Overview of the current knowledge of cutaneous manifestations associated with SARS-CoV-2 and COVID-19

1. Skin manifestations
associated
with
COVID-19
Nicolas Kluger
Dermatology
Helsinki University Hospital

2. COVID-19 worlwide and in Finland, 18 Aug
World wide Finland
Confirmed cases 21 549 706 7 731
Confirmed death 766 158 333
https://covid19.who.int
https://thl.fi/

3. @MarkkuPeltonen, 27May 2020

4. @MarkkuPeltonen, 18 Aug 2020

5. Encephalopathy
Myocardial injury
Heart failure
Pneumonia with
hypoxemia
Embolia
SARS
Acute kidney injury
Disseminated intra-
vascular disorder
Fever
Fatigue
Myalgia
Cough
Sore throat
Runny nose
Sneezing
Nausea
Vomiting
Abdominal pain
Diarrhea
Anosmia
Dysgueusia

6. • COVID-19 SARS-CoV-2 preprints
• medRxiv 6173 articles
• bioRxiv 1629 articles
• (COVID or COVID-19 or SARS-CoV-2) AND Skin
• 513 articles
19 Aug 2020

7. Issues regarding publications in dermatology
Kittler, J Eur Acad Dermatol Venereol 2020
Kluger, J Eur Acad Dermatol Venereol 2020
Kluger, Dermatology 2020
Peer-review delay
Redondancy, duplication of patients
High volume of publication
253 articles about COVID-19 in 6
months !
IF>8
170 articles !

8. Cutaneous manifestations

9. Virus
Drug-
induced
reaction
Flare
of
dermatosis
Contact or
irritation
dermatitis
Cutaneous manifestations
Post-COVID-19 (?)

10. COVID Dermatology registry
Total cases n=682 Confirmed cases n=171
Pernio-like 72%
Morbilliform 9.2%
Urticaria 8.1%
Macular erythema 7.6%
Vesicular 7.2%
Papulosquamous 4.7%
Retiform purpura 2.6%
Morbilliform 22%
Pernio-like 18%
Urticaria 16%
Macular erythema 13%
Vesicular 11%
Papulosquamous 9.9%
Purpura 6.4%
• 716 cases from 31 countries, 89% from the USA
Freeman, J Am Acad Dermatol 2020

11. Acute urticaria
• 19% of cutaneous manifestations
• Acral, trunk or generalized
• Itchy
• Before or at onset of COVID’s symptoms
• Fever, chills, myalgia, headaches, cough…
• Familial clusters
• Nasal PCR SARS-CoV-2 +
• Mean length 6.8 days
• No sequelae
Galvan Casas, J Eur Acad Dermatol Venereol 2020
Van Damme, J Eur Acad Dermatol Venereol 2020
Henry, J Eur Acad Dermatol Venereol 2020
Cepeda-Valdes, Clin Exp Dermatol 2020

12. Maculo-papular exanthema
• 47% of cutaneous manifestations
• Perifollicular rash
• ± Purpura
• ± Pityriasis rosea – like
• ± Flexural
• Histology: superficial perivascular
lymphocytic infiltration
• Nasal PCR SARS-CoV-2 +
• Mean length 8.6 days
• No sequelae
Galvan Casas, J Eur Acad Dermatol Venereol 2020
Gianotti, Acta Dermatol Venereol 2020
Mahé, J Eur Acad Dermatol Venereol 2020
Jimenez-Cauhe, J Eur Acad Dermatol Venereol 2020

13. Pityriasis rosea
Ehsani, J Eur Acad Dermatol Venereol 2020

14. « Varicella »-like eruption/Vesicles
• 9% of cutaneous manifestations
• Series from Italy (n=22) and Spain
(n=24)
• Median age 45-60 years
• Median delay 3 to 14 days
• but could precede them from 48 h
• Papulo-vesicular rash of the trunk,
lack/mild itch.
• Median length 8(-10) days
• Histology favors viral eruption,
acantholysis
• Skin PCR negative (n=4)
• No sequelae
• Intermediate severity
Galvan Casas, J Eur Acad Dermatol Venereol 2020
Marzano, J Am Acad Dermatol 2020
Fernandez-Nieto, Clin Exp Dermatol 2020
Mahé, J Eur Acad Dermatol Venereol 2020

