A Case of Autoimmune Pulmonary Alveolar Proteinosis that Improved after a COVID-19 Episode.

Autoimmune pulmonary alveolar proteinosis (APAP) is caused by macrophage dysfunction owing to the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. A 77-year-old man with APAP was referred to our hospital for whole-lung lavage (WLL) due to oxygenation exacerbation and pulmonary shadows. The patient had had coronavirus disease 2019 (COVID-19) during the APAP evaluation before WLL. About three months after COVID-19 resolved, his oxygenation and shadow reflecting APAP had obviously improved, thus avoiding the need for WLL. We suspected that the improvement in APAP was due to various immunological reactions induced by COVID-19.

Mild and Asymptomatic COVID-19 Convalescents Present Long-Term Endotype of Immunosuppression Associated With Neutrophil Subsets Possessing Regulatory Functions.

The SARS-CoV-2 infection [coronavirus disease 2019 (COVID-19)] is associated with severe lymphopenia and impaired immune response, including expansion of myeloid cells with regulatory functions, e.g., so-called low-density neutrophils, containing granulocytic myeloid-derived suppressor cells (LDNs/PMN-MDSCs). These cells have been described in both infections and cancer and are known for their immunosuppressive activity. In the case of COVID-19, long-term complications have been frequently observed (long-COVID). In this context, we aimed to investigate the immune response of COVID-19 convalescents after a mild or asymptomatic course of disease. We enrolled 13 convalescents who underwent a mild or asymptomatic infection with SARS-CoV-2, confirmed by a positive result of the PCR test, and 13 healthy donors without SARS-CoV-2 infection in the past. Whole blood was used for T-cell subpopulation and LDNs/PMN-MDSCs analysis. LDNs/PMN-MDSCs and normal density neutrophils (NDNs) were sorted out by FACS and used for T-cell proliferation assay with autologous T cells activated with anti-CD3 mAb. Serum samples were used for the detection of anti-SARS-CoV-2 neutralizing IgG and GM-CSF concentration. Our results showed that in convalescents, even 3 months after infection, an elevated level of LDNs/PMN-MDSCs is still maintained in the blood, which correlates negatively with the level of CD8+ and double-negative T cells. Moreover, LDNs/PMN-MDSCs and NDNs showed a tendency for affecting the production of anti-SARS-CoV-2 S1 neutralizing antibodies. Surprisingly, our data showed that in addition to LDNs/PMN-MDSCs, NDNs from convalescents also inhibit proliferation of autologous T cells. Additionally, in the convalescent sera, we detected significantly higher concentrations of GM-CSF, indicating the role of emergency granulopoiesis. We conclude that in mild or asymptomatic COVID-19 convalescents, the neutrophil dysfunction, including propagation of PD-L1-positive LDNs/PMN-MDSCs and NDNs, is responsible for long-term endotype of immunosuppression.

Does hereditary angioedema make COVID-19 worse?

The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, enters host cells via angiotensin-converting enzyme 2 (ACE2) and depletes ACE2, which is necessary for bradykinin metabolism. The depletion of ACE2 results in the accumulation of des-Arg (9)-bradykinin and possible bradykinin, both of which bind to bradykinin receptors and induce vasodilation, lung injury, and inflammation. It is well known that an overactivated contact system and excessive production of bradykinin comprise the key mechanisms that drive the pathogenesis of hereditary angioedema (HAE). It is reasonable to speculate that COVID-19 may increase disease activity in patients with HAE and vice versa. In this review, we explore the potential interactions between COVID-19 and HAE in terms of the contact system, the complement system, cytokine release, increased T helper 17 cells, and hematologic abnormalities. We conclude with the hypothesis that comorbidity with HAE might favor COVID-19 progression and may worsen its outcomes, while COVID-19 might in turn aggravate pre-existing HAE and prompt the onset of HAE in asymptomatic carriers of HAE-related mutations. Based on the pathophysiologic links, we suggest that long-term prophylaxis should be considered in patients with HAE at risk of SARS-CoV-2 infection, especially the prophylactic use of C1 inhibitor and lanadelumab and that HAE patients must have medications for acute attacks of angioedema. Additionally, therapeutic strategies employed in HAE should be considered for the treatment of COVID-19, and clinical trials should be performed.