May 20, 2022

Paracetamol in the home treatment of the first symptoms of COVID-19: a possible enemy rather than a friend for elderly patients? – Pandolfi – 2021 – Journal of Medical Virology

In October 2020, Sestili and Fimognari reported that acetaminophen (NOT-ethyl-para-aminophenol), commonly known as paracetamol, induces or worsens the consumption of glutathione (GSH) in elderly patients affected by early or mild coronavirus disease 2019 (COVID-19), thus greatly increasing the risk of COVID exacerbation- 19 in these patients.1 By early COVID-19 we mean the typical or commonly recognized symptomatology associated with the early stages of COVID-19, usually occurring when a patient is staying at home i.e. fever and dyspnea, in addition to weakness and pain,2 although the symptoms of COVID-19 are particularly variable and complex, and only 50% of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop clear symptoms.2 Either way, fever is one of the most common symptoms during the early stages of COVID-19, where people use paracetamol fairly exclusively.

Reducing GSH is a particularly serious condition for an individual’s antioxidant and anti-inflammatory response, and it’s understandable that his depletion is crucial for the worsening of COVID-19. In addition, Zhang and colleagues recently showed that SARS-CoV-2 hijacks the metabolism of folate and single carbon in the infected cell, reshaping their biochemical turnover at the post-transcriptional level and continuing de novo synthesis of purines. .3 Figure 1 shows the fundamental role of GSH in one-carbon metabolism. SARS-CoV-2 uses cytosolic serine hydroxymethyltransferase-1 to activate one-carbon metabolism for de novo purine synthesis2 and the subtraction of serine, and its precursor, folic acid, diverts serine from the production of cystathionine and therefore from GSH (Figure 1). Reduction in plasma and intracellular GSH levels is typical in elderly patients,4 in particular in the event of metabolic syndrome,5 Therefore, if Sestili and Fimognari are correct, elderly patients with prodromal symptoms of COVID-19 should not be treated with NOT-acetyl-para-aminophenol.

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 the synthesis of cystathionine and the absorption of folate, deregulating the one-carbon metabolism. Folate can be reduced to tetrahydrofolate (THF) and then converted to 5-methyl THF, while a reaction catalyzed by methionine synthetase transfers the methyl group from 5-methyl-THF to homocysteine, generating methionine. SARS-COV-2 also impairs other thiol exchange pathways, such as Cys. On the other hand, paracetamol can inhibit the serine pathway and the sulfur amino acid pathway (see Mast C, Dardevet D, Papet I. Impact of medicine on protein and amino acid metabolism in the senior: the sulfur amino acid and paracetamol case. Nutr Res Rev. 2018 Dec; 31 (2): 179-192.) and also GSH reductase (see Rousar T, Pařík P, Kucera O, Bartos M, Červinková Z. Glutathione reductase is inhibited by the acetaminophen- conjugate. glutathione in vitro. Physiol Res. 2010; 59 (2): 225-232.). Arrows with red circle and minus sign = inhibition. BHMT, betaine homocysteine ​​methyltransferase; GSH, glutathione; GSSG, oxidized GSH; HSA, S-adenosyl homocysteine; SAM, S-adenosylmethionine; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2

Additionally, Sestili and Fimognari considered the hypothesis that the severity of COVID-19 could be caused by a deficiency in glucose-6-phosphate dehydrogenase, which parallels the decrease in GSH.6, 7 Indeed, in these cases, a warning has been sent concerning the use of Tylenol®-paracetamol, which is ultimately not recommended.8 Despite some wise recommendations, Linda Geddes spoke of the ‘fever paradox’, reporting how much paracetamol has been abused in the healthcare market to treat symptoms of COVID-19 in its early development and to avoid hospitalization overcrowding.9 In Italy, a general outcry from some doctors, practitioners and family physicians is widening the debate, even in politics, over how best to treat COVID-19 at home. The civil inheritance of these professionals has been arranged to avoid the immense worry of the elderly treated with simple paracetamol, advised to wait on paracetamol treatment for reduced symptoms, but then often undergoing rapid exacerbation and in many cases even death during their hospitalization.

