underpaid and underappreciated.

  1. Honorary mentions: RAWRER, the Cretacian version of an imagined dinosaur version of Twitter, is a game where the dinosaur community circulates news about the ongoing Volcano crisis and tries to spread the word on how they should best address the situation:

Team: Olga Chatzifoti (Glasgow Schol of Art), Christina Chrysanthopoulou (Game Developer)
According to the Jury this entry addresses the infodemic via a fantasy world, in which a population of dinosaurs discussing the severity of an impending threat in a manner analogous to the discussion around the COVID-19 pandemic. The developers created an impressive and detailed system for the interactor to explore.

  1. Rabid is a point and click adventure game where, as a mayor, you need to make decisions that will influence the lives of the anthropomorphic animals living in your town. You can decide which information to rely on, which to investigate further, but the issues you have to face might not be black and white, and sometimes you need to pick priorities or the lesser evil.

Team: Ágnes Fábián, Viktória Fehér, Ádám Kovács, Rebeka Kovács, Miklós Levente Papp, Noémi Rózsa, Eszter Szabó-Zichy
According to the Jury this experience was created with much love for detail and description. The interactor experiences the complexity of decision-making in a friendly environment that could also work for younger audiences.

All games are available at:
The event was supported by the COST Action INDCOR, COST – European Cooperation in Science and Technology (,, MOME – Moholy-Nagy Univesriyt of art and Design, National Research, Development and Innovation Office, Hungary (

Press release. INDCOR (1, 2)

Scientists identify a temperature tipping point for tropical forests

point tropical forests
An aerial view of a tropical forest along the eastern Pacific Ocean shoreline of Barro Colorado Island, Panama. Credit: Smithsonian Tropical Research Institute photo

A study in Science by 225 researchers working with data from 590 forest sites around the world concludes that tropical forests release much more carbon into the atmosphere at high temperatures.

All living things have tipping points: points of no return, beyond which they cannot thrive. A new report in Science shows that maximum daily temperatures above 32.2 degrees Celsius (about 90 degrees Fahrenheit) cause tropical forests to lose stored carbon more quickly. To prevent this escape of carbon into the atmosphere, the authors, including three scientists affiliated with the Smithsonian Tropical Research Institute in Panama, recommend immediate steps to conserve tropical forests and stabilize the climate.

Carbon dioxide is an important greenhouse gas, released as we burn fossil fuels. It is absorbed by trees as they grow and stored as wood. When trees get too hot and dry they may close the pores in their leaves to save water, but that also prevents them from taking in more carbon. And when trees die, they release stored carbon back into the atmosphere.

Tropical forests hold about 40 percent of all the carbon stored by land plants. For this study, researchers measured the ability of tropical forests in different sites to store carbon.

“Tropical forests grow across a wide range of climate conditions,” said Stuart Davies, director of Smithsonian ForestGEO, a worldwide network of 70 forest study sites in 27 countries. “By examining forests across the tropics, we can assess their resilience and responses to changes in global temperatures. Many other studies explored how individual forests respond to short-term climatic fluctuations. This study takes a novel approach by exploring the implications of thermal conditions currently experienced by all tropical forests.”

By comparing carbon storage in trees at almost 600 sites around the world that are part of several different forest monitoring initiatives: RAINFORAfriTRONT-FORCES and the Smithsonian’s ForestGEO, the huge research team led by Martin Sullivan from the University of Leeds and Manchester Metropolitan University found major differences in the amount of carbon stored by tropical forests in South America, Africa, Asia and Australia. South American forests store less carbon than forests in the Old World, perhaps due to evolutionary differences in which tree species are growing there.

They also found that the two most important factors predicting how much carbon is lost by forests are the maximum daily temperature and the amount of precipitation during the driest times of the year.

As temperatures reach 32.2 degrees Celsius, carbon is released much faster. Trees can deal with increases in the minimum nighttime temperature (a global warming phenomenon observed at some sites), but not with increases in maximum daytime temperature.

