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CORRESPONDENCE
Year : 2022  |  Volume : 67  |  Issue : 5  |  Page : 617-619
Erythema and induration at BCG Site in IPEX syndrome


1 Department of Clinical Immunology, Instituto Nacional de Pediatria, Mexico City, Mexico
2 Department of Dematology, Intituto Nacional de Pediatria, Mexico City, Mexico
3 Department of Dermatopathology, Hospital General “Dr. Manuel Gea González”, Mexico City, Mexico
4 Immunodeficiencies Research Unit, Instituto Nacional de Pediatria, Mexico City, Mexico

Date of Web Publication29-Dec-2022

Correspondence Address:
Marco Antonio Yamazaki-Nakashimada
Department of Clinical Immunology, Instituto Nacional de Pediatria, Mexico City
Mexico
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.ijd_973_21

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How to cite this article:
Castano-Jaramillo LM, Toledo-Salinas C, Saez-de-Ocariz Md, Toussaint-Caire S, Bustamante Ogando JC, Rivas-Larrauri F, Scheffler-Mendoza S, Yamazaki-Nakashimada MA. Erythema and induration at BCG Site in IPEX syndrome. Indian J Dermatol 2022;67:617-9

How to cite this URL:
Castano-Jaramillo LM, Toledo-Salinas C, Saez-de-Ocariz Md, Toussaint-Caire S, Bustamante Ogando JC, Rivas-Larrauri F, Scheffler-Mendoza S, Yamazaki-Nakashimada MA. Erythema and induration at BCG Site in IPEX syndrome. Indian J Dermatol [serial online] 2022 [cited 2023 Jan 30];67:617-9. Available from: https://www.e-ijd.org/text.asp?2022/67/5/617/366145




Sir,

A 7-month-old boy presented with chronic diarrhea, failure to thrive, and generalized dermatitis with diffuse erythema. His family history was relevant for a brother deceased at 1 year of age with a similar phenotype. Physical examination revealed erythema, edema, induration, and ulceration at the BCG vaccination site applied at birth [Figure 1]. There was no evidence of diabetes, nor alteration in the thyroid or adrenal function. He did not present hemolytic anemia, neutropenia, lymphopenia, or thrombocytopenia. PCR for Mycobacterium tuberculosis in the gastric fluid was negative and abdominal ultrasound did not show any relevant findings. His immunologic workup revealed normal IgG (454 mg/dL), IgM (85 mg/dL), IgA (19.2 mg/dL), and elevated IgE (291 mg/dL). Lymphocyte subsets were within normal limits for age (CD3 74% 6,038 cells/μL, CD4 54% 4,406 cells/μL, CD8 20% 1,632 cells/μL, CD19/20 15% 1224 cells/uL, CD16/56 4% 326 cells/μL). The differential diagnosis included IPEX, IPEX-like, Omenn syndrome, and neonatal graft versus host disease.
Figure 1: The site of the BCG application. (a) On arrival, it was erythematous-edematous, indurated, and ulcerated. (b) Response after 4 days of oral sirolimus

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A 207-gene primary immunodeficiency NGS panel identified a pathogenic variant c. 1099T > C (p.Phe367Leu) in the forkhead domain of the FOXP3 gene, confirming the diagnosis of IPEX syndrome. After diagnostic confirmation, the patient was started on sirolimus at 0.8 mg/m2 per dose twice daily, and the skin improved significantly overall, including the BCG site reaction [Figure 1]. He received an initial dose of intravenous immunoglobulin at 1 g per kg per dose, and given the patient's difficult vascular access, treatment was continued with subcutaneous immunoglobulin at 1 g per kg per month.

One month later, a generalized eczematous dermatitis, with major involvement of perioral and diaper areas, and erythema and induration at the BCG site were observed. A punch biopsy of the BCG site showed marked epidermal spongiosis with parakeratosis, and dermal capillary dilatation with a slight perivascular and periadnexal infllammatory infiltrate of lymphocytes and eosinophils. There was no evidence of granuloma formation, and Fite–Faraco, Ziehl–Neelsen, and PAS stains were negative for infectious microorganisms [Figure 2]. Cyclosporine at 1 mg per kg per day was added to improve skin lesions. Unfortunately, the patient died due to infection and septic shock while waiting for hematopoietic stem cell transplantation.
Figure 2: (a) BCG site skin biopsy showing a superficial and mid-perivascular and periadnexal inflammatory infiltrate. (b) Epidermal spongiosis, parakeratosis, and dilated capillary blood vessels in the superficial dermis. (c) Mixed inflammatory infiltrate of lymphocytes and eosinophils

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   Discussion Top


Bacillus Calmette–Guerin (BCG) vaccine is a live attenuated bacterial vaccine derived from Mycobacterium bovis. Adverse reactions after BCG are rare; however, immunocompromised individuals are prone to develop vaccine-derived complications.[1] Erythema and induration at the BCG site might be due to BCGitis, which is a known complication of inborn errors of immunity with susceptibility to mycobacterial infection. IPEX syndrome is a rare monogenic inborn error of immunity due to mutations in FOXP3, a key transcription factor for naturally occurring regulatory T cells (Tregs).[2] We present the case of a male infant diagnosed with IPEX syndrome who presented with a generalized rash with a BCG site reaction several months after vaccination. However, in our patient, this dermatological manifestation might be secondary to immune dysregulation like that observed in Kawasaki disease patients, given the important role of Tregs and Th17 cells in mycobacterial immunity.

