Henry Ford Health System Henry Ford Health System Henry Ford Health System Scholarly Commons Henry Ford Health System Scholarly Commons Dermatology Articles Dermatology 7-2-2020 The spectrum of COVID-19-associated dermatologic The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 manifestations: an international registry of 716 patients from 31 countries countries Esther E. Freeman Devon E. McMahon Jules B. Lipoff Misha Rosenbach Carrie Kovarik See next page for additional authors Follow this and additional works at: https://scholarlycommons.henryford.com/dermatology_articles Recommended Citation Recommended Citation Freeman EE, McMahon DE, Lipoff JB, Rosenbach M, Kovarik C, Desai SR, Harp J, Takeshita J, French LE, Lim HW, Thiers BH, Hruza GJ, and Fox LP. The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries. This Article is brought to you for free and open access by the Dermatology at Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Dermatology Articles by an authorized administrator of Henry Ford Health System Scholarly Commons. brought to you by CORE View metadata, citation and similar papers at core.ac.uk provided by Henry Ford Health System Scholarly Commons
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Henry Ford Health System Henry Ford Health System
Henry Ford Health System Scholarly Commons Henry Ford Health System Scholarly Commons
Dermatology Articles Dermatology
7-2-2020
The spectrum of COVID-19-associated dermatologic The spectrum of COVID-19-associated dermatologic
manifestations: an international registry of 716 patients from 31 manifestations: an international registry of 716 patients from 31
countries countries
Esther E. Freeman
Devon E. McMahon
Jules B. Lipoff
Misha Rosenbach
Carrie Kovarik
See next page for additional authors
Follow this and additional works at: https://scholarlycommons.henryford.com/dermatology_articles
Recommended Citation Recommended Citation Freeman EE, McMahon DE, Lipoff JB, Rosenbach M, Kovarik C, Desai SR, Harp J, Takeshita J, French LE, Lim HW, Thiers BH, Hruza GJ, and Fox LP. The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries.
This Article is brought to you for free and open access by the Dermatology at Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Dermatology Articles by an authorized administrator of Henry Ford Health System Scholarly Commons.
brought to you by COREView metadata, citation and similar papers at core.ac.uk
provided by Henry Ford Health System Scholarly Commons
Authors Authors Esther E. Freeman, Devon E. McMahon, Jules B. Lipoff, Misha Rosenbach, Carrie Kovarik, Seemal R. Desai, Joanna Harp, Junko Takeshita, Lars E. French, Henry W. Lim, Bruce H. Thiers, George J. Hruza, and Lindy P. Fox
This article is available at Henry Ford Health System Scholarly Commons: https://scholarlycommons.henryford.com/dermatology_articles/463
Lars E. French, MD,g,h Henry W. Lim, MD,i Bruce H. Thiers, MD,j George J. Hruza, MD, MBA,k andLindy P. Fox, MDl
Boston, Massachusetts; Philadelphia, Pennsylvania; Dallas and Plano, Texas; New York, New York;
Munich, Germany; Miami, Florida; Detroit, Michigan; Charleston, South Carolina; St Louis, Missouri; and
San Francisco, California
Background: Coronavirus disease 2019 (COVID-19) has associated cutaneous manifestations.
Objective: To characterize the diversity of cutaneous manifestations of COVID-19 and facilitateunderstanding of the underlying pathophysiology.
Methods: Case series from an international registry from the American Academy of Dermatology andInternational League of Dermatological Societies.
Results: The registry collected 716 cases of new-onset dermatologic symptoms in patients with confirmed/suspected COVID-19. Of the 171 patients in the registry with laboratory-confirmed COVID-19, the mostcommon morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%),vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%). Pernio-like lesions were common inpatients with mild disease, whereas retiform purpura presented exclusively in ill, hospitalized patients.
Limitations: We cannot estimate incidence or prevalence. Confirmation bias is possible.
Conclusions: This study highlights the array of cutaneous manifestations associated with COVID-19. Manymorphologies were nonspecific, whereas others may provide insight into potential immune or inflammatorypathways in COVID-19 pathophysiology. ( J Am Acad Dermatol https://doi.org/10.1016/j.jaad.2020.06.1016.)