15. Erythema multiforme lesions
• Delay of onset 19 days (16-24 d)
• Presentation
• Erythematous papules, progressively turned to
erythemato-violaceous patches with a dusky
center, and a pseudo-vesicle in the middle
• Palms
• Mucosa: palatal macules and petechias
• Lymphocytic perivascular and interstitial
infiltrate ± interface dermatitis
• Favorable evolution with CS
• Post-viral reaction
• Always rule out drug-induced EM
Jimenzez-Cauhe, Clin Exp Dermatol 2020
Janah, J Eur Acad Dermatol Venereol 2020

16. Oral lesions
Carrer-Presas, Oral Dis 2020
Riad, Oral Dis 2020
Jimenez-Cauhe, JAMA Dermatol 2020
• Polymorphous
• Tongue, hard palate, lips
• Unclear mechanisms
• SARS-CoV-2
• Other virus (HSV, VZV)
• Drug
• Confinement
• …

17. Acute
urticaria
Infection
Hepatitis A,B,C
Exanthema
Measles, Roseola,
Rubella,..
EBV, CMV, HIV..
Zika, Chikungunya,
Dengue..
Vesicles
Chickenpox and zoster
(VZV)
Herpes (HSV)
Flexural
(APEC)
Erythema
multiforme
HSV
Pityriasis
rosea
HHV-6, HHV-7
?
Enanthema
Measles, Roseola
EBV, Herpangina,
HFM disease
HSV, VZV
Zika, Chikungunya,
Dengue

18. Miscellaneous
Kalner, JAAD Case reports 2020
Taskin, J Eur Acad Dermatol Venereol 2020
Suter, BMJ Case Rep 2020
Atypical Sweet’s syndrome
Periorbital dyschromia before onset
Erythema nodosum

19. Purpura, livedo and necrosis
• (L) Fishnet-like purpura
• (P) Exanthema with purpuric evolution
• (P) Thrombocytopenia
• (P/N) Thrombosis and coagulopathy
Galvan Casas, J Eur Acad Dermatol Venereol 2020
Abrar-Ahmad, New Engl J Med 2020
Bouaziz, J Eur Acad Dermatol Venereol 2020
Magro, Translation research 2020
Llamas-Velasco, Br J Dermatol 2020

20. Wrong
Diagnosis !
SARS-CoV-2Drug-
induced
vasculitis ?
Cutaneous vasculitis during COVID-19
Mayor-Ibarguen, JEADV 2020
Dominguez-Santas, JEADV 2020
Papa, Pain Ther 2020Vanegas Ramirez, JEADV 2020 Castelnovo, JEADV 2020

21. Pseudo-chiblains
• Increasing number of patients presenting with
chilblains-like lesions on the feet especially
• Reported in Southern Europe (France, Italy, Spain)
and USA
• No specific report from China
• Weather currently warm (“pseudo-chilblains”)
• No past history of chilblains (3%)
• Mainly seen in private practices
• Spread via social medias (Twitter, Whatsapp)
Duong TA , J Eur Acad Dermatol Venereol 2020

22. Pseudo-chiblains
• Mainly young patients
• Delayed manifestations (9 d after, 3-30 d)
• SARS-CoV-2 PCR rarely positive
• Pauci-symptomatic/mild symptoms
• No pneumopathy
• Feet (toes) > hands (fingers) or both
• ± Soles, heals
• Purplish papules/nodules
• ± vesicles or blisters, ± itchy or painful
• Possible familial cases
• Last 12 days
Piccolo V, J Eur Acad Dermatol Venereol 2020
Recalcati S, J Eur Acad Dermatol Venereol. 2020
Fernandez-Nieto, J Am Acad Dermatol 2020
Galvan Casas, J Eur Acad Dermatol Venereol 2020
Kolivras, JAAD Case reports 2020
Andina, Clin Exp Dermatol 2020

23. Negativity of PCR
during chiblains
False negative
Quality
Low viral load
Delayed reaction Wrong diagnosis
Post-viral reaction in
asymptomatic forms
Presentation in a
subgroup of
patients with
peculiar immune
response
Other diagnosis
Role of
confinement?
Omer, JAMA 2020
Bouzaziz, J Eur Acad Dermatol Venereol 2020
Torres-Navarro, Clin Exp Dermatol 2020
Docampo Simon, J Eur Acad Dermatol Venereol 2020
Herman, JAMA Dermatol 2020
NP PCR +
14-25%
Skin PCR +
0%

