Dermatologic Findings in COVID-19: A Review of the Literature

By Jacob Mathew, Jr., DO, FACOI, FACP, CHSE, FAWM

First, some background.

In late December 2019, a novel form of coronavirus (termed SARS-CoV-2) was discovered after a clustered group of patients in the Hubei province of Wuhan, China presented with unexplained cases of pneumonia that led to severe respiratory distress. (Contini, et al., 2020) The spectrum of disease caused by this coronavirus was dubbed COVID-19, a short-hand for COronaVIrus Disease 2019. The World Health Organization (WHO) classified the virus as a pandemic March 11, 2020, with spread to over 37 countries, including the United States. While there were a lot of unknowns surrounding the virus (eg, Are there any specific symptoms to watch out for? How contagious is it? How does it spread?), we did start to learn that respiratory symptoms such as cough and dyspnea were almost universal among patients. We have since expanded our screening to include patients with fevers, ageusia, anosmia, and diarrhea. Beyond the respiratory and gastrointestinal manifestations, one interesting discovery has recently emerged: unique and unexplained dermatologic manifestations.

How common are rashes with viral infections?

Many viral processes are associated with exanthemas. COVID-19 is no different given that it is caused by a variant RNA virus, which have been well-documented to be associated with cutaneous lesions such as maculopapular rashes and enanthems (See Table 1).

What are dermatologists seeing?

As the virus spread around the world, we saw larger initial clusters in Southeast Asia and Italy. Although rare (only seen in 2 of the 1,099 patients with COVID-19 in China), increasing numbers of reports of skin manifestations that are being directly attributed to the virus are now surfacing worldwide. (Alramthan & Aldarajj, 2020) (Mahe, Birckel, Krieger, Merklen, & Bottlaender, 2020) Unfortunately, given the gravity of the situation as well as the large unknown that remains, clinical photos are largely unavailable. Instead, we have relied solely on descriptions of the lesions reported. As a result, it may be prudent to review the terminology that you may encounter when reading case reports or health records (See Table 2).

The clinical significance of the lesions remains to be determined; however, it could be an early marker of COVID-19 if the rash precedes classic respiratory symptoms as described above. (Castanedo, et al., 2020)

As reported by Sebastiano Recalcati in the Journal of the European Academy of Dermatology and Venereology, of the 88 patients observed and admitted with confirmed COVID-19, over 20% of the patients had cutaneous findings on exam attributed to the virus itself with half having manifestations after hospitalization (Recalcati, 2020). These findings included a nonspecific erythematous rash, urticaria, and vesicles that resembled chickenpox. While the urticaria and vesicles were widespread, the trunk was almost universally involved in all patients, with no association found between lesion occurrence and disease severity overall. Subjectively, there was very little associated pruritus with the skin lesions, which collectively resolved within days after initial presentation. Castanedo et al. published a case report in a patient also with an urticarial rash and edema with papules involving the thighs, arms, and forearms but sparing of the palms and soles. (Castanedo, et al., 2020) Similar to Recalcati’s cases, this patient had limited associated pruritus.

Used with permission from Lindy P. Fox, MD

While not all cases have been followed with histological analysis, those that were biopsied revealed lymphocytic infiltrates with papillary edema and vacuolar interface dermatitis. (Amatore, et al., 2020) What does this mean for the non-dermatologist? The rashes in those with COVID-19 may not be unique at all but instead resemble nonspecific viral exanthems. (Amatore, et al., 2020)

The non-specific appearance of the rash can also lead to misdiagnosis. Joob et al. reported that patients out of Thailand who presented with petechiae were potentially being misdiagnosed as having Dengue fever, given the concurrent hematologic manifestations that can occur in both Dengue fever and COVID-19. (Joob & Wiwanitkit, 2020) Mahe et al. describes the maculopapular rash resembling Symmetrical Drug-Related Intertriginous and Flexural Exanthema (SDRIFE) in a COVID patient taking paracetamol. (Mahe, Birckel, Krieger, Merklen, & Bottlaender, 2020) These cases illustrate the importance of not only casting a wide net for the differential diagnoses considered, but knowing local and ethnic infectious disease patterns.

