Objectives: Acceptance and high uptake of COVID-19 vaccines continues to be critical for controlling the COVID-19 pandemic. This narrative review aimed to summarise findings on factors influencing acceptance of COVID-19 vaccines in the period leading up to the approval and rollout.Methods: We conducted a narrative review of literature published in 2020 on factors influencing acceptance of hypothetical COVID-19 vaccines in adults in high income countries with well-established health systems.Results: Facilitators of acceptance included confidence in vaccine safety and effectiveness, high COVID-19 disease risk perception and trust in health authorities and other vaccine stakeholders, including government. Barriers included safety and effectiveness concerns, perceived scientific uncertainty, low disease risk perception, and low trust in authorities and other stakeholders.Conclusion: Evidence on facilitators and barriers to COVID-19 vaccine acceptance, at a time prior to vaccine rollout, can help health authorities address hesitancy and may inform approaches to support acceptance of novel pandemic vaccines in the future. Future research should include in-depth qualitative research to gather more nuanced evidence. Uptake of COVID-19 vaccines continues to be critical for controlling the COVID-19 pandemic and returning society to normal functioning . AcceptaAs with other vaccines, various factors have potential to affect COVID-19 vaccine acceptance and uptake, including perceptions of safety and effectiveness, perceptions of disease risk, social norms, motivational factors, misinformation, and practical factors , 6. WhilIn light of the above, the aim of this narrative review was to explore themes relating to factors influencing acceptance of COVID-19 vaccines in the period leading up to approval and rollout of the vaccines. We focused on acceptance in adults in high income countries with well-established health systems, including the United States, United Kingdom, Australia, New Zealand, Canada, and European countries. The purpose of the review was to reflect on how this summary of evidence can inform health authority responses, in particular communications, to support acceptance of COVID-19 vaccines.An experienced medical librarian conducted a series of database searches designed to identify literature on COVID-19 vaccine knowledge, misinformation, attitudes and practices among adults, including sub populations such as healthcare workers (HCWs). A series of searches were developed in OVID Medline and adapted for OVID PsycINFO. These databases were chosen to provide a complementary mix of both the broad biomedical literature  as indexed by Medline and more specific psychological literature as included in PsycINFO. Database-specific controlled vocabulary terms including “Coronavirus,” “Coronavirus Infections,” “Vaccines,” and “Health Knowledge, Attitudes, Practice” were used in combination with relevant text words, including specific terms for COVID-19 and SARS-COV-2 and terms representing concepts related to attitudes and vaccine misinformation and vaccine uptake. The searches were conducted between 22 November and December 22, 2020. The Medline search strategies used to underpin this narrative review are available in the Although the primary focus was on research published in peer-reviewed scientific journals, we also reviewed grey literature identified via the reference lists of articles retrieved through the database searches, as well as relevant research published on preprint servers. We included these types of studies in our search due to the urgency of using research findings to better respond to the COVID-19 pandemic.• empirical research• publication date between January 1, 2020 to December 22, 2020• full-text article available in English• adult study subjects• study conducted in high income countries with well-established health systemsWe included items meeting the following criteria in the review:We excluded studies in populations in non-comparable countries with different social, cultural and healthcare contexts, as well as studies that focused on aspects of COVID-19 vaccination not related to acceptance.Two members of the research team screened 325 titles and abstracts from the initial search and 16 articles and reports identified through other sources, including six preprint articles and 10 grey literature, against the inclusion and exclusion criteria. After screening and removing duplicates, we retrieved 42 papers and reports for a full text review. The final analysis included 27 studies, including 20 articles (including three preprint articles) and seven grey literature reports see .We intended the review to be primarily descriptive in nature. We extracted data from the articles and summarised the following variables and findings in tabular form using Microsoft Excel: setting (country), study design, population, sample size, month of data collection, as well as sociodemographic characteristics associated with, facilitators of, and barriers to COVID-19 vaccine acceptance. Because vaccine acceptance is described in different ways, we used a range of measures and terminology to indicate vaccine acceptance, including willingness, likelihood or intention to vaccinate; acceptance, confidence and hesitancy, and agreement with positive statements about COVID-19 vaccines.We describe included studies and their characteristics in n = 19) of studies focused on general adult participants. In terms of subgroups, two studies focused specifically on parents [The majority  of articles collected data using online cross-sectional surveys. Other study methods included a combination of survey and qualitative in-depth interviews [The majority  collected data in the second quarter of 2020 (April–June).• four were collected in the first quarter of 2020 (January–March) , 15, 17;• 13 were collected in the second quarter of 2020 (April–June) –9, 18–27• five were collected in the third quarter of 2020 (July–September) , 28–31;• five were collected in the fourth quarter of 2020 (October-December) , 32, 33.The timing of data collection ranged from February 2020 to December 2020. Most articles  , 17, 26;• female gender  , 22, 26;• having a lower household income or socioeconomic status  , 8, 31;• having a lower health literacy or education level  , 26, 31;• living in a rural area (United States) .Various studies found the following socio-demographic characteristics to be significantly associated with lower acceptance of COVID-19 vaccines:• age 55 or older (multiple countries) , 23, 31;• male gender  , 27, 31;• having a chronic health condition  ;• holding private health insurance  ;• having a liberal political leaning (United States) , 28, 33;• having had a previous influenza vaccination or intending to get a future influenza vaccination, among both healthcare workers (Israel)  and adul• among healthcare workers, being a doctor/physician (as opposed to a nurse or paramedic)  –14.Various studies found the following socio-demographic characteristics to be significantly associated with higher acceptance of COVID-19 vaccines:Included articles suggested seven factors acting as potential barriers to COVID-19 vaccine acceptance. We describe these below.Vaccine safety concerns were commonly reported as a barrier to COVID-19 vaccine acceptance, including among adults  , 30, 32,p < 0.001) [For example, an online survey of 10,093 US adults found that more than three-quarters of respondents were concerned that approval processes were moving too fast (78%) and that COVID-19 vaccines would be approved before their safety was fully understood (77%) . SeveralDoubts about how well the vaccine would work in trials (efficacy) and in practice (effectiveness), and how long immunity from the vaccine would last, were also reported as a potential barrier to acceptance of COVID-19 vaccines among adults  , parentsIn a study of 609 healthcare workers conducted in September-October 2020 in California, United States, respondents cited the perceived evolving and uncertain science around COVID-19 vaccines as a reason for wanting to delay receiving a COVID-19 vaccine . The surLow perceived risk of developing severe COVID-19 disease was identified as a barrier to acceptance of COVID-19 vaccines among Australian parents, American and Israeli adults, and Israeli healthcare workers , 12, 21.For example, in a survey of 2,108 Australian parents, conducted in June 2020, 27% of participants who were unsure or unwilling to accept a COVID-19 vaccine did not believe a COVID-19 vaccine was necessary .Perceived exaggeration of the threat posed by the COVID-19 pandemic by health authorities or the media was identified by several studies as a barrier to acceptance of COVID-19 vaccines  , 25. ForSubscribing to misinformation or conspiracy theories was identified as a barrier to COVID-19 vaccine acceptance among adults in several countries , 27. In p < 0.001) [A lack of trust in health authorities and suspicion about the motives of other stakeholders involved in vaccine development, such as pharmaceutical companies, was identified as a barrier to accepting COVID-19 vaccines in several studies  , 19, 26.Included articles suggested five factors acting as facilitators of COVID-19 vaccine acceptance. We describe these below.High perceived risk of developing severe disease was identified as facilitating COVID-19 vaccine acceptance among adults  , 20, 33 For example, an online survey of 527 older United Kingdom adults and people with chronic respiratory disease found that fears about the potential severity of COVID-19 disease on personal health and fears of dying from COVID-19 facilitated intention to receive a COVID-19 vaccine . In termConfidence in COVID-19 vaccine safety and the vaccines’ ability to offer protection, including longer duration of protection and low instances of side effects, were identified as facilitators of COVID-19 vaccine acceptance in adults  , 29. ForTrust in vaccine development processes and scientists was found to facilitate COVID-19 vaccine acceptance among adults  , 33. AduTrust and confidence in government or health systems was found to be associated with positive COVID-19 vaccine intentions , 31. ForA US-based study of 2,006 adults found participants were more likely to accept COVID-19 vaccines if they thought their healthcare provider would recommend them . A surveThis narrative review of 27 articles and reports explores themes relating to factors influencing acceptance of COVID-19 vaccines in the period leading up to the approval and rollout of the vaccines. Many studies identified concerns about safety and effectiveness as factors influencing COVID-19 vaccine acceptance. These findings are in line with previous findings on other vaccines , 34–36. Several studies identified low disease risk perception as a barrier to COVID-19 vaccine acceptance. We hypothesise that this barrier may be relevant in countries where COVID-19 has been politicised, for example the US, or in countries like Australia where the pandemic was well contained for an extended period of time. In contrast, several studies found that high perceived risk of developing COVID-19 disease facilitated COVID-19 vaccine acceptance. Similarly, perception of disease risk has been shown to play a role in motivating people to vaccinate against influenza .Several studies reported trust—in health authorities, in governments, in scientists and the vaccine development process—as a facilitator of COVID-19 vaccine acceptance. Given that uncertainty, exacerbated by rapidly changing public health recommendations, may have characterised many people’s experience of the COVID-19 pandemic more broadly, engendering public trust in public health experts who address uncertainty about vaccines may be particularly important. Some studies found that healthcare provider recommendations were a facilitator of COVID-19 vaccine acceptance; trust may in part explain this finding. In studies of acceptance of routine vaccinations, trust in healthcare providers has been found to support vaccine confidence and acceptance, while primary healthcare providers are consistently