They predict that South American forests will be the most affected by global warming because temperatures there are already higher than on other continents and the projections for future warming are also highest for this region. Increasing carbon in the atmosphere may counterbalance some of this loss but would also exacerbate warming.

Forests can adapt to warming temperatures, but it takes time. Tree species that cannot take the heat die and are gradually replaced by more heat-tolerant species. But that may take several human generations.

“This study highlights the importance of protecting tropical forests and stabilizing the Earth’s climate,” said Jefferson Hall, co-author and director of the Smithsonian’s Agua Salud Project in Panama. “One important tool will be to find novel ways to restore degraded land, like planting tree species that help make tropical forests more resilient to the realities of the 21st century.” The Agua Salud project asks how native tree species adapted to an area can be used to manage water, store carbon and promote biodiversity conservation at a critical point where North and South America connect.

An aerial view of a tropical forest on the eastern Pacific Ocean shoreline of Barro Colorado Island, Panama. Credit: Smithsonian Tropical Research Institute photo
A relevant note:

One of the oldest permanent tropical forest study sites, located on Barro Colorado Island in Panama, is not being monitored for the first time in 40 years as a result of the COVID-19 pandemic, giving scientists less of a handle on any climate change effects that may be taking place.

Steve Paton, director of STRI’s physical monitoring program notes that in 2019 there were 32 days with maximum temperatures over 32 degrees Celsius at a weather station in the forest canopy on the Island and a first glance at his data indicates that these exceptionally hot days are becoming more common.

The Smithsonian Tropical Research Institute, headquartered in Panama City, Panama, is a unit of the Smithsonian Institution. The Institute furthers the understanding of tropical biodiversity and its importance to human welfare, trains students to conduct research in the tropics and promotes conservation by increasing public awareness of the beauty and importance of tropical ecosystems.

The paper Long-term thermal sensitivity of Earth’s tropical forests is published in Science 22 May 2020 (DOI: 10.1126/science.aaw7578)


Press release from the Smithsonian Tropical Research Institute

A roadmap for effective treatment of COVID-19

Study outlines key immunological factors underlying COVID-19 disease progression and proposes a range of drugs that may be repurposed to treat the disease

Picture by Steve Buissinne

Due to the devastating worldwide impact of COVID-19, the illness caused by the SARS-CoV-2 virus, there has been unprecedented efforts by clinicians and researchers from around the world to quickly develop safe and effective treatments and vaccines. Given that COVID-19 is a complex new disease with no existing vaccine or specific treatment, much effort is being made to investigate the repurposing of approved and available drugs, as well as those under development.

In Frontiers in Immunology, a team of researchers from the U.S. Food and Drug Administration review all of the COVID-19 clinical and research findings to date. They provide a breakdown of key immunological factors underlying the clinical stages of COVID-19 illness that could potentially be targeted by existing therapeutic drugs.

Dr. Montserrat Puig of the U.S. Food and Drug Administration, senior author of the review, stated that “there are multiple factors involved in determining if the patient’s immune response will be insufficient or successful in combating the infection. Our review is an overview of these factors and how they can be considered to define the context in which medications currently used for other diseases, or development of novel agents, can be utilized to prevent, ameliorate or cure COVID-19.”

We know that during the early stage of COVID-19 people can show no symptoms or mild symptoms, and for many the disease resolves.

For others it can be catastrophic. The illness can progress to a severe stage with manifestations including Acute Respiratory Distress Syndrome, accompanied by severe lung inflammation and damage. Patients with severe COVID-19 are often admitted to intensive care units and require life support with medical ventilation.

This review compiles and summarizes published up-to-date studies unraveling the factors leading to the cytokine storm and its consequences observed in COVID-19, including the immunological events underlying the severe manifestation of the disease.

The analysis is further supplemented with knowledge previously acquired from other coronaviruses including SARS-CoV and MERS-CoV.

