Epidemiological survey on the benefit of neuraminidase inhibitors on severe acute respiratory syndrome due to COVID-19

Levantamento epidemiológico do benefício de inibidores de neuraminidase na síndrome respiratória aguda grave por COVID-19

Encuesta epidemiológica del beneficio de inhibidores de neuraminidase en síndrome respiratorio agudo severo por COVID-19

Esta obra está bajo una Licencia Creative Commons Atribución 4.0 Internacional.

By mid-2016, the Coronavirus family of viruses had caused two pandemics that, despite the higher case fatality rate, did not present such a high transmissibility¹. In 2019, a new viral pathology originating in Wuhan, China, which is caused by a new virus of the Coronavirus family, SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), COVID-19, has caused more than 6 million deaths worldwide, with excess mortality — more than the expected deaths from all causes — estimated at 18 million.^2,3

Its most severe symptom, the severe acute respiratory syndrome (SARS), is defined as bilateral pulmonary infiltrates and hypoxemia without evidence of cardiogenic pulmonary edema, commonly leading to death. SARS consists of inflammation-mediated pulmonary changes, such as increased permeability of the alveolar-capillary membrane, pulmonary edema with consequent reduction in pulmonary compliance, and changes in the ventilation/perfusion ratio.^4-8

The clinical management of SARS consists of several pharmacological and non-pharmacological alternatives with the objective of containing viral proliferation and its consequent inflammatory response⁹. One of the alternatives are anti-influenza drugs, which act by inhibiting the viral enzyme neuraminidase, such as zanamivir and oseltamivir.

In this sense, it is observed that many patients were submitted to the use of neuraminidase inhibitors because these were already prescribed for the treatment of common influenza, since it is also viral-caused.¹⁰In vitro and in vivo studies suggest that the antiviral effect of these drugs is not directly on the virus, but rather by modulating the immune system, especially neutrophils, to fight the viral infection.^11,12 Because this class of drugs inhibits the active site of neuraminidase, which is similar to that of the S1 spike protein of SARS-CoV-2, it possibly offers similar pharmacological benefits. However, the impact of the use of these drugs on SARS mortality and its relationship with the etiologic agent needs more clinical evidence.

In this observational and retrospective study, data was gathered from secondary sources from the Ministry of Health. The variables analyzed were: hospitalizations for SARS regardless of cause, use of neuraminidase inhibitors, age, sex, length of stay, need for intubation, hospitalization in intensive care unit and mortality.¹³

The total study population was 1,048,575 individuals who entered Brazil's public health system due to COVID-19 symptoms. This system collected medical records from all parts of the country, removed the identification of patients and made the compilation of data publicly accessible in a Microsoft Excel spreadsheet. Because the records were filled during the peak of COVID-19, some data was considered "ignored" in the database, thus being excluded from the sample. In addition to the ignored data, individuals with SARS that was not caused by COVID-19 or whose tests were inconclusive were also excluded, totaling 146,160 exclusions.

Statistical tests for association were used (χ² univariate analysis or Fisher's exact test), the correlation was performed by Spearman's correlation coefficient with Bonferroni correction to analyze the association of deaths with the use of neuraminidase inhibitors. The Statistical Package for the Social Sciences - SPSS (version 21) software was used for all statistical analyses. The data reported in this article is publicly available without personal identifiers.

In the period analyzed, it was identified that 1,048,575 individuals entered the database of the Ministry of Health due to SARS symptoms; of these, 146,160 were listed as ignored and were excluded from the analyses. The classification of SARS is shown in Table 1.

Table 1
Classification of SARS cases Brazil 2021 n902415

It was observed that 82.9% (n=747,925) of SARS cases were due to SARS-CoV-2, the etiologic agent of COVID-19, and that the other causes added together were responsible for the remaining 16.9% (n=154,490) of hospitalizations. The profile of hospitalizations by SARS classification is shown in Table 2.

Table 2
SRAG profile Brazil 2021 n902415

When analyzing table 2, it was observed that male sex was predominant in all types of SARS, the same occurring with the ethnicity that was predominantly white. The occurrence of SARS stratified by schooling was variable, where in SARS due to influenza (26.5%), in unknown etiological agent (27.1%) and not specific (25.7%), individuals with elementary education between 1st and 5th grade were predominant, while in SARS by other etiological agents there was a higher occurrence in individuals where schooling is not applied, such as immigrants or indigenous people, and in SARS due to COVID-19, the predominant level of schooling was high school (33.1%). The predominant place of residence in all types of SARS was urban.