found to be the most trusted source of information on routine vaccinations including influenza .Findings indicate that, at the time of this review, COVID-19 vaccines had not elicited any new types of concerns around vaccine acceptance, with barriers and facilitators presenting in a similar way as for other already established vaccines , 41. ThiThe purpose of this review was to explore themes describing factors influencing COVID-19 vaccine acceptance, and to reflect on how this evidence can inform health authority responses, especially communications. This is in keeping with risk communication literature, which recommends using formative research to inform communication efforts , 43. ComOne factor identified in this narrative review—that safety and effectiveness of new vaccines as well as perceived scientific uncertainty may concern some individuals—suggests that health authorities and other vaccine stakeholders could benefit from adopting approaches aligned with risk communication principles. First, they could be open and forthcoming with information about COVID-19 or other new vaccines and vaccine rollouts. Being transparent with information and providing it in a timely manner can build trust with communities , 43. SecAnother finding of this review—that low perceived risk of developing severe COVID-19 disease and doubts about the seriousness of the pandemic can be a barrier to vaccine acceptance—suggests that individuals should be supported to understand their personal risk of COVID-19 disease, as well as the risks to the broader community. In general, individuals who perceive themselves at low risk of disease may be less willing to vaccinate . InformiExposure to misinformation and conspiracies has potential to affect people’s perception of the safety of COVID-19 vaccines , 57, whiThe articles and reports included in this review were from high income countries with well-established health systems only. Caution should to be taken when interpreting findings and extrapolating to other contexts, particularly low-income countries. Findings from individual studies offer a snapshot at a particular time and in a particular context. Given rapidly evolving knowledge and circumstances surrounding COVID-19 vaccines, factors influencing COVID-19 vaccine acceptance may fluctuate and change over time.Our analysis was intended to be primarily descriptive in nature. We did not perform quality assessment of included studies. Studies that were more representative or of higher quality were not given more weight in the analysis. Given the scope of the included studies, we were not able to tease out barriers and facilitators specific to particular vaccines and vaccine technologies, such as mRNA versus viral vector vaccines.Most studies included in this review report from cross sectional, quantitative surveys. While rapid data collection has been necessary during the COVID-19 pandemic to readily inform the responses of health authorities and other vaccine stakeholders such as regulatory authorities, qualitative interview- or focus group-based research may offer a deeper understanding of COVID-19 vaccine acceptance.Socio-demographic characteristics associated with vaccine acceptance need to be interpreted with caution. Using individual characteristics, for example being female or a nurse, to predict acceptance can be misleading, as such analyses do not account for the complex factors that influence people’s perspectives and intentions. This approach may also lead to profiling individuals and groups as more or less accepting of COVID-19 vaccines, which may lead to stigma and discrimination. A more nuanced approach is needed, underpinned by an understanding of the broader social, economic, and cultural determinants of COVID-19 vaccine acceptance.There are inherent limitations with the use of preprint articles and grey literature as these have not been peer-reviewed. This should be borne in mind when interpreting findings. Preprint articles and grey literature used in this review are clearly differentiated from peer-reviewed articles in Future research should use qualitative methods to further explore and understand people’s perspectives on COVID-19 vaccines, prioritising groups more susceptible to infection and/or severe disease, such as health and aged care workers, older adults, and adults with comorbidities, and groups eligible to receive COVID-19 vaccines at later stages of vaccination programs, such as children. Given the dynamic nature of the pandemic, knowledge on the safety and effectiveness of COVID-19 vaccines, and changing policies and public health recommendations, both qualitative and quantitative data on factors influencing COVID-19 vaccine acceptance should be iteratively collected over time. This should include in countries not covered by this review. Analysis of how factors influencing acceptance over time would also be beneficial to inform future efforts to support acceptance of novel pandemic vaccines.We found that in high income countries with well-established health systems, factors influencing people’s acceptance of COVID-19 vaccines in the period prior to vaccine approval and rollout include concerns about vaccine safety and effectiveness, trust in health authorities and other vaccine stakeholders, and perceived scientific uncertainty.We propose potential communication strategies for consideration by health authorities. These include being open and forthcoming with information about COVID-19 vaccines; engaging with specific questions and concerns; and ensuring that information is straightforward and easy to digest. Individuals must also be supported to understand their personal risk of COVID-19 disease, as well as the risks to the broader community. Emerging misinformation about COVID-19 vaccines receiving considerable attention should be addressed.Mixed-methods and longitudinal approaches are needed to gather more nuanced evidence on COVID-19 vaccine acceptance as the pandemic evolves and vaccination programs expand to include COVID-19 booster vaccines, a range of vaccine choices, the next generation of COVID-19 vaccines, and vaccination of groups previously ineligible to receive COVID-19 vaccines, for example children.Findings and recommendations presented here can inform the public health and communication responses aimed at supporting acceptance of COVID-19 vaccines, with a potential beneficial flow-on effect for other routine and seasonal immunisation programs, and future novel pandemic vaccines.


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global outbreak of a coronavirus disease (herein referred to as COVID-19). Other viruses in the same phylogenetic group have been responsible for previous regional outbreaks, including SARS and MERS. SARS-CoV-2 has a zoonotic origin, similar to the causative viruses of these previous outbreaks. The repetitive introduction of animal viruses into human populations resulting in disease outbreaks suggests that similar future epidemics are inevitable. Therefore, understanding the molecular origin and ongoing evolution of SARS-CoV-2 will provide critical insights for preparing for and preventing future outbreaks. A key feature of SARS-CoV-2 is its propensity for genetic recombination across host species boundaries. Consequently, the genome of SARS-CoV-2 harbors signatures of multiple recombination events, likely encompassing multiple species and broad geographic regions. Other regions of the SARS-CoV-2 genome show the impact of purifying selection. The spike (S) protein of SARS-CoV-2, which enables the virus to enter host cells, exhibits signatures of both purifying selection and ancestral recombination events, leading to an effective S protein capable of infecting human and many other mammalian cells. The global spread and explosive growth of the SARS-CoV-2 population (within human hosts) has contributed additional mutational variability into this genome, increasing opportunities for future recombination. A confluence of historic gene swapping and evolutionary optimizations and adaptations helped make the coronavirus causing COVID-19 so infectious to people. Devika Singh and Soojin Yi from the Georgia Institute of Technology in Atlanta, USA, discuss the molecular evidence for ancestral recombination events and natural selection in the genome of SARS-CoV-2, the coronavirus responsible for COVID-19. In particular, the spike protein that enables viral entry into human cells shows ample signs of these evolutionary processes, which probably facilitated the virus’s spillover from other animals into humans. New variants of SARS-CoV-2 that have rapidly spread during the pandemic point to ongoing evolutionary processes, including effects of both potential functional alteration and random genetic drift. A better understanding of the virus’s evolutionary trajectory could help inform efforts to contain SARS-CoV-2 and prevent future pandemics. A novel coronavirus (CoV) began to circulate among humans in Wuhan, China, around December 2019. Initially, the impact of the virus on humans was poorly understood. Since then, this virus, named “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), has emerged as the source of a global pandemic, with nearly 115 million confirmed cases reported worldwide and over 2.56 million fatalities as of early March 2021. The pervasiveness and detrimental impact of SARS-CoV-2 across the globe has established it among the most notorious pandemics that have ever been recorded in human history.1. Additionally, four strains of coronaviruses are known to cause milder symptoms of the common cold2. These incidences, coupled with the possibility that there may exist other coronavirus infections that went unrecognized, indicate that the spread of new coronaviruses among human populations is a relatively common phenomenon.Unfortunately, several aspects of the pandemic indicate that the current outbreak is not a singular event, nor will it be the last of its kind. First, outbreaks of coronavirus infection have occurred frequently over the last two decades, although previous episodes have remained relatively isolated at the regional level. These incidents include the first SARS outbreak in 2003 and the Middle East respiratory syndrome (MERS) in 2012, both of which induced severe human diseases6. Many of these viruses have the potential to infect humans7. The prevalence of these coronaviruses, paired with the high number of human activities involving close contact with wild mammals harboring these viruses, provides abundant opportunities for future transfers between species. In particular, SARS-related coronaviruses appear frequently in bats8, the likely proximal source of SARS-CoV-2 (see below). Consequently, future zoonotic transmission of coronaviruses to human populations is inevitable. Elucidating the origin and evolution of coronaviruses, as well as of other viruses, is critical to understanding the dynamics of future outbreaks and developing informed strategies to prevent subsequent global spread. In this review, we will discuss molecular evidence of the origin of SARS-CoV-2. We also discuss molecular evolutionary insights into the selective forces leading to the current pandemic, as well as the future evolutionary trajectories of SARS-CoV-2.Second, these outbreaks exemplify the potential transmission of viruses from nonhuman animals to human populations. Importantly, there is ample evidence indicating that coronaviruses related to those responsible for recent epidemic outbreaks are abundant in other mammals6. Based on genetic and serological characterization, coronaviruses are divided into four distinctive genera, namely, Alphacoronavirus , Betacoronavirus (beta-CoV), Gammacoronavirus (gamma-CoV), and Deltacoronavirus (delta-CoV)9. These groups of coronaviruses are thought to have diverged from each other at ~2400–3000 BC4 and tend to infect different groups of animals .Coronaviruses also undergo frequent recombination17, encoding four structural proteins, including the spike protein (S), envelope protein (E), membrane protein (M), and nucleocapsid protein (N)  Fig. . In addi15. This strain