Sex: F
Vaccine: MMR, MMR
Symptoms: Thrombocytopenia, Tryptase, Ulcer
Clinical narrative: RuV-associated granulomatous inflammation/Rubella virus-associated necrotizing neutrophilic granuloma; Vaccine-derived RuV/positive rubella IgG; enlarging right knee lesions/ Granulomatous lesion; violaceous verrucous papules; crusted plaques from the right knee to the distal anterior shin; crusted plaques from the right knee to the distal anterior shin; occasionally the right knee plaque would ulcerate; hyperpigmented; scaly papules; This serious case was reported in a literature article and described the occurrence of granulomatous inflammation in a 46-year-old female patient who received MMR (MMR vaccine) for prophylaxis.  Co-suspect products included MMR (MMR vaccine) for prophylaxis.   The patient's past medical history included common variable immunodeficiency (over 20 years) and injury (right knee prior to lesion onset.).   On an unknown date, the patient received the 1st dose of MMR vaccine and the 2nd dose of MMR vaccine. On an unknown date, an unknown time after receiving MMR vaccine and MMR vaccine, the patient experienced granulomatous inflammation (Verbatim: RuV-associated granulomatous inflammation/Rubella virus-associated necrotizing neutrophilic granuloma) (serious criteria other: other serious), rubella (Verbatim: Vaccine-derived RuV/positive rubella IgG), skin lesion (Verbatim: enlarging right knee lesions/ Granulomatous lesion), papule (Verbatim: violaceous verrucous papules), crust (Verbatim: crusted plaques from the right knee to the distal anterior shin), skin plaque (Verbatim: crusted plaques from the right knee to the distal anterior shin), ulcer (Verbatim: occasionally the right knee plaque would ulcerate), skin hyperpigmentation (Verbatim: hyperpigmented) and scales (Verbatim: scaly papules). The patient was treated with silver nitrate, ulobetasol (Halobetasol) and dapsone. The outcome of the granulomatous inflammation, skin lesion, skin plaque and ulcer were resolving and the outcome of the rubella, papule, crust, skin hyperpigmentation and scales were not reported.   The reporter considered the granulomatous inflammation, rubella, skin lesion, papule, crust, skin plaque, ulcer, skin hyperpigmentation and scales to be related to MMR vaccine and MMR vaccine.   The company considered the granulomatous inflammation, rubella, skin lesion, papule, crust, skin plaque, ulcer, skin hyperpigmentation and scales to be related to MMR vaccine and MMR vaccine.   Additional Information: GSK receipt date: 4 Sep 2023 A 46-year-old female with a history of CVID (common variable immunodeficiency)presented with nontender, non-pruritic, enlarging right knee lesions present for over 20 years. She reported a history of trauma of the right knee prior to lesion onset. Physical exam showed violaceous verrucous papules and crusted plaques from the right knee to the distal anterior shin. She reported that occasionally the right knee plaque would ulcerate, for which she self-treated with silver nitrate. There was no other prior treatment. Punch biopsy specimen of a representative lesion showed pseudoepitheliomatous hyperplasia overlying palisaded granulomatous infiltrate with epithelioid histiocytes and multinucleated giant cells throughout the dermis and subcutis. CD68 highlighted the histiocytes surrounding a center of acellular debris and necrosis. Neutrophils, highlighted by myeloperoxidase (MPO), were present in loose aggregates at the periphery of the necrosis. Gram, Grocott's methenamine silver (GMS), acid-fast bacilli (AFB) stains, and tissue cultures were negative for bacterial, fungal, and mycobacterial infection. The patient had received two doses of MMR vaccine in childhood. In the context of reports emerging in recent years of RuV-associated granulomatous inflammation in patients with IEI, rubella virus (RuV) was suspected to be involved in her skin pathology. Fresh tissue from a granulomatous skin lesion, nasopharyngeal (NP) swab, and whole blood were sent to the Centers for Disease Control and Prevention (CDC) for RuV molecular testing, and serum was submitted for rubella serology. Vaccine-derived RuV was detected in the skin biopsy specimen by RT-PCR and viral RNA sequencing. The NP swab and neutrophils isolated from the whole blood were negative for RuV by RT-PCR. Serum was negative for rubella IgM and positive for rubella IgG (ISR = 3.45) by enzyme-linked immunosorbent assay with the rubella neutralization titer (NT50) of 160. On formalin-fixed paraffin embedded tissue (FFPE), CD206 antibody staining revealed that M2 macrophages contributed predominantly to the granuloma formation, but these cells were not co-stained with RVC antibody However, co-staining with MPO antibody demonstrated RVC localization to neutrophils on the periphery of necrotic areas. Globules of rubella antigen were also detected among cellular debris in the necrotic areas. At the same time, the patient underwent a bone marrow biopsy due to leukopenia (2.2 x109 /L, reference range 4.0-11.0 x 109 /L) and thrombocytopenia (53 x109 /L, reference range 150-450 x109 /L). Bone marrow specimen showed mast cells (15%-20%) in a hypercellular marrow with trilineage maturing hematopoiesis, thought to be reactive, as serum tryptase was within normal limits. No c-KIT mutation was detected by PCR. IHC staining of FFPE sections of bone marrow specimen showed sporadic dual RVC- and MPO-positive cells, suggestive of granulocytes. The patient declined repeat bone marrow biopsy therefore fresh bone marrow tissue was not obtained for further investigation for RuV. Her cytopenias were stable with monitoring by hematology without further intervention. The granulomatous skin lesions improved after 1 year of topical halobetasol 0.05% cream twice daily under occlusion, becoming hyperpigmented, flat to atrophic patches, and thin plaques with minimal scale. However, a few scaly papules, including several reported by the patient to be new lesions, were present on the distal lower leg. Repeat biopsy specimen of one of the small papules showed persistent necrotizing granulomatous and neutrophilic inflammation in the same histopathologic pattern as in her prior biopsies. Addition of topical dapsone and topical calcineurin inhibitors therapy did not yield further improvement. Subsequently, the patient was started on oral dapsone 25 mg for 3 months increasing to 50 mg for an additional 3 months. There was mild improvement in lesion texture and discoloration, with further flattening of some previously raised papules. We plan to up-titrate dapsone dosage pending further clinical response and patient tolerance. The developed necrotizing epithelioid granulomas palisading around a central acellular area with RVC positive scattered neutrophils loosely confined to periphery of the necrotic area. RVC may be present within only neutrophils without being present in closely associated macrophages.  The patient reported development of granulomatous lesions after initial trauma to the right knee, supporting the hypothesis of local tissue inflammation initiating the cascade toward cutaneous granuloma formation. In addition, patient's bone marrow contained dual RVC- and MPO-positive granulocytes. The case raises the possibility that RuV-infected granulocytes or a myeloid precursor cell type may provide a reservoir for inflammation. There was also a possibility that an additional, still unknown pathogen was driving granulomatous inflammation in this patient in combination with RuV. The patient reported development of granulomatous lesions after initial trauma to the right knee, supporting the hypothesis of local tissue inflammation initiating the cascade toward cutaneous granuloma formation. In addition, patient's bone marrow contained dual RVC- and MPO-positive granulocytes. The case raises the possibility that RuV-infected granulocytes or a myeloid precursor cell type may provide a reservoir for inflammation. There was also a possibility that an additional, still unknown pathogen was driving granulomatous inflammation in this patient in combination with RuV. This article is not available for regulatory reporting purpose due to copyright restriction.