In recent literature, there have been multiple reports of chilblain-like lesions in the toes that suggests that the dermatologic manifestations may be an immune reaction to the virus. (Ahouach, et al., 2020) (Alramthan & Aldarajj, 2020) The upper extremities may not be spared, as case reports out of the Middle East also describe patients who tested positive for the disease with maculopapular rashes on their fingers bilaterally. (Alramthan & Aldarajj, 2020) Why do these lesions occur in the extremities? It is hypothesized that with the known hypercoagulable state that often occurs with more severe COVID-19 cases, it could be signs of ischemia that are occurring. (Zhonghua, Ye, & Za, 2020)  (Magro, et al., 2020) As a result, any extremity involvement should be followed by a through vascular exam to ensure the limb is not threatened.

covid_fingers_huang.jpg
Used with permission from Jennifer Huang, MD

Rashes have not been isolated to adults but are now appearing in children as well. In early May 2020, 15 children in the New York City area were found to have clinical presentations resembling atypical Kawasaki disease (KD). (Haelle, 2020) Kawasaki disease is a vasculitic condition affecting medium-caliber blood vessels in young children that can lead to cardiovascular pathology, with a reported incidence rate of 1:4000. (Sundel, 2014) It is considered to be an autoimmune reaction commonly due to an underlying concurrent infection. Serum analysis of the affected children showed biomarkers (ie, ESR, C-RP, coronavirus RT-PCR) consistent with severe COVID-19. Identification of co-existing KD is imperative as patients may require IVIG to prevent coronary manifestations such as aneurysms. (Harahsheh, et al., 2020)

Overall, the initial speculation is that the presenting dermatologic findings may be expected with any viral condition and may not be unique to COVID-19 itself; however, with time we may be able to evaluate cases to determine if unique characteristics do exist that may warrant individualized treatments.

TABLE 1 | Non-inclusive differential diagnosis of fever and rash (Castanedo, et al., 2020) (Matthews, 2017)(VisualDX) (Muzumdar Sonal, 2018) (Anderson, Horn, Hoang, Gottlieb, & Bennin, 2004)
Condition
Background
Cutaneous Manifestation

Parvovirus B-19

 

  • Due to single-stranded DNA virus
  • Mostly transmitted via respiratory droplets
  • Cutaneous symptoms may only occur in school-aged children with risk for vertical transmission
  • May present with arthropathy in adults
  • Erythema infectiosum (Fifth’s disease)
  • Erythematous malar rash
  • Reticulated rash on trunk/limbs

Rubella

  • Also known as German measles
  • Respiratory transmission that can incubate for 14-21 days
  • Rash, which may present in only 75% of patients, can take up to 1 week to manifest
  • Petechial macules on soft palate (Forcheimer spots)
  • Small papules (remain isolated on extremities)
  • Coalescence (in the trunk) with later desquamation

Rubeola

  • Caused by single-stranded RNA virus
  • Primarily seen in late winter and spring
  • Can occur in adults but is more often seen in children
  • Declared eliminated from the US in 2000
  • Rash occurs after fever, nasal congestion, and cough but may be absent if patient is immunocompromised
  • Koplik spots are lesions within the oral buccal mucosa that are hypopigmented near the second molars

Zika Virus

Source: CDC 

  • Associated with recent travel history to endemic regions (eg, Africa, Southeast Asia, Caribbean islands)
  • May not have associated systemic symptoms
  • Maculopapular rash initially on the face then progressing to the trunk and eventually legs
  • High concern in those who are pregnant or are around someone pregnant

West Nile Virus

  • Associated with recent travel history to endemic regions (eg, Africa, Europe, West Asia)
  • Systemic symptoms of fever, myalgias, headaches common along with altered mental status
  • Nonspecific maculopapular exanthem on the trunk

Human Immunodeficiency Virus

  • In early presentation, may be associated with fevers
  • May be mistaken for mononucleosis
  • High suspicion based on risk factors: intravenous drug use, high-risk sexual behaviors, recent incarceration
  • Maculopapular rash on the face, hands, trunk
  • Rash within first 2-6 weeks of infection may only last 7 days

 

TABLE 2 | Essential morphological terms used to describe primary skin lesions (Kang, 2015) (Linton, 2011)
Lesion
Description
Example
Macule

Flat, circumscribed area of discoloration, with no skin elevation or depression; less than 10 mm.

Freckle
Papule Solid, raised lesion up to 10 mm in greatest diameter. Wart
Nodule Similar to papule but located deeper in the dermis or subcutaneous tissue; larger than 10 mm. Dermatofibroma
Plaque Elevation of skin occupying a relatively large area (> 10 mm) in relation to height, well circumscribed. Psoriasis
Pustule Circumscribed elevation of skin containing purulent fluid (composed of neutrophils) of varying colors (white, yellow) that may or not be infectious in etiology. Bacterial folliculitis
Vesicle Circumscribed, elevated, fluid containing lesion < 10 mm in diameter that is superficial in location. Fluid may be clear, serous, or hemorrhagic. Herpes zoster
Bulla Same as vesicle, except lesion is > 10 mm in greatest diameter Pemphigus vulgaris
Patch Similar to the description of a macule but larger in size (> 10 mm). Vitiligo
Tumor Solid lesion that is > 20 mm in diameter that may be below the skin surface. Metastatic cancer

 What about dermatologic conditions in COVID-19 healthcare workers?