is referred to as “RaTG13” . It is commonly acknowledged that the genome sequence of this strain is 96% similar to that of SARS-CoV-215. At first glance, a similarity of 96% might suggest a relatively close relationship between these two viral strains. In principle, given that we have some prior knowledge on how fast coronavirus sequences accumulate nucleotide substitutions over time20, we can estimate the time to the most recent common ancestor (tMRCA) of the two strains.As of the writing of this article, one of the closest known relative of SARS-CoV-2 is a coronavirus strain found in a bat sample from Yunnan Province, China, in 201321. Nonsynonymous substitutions, because they change the underlying amino acids, can alter the functional properties of the resulting proteins. Consequently, they are likely to be subject to natural selection. In comparison, synonymous substitutions are less “visible” to natural selection because they do not affect the resulting proteins. Although some synonymous substitutions may be influenced by natural selection23, in many species, they are largely affected by underlying mutation rates, as well as by random genetic drift25.Before doing so, however, we need to consider the following characteristics of coronavirus genome evolution. As shown above, the genome of SARS-CoV-2 consists nearly entirely of protein-coding sequences, a trait shared with other coronaviruses. When examining the evolution of protein-coding sequences, it is important to separately consider nucleotide substitutions that alter amino acids  from those that do not affect amino acids. These two types of substitutions, referred to as “nonsynonymous substitutions” and “synonymous substitutions”, respectively, are expected to evolve at different rates26. For the SARS-CoV-2 genome, the ratio of nonsynonymous substitutions to synonymous substitutions is 0.028 when examined across 9 ORFs in this genome27. There are two insights that can be gained from this observation. First, the ORFs in SARS-CoV-2 are largely maintained by purifying selection to exclude (likely deleterious) mutations. In fact, the observed ratio of nonsynonymous to synonymous substitutions is much lower than the estimates obtained from other coronaviruses20, indicating that the SARS-CoV-2 genome is under extremely strong purifying selection. We will discuss this further in a later section. Second, to obtain a better estimate of the time of divergence of SARS-CoV-2 from other strains, it is better to use synonymous substitutions than nonsynonymous substitutions. This is because synonymous substitutions are largely determined by the underlying mutation rates, which are likely to be more stable than selection for specific amino acid sequences. If we examine synonymous substitutions alone, the average similarity between RaTG13 and SARS-CoV-2 is only 83%, rather than 96%27, indicating a much more distant relationship than the initial 96% implies.In most genomic comparisons, nonsynonymous substitutions occur much less frequently than synonymous substitutions due to purifying natural selection, which shields the existing proteins against potentially deleterious changes in amino acid sequences. For example, in human proteins, the ratio of nonsynonymous substitutions to synonymous substitutions is on average ~0.228. A previous study analyzed synonymous substitutions in coronavirus genomes and estimated that synonymous substitution rates range from 1.67 to 4.67 × 10−3/site/year20. More recent studies of mutation rates in coronaviruses, including SARS-CoV-2, have provided similar estimates. For example, Li et al.29 and Chaw et al.30 estimated that the mutation rates in SARS-CoV-2 were 1.19–1.31 × 10−3/site/year and 1.5–3.3 × 10−3/site/year, respectively. Comparing these values, the divergence time between SARS-CoV-2 and RaTG13 may range from 18 to 71.4 years. Studies using more sophisticated methods for the assessment of divergence times have reported similar estimates28. Specifically, using a Bayesian phylogenetic approach, Boni et al.28 conservatively estimated that the MRCA of RaTG13 and SARS-CoV-2 likely existed in 1969 (95% highest posterior density [HPD]: 1930–2000). Given that the generation times of viruses are extremely short , SARS-CoV-2 and RaTG13 are, in fact, rather divergent. It is highly probable that there exist other coronaviruses that are much more closely related to SARS-CoV-2. Given that there is tremendous diversity of coronaviruses in bats and other mammals, surveillance sequencing of such coronaviruses should yield a coronavirus strain more closely related to SARS-CoV-2.We can utilize this metric to estimate the time of divergence between SARS-CoV-2 and RaTG1332). In genome sequence comparisons, some amount of variation across genomic regions is often observed due to the underlying variation in mutation rates . However, phylogenetic comparisons to other coronavirus strains and previously detected recombination events between coronavirus strains suggest that SARS-CoV-2 underwent complex recombination events during its evolution. Consequently, the evolutionary histories of different genomic segments can be distinct from each other, and different regions of the SARS-CoV-2 genome may share closer genetic divergence with coronavirus strains other than RaTG13. We will examine this observation in greater depth in the next section.The second point to consider is that even though RaTG13 is closely related to SARS-CoV-2, there is a substantial amount of variation in sequence similarity across the genomes of these two viruses, ranging between 93.1 and 99.6%  of the spike protein of SARS-CoV-2 shows more divergence from the RaTG13 strain than other regions, suggesting some alteration in the binding affinity to human ACE237. Overall, the evolutionary history of the S protein of SARS-CoV-2 appears to be highly complex; the entirety of the S protein sequence consists of several segments with different phylogenetic relationships among the examined Sarbecovirus strains28.Recombination events in the evolutionary history of the S protein have particular significance for the current pandemic. This protein, encoding the spike structural protein that gives coronaviruses the appearance of a “corona”, as in their namesake35 Fig. , is esse28) shows a close phylogenetic relationship to the common ancestor of SARS-CoV-2 and RaTG13 . Region 3 (R3) in Fig. 32  may have been an intermediate host of SARS-CoV-238. It should be stated that the pangolins from which these viruses were obtained were rescued from illegal smuggling operations and that efforts to identify coronaviruses from wild pangolins were unsuccessful41. Therefore, the conclusion that wild pangolins serve as a direct intermediary host is still under debate. It is possible that there was an ancestral recombination event between the lineages leading to the pangolin-CoV and SARS-CoV-2 that took place in bats or in another intermediate host. At the very least, the presence of multiple different phylogenetic patterns indicates that coinfection and genetic recombination of coronaviruses from distantly related mammals have occurred in the recent evolutionary history of SARS-CoV-2. Even though we cannot state with confidence whether the transmissions between species occur by direct transmission or via an intermediate host, we can use these findings to propose practical and useful implications to inform strategies for working in close proximity with wild mammals to avoid future outbreaks due to continuously evolving recombinants.Pangolin Guangdong 2019 (from Guangdong) and other coronaviruses from pangolins (sampled in 2017 from Guangxi) are phylogenetically located within the same clade as coronaviruses from batsr40 Fig. . Consequ45. In contrast to the S protein of other bat coronaviruses, the S protein of SARS-CoV-2 is particularly efficient at binding human ACE2 and thus promotes the rapid spread of the virus throughout global populations47. It would be fascinating to investigate whether the molecular properties of the S protein that allow it to bind to human ACE2 were driven by adaptive evolution  in SARS-CoV-2 prior to entering the human population.SARS-CoV-2 has infected global human populations with astonishing efficiency, giving rise to some compelling questions. For example, was this pandemic fueled by the adaptive evolution of SARS-CoV-2? To explore this topic, recent work has focused on the molecular evolution of the S protein, which binds human ACE2 and thus facilitates infection in the human body48. Tang et al.27 compared the sequences of 13 ORFs from SARS-CoV-2 with those of several other closely related coronaviruses, including those from bats, pangolins, and SARS-CoV, which caused the previous SARS epidemic in 2002–2003. They found that in all pairwise comparisons, the ω values of the examined ORFs ranged between 0.044 and 0.124. Thus, all SARS-CoV-2 ORFs exhibit signs of strong purifying selection, rather than positive selection, compared to the ORFs of these other viruses.Comparing genomic sequences of different coronaviruses can provide clues to the presence and target regions of positive selection during the evolutionary histories of the viruses of interest. One of the most widely used methods involves examining the ratio of nonsynonymous to synonymous substitutions, often referred to as “dN/dS” or “ω”. A small ω indicates the occurrence of purifying selection to remove deleterious new mutations. On the other hand, this value increases if positive selection facilitates the maintenance of nonsynonymous substitution(s). Analyses of dN/dS, in a framework of log-likelihood tests, are powerful methods to detect positive selection27 further examined whether signatures of positive selection for specific amino acid positions exist, they found that their data were better explained by a model including positive selection on some positions than by one without any positive selection27. In their analysis of 9 ORFs, they detected 10 nonsynonymous positions that may have been subjected to positive selection. Interestingly, 3 of the 10 positions were found in the S protein, in or around the RBD  that are not necessarily associated with amino acid sequences. For example, the stability of the negative RNA template used for replication of the positive-strand RNA genome could be a target of natural selection: a more stable RNA molecular structure could be favored, allowing rapid and stable replication of the positive-strand viral genome. Berrio et al.52 found several genomic regions bearing signatures of positive selection, including some sites on the S protein (but not in the RBD).Natural selection may act on features of the SARS-CoV-2 genome independent of its proteins. Berrio et al.53. These studies provide useful targets of future studies to determine the functional significance of molecular evolutionary signatures of the SARS-CoV-2 genome  repertoire and the Nextstrain database). With the availability of large SARS-CoV-2 genome sequence datasets, scientists can monitor the evolution of SARS-CoV-2 from its initial introduction to the human population and determine if any specific sites show evidence of adaptive evolution. Such studies will help us understand the dynamics of coronavirus spread and its impact on public health while also aiding in identifying targets and candidates for vaccines and therapeutic interventions. Undoubtedly, this is an extremely active area of ongoing research, with many more insights to be gained in the near future, potentially in the coming months.55 and references therein). To date, at least 12 major lineages of SARS-CoV-2 have been identified, each with several distinguishing single-nucleotide polymorphisms (SNPs)58 58 Fig. . Inferri58  has increased worldwide since the beginning of the pandemic, and it has now become the dominant global strain58 Fig. . Molecul59. On the other hand, this variant was associated with increased viral loads in COVID-19 patients56. However, viral loads may depend on other variables, such as genetic and environmental factors specific to patients. In addition, it is difficult to definitively