10.5826/dpc.1204a170
The coronavirus pandemic has caused massive damage to global health care and the economy. COVID-19 vaccination and following the government protocols is the only way to tackle this situation. The vaccination program has been paced around the globe to return as soon as possible to pre-COVID time. Although all the vaccines have been approved after the rigorous clinical and safety trials, some adverse effects have surfaced and are being reported from different parts of the world. One such side effect is chilblain-like lesions following the COVID vaccination. Chilblain lesions, also known as pernio, are an inflammatory condition usually affecting the acral regions of the body. It is mostly reported from cold and damp areas and has multiple causes associated with it. Reporting of such similar lesions has raised concern amongst the scientific community and has led to vaccine hesitancy amongst the general population. The exact mechanism behind these lesions is still unknown. Although the incidence of this condition is low, it still requires attention from the authorities. This study aims to review the publicly available data and to provide concise and comprehensive information on chilblain-like lesions post-COVID-vaccination.
text/xml
2160-9381
2161
en
Vincenzo  Piccolo
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
Post COVID-19 Vaccination
SARS-CoV-2 Vaccination and Chilblain-like Lesions: What Do We Know So Far?
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2022-10-31
2021-11-12
2022-10-31
2022-12-01
e2022170
Dermatol Pract Concept
The coronavirus pandemic has caused massive damage to global health care and the economy. COVID-19 vaccination and following the government protocols is the only way to tackle this situation. The vaccination program has been paced around the globe to return as soon as possible to pre-COVID time. Although all the vaccines have been approved after the rigorous clinical and safety trials, some adverse effects have surfaced and are being reported from different parts of the world. One such side effect is chilblain-like lesions following the COVID vaccination. Chilblain lesions, also known as pernio, are an inflammatory condition usually affecting the acral regions of the body. It is mostly reported from cold and damp areas and has multiple causes associated with it. Reporting of such similar lesions has raised concern amongst the scientific community and has led to vaccine hesitancy amongst the general population. The exact mechanism behind these lesions is still unknown. Although the incidence of this condition is low, it still requires attention from the authorities. This study aims to review the publicly available data and to provide concise and comprehensive information on chilblain-like lesions post-COVID-vaccination.
Vincenzo  Piccolo
2022/10/31
10.5826/dpc.1204a170
e2022170
University of Campania Luigi Vanvitelli
2160-9381
Post COVID-19 Vaccination
en
e2022170
SARS-CoV-2 Vaccination and Chilblain-like Lesions: What Do We Know So Far?
https://dpcj.org/index.php/dpc/article/download/2161/1820
 SARS-CoV-2 Vaccination and Chilblain-like Lesions:
            What Do We Know so Far?
    Taha Gul Shaikh1, Summaiyya Waseem1, Syed Hassan Ahmed1, Nashwa Abdul Qadir1,
                                  Vincenzo Piccolo2


1 Dow University of Health Sciences, Karachi, Pakistan
2 Dermatology Unit, University of Campania Luigi Vanvitelli, Naples, Italy



Key words: COVID-19, COVID-19 vaccine, chilblain-like lesion, pernio-like lesion, post COVID-19 vaccination
Citation: Shaikh T, Waseem, Ahmed SH, Qadir NA, Piccolo V. SARS-CoV-2 Vaccination and Chilblain-like Lesions: What Do We Know So
Far? Dermatol Pract Concept. 2022;12(4):e2022170. DOI: https://doi.org/10.5826/dpc.1204a170
Accepted: February 14, 2022; Published: October 2022
Copyright: ©2022 Shaikh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding author: Summaiyya Waseem, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan.
E-mail: summaiyyawaseem@gmail.com




  ABSTRACT             Introduction: The coronavirus pandemic has caused massive damage to global health care and the
                       economy. The vaccination program has been paced around the globe to return as soon as possible to
                       pre-COVID time. Although all the vaccines have been approved after the rigorous clinical and safety
                       trials, some adverse effects have surfaced and are being reported from different parts of the world.
                       One such side effect is chilblain-like lesions following the COVID vaccination. Chilblain lesions, also
                       known as pernio, are an inflammatory condition usually affecting the acral regions of the body. It is
                       mostly reported from cold and damp areas and has multiple causes associated with it.
                       Objective: This study aims to review the publicly available data and to provide concise and compre-
                       hensive information as well as evaluate the potential pathology, clinical approach, and management
                       of CLL post-vaccination.
                       Methods: An extensive literature search over PubMed, Cochrane library, Google Scholar, and
                       ­Clinicaltrails.gov from inception till 5th October 2021, without any restriction of language was
                        ­carried out. All the recruited articles were reviewed, and their bibliographies were also screened for
                         any relevant information.
                       Results: 12 studies (10 case reports and 2 case series) were retrieved reporting the incidence of CLL
                       post-vaccination. 8 studies reported incidence in female patients while 5 reported in males, with one
                       study mentioning no gender. Moreover, most of them were either from Europe or the United States of
                       America, except for two cases, reported from Turkey.
                       Conclusions: Although the overall incidence of Chilblains following COVID-19 vaccination is low,
                       there is still a strong need to find out the exact mechanism behind this to redefine the safety and
                       ­administration criteria of the vaccines and to formulate a proper management protocol.


