Melatonin as adjuvant treatment for coronavirus disease 2019 pneumonia patients requiring hospitalization (MAC-19 PRO): a case series

Abstract

Treatment for coronavirus disease 2019 (COVID19) pneumonia remains empirical and the search for therapies that can improve outcomes continues. Melatonin has been shown to have anti-inflammatory, antioxidant, and immune-modulating effects that may address key pathophysiologic mechanisms in the development and progression of acute respiratory distress syndrome (ARDS), which has been implicated as the likely cause of death in COVID19. We aimed to describe the observable clinical outcomes and tolerability of high-dose melatonin (hdM) given as adjuvant therapy in patients admitted with COVID19 pneumonia. We conducted a retrospective descriptive case series of patients who: 1) were admitted to the Manila Doctors Hospital in Manila, Philippines, between March 5, 2020 and April 4, 2020; 2) presented with history of typical symptoms (fever, cough, sore throat, loss of smell and/or taste, myalgia, fatigue); 3) had admitting impression of atypical pneumonia; 4) had history and chest imaging findings highly suggestive of COVID19 pneumonia, and, 5) were given hdM as adjuvant therapy, in addition to standard and/or empirical therapy. One patient admitted to another hospital, who one of the authors helped co-manage, was included. He was the lone patient given hdM in that hospital during the treatment period. Main outcomes described were: time to clinical improvement, duration of hospital stay from hdM initiation, need for mechanical ventilation (MV) prior to cardiopulmonary resuscitation, and final outcome (death or recovery/discharge). Of 10 patients given hdM at doses of 36-72mg/day per os (p.o.) in 4 divided doses as adjuvant therapy, 7 were confirmed COVID19 positive (+) by reverse transcription polymerase chain reaction (RT-PCR) and 3 tested negative (-), which was deemed to be false (-) considering the patients’ typical history, symptomatology, chest imaging findings and elevated bio-inflammatory parameters. In all 10 patients given hdM, clinical stabilization and/or improvement was noted within 4-5 days after initiation of hdM. All hdM patients, including 3 with moderately severe ARDS and 1 with mild ARDS, survived; none required MV. The 7 COVID19(+) patients were discharged at an average of 8.6 days after initiation of hdM. The 3 highly probable COVID19 patients on hdM were discharged at an average of 7.3 days after hdM initiation. Average hospital stay of those not given hdM (non-hdM) COVID19(+) patients who were admitted during the same period and recovered was 13 days. To provide perspective, although the groups are not comparable, 12 of the 34 (35.3%) COVID19(+) non-hdM patients admitted during the same period died, 7/34 (20.6%) required MV; while 6 of 15 (40%) non-hdM (-) by RT-PCR but highly probable COVID19 pneumonia patients also died, 4/15 (26.7%) required MV. No significant side-effects were noted with hdM except for sleepiness, which was deemed favorable by all patients, most of whom had anxiety- and symptom-related sleeping problems previously. HdM may have a beneficial role in patients treated for COVID19 pneumonia, in terms of shorter time to clinical improvement, less need for MV, shorter hospital stay, and possibly lower mortality. HdM was well tolerated. This is the first report describing the benefits of hdM in patients being treated for COVID19 pneumonia. Being a commonly available and inexpensive sleep-aid supplement worldwide, melatonin may play a role as adjuvant therapy in the global war against COVID19.

Elderly as a High-risk Group during COVID-19 Pandemic: Effect of Circadian Misalignment, Sleep Dysregulation and Melatonin Administration

“…In light of the public health problem triggered by the spread of COVID-19 and in the face of essentially null options for prevention or treatment presently available, the use of melatonin has been proposed to possibly control the consequences of this serious disease. A preliminary report supports this effect [64]. Based on the safety of melatonin, and to maximize its therapeutic efficacy, doses in the order of 50-100 mg p.o.…”

Clinical Trials for Use of Melatonin to Fight against COVID-19 Are Urgently Needed

“…Furthermore, in advanced ALI/ARDS patients who display severe inflammation, hypoxemia, and ventilation problems, Sarma and Ward [45] noticed elevated concentrations of oxygen leading to massive oxidant generation. Regarding the beneficial roles of melatonin in COVID-19 treatment, this indoleamine was successfully applied in infants with respiratory disease [46,47] and in advanced COVID-19 pneumonia patients [8], confirming its anti-oxidative and anti-inflammatory actions in the lung. An overview of the most important functions of melatonin is provided in Figure 2.…”

“…Currently reported COVID-19-affected patients present varying symptoms including fever, dry cough, myalgia, fatigue, or diarrhea. In other cases, the acute progression of the disease results in ALI/ARDS, respiratory failure, heart failure, sepsis, and sudden cardiac arrest within a few days [7][8][9]. The pathogenic examination of lungs from mild COVID-19 patients revealed edema, proteinaceous exudate with globules, patchy inflammatory cellular infiltration, and moderate formation of hyaline membranes [10].…”

“…In the early stages of coronavirus infections, dendritic and epithelial cells are activated and cause a reported "deluge" of pro-inflammatory cytokines, i.e., elevated levels of interleukin-1β (IL-1β), IL-6, interferon-γ (IFN-γ), interferon-inducible protein 10 (IP-10) or IL-4, IL-10, and IL-17 [5,9]. It was documented that repressed immune functions in COVID-19 patients are accompanied by lymphopenia and neutropenia, as well as a decreased number of CD8+ T cells [7][8][9]. Furthermore, recent reports suggest that some COVID-19 patients, although negative for the viral nucleic acid assay, still sometimes present with a high level of inflammation.…”

Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19

“…Due to its antioxidant, anti-inflammatory, as well as other properties [ 20 , 21 , 22 , 23 , 24 , 25 ], it has been speculated to be a promising molecule for treating COVID-19 patients [ 18 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ], and also other deadly viral infectious diseases [ 48 , 49 , 50 , 51 ]. A small scale clinical trial has also shown promising results [ 52 ]. The major activities of melatonin are not directed towards the virus per se and, thus, it does not kill the virus, but rather buffers the immune response of the host and increases the tolerance of the host to the virus infection [ 26 ].…”