The authors underscore key immunological events that might tip the balance from a protective to a hyperinflammatory response leading to life-threatening conditions. They outline a promising list of currently available drugs that are either under study or under consideration for use in COVID-19 based on their potential to influence these key immunological events.

These drugs include those that could inhibit SARS-CoV-2 entry into host cells, antivirals with the potential to block SARS-CoV-2 replication or factors that could boost the antiviral response, monoclonal antibodies targeting pro-inflammatory cytokines that drive the hyperinflammatory response and therapeutics that could improve the function of the lungs.

Puig states that “approaches to therapy in the early stage of the disease will differ from those in its severe late stage.” Adding that “as the results of clinical trials become available, it may become increasingly clear that there is likely no single magic bullet to resolve the disease but a combination of several interventions that target different key factors of COVID-19 may well be required.”

Puig cautions that “the research and data obtained from COVID-19 studies are rapidly evolving and continuously updated. Thus, as clearly stated in our review, the information provided is a ‘lessons learned’ to date and describes the knowledge available at the time of the publication of the review.”

The description of the immunological profile of the clinical stages of COVID-19 provided in this review will enable more informed decisions about the type and timing of treatments to be evaluated in clinical trials.

Puig explains that “our hope is that the information contained in our review will help professionals in COVID-19 research develop new tools and agents to better treat those at high risk of severe COVID-19.”


Press release on the roadmap for the COVID-19 treatment from Frontiers

Predicted versus observed epidemic curves over time. (copyright: Nature) Our model aggregates population outflow from Wuhan from January 1 to 24, 2020 to provide a reference growth pattern (i.e. epidemic curves) for COVID-19’s spread. Differences in the predicted and confirmed growth in confirmed cases can signal higher levels of COVID-19 community transmission.

An international research team led by the University of Hong Kong (HKU) developed a new method to accurately track the spread of COVID-19 using population flow data, and establishing a new risk assessment model to identify high-risk locales of COVID-19 at an early stage, which serves as a valuable toolkit to public health experts and policy makers in implementing infectious disease control during new outbreaks.  The study findings have been published in the journal Nature today (April 29).

Dr. Jayson Jia, Associate Professor of Marketing at the Faculty of Business and Economics of HKU and lead author of the study, and his co-authors used nation-wide data provided by a major national carrier in China to track population movement out of Wuhan between 1 January and 24 January 2020, a period covering the annual Chunyun mass migration before the Chinese Lunar New Year to a lockdown of the city to contain the virus. The movement of over 11 million people travelling through Wuhan to 296 prefectures in 31 provinces and regions in China were tracked.

Differing from usual epidemiological models that rely on historical data or assumptions, the team used real-time data about actual movements focusing on aggregate population flow rather than individual tracking. The data include any mobile phone user who had spent at least 2 hours in Wuhan during the study period.  Locations were detected once users had their phones on. As only aggregate data was used and no individual data was used, there was no threat to consumer privacy.

Combining the population flow data with the number and location of COVID-19 confirmed cases up to 19 February 2020 in China, Dr Jia’s team showed that the relative quantity of human movement from the disease epicentre, in this case, Wuhan, directly predicted the relative frequency and geographic distribution of the number of COVID-19 cases across China. The researchers found that their model can explain 96% of the distribution and intensity of the spread of COVID-19 across China statistically.

COVID-19 big data
Illustrative example of using model to track COVID-19 community spread risk. (copyright: Nature) Our model uses population movement to predict expected cases. The predicted spread of the SARS-CoV-2 virus can be used as a benchmark to identify which locales are ‘outliers’, which have significantly more or less cases than expected (given the movement data). The graph is an illustration of what our model showed on January 29. Prefectures to the left of the dashed line are outliers that have significantly more than expected cases, i.e., a higher level of unexplained or community transmission. Our model identified Wenzhou as having the most severe community transmission risk on January 29, 2020. The government announced a full quarantine of the prefecture on February 2, 2020.