COVID-19, caused by severe acute respiratory syn-drome coronavirus 2 (SARS-CoV-2), has associatedcutaneous manifestations.1 Case series have docu-mented pernio-like lesions,2-7 erythematous maculesor papules,5,6,8 urticarial,8,9 morbilliform,9 varicelli-form,5,6,8-10 papulosquamous,11 petechial erup-tions,9,12 livedo reticularis-like rashes,5,9 purpuriclesions,5 acro-ischemiclesions,13 and retiform pur-pura.14 The timing of erup-tions in the disease courseand potential associations be-tween morphologic subtypeswith different COVID-19eas-sociated syndromes and/oroutcomes remain unclear.
Dermatologic manifesta-tions of infectious diseasesare important for identifyingand treating viral illnessesincluding HIV, dengue, andchikungunya. Expert guid-ance in recognizing thesesigns represents an opportu-nity to improve diagnosis and management.Identification and characterization of COVID-19skin lesions, like the well-described associationwith anosmia, may prompt suspicion for SARS-CoV-2 infection.15 Thus, dermatologists at HarvardMedical School and Massachusetts General Hospitalcreated the COVID-19 Dermatology Registry and, incollaboration with the American Academy ofDermatology (AAD) and International League ofDermatologic Societies (ILDS), invited health careworkers globally to submit data for possible cuta-neous manifestations of confirmed or suspectedCOVID-19.16
For this study, we aimed to (1) characterizeinternationally representative cutaneous manifesta-tions of confirmed/suspected COVID-19 and 2)identify cutaneous manifestations that may provideinsight into the pathophysiology and disease courseof COVID-19.
METHODSIn collaboration with the AAD and ILDS, we
established an international registry to collect casesof COVID-19 cutaneous manifestations (www.aad.org/covidregistry); the registry is open to medicalprofessionals only, from any specialty.7 No protectedhealth information was collected, and all data weredeidentified. The registry collected COVID-19diagnosis type (suspected vs laboratory confirmed),demographics, comorbidities, dermatologic condi-tion details, timing of symptoms, skin biopsy results,
COVID-19 symptoms and outcomes, includinghospitalization, oxygen and ventilator requirements,and deaths. Providers were prompted by e-mail forcase updates.
Suspected or laboratory-confirmed COVID-19cases with new-onset dermatologic findingswere eligible for inclusion in the initial
analysis. Patients whoseeruptions were identified asdrug induced by submittinghealth care providerswere analyzed separately.Additional analysis was per-formed on the laboratory-confirmed COVID-19 patientsubgroup. For patients withpernio-like lesions, weexcluded those with priorpernio history. Data wereanalyzed by using Stata(version 16). The PartnersHealthcare institutional re-view board approved thisstudy, which did not meet
the definition of human subjects research.
RESULTSFrom April 8 to May 17, 2020, 716 cases of
new-onset dermatologic manifestations in the settingof confirmed/suspected COVID-19 were enteredinto the registry by dermatologists (54%), otherphysicians (32%), midlevel practitioners (7.3%),nurses (2.8%), and other medical professionals(3.4%). Cases were reported from 31 countries,most (89%) from the United States. Seven casesdesignated by providers as medication-inducedwere analyzed separately and excluded fromsubgroup analysis of laboratory confirmed cases(Supplemental Table I; available via Mendeley athttp://doi.org/10.17632/gh945hpwy3.1), and 27cases with prior pernio history were excluded. Atotal of 171 cases (25%) were laboratory confirmed:135 by polymerase chain reaction (PCR), 19 byantibody, and 17 by unspecified testing (positiveresult on COVID-19 laboratory assay, but the specifictest performed was unreported or unknown). Themedian age of patients with laboratory-confirmedCOVID-19 was 44 years (interquartile range [IQR],28-61), and 54% were female (Table I).
