Esther E Freeman, Ignacio Garcia-Doval, Luigi Naldi, Roderick J Hay British Journal of Dermatology, Volume 189, Issue 1, July 2023, Pages 1–, https://doi.org/10.1093/bjd/ljad131

In early 2020 there were reports of a new and potentially fatal viral infection affecting large numbers of people in Wuhan, China. Over the following 3 months it had spread throughout most of the world, with all countries introducing emergency measures. On 11 March 2020, the World Health Organization declared that infections caused by the coronavirus SARS-CoV-2 had reached the status of a pandemic. Worldwide, more than 764 million people have been affected by the virus and more than 6.9 million people have died as a result of infection, as of 26 April 2023 (https://covid19.who.int/). As of 24 April 2023, over 13.3 billion doses of COVID-19 vaccine have been administered, which, along with other public health measures, have slowed the pandemic. However, new variants continue to emerge and ‘long COVID’ continues to cause significant morbidity across the world.

Early observations by dermatologists were key in identifying novel signs and symptoms of COVID-19. In May 2020 the BJD published the first comprehensive analysis of cases seen by Spanish dermatologists that categorized the different changes seen in the skin as a result of COVID-19.¹ It included a classification of dermatological manifestations seen in 375 patients: pseudo-chilblains; urticaria; maculopapular eruptions; other vesicular eruptions; and livedo and necrosis. Since then, the dermatological literature has provided descriptions of other skin manifestations and research papers on pathogenesis and immunology, treatment and the after-effects of infection or post-COVID syndrome (long COVID).² Longer-term skin manifestations may include chronic urticaria, recurrent pernio, telogen effluvium, capillaritis and exacerbation of pre-existing skin conditions such as eczema and seborrhoeic dermatitis, as well cutaneous changes attributable to the different COVID-19 vaccines. Three years into the pandemic, there are more than 4200 publications in PubMed on ‘COVID-19 and skin’, as of March 2023. The impact of COVID-19 stretches well beyond the toll of clinical cases alone, with paradigm changing shifts in research, clinical care and public policy.

International collaboration has been key in understanding the disease, and has led to the creation of well-organized national and international study groups. For example, the American Academy of Dermatology and International League of Dermatologic Societies COVID-19 Dermatology Registry (https://www.aad.org/member/practice/coronavirus/registry) is an active and productive global collaboration, containing the details of >2500 cases of dermatological manifestations of COVID-19 and COVID-19 vaccine skin reactions across 72 countries.³ More than seven registries are now active, some of which are general, while others concentrate on COVID-19 in the context of specific diseases such as psoriasis. The benefit of these initiatives has led to similar collaborations to track and record the cutaneous effects of the more recent ‘mpox’ (monkeypox) epidemic,^4,5 and could provide infrastructure for future outbreaks.

Dermatologists also played a key role in identifying cutaneous reactions to novel mRNA vaccines.⁶ These reactions have included local injection site reactions, novel delayed large local reactions (7–8 days after mRNA vaccination) and more generalized eruptions, including urticaria and vaccine-related eruption of papules and plaques,⁷ although establishing causality remains challenging. In addition to identifying reactions, dermatologists’ engagement with the lay press was critical for public perception regarding vaccine skin reactions and confidence in vaccination. Engagement with the media, including social media, has been particularly important in either combatting or promoting vaccine hesitancy.⁸