Review | Dermatol Pract Concept. 2022;12(4):e2022170                                                                                1
Introduction                                                             perivascular lymphocytic infiltrates, caused by exposure to
                                                                         non-freezing, and cold conditions. It is clinically character-
In December 2019, a zoonotic RNA virus SARS-Cov-2                        ized by bluish-purple papules on acral surfaces, as shown
was isolated in a Chinese patient. The disease caused by                 in Figure 2. The causes vary from idiopathic acrosyndrome
it was termed COVID-19 that has spread at an enormous                    and Raynaud’s phenomenon to systemic diseases such as au-
rate throughout the globe [1]. The high infectivity rate and             toimmune disorders, and rarely in Epstein-Barr virus (EBV)
­asymptomatic transmission have caused the quick spread                  [13–15].
leading to a pandemic [2].
    The body requires time to respond to the viral attack;
                                                                         Objectives
hence symptoms usually develop 2 to 14 days post-exposure,
typically presenting with fever, cough, dyspnea, fatigue, am-            This study aims to review the publicly available data and
nesia, and ageusia [3,4]. In acute conditions, there are inci-           to provide concise and comprehensive information as well
dents of hemoptysis and ground-glass opacities [5]. While                as evaluate the potential pathology, clinical approach, and
SARS-CoV-2 mainly causes respiratory diseases, clinicians                management of CLL post-vaccination.
have noticed other handful of extrapulmonary manifesta-
tions [6,7].
                                                                         Methods
    The only way to restore routine life is to speed up the
vaccination programs. All the currently available vaccines               Here, we scrutinize the association between coronavirus vac-
underwent rigorous trials and were approved after demon-                 cines and post-vaccination CLL by performing an extensive
strating an acceptable safety profile[8]. The most common                literature search over PubMed, Cochrane library, Google
post-vaccination adverse effects are pain at the injection site,         Scholar, and Clinicaltrails.gov from inception till 5th Octo-
fatigue, and chills. However, these effects are ­transient [9].          ber 2021, without any restriction of language. To achieve
However, some severe side-effects have been reported as                  comprehensive results, the keywords used in the search string
well including splanchnic venous thrombosis [10] and                     included “SARS-CoV-2 Vaccine”, ­“Coronavirus ­Vaccine”,
vaccine-induced immune thrombotic thrombocytopenia                       “Corona Vaccine”, “COVID-19 Vaccine”, “COVID Toes”,
[11]. There is a need to address them since reports of adverse           “Chilblain”, “Pernio”, “Blue toes”. The terms were sepa-
events have been regarded as one of the leading motives be-              rated by BOOLEAN operators “OR” and “AND”. All the
hind vaccine hesitancy in low- and middle-income countries               recruited articles were reviewed, and their bibliographies
(LMICs) [12].                                                            were also screened for any relevant information. Ultimately,
    One recently reported adverse event attributed to the                12 studies (10 case reports and 2 case series) were retrieved,
COVID-19 vaccine is Chilblain or Chilblain-like lesions,                 tabulated in Table 1. This review evaluates the potential
­illustrated in Figure 1. Chilblain (pernio) is an inflammatory          pathology, clinical approach, and management of CLL
condition, histologically characterized by dermal edema with             post-vaccination.




Figure 1. Chilblain-like lesions post vaccination. (A) Purpuric patches on the marginal side of fingers [17] (B) Non-painful violaceous lesions
on the big toe, the third toe and the fourth toe [78].



2                                                                                     Review | Dermatol Pract Concept. 2022;12(4):e2022170
Figure 2. Chilblain-like lesions appearance. (A) Characteristic appearance on ventral aspect of feet. (B) close-up of CLL on ventral aspect
of feet.