In the 171 patients with laboratory-confirmedCOVID-19, the most common morphologies weremorbilliform (22%), pernio-like (18%), urticarial(16%), macular erythema (13%), vesicular (11%),papulosquamous (9.9%), and retiform purpura(6.4%) (for clinical photos, see Supplemental Fig 1;
CAPSULE SUMMARY
d In this international registry, the mostcommon dermatologic morphologies in171 COVID-19 laboratory-confirmedcases included morbilliform (22%),pernio-like (18%), urticarial (16%),macular erythema (13%), vesicular (11%),papulosquamous (9.9%), and retiformpurpura (6.4%).
d Pernio-like lesions were noted in milddisease, whereas retiform purpura wasseen exclusively in critically ill patients.
available via Mendeley at http://doi.org/10.17632/gh945hpwy3.1). A subgroup analysis of patients sub-mitted by dermatologists showed similar distribution(Supplemental Table II; available via Mendeley athttp://doi.org/10.17632/gh945hpwy3.1). A minorityof patients presented with multiple morphologies,including 4 cases of morbilliform plus urticarial rash,and 2 cases of morbilliform plus pernio. Six reportsinvolvedmucousmembranes (4 of oral mucosa and 2of conjunctivae). Of 17 reports of edema, most (71%)were associated with another cutaneous finding.
Skin symptoms and affected body sites varied bymorphology (Table II). For example, morbilliformmorphologies were often pruritic and involved thetrunk, whereas pernio morphologies often causedpain/burning and involved the feet/hands. The facewas involved in 21% of morbilliform rashes. Retiformpurpura were on the extremities and buttocks. Thefull course of laboratory-confirmed rashes lasted amedian of 7 days (IQR, 3-10). Pernio, however, had alonger course, with a median of 14 days (IQR, 8-24).Full duration could be determined only for resolvedlesions. Most patients (72%) had ongoing lesions;therefore, these values may underestimate duration.
Lesions generally occurred after (64%) or concur-rent (15%) with other COVID-19 symptoms. Inparticular, skin lesions occurred after COVID-19symptoms for morbilliform (76%), pernio-like(48%), urticarial (67%), macular erythema (57%),vesicular (72%), papulosquamous (53%), and reti-form purpura (91%) morphologies. A minorityoccurred before other COVID-19 symptoms (12%).
Many patients with laboratory-confirmed COVID-19 and dermatologic findings had no clear docu-mented COVID-19 exposure (Table III). The mostcommon COVID-19 symptoms among laboratory-confirmed cases included fever (61%) and cough(59%). With respect to Centers for Disease Controland Prevention (CDC)edefined PCR test qualifyingsymptoms, patients with pernio-like skin lesions metfewer CDC testing criteria, meeting 3 or more criteriain 29%, compared to morbilliform eruptions (55%),urticaria (70%), macular erythema (74%), or vesiculareruptions (61%).17 An additional 8.8% of patients withlaboratory-confirmed COVID-19 were asymptomatic
aside from rash. Pernio-like lesions were not associ-ated with other COVID-19 symptoms in 19%.
The most common medical comorbiditiesincluded hypertension (16%), diabetes (12%), andsmoking (12%). Most patients did not receiveCOVID-19especific treatment (60%). For the 69patients receiving COVID-19 treatment, 55%received antimalarial agents, and 50% receivedantibiotics including azithromycin (56%), ceftriax-one (37%), vancomycin (37%), piperacillin-tazobactam (29%), and doxycycline (27%).Treatment preceded the COVID-19eassociateddermatologic condition in 56%. For morbilliformrashes, 37% received no treatment, 15% receivedtreatment before morbilliform rashes started, and48% received treatment after morbilliform rash onset.
Hospitalization varied: 16% of patients withpernio-like lesions were hospitalized, compared to35% for all other COVID-19 dermatologic manifes-tations. Patients with retiform purpura tended to besicker; 100% were hospitalized and 82% had acuterespiratory distress syndrome (Table III and Fig 1).For the 60 hospitalized patients with laboratory-confirmed COVID-19, 24 (40%) required invasivemechanical ventilation and/or extracorporeal mem-brane oxygenation, and 17 (28%) required supple-mental oxygen. Themost common complicationwasacute respiratory distress syndrome, in 23 (38%). Tenpatients died, including those with morbilliform rashand macular erythema (n = 2), urticaria (n = 1),acrocyanosis and pernio-like lesions (n = 1), acro-cyanosis (n = 1), livedo-reticularis (n = 1), retiformpurpura (n = 2), livedo racemosa (n = 1), retiformpurpura and livedo racemosa (n = 1), and pernio-likelesions, acrocyanosis, and petechiae (1).