Lastly, we cannot forget those who are taking care of COVID-19 patients around the world. Due to the highly infectious nature of this coronavirus, we are seeing escalating cases of contact dermatitis and eczema related to the infection-prevention measures instituted in the hospital systems (eg, persistent washing of hands with soap and water, using alcohol-based solutions, wearing non-latex gloves). (Lan J, 2020) (Organization, 2009) (America, 2020) In a questionnaire of healthcare providers sent by Lan et al, they found that 97% of first-line healthcare workers reported some form of skin damage. Reported areas of involvement included the nasal bridge (masks), cheeks, forehead, and hands (dryness, desquamation). The concern with the dermatologic findings on the hands specifically is for the desquamation acting as a potential nidus for eventual infection.

What can be done? Carrying a pocket tube of moisturizer and applying it to the hands after washing with soap and warm water can help prevent dryness from occurring. No specific moisturizer is recommended by the WHO. If the moisturizer does not seem to be effective, then reaching out to your primary care provider for a prescription-strength topical therapy for eczema may be required. Finally, given the widespread use of antiseptic wipes, clinical staff should use gloves when handling these items as they can be irritating or toxic to the skin.

References

Ahouach, B., Harant, S., Ullmer, A., Martres, P., Begon, E., Blum, L., . . . Bachmeyer, C. (2020). Cutaneous lesions in a patient with COVID-19: are they related? British Journal of Dermatology.

Alramthan, A., & Aldarajj, W. (2020). A case of COVID-19 presenting in clinical picture resembling chilblains disease. First report from the Middle East. Clin Exp Dermatol. .

Amatore, F., Macagno, N., Mailhe, M., Demarez, B., Gaudy-Marqueste, C., & Grob, C. (2020). SARS-CoV-2 infection presenting as a febrile rash. Journal of the European Academy of Dermatology and Venereology.

America, A. a. (2020, March 12). Eczema, Hand-Washing and the New Coronavirus (COVID-19): Protecting Yourself and Your Skin. Retrieved from Asthma and Allergy Foundation of America Community Services: https://community.aafa.org/blog/eczema-wash-hands-coronavirus-covid19-prevention

Anderson, R. C., Horn, K. B., Hoang, M. P., Gottlieb, E., & Bennin, B. (2004). Punctate exanthem of West Nile Virus infection: Report of 3 cases. Journal of hte American Academy of Dermatology.

Castanedo, L. Q., Feito-Rodriguez, M., Valero-Lopez, I., Chiloeches-Fernandez, C., Sendagorta-Cudos, E., & Herranz-Pinto, P. (2020). Urticarial exanthem as early diagnostic clue for COVID-19 infection. JAAD Case Reports.

Contini, C., Di Nuzzo, M., Barp, N., De Giorgio, R., TOgon, M., & Rubino, S. (2020). The novel zoonotic COVID-19 pandemic: An expected global health concern. J Infect Dev Ctries.

Haelle , T. (2020). Novel Inflammatory Syndrome in Children Possibly Linked to COVID-19. Medscape Internal Medicine.

Harahsheh, A. S., Dahdah, N., Newburger, J., Portman, M., Piram, M., Tulloh, R., . . . Ferranti, S. (2020). Missed or Delayed Diagnosis of Kawasaki Disease During the 2019 Novel Coronavirus Disease (COVID-19) Pandemic. J Pediatr.

Joob, B., & Wiwanitkit, V. (2020). COVID-19 can present with a rash. Journal of the American Academy of Dermatology.

Kang, J. H. (2015). Febrile Illness with Skin Rashes. Infect Chemother, 155-166.

Lan J, S. Z. (2020). Skin damage among health care workers managing coronavirus disease-2019. J Am Acad Dermatol.

Linton, C. (2011). Essential Morphologic Terms and Definitions. Journal of the Dermatology Nurses Association.

Magro, C., Mulvey, J., Berlin, D., Nuovo, G., Salvatore, S., Harp, J., . . . Laurence, J. (2020). Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Translational Research.

Mahe, A., Birckel, E., Krieger, S., Merklen, C., & Bottlaender, L. (2020). A distinctive skin rash associated with Coronavirus Disease 2019? Journal of the European Academy of Dermatology and Venereology.

Matthews, P. C. (2017). Tropical Medicine Notebook: Infections caused by RNA viruses. Retrieved from Oxford Medicine Online.

Muzumdar Sonal, R. M.-K. (2018). The Rash with Maculopapules and Fever in Adults. Clinics in Dermatology.

Organization, W. H. (2009). Skin reactions related to hand hygiene. WHO Guidelines on Hand Hygiene in Health Care: First Global Patient Safety Challenge Clean Care Is Safer Care. .

Recalcati, S. (2020). Cutaneous manifestations in COVID-19: a first perspective. Journal of the European Academy of Dermatology and Venereology.

Sundel, R. P. (2014). Kawasaki Disease. Rheumatic Disease Clinics of North America.

Zhonghua, X., Ye, X., & Za, Z. (2020). Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. CMAPH.

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