Results                                                                    It is established that the Angiotensin-converting en-
                                                                       zyme2 (ACE2) serves as a cell receptor mediating the entry of
Epidemiology                                                           SARS-CoV-2 with the help of transmembrane protease ser-
Most of the cases included in this review reported incidence           ine 2 (TMPRSS2). This process downregulates ACE2 in cells
in female patients, hammering the previously mentioned fact            since it is removed from the external membrane site [21]. Al-
that they have a connection with XX gender [16]. More-                 though it allows the entry of the virus into the cell, ACE2 also
over, most of them were either from Europe or the USA, ex-             provides a vaso-protective function by converting Angioten-
cept for two from Turkey [17]. While there is still a long             sin II to Angiotensin (1-7). High levels of Angiotensin II lead
way to ­predict the reason behind one region reporting more            to endothelial dysfunction and results in vasoconstriction
cases than the other, it highlights potential pathophysiology,         and activation of immune cells and cytokines [22]. It is hy-
i.e., cold environment. Moreover, Cribier B et al. reported            pothesized that binding of coronavirus spike proteins leads
a high prevalence of these lesions in cold countries, hence,           to shedding and loss of protective function of ACE2 receptor,
in affirmation with the cases’ findings [18]. The location of          since Angiotensin (1-7) cannot be formed, and leads to accu-
­included cases is mapped in Figure 3.                                 mulation of Angiotensin II at the tissue level [23]. Similarly,
                                                                       we hypothesize that the spike proteins produced by mRNA
Pathophysiology                                                        (Moderna and Pfizer) and adenovirus vaccines (AstraZeneca)
Chilblain is a superficial and localized inflammatory condi-           leads to the accumulation of Angiotensin II, by inhibiting the
tion usually occurring in acral regions, especially the toes           action of ACE2, leading to endovascular damage.
and fingers, and presents as multiple erythematous edema-                  Another proposed mechanism for CLL post-vaccination
tous papules. It occurs mostly in females and primarily is an          is the excess of interferons. The way mRNA vaccines may
abnormal vascular response to nonfreezing cold conditions.             trigger CLL is by increasing interferon-alpha. Upon entry
It is usually an idiopathic and acute condition. The lesions           into the cell, the ssRNA and dsRNA are recognized in the
are associated with tenderness and burning. In severe cases,           cytosol by endosomes and then take part in the innate im-
ulceration, and scars may occur. These lesions may develop             mune response. Endosomal Toll-like Receptors (TLR) bind
as a secondary disorder to connective tissue disease, blood            to ssRNA in the endosome, while the components of inflam-
hyper-viscosity, and genetic diseases.                                 masome bind to ssRNA and dsRNA in the cytosol resulting
    The association between CLL and COVID-19 vaccine                   in INF-1 production alongside multiple inflammatory medi-
is ambiguous. Various potential explanations have been                 ators [24,25]. Although mRNA vaccines are encoded with
proposed. Some studies mentioned the indirect effect of                nucleotides to reduce binding to TLR and reduce high levels
angiotensin and interferon [19], while other studies men-              of interferon, there might be some unknown pathology, re-
tioned positive immunohistochemistry using monoclonal                  sponsible for excessive production of INF-1.
antibodies against the viral spike proteins and the presence               Similarly, the adenovirus vaccine once injected causes
of coronavirus-like particles. It is assumed that the immune           innate immunity activation by stimulating macrophages. It
response to vaccine or the spike proteins is responsible for           engages multiple pattern-recognition receptors, especially
this condition [20].                                                   TLR9, to induce INF-1 production [25].