Dermatopathology (Table IV) was available from 14laboratory-confirmed cases (15 total biopsies). Sixpatients with clinical retiform purpura and/or livedoracemosa showed thrombotic vasculopathy. One pa-tient with clinically described buttock pressure injuryalso showed thrombotic vasculopathy. Another patientwith a complicated hospital course also developedbuttock pressure injury and retiform purpura, but thebiopsy showed only clotting and pressure necrosis.One patient with palpable purpura with ulcerationshowed leukocytoclastic vasculitis. Two patients withpapulosquamous morphologies showed spongiosisand dermal inflammation. One patient with pernio-like lesions had vacuolar interface dermatitis, subepi-dermal edema, and superficial and deep lymphocyticinflammation. One patient with an acrally distributedpetechial, macular, and urticarial eruption showeddiffuse vacuolar interface dermatitis with numerousdyskeratotic keratinocytes, sparse perivascular
Abbreviations used:
AAD: American Academy of DermatologyIQR: interquartile rangePCR: polymerase chain reactionSARS-CoV-2: severe acute respiratory syndrome
lymphohistiocytic inflammation, and rare dermaleosinophils.
DISCUSSIONThis study highlights the wide variety of
cutaneous manifestations of COVID-19 reportedconcurrently with or after COVID-19 diagnosis. Themost common morphologies in laboratory-
confirmed cases in our registry include morbilliform,pernio-like, urticarial, macular erythematous, vesic-ular, papulosquamous, and retiform purpura. Manyof these morphologies occur with different viralinfections and, thus, may not provide specific insightinto pathophysiology or treatment targets. However,others may suggest potential immune or inflamma-tory pathways involved in COVID-19 pathogenesis.Furthermore, by documenting this constellation of
Table II. Dermatologic findings in patients with laboratory-confirmed COVID-19
Characteristics
Laboratory-confirmed COVID-19
Morbilliform
(n = 38)*
Pernio
(n = 31)
Urticarial
(n = 27)
Macular
erythema
(n = 23)
Vesicular
(n = 18)
Papulosquamous
(n = 17)
Retiform
purpura
(n = 11)
Age, y, median (IQR) 52 (36-66) 35 (22-59) 42 (29-54) 31 (27-55) 55 (36-58) 28 (27-38) 66 (51-73)Female sex, n (%)y 19 (50) 16 (52) 21 (78) 16 (70) 10 (56) 7 (41) 2 (18)Body site affected, n (%)Face 8 (21) d 8 (30) 6 (26) 6 (33) 4 (24) dHead (excluding face) 2 (5.3) d 4 (15) 1 (4.3) 1 (5.6) d dNeck 10 (26) d 5 (19) 6 (26) 1 (5.6) 4 (24) dChest 19 (50) d 8 (30) 8 (35) 6 (33) 8 (47) dAbdomen 24 (63) d 11 (41) 9 (39) 8 (44) 11 (65) dBack 23 (61) d 11 (41) 11 (48) 6 (33) 11 (65) dArm 21 (55) d 13 (48) 11 (48) 8 (44) 11 (65) 2 (18)Hand 7 (18) 10 (32) 7 (48) 4 (18) 7 (39) 3 (18) 3 (27)Genitals 2 (5.3) d 1 (3.7) d 2 (11) 2 (12) dLegs/buttocksz 22 (58) d 14 (52) 10 (44) 8 (44) 11 (65) 7 (64)Foot 7 (18) 26 (84) 6 (22) 5 (22) 3 (17) 2 (12) 2 (18)Entire body 4 (11) d 4 (15) 1 (4.3) d d d
Before COVID-19 symptoms 3 (7.9) 5 (16) 2 (7.4) 2 (8.7) 1 (5.6) 3 (17.6) 1 (9.1)After COVID-19 symptoms 29 (76) 15 (48) 18 (67) 13 (57) 13 (72) 9 (53) 10 (91)At the same time as COVID-19 5 (13) 3 (9.7) 6 (22) 7 (30) 4 (22) 4 (24) dNo other COVID-19 symptoms 1 (2.6) 6 (19) 1 (3.7) 1 (4.3) d 1 (5.9) d
Most likely etiology, as determinedby health care provider, n (%)x
COVID-19 related 27 (71) 28 (90) 20 (74) 21 (91) 16 (89) 13 (77) 9 (82)Related to another virus 4 (11) 2 (6.5) 4 (15) d d 2 (12) dPostviral rash 6 (16) d 3 (11) 1 (4.3) 2 (11) 2 (12) dUnsure 1 (2.6) 1 (3.2) d 1 (4.3) d d 2 (18)
Comorbid dermatologic conditionContact dermatitis 1 (2.6) d d 1 (4.3) d 3 (18) dAlopecia areata d d 1 (3.7) 1 (4.3) d 2 (12) dMelanoma 2 (5.3) 1 (3.2) d d d d dHidradenitis suppurativa d 1 (3.2) d d 1 (5.6) d d
IQR, Interquartile range.
