COVID-19 and dermatology

By Emily Margosian, Assistant Editor, December 1, 2021

While the immediate and long-term effects of COVID-19 on the human body are still being studied, new research regarding the cutaneous manifestations of the virus and the vaccines has emerged. 

This month, DermWorld speaks with dermatology and immunology experts to learn more about what is known so far about common cutaneous signs of COVID, COVID-related dermatoses in children, skin reactions to the COVID-19 vaccines, and how to counsel patients who have concerns about adverse reactions to the COVID vaccines. 

Common cutaneous morphologies associated with COVID

“There have been several studies now that have looked at all of the manifestations from the beginning of the pandemic up until more recently, and I think it’s pretty clear that there are some patterns emerging,” said Lindy Fox, MD, FAAD, professor of dermatology at the University of California, San Francisco School of Medicine.

“The most common reactions would be maculopapular — basically pink papules and macules. Pseudo-chilblains-like lesions, what’s called ‘COVID toes’ or pernio-like lesions, would also be considered common. Others might include urticarial lesions, vesicular lesions, and papulosquamous lesions. Other manifestations can include vascular lesions, which can vary from purpuric lesions like vasculitis to livedo/vaso-occlusive lesions.” 

While these manifestations have been commonly observed in COVID-19 patients, there is no definitive data on their prevalence. “There’s no real denominator. You’d have to take all COVID-positive people and determine how many of them had a rash. We don’t have that number,” explained Dr. Fox. Esther Freeman, MD, PhD, FAAD, principal investigator of the COVID-19 Dermatology Registry, and director of global health dermatology at Massachusetts General Hospital, adds that “we are starting to get a sense of how frequent these findings are. A recent population-based study from the United Kingdom found that about 9% of people testing positive for SARS-CoV-2 have skin symptoms, though earlier studies from the hospitalized population in Italy found as many as 20% of cases had skin findings.”

Thus far, the emergence of different COVID variants seems to have had little impact on the frequency or variety of associated skin findings reported. “Nothing has changed to my knowledge. I haven’t seen anything strikingly trending in the literature,” said Dr. Fox. Dr. Freeman adds, “I think we will see more data in the future about how the Delta variant’s symptoms compare to prior variants, on a population level — not just in terms of skin, but also if there are changes in symptom frequency with respiratory symptoms, runny nose, and sore throat.”

One cutaneous controversy that has emerged recently is whether pernio-like lesions are truly associated with COVID infection. “You may come across articles that say the pernio-like lesions have nothing to do with COVID, and it’s all about timing because people were confined to their homes and not wearing shoes at the same time that COVID was roaring through our communities,” said Dr. Fox. “Further arguments have been made that if you do test people for COVID when they have their pernio-like lesions, they will test negative by PCR. However, pernio-like lesions occur much later in the disease course, and there is some evidence that people who get very mild disease and clear COVID do so without making antibodies. It may be that you have such a good immune response that it creates an immune reaction that results in ‘COVID toes,’ but doesn’t produce enough antibodies to be detected by our testing. I’m not arguing that there’s no environmental factor, but having seen as many cases as I have, I do think there are instances where pernio-like lesions are absolutely related to COVID infection.” 

Duration and timing of COVID-19 dermatologic symptoms

Recent analysis of data reported in the COVID-19 Registry has provided some insights into the duration of common dermatologic manifestations of COVID-19. A March 2021 Lancet Infectious Diseases study by Dr. Freeman, Dr. Fox, and colleagues examined the mean duration of cutaneous eruption in laboratory-confirmed or suspected COVID-19 cases. Median duration of signs was 13 days (IQR 7-21) for all patients, and seven days (IQR 5-14) for the subset of patients with laboratory-confirmed disease. The study also calculated the duration of skin signs for each observed dermatologic condition: 

• Urticaria: Median of 4 days (IQR 2-10), with a maximum duration of 28 days

• Morbilliform eruptions: Median of 7 days (IQR 5-10)