identify independent effects of D614G because the D614G mutation cooccurs with other SNPs in linkage disequilibrium. In additional studies, scientists engineered D614 and G614 mutations in other viruses60 and in the reference SARS-CoV-2 strain61 in an attempt to directly measure functional effects. Even in such settings, elucidating the selective advantage or disadvantage of a specific mutation is challenging, given the complexity of viral infections and the immune response. Nevertheless, the immense potential of such functional studies to disentangle the effects of different mutations arising in the SARS-CoV-2 population would provide insights with tremendous implications for treating COVID-19 patients and devising public health strategies.Determining whether this mutation confers a selective advantage to SARS-CoV-2 in its infection of human populations is an ongoing topic of research with no definitive conclusion thus far. Protein structure analyses by cryogenic electron microscopy and computation modeling were unable to provide evidence that this mutation would significantly increase the interaction between the S protein and ACE262. Other positions, such as the asparagine [N] at residue 501, have been found to harbor different mutations in different SARS-CoV-2 lineages, and at least two variants at this position (N501T and N501Y) are currently circulating (Fig. 64.Despite the low mutation rate, the extremely large population size and prolonged duration of the pandemic have fueled the introduction of new variants into SARS-CoV-2 genomes worldwide. In addition, the rapid population growth of SARS-CoV-2 can facilitate the enrichment of specific mutations via founder effects. We show the dynamics of SARS-CoV-2 variants harboring mutations at two additional positions of the S protein in Fig. ing Fig. 63,64.65. Such cross-specific transmission can further enable the emergence of potentially dangerous recombinant SARS-CoV-2 strains. It is imperative that epidemiological, genetic, and functional studies of variants be fully utilized to determine how to slow down and ultimately eradicate within- and between-species transmissions.Therefore, the S protein of SARS-CoV-2 continues to diversify due to its propensity for mutation and recombination. In addition, widespread infection among humans is now posing additional threats to other mammals that interact with human populations, as secondary and even tertiary transmissions between humans and other mammals can occurMolecular evolutionary analyses of the SARS-CoV-2 reference genome indicate that SARS-CoV-2 originated from virus reservoirs in nonhuman mammals, such as bats, through recombination and purifying selection. These observations suggest that transmission events of coronaviruses between mammals, including humans, can occur and that coronavirus genomes can accumulate new variants via recombination between divergent strains residing in different host species. The COVID-19 pandemic has facilitated scientific communication and data sharing in the public domain, enabling scientists to trace recombination and transmission events occurring in the SARS-CoV-2 population in real time. The current pandemic, rapid accumulation of data, and explosive scientific analyses provide ample opportunities to develop gold standard science-guided policies for the design and implementation of epidemiological practices to prevent future outbreaks.


Specialist palliative care team (SPCT) involvement has been shown to improve symptom control and end-of-life care for patients with cancer, but little is known as to how these have been impacted by the COVID-19 pandemic. Here, we report SPCT involvement during the first wave of the pandemic and compare outcomes for patients with cancer who received and did not receive SPCT input from multiple European cancer centres.N = 1318), we analysed cancer patients aged ⩾18 diagnosed with COVID-19 between 26 February and 22 June 2020 who had complete specialist palliative care team data .From the OnCovid repository (versus 3.7%) and during admission , with more SPCT+ patients deemed suitable for treatment escalation . SPCT involvement was associated with higher discharge rates from hospital for end-of-life care . End-of-life anticipatory prescribing was higher in SPCT+ patients, with opioids (96.3% versus 47.1%) and benzodiazepines (82.9% versus 41.2%) being used frequently for symptom control.Of 555 eligible patients, 317 were male (57.1%), with a median age of 70 years (IQR 20). At COVID-19 diagnosis, 44.7% were on anti-cancer therapy and 53.3% had ⩾1 co-morbidity. Two hundred and six patients received SPCT input for symptom control (80.1%), psychological support (54.4%) and/or advance care planning (51%). SPCT+ patients had more ‘Do not attempt cardio-pulmonary resuscitation’ orders completed prior to (12.6% SPCT referral facilitated symptom control, emergency care and discharge planning, as well as high rates of referral for psychological support than previously reported. Our study highlighted the critical need of SPCTs for patients with cancer during the pandemic and should inform service planning for this population. Whilst studies have been conducted to understand how palliative care services have rapidly responded to those who have been affected by COVID-19,1316 such as providing education and protocols for symptom control and end-of-life care for non-specialist healthcare practitioners, leading psychological support and bereavement care services, and utilising community services, little is known with concern to their specific role in patients with cancer. The pandemic has reinforced the importance of individualised emergency care planning  by forcing physicians to consider what is important to the patient weighed against the availability of resources.17 However, the translation of this practice for patients with concomitant COVID-19 and cancer is unknown. As COVID-19 continues to impose an ongoing threat to patients with cancer, it is important to develop direct knowledge of the needs of these patients using an evidence-based approach. Here, we aim to describe the demographics of patients with cancer hospitalised with COVID-19, describe the patterns of referral to SPCTs, and compare emergency care planning and care in the last days of life among patients referred to and not referred to SPCTs. To address these aims, we evaluated the natural histories and outcomes of over 500 patients with cancer recruited to the OnCovid study.In addition, whilst patients with cancer and concomitant COVID-19 may benefit from SPCT input to address their symptomatic needs,6 Briefly, main eligibility criteria for OnCovid included being ⩾18 years of age, having a confirmed diagnosis of SARS-CoV-2 infection by reverse-transcriptase polymerase chain reaction (RT-PCR) of a nasopharyngeal swab, and history of solid or haematologic malignancy, either active (those receiving anti-cancer treatment) or in remission at the time of COVID-19 diagnosis. Patients with a history of non-invasive/premalignant lesions or with low malignant potential  were excluded. For haematologic malignancies, only patients carrying an oncological diagnosis of defined malignant behaviour  were included. For the purpose of the current analysis, participating investigators performed an ad hoc review of medical records of hospitalised patients for COVID-19 to assess whether or not referral to SPCT was made during hospitalisation. From 26 February 2020 to 22 June 2020, 1318 patients were consecutively accrued to OnCovid across 24 European academic centres. Of these 1318 patients, 555 patients (42%) who had been hospitalised for COVID-19 from 13 European academic centres had complete SPCT referral records and were included in this study [Supplemental material Table 1 online]. All patients were observed from the time of COVID-19 diagnosis, defined by SARS-CoV-2 PCR positivity until date of death or, in COVID-19 survivors, date of discharge from hospital or last outpatient follow-up post-discharge.This study focuses on a subset of patients accrued to the main OnCovid registry for whom data regarding SPCT referral was available for analysis. Methodology and clinical outcomes of the first 890 patients included in the main OnCovid study have been previously reported.Supplemental Table 2). Competent authorities waived prospective informed consent due to the retrospective nature of data collection and the use of anonymised data. In order to maintain confidentiality standards, each patient enrolled into the study was assigned a unique pseudonymisation code through assignment of an identification number. Clinical data including patients’ demographics, laboratory tests and radiologic results were reviewed retrospectively by clinicians and collated into a case report form designed using the Research Electronic Data Capture  tool hosted by the Medical Statistics Unit in Novara, Italy,19 which coordinated database access and curation.Within the UK, OnCovid was granted central ethical approval by the Health Research Authority (20/HRA/1608). Outside of the UK, this study was granted ethical approval by the corresponding ethics review boards at each participating site  for referral to the SPCT, patient outcome , symptomatology and use of anticipatory medications  in the final 72 h of life. All medical records of cases recruited to this study were reviewed by physicians involved in delivering patients’ care, with the final follow-up date for all patients being 22 June 2020.Alongside data concerning features of COVID-19, including co-morbidities and requirement for and length of hospitalisation,20 All patients recruited to this study were confirmed positive for SARS-CoV-2 infection following RT-PCR testing of nasopharyngeal swab samples using validated methodology. Nosocomial SARS-CoV-2 contraction was defined in patients who developed symptoms and tested positive for COVID-19 whilst admitted to the hospital for other reasons. Recognising the significant heterogeneity in the referral pathways to palliative care across centres and countries, we elected to present patients who were referred to SPCT prior to COVID-19 and those who were referred at the point of COVID-19 diagnosis in a joint category (SPCT+).The diagnosis of COVID-19 and description of the clinical syndromes associated with the disease, including acute respiratory distress syndrome (ARDS), followed criteria published by the World Health Organization.U test was utilised for continuous data following non-parametric distribution and Fisher’s exact test or the chi-squared test employed for analysis of categorical variables.Continuous data following non-parametric distribution are presented as median with interquartile range (IQR). Categorical data are described as percentages. To determine statistical significance of results, the Mann–Whitney Wellcome Trust Strategic Fund  and Associazione Italiana per la Ricerca sul Cancro  provided grant support. Cancer Research UK Imperial Centre and the Imperial NIHR BRC have provided infrastructural support., Spain , Belgium  and Germany . The median follow-up time was 28 days (IQR 47). Most patients were male  with a median age of 70 years (IQR 20), carried a diagnosis of active malignancy  and had localised disease , breast  and lung . The majority of patients had at least one co-morbidity , most commonly hypertension  and diabetes . At COVID-19 diagnosis, 248 (44.7%) patients were on systemic anti-cancer therapy, of whom 57 (10.3%) received therapy with palliative intent; 285 (51.4%) patients were not on active treatment.Of the 1318 patients within the OnCovid database at data censoring (22 June 2020), 555 patients had SPCT date collected and were eligible for inclusion in this study . Patient and cough . Of the 488 (87.9%) patients admitted to hospitals, ward-based care was deemed appropriate in 133 (24%) patients, whereas escalation to intensive or high-dependency care was deemed necessary in 62 (11.2%) patients. Hospitalisation lasted for a median duration of 10 days (IQR 10.5), whereas median stay in intensive or high-dependency care was 7 days (IQR 