We read with interest the Comment on our paper “To clarify the safety profle of paracetamol for home-care patients with COVID-19: a real-world cohort study, with nested case–control analysis, in primary care”[1] by Chirumbolo and co-workers [2]. The authors raised some critical points, which need to be tackled to bring the discussion back to methodological and clinical aspects instead of authors’ curriculum vitae.

First, the list of producers of paracetamol (or acetaminophen) should be largely extended, given that its patent expired some decades ago.

Second, as per the Cambridge Dictionary, the definition pedigree pertains “the parents and other family members of a particular animal, or a record of them”. Such a term can be used for persons, ideas, or activities in their history as well [3]. Instead, a discussion on home-care therapy of COVID-19 should adopt an “evidence-based” vocabulary. It is true that there is no evidence-based concern on paracetamol safety when it is used to treat early and mild-moderate symptoms of COVID-19, as well as for the preferential use of some NSAIDs/COXIBs for this same condition. The same arguments provided to support the use of these NSAIDs/COXIBs vs. paracetamol are indeed based on pre-clinical evaluations only [4, 5]. In contrast, we provided clinical (and not pre-clinical) evidence on the safety profile of paracetamol when used early for COVID-19 in an attempt to properly deal with several methodological issues, such as protopathic bias [1, 6].

Third, the statement “the daily dosage able to cause a relevant depletion of GSH should reach 15 g/daily (for an adult of 65–70 kgs), which is fivefold higher than the maximum allowed daily dose…[7]” is supported by an ‘outdated’ paper because this is still a valid concept. As we stated in our prior work, paracetamol is used since 1877 and currently included in the WHO Model List of Essential Medicines being updated in 2021 [8]. Irrespective of being excellent representatives of SIMG, the members of a scientific society have the mission to produce and spread scientific evidence and take a stand for an effective and fair patients’ care. In this respect, we agree that, as for all medications, paracetamol has to be used according to its risk/benefit ratio in keeping with the indication of use. Along this line, general practitioners (GPs) have to remind patients to avoid the “self-overuse” of paracetamol, as other Over The Counter (OTC) medications, especially in older and frail patients.

Fourth, we agree on the fact that SARS-CoV-2 might sensibly deplete GSH especially in elderly patients. In this respect, the Letter [2] reported the paper of Nuttal and co-workers [9] in which the use of 1 g/day of paracetamol was associated with a reduction of total serum antioxidant capacity in which, differently from the intracellular site, GSH does not represent the main antioxidant active compound. In that study, antioxidant capacity of plasma was based on a luminometric principle which actually measures the total antioxidant activity of serum but it is not a direct measurement of GSH concentration. Any correlation between paracetamol and GSH remains, therefore, indirect and anecdotical. In addition, the dosage of 1 g/day of paracetamol was only initially adopted to perform pharmacokinetic studies. Indeed, the daily dosage was subsequently increased to 4 g/day for 14 days, so being clearly overdosed. The authors themselves hypothesized that such an effect could impair respiratory function in asthma sufferers (a paracetamol overdose should be, therefore, etiologically plausible), and concluded that further studies were needed to assess the impact of paracetamol on antioxidant capacity of respiratory system. Obviously, we agree on this final statement along with the fact that the study of Nuttal et al. [9] cannot be automatically transferred to the home-care therapy of COVID-19. Once again, there is no clinical setting in which the correlation between COVID-19, GSH depletion and paracetamol-related progression of the SARS-CoV-2 infection has been demonstrated. To remove paracetamol in home-care therapy in elderly patients, proposing some NSAIDs, but particularly COXIBs should, therefore, raise concerns on concurrent cardiovascular and renal conditions. In this respect, we will provide further discussion soon.

In the light of these responses, we hope to renew the attention of GPs toward and appropriate use of paracetamol and NSAIDs for the early treatment of mild-moderate symptoms of COVID-19 as recommended by AIFA [10] and other health Italian and foreign authorities [11]. Further Randomized Clinical Trials and sound Real-World Evidence studies are still needed before casting doubts on official recommendations.