Review | Dermatol Pract Concept. 2022;12(4):e2022170                                                                                     3
4
                                                                                                         Table 1. Case reports and series with characteristic findings.
                                                                                                                                                    Days from
                                                                                                                                                    vaccination
                                                                  Age,              Vaccine        Previous Medical                                 to onset of     Significant examination and
                                                       Author     Sex     Country Administered          History          Presenting Complaint       symptoms           Investigations finding              Treatment         Outcome
                                                       Davido     41, F   France   Pfizer-       Bipolar disorder, for   Sudden toe pain with       4 days after    Physical examination revealed    Apixaban and low-      Recovered
                                                       et al [78]                  BioNTech-     which she was taking    walking impairment         first dose      non-tender, violaceous toes of   dose aspirin until     after
                                                                                   162b2         valproate for >10       and itching at night,                      the left foot.                   circulating immune     150 days
                                                                                                 years.                  chilblain-like skin                        WBC= 70 mmol/L                   complexes were
                                                                                                                                                                    CRP= 1 mg/L                      obtained <3 μg
                                                                                                                                                                    anti-Spike (S) antibodies=       Eq/ml after 14 day
                                                                                                                                                                    0.642 UI/m
                                                       Piccolo    41, F   Italy    Pfizer-       Not significant         Painful, chilblain-like    24 hours        High levels of IgG anti-spike    Oral cinnarizine       Recovered
                                                       et al [79]                  BioNTech-                             lesion on the volar        after second    antibodies, determining          (75 mg twice per       after
                                                                                   162b2                                 aspects of the second      dose            the positive response to the     day)                   one month
                                                                                                                         and the third fingertip                    vaccine.
                                                                                                                         of right hand
                                                       Cameli     60,     Italy    Pfizer-       Not significant         Pernio-like lesions        14 days after   Physical examination showed      N/A                    N/A
                                                       et al [20] N/A              BioNTech-                             on both hands,             second dose     erythematous-violaceous
                                                                                   162b2                                 accompanied by itching                     patches and swelling on the
                                                                                                                         and burning sensation                      fingers.
                                                                                                                                                                    Occasional appearance
                                                                                                                                                                    of livedo reticularis-like
                                                                                                                                                                    manifestations on the lower
                                                                                                                                                                    limbs.
                                                       Lesort     82, F   France   Pfizer-       History of psoriasis    Slightly painful lesions   24 hours        Physical examination revealed    Topical clobetasol     Recovered
                                                       et al [30]                  BioNTech-     and has been on         on both hands and feet     after first     macular violaceous and           cream, second
                                                                                   162b2         methotrexate for >                                 dose            erythematous lesions of the      vaccine dose, she
                                                                                                 10 years                                                           fingers and toes.                developed chilblain-
                                                                                                                                                                                                     like lesions again
                                                                                                                                                                                                     after second dose
                                                                                                                                                                                                     that were treated
                                                                                                                                                                                                     similarly.




Review | Dermatol Pract Concept. 2022;12(4):e2022170
                                                                                                                                                       Days from
                                                                                                                                                       vaccination
                                                                  Age,              Vaccine        Previous Medical                                    to onset of      Significant examination and
                                                       Author     Sex     Country Administered          History            Presenting Complaint        symptoms            Investigations finding              Treatment         Outcome
                                                       Holmes     48, F   USA     Moderna        Allergic contact          Subtle chilblains-like      10 days after    initial dermatology evaluation   Patient was           Recovered
                                                       et al [31]                                dermatitis to             papules overlying the       the first dose   suggested hypernasality          taking topical        after
                                                                                                 fragrances and positive   joint spaces of the                          reaction after which biopsy      hydrocortisone        23 days post
                                                                                                 antinuclear antibodies    hands and feet, tender                       was recommended.                 when she presented,   vaccination
                                                                                                 without rheumatologic     at palpation.                                                                 which was
                                                                                                 disease manifestations                                                                                  continued as it
                                                                                                                                                                                                         seemed effective.
                                                       Meara      33, F   USA     Moderna        Mild persistent           Painful new-onset blue      1 week after     Normal blood work with           Corticosteroids       Recovered
                                                       et al [32]                                asthma, hence, a          and purple nodules on       her first dose   negative inflammatory
                                                                                                 regular user of inhaled   the tips of 3 fingers and                    markers and autoimmune
                                                                                                 corticosteroid            2 toes                                       serologies.




Review | Dermatol Pract Concept. 2022;12(4):e2022170
                                                       Lopez      64, M USA       Pfizer-        Not significant           Violaceous skin             3 days after     Laboratory workup was            Clobetasol 0·05%      Recovered
                                                       et al [33]                 BioNTech-                                discoloration for 10        second dose      unrevealing                      ointment for the
                                                                                  162b2                                    days that started on                                                          affected toes with
                                                                                                                           the left hallux and                                                           a plan to follow-up
                                                                                                                           gradually spread to all                                                       in the outpatient
                                                                                                                           toes on the bilateral                                                         dermatology clinic
                                                                                                                           feet.                                                                         in 2 weeks
                                                       Pileri     42, M Italy     Pfizer-        Not significant           Nonpainful               12 days after       Antibodies and blood tests       N/A                   N/A
                                                       et al [80]                 BioNTech-                                erythematous-to-         first dose          were negative
                                                                                  162b2                                    purplish patches located
                                                                                                                           on his distal phalanges
                                                                                                                           and nail bed, along
                                                                                                                           with an acrocyanosis of
                                                                                                                           the hands
                                                       Temiz      44, M Turkey    CoronaVac      Not significant           Chilblain-like lesions      7 days after     Dermatological examination       Topical               Recovered
                                                       et al [17]                                                          on the dorsal hands         the vaccine      revealed mildly pruritic,        corticosteroids and
                                                                                                                                                                        edematous violaceous plaques     antihistamines
                                                                                                                                                                        and nodules on the dorsal
                                                                                                                                                                        hands
                                                       Temiz      53, M Turkey    CoronaVac      Not significant           Chilblain-like lesions      7 days after     Erythematous-to-violaceous      Topical                Recovered
                                                       et al [17]                                                          on the dorsal hands         the vaccine      patches on the marginal side    corticosteroids and
                                                                                                                                                                        of the fingers of both hands-on antihistamines
                                                                                                                                                                        examination