12.8). Supplemental oxygen therapy was required for 299 (53.8%) patients, including high-flow delivery for 144 (25.9%) patients. Mechanical ventilation was initiated on 45 patients (8.1%), including non-invasive ventilation  and endotracheal intubation . In total, 314 (56.6%) patients received at least one form of treatment for COVID-19, most frequently broad-spectrum antibiotics , followed by hydroxychloroquine or chloroquine  and lopinavir/ritonavir . In total, 234 (42.2%) patients developed complicated COVID-19 disease, defined as the development of acute respiratory failure (ARDS), acute kidney injury, secondary infection, sepsis, septic shock, acute cardiac injury, acute liver injury, or other conditions, including disseminated intravascular coagulation.In the 555 eligible patients , the mosn = 141, 68.4%; SPCT− n = 214, 61.3%; p = 0.091) and those with higher co-morbid burden (i.e. ⩾2 co-morbidities) were similar across groups . Compared with the SPCT− cohort, SPCT+ patients were more likely to have metastatic disease at COVID-19 diagnosis  and more likely to have developed a greater number of COVID-19 complications during observation . A significantly larger proportion of SPCT+ patients were undergoing anticancer therapy  and systemic anticancer therapy with palliative intent  at COVID-19 diagnosis. Of the 206 SPCT+ patients, the majority had not previously received palliative care and were newly referred to the hospital SPCT . A smaller proportion of patients had previously received palliative care and were known to both hospital and community teams  or to community teams only . , psychological support  and/or advance care planning .Of all 555 eligible patients, 206 patients (37%) were referred to their respective SPCT during the observation time (SPCT+), whereas 349 patients (63%) were not SPCT−; . As descn = 117, 56.8%; SPCT− n = 85, 24.4%; p = 0.008). In this study, there were 145 patients with nosocomial SARS-CoV-2 infection  and 343 patients with community-acquired SARS-CoV-2 . Patient outcome from COVID-19 infection  was recorded in 518 patients . In total, 355 patients were discharged home following recovery from COVID-19 . Twenty (9.7%) SPCT+ patients were discharged home for end-of-life care, whereas 115 patients died on oncology  or general medical wards . Twenty-eight patients died in high-dependency or intensive care units . The median time from COVID-19 diagnosis to discharge was 9 days (IQR 11), whereas the median time from COVID-19 diagnosis to death amongst in-hospital decedents was 8 days (IQR 9). Emergency care plans, defined as written documentation of an escalation plan or a do not attempt cardio-pulmonary resuscitation (DNACPR) order, were completed for 219 (39.5%) patients. SPCT+ patients had more DNACPR orders completed prior to admission  and during admission . The distribution of symptoms in the last 72 h of life is illustrated in n = 100, 86.2%), agitation/restlessness , confusion/delirium  and respiratory secretions  comprising the most common terminal symptoms. The median number of terminal symptoms was 3 (IQR 2), with 70 (60.3%) patients experiencing ⩾3 symptoms in the last days of life , followed by benzodiazepines or antipsychotics for agitation . Ninety patients were simultaneously prescribed more than one class of symptomatic medication . The vast majority of patients prescribed anticipatory medications were in the SPCT+ cohort [n = 116), continuous subcutaneous infusions (CSCIs) were prescribed for 25 patients . Opioids constituted the most common class of symptomatic therapy delivered via CSCI , followed by benzodiazepines or antipsychotics . Given the high burden of end-of-life symptoms, we evaluated patterns of prescription of anticipatory medications. For in-hospital decedents, opioids were most commonly prescribed for pain and breathlessness  was in fact the predominant reason for SPCT referral in over 80% of our patients, most of whom suffered from a multitude of symptoms as a likely consequence of higher tumour burden and higher complication rates from COVID-19.26 and Australia27 identified much lower referral rates for emotional issues (22% and <40% respectively) than those found in our analysis (54.4%). It is possible that the increase observed during the pandemic is related to the fact that many of these patients with cancer are being cared for outside of oncology and palliative wards and thus healthcare staff in these different settings may feel less prepared to deal directly with the emotional and psychological issues at end-of-life compared with the specialist oncology workforce. Furthermore, anxiety has been shown to be prevalent amongst hospitalised patients due to isolation from families and fear of deterioration.28The second leading cause instigating SPCT review was psychological support. This is a particularly interesting finding given that previous studies demonstrate SPCT referral for emotional and psychological support to be much less frequently cited reasons for referral: previous literature from Japan22 In the case of cancer, patients’ families may be expecting this support towards end-of-life. Where COVID-19 infection has prompted an unexpectedly rapid health decline, that usual level of psychosocial and emotional support for family members may be difficult – if not impossible – to access. SPCTs will be more aware of this and, perhaps, more able to provide a heightened level of support for these patients’ families.It is important also to be cognisant that a paramount component of the ethos of SPCTs is to provide psychological support not only to the patient but also to their families and loved ones.17 Clear documentation of a designated treatment escalation plan is of utmost importance in patients with cancer as it prevents distressing or unnecessary investigations that are inappropriate in patients with limited life expectancy, whilst on the other hand recognises circumstances where aggressive medical treatment and end organ support are warranted where chances of recovery are reasonable.30 SPCTs have been shown to help facilitate and lead this decision-making process, especially when patients are being primarily cared for by generalist staff.31An important aim of our research was to describe emergency care planning in patients with cancer in the context of a COVID-19 diagnosis, a theme of high clinical interest given the unprecedented strain on healthcare systems imposed by a rapidly diffusing infection with heightened strain on intensive care capacity at the peak of the SARS-CoV-2 pandemic, posing difficult ethical issues of healthcare rationing.Careful review of patients’ records revealed that >90% of SPCT+ patients had documented evidence of an escalation plan compared with approximately 40% of SPCT− patients. Whilst it may be argued that the higher frailty of the SPCT+ subgroup might have favoured clinicians’ increased engagement in DNACPR discussions with SPCTs, our data surprisingly demonstrate that almost one-third of SPCT+ patients were deemed appropriate for CPR during admission. Whilst it should be remembered that our study is a retrospective account of routine clinical practice during the COVID-19 pandemic, we believe this to be a clinically important finding as it suggests that SPCT input in the context of the multi-disciplinary team is essential not only to prevent futile interventions in clinical care but also to support clinical decision making and address the needs of patients whose clinical deterioration is deemed reversible.32In cases where SPCT support was sought, we noted a significantly longer interval between DNACPR order completion and death compared with patients with no documented SPCT input, highlighting that SPCT involvement may facilitate earlier end-of-life care discussions and planning, avoiding treatment escalation decisions in the final days of life, a time in which involvement of patients and relatives becomes increasingly difficult and potentially distressing.33 or at home,34 and that those patients with cancer who die in hospital or intensive care units typically experience greater emotional distress and poorer quality of end-of-life.35 Death in a hospital setting is likely appropriate where symptom burden is higher, and the increase of deaths in the hospital setting during the first wave36 is known to have negatively impacted caregiver bereavement outcomes when compared with death at home.37 This is especially relevant in the case of COVID-19 related deaths where access to SPCT for families may be reduced more than usual.A further aim of our study was to describe patterns of deterioration and symptomatic burden in patients who succumbed to COVID-19. Interestingly, our study shows that the vast majority of in-hospital deaths occurred in clinical areas not specifically dedicated to the care of oncology patients . This is an important finding giving that preferred place of death for patients with cancer is usually either a specialist palliative care (hospice) setting38 The majority of in-hospital decedents displayed multiple symptoms, highlighting the complex symptomatic needs of this patient population. Consequently, most patients required more than one therapeutic class of symptomatic agent, including opioids to reduce breathlessness and pain, and benzodiazepines or neuroleptics to address terminal restlessness. Generalist medical staff may lack confidence in the prescription of anticipatory end-of-life medications, and the support of SPCTs can ensure adequate higher dose prescriptions to meet patients’ symptomatic needs.39 Taken together, these findings further reinforce that the involvement of SPCT is crucial in patients with cancer who have a high symptomatic burden, as this allows (i) adequate recognition of deteriorating patients, (ii) judicious and effective anticipatory prescribing, and (iii) better management of psychosocial concerns, leading to improved quality of life and affective state.41 Our study is consistent with previous knowledge in this field as it highlights more prevalent use of pharmacologic symptomatic care in patients with access to SPCT input.42 This is particularly true when we consider prescription of CSCI, a safe and effective drug administration route that can optimise symptom control in patients who cannot tolerate oral medications. Perhaps unsurprisingly, prescription of CSCI was significantly higher in the SPCT+ cohort in our study.In addition, symptom burden in the last days of life was prevalent, with breathlessness and agitation being the most prevalent symptoms in the final hours of life, reflecting the symptoms experienced by a non-selected population of patients dying with COVID-19.43 Meeting preferred place of end-of-life care can be challenging in a pandemic due to risk of transmission and an unpredictable course of patient deterioration. Here, we show that planning of domiciliary end-of-life care was possible in 10% of patients, all of whom had received input from SPCT. Whilst challenging, planning end-of-life care outside of hospital is deliverable, clinically appropriate in a subset of patients with concomitant SARS-CoV-2 infection and cancer, and supports patient and family preferences for care delivery.OnCovid and other studies have shown that the mortality from SARS-CoV-2 can be as high as 30% in patients with cancer.44 Therefore, the practices described in this investigation may disproportionately reflect practice within the UK than in other European countries. In addition, the provision of symptomatic care and SPCT capacity may be different across these countries. Furthermore, the data presented focus on patients managed within large tertiary hospitals, and there may be valuable lessons to be learnt from the challenges faced in SPCT provision in smaller centres and in the community setting.45It is important to acknowledge a number of limitations to our study. OnCovid is a retrospective study and appraisal of the sources of patient data shows a clear imbalance of SPCT data, where four centres (one in Spain and three in the UK) contributed to >75% of the patients. SPCT referral data in this study were in fact mainly