Morbidity and Mortality From COVID-19 Are Not Increased Among Children or Patients With Autoimmune Rheumatic Disease-Possible Immunologic Rationale: Comment on the Article by Henderson et al.

To the Editor:

We read with great interest the article by Henderson et al (1) on the therapeutic rationale for using glucocorticoids to treat the hyperinflammation and cytokine storm phases of severe acute respiratory syndrome coronavirus 2 (SARS–CoV‐2) infection. We would like to expand on their analysis and discuss the data reported to date on the likelihoood of serious outcomes of infection in children and patients with autoimmune rheumatic diseases (rheumatoid arthritis [RA] and systemic lupus erythematosus [SLE]).

To date, children and patients with autoimmune disease have rarely experienced progression of their infection to cytokine release syndrome, the third phase of coronavirus disease 2019 (COVID‐19), with few being admitted to intensive care units (ICUs). Based on reports to date from China, Europe, and the US, patients with rheumatic diseases are not necessarily at increased risk for severe outcomes. The latest report from the COVID‐19 Global Rheumatology Alliance (2) shows that of 334 registered patients infected with COVID‐19 (of whom 74.25% were women and 25.75% were men), only 38 were hospitalized and 19 (5.69%) died. Within this population of patients with COVID‐19, there were 121 patients with RA, 33 with psoriatic arthritis, 58 with SLE, 28 with axial spondyloarthritis, 27 with vasculitis, and 19 with primary Sjögren’s syndrome. In China, of 171 children with COVID‐19 infection, only 12 experienced radiologic pneumonitis and only 1 died in the pediatric ICU (3). This percentage does not appear to be higher than the percentage in the general population, despite the fact that >65% of adult patients with rheumatic diseases were treated with disease‐modifying antirheumatic drugs (DMARDs): 5.39% with JAK inhibitors, 36.5% with biologic DMARDs, and 30.2% with glucocorticoids. Only 25.7% were treated with hydroxychloroquine (HCQ) (2). The Global Rheumatology Alliance data on patients with rheumatic diseases showed that the number of women infected with COVID‐19 was higher than the number of men. This is expected, based on data from the general population showing that women with rheumatic diseases are more often hospitalized and more often have a worse disease course. Meanwhile, no proven cases of macrophage activation syndrome or hemophagocytic lymphohistocytosis in children with COVID‐19 infection have been described to date. The recently described Kawasaki‐like illness (4) still needs to be well defined.

In addition to the potential role of sex, we would like to speculate on the immunologic basis for rheumatic disease patients not having more severe outcomes, as might have been expected at the onset of this pandemic. In the early phases of infection, the lungs of patients with COVID‐19 exhibit edema, a patchy inflammatory infiltrate, and multinucleated giant cells (MGCs), with lymphopenia in the peripheral blood. Evidence from animal models demonstrates that macrophage colony‐stimulating factor and granulocyte–macrophage colony‐stimulating factor stimulate the differentiation of rat alveolar macrophages into MGCs with distinct phenotypes (type 1 and type 2 MGC) and that neutralization of endogenous interleukin‐6 (IL‐6) during alveolar macrophage differentiation into MGCs significantly inhibits the formation of type 2 MGCs (up to 50%) (5). Of interest, another type of key immune cell, type 2 innate lymphoid cells (ILC2), which are important for maintaining lung integrity, do not efficiently migrate from the bone marrow to the lungs with aging. In mice, transfer of young ILC2 to the old lung enhances resistance to infection. In addition, levels of tumor necrosis factor and IL‐6 and numbers of neutrophils increase with age and may contribute to increased inflammation in the lungs. Furthermore, it is well known that IL‐6 inhibits natural killer (NK) cell cytotoxicity. Therefore, IL‐6 appears to be a key molecule.

Numbers of NK cells are higher in infancy and decrease progressively with aging. Lymphocyte number and function also decline with age, and CD8+ T cells decline in number and weaken with aging, a feature of immunoesenescence (6). We do not yet know if vaccinations administered in early childhood play a role in stimulating the immune system. This is an area of intense clinical research. It has been suggested that SARS–CoV‐2 may enter type II alveolar epithelial cells (AECs) through angiotensin‐converting enzyme 2 (ACE2) present on the membrane of type II AECs and employs serine protease TMPRSS2 for priming (7). Once type II AECs are infected, they provoke an innate immune response and synthesize type I interferon (IFNα/β), type II IFN (IFNγ), IL‐6, and IL‐8 (8). In the majority of patients with this response, the infection clears. Once the SARS–CoV‐2 single‐stranded RNA is released inside the type II AECs, it is recognized by Toll‐like receptor 7 (TLR‐7) and TLR‐8. TLR‐7 ligation induces signal transduction via the adaptor protein myeloid differentiation factor 88, and the activation leads to synthesis and release of cytokines and chemokines. This may explain the inflammatory and lung symptoms (Figure 1).

Figure 1

Initial phase of viral infection. In this phase, nonspecific viral agents (while specific agents are awaited), antimalarials, or anti–interleukin‐6 (anti–IL‐6) (or other anticytokine) agents may be used to shut down the inflammatory process before it evolves into acute respiratory distress syndrome–induced lung failure. SARS–Cov‐2 = severe acute respiratory syndrome coronavirus 2; ACE2 = angiotensin‐converting enzyme 2; IFNα/β = interferon α/β; TLR‐7 = Toll‐like receptor 7; ssRNA = single‐stranded RNA; AT 2 = type II alveolar epithelial cells; Myd88 = myeloid differentiation factor 88; TNF = tumor necrosis factor; MCP‐1 = monocyte chemotactic protein 1.

Treatment that targets the TMPRSS2 protease camostat mesylate, thus inhibiting priming of SARS–Cov‐2 spike‐S1 protein and its binding to ACE2, may protect against severe outcomes (9). If ACE2 expression is shut down by COVID‐19, the inflammation progresses, with release of IL‐6 and other cytokines and chemokines. The inflammation may progress to acute respiratory distress syndrome (ARDS) and cytokine storm (1).

RA and SLE have a type I IFN signature (10), which might explain why children and patients with autoimmune diseases may not be affected more severely than the general population. This is why scientific societies support the idea of continuing treatments (IL‐6 inhibitors for juvenile idiopathic arthritis, DMARDs or JAK inhibitors for adult RA, and mycophenolate mofetil or HCQ for SLE). While specific antivirals are awaited, these drugs may help in the hyperinflammatory phase of the infection, and, in fact, several trials are underway using anti–IL‐6, other cytokines, or JAK1/2 inhibitors (ClinicalTrials.gov). The key question is whether, or when, to prescribe glucocorticoids, since the American Thoracic Society and Infectious Diseases Society of America (11) did not strongly support the use of glucocorticoids once the hyperinflammatory phase progresses to the cytokine release syndrome and ARDS‐like phase. Data from clinical trials and the real world are badly needed to support these theories.

Dr. Gremese has received speaking fees from MSD, Roche, Novartis, Eli Lilly, and AbbVie (less than $10,000 each). Dr. Ferraccioli has received consulting fees from Novartis and Gilead (less than $10,000 each).