key: cord-0943037-1z40egwi
authors: Santaniello, Alessandro; Vigone, Barbara; Beretta, Lorenzo
title: Letter to the editor: Immunomodulation by phosphodiesterase-4 inhibitor in COVID-19 patients
date: 2020-06-20
journal: Metabolism
DOI: 10.1016/j.metabol.2020.154300
sha: 9a60e2690c2a1b800ad095f3d70b4ffbf1f1ad2d
doc_id: 943037
cord_uid: 1z40egwi

nan

Letter to the editor: Immunomodulation by phosphodiesterase-4 inhibitor in COVID-19 patients

To the Editor,

We read with interest the commentary by Dalamaga and colleagues [1] that brought to the attention of the scientific community the potential role of Phosphodiesterase 4 (PDE4) inhibitors in the treatment of SARS-CoV-2 infection. Coronavirus disease 2019 (COVID-19) is associated with a variable clinical picture, ranging from mild "flu-like" cases to severe interstitial pneumonia leading to fatal respiratory insufficiency. This heterogeneity is attributed to the degree of the host's inflammatory reaction and cytokine production [2] . In the commentary it was suggested that Phosphodiesterase 4 (PDE4) could be a potential target of immunomodulation during the early phases of SARS-CoV-2 pneumonia, ideally preventing the overproduction of cytokines that characterizes the more severe forms of COVID-19 [3] . PDE4 regulates the balance between pro-and anti-inflammatory mediators and its inhibition dampens multiple cytokine signalling pathways allowing the restoration of the homeostatic cellular state [4] . In animal model PDE4 inhibitors prevented carfilzomib-induced lung injury via the inhibition of TNF-α and NF-κB activation suggesting a potential efficacy in inflammatory-mediated pneumonia [5] . Most noticeably, previous reports indicate that PDE4 inhibitors can safely be used in patients with chronic viral infection [6] [7] [8] . The safety profile of PDE4 inhibitors in SARS-CoV-2 infection is documented in a report describing a patient with psoriasis and COVID-19 who did not discontinued treatment with Apremilast (oral PDE4-inhibitors) with a rapid and positive outcome [9] .

Herein, we describe, for the first time, four cases of SARS-CoV-2 related pneumonia successfully treated with Apremilast. All the patients had a confirmed SARS-CoV-2 infection by nasopharyngeal swab and a severe lung involvement, defined as respiratory rate ≥30 breaths/min OR oxygen saturation ≤93% at rest OR PaO 2 /inspired oxygen fraction b300 mmHg AND/OR lung infiltrates ≥50% on chest x-rays [2] . The patients' clinical characteristics and main indication for Apremilast use are reported in the Table 1 . Apremilast was given at the dose of 30 mg bid for 14 days (without titration) on compassionate use and after Metabolism Clinical and Experimental 110 (2020) 154300 p/f, PaO 2 to inspired oxygen fraction FiO 2 rate; Extent lung involvement on chest x-rays; CRP, C-reactive protein; values at admission and (***) after therapy with Apremilast; IL-6, interleukin 6 as measured before and after *5 days or **7 days of therapy with Apremilast. Discharge criteria: absence of fever for 3 days and SaO 2 ≥ 94% and RR b 24 at rest at room air and resolution of constitutional symptoms. 

Metabolism Clinical and Experimental Apremilast rapidly led to defervescence and to the improvement of gas exchanges in those otherwise unresponsive to supportive therapy. Treatment was well tolerated and only one patient developed mild and self-limiting diarrhoea.

In conclusion, we provide initial evidence that Apremilast is safe and beneficial in SARS-CoV-2 pneumonia also in patients with negative prognostic factors, such as older age, cardio-vascular comorbidities, lower lymphocyte count, greater extent of lung involvement and higher IL-6 levels. Our experience supports the use of PDE4-inhibitors in SARS-CoV-2 pneumonia as hypothesised by Dalamaga and colleagues [1] . Further studies are however needed to confirm these findings and to identify the patients would most benefit from this treatment.

AS, BV and LB all contributed to the conceptual design, drafting and revision of the manuscript and to the collection of data.

The authors declare no conflict of interest.

Commentary: phosphodiesterase 4 inhibitors as potential adjunct treatment targeting the cytokine storm in COVID-19

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention

The trinity of COVID-19: immunity, inflammation and intervention

Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis

Apremilast ameliorates carfilzomib-induced pulmonary inflammation and vascular injuries

Apremilast for a psoriasis patient with HIV and hepatitis C

Apremilast efficacy and safety in a psoriatic arthritis patient affected by HIV and HBV virus infections

A phase I, randomized, controlled clinical study of CC-11050 in people living with HIV with suppressed plasma viremia on antiretroviral therapy (APHRODITE)

COVID-19 pulmonary infection in erythrodermic psoriatic patient with oligodendroglioma: safety and compatibility of apremilast with critical intensive care management

Vigone Lorenzo Beretta Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano

E-mail addresses: alessandro.santaniello@policlinico.mi.it (A. Santaniello), barbara.vigone@policlinico.mi.it (B. Vigone), lorenzo.beretta@policlinico.mi.it (L. Beretta)