5
                                                                                                                                                                                                                               Table 1 continues
6
                                                                                                                                                                    Days from
                                                                                                                                                                    vaccination
                                                                    Age,               Vaccine                Previous Medical                                      to onset of     Significant examination and
                                                        Author      Sex      Country Administered                  History             Presenting Complaint         symptoms           Investigations finding             Treatment          Outcome
                                                        Connie   70, F       USA         Moderna           Pityriasis lichenoides     Pruritic papular rash        2 days after     Physical examination revealed     Clobetasol 0.05%      Recovered,
                                                        Kha,                                               chronica (PLC), which      on the digits of her         first dose       a few lesions located on          ointment twice        however got
                                                        MD et al                                           remained clinically        right hand. Associated                        the extensor surfaces of          daily.                the same rash
                                                        [34]                                               stable with clobetasol     symptoms were pain                            the extremities. A complete                             3 days after
                                                                                                           0.05% ointment             with movement of                              blood count, erythrocyte                                second dose.
                                                                                                                                      the right proximal                            sedimentation rate, C-reactive
                                                                                                                                      interphalangeal joints                        protein, rheumatoid factor,
                                                                                                                                      of the 4th and 5th                            Sjögren antibodies (anti-SS-A/
                                                                                                                                      digits that resolved on                       anti-SS-B), and antinuclear
                                                                                                                                      10th day.                                     antibody were either within
                                                                                                                                                                                    normal limits or negative.
                                                        Nebreda N/A,         Spain       Moderna           Not significant            Itchy edematous              N/A              Superficial perivascular          Topical               Recovered
                                                        et al [81] F                                                                  erythematous papules                          lymphocytic infiltrates with      corticosteroids and
                                                                                                                                      on the back of the                            vascular damage and red cell      lesions
                                                                                                                                      hands and fingers and                         extravasation, with Papillary
                                                                                                                                      erythematous spots in                         dermal oedema
                                                                                                                                      palms
                                                        Nebreda N/A,         Spain       Moderna           Not significant            Itchy edematous              N/A              Deep perivascular lymphocytic Topical                   Recovered
                                                        et al [81] F                                                                  erythematous lesions in                       infiltrates surrounding the    corticosteroids and
                                                                                                                                      fingers                                       sweat glands. Papillary dermal lesions
                                                                                                                                                                                    oedema was also present
                                                        Nebreda N/A,         Spain       Moderna           Not significant            Itchy edematous              N/A              Superficial perivascular          Topical               Recovered
                                                        et al [81] M                                                                  erythematous lesions in                       lymphocytic infiltrates           corticosteroids and
                                                                                                                                      fingers                                                                         lesions

                                                       CBLL = chilblain-like lesions; CRP = C-reactive protein; F = female; M = male; N/A = Not available; USA = United States of America; WBC = white blood count.




Review | Dermatol Pract Concept. 2022;12(4):e2022170
Figure 3. Epidemiology of included cases.