• Papulosquamous rashes: Median of 20 days (IQR 14-28)

• Pernio-like lesions: Median of 15 days (IQR 10-30) in patients with suspected COVID-19, and 12 days (IQR 7-23) in laboratory-confirmed cases 

“Duration depends on the morphology,” explained Dr. Fox. “Pernio-like lesions typically last about two weeks and appear later in the course of disease. In other words, you already would have been infected with and cleared COVID by the time these lesions show up. The morbilliform or maculopapular rash is the most common and tends to occur at the same time that you have your primary COVID symptoms. Your disease tends to be more active, meaning you tend to be more symptomatic. The rash tends to last about a week for that one. Urticaria usually comes early on with infection and it’s associated with more active disease meaning you’re more symptomatic — although not necessarily sick or in the hospital — and has a shorter duration of four or five days. The vesicular-like lesions can occur after the systemic symptoms start. So, you tend to have them when you feel ill, although they can precede other symptoms of COVID.” 

As far as the timing of dermatologic symptoms relative to other signs of COVID-19, some clear patterns have been observed. “While these are generalizations, I think they can help us understand where in the disease course someone might be,” said Dr. Fox. “Technically, any of these manifestations can happen at any time, however the vesicular lesions and urticarial lesions tend to happen earlier on in your COVID symptom course. The maculopapular or morbilliform, papulosquamous, and vascular lesions — meaning either vasculitis or vaso-occlusive lesions, tend to occur in the middle of the disease. Then, later on, after you’ve cleared a disease, that’s when your pernio-like lesions tend to show up.” 

COVID-related dermatoses in children

What do we know about COVID-related dermatoses in the pediatric population? So far, research and preliminary observations suggest that cutaneous symptoms may be the predominant or only sign of a pediatric COVID infection because many children do not have ‘typical’ COVID symptoms like respiratory changes. Likewise, cutaneous signs of COVID-19 in children are not uncommon. “One study in New York reported four of 12 children (33%) in the hospital with rash or mucous membrane signs. A separate analysis of 61 admitted children identified five (8.2%) with rash. With increasing numbers of SARS-CoV2 infections in children, we are expecting more data regarding the prevalence of skin findings in infected patients,” said Elena Hawryluk, MD, PhD, FAAD, associate professor of dermatology at Harvard Medical School. 

While reports of cutaneous symptoms in pediatric COVID patients are highly variable, they range from non-specific rashes, pernio-like lesions (PLL or “COVID toes”), and changes of the tongue and eyes. COVID-related PLL in particular have been observed as more likely to manifest in children and young adults than in older adults. “A notable trend in pediatric patients is ‘COVID toes.’ In one study of 318 patients from eight countries, over one quarter (29%) of all PLL cases were found to be in children or adolescents,” said Dr. Hawryluk. “It has been suggested that this may be a function of the immune system’s response, which may be more vigorous in younger patients.” 

However, according to Dr. Hawryluk, a particular challenge in interpreting skin findings in children with COVID-19 is understanding whether the two findings are related. “There are many reasons why a child can develop a rash, despite having COVID-19. It can be difficult to deduce from retrospective studies whether or not COVID-19 is the underlying cause of skin changes.” Although the relationship between COVID and the skin is still being unpacked, lifestyle changes due to the pandemic have had a discernible impact on pediatric patients’ skin. “At the same time as the increase in pediatric COVID-19 cases, we are experiencing an increase in many viral infections from RSV to coxsackie. Seasonal and environmental changes are compounded by changes in our routine during the pandemic. In the pediatric population, we’ve seen everything from frequent hand washing to pandemic home-bound reduction in bathing frequency, and these changes also have big impacts on the skin,” said Dr. Hawryluk. 

Among pediatric cases, MIS-C is a sometimes life-threatening, post-viral consequence of COVID-19 infection in children. Fortunately, MIS-C is a rare complication. “According to CDC data, during a peak COVID-19 wave on Jan. 9, 2021, there were 22 MIS-C cases and 254,016 COVID-19 cases. Thus, at that time MIS-C accounted for roughly 0.009% of cases,” said Dr. Hawryluk.