collected from tertiary cancer centres in London, UK and Barcelona, Spain. Not all the centres involved in the OnCovid study group had the capacity to input SPCT data. This could limit the generalisation of our findings and reflect improved access to SPCT services in these cities. The majority of patients enrolled in this sub-study were from the UK, which is known for its high standards in end-of-life care, with comprehensive national policies and a strong hospice movement.The aim of this study was not to prospectively assess patient characteristics leading to referral to SPCT and subsequently compared outcomes. This retrospective analysis is a description of referral patterns to SPCT. The key part of our analysis was to attempt and describe reasons for referral and symptomatic needs of patients so that clinical services can subsequently capitalise on these data in the context of an unresolved pandemic. Sufficiently powered prospective studies may help understand any statistical significance differences between the outcomes for patients referred to SPCT and those who were not. Furthermore, prospective studies may facilitate better understanding of the decision-making processes clinicians use when referring patients to SPCTs.In conclusion, this study describes the challenges of implementing SPCT in patients with COVID-19 and cancer and highlights the value of SPCT involvement in the management of these patients. We found that patients accessing SPCT support often have a higher number of co-morbidities, higher tumour burden and complex clinical needs. We have shown that the multifaceted role of SPCTs extends beyond symptom control as it frequently embraces broader roles, including assistance with complex clinical decision making, discharge planning, end-of-life care and psychological support. We found SPCT referral for psychological concerns to be at a higher rate than elsewhere reported, raising important questions about the availability of adequate psychosocial support for patients and their families. End-of-life was characterised by high symptomatic burden, suggesting the need for specialist oversight of pharmacological and non-pharmacological interventions to best support deteriorating patients. Therefore, integration of SPCTs in the management of patients with cancer and COVID-19 is necessary to provide equitable, specialist care for this vulnerable population.Click here for additional data file.Supplemental material, sj-docx-1-tam-10.1177_17588359211042224 for Specialist palliative and end-of-life care for patients with cancer and SARS-CoV-2 infection: a European perspective by Gehan Soosaipillai, Anjui Wu, Gino M Dettorre, Nikolaos Diamantis, John Chester, Charlotte Moss, Juan Aguilar-Company, Mark Bower, Christopher CT Sng, Ramon Salazar, Joan Brunet, Eleanor Jones, Ricard Mesia, Amanda Jackson, Uma Mukherjee, Ailsa Sita-Lumsden, Elia Seguí, Diego Ottaviani, Anna Carbó, Sarah Benafif, Rachel Würstlein, Carme Carmona, Neha Chopra, Claudia Andrea Cruz, Judith Swallow, Nadia Saoudi, Eudald Felip, Myria Galazi, Isabel Garcia-Fructuoso, Alvin J. X. Lee, Thomas Newsom-Davis, Yien Ning Sophia Wong, Anna Sureda, Clara Maluquer, Isabel Ruiz-Camps, Alba Cabirta, Aleix Prat, Angela Loizidou, Alessandra Gennari, Daniela Ferrante, Josep Tabernero, Beth Russell, Mieke Van Hemelrijck, Saoirse Dolly, Nicholas J Hulbert-Williams, David J Pinato in Therapeutic Advances in Medical Oncology


We stratified post-COVID patients into four newly established clinical groups based on the presence or absence of at least one subjective respiratory symptom and at least one objective sign of pulmonary involvement. Nearly half of outpatients and one third of hospitalized post-COVID patients had objective signs of pulmonary involvement without accompanying subjective respiratory symptoms three months after diagnosis. By 29nd January 2021, 100 million cases and 2.1 million deaths due to COVID-19 occurred globally . ConsideIn spring and summer 2020, the incidence of COVID-19 in the Czech Republic was significantly lower than in some other European countries. The Hradec Kralove District (551.000 inhabitants) had just 182 SARS-CoV-2 PCR-positive patients, of which 24 were hospitalized and three died. All survivors above 18 years of age were offered participation in our one-year prospective observational study. A total of 102 patients were included in the present analysis . Of these, 15 were hospitalized  and 87 treated as outpatients . The first follow-up took place 3 months after the COVID-19 diagnosis. In winter 2020–2021, we continued our prospective data collection to elucidate the real trajectory of patients who recovered from acute COVID-19. Currently, more than 400 patients are followed. We are writing this letter to present the first preliminary results and to introduce a proposal for a novel simple stratification of post-COVID patients to navigate their follow-up care.We use patients’ demographics and personal history as documented in hospital records. Subjective respiratory and extra-pulmonary symptoms were assessed with a structured physician–patient interview using validated questionnaires assessing respiratory symptoms, anxiety, depression and posttraumatic syndrome. Functional pulmonary examination, 6-min Walk Test (6-MWT) and chest high resolution computer tomography (HRCT) is used to assess objective signs of pulmonary involvement (PI) in all patients. Laboratory results including antibodies against SARS-CoV-2, cellular immunity parameters, C-reactive protein (CRP), and D-dimers are also recorded. HRCTs are assessed by a multidisciplinary committee. Only the HRCT findings that cannot be explained with patient personal history and have not been seen in a control cohort  are considered as pathological. The control cohort is comparable to the study group with respect to gender, age, BMI, any respiratory comorbidities and nicotine exposure.A total of 102 patients were included in the study between June and October 2020 and had their first follow-up examination three months from the COVID-19 diagnosis. The mean age was 46.7 years, there were slightly more women (55 women) and the majority of patients (75%) had no comorbidities. The majority of patients were symptomatic at the time they were PCR-positive . Three months from the onset of the disease, 56 (55%) patients had persistent subjective symptoms they did not have prior to COVID-19. Respiratory symptoms were reported by 35% of patients , non-pulmonary symptoms mostly included fatigue (22%) and anosmia (21%) more in Table We stratified post-COVID patients into four groups based on the presence or absence of at least one subjective respiratory symptom and at least one objective sign of PI, i.e. reduction in pulmonary diffusion and/or exertion desaturation of oxygen and/or HRCT pathology with suspected post-COVID aetiology. Group A patients do not have any symptoms or signs of PI. Group B patients have symptoms without objective signs of PI. Group C patients have no symptoms but do have objective signs of PI. Group D patients suffer from symptoms and objective signs of PI. Moreover, to enable a comprehensive evaluation of the data, patients with extra-pulmonary symptoms in each group were additionally marked with letter E. The stratification is detailed in the Fig. When applied to our study cohort, our post-COVID patient stratification was independent of patient gender, BMI or smoking history, while it correlated with age. In the outpatient cohort (n = 87) three months post diagnosis, 23% of patients were in group A (no subjective respiratory symptoms and no objective signs of PI), 8% in group B (symptoms with no signs of PI), 46% in group C (no symptoms with signs of PI) and 23% in group D (symptoms and signs of PI). Extra-pulmonary symptoms were reported by 43% of outpatient cohort (added E). In hospitalized patients n = 15), the stratification three months after the diagnosis was as follows: A—13%, B—0%, C—33%, D—54% and 67% with added E  and higher level of anxiety (Beck) and depression (Zung). We have observed a clear trend towards more frequent hyper-inflammatory and hyper-coagulation status in Groups C and D.With the ongoing pandemic, more data on chronic impact of COVID-19 called post-COVID are available. Even though pulmonary tissue is the predominant system involved during the acute phase of COVID-19 and the available data suggest that, in addition to fatigue, respiratory symptoms are the main post-COVID symptoms, the chronic consequences might involve multiple organs –6. In paHowever, other organ systems must not be overlooked and it is likely that other non-pulmonary complications/sequelae of COVID-19 will be seen more frequently. In addition to assessing respiratory symptoms and objective signs of PI, our study will continue to also gather data on extra-pulmonary signs of post-COVID and the extra-pulmonary signs are also included in the proposed stratification.The National Institute for Health and Care Excellence defines post-COVID syndrome as a group of signs and symptoms that continue for 12 weeks or longer from the disease onset . AccordiOur data mainly advert to the patients who have no respiratory symptoms three months post-COVID-19 diagnosis but have objective signs of PI . Therefore, these patients (Group C patients in the proposed stratification) may not fulfil the aforementioned post-COVID definitions focusing on the presence of subjective symptoms. This group can frequently be seen among COVID-19 outpatients.The small single-centre patient sample size certainly needs to be recognized as a limitation of the present data. It should, nevertheless, be acknowledged that the cohort included more than 50% of all post-COVID patients from the first wave of pandemic in spring 2020. We are also aware that the proposed stratification tool might be more suitable for healthcare systems with wide availability of pulmonary diffusion measurement in the care of post-COVID patients. Our data are also limited by the lack of baseline pre-COVID HRCTs in outpatients with mild course of the disease. Moreover, in the absence of sufficient data, it is uncertain, whether the PI we observed can be considered as a COVID-19-specific viral pneumonia in terms of long-term radiological changes and their clinical relevance . FurtherThe clinical relevance of our proposed post-COVID patient clinical stratification tool must, understandably, be validated and possibly corrected using data from other centres. This correspondence is an invitation to such a joint activity.Considering the continuation of the global COVID-19 pandemic and the growing data on its chronic impact, there is a clear need for a simple clinical tool to triage post-COVID patients and organize follow-up medical care. We established a new tool for rapid stratification of post-COVID patients based on a targeted search for respiratory and extra-pulmonary symptoms and assessment of objective signs of pulmonary involvement. When applied to our patient cohort comprising 57% of all positive „spring 2020 cases “, this stratification identified a high-risk group of patients with post-COVID syndrome and objective pulmonary involvement (group D), a group with post-COVID syndrome but without objective pathology (group B) and, importantly, an asymptomatic group with pulmonary involvement (group C). In our opinion, this group (C) warrants increased attention. Even though at present, these patients have no respiratory symptoms, the exertional respiratory insufficiency and/or reduced pulmonary diffusion and/or some of the CT/X-ray findings have a potential to develop into symptomatic progression and permanent damage. This is supported by the clear trend towards more frequent hyper-inflammatory and hyper-coagulation status we observed in these patients (similarly to group D). However, since this group is not meeting the current criteria for post-COVID syndrome based on symptoms only, it might be slipping the attention of health care providers. In addition, our stratification identifies patients requiring care of medical specialities other than pneumologists (the added E group).