   The type 1 interferon is crucial for the host anti-viral re-       The common histological finding in the included cases
sponse. It leads to activation of the Janus kinase/signal Trans-   was perivascular lymphocytic infiltrate. This finding is in line
ducers and Activators of transcription (JAK-STAT pathway)          with that of Boada et al.[35], where Idiopathic Pernio had
to prevent viral replication. Note that the early and exagger-     89% of cases having the same histopathology. In Connie Kha
ated response to INF-1 before the humoral activity is con-         et al. [34] immunohistochemical demonstrated the presence
sidered responsible for the lesions [19,26]. In contrast, the      of CD31 T cells. This hammers up the finding by Cribier et al
delayed response may lead to hyper-cytokinemia [26].               [18], where they presented how chilblains have predominant
   Another cause of these lesions could be the excessive           T-lymphocytic infiltration, with only a few B cells. Mild su-
production of pro-inflammatory proteins. Although there is         perficial edema was also seen in Meara et al [32].
insufficient evidence of cytokine storm post COVID-19 vac-            Holmes et al [31] highlighted the case of a patient with the
cination in humans, a recent article regarding it in monkeys       presence of interstitial eosinophils. In the case by Lesort et al
has raised concerns [27]. It is also documented that some          [30] blood vessel endothelial cells of the mid dermis were also
vaccines can activate the myeloid immune system, which             seen as a prominent structure. This was also seen in a previous
can then cause cytokine storm [28]. There is an increase in        study. While working on the histology of COVID-19 associated
IL-6, IL-1, TNF- α, and interferon. This causes the influx         pernio, Recalcati et al [36] observed 14 cases, that had a prev-
of macrophages, and neutrophils from the blood into the            alent perivascular pattern, and signs of endothelial activation.
damaged site. These cells damage endothelial cells, and cap-          Detailed biopsy reports of included studies are summa-
illaries. In severe cases, multi-organ failure and death may       rized in Table 2. While there exists, much research describing
occur [29].                                                        the histopathological finding in different types of chilblains,
   While there are multiple explanations for CLL post-             the ones occurring after COVID-19 vaccination is still un-
vaccination, the exact mechanism is still unknown, leaving         clear. Hence, leaving room for potential working. Figure 4
behind room for future studies.                                    shows how CLL appears histopathologically in haematoxy-
                                                                   lin–eosin–saffron stain.
Histopathology
The use of biopsy to diagnose pernio has been long debated.
Despite that it helps in revealing the extent of damage, dif-      Diagnosis
ferentiating the types with it is controversial. Moreover, the     The criterion for CLL diagnosis is unestablished and differs
pain on the incision is one major concern explaining the hes-      between physicians. Some recommend history and exam-
itancy of its use as a primary diagnostic tool. This may be the    inations to be sufficient while others prefer going for labo-
potential explanation that only five of the included cases in      ratory testing, including CBC, cold agglutinins, antinuclear
this review opted for biopsies [30–34].                            antibodies, and cryoglobulins. Some even prefer skin biopsy,



Review | Dermatol Pract Concept. 2022;12(4):e2022170                                                                              7
                                Table 2. Histopathological findings of included cases.
          Author                   Procedure                                               Findings
 Lesort et al [30]           Skin Biopsy               partly necrotic epidermis overlying a dense dermal lymphocytic
                                                       infiltrate forming rather well-circumscribed aggregates around blood
                                                       vessels, eccrine sweat glands and occasionally nerves (Figure 4).
                                                       The endothelial cells of the blood vessels of the mid dermis were
                                                       occasionally prominent.
 Holmes et al [31]           Skin Biopsy               psoriatic and spongiotic dermatitis with superficial and deep perivascular
                                                       lymphocyte-predominant inflammation as well as numerous perivascular
                                                       and interstitial eosinophils. There was no evidence of vasculitis.
 Meara et al [32]            Skin Biopsy               Superficial and mid-dermal perivascular cuffed lymphocytic infiltrate.
                                                       Mild superficial dermal edema is present. No inter-face changes are
                                                       present. There is no evidence of vasculitis or vasculopathy.
 Lopez et al [33]            Punch Biopsy              Superficial and deep infiltrate of lymphocytes around vessels and eccrine
                                                       glands, with papillary dermal oedema. No thrombi or vasculitis are seen.
 Connie Kha et al [34]       Punch Biopsy and          Dense and predominantly perivascular lymphocytic infiltrate within the
                             Immunochemical            superficial-to-deep reticular dermis. The epidermis appeared normal
                             analysis                  with no vacuolar changes at the epidermal-dermal junction. There was
                                                       a notable papillary dermal edema. Within the superficial dermis, some
                                                       vessels exhibited slightly thickened walls with trophism of lymphocytes,
                                                       although vascular wall hyalinization, neutrocytosis, or intravascular
                                                       thrombi were not evident. Immunohistochemical analysis demonstrated a
                                                       majority of CD3+ T cells in the lymphocytic infiltrate.




Figure 4. Skin biopsy of the lesion. (A) Necrotic epidermis and a dense dermallymphocytic infiltrate. (B) aggregation of infiltrates around
blood vessels. (C) infiltration around sweat glands (Stain: haematoxylin–eosin–saffron stain) [30]



8                                                                                   Review | Dermatol Pract Concept. 2022;12(4):e2022170
Moreover, one study demonstrated dermoscopy usage to                long debated for their efficacy in CLL. Numerous trials and
evaluate background vessels and additional features [37].           works have been done in this area. Of them all, Nifedipine
    Cappel et al. studying patients at Mayo Clinic recom-           has been widely recognized, with trials comparing its effect
mend following a systemic approach, starting from history           with placebo [45], diltiazem [46], topical 5% minoxidil
and physical examination to ordering labs and skin biopsy           [47,48], and topical glyceryl trinitrate [49], proving its su-
for those with advanced disease [14].                               periority to them. However, it is still a conflicting treatment
                                                                    option as Souwer et al showed that there was no difference
Clinical Management                                                 in results in placebo versus nefipidine [50].

