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 Table of Contents  
CASE BASED REVIEW
Year : 2022  |  Volume : 17  |  Issue : 2  |  Page : 170-173

Bacillus calmette–Guérin scar inflammation after COVID vaccination


Department of Rheumatology, Consultant Rheumatologist, Apollo BGS Hospital, Mysore, Karnataka, India

Date of Submission29-Aug-2021
Date of Acceptance12-Nov-2021
Date of Web Publication20-May-2022

Correspondence Address:
Dr. B N Shiva Prasad
Apollo BGS Hospital, Mysore, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_194_21

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  Abstract 


Bacillus Calmette–Guérin (BCG) scar inflammatory reactions have been commonly reported with Kawasaki disease in children and less commonly with other viral infections. Postvaccination BCG scar inflammation has only been reported with the influenza vaccine. Two cases of post-COVID vaccination BCG scar inflammation has been recently reported. we report a case of BCG scar inflammation appeared after 24 h of vaccination of both the doses of vaccine.

Keywords: Bacillus Calmette–Guérin scar, COVID vaccination, scar inflammation


How to cite this article:
Shiva Prasad B N. Bacillus calmette–Guérin scar inflammation after COVID vaccination. Indian J Rheumatol 2022;17:170-3

How to cite this URL:
Shiva Prasad B N. Bacillus calmette–Guérin scar inflammation after COVID vaccination. Indian J Rheumatol [serial online] 2022 [cited 2022 Jul 4];17:170-3. Available from: https://www.indianjrheumatol.com/text.asp?2022/17/2/170/345616




  Introduction Top


Bacillus Calmette–Guérin (BCG) scar inflammation has been described with vasculitic diseases, infections, and postvaccination in the pediatric age, particularly in the first 2 years of life. Reactivation in BCG scar is described in about 30%–50% of Kawasaki disease (KD)patients.[1],[2] The inflammatory reactivation of the BCG scar was first highlighted in the Japanese literature as a specific early sign of KD.[1],[2] This phenomenon is characterized by erythema, induration, ulceration, and/or crust formation at the inoculation site. However, it has also been seen with measles and human herpes virus type 6 infections.[3],[4] BCG scar inflammation following immunization has only been reported in two children from Japan and Mexico following influenza vaccination.[5],[6] Recently, BCG scar inflammation following COVID-19 vaccine has been reported in two health-care workers from Costa Rica and the United States of America (USA).[7] BCG scar inflammatory reaction occurred following the second dose administration of the two currently available messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccines (BNT162b2 and mRNA-1273).

We describe the first report in world literature of local BCG inflammation following both doses of viral vector Covishield vaccine (chAdoX1 nCoV-19), in a health-care worker from India with inflammatory polyarthritis.

A MEDLINE, PubMed, and Cochrane library literature search was conducted to identify articles published during the last 50 years was made to find all articles using the MeSH terms BCG scar inflammation and COVID vaccination. In addition, the bibliographies of all articles and cohort series were systematically scanned for references not identified in the initial search.


  Case Report Top


A 27-year-old female health-care worker from India received the first dose of viral vector Covishield vaccine on the left arm on March 5, 2021. She experienced minimal pain at the site of injection on day 1. Twenty-four hours later, she noticed erythema, tenderness, and induration of the exactly over the site of her BCG scar, 4 cm below the injection site which measured 2 cm in length [Figure 1]. The inflammation over the BCG scar site subsided on its own within a span of the next 48 h uneventfully. Subsequently, she took her second dose 56 days apart on April 30, 2021, following which she noticed minimal pain at the site of injection. Similar to the sequence of events after her first dose, she noticed erythema, induration, and tenderness of the BCG scar site measuring 1.5 cm. This episode subsided on its own within a span of 24 h. The COVID vaccination site was not inflamed. The health-care worker is a known case of seronegative (RF, anti-CCP antibody, and ANA [IF] negative) inflammatory polyarthritis, currently on tablet methotrexate 20 mg/week. Additional laboratory investigations such as HIV (enzyme-linked immunosorbent assay), hemogram, and absolute lymphocyte count were normal.
Figure 1: Bacillus Calmette–Guérin scar inflammation after COVID vaccination

