Severe multisystem inflammatory syndrome in a vaccinated adult with COVID-19

Discussion

Current adult models of COVID-19 disease typically involve three clinical phases. First, there is an initial viral response phase where patients mostly have mild constitutional symptoms, followed by a pulmonary phase where there is an overlap of host inflammatory response and viral replication effects. Lastly, there is a hyperinflammatory phase where the pathophysiology is driven by the host immune response. Such progression occurs within 1–2 weeks of SARS-CoV-2 infection.6 MIS-A may be a late sequela of the hyperinflammatory phase or a delayed inflammatory phase, driven by a dysregulated immune response or autoimmunity. Unlike MIS-A, COVID-19 hyperinflammatory syndrome (cHIS) does not have a defined clinical presentation and may exhibit a mix of features of severe COVID-19 disease, multi-inflammatory syndrome (MIS) and other known hyperinflammatory syndromes such as haemophagocytic lymphohistiocytosis, macrophage activation syndrome and cytokine release syndrome. Differentiation of severe COVID-19 infection and cHIS versus MIS remains a challenge.

The true incidence of MIS-A is not known. MIS-A is likely underdiagnosed due to overlapping symptoms with severe, acute biphasic COVID-19 disease and cHIS. cHIS is more difficult to define clinically and likely has a more heterogeneous presentation. Although both are similar in terms of fever, extremely elevated inflammatory markers and multiorgan dysfunction, they are clinically distinct syndromes. MIS-A likely has a more severe presentation, involving severe multiorgan failure, shock and cardiac involvement, additionally it typically occurs some time (1+ weeks) after the initial infection. The onset of cHIS is also heterogenous: it may be concurrent with COVID-19 or take more of a delayed course. MIS-A and cHIS should be considered on a spectrum of hyperinflammation concurrent with or following after SARS-CoV-2 infection. Table 2 details differences between severe COVID-19/cHIS and MIS-A.7–11 Differential diagnoses should also include Kawasaki disease, hemophagocytic lymphohistiocytosis, toxic shock syndrome, macrophage activation syndrome and severe Kawasaki shock. It is critical to distinguish MIS-A from alternative diagnoses as the clinical management can differ significantly. A thorough history and physical examination, laboratory workup and high clinical suspicion can provide a degree of clinical certainty.

The exact pathophysiology is unclear. First, antibodies to SARS-CoV-2 might enhance antibody-dependent viral entry into cells and amplify viral replication. Second, there could be autoantibody or T-cell-mediated direct cell damage by attacking cells that express viral antigens or host antigens, which mimic viral antigens. Third, there can be activation of the host inflammatory response through immune complex formation. Immune complexes may also be responsible for vascular and coronary injury by activation of inflammatory responses through the Fc-γ receptor or complement activation, such as Kawasaki disease. Antibodies against SARS-CoV-2 are also associated with interleukin (IL)-16 and IL-18 activation, and activation of natural killer cell, lymphocytes and monocytes. Lastly, there may also be viral superantigen sequences that activate the host immune cells.12–14

Currently, there are only preliminary definitions for MIS-A, some of which are similar to criteria used to diagnose MIS-C. Our patient met the CDC criteria for MIS-A (presence of fever, severe cardiac illness, encephalopathy, thrombocytopenia, hypotension, significantly elevated inflammatory markers and positive SARS-CoV-2 test by RT-PCR).15 There were no alternative diagnoses to explain his clinical presentation. An extensive workup revealed no other aetiologies. As per CDC criteria, MIS-A patients usually have minimal respiratory system involvement. Our patient was intubated for airway protection due to acute encephalopathy and was extubated after 8 days following treatment for aspiration pneumonia. Vogel et al described three categories of patients in his article on MIS-C/A. There may be SARS-CoV-2 naïve patients who are vaccinated against SARS-CoV-2 and then develop MIS-C/A; there may be patients with history of COVID-19, subsequently get vaccinated and then develop MIS-C/A; lastly, patients who have already been vaccinated may then become infected or reinfected with SARS-CoV-2 and then develop MIS-C/A.16 Our patient would fit under category three where he was already vaccinated; however, got infected with SARS-CoV-2 and developed MIS-A.

COVID-19 mRNA vaccines elicit an immune response to the spike protein, and these patients are expected to have anti-spike protein (anti-S) and anti-receptor binding domain (anti-RBD) antibodies but not antinucleocapsid antibodies. However, patients infected with COVID-19 have both antispike and antinucleocapsid antibodies. This can be used to distinguish the immune response to vaccination from that resulting from natural COVID-19 infection.17 Most MIS-A patients have positive anti-S IgG antibodies, and these levels are comparable to adult individuals that survived severe COVID-19, suggesting that MIS-A is associated with a strong immune response. MIS-A is also noted to have low or absent anti-S IgM, supporting the idea of a postinfectious phenomenon. Clinical response to immunomodulation with glucocorticoids, intravenous IG suggests that MIS-A is likely driven by postinfectious immune dysregulation rather than directly by the viral infection. In our patient, significantly elevated levels of anti-RBD IgG (>25 000, normal <50 AU/mL) and antinucleocapsid IgG (8.67, normal <1.40 index) antibodies and negative anti-S IgM levels were suggestive of a postinfectious immune dysregulation phenomenon. In addition, the dramatic response to the immunomodulation therapy supports an immune dysregulation pathology.

Treatment largely depends on guidelines adopted from treatment of MIS-C. It involves immunomodulation with intravenous IG, high-dose glucocorticoids, IL-1 or IL-6 antagonists either alone or in combination. Intravenous IG causes induction of regulatory T cells, which help control inflammation. The antibodies in intravenous IG might also compete with endogenous antibody and alter the immune complexes or may compete with the immune complex binding sites.18 Based on its mechanism of action, intravenous IG is considered a first-line therapy. The proposed starting dose of intravenous IG is 2 gm/kg daily. High-dose glucocorticoids are often used in conjunction with intravenous IG. Typical starting dose of methylprednisolone is 2 mg/kg/day. In patients who are refractory to these treatments or have contraindications to them, IL-1 and IL-6 antagonists can be used. Anakinra, a recombinant IL-1 receptor antagonist, is typically started at 4 mg/kg/day intravenous, with a gradual plan to taper the dose based on clinical improvement and resolution of inflammatory markers. Tocilizumab may also be alternatively used if there is a shortage of IL-1 antagonists; however, the risk of bacterial and fungal infection remains high.19

In conclusion, MIS-A and cHIS are rare but increasingly recognised, sequelae/complications of COVID-19 disease. Clinicians must have a high index of suspicion to diagnose these poorly understood conditions as initial SARS-CoV-2 PCR tests may be negative. Patients may need further serologic assays to establish prior infection with SARS-CoV-2. Early recognition of a hyperinflammatory state associated with COVID-19 (MIS-A, cHIS) is essential for timely initiation of appropriate therapy to reduce morbidity and mortality. Many questions remain regarding the immunopathogenesis and optimal management of the spectrum of hyperinflammation and delayed inflammatory sequelae of COVID-19. Larger studies are needed to further elucidate risk factors and biomarkers to distinguish MIS-A from severe COVID-19/cHIS to help with prognostication and treatment decisions.