The State that had the most SARS cases was São Paulo (21.1 %), followed by Minas Gerais (11.7%), Rio de Janeiro (7.4%) and Paraná (7.3%). The distribution of cases by region was as follows: Southeast (48.8%), Northeast (20.6%), South (17.7%), Midwest (9%) and North (6.5%).

In the population analyzed, 4.3% (n=29,845) of the individuals were prescribed neuraminidase inhibitors, whose prescription profile is shown in table 3.

Table 3
Profile of the use of neuraminidase inhibitors Brazil 2021 n902415

The mean age of individuals who used neuraminidase inhibitors was 50.08 years (± 24.52) and of those who did not use was 54.31 years (±20.55).

The prescription of neuraminidase inhibitors was associated with ethnicity (p<0.001), schooling (p<0.001) and zone of residence (p<0.001), with no association with gender.

The presentation of symptoms in individuals who were prescribed neuraminidase inhibitors was significantly different when compared to those who did not have the prescription, as can be analyzed in Table 4.

Table 4
Comparison of symptoms versus antiviral use Brazil 2021 n902415

Individuals who were prescribed neuraminidase inhibitors were more likely to have fever (1.250; CI: 1.229 to 1.296), cough (1.539; CI 1.491 to 1.588), sore throat (1.273;CI: 1236 to 1.310), dyspnea (1.218 CI: 1.181 to 1.256), respiratory distress (1.413; CI: 1.374 to 1.454), changes in O. saturation (1.109: CI;1.077 to 1.141), diarrhea (1.205;CI: 1.167 to 1.243), abdominal pain (1.119:CI; 1.072 to 1.169), fatigue (1.233;CI: 1.201 to 1.265), loss of smell (1.273; CI: 1.229 to 1.320), loss of taste (1.303; CI: 1.258 to 1.350) and vomiting (1.191: CI; 1.191 to 1.147).

The fact that the symptoms were more prevalent did not translate into a higher rate of hospitalization in the intensive care unit (ICU) or use of ventilatory support, with 30.2% (n=7,783) of the individuals who used neuraminidase inhibitors being admitted to the ICU against 30.8% (n=189,485) of those who did not. In fact, there is an inverse association of the use of neuraminidase inhibitors and ICU admission, with a higher risk for individuals who were not prescribed (1.001; CI 1.000 to 1.002, p=0.023).

Regarding the use of ventilation, individuals who used neuraminidase inhibitors had a higher percentage of noninvasive ventilation use (63.7%), followed by no use of ventilatory support (18.4%) and only 17.9% (n=4,650) used invasive ventilation. Those who did not use neuraminidase inhibitors had similar rates, with 63.4% (n=378,369) using noninvasive ventilation, 20.0% (n=123,179) not using ventilatory support and 18.7% (115,071) using invasive ventilation. There was an inverse association between the use of neuraminidase inhibitors and ventilatory support (p<0.001). Non-prescription of neuraminidase inhibitors increased the chance of using invasive mechanical ventilation by 1.159 (CI: 1.056 to 1.273).

Death occurred in 34.3% (n=174,028) of the cases. Of these, 3.9% (n=6,701) had been prescribed neuraminidase inhibitors and 96.1% (n=167,327) had no prescription. The use of neuraminidase inhibitors was associated with a higher chance of cure (p<0.001), increasing it by 1.055 times (CI: 1.045 to 1.065).

There was no difference between the classes of neuraminidase inhibitors (p=0.076).

In predicting cure, the antiviral drug Oseltamivir had prediction, with significance of p=0.027 and Exp(β) of 1.095 (CI: 1.010 to 1.187).

The use of neuraminidase inhibitors was associated with a higher incidence of symptoms, probably as a result of the greater severity of the patients’ clinical case with prescription indication. Some studies indicate that although there is a positive association between the use of neuraminidase inhibitors and increased symptoms, the risk of admission to the ICU was higher for patients who did not use these drugs.¹¹As large-scale ICU admission overwhelms the health system, the adoption of neuraminidase inhibitors for symptomatic patients becomes a very relevant public health tool.