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  Discussion Top


To summarize the cases, all are female health-care workers, nearly the same age developing BCG scar inflammation post-COVID vaccination when given in the same arm where BCG scar was present. All recovered spontaneously without any sequelae till date. Although there are similarities in the cases, there are differences too [Table 1]. In the previous two cases, BCG scar was in right hand and scar inflammation occurred when the second dose was given in the right hand.[7] The first dose was given on the left arm and there was no scar inflammation. Both the cases reported swelling, erythema, and induration at the site of BCG vaccination when vaccination was given on ipsilateral arm, i.e., right arm. In our case, BCG scar inflammation occurred both time when COVID vaccine was given in proximity to the BCG scar on the left arm. In India, BCG is given as a part of national immunization program in the left arm. BCG vaccination is not a part of universal immunization in USA. In India, both doses of vaccination are being given on the left arm. This is too early to decide about the reason for the BCG scar flare when vaccinated in the ipsilateral arm but did not occur when given in contralateral arm. One case had systemic features with lymphadenopathy, but our case did not have any systemic features. There are differences in the practice of BCG vaccination and COVID vaccination in different parts of the world.
Table 1: Comparison of the 3 cases

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The BCG reaction in KD is well known and has been theoretically been attributed to cross-reactivity between mycobacterial heat shock protein (HSP) 65 and a human homolog HSP 63.[8] The relation between BCG vaccine and KD is bidirectional. BCG immunization has been used in animal models of KD. Nakamura et al. demonstrated development of coronary arteritis from the combination of a primary immunization with BCG and a secondary immunization with a ubiquitous microorganism.[9] They hypothesized that a microorganism that shares a cross-reactive antigen with BCG might induce an immunopathologic reaction to both BCG and vascular antigens. A homolog of peroxiredoxin-2 is conserved in many microorganisms, and this homolog is also expressed in BCG.[10] Karasawa et al. reported that autoantibodies to peroxiredoxin-2 are found in patients with vasculitis.[11]

There are another two cutaneous reactions post-COVID-19 vaccination. Delayed injection-site reactions with onset on or after day 8 were noted in 244 participants (0.8%) after the first dose and in 68 participants (0.2%) after the second dose in phase III trial of the vaccine.[12] Reactions were characterized by erythema, induration, and tenderness, and they resolved over the following 4–5 days. Blumenthal et al. described delayed local-adjacent cutaneous reactions postadministration of the mRNA-1273 vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 12 patients of a phase 3 trial.[13] The skin changes were noted in proximity to the injection site after 8 days of getting inoculated after all the local and systemic symptoms associated with vaccination had resolved. They reported that all the patients received symptomatic treatment and there was complete resolution of the symptoms 6 days postonset. These delayed reactions were morphologically annular, edematous, targetoid, and/or wheal like, some of which with considerable induration near the vaccination site. A skin biopsy performed on one patient showed superficial perivascular and perifollicular lymphocytic infiltrate with rare eosinophils and scattered mast cells.

Cases of delayed inflammatory reactions (DIR) to hyaluronic acid (HA) dermal fillers after exposure to the COVID-19 spike protein have also been described recently. Dermal filler reactions have also been described secondary to many causes, but here, we look into reactions caused by COVID-related aspects.[14],[15] This reaction was observed in patients who received HA filler injections as facial “rejuvenation” treatment. It was characterized by the appearance of facial edema and erythema. This has been described in both Pfizer and Moderna vaccines. It has also been described post-COVID 19 infections also. The mechanism of DIR to HA fillers in COVID-19-related cases has been thought to be due to binding and blockade of angiotensin 2-converting enzyme receptors, which are targeted by the SARS-CoV-2 virus spike protein to gain entry into the cell.[16]

The immunological and clinical significance of these reaction to the SARS-CoV-2 vaccines can still be considered as an enigma which needs further introspection and research. Further reporting and pharmacovigilance is necessary to understand the pathomechanism behind these reactions. The clinical and immunological consequences/sequelae of the BCG scar inflammation in long term remain unknown, which needs to be further evaluated. Reports following adult COVID vaccination would help understand these findings. Most recently described entity, pediatric multisystem inflammatory syndrome associated with COVID-19 (MIS-C) shares very similar clinical and immunologic findings as KD.[17] It is important and imperative to follow the COVID infection and pediatric age and the BCG scar inflammation after COVID vaccination and in MIS-C, which may lead to novel immune pathomechanism.