The pathogenesis of COVID-19-associated cutaneous manifestations is still not well understood, whether through binding of SARS-CoV-2 spike protein to angiotensin-converting enzyme 2 (ACE2) on target cells such as keratinocytes or through the intervention of transmembrane serine protease 2 (TMPRSS2) on the target cell, facilitating SARS-CoV-2 entry. The severity of COVID-19 has been linked to different skin manifestations, suggesting that the host immune response to the virus is critical both for viral control and also in observable viral or reactive manifestations. In severe COVID-19, ACE2-mediated endothelial damage by SARS-CoV-2 and the high level of inflammatory cytokines such as interleukin-6 in livedo reticularis may facilitate the formation of thrombi, resulting in the appearance of thrombotic multiorgan vasculopathy, which, critically, also affects the lungs.⁹ Patients with COVID-19 develop vascular damage through a variety of different mechanisms such as dysregulated type I interferon (IFN) activity, including lymphocytic perivascular cuffing, immune complex deposition leading to leukocytoclastic vasculitis, urticarial vasculitis, IgA-mediated vasculitis and antineutrophil cytoplasm antibody-associated vasculitis; some of these forms can also occur post-vaccination.⁹

In milder COVID-19, pernio (chilblains), also known as ‘COVID toes’, has been described, with ongoing debate regarding the mechanism behind it. A robust IFN-α response may lead to perniosis and relatively rapid control of the virus with a lower antibody response. The connection between COVID-19 and perniosis (COVID toes) has been questioned as there is a weak correlation between the incidence of COVID-19 and chilblains in patients examined in the USA, as well as high rates of negative SARS-CoV-2 polymerase chain reaction tests, leading to the suggestion that this may be an epiphenomenon.¹⁰ This is still very much at the centre of scientific discussion as there are other factors that are difficult to ignore; for instance, there is a clear relation between COVID-19 immunization and the development of perniosis.¹¹ Our knowledge of this phenomenon and the role of IFN continues to evolve.

Apart from the direct effects of the virus on skin, there have been reports of an increase in the incidence and appearance of other skin diseases, including herpes zoster, both during the pandemic and after vaccination.^12,13 These are not confined to infections, and autoimmune conditions such as alopecia areata have been highlighted as possible sequelae of COVID-19, as well as immunization.¹⁴ Establishing a causal relationship between dermatoses and COVID-19, and between dermatoses and vaccines, will require larger-scale, rigorous epidemiological data beyond what can be provided by disease registries.¹⁵

COVID-19 variants continue to emerge, and symptoms of the disease are also evolving. The early wild-type virus had a predominance of cough and anosmia symptoms; later variants such as Omicron have resulted in other symptoms such as a sore throat. Similarly, in skin, presentations have varied over time. The ZOE Skin Symptom study of > 348 000 individuals in the UK identified shifts in clinical presentation over time – patients are noting fewer skin symptoms, and certain skin symptoms, such as acral rash, were more predictive of a positive SARS-CoV-2 test earlier in the pandemic, for example with the Delta wave, than they have been later in the pandemic with the Omicron wave.¹⁶

The impact of COVID-19 on dermatological practice has been broader than factors related to the expression of the disease itself, as it has affected the way in which clinical and academic duties are delivered, including the use of protective clothing, transport to workplaces and hospital behaviours. COVID-19 has changed working practices for the foreseeable future. Many of these changes were designed to limit transmission through distancing and enhanced protective measures in outpatients and surgical or biopsy rooms. The benefits and disadvantages of telemedicine (TELEderm) were also exposed. However, it is likely that the positive aspects of TELEderm are likely to remain and be absorbed into daily practice.¹⁷ The need to limit the number of procedures, as well as consultations during the outbreak, led to delays in the provision of care, including increased waiting times before effective surgical interventions, increased procedure complexity and a higher risk of tumour spread.¹⁸ Other procedures involving close contact, from iontophoresis and patch testing to phototherapy, were also affected. To what extent this has increased the health risk to our patients remains suspected but largely unmeasured.

We should recognize our colleagues in dermatology who kept working throughout this very difficult period, at the height of the pandemic and, in particular, those who volunteered to work outside their normal comfort zone, in emergency care and intensive care units. Their experience, unique as it was, will have been both shocking and rewarding, and they will not forget it. Finally, we recognize with sadness the great toll that the pandemic has taken on our patients and the more than 6.9 million people who have died worldwide as a result.