Case of adult-onset Kawasaki disease and multisystem inflammatory syndrome following SARS-CoV-2 vaccination

Discussion

We report a man that demonstrated symptoms consistent with KD and concerning for MIS-V 4 weeks after the second dose of the Pfizer-BioNTech mRNA SARS-CoV-2 vaccine. No evidence of concurrent or prior SARS-CoV-2 infection was detected, though high levels of antibodies against the SARS-CoV-2 spike protein, measured to assess immune response to vaccination, were detected. Extensive investigation did not reveal evidence of an alternative aetiology and resolution of symptoms followed courses of IVIg and oral prednisone.

MIS is a rare response to SARS-CoV-2 exposure in children and adults. The recently proposed Brighton Collaborative case definition of MIS notes similarities to KD, and establishes levels of diagnostic confidence based on presence of persistent fever, multiorgan dysfunction, hypotension, elevated serum inflammatory markers, confirmed exposure to SARS-CoV-2, or within 12 weeks of vaccination if known exposure has not occurred.10 This patient presented with persistent fever over 5 days, mucocutaneous and gastrointestinal symptoms, elevated liver enzymes, microscopic haematuria, elevated inflammatory markers, and recent SARS-CoV-2 vaccination without known or suspected SARS-CoV-2 exposure. No compelling alternative aetiology was identified and prompt improvement in symptoms and disease markers followed treatment with IVIg and steroids. Therefore, by current criteria this patient may be classified as probable MIS-V. Development of symptoms approximately 4–6 weeks following exposure and response to IVIg are consistent with prior reports of MIS in adults.10 13 This patient did not experience severe organ dysfunction and did not require intensive care; therefore, he experienced a comparatively milder condition than those previously reported. Early administration of IVIg resulted in prompt improvement and may have prevented progression to a more severe condition.

In addition to probable MIS-V, this patient’s presentation and clinical course met criteria for the diagnosis of KD. At the time of hospital admission, he had experienced persistent fevers for more than 5 days and met all five of the additional American Heart Association (AHA) criteria proposed for the diagnosis of KD: painful erythematous swelling of the hands and feet, extensive erythematous rash, oropharyngeal erythema marked by cheilitis and strawberry tongue, cervical lymphadenopathy, and conjunctival injection without exudate.19 Desquamation of the palms and soles of the hands and feet during convalescence is considered pathognomonic of KD.19 Treatment with IVIg and steroids resulted in prompt improvement in symptoms and disease markers.

The overlap of non-specific features that characterise both KD and MIS limits clear differentiation of the two conditions.20 Both believed to result from untoward immune activation following an infectious trigger, these conditions may be considered related manifestations of similar underlying mechanisms in response to SARS-CoV-2 antigens. Reports document response to immunomodulatory therapies in both conditions, and therefore each may be treated similarly with IVIg and steroids, among other therapies.1–3 7 The presence of gastrointestinal symptoms, elevated liver chemistry tests, haematuria, highly elevated CRP and the absence of coronary artery involvement are more typical of MIS7 10; nonetheless, this patient fulfilled all criteria for the diagnosis of complete KD and was therefore managed in accordance with guidelines for the treatment of KD. Designating this patient as probable MIS-V in addition to KD increased vigilance for progressive multiorgan dysfunction and for resistance to treatment with IVIg, neither of which occurred. The use of steroids in KD is associated with decreased duration of symptoms and improved cardiac outcomes21; therefore, the use of prednisone in this patient may have affected early symptom control. No cardiac sequelae have been detected during 3 months of surveillance.

Novel to the growing reports of inflammatory syndromes associated with SARS-CoV-2 is the manifestation of KD in an adult following vaccination in absence of concurrent or prior SARS-CoV-2 infection. While we cannot entirely exclude the possibility of occult SARS-CoV-2 infection, this patient experienced no prodromal or concomitant features of COVID-19, tested negative for infection via RT-PCR of nasopharyngeal swab specimens, tested negative for SARS-CoV-2 nucleocapsid antibodies and demonstrated extremely high levels of SARS-CoV-2 spike protein antibodies. The onset of symptoms occurred between 4 and 6 weeks after the second dose of vaccine, approximately the same interval over which inflammatory syndromes are expected to occur following exposure to SARS-CoV-2 viral triggers.10 The patient denied exposure to sick individuals in the weeks prior to presentation, including exposure to known or suspected cases of COVID-19. SARS-CoV-2 spike protein antibody levels have been used in prior investigations to assess the immune response to vaccination,22 particularly when accompanied by the absence of SARS-CoV-2 nucleocapsid antibodies and the absence of viral RNA detected by RT-PCR to exclude prior or concurrent infection.23

While KD has been described following SARS-CoV-2 infection in adults and children,20 24 25 only one prior report documents KD following vaccination against SARS-CoV-2.26 That man in his teens experienced symptoms 3 weeks after the first dose of a SARS-CoV-2 vaccine and similarly responded to treatment with IVIg. Exclusion of prior or concurrent SARS-CoV-2 infection was not specified. Prior to the COVID-19 pandemic KD was observed following vaccination, and although multiple investigations failed to establish a causal link, a temporal relationship between vaccination and KD persisted.6 27 Recent reports describe MIS-V in adult patients after receiving SARS-CoV-2 vaccines, many of whom experienced multiorgan failure and responded to high-dose steroids or IVIg.13 15–18 Most of these patients had prior SARS-CoV-2 infections and develop symptoms shortly after vaccination. Few among these patients experienced minor erythematous rashes on their torso or extremities; however, they did not demonstrate additional features of KD.13 15–18

Alternative aetiologies appear unlikely in this patient. Though the rash involved mucocutaneous surfaces, no ulceration, necrosis or vesicular changes were observed and the appearance of rash predated the use of antibiotics, altogether suggesting against a drug allergy syndrome. The patient denied any history to suggest autoimmune disease and rheumatological serum studies including markers of systemic vasculitis were negative. He denied prodromal symptoms to suggest infection and the results of multiple microbial cultures were negative. He denied exposure to ticks, no bite wounds were evident, and extensive investigation revealed no evidence of concurrent tick-borne or occult viral, bacterial, or plasmodial disease. Increased band cells were noted, a non-specific finding that has been observed in KD.28 Short courses of amoxicillin and doxycycline were ineffective; fever and other symptoms persisted until administration of IVIg. Although serum inflammatory markers were mildly elevated, peak levels and absence of severe illness suggest against severe immune hyperactivation syndromes such as macrophage activation syndrome or haemophagocytic lymphohistocytosis. Considering the absence of alternative explanations, the temporal relationships between symptom onset and vaccination, and the isolated elevation in spike protein antibody levels without evidence of concurrent or prior SARS-CoV-2 infection, a postvaccination inflammatory syndrome presenting as KD and meeting criteria for MIS-V appears most likely.

Importantly, temporal association between inflammatory syndromes and vaccination is not tantamount to causation. Vaccine hesitancy that results from misattribution of rare inflammatory syndromes to vaccination may indeed blunt the use of an essential tool in the battle against COVID-19.29 Thorough investigation of temporally related events, as presented in this report, and ongoing efforts to support widespread vaccination against SARS-CoV-2 are critical to safely and effectively combating COVID-19. Nonetheless, early recognition and intervention may limit progression in both MIS and KD and may forestall the development of cardiac dysfunction after KD. As widespread vaccination against SARS-CoV-2 continues, increased vigilance and prompt intervention is necessary to limit the effects of rare postvaccination inflammatory syndromes.