Some literature suggests no treatment plan for chilblains,             In the case of chilblains following COVID-19 vaccina-

as it resolves itself [38]. Whilst some recommend treatment         tion, none of the case reports included in this review ­(Table 1)

with avoidance of cold and damp conditions. Many studies            used it as a treatment regimen, the plausible reason being

are determining potential therapeutic measurements in cases         the etiology was considered different. However, medicines,

of severe disease[15,39]. Pharmacologically, calcium channel        that increase blood flow to affected organs have been rec-

blockers, such as nifedipine, are reportedly helpful in reliev-     ommended and used in CLL following COVID-19 infection

ing the condition [16,40-42].                                       [38]. Hence, this may highlight the fact that calcium channel

    Herein, we summarize and present a systematic ap-               blockers can play an important role in vaccine-induced le-

proach to a patient with such lesions based on the current          sions as well. Nevertheless, strong research data are required

data and treatment plans that worked for patients presented         to connect the dots.

in Table 1.
                                                                    Topical Nitroglycerin
Exposure                                                            This drug, having the same effects as that of calcium channel

Previously, these lesions were supposed to be caused and            blockers, acts by releasing free radical NO, hence relaxing

­aggravated by a cold environment [15,43]. Even though the          smooth muscles and increasing the blood flow [51].

etiology in post-COVID-19 vaccine CLL is not linked to the             Topical nitroglycerine (0.2%) showed improvement in

weather, physicians, dealing with such cases, may consider          outcomes of Chilblains in a study by Verma P et al [52].

the environment as an aggravating factor, as depicted in the        Moreover, a case report by Weingarten et al [53], used it as

cases from colder countries, hence preventing cold weather          a treatment option for COVID-19 induced CLL and found

shall be chosen as a first-line management plan. Moreover,          it effective. However, the first study tested a small sample

adding on heat provision may also improve symptoms dras-            group (22 patients), while the case only used it for one pa-

tically, as proposed by Nyssen et al [15].                          tient, hence, more work on a greater sample size can be done
                                                                    in the area to weigh the efficacy of this option.
Corticosteroids
                                                                    Pentoxifylline
Topical corticosteroids remained the choice of management
                                                                    This drug works by improving the red blood cell flexibility
in four cases [17,31–33]. However, despite widespread usage,
                                                                    by increasing erythrocyte ATP and cyclic nucleotide levels.
the level of clinical evidence suggesting it is a possible treat-
                                                                    Current evidence goes in the favor of this option [54]. In
ment measure is insufficient [39,44]. Souwer et al compared
                                                                    the trial by Noaimi, 55% of patients showed improvement
the efficacy of topical betamethasone vs placebo to treat
                                                                    in symptoms when treated with pentoxifylline compared
chilblains and no significant differences were perceived [44].
                                                                    to only 27.2% in the group taking prednisolone 0.5mg/kg
However, Mayo Clinic demonstrated their efficacy, benefit-
                                                                    and topical clobetasol ointment [55]. Another research by
ting 6 of 8 patients [14]. This supports the treatment plan
                                                                    Al-Sudany NK et al showed a significant improvement in
followed in included cases. Nevertheless, the contradiction
                                                                    lesion healing compared with placebo [56]. Moreover, Assi-
in trial results and actual benefits received by the patients
                                                                    makopoulos et al proposed how this option can be used to
­requires a thorough and strong evaluation. Moreover, the
                                                                    resolve other severe complications of COVID-19, highlight-
cases lack reporting of adverse effects that may have oc-
                                                                    ing the possible efficacy of this drug [57].
curred as a result of steroids, hence clinical work in this as-
                                                                       Based on this, pentoxifylline can be considered a part of
pect is crucial.
                                                                    the treatment plan in patients with CLL.
Calcium Channel Blockers
Calcium channels induce the inhibition of calcium entry into        Hydroxychloroquine
the cells, hence playing a vital role in vasodilation. Since        This drug is often used as a first-line treatment in several
vasospasm due to cold is one of the presumed pathophys-             autoimmune diseases[58]. In a retrospective study by Yang
iology for chilblains, calcium channel blockers have been           et al, four of five perniosis patients responded well to



