We read with interest the article by Lee et al.1 about a 52-year-old male who developed clinical manifestations of multisystem inflammatory syndrome (MIS) three weeks after the second dose of the BNT162b2 vaccine. On hospital day 3 (hd-3) he developed shock and required catecholamines, oxygen via a high flow nasal canula, and antibiotics.1 For MIS he received prednisolone and colchicine for two months from hd-3.1 He recovered completely within two months of follow-up.1 The study is appealing but raises concerns that warrant further discussion.

It is not clear why the patient was treated with colchicine.1 It is well-known that colchicine is ineffective in SARS-CoV-2 infections and there is no evidence that it has an effect on long-SARS-CoV-2 vaccination syndrome (LSCVS).2 In addition, there is evidence that colchicine can cause serious side effects such as myopathy, nausea, vomiting, diarrhoea, abdominal pain, paresthesias, hepatopathy, renal insufficiency, pancytopenia, and hair loss. Even a number of cases with colchicine-induced rhabdomyolysis have been described.3 We should know what daily dosage of cholchicine was administered and whether the patient tolerated colchicine without major side effects. Particularly the combination of colchicine with steroids can be myotoxic.4

An argument for a myotoxic effect of the combination colchicine plus steroids is that liver transaminases were normal on hd-1 but increased 100-fold on hd-6, three days after the start of steroids plus colchicine. We should know whether the sudden increase in liver transaminases was due to hepatotoxicity of any newly administered drug or due to skeletal muscle involvement. In this respect we should know whether the creatine-kinase (CK) was also elevated, which would speak more for a myopathy than a hepatopathy.

The patient had dyspnoea for 6 days and experienced hypoxia, but no explanation was given as to the cause of the hypoxia.1 Pneumonia, heart failure, and pulmonary embolism have been ruled out as causes of hypoxia but it is conceivable that hypoxia was due to involvement of the central nervous system (CNS) or the respiratory muscles in toxic myopathy. We should know whether metabolic or respiratory acidosis has been ruled out as the cause of hypoxia.

A further limitation of the study is that the causal relation between the second dose of BNT126b2 and MIS remains unproven. Arguments against a causal relationship are that the latency between vaccination and onset of clinical manifestations was three weeks, the patient tolerated the first dose of the vaccine without major side effects, and MIS after a SARS-CoV-2 vaccination has been only rarely reported in adults.5

The patient had headache on admission but nothing is reported about the course, processing, and outcome of the headache. Since D-dimer was repeatedly significantly elevated, it is crucial that venous sinus thrombosis (VST) was ruled out by magnetic resonance venography (MRV) with contrast medium. VST often presents with headache, which resolves after recanalization of the cerebral veins by thrombectomy or anticoagulation.

There is limited information regarding several other issues. There was no documentation of cytokines IL-6, IL-8, IL-12, IL-1a, and TNF-alpha, which may be elevated in MIS. Procalcitonin was elevated, suggesting that shock in the index patient was due to sepsis. It is unclear if lymphadenopathy resolved together with the other clinical manifestations.

Overall, the study carries obvious limitations that require re-evaluation and discussion. Clarifying these weaknesses would strengthen the conclusions and could improve the study. Before establishing a causal relationship between SARS-CoV-2 vaccination and MIS, alternative explanations should be thoroughly ruled out.

We diagnosed our patient as having multisystem inflammatory syndrome in an adult (MIS-A) after vaccination, not long post-COVID-vaccination syndrome (LPCVS). Your recent article described LPCVS as the clinical conditions in which subacute or chronic adverse reactions to SARS-CoV-2 vaccinations persist for more than 4 weeks.2 We think that the most crucial difference between MIS-A and LPCVS is the evidence of hyperinflammation. Your cases showed no or minimal abnormal findings on clinical and instrumental investigations. In contrast, various inflammatory markers were significantly elevated in our case. And that is why we considered colchicine, an anti-inflammatory agent, as a treatment for our case. We presented the daily dosage of colchicine (0.6 mg twice daily) in our original article, and colchicine was well tolerated in our case.

In Fig. 1. of our original article, the number of days refers to the number of days from symptom onset.1 Our case was admitted on the fourth day after symptom onset (Day 4), and steroids with colchicine were started after the results of laboratory tests were obtained on the sixth day after symptom onset (Day 6). We think that elevated liver enzymes reflected acute liver injury as one of the multiple organ failures due to shock. In our case, creatine phosphokinase was consistently within the normal range during the follow-up period, and any symptoms related to myopathy did not develop.

Chest computed tomography (CT) showed no evidence of pneumonia and pulmonary thromboembolism, and transthoracic echocardiography showed preserved left ventricular contractility. At the time hypoxia occurred, the patient’s mental status was alert and blood gas analysis did not show carbon dioxide retention and metabolic or respiratory acidosis. We presume that disseminated intravascular coagulation and a significant amount of pericardial effusion may have contributed to dyspnea and hypoxia.

There were some contents that could not be presented in our case report due to the limitation of word count and number of figures according to the Information for Contributors. There were no abnormal findings in brain CT angiography, and we could exclude the possibility of venous sinus thrombosis. The danger signs or other features suggesting a secondary headache source did not develop and headache was resolved after steroids with colchicine therapy. Lymphadenopathy was also resolved with other symptoms.

Unfortunately, inflammatory cytokines such as IL-6, IL-8, IL-12, IL-1α, and TNF-α are not available in our institution’s routine clinical practice, and we have not been able to perform those tests in our case. However, the inflammatory markers (C-reactive protein, erythrocyte sedimentation rate, ferritin, and procalcitonin) that are included in the case definition of MIS-A were all significantly elevated.3

It is very difficult to prove the causal relationship between the symptoms and vaccination in MIC-A cases following immunization. The case definition of MIS-A was created to standardize the clinical conditions that show various levels of diagnostic certainty. One of the critical components of the case definition of MIS-A is the exclusion of clear alternative diagnosis. We did our best to rule out the possibility of other diseases. According to the rationale for timing of vaccination about the case definition of MIS-A, the Brighton Collaboration Working Group did not include specific time frames for onset of symptoms following immunization to avoid selection bias. Instead, they suggested that up to 12 weeks after vaccination is a reasonable timeline in vaccine-related MIS-A, similar to MIS-A after natural infection.4

Thus far, there have been only a few case reports of MIC-A following SARS-CoV-2 vaccination. The current understanding of the pathophysiology of MIC-A is still limited. In the future, as more data are collected over time, it is possible to enhance the case definition and promote a scientific understanding of these clinical conditions.