  Conclusion Top


This is the first case reported from India of BCG scar inflammation as a reaction following mRNA COVID-19 vaccine administration in a health-care worker with inflammatory polyarthritis. BCG scar reactions should be kept under the radar following COVID-19 vaccines, particularly in countries where BCG is a part of their national immunization programs. It needs further vigilance from the clinicians and vaccinators to identify the cases and look for the pathophysiology for the same and look for the long-term consequences. It is also important to look for MIS-C and BCG scar association.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Lai CC, Lee PC, Wang CC, Hwang BT, Meng CC, Tsai MC. Reaction at the Bacillus Calmette-Guérin inoculation site in patients with Kawasaki disease. Pediatr Neonatol 2013;54:43-8.  Back to cited text no. 1
    
2.
Uehara R, Igarashi H, Yashiro M, Nakamura Y, Yanagawa H. Kawasaki disease patients with redness or crust formation at the Bacille Calmette-Guérin inoculation site. Pediatr Infect Dis J 2010;29:430-3.  Back to cited text no. 2
    
3.
Muthuvelu S, Lim KS, Huang LY, Chin ST, Mohan A. Measles infection causing Bacillus Calmette-Guérin reactivation: A case report. BMC Pediatr 2019;19:251.  Back to cited text no. 3
    
4.
Kakisaka Y, Ohara T, Katayama S, Suzuki T, Sasai S, Hino-Fukuyo N, et al. Human herpes virus type 6 can cause skin lesions at the BCG inoculation site similar to Kawasaki Disease. Tohoku J Exp Med 2012;228:351-3.  Back to cited text no. 4
    
5.
Chavarri-Guerra Y, Soto-Perez-de-Celis E. Erythema at the Bacillus Calmette-Guerin scar after influenza vaccination. Rev Soc Bras Med Trop 2019;53:e20190390.  Back to cited text no. 5
    
6.
Kondo M, Goto H, Yamamoto S. First case of redness and erosion at Bacillus Calmette-Guérin inoculation site after vaccination against influenza. J Dermatol 2016;43:1229-31.  Back to cited text no. 6
    
7.
Lopatynsky-Reyes EZ, Acosta-Lazo H, Ulloa-Gutierrez R, Ávila-Aguero ML, Chacon-Cruz E. BCG scar local skin inflammation as a novel reaction following mRNA COVID-19 vaccines in two international healthcare workers. Cureus 2021;13:e14453.  Back to cited text no. 7
    
8.
Sireci G, Dieli F, Salerno A. T cells recognize an immunodominant epitope of heat shock protein 65 in Kawasaki disease. Mol Med 2000;6:581-90.  Back to cited text no. 8
    
9.
Nakamura T, Yamamura J, Sato H, Kakinuma H, Takahashi H. Vasculitis induced by immunization with Bacillus Calmette-Guérin followed by atypical mycobacterium antigen: A new mouse model for Kawasaki disease. FEMS Immunol Med Microbiol 2007;49:391-7.  Back to cited text no. 9
    
10.
Karasawa R, Kurokawa MS, Yudoh K, Masuko K, Ozaki S, Kato T. Peroxiredoxin 2 is a novel autoantigen for anti-endothelial cell antibodies in systemic vasculitis. Clin Exp Immunol 2010;161:459-70.  Back to cited text no. 10
    
11.
Fujieda M, Karasawa R, Takasugi H, Yamamoto M, Kataoka K, Yudoh K, et al. A novel anti-peroxiredoxin autoantibody in patients with Kawasaki disease. Microbiol Immunol 2012;56:56-61.  Back to cited text no. 11
    
12.
Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2021;384:403-16.  Back to cited text no. 12
    
13.
Blumenthal KG, Freeman EE, Saff RR, Robinson LB, Wolfson AR, Foreman RK, et al. Delayed large local reactions to mRNA-1273 vaccine against SARS-CoV-2. N Engl J Med 2021;384:1273-7.  Back to cited text no. 13
    
14.
Shome D, Doshi K, Vadera S, Kapoor R. Delayed hypersensitivity reaction to hyaluronic acid dermal filler post-COVID-19 viral infection. J Cosmet Dermatol 2021;20:1549-50.  Back to cited text no. 14
    
15.
Munavalli GG, Knutsen-Larson S, Lupo MP, Geronemus RG. Oral angiotensin-converting enzyme inhibitors for treatment of delayed inflammatory reaction to dermal hyaluronic acid fillers following COVID-19 vaccination-a model for inhibition of angiotensin II-induced cutaneous inflammation. JAAD Case Rep 2021;10:63-8.  Back to cited text no. 15
    
16.
Munavalli GG, Guthridge R, Knutsen-Larson S, Brodsky A, Matthew E, Landau M. “COVID-19/SARS-CoV-2 virus spike protein-related delayed inflammatory reaction to hyaluronic acid dermal fillers: A challenging clinical conundrum in diagnosis and treatment”. Arch Dermatol Res. 2022;314:1-15. [doi: 10.1007/s00403-021-02190-6].  Back to cited text no. 16
    
17.
Jiang L, Tang K, Levin M, Irfan O, Morris SK, Wilson K, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis 2020;20:e276-88.  Back to cited text no. 17
    


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