24. Sethuraman, JAMA 2020

25. SARS-CoV-2 antibodies rarely found with
chilblains
Denina, J Am Acad Dermatol 2020
Herman, JAMA Dermatol 2020
Hébert, J Am Acad Dermatol 2020
24 children (mean age 13 y), Italy
ELISA and chemiluminescence : 3 +/+ (12.5%) and 1+/-
Certainty of exposure to SARS-CoV-2: 2 (8%)
31 young adults ( median age 22), Belgium
NP RT-PCR negative (n=31), skin RT-PCR negative (n=22), serology negative (0%, n=31)
33 young adults (mean age 23.4), France
IIF assay and skin RT-PCR negative (n=5/5), home made Ab test negative (0%, n=33/33)

26. Exanthema
Interface dermatitis
Acantholysis,
dyskeratotic and
ballooning herpes
like keratinocytes,
Superficial
perivascular infiltrate
Vascular
Thrombosis
Complement
deposits
Vasculitis
Chilblains:
dermal oedema,
lymphocytic
perivascular and
perieccrine infiltrate
Skin PCR
Negative to date in
all kind of samples
except one case of
exanthema
Zengarini, J Eur Acad Dermatol 2020
Gianotti, Acta Dermato Venereol 2020
Fernandez-Nieto, Clin Exp Dermatol 2020
Mahé, J Eur Acad Dermatol 2020
Modified from
Salmivuori
Magro, Transl Res 2020
Bouzaziz, J Am Acad Dermatol 2020
Colonna, Ped Dermatol 2020
Jamialkowski, Lancet 2020

27. Endotheliitis during COVID-19
• Observation of direct viral infection of the
endothelial cell and diffuse endothelial
inflammation (endotheliitis) in various
organs (lung, heart, kidney, liver, small
intestine)
• SARS-CoV-2 infection facilitates the
induction of endotheliitis in several organs
as a direct consequence of viral involvement
(as noted with presence of viral bodies) and
of the host inflammatory response
Varga, Lancet 2020

28. Immunohistochemisty in a series of 7 patients with
chilblains?
Presence
of viral particles in one
case using transmission
electron microscopy
Does not look like SARS-
CoV-2Colmenero, Br J Dermatol 2020
Baeck, Br J Dermatol 2020
No control group
Positivity of all
7/7 cases despite
time differences
in biopsies

29. Immunov.fr
Sallard, Antiviral Res 2020
Gruber, Nat Rev Immunol 2020
Trouilllet-Assant J All Clin Immunol 2020

30. Damsky, J Am Acad Dermatol 2020
Lipsker, Med Hypotheses 2020

31. Interferonopathies
• Group of monogenic diseases in
which a constitutive upregulation of
type I IFN production
• Aicardi-Goutieres syndrome
• Familial chilblains lupus
• SAVI
• PRAAS
• Singleton–Merten syndrome
• Spondylochondromatosis
Munoz, Ann Dermatol Venereol 2015

32. STING-Associated Vasculopathy with onset in Infancy (SAVI)
• Autoinflammatory disease (2014)
• AD, mutation TMEM173 (GoF)
• ↗ STING-interferon pathway
• Symptoms
• Early in life (< 6 mo)
• Low-grade fever + severe vasculopathy + lung
inflammation + systemic inflammation
• Autoimmunity (ANA, ANCA)
• Blockade of interferon pathway
Liu Y, et al. N Engl J Med 2014
STimulator of INterferon Genes

33. Kawasaki - like disease associated with COVID-19
(Kawa-COVID-19)
Jones, Hosp Pediatrics 2020

34. Kawa-COVID-19
• Epidemic cases of multi-systemic inflammation
frequently associating circulatory failure with elements
in favor of myocarditis sometimes can look like an
incomplete Kawasaki’s disease
• SARS-CoV-2 Co-infection documented 2-4 weeks before
• Emerging cases in the UK, France, Belgium, Italy, Spain,
USA
• Monthy incidence x 30 in Italy in March 2020 compared
to the past 5 years
Riphagen, Lancet 2020
Verdoni, Lancet 2020
Pouletty, Ann Rheum Dis 2020

35. Symptoms
Fever (38–40°C)
Variable rash,
conjunctivitis
Peripheral oedema
Generalized
extremity pain
GI symptoms
Shock
Vasoplegic shock
Mechanical ventilation
Fluid support
Intropic support
Inflammation
In some cases,
PCR SARS-CoV-2 +
Serology often +
↗ CRP, ferritine, fibrinogen,
procalcitonine, D-dimers,
triglycerids
↗ Troponine
Macrophage activation
syndrome
Riphagen, Lancet 2020
Verdoni, Lancet 2020

