Hydroxychloroquine (https://rheum-covid.org). As expected females here prevail over males, who are more often hospitalized and more often present a worse course in the general population.
Meanwhile we can state that no proven cases of MAS ( macrophage activation syndrome ) nor HLH ( hemophagocytic lymphohistocytosis ) in kids have been described so far. The most recently described Kawasaki's like illness still needs to be well defined (3) .
This article is protected by copyright. All rights reserved In addition to the role played by gender , (females prevail in the previous report), we would like to speculate, on the immunological basis that can help to interpret why these patients are not the most fragile category as we could hypothesize at onset of the pandemia.
The lungs of Covid-19 infected patients in the early phases show, edema, patchy inflammatory infiltrate, plus multinucleated giant cells , and lymphopenia in the peripheral blood .The evidence in the literature from the animal models, is that Macrophage colony-stimulating factor (M-CSF) and Granulocyte-macrophage (GM)-CSF stimulate the differentiation of rat alveolar macrophages (AM) into multinucleated giant cells (MGC) with distinct phenotypes (type 1 and type 2 MCC), and that neutralization of endogenous IL-6 during AM differentiation into MGC inhibited significantly (up to 50%) the formation of type 2 MGC (4) . Of interest another key immune cell, the Innale Lymphoid Cells type 2 (ILC2) , which are so important to keep lung integrity, do not migrate efficiently from the bone marrow to the lungs with aging. Transfer of young ILC2 to the old lung enhances mice resistance to infection. In addition TNF IL6 levels and neutrophils increase with age. and may contribute to increased inflammation in the lungs. Furthermore it is well known that IL6 inhibits NK cell cytotoxicity. Therefore IL6 appears certainly a key molecule.
In infancy NK cells are higher and decrease progressively with aging. Lymphocyte number and function also decline with age (5). CD8 T cells also decline and weaken with aging, a feature of immunesenescence (5). We do not know yet which is the relevance of vaccinations performed in early childhood as a tool to stimulate the system. This is an area of intense clinical research.. It has been suggested that SARS.CoV2 may enter into Alveolar Type 2 (AT2) epithelial cells, through ACE2 (angiotensin converting enzyme 2) present on the membrane of AT2 and employs the serine protease TMPRSS2 for priming (6) . Once AT2 are infected they provide an innate immune response and synthesize Interferon type 1 (IFN), type 2 (IFN), IL6 and IL8 (7). The majority of the patients with this response, clear the infection. Once the SARS.CoV2 ssRNA, is released inside the AT2 cells, it is recognized by the Toll like receptors 7-8 (TLR 7-8). TLR 7 ligation induces signal transduction via the adaptor protein MyD88 and the activation leads to synthesize and release cytokines and chemokines.This may explain the inflammation and lung symptoms (Fig. 1) .
Targeting the TMPRSS2 protease ( camostat-nafamostat mesylate), thus inhibiting priming of SARS.CoV 2 spike-S1 protein and its binding to ACE2, may protect from infection. (Clinical trials.gov#NCT04287686), (8) . If ACE 2 expression is shut-down by Covid-19, the inflammation
This article is protected by copyright. All rights reserved progresses, with IL6, other cytokines and chemokines. The inflammation may progress to ARDS and might become a target in the acute respiratory distress syndrome (ARDS) with cytokine storm.
(1).
RA and SLE have an IFN type 1 signature (9) , which may be of help. This complex biology might explain why Children and Autoimmune patients, may be affected not more than the general population. This is the reason why the Scientific Societies support the idea of continuing 