The research team then used this empirical relationship to build a new risk detection toolkit. Leveraging on the population flow data, the researchers created an “expected growth pattern” based on the number of people arriving from the risk source, i.e. the disease epicentre. The team thereby developed a new risk model by contrasting expected growth of cases against the actual number of confirmed cases for each city in China, the difference being the “community transmission risk”.

“If there are more reported cases than the model expected, there is a higher risk of community spread. If there are fewer reported cases than the model expected, it means that the city’s preventive measures are particularly effective or it can indicate that further investigation by central authorities is needed to eliminate possible risks from inaccurate measurement,” explained Dr Jia.

“What is innovative about our approach is that we use misprediction to assess the level of community risk.  Our model accurately tells us how many cases we should expect given travel data.  We contrast this against the confirmed cases using the logic that what cannot be explained by imported cases and primary transmissions should be community spread. ” He added.

The approach is advantageous because it requires no assumptions or knowledge of how or why the virus spreads, is robust to data reporting inaccuracies, and only requires knowledge of relative distribution of human movement. It can be used by policy makers in any nation with available data to make rapid and accurate risk assessments and to plan allocation of limited resources ahead of ongoing disease outbreaks.

“Our research indicates that geographic flow of people outperforms other measures such as population size, wealth or distance from the risk source to indicate the gravity of an outbreak.” said Dr Jia.

Dr Jia is currently exploring with fellow researchers the feasibility of applying this toolkit to other countries, and extending it to situations where there are multiple COVID-19 epicentres. The team is working with other national telecom carriers and seeking additional data partners.



The study’s co-authors are Jianmin Jia, Presidential Chair Professor at the Chinese University of Hong Kong, Shenzhen (corresponding author); Nicholas A. Christakis, Sterling Professor of Social and Natural Science at Yale; Xin Lu, the National University of Defense Technology in Changsha, China, and the Karolinska Institutet in Stockholm, Sweden; Yun Yuan, Southwest Jiaotong University; Ge Xu, Hunan University of Technology and Business.

Press release from The University of Hong Kong.

Researchers from the Hubrecht Institute in Utrecht, Erasmus MC University Medical Center Rotterdam, and Maastricht University in the Netherlands have found that the coronavirus SARS-CoV-2, which causes COVID-19, can infect cells of the intestine and multiply there. Using state-of-the-art cell culture models of the human intestine, the researchers have successfully propagated the virus in vitro, and monitored the response of the cells to the virus, providing a new cell culture model for the study of COVID-19. These findings could explain the observation that approximately one third of COVID-19 patients experience gastrointestinal symptoms such as diarrhea, and the fact that the virus often can be detected in stool samples. The results of this study were published in the scientific journal Science on the 1st of May 2020.

Patients with COVID-19 show a variety of symptoms associated with respiratory organs – such as coughing, sneezing, shortness of breath, and fever – and the disease is transmitted via tiny droplets that are spread mainly through coughing and sneezing. One third of the patients however also have gastrointestinal symptoms, such as nausea and diarrhea. In addition, the virus can be detected in human stool long after the respiratory symptoms have been resolved. This suggests that the virus can also spread via so-called “fecal-oral transmission”.

Though the respiratory and gastrointestinal organs may seem very different, there are some key similarities. A particularly interesting similarity is the presence of the ACE2 receptor, the receptor through which the COVID-19 causing SARS-CoV-2 virus can enter the cells. The inside of the intestine is loaded with ACE2 receptors. However, until now it was unknown whether intestinal cells could actually get infected and produce virus particles.

