Letter to the editor: Immunomodulation by phosphodiesterase-4 inhibitor in COVID-19 patients
Authors: Alessandro Santaniello, Barbara Vigone, Lorenzo Beretta
Journal: Metabolism (2020)

We read with interest the commentary by Dalamaga and colleagues [[1]Dalamaga M. Karampela I. Mantzoros C.S. Commentary: phosphodiesterase 4 inhibitors as potential adjunct treatment targeting the cytokine storm in COVID-19 [published online ahead of print, 2020 Jun 1].Metabolism. 2020; 109: 154282https://doi.org/10.1016/j.metabol.2020.154282Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar] 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]Wu Z. McGoogan J.M. 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.JAMA. 2020; ([published online ahead of print, 2020 Feb 24])https://doi.org/10.1001/jama.2020.2648Crossref Scopus (11871) Google Scholar]. 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]Tay M.Z. Poh C.M. Rénia L. MacAry P.A. LFP Ng The trinity of COVID-19: immunity, inflammation and intervention.Nat Rev Immunol. 2020; ([published online ahead of print, 2020 Apr 28]): 12https://doi.org/10.1038/s41577-020-0311-8Crossref Scopus (2691) Google Scholar]. 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]Schafer P.H. Parton A. Gandhi A.K. et al.Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis.Br J Pharmacol. 2010; 159: 842-855https://doi.org/10.1111/j.1476-5381.2009.00559.xCrossref PubMed Scopus (319) Google Scholar]. 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]Imam F. Al-Harbi N.O. Al-Harbi M.M. et al.Apremilast ameliorates carfilzomib-induced pulmonary inflammation and vascular injuries.Int Immunopharmacol. 2019; 66: 260-266https://doi.org/10.1016/j.intimp.2018.11.023Crossref PubMed Scopus (11) Google Scholar]. Most noticeably, previous reports indicate that PDE4 inhibitors can safely be used in patients with chronic viral infection [6Reddy S.P. Shah V.V. Wu J.J. Apremilast for a psoriasis patient with HIV and hepatitis C.J Eur Acad Dermatol Venereol. 2017; 31: e481-e482https://doi.org/10.1111/jdv.14301Crossref PubMed Scopus (24) Google Scholar, 7Manfreda V. Esposito M. Campione E. Bianchi L. Giunta A. Apremilast efficacy and safety in a psoriatic arthritis patient affected by HIV and HBV virus infections.Postgrad Med. 2019; 131: 239-240https://doi.org/10.1080/00325481.2019.1575613Crossref PubMed Scopus (5) Google Scholar, 8Boulougoura A. Gabriel E. Laidlaw E. et al.A phase I, randomized, controlled clinical study of CC-11050 in people living with HIV with suppressed plasma viremia on antiretroviral therapy (APHRODITE).Open Forum Infect Dis. 2019; 6: ofz246https://doi.org/10.1093/ofid/ofz246Crossref PubMed Scopus (4) Google Scholar]. 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]Mugheddu C. Pizzatti L. Sanna S. Atzori L. Rongioletti F. COVID-19 pulmonary infection in erythrodermic psoriatic patient with oligodendroglioma: safety and compatibility of apremilast with critical intensive care management.J Eur Acad Dermatol Venereol. 2020; (May 9)https://doi.org/10.1111/jdv.16625Crossref Scopus (28) Google Scholar]. 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 PaO2/inspired oxygen fraction <300 mmHg AND/OR lung infiltrates ≥50% on chest x-rays [[2]Wu Z. McGoogan J.M. 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.JAMA. 2020; ([published online ahead of print, 2020 Feb 24])https://doi.org/10.1001/jama.2020.2648Crossref Scopus (11871) Google Scholar]. 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 signing informed consent about the off-label nature of the treatment. 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.Table 1clinical and demographic characteristicsPatient 1Patient 2Patient 3Patient 4Age, years29845780SexMMMFMedical historyHBV infectionHypertension, nephrectomy for renal cancer, benign prostatic hyperplasiaHypertension, psoriasisHypertension, prosthetic mitral valve, atrial fibrillationHome therapyNoneBeta-blockers, FinasterideCalcium-channel blockers, angiotensin receptor blockersBeta-blockers, AcenocoumarolSymptoms at admission12-days fever, dry cough, dyspnoea14-days fever, dry cough, dyspnoea11-days dry cough, vomiting, 4-days fever, dyspnoea2-days fever, dyspnoeap/f, mmHg at room air342267362250Respiratory rate at room air30243224Extent lung involvement, %50704060Lymphocytes, cells/μL1590 - 2680***870 - 920***1114 - 1290***880 - 970***CRP, mg/dL4.8 - 0.59***7.7 - 2.6***9.75 - 0.83***8.2 - 1.8***Ferritin, μg/L2960 - 898***843 - 475***1222 - 800***503 - 471***Fibrinogen, mg/dL626 - 481***567 - 410***567 - 459***459 - 337***D-Dimer, μg/L4800 - 1870***13189 - 4570***500 - 203***694 - 782***IL-6, ng/L21 - 2.5*60 - 33**37.2 - 3.5*67 - 29**Therapy from hospitalizationHydroxychloroquine 200 mg bid; enoxaparin 4000 IU/day; O2 therapy (up to FiO2 28%)Hydroxychloroquine 200 mg bid; enoxaparin 4000 IU/day; azythromycin 500 mg/day; ceftriaxone 2 g/day; O2 therapy (up to FiO2 40%)Hydroxychloroquine 200 mg bid; Enoxaparin 4000 IU/day; azythromycin 500 mg/day; ceftriaxone 2 g/day; O2 therapy (up to FiO2 28%)Hydroxychloroquine 200 mg bid; enoxaparin 4000 IU/day; azythromycin 500 mg/day; ceftriaxone 2 g/day; O2 therapy (up to FiO2 35%)Hospitalisation before Apremilast, days4867Main indication for Apremilast therapyPersistent fever and tachypneaIncreased oxygen requirementsPersistence fever, fatigue, severe myalgia and tachypneaPersistent fever, increased oxygen requirementsOutcomeDischarge after 5 days of Apremilast therapyDischarge after 7 days of Apremilast therapyDischarge after 5 days of Apremilast therapyDischarge after 12 days of Apremilast therapyNegative swab after discharge, days21142821p/f, PaO2 to inspired oxygen fraction FiO2 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 SaO2 ≥ 94% and RR < 24 at rest at room air and resolution of constitutional symptoms. Open table in a new tab p/f, PaO2 to inspired oxygen fraction FiO2 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 SaO2 ≥ 94% and RR < 24 at rest at room air and resolution of constitutional symptoms. 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]Dalamaga M. Karampela I. Mantzoros C.S. Commentary: phosphodiesterase 4 inhibitors as potential adjunct treatment targeting the cytokine storm in COVID-19 [published online ahead of print, 2020 Jun 1].Metabolism. 2020; 109: 154282https://doi.org/10.1016/j.metabol.2020.154282Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. 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.