We read with great interest the meta-analysis by Akiyama et al showing that out of 62 studies with over 300 000 patients with autoimmune diseases, glucocorticosteroids (GC) therapy was significantly associated with an increased risk of COVID-19.1

These data raise interest on the use of GC in the therapeutic approach to inflammatory pneumonia associated with SARS-CoV-2 infection. A recent editorial entitled ‘Curing COVID-19’ in the October issue of the Lancet Infectious Disease discussed in fact the role of steroids to treat COVID-19 pneumonia. Dexamethasone is suggested by the WHO as part of the therapeutic approach.2 The evidence is that data on steroids are partly positive (RECOVERY and REMAP-CAP doi:10.1001/jama0.2020.17022) and partly negative (CAPE-COD-doi:10.1001/jama. 2020.16761), yet the meta-analysis of the randomised trials shows a statistical effect on mortality in very severe cases, with differences among the different steroids.3 The differences between steroids and standard of care treatment are significant, yet far away from solving the puzzle of the best therapy. Certainly, the inflammation occurring in SARS-CoV-2 pneumonia, certified by increased C-reactive protein (CRP), interleukin (IL)-6 and sometimes by ferritin, strongly suggests that GC might help to control the course of the disease. Yet recent data by Carsana et al 4 and Grasselli et al 5 suggest that pneumonitis may have at least two pathophysiology backgrounds and that ‘subsetting’ might be the key. The AA focused on the pathophysiology of COVID-19-related acute respiratory distress syndrome (ARDS) and the two studies, postmortem histopathology and clinical–laboratory–imaging data in intensive care unit (ICU) patients, respectively, suggest that the identification of the possible pathogenetic events might lead to better therapy. The major findings were that in severe ARDS of COVID-19, coagulopathy–leucothrombosis and hyperinflammation are separate or coexisting factors.4 In all cases (n=38), diffuse alveolar damage, capillary congestion, pneumocytes necrosis and inflammatory infiltrate were seen, and in 86%, platelet-fibrin thrombi in small arterial vessels consistent with coagulopathy were coexistent.3 In particular, in the ICUs, the study assessment of in vivo pathophysiology revealed that in mechanically ventilated patients, static lung compliance values were statistically higher than in classical ARDS, yet a subgroup had very low compliance.5 Of special interest, D-dimers levels also were within the expected median values, yet a subset had very high levels. Having very high D-dimers (thromboinflammation) and very low compliance is associated with high mortality. The latter subset is the one that presents according to several studies with hyperinflammation (high CRP, high ferritin, high IL-6).6 Other reports suggest that with D-dimers higher than 1000 ng/mL but without lung CT emboli, clear-cut perfusion abnormalities can be observed, with hyperperfusion around areas of hypoperfusion (leucothrombosis); while generally peripheral opacities with hypoperfusion can be seen in pulmonary infarction, yet these patients had no emboli.7 We described patients with D-dimers levels lower than 1000 ng/mL, not in distress, in whom hyperperfused areas around hypoperfused areas were present since the onset of the disease.8 In one of these patients (swab test=positive, PaO2/FiO2=265, CRP=100 mg/L, D-dimers=625 ng/mL, ferritin=1145 ng/mL, IL-6=87 pg/mL), treated with enoxaparin and anti-IL-6R, without steroids, 10 days later, a general improvement of clinical conditions and CT scan, in which lung blood volume (LBV, volume of blood in a given amount of lung tissue), lung blood flow (LBF, volume of blood passing through a given amount of lung tissue per unit of time) and mean transit time (MTT, average time, in seconds, that red blood cells spend within a determinate volume of capillary circulation) maps were obtained; a fair recovery of perfusion was seen in all perfusion maps (figure 1). These data suggest that the vasculopathy with microthrombi can be hypothesised and demonstrated through a CT perfusion scan, that it can be monitored over time and accordingly treated. The follow-up, of note, showed that these hypoperfused areas did progress towards fibrosis. Since the leucothrombosis subset may be identified through laboratory tests (D-dimers levels) and imaging techniques (lung perfusion CT scan, dual-energy CT scan), COVID-19 pneumonia with both manifestations (hyperinflammation and leucothrombosis) should reasonably be treated aggressively for the hyperinflammation (ie, dexamethasone, hydrocortisone, anticytokines) and for the leucothrombosis (ie, heparin and colchicine, Bruton tyrosine kinase inhibitors to reduce NETosis and platelet microclots),9 whereas patients with hyperinflammation only might benefit more from the full control of the cytokine release syndrome (anti-IL-1, anti-IL-6, baricitinib).10 To treat the coagulopathy and microclots is still a matter of intense scientific debate.11 Subsetting might finally be the key and randomised trials should be in the research agenda especially in front of the new wave of the pandemia, to address the two major pathogenetic mechanisms leading to organ failure. Summarising, steroids do not prevent SARS-CoV-2-related inflammation, may be of help for some critical patients and should not be considered the unique tool to dampen lung (and systemic) inflammation especially when microangiopathy (with microclots) can be demonstrated.

CT at admission (left side). (A) The morphological scan shows ground-glass opacity (GGO) in the right upper lobe and at the apical segment of the left lower lobe also with vessel enlargement; (B) lungblood volume (LBV); (C) lungblood flow (LBF); (D) lungblood flow (MTT): the perfusion maps show LBV and LBF reduction and MTT alterations (arrows) related to microcirculation damage. However, these alterations present wider distribution than the opacity and are recognisable also in lung areas without any morphological changes. Control CT after 10 days (right side). (A) The morphological scan showing general improvement in parenchymal conditions (reduction of extension of GGO); (B) LBV; (C) LBF; (D) MTT: fair recovery of perfusion (minor extension) is recognised in all perfusion maps. In perfusion maps, the red bands recognisable in the heart and front are the effect of the images processed without motion correction (respiratory artefacts).

Obtained.

Ethical Committee approved the study through CT lung scan in patients.