Intestinal organoids

COVID-19 intestine
Intestinal organoid infected with coronavirus SARS-CoV-2. The coronavirus is colored white, the organoids themselves are colored blue and green. Credits: Joep Beumer, copyright: Hubrecht Institute

Researchers from the Hubrecht Institute, Erasmus MC and Maastricht University set out to determine whether the SARS-CoV-2 virus can directly infect the cells of the intestine, and if so, whether it can replicate there as well. They used human intestinal organoids: tiny versions of the human intestine that can be grown in the lab. Hans Clevers (Hubrecht Institute): “These organoids contain the cells of the human intestinal lining, making them a compelling model to investigate infection by SARS-CoV-2.”

Infection of intestinal cells

Illustration of a villus in the intestine with a zoom-in to an electron microscopy image of coronavirus SARS-CoV-2 (dark circles) at the edge of an intestinal cell. Credits: Credit: Kèvin Knoops, Raimond Ravelli and Maaike de Backer, copyright: Maastricht University

When the researchers added the virus to the organoids, they were rapidly infected. The virus enters a subset of the cells in the intestinal organoids, and the number of cells that are infected increases over time. Using electron microscopy, an advanced way to visualize different components of the cell in great detail, the researchers found virus particles inside and outside the cells of the organoids. Peter Peters (Maastricht University): “Due to the lockdown, we all studied virtual slides of the infected organoids remotely from home.”

COVID-19 intestine
Intestinal organoids, the right one infected with coronavirus SARS-CoV-2. The coronavirus is colored white, the organoids themselves are colored blue and green. Credits Joep Beumer, copyright Hubrecht Institute

The researchers investigated the response of the intestinal cells to the virus with RNA sequencing, a method to study which genes are active in the cells. This revealed that so-called interferon stimulated genes are activated. These genes are known to combat viral infection. Future work will focus on these genes more carefully, and on how they could be used to develop new treatments.

The researchers also cultured the organoids in different conditions that result in cells with higher and lower levels of the ACE2 receptor, through which SARS-CoV-2 can enter the cells. To their surprise, they found that the virus infected cells with both high and low levels of the ACE2 receptor. Ultimately, these studies may lead to new ways to block the entry of the virus into our cells.


Bart Haagmans (Erasmus MC): “The observations made in this study provide definite proof that SARS-CoV-2 can multiply in cells of the gastrointestinal tract. However, we don’t yet know whether SARS-CoV-2, present in the intestines of COVID-19 patients, plays a significant role in transmission. Our findings indicate that we should look into this possibility more closely.” The current study is in line with other recent studies that identified gastrointestinal symptoms in a large fraction of COVID-19 patients and virus in the stool of patients free of respiratory symptoms. Special attention may be needed for those patients with gastrointestinal symptoms. More extensive testing using not only nose and throat swabs, but also rectal swabs or stool samples may thus be needed.

In the meantime, the researchers are continuing their collaboration to learn more about COVID-19. They are studying the differences between infections in the lung and the intestine by comparing lung and intestinal organoids infected with SARS-CoV-2.



SARS-CoV-2 productively Infects Human Gut Enterocytes. Mart M. Lamers*, Joep Beumer*, Jelte van der Vaart*, Kèvin Knoops, Jens Puschhof, Tim I. Breugem, Raimond B.G. Ravelli, J. Paul van Schayck, Anna Z. Mykytyn, Hans Q. Duimel, Elly van Donselaar, Samra Riesebosch, Helma J.H. Kuijpers, Debby Schipper, Willine J. van de Wetering, Miranda de Graaf, Marion Koopmans, Edwin Cuppen, Peter J. Peters, Bart L. Haagmans† and Hans Clevers†. Science 2020. DOI * Equal contribution, † equal contribution.

This study was a collaboration between the Hubrecht Institute in Utrecht, the Erasmus MC University Medical Center Rotterdam, Maastricht University, the UMC Utrecht and Single Cell Discoveries in the Netherlands. The microscopy data are publicly available via the Image Data Resource (idr0083, – with help from the University of Dundee and the European Bioinformatics Institute) and the genomic data are publicly available via the Gene Expression Omnibus (GSE149312,, to ensure efficient sharing of data related to COVID-19 between researchers all across the world.