The clinical features observed in our patient, including the severe skin involvement and the presence of BCG-site changes, were initially considered to be a part of an X-linked inborn error of immunity (IEI) associated with a BCG vaccine-derived complication. In our patient, the BCG vaccination site turned erythematous and ulcerated within 2 months. Several IEIs have been classically associated with complications related to BCG vaccines, and recently, a newly described IEI with complications with BCG has been reviewed. Interestingly, patients with APDS (activated PI3kd syndrome), also characterized by immune dysregulation, have also had BCG local reactions.[1]

To our knowledge, BCG-site reactions have not previously been described as a clinical manifestation of the IPEX syndrome. IPEX syndrome has been associated with infections;[2] however, a clear causative role of pathogens in the onset of autoimmunity has not been demonstrated and infections might be the consequence of immunosuppressive therapy. A balance between Tregs and Th17 cells is thought to be important for the development of mycobacterial infection.[3] It has been shown in mice that Tregs, recognizing Mycobacterium tuberculosis-derived antigens, specifically and potently restrict protective immune responses during tuberculosis. In the context of immunosuppression, where Tregs are predominant over Th17, the Mycobacteria spread more easily.[3] The patient was started on sirolimus, as it has been shown to increase regulatory T cells with clinical benefit in IPEX syndrome.[4] Because of the refractory nature of skin lesions, cyclosporine was added to the treatment. Because of immune dysregulation, sirolimus and cyclosporine were used in our patient, and the skin inflammation, including on the BCG site, was controlled.

This exclusively local BCG complication resembles the inflammatory reaction seen in Kawasaki disease (KD), and may not represent a specific susceptibility to the bacillus.[5] In our patient, the histopathological findings were similar to those reported at the BCG site in KD, with edema in the papillary dermis, capillary dilatation, and mononuclear cell infiltration without granuloma formation.[6] Importantly, an extensive work-up and histopathology findings in the BCG site excluded the presence of the bacillus in our patient. Interestingly, CD4+CD25+FOXP3+ regulatory T cells have been found to be lower during the acute phase of KD compared to healthy controls.[7]

Contrasting with other IEI, the BCG site reaction in IPEX syndrome appears to be an inflammatory reaction not associated with active BCG infection. In our patient, the BCG site reaction worsened when skin dermatitis flared up, suggesting an association with immune dysregulation. Despite the inflammation of the BCG site resembling KD, our patient did not improve after using an immunomodulatory dose of Intravenous Immunoglobulin (IVIG).[7]

In summary, erythema and induration at the BCG site add to the plethora of clinical manifestations of IPEX syndrome; however, its pathogenesis may be different from other IEI, focusing on the role of Tregs and Th17 cells in the mycobacterial immunity.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names 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.
Fekrvand S, Yazdani R, Olbrich P, Gennery A, Rosenzweig SD, Condino-Neto A, et al. Primary immunodeficiency diseases and Bacillus Calmette-Guérin (BCG)-vaccine-derived complications: A systematic review. J Allergy Clin Immunol Pract 2020;8:1371-86.  Back to cited text no. 1
    
2.
Bacchetta R, Barzaghi F, Roncarolo M-G. From IPEX syndrome to FOXP3 mutation: A lesson on immune dysregulation. Ann N Y Acad Sci 2018;1417:5-22.  Back to cited text no. 2
    
3.
Cardona P, Cardona P-J. Regulatory T cells in mycobacterium tuberculosis infection. Front Immunol 2019;10:2139.  Back to cited text no. 3
    
4.
Yong PL, Russo P, Sullivan KE. Use of sirolimus in IPEX and IPEX-like children. J Clin Immunol 2008;28:581-7.  Back to cited text no. 4
    
5.
Yamazaki-Nakashimada MA, Unzueta A, Berenise Gámez-González L, González-Saldaña N, Sorensen RU. BCG: A vaccine with multiple faces. Hum Vaccin Immunother 2020;16:1841-50.  Back to cited text no. 5
    
6.
Sato N, Sagawa K, Sasaguri Y, Inoue O, Kato H. Immunopathology and cytokine detection in the skin lesions of patients with Kawasaki disease. J Pediatr 1993;122:198-203.  Back to cited text no. 6
    
7.
Olivito B, Taddio A, Simonini G, Massai C, Ciullini S, Gambineri E, et al. Defective FOXP3 expression in patients with acute Kawasaki disease and restoration by intravenous immunoglobulin therapy. Clin Exp Rheumatol 2010;28:93-7.  Back to cited text no. 7
    


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