However, despite its rarity, skin involvement is relatively common in MIS-C, with a wide reported range (47-83%) of affected children experiencing changes to the skin or mucous membranes. Observed changes to mucous membranes include conjunctival injection, redness of the lips, and a strawberry tongue, while common skin findings include redness or swelling of the hands and feet, redness or swelling around the eyes, malar erythema, retiform purpura, as well as urticarial, morbilliform, targetoid, and nonspecific eruptions.  

Can skin lesions of COVID be associated with prognosis or disease severity? 

The short answer is yes. Preliminary data and observations suggest certain cutaneous manifestations are more likely to be present in either mild or severe COVID cases. As with many other conditions, the skin may act as a bellwether indicating the severity of a disease course. 

“Chilblains-like lesions and vesicular lesions tend to be in patients with mild disease. The urticaria-like lesions and maculopapular lesions tend to be associated with patients with mild-to-moderate disease. Vascular lesions, meaning acral necrosis or livedo lesions, tend to be in patients with much more severe disease, and with a stronger association with death,” said Dr. Fox. “Usually those patients are really ill; they’re in the hospital. Not because the skin lesions are bad, or going to cause death, but because you’re usually super sick in order to have the pathophysiology that gives you those skin lesions.” For a visual breakdown of the severity of COVID-19 dermatologic manifestations, view Figure 1.

Skin reactions to the COVID-19 vaccines

Since the COVID-19 vaccines became available to the public in late 2020, a broad spectrum of different reactions have been observed, including those on the skin. “In some ways, this isn’t surprising. COVID itself causes such a range of different skin manifestations which are related to the immune response to the virus,” explained Dr. Freeman. “It makes sense that people will have different reactions to the vaccines based on their immune response to the different vaccine components.” 

The most commonly observed skin reactions to the COVID-19 vaccines include: 

• Local injection-site reactions

• Delayed, large local reactions 

• Urticaria

• Morbilliform eruptions 

However, there has been some variation in reaction depending on the type of vaccine received. “We’re typically seeing these delayed, large reactions with the mRNA vaccines, more with Moderna than with Pfizer. Patients will develop this delayed reaction about seven or eight days later, and there will be a big, robust, bright red plaque at the site of vaccination,” said Dr. Freeman. “I think what was surprising to people was that this was occurring approximately a week later. Initially there was some concern that this could be cellulitis. However, it’s not cellulitis; it doesn’t need antibiotics.”  

Less common cutaneous reactions to the COVID-19 vaccines include pernio, flares of pre-existing conditions such as psoriasis and bullous pemphigoid. “Another condition we’ve observed is a spectrum of reactions called ‘vaccine-related eruptions of papules and plaques,’ or ‘V-REPP.’ In more mild instances it can almost look like atopic dermatitis; in moderate cases it can look like pityriasis rosea; and on the severe end it can look vesicular or almost varicella-like,” explained Dr. Freeman. “These rashes can look a bit different, but when we did histopathology correlation, we could see that these are actually a spectrum of one condition. We’re seeing this pop up relatively commonly in clinic, and I think it’s important for people to recognize that it’s actually a spectrum of the same process.” 

The mechanism of allergic reaction to the COVID-19 vaccines has yet to be fully determined. Early on, there was question of whether polyethylene glycol (PEG) might be a possible culprit. The mRNA COVID-19 vaccines (Pfizer, Moderna) contain PEG, which has been implicated as an allergen in anaphylactic reactions to other PEG-containing products and medications. “Initially, as far as the immediate allergic reactions, it was very confusing to think about what could cause an allergic reaction to these vaccines, because there’s really nothing much in them. PEG was really the only thing we had seen anaphylaxis to in the past,” explained Kimberly Blumenthal, MD, MSc, an allergist, immunologist, and drug allergy researcher at Massachusetts General Hospital, and assistant professor of medicine at Harvard Medical School. However, “As we’ve been getting more data on this, PEG IgE-mediated allergic reaction doesn’t seem to be the primary cause of allergic responses, because the epidemiology doesn’t really fit. We’ve also been able to vaccinate some of our PEG-allergic patients with mRNA vaccines, and they have done fine. So, PEG IgE is still possible as one potential mechanism for a group of people, but it doesn’t seem like it’s the predominant way that people are having allergic responses.” 