To assess the impact of the closure of group-based cardiac rehabilitation (CR) training during the first COVID-19 lockdown in spring 2020 on patients’ physical activity, cardiorespiratory fitness, and cardiovascular risk, and to describe the patient experience of lockdown and home-based exercise training during lockdown.Mixed methods study. Prospectively collected post-lockdown measurements were compared to pre-lockdown medical record data. Quantitative measurements were supplemented with qualitative interviews about the patient experience during lockdown.Outpatient CR centre in Salzburg, Austria.Twenty-seven patients  who attended weekly CR training sessions until the first COVID-19 lockdown in March 2020.Quantitative: exercise capacity , cardiovascular risk . Qualitative: individual semi-structured interviews.p < 0.001; submaximal ergometer training 99 (40) vs. 97 (40), p = 0.038. There was no significant difference in Framingham risk score and other cardiovascular risk factors. Qualitative data showed that almost all patients had kept physically active during lockdown, but 17 (63%) said they had been unable to maintain their exercise levels, and 15 (56%) felt their cardiorespiratory fitness had deteriorated. Many patients missed the weekly CR training and the motivation and sense of community from training together with others. Several patients stated that without professional supervision they had felt less confident to carry out home-based exercise training at high intensity.Exercise capacity had significantly reduced from pre- to post-lockdown: mean (SD) power (W) in maximal ergometry 165 (70) vs. 151 (70), This study highlights the importance of group-based supervised exercise training for patients who engage well in such a setting, and the detrimental impact of disruption to this type of CR service on physical activity levels and exercise capacity. Additionally, learning from the COVID-19 pandemic may inform the development and implementation of remote CR modalities going forward. The Coronavirus Disease 2019 (COVID-19) pandemic has resulted in extraordinary worldwide public health orders of social distancing and self-isolation. This has led to widespread disruption of centre-based cardiac rehabilitation (CR) programmes and other social opportunities for cardiovascular disease (CVD) patients to engage in heart-healthy exercise. Heart-healthy exercise, in this context, refers to the medically recommended amount and intensity of regular physical activity (PA) to achieve a positive effect in the secondary prevention of CVD. This includes leisure activities and activities of daily living  as well as targeted endurance and strength training .In Austria, the first COVID-19 lockdown was initiated in mid-March 2020, with closure of all outpatient CR centres and restriction of inpatient rehabilitation to patients with urgent medical indications only . During The COVID-19 pandemic has presented a twofold risk for CVD patients. Firstly, pre-existing cardiovascular co-morbidity exposes CVD patients to high risk of adverse outcome in case of COVID-19 infection . The BriWe conducted a study to investigate the impact of the COVID-19-related national lockdown and public health restrictions in Austria on CR patients, with respect to maintenance of PA for secondary CVD prevention. The purpose was (1) to assess the impact of the closure of group-based CR training during the first COVID-19 lockdown in spring 2020 on patients’ physical activity, cardiorespiratory fitness, and cardiovascular risk, and (2) to describe the patient experience of lockdown and home-based exercise training during lockdown.ClinicalTrials.gov (identifier NCT04501432).We conducted a mixed methods study with sequential quantitative – qualitative design, in which qualitative data were used to elucidate quantitative data . The stuWe recruited participants from a cohort of CR patients who had regularly attended weekly group-based exercise training at the University Institute of Sports Medicine, Prevention and Rehabilitation, Salzburg, Austria, until the COVID-19-related lockdown came into force in mid-March 2020. Patients were in phase IV of CR and had previously completed phase II and/or phase III CR programmes. Phase IV CR describes a patient’s lifelong self-managed heart-healthy lifestyle and includes a recommendation for regular targeted exercise training .As part of their phase IV CR, patients had been attending weekly group-based training sessions at the study site for several months and up to several years prior to March 2020. These supervised training sessions comprise submaximal cycle ergometer training with 3-lead ECG monitoring followed by resistance training using medical-grade gym equipment. Intensity/resistance of training is regularly revisited and adjusted by staff at the centre, aiming toward medically recommended training targets for CR patients . PatientAt the time of the first COVID-19-related lockdown, the centre was not set up to provide telehealth or telerehabilitation services. During the first weeks of lockdown, staff produced motivational videos with exercise instructions and short training routines for indoor training. Patients were informed by letter that such videos had been produced and were freely accessible to them online.Participants were recruited from mid-July 2020, when patients were invited to return to train at the centre following lockdown. Eligibility criteria were: pre-lockdown completion of a maximal cycle ergometer test, no new contraindications for maximal exercise testing, no new complaints limiting exercise performance, and no language barrier for qualitative interviews. All participants gave written informed consent to the study.Clinical and socio-demographic data were collected from medical records, including most recent pre-lockdown maximal cycle ergometer test results and submaximal cycle ergometer training session recordings.The first study visit included post-lockdown medical history and physical exam, anthropometry, resting blood pressure, resting 12-lead electrocardiogram (ECG), and venous blood samples . Overall CVD risk was estimated using the Framingham risk score (FRS) for recurrent cardiovascular events . Self-re® ergoselect 100, Erlangen, Germany) as high-intensity interval or pyramid training for 40–50 min. The selection between high-intensity interval or pyramid training at the study site is decided by patient preference, as these modalities achieve similar improvements in CR training . Individual pre-post ergometry results for maximal exercise capacity were categorised  applying a threshold for minimal detectable difference of 13 W (Quantitative data were summarised using descriptive statistics. Within-group comparisons of cardiorespiratory fitness and CVD risk status before  of 13 W . StatistInterview recordings  were transcribed verbatim, anonymised, coded in qualitative analysis software QDA Miner Lite v2.0.8 and interpreted using framework analysis . FramewoData integration was conducted using a mixed methods matrix , in whicGroup-based exercise training at the outpatient CR centre was suspended from 16th March until 17th July 2020. From mid-July until the end of October 2020, we recruited 28 (57%) of 49 eligible patients. One withdrew, and 27 completed all study procedures . ParticiTwo participants were excluded from analysis of cardiorespiratory fitness data, due to subsequent diagnosis of new non-cardiac complaints limiting exercise performance. The median (IQR) time period between participants’ most recent pre-lockdown maximal cycle ergometer tests and the beginning of lockdown was 6  months. The median (IQR) time period between pre- and post-lockdown maximal cycle ergometer tests was 11  months. The median (IQR) time period between pre-lockdown submaximal cycle ergometer training session and the beginning of lockdown was 1  week. The median (IQR) time period between pre- and post-lockdown submaximal cycle ergometer training sessions was 5  months. With regard to individual exercise capacity, 14 (56%) participants had worsened, 10 (40%) were unchanged, and 1 (4%) had improved post-lockdown. FRS for recurrent cardiovascular events had worsened in 7 (26%), remained unchanged in 12 (44%), and improved in 8 (30%) participants. At group level, maximal and submaximal exercise capacity had significantly reduced, whereas CVD risk factors remained unchanged from pre- to post-lockdown .n = 25) stated that they had found alternatives to keep physically active. Activities included self-directed training at home or outdoors , going for walks and hikes, and household activities such as gardening and chopping firewood. Despite this, 17 (63%) said they had not been able to maintain the amount and intensity of exercise smoking C11, . Most pap = 0.04). Only 3 (11%) participants overestimated their cardiorespiratory fitness . This indicates good judgement and supports the credibility of patients’ reflections on PA during lockdown.In the integration of quantitative and qualitative data, self-estimated levels of cardiorespiratory fitness from qualitative interviews  matched findings from maximal ergometry in 18 (67%) participants, showing fair agreement . These changes were associated with changes in blood lipid levels from pre- to post-lockdown, but not with other parameters . CholestIn this cohort of CR patients, cardiovascular risk factors had remained unchanged after lockdown, but maximal exercise capacity had significantly reduced by 8.5%. Despite self-directed physical activities during lockdown, patients were unable to maintain exercise levels equivalent to regular group-based CR training. To put these findings into context, 6–12 months of weekly outpatient CR training in this setting typically achieve a 10% increase in maximal exercise capacity . ConsideFor the majority of patients, pre-lockdown data for submaximal exercise capacity were available from within 1 to 2 weeks of the beginning of lockdown. These data showed a statistically significant reduction by 2% following lockdown, which corroborates the trend seen in maximal exercise capacity and further supports the temporal aspect of the impact of lockdown.We emphasise that our findings do not speak to a comparison of centre-based versus home-based CR programmes, for which there is high-level evidence of similar effectiveness . Rather,Key findings from this study are in line with other research on PA behaviour during the COVID-19 pandemic. Already early on in the COVID-19 pandemic, concerns were raised about potential negative consequences of social isolation on preventive health behaviour and subsequent worsening of non-communicable chronic diseases . One yeaThis evidence derives mainly from self-reported PA data in healthy and non-cardiac patient populations, but some studies also provide objectively tracked data from cardiac patient