*Because providers could select more than 1 rash morphology, some patients are double counted (ie, patient had both morbilliform rash
and pernio).yDefined as sex assigned at birth.zLegs and buttocks were combined because of the questionnaire design, which changed slightly over the course of the study.xCases determined to be due to a drug have been excluded from this table and are included in the Supplemental Materials (available via
Mendeley at http://doi.org/10.17632/gh945hpwy3.1).
cutaneousmanifestations, we hope to help providersmore accurately identify signs of COVID-19.Cutaneous COVID-19 manifestations generallypresented simultaneous to or after other COVID-19symptoms. However, 12% occurred before otherCOVID-19 signs, highlighting their importance inassisting COVID-19 detection.
Similar to previous reports, pernio-like lesionswere reported more than other dermatologicmanifestations.1,7,9 The high frequency of these re-ports may reflect the media attention pernio-likelesions received, especially in April/May 2020, withproviders potentially sensitized to enter cases evenwithout laboratory confirmation.18,19 However, whenrestricted to laboratory-confirmed subgroup analysis,morbilliform and/or macular erythema presentationswere more common. Similarly, a Spanish case seriesreported half of laboratory-confirmed COVID-19dermatologic manifestations as maculopapular, 19%as pernio-like, and 19% as urticarial.6
Thirty-one patients with pernio-like lesions hadlaboratory-confirmed COVID-19dincluding 16 whohad positive results on PCRdand, therefore, were
possibly infectious. Given public health risks posedby COVID-19, new onset of pernio-like lesionsshould prompt patient-provider discussionsregarding both testing with PCR and/or antibodyassays and the role of self-isolation in concordancewith local and national guidelines. Reassuringly,pernio-like lesions usually appeared in patientswith relatively mild COVID-19 disease courses; thesepatients had fewer other COVID-19 symptoms andlesser severity (5/31 hospitalized, 2 deaths). How thisrelates to immune response to the virus andlikelihood for complications remains unclear. If notcoincidental, perhaps the underlying mechanismthat predisposed patients to pernio-like lesions isprotective, suggesting that perniomay be amarker ofa robust, effective host antiviral response limitingCOVID-19 complications.7 Although we cannotcompletely exclude epiphenomena, becausepatients may notice foot lesions more and be morelikely to seek care, this cluster is unusual. New casesappeared in geographies where winter temperaturesremained [108C and continue even during latespring’s warmer weather.