Suter and his colleagues recently created an algorithm of the best and easiest home therapy for mild symptoms at the onset of COVID-19, to prevent hospitalization.ten In their retrospective observational study, the control cohort (45 of 77 patients; 58.44%) received paracetamol as home treatment, whereas in the cohort of patients following a recommended protocol, only 6 of 86 (6.98%) %) used paracetamol as the main treatment. The hospitalization rate was 1.2% for patients on the recommended protocol and 13.1% (p= 0.007) for patients mainly using paracetamol, i.e. 44 cumulative days of hospitalization (recommended) versus 481 (controls).ten This evidence shows that the use of paracetamol at home to treat mild symptoms of COVID-19, especially in the elderly with comorbid conditions, significantly increased the risk of hospitalization for dyspnea due to interstitial pneumonia, thus increasing the risk of interstitial pneumonia dyspnea. huge concern of overcrowding intensive care units. The possible causes of this exacerbation could be the activation of prothrombotic mechanisms, currently reported as the main pathogenic cause of COVID-19, alongside endothelial dysfunction.11 In fact, GSH modulates platelet functions12 and deep vein thrombosis, which can occur in severe cases of COVID-19, and worsens GSH levels by enhancing glutathione peroxidase.13 In addition, hospitalization also includes the additional risk of worsening COVID-19 pneumonia due to nosocomial infections, even increasing the death rate.14

The use of paracetamol to reduce fever should be considered particularly safe, if mild COVID-19 has not yet been diagnosed, at least with the professional intention of the majority of physicians. On the other hand, fever is one of the first symptoms of a possible SARS-CoV-2 infection. Fever is usually associated with inflammatory symptomatology (asthenia, muscle pain, cough) and, if more correct treatment information is prevalent among healthcare professionals, other therapies, such as nonsteroidal anti-inflammatory drugs, should be considered. priority in their recommendation.ten

In 2019, according to the Italian Agency for Therapeutic Medicines (AIFA), paracetamol (or acetaminophen, single active ingredient) represented 11.4% of the total economic burden of therapeutic drugs in Italy and the first drug purchased by health units localities of the country. with its own expenses. This ranking has increased considerably in 2020, reaching an improvement of around 50 packages / day per 10,000 inhabitants in January-February 2020, compared to the 16 to 20 packages purchased in December 2019. These data are easily retrievable on the website of the IAAF. Certainly, it would be particularly embarrassing to state that the huge increase in the number of elderly patients entering intensive care units, or the number of deaths from acute and severe respiratory distress from COVID-19, may have the causal source in consumption. of single paracetamol while staying at home, awaiting a new medical consultation or hoping that the painful symptoms will disappear. However, it seems undoubtedly confirmed that patients using paracetamol as elective home treatment in the early stage of SARS-CoV-2 infection had a higher risk of being hospitalized.ten

Guidance documentation provided by the Ministry of Health on November 30, 2020, then updated on April 26, 2021 by adding non-steroidal anti-inflammatory drugs for the home management of patients with COVID-19 and discouraging being hospitalized, suggested: “an attitude of watchful waiting. ”And“ paracetamol to treat symptoms ”(Note 1). On the date indicated, based on data reported by the Ministry of Health in Italy as of November 30, 2020, the relative risk that we have calculated of being hospitalized following these recommendations should be close to 1.7981 (CI95= 1.7234-1.8760, p95= 1.7507-1.9094, pten In addition, the probability of being hospitalized in intensive care within 10 days of “watchful waiting” can be greater than 65% (65.18%) in a Bayesian calculation. Therefore, based on this estimate, a possible conclusion must be drawn. The pharmacological reasons for this failure have been introduced in this manuscript and must be seriously considered in formulating new treatment protocols and approved guidelines.

The warning should be taken into account when considering paracetamol in the elderly with presumptive symptoms of SARS-CoV-2 infection, before being confirmed by swabbing. Although, as reported in Suter et al.,ten AIFA’s initial recommendations in 2020 included paracetamol as an elective and practical therapy at home to reduce symptoms of COVID-19 and loosen the grip on hospitals, the new recommended protocols, proposed by a group of doctors, may provoke criticism of the handling of the pandemic by politicians and academics in Italy.

Scientific research must always lead the debate towards the improvement of any good proposal and avert this crude and worrying urgency.


The authors declare that there are no conflicts of interest.


Sergio Pandolfi designed the rationale, helped design the document, helped draft the document, and revised the document. Vincenzo Simonetti revised the document. Giovanni Ricevuti edited the document and contributed statistics. Salvatore Chirumbolo designed the article, conducted the study, wrote the manuscript and submitted the manuscript.