High density of IgG4-secreting plasma cells in the fibrotic tissue from a surgically resected tracheal ring impaired by complex subglottic stenosis post-tracheostomy as immune expression of a Th2 response due to severe COVID-19.

Dear Editor,

Coronavirus disease 2019 (COVID-19) is a global health emergency without precedents, that is causing hundreds of thousands of victims and impairing, to some extent, the quality of life of those patients survived to the most severe form of the disease [1, 2]. In this regard, a 67-year-old male patient was admitted to the intensive care unit for bilateral pneumonia from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, as proven by nasopharyngeal swab positivity. The clinical picture was so serious that endotracheal intubation and then tracheostomy were required; despite all, the patient was saved, and he was discharged from the hospital. Three and a half months after admission, a second hospitalization was necessary due to complex subglottic stenosis, and the surgical resection of a tracheal ring was performed. Besides exuberant fibrosis, histology and immunohistochemistry revealed a high localized density of immunoglobulin G4 (IgG4)-secreting plasma cells inside the fibrotic tissue (Fig. 1); contrariwise, IgG4 dosage on serum was found within the normal range (43 mg/dL). As well known, IgG4-related disease (IgG4-RD) is a chronic immune-mediated condition, which occurs most frequently in middle-aged and elderly men, characterized by tissue infiltration with lymphocytes and IgG4-secreting plasma cells, various degrees of storiform fibrosis, and a usually prompt improvement by oral steroids [3]. The connective deposition in the affected anatomical site can lead to mass-forming tumor-like lesions and organ dysfunctions [3]. Severe SARS-CoV-2 infections are associated with marked T cytotoxic (Tc) lymphopenia [4], and, in these life-threatening cases, the immune system is forced to mount a T helper 2 (Th2) response (humoral immunity), the only one still mountable in the attempt to counteract the viral load, rather than a T helper 1 response (cell-mediated immunity), which would keep the infection under control by means of Tc lymphocytes and macrophages [5-8]. Because regulation of IgG4 switching is dependent by Th2 cells [9], it is possible that the Th2 response, induced by serious SARS-CoV-2 infections, triggers in some patients a localized IgG4 hyperproduction with subsequent scarring sequelae, in particular at the level of the respiratory tract, even in the absence of IgG4-RD. In addition, since advanced age, male sex, and chronic comorbidities are risk factors for COVID-19 mortality [10], IgG4-RD patients appear at higher risk of progressing to critical state once infected, and thus need to be identified and properly managed.

Fig. 1

Histological section of the tracheal ring with fibrosis and plasma cell infiltration (a, hematoxylin & eosin, × 10 objective); Masson’s trichrome stains in blue the disrupting fibrotic reaction (b, × 10 objective); on immunohistochemistry, plasma cells are mainly IgG-secreting elements (c, polyclonal, × 10 objective), with a high tissue density of IgG4 subclass (d, MRQ-44 clone, × 10 objective), in number significantly superior to IgA- (e, polyclonal, × 10 objective) and IgM-secreting plasma cells (f, polyclonal, × 10 objective) (brownish chromogen: 3,3′-diaminobenzidine tetrahydrochloride)