Review | Dermatol Pract Concept. 2022;12(4):e2022170                                                                               9
Hydroxychloroquine [59]. This can be due to their under-             Piccolo V et al [72] in their research noted that feet alone
lying anti-inflammatory action, which results from their in-      were mostly affected (85.7%) while those having both feet
terference with antigen processing in macrophages and other       or hands affected together, and hands alone contributed only
antigen-presenting cells [60].                                    7% and 6% respectively. Similar evidence was observed in
                                                                  the study by Recalcati et al [73] whereof 14 described cases,
Acupuncture                                                       two cases had both extremity involvement, eight had feet
In a study by Xiang et al, in 2005, the acupuncture group,        while only four had hands involvement.
combined with massage, showed a 100% effective rate for              However, the major concern is many patients reported,
CLL treatment compared to 76.6% in medicine [61]. Acu-            was that they had negative PCR results. Research postulates
puncture is an old Chinese alternative medicine practice,         several theories behind it [13]. One of them specified the rel-
which works by inserting needles into the body, to improve        atively late CLL lesion appearance in COVID-19, during the
blood flow. While there are reservations to alternative med-      convalescent phase, by which the viral products are no longer
icine, based on this study, more trials should be performed       detectable on PCR [13,74]. Another clue to pathophysiology
to verify and to check this therapeutic line of management        has been postulated by considering CLL as a cutaneous ex-
for CLL.                                                          pression of a type 1 interferon (IFN-1) response. This may
     Temiz et al [17] used antihistamines as a management         lead to viral product clearance before immunoglobulin pro-
option, however, there are insufficient data to evaluate their    duction, manifesting as failed serological detection [75,76].
efficacy in CLL; hence, more studies are needed in this regard.   An escalated interferon score was observed in 40% of patients
                                                                  in the study by Lesort et al [77]. Hence, we may hypothesize
                                                                  that high IFN response benefitted the patients, reducing viral
Other cutaneous Manifestations of
                                                                  replication and defining why the patients were asymptomatic.
COVID-19 Vaccines
During the vaccines trial, the typical adverse cutaneous re-
actions were local injection site reactions while erythema,       Conclusions
induration, and tenderness, were specifically reported in
                                                                  There are several limitations in the study highlighting which
Moderna phase III trial [62].
                                                                  can lead to a specific conclusion in the future. Firstly, the
     However, as the vaccines entered the real world, diverse
                                                                  studies included in this review are limited. Studies with larger
cutaneous adverse events have been documented. Mazza-
                                                                  sample sizes are required to draw associations between
tenta et al [63], reported case series, comprising three cases
                                                                  chilblain-like lesions and COVID vaccination. Secondly, the
of purpuric eyelid lesions following the Pfizer vaccine, which
                                                                  treatment regimen reported in the cases differs drastically
may be a manifestation of vaccine-induced microangiopathy.
                                                                  with no background reasoning for the choices. Thirdly, one
Similarly, in another case, the patient experienced urticarial
                                                                  of the included study, Nebreda et al did not specify patients
rash along with a flare-up of his previously well-controlled
                                                                  age. More importantly, the cases did not report the side ef-
atopic dermatitis [64]. Morbilliform rashes [65,66], urti-
                                                                  fects of the medications, which is crucial in determining the
caria [67,68], pityriasis rosea [68,69], lichen planus [70],
                                                                  future of the treatment. It also would have highlighted if the
and many other cutaneous reactions following COVID-19
                                                                  patient recovered via medicines or the pernio self-resolved.
vaccination are present in the literature. Notable is the fact
                                                                  Lastly, Nebreda et al only provided an overview and did not
that women comprised the majority, which may help draw
                                                                  list any specifications for each caseAlthough the overall inci-
a relation between any sex-linked reactions. Nevertheless, a
                                                                  dence of Chilblains following COVID-19 vaccination is low,
thorough evaluation is the need of time to establish complete
                                                                  there is still a strong need to find out the exact mechanism
links [17].
                                                                  behind this to redefine the safety and administration crite-
                                                                  ria of the vaccines and to formulate a proper management
Chilblains like Lesions Following COVID-19                        protocol. Similarly, there is a need to address the association
Infection                                                         between these chilblain-like lesions with gender and different
While COVID-19 vaccines may induce Chilblain-like le-             demographic settings. There is an overwhelming need to ad-
sions, similar lesions have been witnessed in mildly infected     dress issues related to vaccines and their hesitancy amongst
coronavirus patients as well. The current literature reports      the population to successfully restore normal life.
numerous cases of COVID-19 infection-associated chil-
blains [15,71]. In a study by Casas et al [71] involving 375
COVID-19 patients, 19% of cutaneous reactions were man-           References
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Review | Dermatol Pract Concept. 2022;12(4):e2022170                                                                                         13
