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Despite recent therapeutic advances, deaths in Intensive Care Units still range between 34 and 72%, comprising substantial unmet need as we move to an endemic phase. The general agreement is that in the first few days of infection, antiviral drugs and neutralizing monoclonal antibodies should be adopted. When the patient is hospitalized and develops severe pneumonia, progressing to a systemic disease, immune modifying therapy with corticosteroids is indicated. Such interventions, however, are less effective in the context of comorbidities (e.g., diabetes, hypertension, heart failure, atrial fibrillation, obesity and central nervous system\u2010CNS diseases) which are by themselves associated with poor outcomes. Such comorbidities comprise common and some distinct underlying inflammatory pathobiology regulated by differential cytokine taxonomy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Searching in the PubMed database, literature pertaining to the biology underlying the different comorbidities, and the data from the studies related to various immunological treatments for the Covid\u201019 disease were carefully analyzed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Several experimental and clinical data have demonstrated that hypertension and atrial fibrillation present an IL\u20106 dependent signature, whereas diabetes, obesity, heart failure and CNS diseases may exhibit an IL\u20101a\/b predominant signature. Distinct selective cytokine targeting may offer advantage in treating severe COVID\u201019 illness based on single or multiple associated comorbidities. When the patient does not immediately respond, a broader target range through JAKs pathway inhibitors may be indicated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Herein, we discuss the biological background associated with distinct comorbidities which might impact the SARS\u2010CoV\u20102 infection course and how these should to be addressed to improve the current therapeutic outcome.<\/jats:p><\/jats:sec>","DOI":"10.1111\/eci.14096","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T13:38:19Z","timestamp":1695130699000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["COVID\u201019 illness: Different comorbidities may require different immunological therapeutic targets"],"prefix":"10.1111","volume":"53","author":[{"given":"Elisa","family":"Gremese","sequence":"first","affiliation":[{"name":"Clinical Immunology Unit Fondazione Policlinico Universitario A. 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