36. Pouletty, Ann Rheum Dis 2020

37. Exanthema
Urticaria
Flexural rash
Varicella-like
Pityriasis rosea
Chilblain - like lesions
Purpura
Livedo
NP SARS-CoV-2 PCR positivity
Mostly ”vascular” symptoms
(delayed)
Kawasaki-like syndrome
Exanthematic symptoms
(rapid)
Erythema
multiforme -
like lesions
Onset
of COVID-19
1 to 3 weeks
Prodrome

38. Post-acute COVID-19

39. Carfi, JAMA 2020
Greenhalgh, BMJ 2020
87% of the patients still
have ≥ 1 symptom
Fatigue or dyspnea
Post-acute COVID-19 (Long COVID)
Skin conditions?

40. Effluvium telogen ?
Source Twitter

41. Not all rashes are related to
COVID-19

42. Drug-induced eruption
(any)
new medication OTC COVID-19
HCQ CQ
Acute itch
AGEP
DRESS
SJS/TEN
Well tolerated, but…
Remdesivir
Lopinavir/
Ritonavir
Biologics
Martinez-Lopez, J Am Acad Dermatol 2020

43. Acute exanthematic pustulosis after HCQ and
antiviral treatment
Robustelli Test, J Eur Acad Dermatol Venerol 2020

44. Severe side-effects with HCQ for COVID-19
• To date, four cases of AGEP
• Usually longer latency 10 – 12 days vs 24-72h
after antibiotics
• One case of DRESS
• One case of SJS
Enos, Dermatol Therap 2020
Jimenez, Contact Dermatitis 2020
Davoodi, Oxf Med Case Rep 2020

45. Exacerbation of dermatoses
Psoriasis
Seborrheic eczema
Atopic eczema
Contact dermatitis
….
Stress, anxiety
Confinement
Treatment
withdrawal
Delay in
consultation
Excessive
hygiene
Delay in diagnosis?

46. Herpes zoster during COVID-19
• Reactivation in relation to lymphopenia
Wang, Infect Dis 2020

47. Tejera-Vaquerio, J Eur Acad Dermatol Venerol 2020
Gomolin, J Dermatol Treat 2020
Delay in diagnosis due to lockdown?

48. Delay in diagnosis due to lockdown?
0
0.5
1
1.5
2
2.5
Pre-lockdown (01 Jan - 09
Mar)
Lockdown (10 Mar - 03 May) Post-Lockdown (04 May - 06
Jun)
Mean number of MM diagnosed daily
0
0.5
1
1.5
2
2.5
Pre-lockdown (01 Jan - 09
Mar)
Lockdown (10 Mar - 03 May) Post-Lockdown (04 May - 06
Jun)
Thickness (mm)
24.7%
4.2%
5.9%
5.0%
29.4%
8.3% 8.3%
0.0%
24.4%
17.6%
23.5%
14.7%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
MM in situ Nodular Ulcerated SSM with nodule
Proporitions of different histological MM during the three
COVID-19 phases
Pre-lockdown (01 Jan - 09 Mar) Lockdown (10 Mar - 03 May) Post-Lockdown (04 May - 06 Jun)
Ricci, J Eur Acad Dermatol Venerol 2020

49. Immunosuppressive treatments
Patients should continue all
immune-modulating
treatments
Consider lowering the dose of
any immunomodulator or
temporarily stopping for
2 weeks.
Stop immunomodulator
Wollenberg, J Eur Acad Dermatol Venereol 2020
FAI2R, (Apr 9, 2020)
Rademaker, Australs J Dermatol 2020

50. Gisondi, J Am Acad Dermatol 2020
Ferrucci, J Eur Acad Dermatol Venereol 2020
Conti, J Eur Acad Dermatol Venereol 2020
Messina, J Eur Acad Dermatol Venereol 2020
Balestri, J Eur Acad Dermatol Venereol 2020
Lima, J Eur Acad Dermatol Venereol 2020
Biologics
Anti-TNF alpha
IL-4Ra (Dupilumab)
IL-12/23 (Ustekinumab)
IL-23 (Guselkumab)
IL-17A (Secukinumab,
Ixekizumab)
Systemic therapies
Mycophenolate mofetil
Cyclosporine
Balestri, J Eur Acad Dermatol Venereol 2020

51. Price, J Am Acad Dermatol 2020

52. Thank you for you attention !
https://www.thesun.co.uk/news/11190723/coronavirus-tattoos-social-media-jokers-make-light-killer-virus/