Patients with a known PEG contact allergy may expect a larger local injection response to a mRNA vaccine but aren’t precluded from full vaccination. However, patients with immediate-onset allergic reactions to PEG, including hives, swelling, low blood pressure, or wheezing, should consult with an allergist prior to receiving a mRNA vaccine, or receive the Johnson & Johnson vaccine instead, recommended Dr. Blumenthal. “In an allergist office, we could do more precise history taking, potentially skin testing, and provide guidance on how to be vaccinated safely. However, someone with that history doesn’t mean they can’t be vaccinated against COVID-19.”

“It’s important for people to weigh the overall benefits of being fully protected from a potentially deadly virus against the discomfort of having a rash. It can be very worrisome to patients to have a rash, but it needs to be put into context how important it is to be fully vaccinated against something that could potentially kill you.”

As far as cutaneous contraindications to receiving a COVID-19 vaccine, “there are very few skin reactions that I’ve seen with the first dose that truly preclude patients getting their second dose,” said Dr. Freeman. “Very, very rarely have we seen cases of Stevens-Johnson syndrome reported, and I think it’s very hard to assign causation for those. However, if someone did have a question of developing Stevens-Johnson syndrome or toxic epidermal necrolysis (TEN), after the first vaccine, to me, would probably be one of the few cutaneous contraindications to dose 2, although that’s just my opinion rather than CDC guidance. The other, which is CDC guidance, is if someone is having urticaria or hives as an immediate reaction to the vaccine — specifically within four hours of vaccination — that is someone who should be evaluated by an allergist prior to the second dose. In many cases, it’s still possible for patients with immediate onset urticaria or anaphylaxis to complete their vaccine series, but this is done under allergist supervision.” 

From an allergen standpoint, Dr. Blumenthal agrees that true preclusion from receiving any COVID vaccine available on the market would be extremely rare. “If you think about COVID vaccines, we have to consider Pfizer, Moderna, and Johnson & Johnson — all of which are available in America. You would have to have an immediate-onset allergic reaction to both polyethylene glycol and polysorbate to contraindicate it from an ingredient standpoint, because the polyethylene glycol is in the Pfizer and Moderna, and the polysorbate is in the Johnson & Johnson,” she explained. “However, most patients we have with anaphylaxis to Pfizer or Moderna, can either go get J&J, or are willing to try another dose with pre-medication and observation at a medical center. Through clinical consenting, we’ve had more than 200 people, including those with immediate allergic type reactions as well as some with anaphylaxis, receive a second dose. In our study on 189 people with allergic symptoms, 159 (84%) received their second dose and only 32 (20%) had symptoms again, meaning the remaining 80% didn’t.”  

In the event that patients are not at risk for one of these contraindications, dermatologists should be prepared to counsel and encourage patients to pursue full vaccination, according to Dr. Freeman. “I think it’s really important for people to understand that most of the reactions that we’ve seen to the COVID-19 vaccines are relatively mild and self-limited. For the most part, we can reassure our patients that even if they had a reaction to the first dose, it doesn’t necessarily mean you’re going to have a guaranteed reaction to the second dose, or that it will be worse the second time,” she said. “It’s important for people to weigh the overall benefits of being fully protected from a potentially deadly virus against the discomfort of having a rash. It can be very worrisome to patients to have a rash, but it needs to be put into context how important it is to be fully vaccinated against something that could potentially kill you.”

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