Table III. Cont’d
Characteristics
Laboratory-confirmed COVID-19
Morbilliform
(n = 38)*
Pernio
(n = 31)
Urticarial
(n = 27)
Macular
erythema
(n = 23)
Vesicular
(n = 18)
Papulosquamous
(n = 17)
Retiform
purpura
(n = 11)
Noninvasive ventilation orhigh flow oxygen
d 1 (3.2) 0 d d d 0
Ventilator and/or ECMO required 6 (16) 1 (3.2) 2 (17.4) 4 (17) 1 (5.6) d 10 (91)COVID-19 complications, n (%)None 27 (71) 26 (84) 24 (89) 17 (74) 17 (94) 17 (100) dARDS 4 (11) 1 (3.2) 1 (3.7) 4 (17) 1 (5.6) d 9 (82)Thrombotic event 3 (7.9) 2 (6.5) d 1 (4.3) d d 7 (64)Other infection 1 (2.6) 1 (3.2) 2 (7.4) 1 (4.3) d d 6 (55)Sepsis 4 (11) d 0 2 (8.7) d d 2 (18)Acute kidney injury 3 (7.9) d d 2 (8.7) d d 2 (18)Death 1 (2.6) 2 (6.5) 1 (3.7) 1 (4.4) d d 3 (27)
Comorbid medical conditions, n (%)None 21 (55) 21 (68) 17 (63) 13 (57) 12 (67) 13 (77) 2 (18)Hypertension 8 (21) 4 (13) 3 (11) 4 (17) 3 (17) 3 (18) 7 (64)Diabetes 7 (18) d 4 (15) 1 (4.3) 2 (11) 1 (5.9) 4 (36)Obstructive lung disease 3 (7.9) d 1 (3.7) 2 (8.7) 1 (5.6) 1 (5.9) 6 (55)Other lung disease 3 (7.9) 1 (3.2) 3 (11) 1 (4.3) 1 (5.6) d dRheumatologic disease 1 (2.6) 2 (6.5) d d 1 (5.6) d 1 (9.1)Cardiovascular disease 2 (5.3) 1 (3.2) d 1 (4.3) d d 1 (9.1)Kidney disease 1 (2.6) d d 2 (8.7) d 2 (12) d
ARDS, Acute respiratory distress syndrome; CDC, Centers for Disease Control and Prevention; ECMO, extracorporeal membrane oxygenation;
IL, interleukin; JAK, Janus kinase; PCR, polymerase chain reaction.
*Because providers could select more than 1 rash morphology, some patients are double counted (ie, a patient had both morbilliform rash
and pernio).yImmunoglobulin (Ig) M positive, IgG negative: n = 5; IgM negative, IgG positive: n = 1; IgM unknown, IgG positive: n = 1; unknown type of
antibodies tested: n = 4.zCDC testing criteria reviewed as of May 15, 2020, included fever, cough, sore throat, shortness of breath, myalgia, dysgeusia, anosmia, and
Of patients with other dermatologic manifesta-tions of COVID-19, including morbilliformeruptions, macular erythema, urticaria, and vesicularrashes, 22% to 45% were hospitalized, with 3 deaths.However, fixed livedo racemosa, retiform purpura,and true acral ischemia appeared in critically illpatients, corroborating others’ findings.6,14 Giventhe occurrence on acral surfaces, thesemorphologies should be distinguished frompernio-like lesions. In acral livedo racemosa,retiform purpura, and acro-ischemia, the histopath-ologic findings presented here show noninflamma-tory to pauci-inflammatory thrombi without otherfindings often associated with pernio, such asvacuolar interface changes with associated necrotickeratinocytes, papillary derma edema, and asuperficial and deep dermal lymphocytic infiltrate.This suggests that thrombotic disease in critically illpatients with COVID-19 may extend to the skin inpatients with livedo racemosa/retiform purpura/acro-ischemia, with a morphology distinct frompernio.14 One study implicated activation of thealternative complement pathway cutaneousthrombosis pathophysiology.14 Placentas in motherswith mild COVID-19 showed no viral infection butabnormal thrombus formation in the absence ofcomplement activation, suggesting that systemiccoagulopathy may not involve complement pathwayactivation in all patients.20 Why some patients
develop severe coagulopathy but others do notremains under active investigation.
Accurate evaluation and morphologic descrip-tions of subtle physical examination findings,including consideration of whether lesions areappropriate for skin biopsy, are important inevaluating acral lesions in patients with known/suspected COVID-19. This nuance is especially truein patients with skin of color, for whom theexamination of frank erythema and pernio-likelesions may be challenging. In darker skin types(Fitzpatrick IV-VI), more assiduous examination isimportant because erythema may clinically manifestas subtler dark purple/brown hyperpigmentation.
Beyond assisting with clinical examination, wesought to identify dermatologic manifestations ofCOVID-19 to improve understanding of SARS-CoV-2pathophysiology. Previously, Suchonwanit et al21
proposed that cutaneous manifestations inCOVID-19 may present in 2 mechanistic patterns:(1) clinical features similar to viral exanthems, animmune response to viral nucleotides and(2) cutaneous eruptions secondary to COVID-19systemic consequences, especially vasculitis andthrombotic vasculopathy. Although this suggesteddichotomy is a loose framework, it may prove a goodstarting point to consider our findings.