In cases of hospitalization, the need for invasive mechanical ventilation was lower in patients who used neuraminidase inhibitors. The data reinforces the suggestion that these drugs be used in large scale in the healthcare system. In addition, the death rate was lower in patients who had a prescription. Thus, the results suggest the indication of neuraminidase inhibitors prescription as a treatment for SARS complications, increasing the chance of cure. Other studies suggest a positive correlation between the use of neuraminidase inhibitors before treatment and shorter hospital stays, which also avoids the situation of lack of ICU beds.¹⁴

With the arrival of COVID-19 in Brazil, there was an increase in cases of hospitalization for SARS, a result observed in our etiological analysis. When analyzing the causes of hospitalization for SARS, the main cause identified was the SARS-CoV-2 virus.^2,15

When analyzing the epidemiological characteristics, such as gender, we observed that male sex had a predominance in SARS cases regardless of the etiological agent. This finding converges with those found in other studies already carried out, which indicate greater susceptibility to infections and higher mortality associated with this disease in males.^16,17

Another finding is the predominance of white ethnicity in SARS-CoV-2 SARS cases. This phenomenon is possibly a result of greater access to laboratory tests by this ethnic group, with underreporting occurring in the others as a result of non-testing, and the situation as a whole is a consequence of social inequalities­.^18,19

The data also showed an association between schooling and hospitalization for SARS. It is noticed that cases of SARS by SARS-CoV-2 are more frequent in people with complete high school education, while cases of contagion by influenza, unknown and non-specific etiological agent are more frequent in the population niche of elementary education between 1st and 5th grade. This data suggests that SARS-CoV-2 has a tendency to infect individuals with a higher level of education compared to other etiologic agents, but the possibility of underreporting makes it impossible to be sure of this conclusion. As education level is associated with socioeconomic status, and SARS-CoV-2 possibly had its initial spread by means of tourist transport, such as planes and ships, these restricted to individuals with higher purchasing power, the association between cases and level of education is possibly another reflection of social inequalities.²⁰

In addition, there was a relationship with zone of residence. The results indicate a higher incidence of SARS of all etiological agents in urban areas. This data can be justified by the fact that these regions have a higher rate of contagion due to the difficulty of maintaining social distancing and the fact that the majority of the Brazilian population lives in urban areas, as indicated by the latest data from IBGE (The Brazilian Statistics Bureau).²¹

It is noticed that the most populous states such as São Paulo, Minas Gerais and Rio de Janeiro reported higher numbers of SARS cases, and this results from several factors, such as the proportional relationship between population density and contagion, as evidenced in other studies, and also the late adoption of social distancing by some States, notably Rio de Janeiro.^15,22

Finalizing the relationships between SARS and demographics, a relationship was observed between hospitalizations and percentage of elderly people in the States. The data shows that in the southern States, which have a higher proportion of elderly population, SARS rates are higher, which confirms previous knowledge of other studies that indicate higher rates of complications of the disease in the elderly.^21,23

Another factor that explains the relationship between the proportion of elderly and hospitalization for SARS is the climate. The southern region of the country has a subtropical climate, which increases the rate of contagion.

Regarding the prescription of neuraminidase inhibitors, white patients had proportionally more prescription of neuraminidase inhibitors in relation to other ethnicities, possibly because the latter had on average better economic condition and access to healthcare, as well as higher rates of testing and drug prescription.¹⁸

The prescription of neuraminidase inhibitors was associated with lower schooling. This data may be due to the prophylactic measures instituted by the Ministry of Health, which mostly covers public hospitals, where the profile of the average patient is less educated compared to private hospitals, which have a larger structure and more effective medications. On the other hand, there are studies that demonstrate lower morbidity and mortality in populations with higher educational level in Brazil and the USA.²⁴

The limitations of this study are related to data collection since there is no system of digital medical records in the Brazilian public health system and this fact limits the scope of the data. We can also affirm that there is a limitation associated with filling out the forms, a fact that culminated in the exclusion of medical records.

With the data presented, a patient profile more conducive to hospitalization, need for invasive or non-invasive ventilation and death from SARS can be visualized. This profile can be used as a basis for the preparation of screening protocols in health units, as well as updating treatment guidelines for patients with SARS in their various presentations.²⁵ An association can also be observed between prescription of Zanamivir and Oseltamivir and lower rates of hospitalization and death, as well as less need for invasive and non-invasive ventilation, suggesting the use of these neuraminidase inhibitors as a treatment for patients at risk as well as a public health tool to reduce the rate of bed occupancy in the healthcare system.

The present study was carried out with the support of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES).