Rebecca Candler Clawson, BS

The COVID-19 pandemic has overwhelmed health care facilities and health care providers (HCPs) due to the limited resources available to treat a rapidly expanding patient population. Health care providers have been required to work long hours and put themselves at increased risk of infection by coming into frequent contact with infected patients. In addition to the risk of becoming infected with severe acute respiratory syndrome coronavirus 2, HCPs might be required to wear personal protective equipment (PPE) for the entirety of the workday, which can cause a variety of adverse effects.

During the COVID-19 pandemic, there has been an increase in reported cases of facial acne, pressure injury, urticaria, allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), and exacerbation of underlying cutaneous conditions among health care workers.^1-4 This increase in dermatologic disorders among HCPs has been associated with the increased utilization of and duration of exposure to PPE—particularly N95 respirator masks and surgical masks.^5-7 Most studies of these reactions have attributed them to local pressure, friction, hyperhydration, elevated pH, and occlusion caused by prolonged wearing of the masks, resulting ultimately in acne and other rashes^8-10; however, a few studies have suggested that formaldehyde is a potential culprit underlying the increase in skin reactions to face masks.^11-14

Formaldehyde is a known skin irritant and has been found to cause ACD and ICD from exposure to textiles and cosmetics treated with this chemical.^15-18 Both N95 and surgical masks previously have been found to contain sufficient levels of formaldehyde or formaldehyde-releasing resins (FRRs) to induce ACD or ICD in susceptible people.^12-14 In this article, we focus on the role of formaldehyde in N95 masks as a potential cause of ACD and ICD in HCPs who have been wearing PPE during the COVID-19 pandemic.

Formaldehyde: Benefits With Significant Problems

Formaldehyde is nearly ubiquitous in the textile industry because it confers advantageous properties, including resistance to flames, water, and wrinkling.¹⁵ Despite these advantages, it has long been established that consumers can become sensitized to formaldehyde and FRRs in textiles after chronic exposure.^15-18

A study of Australian HCPs found that 5.2% of those tested had ACD in response to formaldehyde, which was attributed to their PPE.¹¹ In a case report of ACD caused by FRRs, Donovan and Skotnicki-Grant¹² suggested that individuals who are sensitive to formaldehyde are vulnerable to reactions that are exacerbated by friction, warmth, moisture, and tight-fitting materials—all of which can occur when wearing an N95 mask. In that report, a formaldehyde-sensitive patient had a strong positive reaction on patch testing to melamine formaldehyde and to a piece of her N95 mask while taking prednisone 8 mg/d, suggesting that some sensitized patients have a strong reaction to their mask even when they are immunosuppressed.¹²

This finding, along with the known formaldehyde content of some N95 masks, suggests that these masks might be a cause of contact dermatitis in some HCPs. Somewhat complicating the situation is that false-negative patch testing can occur in and might contribute to the underdiagnosis of formaldehyde-induced N95 mask facial dermatitis.^12,13 Some HCPs have reported mild respiratory symptoms and eye irritation associated with the use of an N95 mask—symptoms that are consistent with formaldehyde exposure. In some cases, those symptoms have caused discomfort sufficient to prompt HCPs to take leave from work.^13,14

Development of contact dermatitis in response to an N95 mask is not novel; this problem also was observed during the severe acute respiratory syndrome pandemic of the early 2000s.^9,17 Some HCPs noticed onset of skin reactions after they were required to wear an N95 mask in the workplace, which some studies attributed to material in the mask increasing the likelihood of developing an adverse reaction.^2,6,8 The components of N95 masks and the materials from which they are manufactured are listed in the Table.¹⁹

Face Masks, Adverse Reactions, and Formaldehyde

Allergic contact dermatitis and ICD typically are rare responses to wearing facial masks, but the recent COVID-19 pandemic has forced HCPs to wear masks for longer than 6 hours at a time and to reuse a single mask, which has been shown to increase the likelihood of adverse reactions.^1,4,6 Additionally, humid environments, tight-fitting materials, and skin abrasions—all of which can be induced by wearing an N95 mask—have been found to increase the likelihood of formaldehyde-related contact dermatitis by increasing the release of free formaldehyde or by enhancing its penetration into the skin.^6,20,21

Formaldehyde is an ubiquitous chemical agent that is part of indoor and outdoor working and residential environments. Health care professionals have many opportunities to be exposed to formaldehyde, which is a well-known mucous membrane irritant and a primary skin-sensitizing agent associated with both contact dermatitis (type IV hypersensitivity reaction), and an immediate anaphylactic reaction (type I hypersensitivity reaction).^22-25 Exposure to formaldehyde by inhalation has been identified as a potential cause of asthma.^26,27 More studies on the prevalence of formaldehyde-induced hypersensitivity reactions would be beneficial to HCPs for early diagnosis of hypersensitivity, adequate prophylaxis, and occupational risk assessment.

N95 mask dermatitis also heightens the potential for breaches of PPE protocols. The discomfort that HCPs experience in response to adverse skin reactions to masks can cause an increased rate of inappropriate mask-wearing, face-touching during mask adjustment, and removal of the mask in the health care setting.²⁸ These acts of face-touching and PPE adjustment have been shown to increase microbial transmission and to reduce the efficacy of PPE in blocking pathogens.^29,30

Considering the mounting evidence that widespread use of masks effectively prevents viral transmission, it is crucial that all HCPs wear appropriate PPE when treating patients during the COVID-19 pandemic.^31,32 The recent surge in ACD and ICD among HCPs in response to wearing N95 masks creates a need to determine the underlying cause of these dermatoses and find methods of mitigating sensitization of HCPs to the offending agents. The current epidemiology of COVID-19 in the United States suggests that PPE will be necessary for much longer than originally anticipated and will continue to be worn for long hours by HCPs.

Formaldehyde-Free Alternatives?

Some researchers have proposed that using materials that are free of allergens like formaldehyde might be a long-term solution to the development of contact dermatitis.^15,33 Formaldehyde is used in the finishing process of N95 masks for wrinkle and crease resistance and to prevent mildew. It is possible that formaldehyde could be completely removed from the manufacturing process, although no studies on the effects of such alternatives on mask efficacy have been performed.

Formaldehyde-free alternatives that would confer similar properties on textiles have been explored; the most promising alternative to formaldehyde in cross-linking cellulose fibers is polycarboxylic acid in combination with sodium hypophosphite, which can help avoid the adverse health outcomes and environmental impact of formaldehyde.^34-36 Studies of such alternatives in the manufacturing of N95 masks would be needed to establish the efficacy and durability of formaldehyde-free PPE.

Final Thoughts

Additional studies are needed to confirm the presence of formaldehyde in N95 masks and to confirm that the mask material yields a positive patch test in sensitized individuals. The paucity of available studies that quantify formaldehyde or FRR content of N95 and surgical masks makes it difficult to establish an association between the chemical content of masks and the prevalence of mask dermatitis among HCPs; however, available reports of skin reactions, including contact dermatitis, from PPE suggest that formaldehyde sensitivity might be at least part of the problem. As such, we propose that manufacturers of N95 and surgical masks be required to reveal the chemical components of their products so that consumers can make educated purchasing decisions.

