Clarkson's Disease Episode or Secondary Systemic Capillary Leak-Syndrome: That Is the Question!

To the Editor:

We read with great interest the article by Case et al titled “Systemic Capillary Leak Syndrome secondary to COVID-19.” The authors described a fatal systemic capillary leak syndrome (SCLS) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. They suggest SCLS could be a varied presentation of the multisystemic inflammatory syndromes (MIS) associated with the coronavirus disease 2019 (COVID-19).

We recently reported a SARS-CoV-2-induced crisis of a patient with a 7-year history of IgG Kappa Clarkson’s disease, and several articles lately highlighted the role of lung capillary leakage in the pathophysiologic condition of COVID-19.

These data suggest that COVID-19 can induce both Clarkson’s disease episodes (henceforth primary SCLS) and secondary SCLS. Several considerations must be addressed to determine the nature of the capillary-leak syndrome in the reported patient.

First, COVID-19-related MIS usually affects children or young adults while Clarkson’s disease patients are typically >50 years old. Second, this case is highly typical of primary SCLS: very marked hemoconcentration (>20 g/dL), rapid clinical evolution, and 4-limb compartment syndrome. On the contrary, secondary SCLS usually exhibit incomplete capillary-leak syndrome with less obvious hematocrit level increase and evolves more chronically with unresolving anasarca. Third, although not reported by the authors, the presence of a monoclonal gammopathy is critical to differentiate primary or secondary SCLS. Fourth, inflammatory biomarkers could be useful to distinguish the two hypotheses: being very elevated in MIS but low in primary SCLS episodes (personal data). Fifth, 80% of patients with COVID-19-related MIS had a positive serologic assay, which suggests that MIS occurs in the late phase of COVID-19. However, the authors do not report how the diagnosis of SARS-CoV-2 was done. Last, therapeutic interventions (corticosteroids, IV immunoglobulins) seem to be effective in COVID-19-related MIS, although no treatment has shown its efficacy during primary SCLS severe episodes. Yet, chronic treatment with IV immunoglobulins prevents relapse and improves survival of patients with Clarkson’s disease.

In conclusion, COVID-19 seems to be responsible for both primary and secondary SCLS. In our opinion, the type of capillary-leak syndrome that affected the reported patient remains unclear. Differentiating the two syndromes is crucial because it has very significant therapeutic implications.