For instance, pernio-like lesions may offer anopportunity for deeper understanding of both the
Severity of COVID-19*
*Severity calculated based on percentage of patients hospitalized for COVID-19
Pernio Retiform purpuraVesicular/ Urticarial/ Macular Erythema/ Morbilliform• Feet (84%) and hands (32%)• Pain/burning (71%) and pruritus (36%)• After other COVID- 19 symptoms (49%)• Fever (35%), cough (35%);19% asymptomatic• 16% hospitalized
• Extremities and buttocks• Often asymptomatic (73%)• After other COVID -19 symptoms (91%)• Fever (64%), cough (73%), and shortness of breath (73%) • 100% hospitalized• 82% with ARDS
• Trunk and extremities• Pruritus in 61-74%• Typically after other COVID-19 symptoms (19%)• Fever (65-74%), cough (52-66%), sore throat (39-50%), shortness of breath (28-45%)• 22-45% hospitalized across groups
Fig 1. The spectrum of COVID-19 dermatologic manifestations in all patients, with severity ofdisease calculated based on the percentage of patients with each condition who werehospitalized. ARDS, Acute respiratory distress syndrome.
mechanical ventilation. Hiscourse was complicated byARDS, pulmonaryembolism, and retiformpurpura on the hands, legs,and feet.
PCR positive Thrombotic vasculopathy
Retiform purpura andlivedo reticularis
Patient required invasivemechanical ventilation. Hiscourse was complicated byARDS, pulmonaryembolism, and retiformpurpura and livedoreticularis of the arm.
PCR positive Thrombotic vasculopathy
Retiform purpura Patient was hospitalized andrequired invasivemechanical ventilation.Course was complicated byARDS, DVT, and retiformpurpura of the buttocks.
Livedo racemosa Patient required invasivemechanical ventilation, andher course was complicatedby ARDS, pulmonaryembolism, secondaryinfection, and livedoracemosa of the hand.
PCR positive Thrombotic vasculopathy
Livedo racemosa Patient required invasivemechanical ventilation.Hospital course wascomplicated by ARDS,pulmonary embolism,secondary infection, andasymptomatic livedoracemosa of the arm.
Morbilliform rash, macularerythema, and pressureinjury
At the same time as COVID-19symptoms, patientdeveloped morbilliformrash and macular erythemaover the trunk. The patientrequired invasivemechanical ventilation anddeveloped what appearedto be pressure injury on thebuttocks.
PCR positive Biopsy 1 (abdomen): interfacedermatitis;differential diagnosisincludes a drug eruptionand viral exanthem.
pathophysiology of SARS-CoV-2 and pernio as areaction pattern with multiple etiologies. Theunderlying cause of pernio-like lesions from thepathology collected suggests a primary inflammatoryprocess. Pernio-like lesions are generallynonischemic and, thus far, do not suggest systemicintravascular thromboses, unlike retiform purpuraand acral ischemia. Interferonopathies, genetic con-ditions with overproduction of type I interferons,may present with pernio-like lesions, suggesting arobust interferon response in the pathogenesis ofperniosis.22 Type I interferon is critical for antiviralimmunity, and thus, its heightened production inyoung, healthy people exposed to SARS-CoV-2 isexpected and would lead to successful viral controlbut also, hypothetically, could trigger pernio.23
Indeed, a low/delayed interferon response mightallow for uncontrolled viral replication and asubsequent cytokine storm leading to severe illnessand low incidence of pernio.23 SARS-CoV-2einfected Chinese patients with interferon-inducedtransmembrane protein 3 gene polymorphism maydevelop worsening disease in an age-dependentfashion, suggesting that an interferon-driven antiviralresponse could be necessary for early viral control.24
Our study is limited by the constraints of a caseseries, which cannot accurately estimate theprevalence or incidence of these findings. Theincidence of COVID-19 dermatologic manifestationremains unclear, with studies reporting 0.2% to20%.8,25,26 There also remains the possibility of biasdue to attribution error, given the reliance onproviders’ judgment in entering data regardingwhether findings were virus related, were from amedication, or were from other causes. Althoughproviders were prompted for case updates, mostreports represent a single snapshot, preventing fullobservation of dermatologic manifestations, diseasecomplications, and follow-up testing. Limited testingof COVID-19 remains a persistent issue. Only 25% ofour patients had laboratory-confirmed disease. It isdifficult to parse the effects of poor test access andfalse negative tests on our data. Furthermore, thisregistry represents a small sample of globaldermatologic manifestations; US dermatologynetworks received themost promotion, as our resultsreflect. Additionally, providers may have been morelikely to enter more severe cases.
