key: cord-0685165-1hv6f6yk authors: Pandolfi, Sergio; Simonetti, Vincenzo; Ricevuti, Giovanni; Chirumbolo, Salvatore title: Paracetamol in the home treatment of early COVID‐19 symptoms: A possible foe rather than a friend for elderly patients? date: 2021-06-30 journal: J Med Virol DOI: 10.1002/jmv.27158 sha: b78c3c250d4d2f17bf714a2fef79a60779760dca doc_id: 685165 cord_uid: 1hv6f6yk On October 2020, Sestili and Fimognari reported that acetaminophen (N-aetyl-para-aminophenol), commonly known as paracetamol, induces or worsens glutathione (GSH) consumption in elderly patients affected by early or mild COVID-19 This article is protected by copyright. All rights reserved. Paracetamol in the home treatment of early COVID-19 symptoms: A possible foe rather than a friend for elderly patients? To the Editor, On October 2020, Sestili and Fimognari reported that acetaminophen (N-aetyl-para-aminophenol), commonly known as paracetamol, induces or worsens glutathione (GSH) consumption in elderly patients affected by early or mild coronavirus disease 2019 , thus greatly enhancing the risk of COVID-19 exacerbation in these patients. 1 By early COVID-19, we mean the typical or commonly acknowledged symptomatology associated with the early phases of COVID-19, occurring usually when a patient stays at home, that is, fever and dyspnea, besides weakness and pain, 2 despite the COVID-19 symptoms being particularly variable and complex andl only 50% of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) developing a forthright symptomatology. 2 In any case, fever is one of the most common symptoms during the early stages of COVID-19, where people use paracetamol quite exclusively. Reduction of GSH is a condition particularly severe for the individual's antioxidant and anti-inflammatory response and it is comprehensible that its depletion is crucial for COVID-19 worsening. Moreover, Zhang and colleagues, recently showed that SARS-CoV-2 hijacks folate and one-carbon metabolism in the infected cell, by remodeling their biochemical turnover at the posttranscriptional level and going ahead with the de novo synthesis of purines. 3 Figure 1 shows the fundamental role of GSH in one-carbon metabolism. SARS-CoV-2 uses the cytosolic serine hydroxymethyltransferase-1 to activate the one-carbon metabolism for de novo synthesis of purines 2 and subtracting serine, and its precursor folic acid hijacks serine from producing cystathionine and therefore GSH ( Figure 1 ). Reduction in plasma and intracellular GSH levels is typical in elderly patients, 4 particularly if affected by metabolic syndrome, 5 therefore if Sestili and Fimognari are right, elderly patients with prodromic COVID-19 symptomatology should not be treated with N-acetyl-paraaminophenol. In addition, Sestili and Fimognari considered the hypothesis that COVID-19 severity may be caused via a glucose-6-phosphate dehydrogenase deficiency, which parallels GSH decrease. 6, 7 Actually, in those cases, a warning was forwarded about the use of Tylenol®paracetamol, which finally is not recommended. 8 Despite some wise recommendations, Linda Geddes spoke about "The fever paradox," reporting how much paracetamol was abused in the healthcare market to address the symptoms of COVID-19 in its early development and prevent crowding in hospitalization. 9 In Italy, a civil outcry from some physicians, practitioners, and family doctors, is expanding the debate, even in politics, about how best to treat COVID-19 at home. The civil legacy of these professionals was arranged to prevent the huge concern of elderly people treated with simple paracetamol, counseled to wait under paracetamol therapy for reduced symptoms, yet then often undergoing rapid exacerbation and in many cases even death while being hospitalized. Suter and colleagues recently created an algorithm of the best and simplest home therapy for mild symptoms in early COVID-19, to prevent hospitalization. 10 In their retrospective observational study, the control cohort (45 patients on 77; 58.44%) received paracetamol as home therapy, whereas in the cohort of patients following a recommended protocol only 6 of 86 (6.98%) used paracetamol as the leading therapy. The rate of hospitalization was 1.2% for patients undergoing the recommended protocol and 13.1% (p = .007) for patients using predominantly paracetamol, that is, 44 cumulative days of hospitalization (recommended) versus 481 (controls). 10 This evidence shows that using paracetamol at home to treat mild COVID-19 symptoms, particularly in older adults with comorbidity, greatly enhanced the risk of hospitalization for dyspnea from interstitial pneumonia, so increasing the huge concern of crowding the intensive care units. Possible causes of this exacerbation might be the activation of prothrombotic mechanisms, currently reported as the leading pathogenetic cause of COVID-19, alongside endothelial dysfunction. 11 Actually, GSH modulates platelet functions 12 and deep venous thrombosis, which may occur in severe COVID-19, and worsens GSH levels by enhancing glutathione peroxidase. 13 Moreover, hospitalization includes also the additional risk to get worse COVID-19 pneumonia due to hospital-acquired infections, even increasing the rate of mortality. 14 The use of paracetamol to reduce fever should be considered F I G U R E 1 Cartoon showing the possible mechanism of exacerbation of GSH depletion in subjects infected with SARS-CoV-2 by paracetamol. As explained in the text, SARS-CoV-2 negatively affects the serine pathway leading to cystathionine synthesis and the uptake of folate, dysregulating the one-carbon metabolism. Folate can be reduced to tetrahydrofolate (THF) and then converted to 5-methyl THF, whereas a reaction catalyzed by methionine synthetase, transfers the methyl group of 5-methyl-THF to homocysteine, generating methionine. SARS-COV-2 impairs also other thiolic-exchanging pathways, such as Cys. On the other hand, paracetamol can inhibit the serine pathway and the sulfur amino acid pathway (see Scientific research must always lead the debate towards ameliorating any good proposal and warding off this raw and worrisome emergency. The authors declare that there are no conflicts of interest. Sergio Pandolfi conceived the rationale, contributed in conceiving the paper, contributed in writing the paper, and revised the paper. Vincenzo Simonetti revised the paper. Giovanni Ricevuti revised the paper, and contributed in the statistics. Salvatore Chirumbolo conceived the paper, performed the study, wrote the manuscript, and submitted the manuscript. This is not a Research Paper. Anyway, readers may contact the corresponding author any time for elucidations on this paper. Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness? Predictors of infection, symptoms development, and mortality in people with SARS-CoV-2 living in retirement nursing homes SARS-CoV-2 hijacks folate and onecarbon metabolism for viral replication Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine Is glucose-6-phosphate dehydrogenase enzyme deficiency a factor in Coronavirus-19 (COVID-19) infections and deaths? Pathog Glob Health Glucose-6-phosphate dehydrogenase deficiency enhances Covid-19 infection in elderly people Glucose 6 Phosphate Dehydrogenase Deficiency The fever paradox Home-Therapy Algorithm to Prevent Hospitalization for COVID-19 Patients. A Retrospective Observational Matched-Cohort Study medRxiv Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19 Role of reduced glutathione on platelet functions Oxidative status and antioxidant enzyme levels in deep venous thrombosis patients Estimating COVID-19-caused deaths in hospitals and healthcare units: did hospital acquired infections play the utmost role? Comments with a proposal