This is the first study to our knowledge describing the potential protective effect of antihistamines in an integral public health care population that includes primary care centers and their referral hospital. We are also aware of no other studies describing the progressive infection rate related to polypharmacy in non-vaccinated patients.
The approximate halving of the hospital admission and mortality rates is consistent with our experience in primary care and a nursing home in Yepes (Toledo) [6, 7]. However, the current study did not include azithromycin treatment for patients admitted to the Terrassa Hospital, precluding assessment of the role of combined prescriptions. Despite this, the protective effect of antihistamines is suggested by our results, which is also consistent with other reports in vitro [20] and after nasal administration [21].
The study will have been limited by the lack of precise quantification of cases, and of the vaccinated and hospitalized populations, due to the unavailability of diagnostic tests for the early detection of cases in primary care in the first wave, the multiple points of vaccination in 2021 for people younger than 60 years old, and the existence of a second private hospital in the zone. However, although overall vaccination is probably under-recorded, vaccination rates at public primary care centers in early 2021 were over 90% in those older than 60 years, in whom COVID-19 mortality is high. This allows good comparison of the overall mortality rate.
Diagnostic tests were available for hospital admissions from early in the COVID-19 pandemic, and all patients admitted with respiratory symptoms were tested [22] and were considered to have COVID-19 if they showed bilateral interstitial pneumonia (which is rare in other illness). In primary care, however, tests were only available after the first wave, from June 2020, and the World Health Organization recommended ending active searches of infection in suspected cases from March 24th, 2022 [23]. This meant that only cases identified between June 1st, 2020, and March 23rd, 2022, were included. Furthermore, antigen tests were available to the public via pharmacies from autumn 2020 and were used in primary care centers; however, their sensitivity was reported to be only 78% in the first week of symptoms [24]. The absolute number of infections must, therefore, be interpreted with care. It is likely that the low sensitivity probably affects both groups equally, although it is uncertain if patients with known pathologies requiring antihistamines could test themselves earlier to avoid illness progression, thereby introducing selection bias. For those reasons, the infection, hospital admission, and mortality rates were calculated separately in the present report.
Chronic prescriptions are probably not affected by the existence of other private health services because they are also recorded by the public health service due to cost discounts. It is feasible to assume that any associated bias equally affects infection and hospital admission rates among patients either taking or not taking antihistamines. Finally, although chronic prescription does not necessarily imply daily consumption, patients with polypharmacy tend to use pill boxes with the full authorized prescription, increasing the likelihood that they take all authorized treatments daily.
Among Covid patients in the studies on antihistamines in primary care, 46% received cetirizine because of its safety profile and low rates of side effects and interactions, but 35.7% received dexchlorpheniramine and 1.7% ebastine [7]. In the THC, about 100 primary care physicians and allergologists were prescribing antihistamines, without any specific preference. This suggests that the better evolution quantified may be related to a histamine class-effect due to several underlying mechanisms including neuroprotective ligand receptors [25], that also explain the lack of post-covid complains in primare care patients treated with antihistamines [7].
Other chronic drugs, such amantadine, have also been suggested to be protective [26] and are currently under study in trial NCT05504057. However, fewer than 100 patients are currently receiving treatment with amantadine in the THC. A multicenter study with other collaborations is being sought to study the effect of this drug.
COVID19 Hospital admissions have been triplicated (from 16 patients per million to 62,2 per million) in Catalonia in June 2024 and SARS-CoV-2 is isolated in 16,8% of random samples of symptomatic primare care patients, due to the FLiRT subvariant [27], suggesting that the mutations of virus are still able to produce sudden periodical increases in hospital admissions [28] and that the search of therapies is still of interest. The long term effect of repeated infections is uncertain, since neurological impairment has been described [29] even after suffering a mild infection.
In conclusion, patients with chronic antihistamine prescriptions (alone or with polypharmacy) showed reduced infection, hospital admission, and mortality rates consistent with the results of previous descriptive studies. This suggests the safety of chronic antihistamine treatment, its possible use as symptomatic treatment during the early stages of the COVID infection. and the need to explore its effectiveness in a prospective trial.