The lack of a clear definition for COVID-19eassociated skin findings may restrict extrapolationfrom these data, such as, the nonspecific term COVIDtoes, whichmay incorporate a variety of acral lesions.Only half of medical professionals entering caseswere dermatologists, making morphologic misclas-sification possible; without photographs to confirm,
we cannot ensure consistent description. As moredata emerge, we should examine specific subsets(eg, angulated distal purpura, erythema multiforme-like lesions, and true pernio-like lesions) that mayhave distinct clinical morphologies, histologic pat-terns, and pathophysiology. Nevertheless, webelieve that better recognition of these manifesta-tions, whether from the disease itself or frommedications for COVID-19, will provide insight intodisease characterization and management.27
Our cases lacked diversity in representation, withonly 34 Hispanic/Latino and 13 Black/AfricanAmerican patients. This poor racial/ethnic diversityin the classification of COVID-19 dermatologicmanifestations is problematic, especially given thatphotos of these lesions in darker skin types may helppatients and providers identify early signs ofCOVID-19.28 Disparities in the number ofCOVID-19 hospitalizations and outcomes show adisproportionate impact on these populations.29
Lack of race and ethnicity data reporting in statehealth department registries of COVID-19 cases hascomplicated this issue.30 Early recognition,diagnosis, and management of cutaneousmanifestations of COVID-19 in patients with skin ofcolor provides an additional way in which healthcare providers can help care for underrepresentedminority populations, thereby reducing the healthcare disparities seen with COVID-19.
In conclusion, we show a spectrum ofCOVID-19erelated dermatoses. These cutaneousmanifestations may present with other COVID-19symptoms, and others may represent postviralinflammatory responses. Our study highlights thatpernio-like lesions are associated with milderCOVID-19 disease courses, whereas retiform pur-pura is associated with severe disease in critically illpatients. Further investigation is needed to preciselyascertain the timing of findings, the pathophysiologybehind different morphologies, and potential anti-body response in patients who may have only mildCOVID-19 symptoms.31-35 Dermatologic findingsshould not be overlooked as signs of COVID-19and should prompt discussions between physiciansand patients regarding isolation and possible testing.
We would like to acknowledge Drs Dawn Thompson,James Melia, Kristin Poshkus, Sanah Ali, Laura Braham,Antonia Calvo Cano, Pamela Davis, Javier Gelvez, SamuelGettler, Hector Iglesias, Neelam Neupane, Nicole Rocca,Sabrina Newman, Frankie Marmolejo, Vesna Petronic-Rosic, Noufal Raboobee, Elizabeth Seiverling, DeniseGrace, Andrea Maderal, Adelaida Solomon, JohnBartolini, and Emily Wise for providing clinicalphotographs. We would also like to acknowledge DrsRina Allawh, Rebecca Tamez, Jennifer Abrahams, Clara
Cokonis, Laura Jerome, Edward Butler, and Tess Peters forproviding dermatopathology results. We appreciate all thehealth care providers worldwide who entered cases in thisregistry.
REFERENCES
1. Jia JL, Kamceva M, Rao SA, Linos E. Cutaneous manifestations
of COVID-19: a preliminary review. J Am Acad Dermatol. 2020;
83:687-690.
2. Fernandez-Nieto D, Jimenez-Cauhe J, Suarez-Valle A, et al.
Characterization of acute acro-ischemic lesions in non-
hospitalized patients: a case series of 132 patients during
the COVID-19 outbreak. J Am Acad Dermatol. 2020;83:e61-e63.
3. Piccolo V, Neri I, Filippeschi C, et al. Chilblain-like lesions
during COVID-19 epidemic: a preliminary study on 63 patients.