groups, e.g., demonstrating over 25% reduction in activity data from patients with implantable cardioverter-defibrillators  and a 16In a survey of 1,809 adults in the United States, the most common reason for increasing PA during the COVID-19 pandemic was more time, whereas the most common barriers for PA were motivation and worry/stress . A surveThese findings from quantitative observational studies match qualitative data from our study, in particular with respect to participants’ reflective motivation, family encouragement, and time. Anecdotally, several of the patients who declined participation in our study indicated that this was due fear of COVID-19 infection. Other qualitative research has also provided in-depth and differentiated accounts of individuals’ experiences during lockdown which align with our findings , drawinga priori higher health literacy and greater motivation for PA, rather than representing a cause of increased PA behaviour. Digital interventions for increasing PA have also been shown to be more efficacious for individuals with high (as opposed to low) socio-economic status , as opposed to maximal exercise capacity testing, would have been a preferable measure of cardiorespiratory fitness for our investigation; however, CPET is not conducted routinely for CR patients at the study site, and therefore CPET data were not available for the pre-lockdown timepoint. The time period between participants’ pre-lockdown maximal exercise capacity tests and the beginning of lockdown presents an additional limitation.We acknowledge that our assessment of PA was limited due to the lack of an objective measure such as accelerometry, and that we did not capture quantitative dietary information. We acknowledge the potential for selection bias, whereby study recruits might represent more exercise-conscious patients who were more motivated to return to group-based CR sessions after lockdown. Participants’ mental health in association with PA during lockdown was not explicitly addressed in our study, although it is an important aspect described in the literature .This study adds to the currently limited literature on the impact of COVID-19-related social isolation on patients with CVD. The findings highlight the importance of providing group-based opportunities for supervised high-intensity training to patients who engage well in such a setting, and the detrimental impact of disruption to this type of CR service on PA levels and exercise capacity.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Medical Research Ethics Committee of the County of Salzburg. The patients/participants provided their written informed consent to participate in this study.SK, MS, and JN conceived and designed the study. MS, SD, AE, BM, and BR collected quantitative data. SK, JG, IH, and DW collected qualitative data. SK, MS, and IH conducted data analyses with contributions from all authors to interpretation and analysis. SK drafted the manuscript. All authors reviewed and approved the manuscript for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The collateral damage caused by COVID-19 pandemic-associated public health and governmental measures on patient care has been increasingly assessed in various oncological and non-oncological clinical settings. In order to investigate potential adverse effects in the field of melanoma the present study analyzed the characteristics of primary melanoma diagnoses at an Austrian dermato-pathological referral center before, during, and after the first coronavirus-related lockdown in March 2020. As suspected, we found significant temporary reductions in the number of newly diagnosed melanomas in 2020 compared to previous years, in particular, during the first lockdown period.  On 11 March 2020, the World Health Organization declared the coronavirus disease 2019 (COVID-19) a global pandemic. Subsequently, a broad range of different measures were implemented worldwide to contain further virus spread. Several governments and national authorities imposed so called shut- and lockdowns, during which the population was advised to avoid non-urgent doctor visits.Apart from serious economic and social consequences, the adverse impact of these regulations on health care standards has become apparent in different sectors of national health care systems and across various medical disciplines, including those that are not primarily involved in the management of COVID-19 patients and thus are collaterally affected.In the beginning of the pandemic, for instance, a major reduction in the number of cardiovascular hospitalizations and associated treatment delays of myocardial infarction were reported ,2. LikewMalignant melanoma is the deadliest form of skin cancer. The vertical (Breslow) tumor thickness represents the most important prognostic criterion when evaluating primary tumors . IncreasAssessing the pandemic’s impact on melanoma diagnosis, Ricci et al. observed an increase in the mean Breslow thickness of primary tumors diagnosed in an Italian cohort subsequent to the first COVID-19 lockdown .Against this background, our study was intended to elucidate potential changes in the number and characteristics of primary melanomas diagnosed at our dermatopathology laboratory before, during, and after the first COVID-19-related lockdown period.After approval by the local ethics committee, data were retrospectively collected at our dermatopathology referral center, which analyses the majority of skin tissue samples obtained by dermatologists  within the state of Salzburg and neighboring areas. This institution diagnoses about 14% of the approximately 3300 primary melanomas nationally recorded per year  and provCollected data comprised patient age, sex, melanoma Breslow thickness, and ulceration status. Cohorts were stratified through division into seven different time periods, in order to compare the gradual effects of the lockdown in a targeted manner, each lasting 28 days: pre-lockdown period I (11 January 2020–8 February 2020), pre-lockdown period II (9 February 2020–8 March 2020), lockdown period I (16 March 2020–13 April 2020), post-lockdown period I (14 April 2020–12 May 2020), post-lockdown period II (13 May 2020–10 June 2020), post-lockdown period III (11 June 2020–9 July 2020) and lockdown II (10 November 2020–8 December 2020). To enable comparison, the corresponding time periods of the two years prior to the pandemic (2018 and 2019) were equally assessed.® . For all statistical calculations, IBM SPSS Statistics 24®  was used.We determined the median Breslow index and the percentage of ulcerated and non-ulcerated primary tumors for each time interval. The numbers of melanoma cases diagnosed within each 28 day period were analyzed and compared by the use of univariate statistical methods. The ulceration status of the melanomas was compared between the analyzed time periods using the Chi-quadrat test. All statistical tests were two-sided with the significance level at 0.05. Data processing was performed with Excel 2016 for Microsoft WindowsIn order to evaluate a potential effect of the lockdown measures on our inpatient service, we additionally collected the number of sentinel lymph node biopsies for melanoma at the University Hospital Salzburg in the years 2018, 2019, and 2020. In our institution, this procedure is regularly carried out in an inpatient setting and generally recommended for patients with primary melanomas of more than 1 mm in Breslow thickness [In total, 428, 505, and 432 primary melanomas were diagnosed in 2018, 2019, and 2020, respectively .p < 0.001) as well as between 2019 and 2020 (p = 0.022); i.e., differences were detected between 2018 and 2020 for the first pre-lockdown period I (11 January–8 February), lockdown period I (16 March–13 April), and post-lockdown period I (14 April–12 May). Between 2019 and 2020, a significant difference was found only regarding lockdown period I (16 March–13 April). As depicted in Comparing distinct time periods, as defined above, we found significant differences in the number of melanoma cases between 2018 and 2020 (In the period subsequent to the lockdown in 2020 (post-lockdown period I), the number of melanoma diagnoses continued to decrease compared to previous years . Later on in 2020, the number of diagnoses almost doubled in post-lockdown period II in relation to lockdown period I (18 in lockdown period I in 2020 vs. 37 in post-lockdown period II in 2020). In Although the mean Breslow thickness increased slightly after the first COVID-19 lockdown in 2020 (0.76 mm in lockdown period I vs. 0.83 mm in post-lockdown period I), significant alterations in Breslow thickness were neither observed between the different periods of 2020 nor in comparison to previous years.n = 36), compared to 4.9 (n = 21) and 4.3 (n = 22) in 2018 and 2019, respectively. This difference reached statistical significance when comparing the years 2018 and 2019 with 2020 . During lockdown period I in 2020 11.1% of diagnosed melanomas were ulcerated, compared to 10.5% in post-lockdown period I and 13.5% in post-lockdown period II. The percentages of ulcerated melanomas in 2018/2019 and 2020 are depicted in Regarding the primary tumor ulceration status, the proportion of ulcerated melanomas was 8.3 percent in the year 2020 . As a result, the difference in total melanoma diagnoses between 2020 and previous years may have been attenuated.In conclusion, our results show that governmentally enforced measures to control the COVID-19 pandemic clearly impacted on the diagnosis of primary melanoma. As both quantity and prognostic features of diagnosed melanomas were altered during and shortly after the first lockdown period, these changes most likely resulted from delayed office visits and cancelled skin cancer screening appointments. Continuous monitoring of the present and other “COVID-19 melanoma patient cohorts” will be necessary to better determine a potential adverse impact on long-term mortality from melanoma in these patients.Although the novelty of our findings is limited, as similar developments have been described in other countries, we consider publication of national data to be important in this context, since the dimension of COVID-19-related lockdown measures varied between countries and national experience from the first lockdown in 2020 may guide public decision-making in the future. In general, for potential upcoming pandemic situations, health authorities should be advised that immediate death rates from the infectious disease per se have to be considered in the context of concomitant collateral damage caused by containment measures, such as increased long-term death rates from cancer. Thus, even in a pandemic, routine medical office visits, e.g., skin cancer screening appointments, should not be restricted, but permitted in compliance with specific anti-viral precautionary measures.