The COVID-19 pandemic has overwhelmed health care facilities and health care providers (HCPs) due to the limited resources available to treat a rapidly expanding patient population. Health care providers have been required to work long hours and put themselves at increased risk of infection by coming into frequent contact with infected patients. In addition to the risk of becoming infected with severe acute respiratory syndrome coronavirus 2, HCPs might be required to wear personal protective equipment (PPE) for the entirety of the workday, which can cause a variety of adverse effects.

During the COVID-19 pandemic, there has been an increase in reported cases of facial acne, pressure injury, urticaria, allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), and exacerbation of underlying cutaneous conditions among health care workers.^1-4 This increase in dermatologic disorders among HCPs has been associated with the increased utilization of and duration of exposure to PPE—particularly N95 respirator masks and surgical masks.^5-7 Most studies of these reactions have attributed them to local pressure, friction, hyperhydration, elevated pH, and occlusion caused by prolonged wearing of the masks, resulting ultimately in acne and other rashes^8-10; however, a few studies have suggested that formaldehyde is a potential culprit underlying the increase in skin reactions to face masks.^11-14

Formaldehyde is a known skin irritant and has been found to cause ACD and ICD from exposure to textiles and cosmetics treated with this chemical.^15-18 Both N95 and surgical masks previously have been found to contain sufficient levels of formaldehyde or formaldehyde-releasing resins (FRRs) to induce ACD or ICD in susceptible people.^12-14 In this article, we focus on the role of formaldehyde in N95 masks as a potential cause of ACD and ICD in HCPs who have been wearing PPE during the COVID-19 pandemic.

Formaldehyde: Benefits With Significant Problems

Formaldehyde is nearly ubiquitous in the textile industry because it confers advantageous properties, including resistance to flames, water, and wrinkling.¹⁵ Despite these advantages, it has long been established that consumers can become sensitized to formaldehyde and FRRs in textiles after chronic exposure.^15-18

A study of Australian HCPs found that 5.2% of those tested had ACD in response to formaldehyde, which was attributed to their PPE.¹¹ In a case report of ACD caused by FRRs, Donovan and Skotnicki-Grant¹² suggested that individuals who are sensitive to formaldehyde are vulnerable to reactions that are exacerbated by friction, warmth, moisture, and tight-fitting materials—all of which can occur when wearing an N95 mask. In that report, a formaldehyde-sensitive patient had a strong positive reaction on patch testing to melamine formaldehyde and to a piece of her N95 mask while taking prednisone 8 mg/d, suggesting that some sensitized patients have a strong reaction to their mask even when they are immunosuppressed.¹²

This finding, along with the known formaldehyde content of some N95 masks, suggests that these masks might be a cause of contact dermatitis in some HCPs. Somewhat complicating the situation is that false-negative patch testing can occur in and might contribute to the underdiagnosis of formaldehyde-induced N95 mask facial dermatitis.^12,13 Some HCPs have reported mild respiratory symptoms and eye irritation associated with the use of an N95 mask—symptoms that are consistent with formaldehyde exposure. In some cases, those symptoms have caused discomfort sufficient to prompt HCPs to take leave from work.^13,14

Development of contact dermatitis in response to an N95 mask is not novel; this problem also was observed during the severe acute respiratory syndrome pandemic of the early 2000s.^9,17 Some HCPs noticed onset of skin reactions after they were required to wear an N95 mask in the workplace, which some studies attributed to material in the mask increasing the likelihood of developing an adverse reaction.^2,6,8 The components of N95 masks and the materials from which they are manufactured are listed in the Table.¹⁹

Face Masks, Adverse Reactions, and Formaldehyde

Allergic contact dermatitis and ICD typically are rare responses to wearing facial masks, but the recent COVID-19 pandemic has forced HCPs to wear masks for longer than 6 hours at a time and to reuse a single mask, which has been shown to increase the likelihood of adverse reactions.^1,4,6 Additionally, humid environments, tight-fitting materials, and skin abrasions—all of which can be induced by wearing an N95 mask—have been found to increase the likelihood of formaldehyde-related contact dermatitis by increasing the release of free formaldehyde or by enhancing its penetration into the skin.^6,20,21

Formaldehyde is an ubiquitous chemical agent that is part of indoor and outdoor working and residential environments. Health care professionals have many opportunities to be exposed to formaldehyde, which is a well-known mucous membrane irritant and a primary skin-sensitizing agent associated with both contact dermatitis (type IV hypersensitivity reaction), and an immediate anaphylactic reaction (type I hypersensitivity reaction).^22-25 Exposure to formaldehyde by inhalation has been identified as a potential cause of asthma.^26,27 More studies on the prevalence of formaldehyde-induced hypersensitivity reactions would be beneficial to HCPs for early diagnosis of hypersensitivity, adequate prophylaxis, and occupational risk assessment.

N95 mask dermatitis also heightens the potential for breaches of PPE protocols. The discomfort that HCPs experience in response to adverse skin reactions to masks can cause an increased rate of inappropriate mask-wearing, face-touching during mask adjustment, and removal of the mask in the health care setting.²⁸ These acts of face-touching and PPE adjustment have been shown to increase microbial transmission and to reduce the efficacy of PPE in blocking pathogens.^29,30

Considering the mounting evidence that widespread use of masks effectively prevents viral transmission, it is crucial that all HCPs wear appropriate PPE when treating patients during the COVID-19 pandemic.^31,32 The recent surge in ACD and ICD among HCPs in response to wearing N95 masks creates a need to determine the underlying cause of these dermatoses and find methods of mitigating sensitization of HCPs to the offending agents. The current epidemiology of COVID-19 in the United States suggests that PPE will be necessary for much longer than originally anticipated and will continue to be worn for long hours by HCPs.

Formaldehyde-Free Alternatives?

Some researchers have proposed that using materials that are free of allergens like formaldehyde might be a long-term solution to the development of contact dermatitis.^15,33 Formaldehyde is used in the finishing process of N95 masks for wrinkle and crease resistance and to prevent mildew. It is possible that formaldehyde could be completely removed from the manufacturing process, although no studies on the effects of such alternatives on mask efficacy have been performed.

Formaldehyde-free alternatives that would confer similar properties on textiles have been explored; the most promising alternative to formaldehyde in cross-linking cellulose fibers is polycarboxylic acid in combination with sodium hypophosphite, which can help avoid the adverse health outcomes and environmental impact of formaldehyde.^34-36 Studies of such alternatives in the manufacturing of N95 masks would be needed to establish the efficacy and durability of formaldehyde-free PPE.

