Fig. 6.

Clinically interpretability of IPGS. Panel A shows the GEN-COVID cohort dendrogram and heatmaps of the probabilities of severity based on the 3 different models: sex-age alone, IPGS alone and combined model. In the extreme ends of dendrogram (left and right) the probability of severity based on sex-age alone and IPGS alone is highly discordant (different colors). Selected examples corresponding to the arrows are illustrated in panels B-G. In each panel IPGS score, probabilities of severity and key features useful for bedside clinical management are shown. B) Male patient, in the 46–50 age range, treated with CPAP ventilation, tocilizumab, enoxaparin, hydroxychloroquine and lopinavir/ritonavir; no comorbidities except for asthma have been reported. The patient presented a rare TLR7 mutation that leads to an impaired production of interferon gamma (Made et al. 2020). C) Male patient, in the 51–55 age range, treated with invasive mechanical ventilation, steroids and enoxaparin. He had among comorbidities obesity, anxiety, hypertension and cerebral ischemia. He was found to be homozygous for the SELP rs6127 (p.Asp603Asn). Homozygosity of Asparagine in position 603 of Selectin P makes this endothelial protein more prone to clot formation and male patients more prone to COVID-19 thrombosis (Croci et al. 2021). Hence, the rationale for considering as putative adjuvant therapy in the management of similar cases the anti-Selectin P antibodies, a drug already approved for vascular events of sickle cell anemia. D) Male patient, in the 51–55 age range, treated with CPAP ventilation, tocilizumab, steroids, enoxaparin, hydroxychloroquine and lopinavir/ritonavir; no comorbidities except for diabetes. He was found to have the androgen receptor polyQ repeats > 23. The regular function of the androgen receptor is correlated with a beneficial immunomodulatory effect in those male patients in whom the increase in testosterone levels may overcome the receptor resistance. The rationale is to consider giving testosterone to those male subjects who cannot, on their own, raise the levels enough to overcome the receptor resistance due to poly-glutamine stretch longer than 23 repeats (Daga et al. 2021). E) Female patient, in the 31–35 age range, treated with CPAP ventilation and steroids, enoxaparin and azithromycin; no comorbidities except for hypothyroidism. She was a carrier of an ultra-rare mutation in ADAMTS13. Impaired function of ADAMTS13 leads to reduced cleavage of von Willebrand factor (vWF) and enhanced clot formation. The effect is enhanced in females and responsible for SARS-CoV-2 related thrombosis. Anti-vWF immunoglobulins would be a putative therapeutic option to consider in similar cases. F-G) examples of low IPGS and related key features. F) Male patient, in the 81–85 age range, treated with low-flow oxygen. No information regarding pharmacological therapy during hospitalization is present. Among comorbidities: diabetes mellitus, congestive heart failure and bowel cancer and steroids. He presented an ultra-rare mutation in ACE2. G) Male patient, in the 86–90 age range, treated with low-flow oxygen, steroid, enoxaparin and ceftriaxone plus azithromycin. Among his comorbidities: colon diverticulosis with constipation?, benign prostatic hyperplasia?, anxious-depressive syndrome, sideropenic anemia. He was a carrier of an ultra-rare mutation in AGTR2