Dr Pawankumar PR1*, Dr Prabhakaran M1, Dr Raja A2, Dr Mukunth K3, Dr Selvaraj A3, Dr Santhanam S4

*Corresponding author
1 – DNB Resident, Department of General Medicine, Kauvery Hospital, Chennai.
2 – Consultant Hematologist, Kauvery Hospital, Chennai.
3 – Consultant Orthopaedics, Kauvery Hospital, Chennai.
4 – Consultant Rheumatologist, Kauvery Hospital, Chennai.

The development of any untoward event following vaccination is considered as post vaccine adverse event, though it need not be a causal relationship. Autoimmune syndromes can occur post vaccination with molecular mimicry being the main hypothesis proposed. Similar events have been reported post Covid-19 vaccination and we hereby report a case of non-identical twins (19 year old girl and boy) with serial development of unrelated autoimmune syndromes post booster dose of Covid-19 vaccine (ChAdox1). Initially, four days after the administration of vaccine both developed high grade fever. They were admitted and evaluated for the same. They had pancytopenia with elevated inflammatory markers and all the infectious work up were negative. They had elevated serum ferritin (> 2000 ng/ml) and triglyceride levels. Hence, a diagnosis of hyper-inflammatory syndrome was made and after doing a bone marrow biopsy which was normal, they were started on steroids at 1mg/kg/day. With this the fever settled and both improved. On tapering the steroids, they had severe pain in their joints. On imaging, the girl had avascular necrosis of right shoulder and bilateral hip joints (figure 1a, 1b). They boy had avascular necrosis of bilateral hip joints and left knee joint (figure 1c, 1d). They were evaluated for same and both tested positive for Factor V Leiden mutation. They were treated with bisphosphonates and anti-coagulants. But still, they remained symptomatic with severe joint pain and on PET-CT (figure 1e,1f) they had features of synovitis. The girl had synovitis in her right shoulder and right hip joint and the boy had in his left knee joint. They had low titer rheumatoid factor positivity with raised inflammatory markers. They were started on injection etanercept and methotrexate and improved symptomatically. Though, hyperinflammatory syndrome has been reported post Covid-19 vaccination, the subsequent development of multifocal AVN and undifferentiated arthritis is extremely rare.

Figure 1a: MRI of 19 year old girl showing avascular necrosis of right humerus
Figure 1b: MRI of 19 year old girl showing avascular necrosis of bilateral femoral head
Figure 1c: MRI of 19 year old boy left knee showing avascular necrosis of left lower end of femur with knee joint effusion
Figure 1d: MRI of 19 year old boy showing avascular necrosis of bilateral femoral head
Figure 1e: PET Scan of 19 year old girl showing synovitis in right shoulder and right hip joint
Figure 1f: PET Scan of 19 year old boy showing synovitis in left knee joint

Discussion

⦁ Multi-system hyperinflammatory syndrome (MISC) was first reported in children, post COVID-19 infections. It was also reported in adolescents and adults though less common in comparison to children. Similar phenomenon has been observed post COVID-19 vaccination.
⦁ In a post surveillance study from France, MISC was reported in 12 adolescents post COVID m-RNA vaccine. All patients recovered with severity being relatively less and also the reporting rate was low (1.5 per 1,000,000 doses injected).1
⦁ Our twins, similarly recovered well with steroid dose of 1mg/kg/day with no multi organ involvement except for transaminitis.
⦁ Avascular necrosis (AVN) has been frequently reported post COVID-19 infections, with steroid usage being commonly reported as the probable aetiology. But, multifocal AVN has been rarely reported. There are no case reports of AVN following post Covid-19 vaccine.
⦁ Multifocal AVN is defined as involvement of 3 or more anatomical sites and is seen in only 3-10% of AVN patients. Studies have shown the relative high percent (nearly 50%) of associated pro-thrombotic abnormalities.2 In our twins, both tested heterozygous positive for Factor V Leiden mutation. Though they both got steroids at 1mg/kg/day, presence of Factor V Leiden mutation was a definitely contributory to their Multifocal AVN.
⦁ They also had associated inflammatory arthritis (oligoarticular) with elevated inflammatory markers and low titre positivity for rheumatoid factor. New onset inflammatory arthritis has been reported post COVID-19 vaccination. Adjuvants or the vaccine per se may trigger an autoimmune reaction and inflammation. Molecular mimicry has also been proposed as one of the mechanisms, though the exact relationship has not been well established.
⦁ To conclude, though vaccines can induce autoimmunity the sequential presentation of inflammatory and thrombotic syndromes has not been reported before. The temporal relationship and the similar timeline of events in both the twins favours COVID-19 vaccine to be the definitive risk factor here.

References:

1. Ouldali N, Bagheri H, Salvo F et al. “French Covid-19 Paediatric Inflammation Consortium”£ and the “French Pharmacovigilance network”*. Hyper inflammatory syndrome following COVID-19 mRNA vaccine in children: A national post-authorization pharmacovigilance study. Lancet Reg Health Eur. 2022 Jun;17:100393.
2.Gómez-Puerta JA, Peris P, Reverter JC, et al. High prevalence of prothrombotic abnormalities in multifocal osteonecrosis: description of a series and review of the literature. Medicine (Baltimore). 2013 Nov;92(6):295-304.
3. Rai A, Aashish, Priya, Karmani S, Abbas W, Khatri G. Prevalence of rheumatoid arthritis following COVID-19 vaccine: An autoimmune disorder. Ann Med Surg (Lond). 2022 Oct;82:104628.

Dr Pawan Kumar PR
DNB 2nd Year Post Graduate (General Medicine)
Kauvery Hospital Chennai