Final Thoughts

Additional studies are needed to confirm the presence of formaldehyde in N95 masks and to confirm that the mask material yields a positive patch test in sensitized individuals. The paucity of available studies that quantify formaldehyde or FRR content of N95 and surgical masks makes it difficult to establish an association between the chemical content of masks and the prevalence of mask dermatitis among HCPs; however, available reports of skin reactions, including contact dermatitis, from PPE suggest that formaldehyde sensitivity might be at least part of the problem. As such, we propose that manufacturers of N95 and surgical masks be required to reveal the chemical components of their products so that consumers can make educated purchasing decisions.

The COVID-19 pandemic has overwhelmed health care facilities and health care providers (HCPs) due to the limited resources available to treat a rapidly expanding patient population. Health care providers have been required to work long hours and put themselves at increased risk of infection by coming into frequent contact with infected patients. In addition to the risk of becoming infected with severe acute respiratory syndrome coronavirus 2, HCPs might be required to wear personal protective equipment (PPE) for the entirety of the workday, which can cause a variety of adverse effects.

During the COVID-19 pandemic, there has been an increase in reported cases of facial acne, pressure injury, urticaria, allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), and exacerbation of underlying cutaneous conditions among health care workers.^1-4 This increase in dermatologic disorders among HCPs has been associated with the increased utilization of and duration of exposure to PPE—particularly N95 respirator masks and surgical masks.^5-7 Most studies of these reactions have attributed them to local pressure, friction, hyperhydration, elevated pH, and occlusion caused by prolonged wearing of the masks, resulting ultimately in acne and other rashes^8-10; however, a few studies have suggested that formaldehyde is a potential culprit underlying the increase in skin reactions to face masks.^11-14

Formaldehyde is a known skin irritant and has been found to cause ACD and ICD from exposure to textiles and cosmetics treated with this chemical.^15-18 Both N95 and surgical masks previously have been found to contain sufficient levels of formaldehyde or formaldehyde-releasing resins (FRRs) to induce ACD or ICD in susceptible people.^12-14 In this article, we focus on the role of formaldehyde in N95 masks as a potential cause of ACD and ICD in HCPs who have been wearing PPE during the COVID-19 pandemic.

Formaldehyde: Benefits With Significant Problems

Formaldehyde is nearly ubiquitous in the textile industry because it confers advantageous properties, including resistance to flames, water, and wrinkling.¹⁵ Despite these advantages, it has long been established that consumers can become sensitized to formaldehyde and FRRs in textiles after chronic exposure.^15-18

A study of Australian HCPs found that 5.2% of those tested had ACD in response to formaldehyde, which was attributed to their PPE.¹¹ In a case report of ACD caused by FRRs, Donovan and Skotnicki-Grant¹² suggested that individuals who are sensitive to formaldehyde are vulnerable to reactions that are exacerbated by friction, warmth, moisture, and tight-fitting materials—all of which can occur when wearing an N95 mask. In that report, a formaldehyde-sensitive patient had a strong positive reaction on patch testing to melamine formaldehyde and to a piece of her N95 mask while taking prednisone 8 mg/d, suggesting that some sensitized patients have a strong reaction to their mask even when they are immunosuppressed.¹²

This finding, along with the known formaldehyde content of some N95 masks, suggests that these masks might be a cause of contact dermatitis in some HCPs. Somewhat complicating the situation is that false-negative patch testing can occur in and might contribute to the underdiagnosis of formaldehyde-induced N95 mask facial dermatitis.^12,13 Some HCPs have reported mild respiratory symptoms and eye irritation associated with the use of an N95 mask—symptoms that are consistent with formaldehyde exposure. In some cases, those symptoms have caused discomfort sufficient to prompt HCPs to take leave from work.^13,14

Development of contact dermatitis in response to an N95 mask is not novel; this problem also was observed during the severe acute respiratory syndrome pandemic of the early 2000s.^9,17 Some HCPs noticed onset of skin reactions after they were required to wear an N95 mask in the workplace, which some studies attributed to material in the mask increasing the likelihood of developing an adverse reaction.^2,6,8 The components of N95 masks and the materials from which they are manufactured are listed in the Table.¹⁹

Face Masks, Adverse Reactions, and Formaldehyde

Allergic contact dermatitis and ICD typically are rare responses to wearing facial masks, but the recent COVID-19 pandemic has forced HCPs to wear masks for longer than 6 hours at a time and to reuse a single mask, which has been shown to increase the likelihood of adverse reactions.^1,4,6 Additionally, humid environments, tight-fitting materials, and skin abrasions—all of which can be induced by wearing an N95 mask—have been found to increase the likelihood of formaldehyde-related contact dermatitis by increasing the release of free formaldehyde or by enhancing its penetration into the skin.^6,20,21

Formaldehyde is an ubiquitous chemical agent that is part of indoor and outdoor working and residential environments. Health care professionals have many opportunities to be exposed to formaldehyde, which is a well-known mucous membrane irritant and a primary skin-sensitizing agent associated with both contact dermatitis (type IV hypersensitivity reaction), and an immediate anaphylactic reaction (type I hypersensitivity reaction).^22-25 Exposure to formaldehyde by inhalation has been identified as a potential cause of asthma.^26,27 More studies on the prevalence of formaldehyde-induced hypersensitivity reactions would be beneficial to HCPs for early diagnosis of hypersensitivity, adequate prophylaxis, and occupational risk assessment.

N95 mask dermatitis also heightens the potential for breaches of PPE protocols. The discomfort that HCPs experience in response to adverse skin reactions to masks can cause an increased rate of inappropriate mask-wearing, face-touching during mask adjustment, and removal of the mask in the health care setting.²⁸ These acts of face-touching and PPE adjustment have been shown to increase microbial transmission and to reduce the efficacy of PPE in blocking pathogens.^29,30

Considering the mounting evidence that widespread use of masks effectively prevents viral transmission, it is crucial that all HCPs wear appropriate PPE when treating patients during the COVID-19 pandemic.^31,32 The recent surge in ACD and ICD among HCPs in response to wearing N95 masks creates a need to determine the underlying cause of these dermatoses and find methods of mitigating sensitization of HCPs to the offending agents. The current epidemiology of COVID-19 in the United States suggests that PPE will be necessary for much longer than originally anticipated and will continue to be worn for long hours by HCPs.

Formaldehyde-Free Alternatives?

Some researchers have proposed that using materials that are free of allergens like formaldehyde might be a long-term solution to the development of contact dermatitis.^15,33 Formaldehyde is used in the finishing process of N95 masks for wrinkle and crease resistance and to prevent mildew. It is possible that formaldehyde could be completely removed from the manufacturing process, although no studies on the effects of such alternatives on mask efficacy have been performed.

Formaldehyde-free alternatives that would confer similar properties on textiles have been explored; the most promising alternative to formaldehyde in cross-linking cellulose fibers is polycarboxylic acid in combination with sodium hypophosphite, which can help avoid the adverse health outcomes and environmental impact of formaldehyde.^34-36 Studies of such alternatives in the manufacturing of N95 masks would be needed to establish the efficacy and durability of formaldehyde-free PPE.

Final Thoughts

Additional studies are needed to confirm the presence of formaldehyde in N95 masks and to confirm that the mask material yields a positive patch test in sensitized individuals. The paucity of available studies that quantify formaldehyde or FRR content of N95 and surgical masks makes it difficult to establish an association between the chemical content of masks and the prevalence of mask dermatitis among HCPs; however, available reports of skin reactions, including contact dermatitis, from PPE suggest that formaldehyde sensitivity might be at least part of the problem. As such, we propose that manufacturers of N95 and surgical masks be required to reveal the chemical components of their products so that consumers can make educated purchasing decisions.

There has been a rise in the prevalence of perniolike lesions—erythematous to violaceous, edematous papules or nodules on the fingers or toes—during the coronavirus disease 2019 (COVID-19) pandemic. These lesions are referred to as “COVID toes.” Although several studies have suggested an association with these lesions and COVID-19, and coronavirus particles have been identified in endothelial cells of biopsies of pernio lesions, questions remain on the management, pathophysiology, and implications of these lesions.¹ We provide a practical review for primary care clinicians and dermatologists on the current management, recommendations, and remaining questions, with particular attention to the distinctions for children vs adults presenting with pernio lesions.

Hypothetical Case of a Child Presenting With Acral Lesions

A 7-year-old boy presents with acute-onset, violaceous, mildly painful and pruritic macules on the distal toes that began 3 days earlier and have progressed to involve more toes and appear more purpuric. A review of symptoms reveals no fever, cough, fatigue, or viral symptoms. He has been staying at home for the last few weeks with his brother, mother, and father. His father is working in delivery services and is social distancing at work but not at home. His mother is concerned about the lesions, if they could be COVID toes, and if testing is needed for the patient or family. In your assessment and management of this patient, you consider the following questions.

What Is the Relationship Between These Clinical Findings and COVID-19?
Despite negative polymerase chain reaction (PCR) tests reported in cases of chilblains during the COVID-19 pandemic as well as the possibility that these lesions are an indirect result of environmental factors or behavioral changes during quarantine, the majority of studies favor an association between these chilblains lesions and COVID-19 infection.^2,3 Most compellingly, COVID-19 viral particles have been identified by immunohistochemistry and electron microscopy in the endothelial cells of biopsies of these lesions.¹ Additionally, there is evidence for possible associations of other viruses, including Epstein-Barr virus and parvovirus B19, with chilblains lesions.^4,5 In sum, with the lack of any large prospective study, the weight of current evidence suggests that these perniolike skin lesions are not specific markers of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).⁶

Published studies differ in reporting the coincidence of perniolike lesions with typical COVID-19 symptoms, including fever, dyspnea, cough, fatigue, myalgia, headache, and anosmia, among others. Some studies have reported that up to 63% of patients with reported perniolike lesions developed typical COVID-19 symptoms, but other studies found that no patients with these lesions developed symptoms.^6-11 Studies with younger cohorts tended to report lower prevalence of COVID-19 symptoms, and within cohorts, younger patients tended to have less severe symptoms. For example, 78.8% of patients in a cohort (n=58) with an average age of 14 years did not experience COVID-19–related symptoms.⁶ Based on these data, it has been hypothesized that patients with chilblainslike lesions may represent a subpopulation who will have a robust interferon response that is protective from more symptomatic and severe COVID-19.^12-14

Current evidence suggests that these lesions are most likely to occur between 9 days and 2 months after the onset of COVID-19 symptoms.^4,9,10 Most cases have been only mildly symptomatic, with an overall favorable prognosis of both lesions and any viral symptoms.^8,10 The lesions typically resolve without treatment within a few days of initial onset.^15,16

What Should Be the Workup and Management of These Lesions?
Given the currently available information and favorable prognosis, usually no further workup specific to the perniolike lesions is required in the case of an asymptomatic child presenting with acral lesions, and the majority of management will center around patient and parent/guardian education and reassurance. When asked by the patient’s parent, “What does it mean that my child has these lesions?”, clinicians can provide information on the possible association with COVID-19 and the excellent, self-resolving prognosis. An example of honest and reasonable phrasing with current understanding might be, “We are currently not certain if COVID-19 causes these lesions, although there are data to suggest that they are associated. There are a lot of data showing that children with these lesions either do not have any symptoms or have very mild symptoms that resolve without treatment.”

For management, important considerations include how painful the lesions are to the individual patient and how they affect quality of life. If less severe, clinicians can reassure patients and parents/guardians that the lesions will likely self-resolve without treatment. If worsening or symptomatic, clinicians can try typical treatments for chilblains, such as topical steroids, whole-body warming, and nifedipine.^17-19 Obtaining a review of symptoms, including COVID-19 symptoms and general viral symptoms, is important given the rare cases of children with severe COVID-19.^20,21

The question of COVID-19 testing as related to these lesions remains controversial, and currently there are still differing perspectives on the need for biopsy, PCR for COVID-19, or serologies for COVID-19 in patients presenting with these lesions. Some experts report that additional testing is not needed in the pediatric population because of the high frequency of negative testing reported to date.^22,23 However, these children may be silent carriers, and until more is known about their potential to transmit the virus, testing may be considered if resources allow, particularly if the patient has a known exposure.^10,12,16,24 The ultimate decision to pursue biopsy or serologic workup for COVID-19 remains up to clinical discretion with consideration of symptoms, severity, and immunocompromised household contacts. If lesions developed after infection, PCR likely will result negative, whereas serologic testing may reveal antibodies.

Hypothetical Case of an Adult Presenting With Acral Lesions and COVID-19 Symptoms

A 50-year-old man presents with acute-onset, violaceous, painful, edematous plaques on the distal toes that began 3 days earlier and have progressed to include the soles. A review of symptoms reveals fever (temperature, 38.4 °C [101 °F]), cough, dyspnea, diarrhea, and severe asthenia. He has had interactions with a coworker who recently tested positive for COVID-19.

How Should You Consider These Lesions in the Context of the Other Symptoms Concerning for COVID-19?
In contrast to the asymptomatic child above, this adult has chilblainslike lesions and viral symptoms. In adults, chilblainslike lesions have been associated with relatively mild COVID-19, and patients with these lesions who are otherwise asymptomatic have largely tested negative for COVID-19 by PCR and serologic antibody testing.^11,25,26

True acral ischemia, which is more severe and should be differentiated from chilblains, has been reported in critically ill patients.⁹ Additionally, studies have found that retiform purpura is the most common cutaneous finding in patients with severe COVID-19.²⁷ For this patient, who has an examination consistent with progressive and severe chilblainslike lesions and suspicion for COVID-19 infection, it is important to observe and monitor these lesions, as clinical progression suggestive of acral ischemia or retiform purpura should be taken seriously and may indicate worsening of the underlying disease. Early intervention with anticoagulation might be considered, though there currently is no evidence of successful treatment.²⁸

What Causes These Lesions in a Patient With COVID-19?
The underlying pathophysiology has been proposed to be a monocytic-macrophage–induced hyperinflammatory systemic state that damages the lungs, as well as the gastrointestinal, renal, and endothelial systems. The activation of the innate immune system triggers a cytokine storm that creates a hypercoagulable state that ultimately can manifest as superficial thromboses, leading to gangrene of the extremities. Additionally, interferon response and resulting hypercytokinemia may cause direct cytopathic damage to the endothelium of arterioles and capillaries, causing the development of papulovesicular lesions that resemble the chilblainslike lesions observed in children.²⁹ In contrast to children, who typically have no or mild COVID-19 symptoms, adults may have a delayed interferon response, which has been proposed to allow for more severe manifestations of infection.^12,30

How Should an Adult With Perniolike Lesions Be Managed?
Adults with chilblainslike lesions and no other signs or symptoms of COVID-19 infection do not necessarily need be tested for COVID-19, given the reports demonstrating most patients in this clinical situation will have negative PCRs and serologies for antibodies. However, there have been several reports of adults with acro-ischemic skin findings who also had severe COVID-19, with an observed incidence of 23% in intensive care unit patients with COVID-19.^27,28,31,32 If there is suspicion of infection with COVID-19, it is advisable to first obtain workup for COVID-19 and other viruses that can cause acral lesions, including Epstein-Barr virus and parvovirus. Other pertinent laboratory tests may include D-dimer, fibrinogen, prothrombin time, activated partial thromboplastin time, antithrombin activity, platelet count, neutrophil count, procalcitonin, triglycerides, ferritin, C-reactive protein, and hemoglobin. For patients with evidence of worsening acro-ischemia, regular monitoring of these values up to several times per week can allow for initiation of vascular intervention, including angiontensin-converting enzyme inhibitors, statins, or antiplatelet drugs.³² The presence of antiphospholipid antibodies also has been associated with critically ill patients who develop digit ischemia as part of the sequelae of COVID-19 infection and therefore may act as an important marker for the potential to develop disseminated intravascular coagulation in this patient.³³ Even if COVID-19 infection is not suspected, a thorough review of systems is important to look for an underlying connective tissue disease, such as systemic lupus erythematosus, which is associated with pernio. Associated symptoms may warrant workup with antinuclear antibodies and other appropriate autoimmune serologies.

If there is any doubt of the diagnosis, the patient is experiencing symptoms from the lesion, or the patient is experiencing other viral symptoms, it is appropriate to biopsy immediately to confirm the diagnosis. Prior studies have identified fibrin clots, angiocentric and eccrinotropic lymphocytic infiltrates, lymphocytic vasculopathy, and papillary dermal edema as the most common features in chilblainslike lesions during the COVID-19 pandemic.⁹

For COVID-19 testing, many studies have revealed adult patients with an acute hypercoagulable state testing positive by SARS-CoV-2 PCR. These same patients also experienced thromboembolic events shortly after testing positive for COVID-19, which suggests that patients with elevated D-dimer and fibrinogen likely will have a viral load that is sufficient to test positive for COVID-19.^32,34-36 It is appropriate to test all patients with suspected COVID-19, especially adults who are more likely to experience adverse complications secondary to infection.

This patient experiencing COVID-19 symptoms with signs of acral ischemia is likely to test positive by PCR, and additional testing for serologic antibodies is unlikely to be clinically meaningful in this patient’s state. Furthermore, there is little evidence that serology is reliable because of the markedly high levels of both false-negative and false-positive results when using the available antibody testing kits.³⁷ The latter evidence makes serology testing of little value for the general population, but particularly for patients with acute COVID-19.

Conclusion and Outstanding Questions

There is evidence suggesting an association between chilblainslike lesions and COVID-19.^11,22,38,39 Children presenting with these lesions have an excellent prognosis and only need a workup or treatment if there are other symptoms, as the lesions self-resolve in the majority of reported cases.^7-9 Adults presenting with these lesions and without symptoms likewise are unlikely to test positive for COVID-19, and the lesions typically resolve spontaneously or with first-line treatment. However, adults presenting with these lesions and COVID-19 symptoms should raise clinical concern for evolving skin manifestations of acro-ischemia. If the diagnosis is uncertain or systemic symptoms are concerning, biopsy, COVID-19 PCR, and other appropriate laboratory workup should be obtained.

There remains controversy and uncertainty over the relationship between these skin findings and SARS-CoV-2 infection, with clinical evidence to support both a direct relationship representing convalescent-phase cutaneous reaction as well as an indirect epiphenomenon. If there was a direct relationship, we would have expected to see a rise in the incidence of acral lesions proportionate to the rising caseload of COVID-19 after the reopening of many states in the summer of 2020. Similarly, because young adults represent the largest demographic of increasing cases and as some schools have remained open for in-person instruction during the current academic year, we also would have expected the incidence of chilblains-like lesions presenting to dermatologists and pediatricians to increase alongside these cases. Continued evaluation of emerging literature and ongoing efforts to understand the cause of this observed phenomenon will hopefully help us arrive at a future understanding of the pathophysiology of this puzzling skin manifestation.⁴⁰

There has been a rise in the prevalence of perniolike lesions—erythematous to violaceous, edematous papules or nodules on the fingers or toes—during the coronavirus disease 2019 (COVID-19) pandemic. These lesions are referred to as “COVID toes.” Although several studies have suggested an association with these lesions and COVID-19, and coronavirus particles have been identified in endothelial cells of biopsies of pernio lesions, questions remain on the management, pathophysiology, and implications of these lesions.¹ We provide a practical review for primary care clinicians and dermatologists on the current management, recommendations, and remaining questions, with particular attention to the distinctions for children vs adults presenting with pernio lesions.

Hypothetical Case of a Child Presenting With Acral Lesions

A 7-year-old boy presents with acute-onset, violaceous, mildly painful and pruritic macules on the distal toes that began 3 days earlier and have progressed to involve more toes and appear more purpuric. A review of symptoms reveals no fever, cough, fatigue, or viral symptoms. He has been staying at home for the last few weeks with his brother, mother, and father. His father is working in delivery services and is social distancing at work but not at home. His mother is concerned about the lesions, if they could be COVID toes, and if testing is needed for the patient or family. In your assessment and management of this patient, you consider the following questions.

What Is the Relationship Between These Clinical Findings and COVID-19?
Despite negative polymerase chain reaction (PCR) tests reported in cases of chilblains during the COVID-19 pandemic as well as the possibility that these lesions are an indirect result of environmental factors or behavioral changes during quarantine, the majority of studies favor an association between these chilblains lesions and COVID-19 infection.^2,3 Most compellingly, COVID-19 viral particles have been identified by immunohistochemistry and electron microscopy in the endothelial cells of biopsies of these lesions.¹ Additionally, there is evidence for possible associations of other viruses, including Epstein-Barr virus and parvovirus B19, with chilblains lesions.^4,5 In sum, with the lack of any large prospective study, the weight of current evidence suggests that these perniolike skin lesions are not specific markers of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).⁶

Published studies differ in reporting the coincidence of perniolike lesions with typical COVID-19 symptoms, including fever, dyspnea, cough, fatigue, myalgia, headache, and anosmia, among others. Some studies have reported that up to 63% of patients with reported perniolike lesions developed typical COVID-19 symptoms, but other studies found that no patients with these lesions developed symptoms.^6-11 Studies with younger cohorts tended to report lower prevalence of COVID-19 symptoms, and within cohorts, younger patients tended to have less severe symptoms. For example, 78.8% of patients in a cohort (n=58) with an average age of 14 years did not experience COVID-19–related symptoms.⁶ Based on these data, it has been hypothesized that patients with chilblainslike lesions may represent a subpopulation who will have a robust interferon response that is protective from more symptomatic and severe COVID-19.^12-14

Current evidence suggests that these lesions are most likely to occur between 9 days and 2 months after the onset of COVID-19 symptoms.^4,9,10 Most cases have been only mildly symptomatic, with an overall favorable prognosis of both lesions and any viral symptoms.^8,10 The lesions typically resolve without treatment within a few days of initial onset.^15,16

What Should Be the Workup and Management of These Lesions?
Given the currently available information and favorable prognosis, usually no further workup specific to the perniolike lesions is required in the case of an asymptomatic child presenting with acral lesions, and the majority of management will center around patient and parent/guardian education and reassurance. When asked by the patient’s parent, “What does it mean that my child has these lesions?”, clinicians can provide information on the possible association with COVID-19 and the excellent, self-resolving prognosis. An example of honest and reasonable phrasing with current understanding might be, “We are currently not certain if COVID-19 causes these lesions, although there are data to suggest that they are associated. There are a lot of data showing that children with these lesions either do not have any symptoms or have very mild symptoms that resolve without treatment.”

For management, important considerations include how painful the lesions are to the individual patient and how they affect quality of life. If less severe, clinicians can reassure patients and parents/guardians that the lesions will likely self-resolve without treatment. If worsening or symptomatic, clinicians can try typical treatments for chilblains, such as topical steroids, whole-body warming, and nifedipine.^17-19 Obtaining a review of symptoms, including COVID-19 symptoms and general viral symptoms, is important given the rare cases of children with severe COVID-19.^20,21

The question of COVID-19 testing as related to these lesions remains controversial, and currently there are still differing perspectives on the need for biopsy, PCR for COVID-19, or serologies for COVID-19 in patients presenting with these lesions. Some experts report that additional testing is not needed in the pediatric population because of the high frequency of negative testing reported to date.^22,23 However, these children may be silent carriers, and until more is known about their potential to transmit the virus, testing may be considered if resources allow, particularly if the patient has a known exposure.^10,12,16,24 The ultimate decision to pursue biopsy or serologic workup for COVID-19 remains up to clinical discretion with consideration of symptoms, severity, and immunocompromised household contacts. If lesions developed after infection, PCR likely will result negative, whereas serologic testing may reveal antibodies.

Hypothetical Case of an Adult Presenting With Acral Lesions and COVID-19 Symptoms

A 50-year-old man presents with acute-onset, violaceous, painful, edematous plaques on the distal toes that began 3 days earlier and have progressed to include the soles. A review of symptoms reveals fever (temperature, 38.4 °C [101 °F]), cough, dyspnea, diarrhea, and severe asthenia. He has had interactions with a coworker who recently tested positive for COVID-19.

How Should You Consider These Lesions in the Context of the Other Symptoms Concerning for COVID-19?
In contrast to the asymptomatic child above, this adult has chilblainslike lesions and viral symptoms. In adults, chilblainslike lesions have been associated with relatively mild COVID-19, and patients with these lesions who are otherwise asymptomatic have largely tested negative for COVID-19 by PCR and serologic antibody testing.^11,25,26

True acral ischemia, which is more severe and should be differentiated from chilblains, has been reported in critically ill patients.⁹ Additionally, studies have found that retiform purpura is the most common cutaneous finding in patients with severe COVID-19.²⁷ For this patient, who has an examination consistent with progressive and severe chilblainslike lesions and suspicion for COVID-19 infection, it is important to observe and monitor these lesions, as clinical progression suggestive of acral ischemia or retiform purpura should be taken seriously and may indicate worsening of the underlying disease. Early intervention with anticoagulation might be considered, though there currently is no evidence of successful treatment.²⁸

What Causes These Lesions in a Patient With COVID-19?
The underlying pathophysiology has been proposed to be a monocytic-macrophage–induced hyperinflammatory systemic state that damages the lungs, as well as the gastrointestinal, renal, and endothelial systems. The activation of the innate immune system triggers a cytokine storm that creates a hypercoagulable state that ultimately can manifest as superficial thromboses, leading to gangrene of the extremities. Additionally, interferon response and resulting hypercytokinemia may cause direct cytopathic damage to the endothelium of arterioles and capillaries, causing the development of papulovesicular lesions that resemble the chilblainslike lesions observed in children.²⁹ In contrast to children, who typically have no or mild COVID-19 symptoms, adults may have a delayed interferon response, which has been proposed to allow for more severe manifestations of infection.^12,30

How Should an Adult With Perniolike Lesions Be Managed?
Adults with chilblainslike lesions and no other signs or symptoms of COVID-19 infection do not necessarily need be tested for COVID-19, given the reports demonstrating most patients in this clinical situation will have negative PCRs and serologies for antibodies. However, there have been several reports of adults with acro-ischemic skin findings who also had severe COVID-19, with an observed incidence of 23% in intensive care unit patients with COVID-19.^27,28,31,32 If there is suspicion of infection with COVID-19, it is advisable to first obtain workup for COVID-19 and other viruses that can cause acral lesions, including Epstein-Barr virus and parvovirus. Other pertinent laboratory tests may include D-dimer, fibrinogen, prothrombin time, activated partial thromboplastin time, antithrombin activity, platelet count, neutrophil count, procalcitonin, triglycerides, ferritin, C-reactive protein, and hemoglobin. For patients with evidence of worsening acro-ischemia, regular monitoring of these values up to several times per week can allow for initiation of vascular intervention, including angiontensin-converting enzyme inhibitors, statins, or antiplatelet drugs.³² The presence of antiphospholipid antibodies also has been associated with critically ill patients who develop digit ischemia as part of the sequelae of COVID-19 infection and therefore may act as an important marker for the potential to develop disseminated intravascular coagulation in this patient.³³ Even if COVID-19 infection is not suspected, a thorough review of systems is important to look for an underlying connective tissue disease, such as systemic lupus erythematosus, which is associated with pernio. Associated symptoms may warrant workup with antinuclear antibodies and other appropriate autoimmune serologies.

If there is any doubt of the diagnosis, the patient is experiencing symptoms from the lesion, or the patient is experiencing other viral symptoms, it is appropriate to biopsy immediately to confirm the diagnosis. Prior studies have identified fibrin clots, angiocentric and eccrinotropic lymphocytic infiltrates, lymphocytic vasculopathy, and papillary dermal edema as the most common features in chilblainslike lesions during the COVID-19 pandemic.⁹

For COVID-19 testing, many studies have revealed adult patients with an acute hypercoagulable state testing positive by SARS-CoV-2 PCR. These same patients also experienced thromboembolic events shortly after testing positive for COVID-19, which suggests that patients with elevated D-dimer and fibrinogen likely will have a viral load that is sufficient to test positive for COVID-19.^32,34-36 It is appropriate to test all patients with suspected COVID-19, especially adults who are more likely to experience adverse complications secondary to infection.

This patient experiencing COVID-19 symptoms with signs of acral ischemia is likely to test positive by PCR, and additional testing for serologic antibodies is unlikely to be clinically meaningful in this patient’s state. Furthermore, there is little evidence that serology is reliable because of the markedly high levels of both false-negative and false-positive results when using the available antibody testing kits.³⁷ The latter evidence makes serology testing of little value for the general population, but particularly for patients with acute COVID-19.

Conclusion and Outstanding Questions

There is evidence suggesting an association between chilblainslike lesions and COVID-19.^11,22,38,39 Children presenting with these lesions have an excellent prognosis and only need a workup or treatment if there are other symptoms, as the lesions self-resolve in the majority of reported cases.^7-9 Adults presenting with these lesions and without symptoms likewise are unlikely to test positive for COVID-19, and the lesions typically resolve spontaneously or with first-line treatment. However, adults presenting with these lesions and COVID-19 symptoms should raise clinical concern for evolving skin manifestations of acro-ischemia. If the diagnosis is uncertain or systemic symptoms are concerning, biopsy, COVID-19 PCR, and other appropriate laboratory workup should be obtained.

There remains controversy and uncertainty over the relationship between these skin findings and SARS-CoV-2 infection, with clinical evidence to support both a direct relationship representing convalescent-phase cutaneous reaction as well as an indirect epiphenomenon. If there was a direct relationship, we would have expected to see a rise in the incidence of acral lesions proportionate to the rising caseload of COVID-19 after the reopening of many states in the summer of 2020. Similarly, because young adults represent the largest demographic of increasing cases and as some schools have remained open for in-person instruction during the current academic year, we also would have expected the incidence of chilblains-like lesions presenting to dermatologists and pediatricians to increase alongside these cases. Continued evaluation of emerging literature and ongoing efforts to understand the cause of this observed phenomenon will hopefully help us arrive at a future understanding of the pathophysiology of this puzzling skin manifestation.⁴⁰

There has been a rise in the prevalence of perniolike lesions—erythematous to violaceous, edematous papules or nodules on the fingers or toes—during the coronavirus disease 2019 (COVID-19) pandemic. These lesions are referred to as “COVID toes.” Although several studies have suggested an association with these lesions and COVID-19, and coronavirus particles have been identified in endothelial cells of biopsies of pernio lesions, questions remain on the management, pathophysiology, and implications of these lesions.¹ We provide a practical review for primary care clinicians and dermatologists on the current management, recommendations, and remaining questions, with particular attention to the distinctions for children vs adults presenting with pernio lesions.

Hypothetical Case of a Child Presenting With Acral Lesions

A 7-year-old boy presents with acute-onset, violaceous, mildly painful and pruritic macules on the distal toes that began 3 days earlier and have progressed to involve more toes and appear more purpuric. A review of symptoms reveals no fever, cough, fatigue, or viral symptoms. He has been staying at home for the last few weeks with his brother, mother, and father. His father is working in delivery services and is social distancing at work but not at home. His mother is concerned about the lesions, if they could be COVID toes, and if testing is needed for the patient or family. In your assessment and management of this patient, you consider the following questions.

What Is the Relationship Between These Clinical Findings and COVID-19?
Despite negative polymerase chain reaction (PCR) tests reported in cases of chilblains during the COVID-19 pandemic as well as the possibility that these lesions are an indirect result of environmental factors or behavioral changes during quarantine, the majority of studies favor an association between these chilblains lesions and COVID-19 infection.^2,3 Most compellingly, COVID-19 viral particles have been identified by immunohistochemistry and electron microscopy in the endothelial cells of biopsies of these lesions.¹ Additionally, there is evidence for possible associations of other viruses, including Epstein-Barr virus and parvovirus B19, with chilblains lesions.^4,5 In sum, with the lack of any large prospective study, the weight of current evidence suggests that these perniolike skin lesions are not specific markers of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).⁶

Published studies differ in reporting the coincidence of perniolike lesions with typical COVID-19 symptoms, including fever, dyspnea, cough, fatigue, myalgia, headache, and anosmia, among others. Some studies have reported that up to 63% of patients with reported perniolike lesions developed typical COVID-19 symptoms, but other studies found that no patients with these lesions developed symptoms.^6-11 Studies with younger cohorts tended to report lower prevalence of COVID-19 symptoms, and within cohorts, younger patients tended to have less severe symptoms. For example, 78.8% of patients in a cohort (n=58) with an average age of 14 years did not experience COVID-19–related symptoms.⁶ Based on these data, it has been hypothesized that patients with chilblainslike lesions may represent a subpopulation who will have a robust interferon response that is protective from more symptomatic and severe COVID-19.^12-14

Current evidence suggests that these lesions are most likely to occur between 9 days and 2 months after the onset of COVID-19 symptoms.^4,9,10 Most cases have been only mildly symptomatic, with an overall favorable prognosis of both lesions and any viral symptoms.^8,10 The lesions typically resolve without treatment within a few days of initial onset.^15,16

What Should Be the Workup and Management of These Lesions?
Given the currently available information and favorable prognosis, usually no further workup specific to the perniolike lesions is required in the case of an asymptomatic child presenting with acral lesions, and the majority of management will center around patient and parent/guardian education and reassurance. When asked by the patient’s parent, “What does it mean that my child has these lesions?”, clinicians can provide information on the possible association with COVID-19 and the excellent, self-resolving prognosis. An example of honest and reasonable phrasing with current understanding might be, “We are currently not certain if COVID-19 causes these lesions, although there are data to suggest that they are associated. There are a lot of data showing that children with these lesions either do not have any symptoms or have very mild symptoms that resolve without treatment.”

For management, important considerations include how painful the lesions are to the individual patient and how they affect quality of life. If less severe, clinicians can reassure patients and parents/guardians that the lesions will likely self-resolve without treatment. If worsening or symptomatic, clinicians can try typical treatments for chilblains, such as topical steroids, whole-body warming, and nifedipine.^17-19 Obtaining a review of symptoms, including COVID-19 symptoms and general viral symptoms, is important given the rare cases of children with severe COVID-19.^20,21

The question of COVID-19 testing as related to these lesions remains controversial, and currently there are still differing perspectives on the need for biopsy, PCR for COVID-19, or serologies for COVID-19 in patients presenting with these lesions. Some experts report that additional testing is not needed in the pediatric population because of the high frequency of negative testing reported to date.^22,23 However, these children may be silent carriers, and until more is known about their potential to transmit the virus, testing may be considered if resources allow, particularly if the patient has a known exposure.^10,12,16,24 The ultimate decision to pursue biopsy or serologic workup for COVID-19 remains up to clinical discretion with consideration of symptoms, severity, and immunocompromised household contacts. If lesions developed after infection, PCR likely will result negative, whereas serologic testing may reveal antibodies.

Hypothetical Case of an Adult Presenting With Acral Lesions and COVID-19 Symptoms

A 50-year-old man presents with acute-onset, violaceous, painful, edematous plaques on the distal toes that began 3 days earlier and have progressed to include the soles. A review of symptoms reveals fever (temperature, 38.4 °C [101 °F]), cough, dyspnea, diarrhea, and severe asthenia. He has had interactions with a coworker who recently tested positive for COVID-19.

How Should You Consider These Lesions in the Context of the Other Symptoms Concerning for COVID-19?
In contrast to the asymptomatic child above, this adult has chilblainslike lesions and viral symptoms. In adults, chilblainslike lesions have been associated with relatively mild COVID-19, and patients with these lesions who are otherwise asymptomatic have largely tested negative for COVID-19 by PCR and serologic antibody testing.^11,25,26

True acral ischemia, which is more severe and should be differentiated from chilblains, has been reported in critically ill patients.⁹ Additionally, studies have found that retiform purpura is the most common cutaneous finding in patients with severe COVID-19.²⁷ For this patient, who has an examination consistent with progressive and severe chilblainslike lesions and suspicion for COVID-19 infection, it is important to observe and monitor these lesions, as clinical progression suggestive of acral ischemia or retiform purpura should be taken seriously and may indicate worsening of the underlying disease. Early intervention with anticoagulation might be considered, though there currently is no evidence of successful treatment.²⁸

What Causes These Lesions in a Patient With COVID-19?
The underlying pathophysiology has been proposed to be a monocytic-macrophage–induced hyperinflammatory systemic state that damages the lungs, as well as the gastrointestinal, renal, and endothelial systems. The activation of the innate immune system triggers a cytokine storm that creates a hypercoagulable state that ultimately can manifest as superficial thromboses, leading to gangrene of the extremities. Additionally, interferon response and resulting hypercytokinemia may cause direct cytopathic damage to the endothelium of arterioles and capillaries, causing the development of papulovesicular lesions that resemble the chilblainslike lesions observed in children.²⁹ In contrast to children, who typically have no or mild COVID-19 symptoms, adults may have a delayed interferon response, which has been proposed to allow for more severe manifestations of infection.^12,30

How Should an Adult With Perniolike Lesions Be Managed?
Adults with chilblainslike lesions and no other signs or symptoms of COVID-19 infection do not necessarily need be tested for COVID-19, given the reports demonstrating most patients in this clinical situation will have negative PCRs and serologies for antibodies. However, there have been several reports of adults with acro-ischemic skin findings who also had severe COVID-19, with an observed incidence of 23% in intensive care unit patients with COVID-19.^27,28,31,32 If there is suspicion of infection with COVID-19, it is advisable to first obtain workup for COVID-19 and other viruses that can cause acral lesions, including Epstein-Barr virus and parvovirus. Other pertinent laboratory tests may include D-dimer, fibrinogen, prothrombin time, activated partial thromboplastin time, antithrombin activity, platelet count, neutrophil count, procalcitonin, triglycerides, ferritin, C-reactive protein, and hemoglobin. For patients with evidence of worsening acro-ischemia, regular monitoring of these values up to several times per week can allow for initiation of vascular intervention, including angiontensin-converting enzyme inhibitors, statins, or antiplatelet drugs.³² The presence of antiphospholipid antibodies also has been associated with critically ill patients who develop digit ischemia as part of the sequelae of COVID-19 infection and therefore may act as an important marker for the potential to develop disseminated intravascular coagulation in this patient.³³ Even if COVID-19 infection is not suspected, a thorough review of systems is important to look for an underlying connective tissue disease, such as systemic lupus erythematosus, which is associated with pernio. Associated symptoms may warrant workup with antinuclear antibodies and other appropriate autoimmune serologies.

If there is any doubt of the diagnosis, the patient is experiencing symptoms from the lesion, or the patient is experiencing other viral symptoms, it is appropriate to biopsy immediately to confirm the diagnosis. Prior studies have identified fibrin clots, angiocentric and eccrinotropic lymphocytic infiltrates, lymphocytic vasculopathy, and papillary dermal edema as the most common features in chilblainslike lesions during the COVID-19 pandemic.⁹

For COVID-19 testing, many studies have revealed adult patients with an acute hypercoagulable state testing positive by SARS-CoV-2 PCR. These same patients also experienced thromboembolic events shortly after testing positive for COVID-19, which suggests that patients with elevated D-dimer and fibrinogen likely will have a viral load that is sufficient to test positive for COVID-19.^32,34-36 It is appropriate to test all patients with suspected COVID-19, especially adults who are more likely to experience adverse complications secondary to infection.

This patient experiencing COVID-19 symptoms with signs of acral ischemia is likely to test positive by PCR, and additional testing for serologic antibodies is unlikely to be clinically meaningful in this patient’s state. Furthermore, there is little evidence that serology is reliable because of the markedly high levels of both false-negative and false-positive results when using the available antibody testing kits.³⁷ The latter evidence makes serology testing of little value for the general population, but particularly for patients with acute COVID-19.

Conclusion and Outstanding Questions

There is evidence suggesting an association between chilblainslike lesions and COVID-19.^11,22,38,39 Children presenting with these lesions have an excellent prognosis and only need a workup or treatment if there are other symptoms, as the lesions self-resolve in the majority of reported cases.^7-9 Adults presenting with these lesions and without symptoms likewise are unlikely to test positive for COVID-19, and the lesions typically resolve spontaneously or with first-line treatment. However, adults presenting with these lesions and COVID-19 symptoms should raise clinical concern for evolving skin manifestations of acro-ischemia. If the diagnosis is uncertain or systemic symptoms are concerning, biopsy, COVID-19 PCR, and other appropriate laboratory workup should be obtained.

There remains controversy and uncertainty over the relationship between these skin findings and SARS-CoV-2 infection, with clinical evidence to support both a direct relationship representing convalescent-phase cutaneous reaction as well as an indirect epiphenomenon. If there was a direct relationship, we would have expected to see a rise in the incidence of acral lesions proportionate to the rising caseload of COVID-19 after the reopening of many states in the summer of 2020. Similarly, because young adults represent the largest demographic of increasing cases and as some schools have remained open for in-person instruction during the current academic year, we also would have expected the incidence of chilblains-like lesions presenting to dermatologists and pediatricians to increase alongside these cases. Continued evaluation of emerging literature and ongoing efforts to understand the cause of this observed phenomenon will hopefully help us arrive at a future understanding of the pathophysiology of this puzzling skin manifestation.⁴⁰