The Modes of Transmission and Risk Factors for SARS-COV-2

Introduction

The outbreak of severe acute respiratory coronavirus type 2 (SARS-COV-2) in December 2019, which is still spreading around the world, has been classified by the World Health Organization as a global pandemic with some impact on health care systems and global socioeconomic balance [1]. As a β-coronavirus with high infectivity, SARS-COV-2 causes a respiratory disease known as coronavirus disease 2019 (COVID-19) [2]. Currently, SARS-CoV-2 is thought to be transmitted mainly from person to person through close contact or respiratory droplets (> 5–10 μm in diameter) from an infected person over short distances (<1–2 m) by coughing, sneezing, talking, etc [3]. Based on the mode of transmission of the virus, a series of prevention and control measures were taken to reduce the risk of transmission of SARS-COV-2, including avoiding close contact with infected people, wearing masks in public places, travel and airport screenings, isolation, and quarantine.

However, the SARS-CoV-2 epidemic remains rampant around the world, putting enormous pressure on global health care systems. Therefore, clinical staff should pay attention to this dilemma and identify the risk factors that may cause the spread of SARSCOV- 2 and enhance the susceptibility of the population as soon as possible. In addition, the risk of infection can be reduced through rational allocation of medical resources and timely adjustment of prevention and control measures. This article focuses on both the modes of transmission of SARS-CoV-2 and the risk factors for infection among populations.

Modes of Transmission

Currently, SARS-CoV-2 is predominantly transmitted by both respiratory droplets and close contact. Common modes of transmission are through coughing, sneezing, inhalation of droplets, and contact with the oral, nasal, and eye mucous membranes of people infected with SARS-CoV-2 during daily life. In addition to the above modes of dissemination, aerosol, as a common mode of respiratory infectious disease, the current research on the transmission of SARS-COV-2 remains unclear. Evidence for aerosol transmission of SARS-COV-2 is still being collected (Asadi, et al. [4]). found that SARS-COV-2 particles ≤1 μm in diameter are released during normal breathing, coughing, and conversation, while small, aerosolized particles (<5 μm in diameter) containing the virus can remain in the air for a certain time and propagate over long distances (distances > 1 m). Aerosol transmission distances far exceed droplet transmission (1–2 m) and can even reach 8 m. The transmissibility and infectivity of aerosols also depend on the presence of particulate matter in the air, which can transmit and release microorganisms, including viruses. An NIH study [5] showed that the novel coronavirus can survive in the air as an aerosol for at least 3 h, which can cause mutual infection in persons who are not in direct contact in the same confined space. Moreover, sewage pipes allow the virus to spread as aerosols between tall buildings, such as bathrooms and bedrooms. In addition, SARSCOV- 2 can survive for many days on a variety of surfaces. For example, it can survive for up to seven days on the outer surface of a surgical mask. Therefore, aerosol transmission is an important mode of transmission of SARS-COV-2.

In addition, (Chirico, et al. [6]) reviewed the literature on whether air conditioning systems contribute to the transmission of severe acute respiratory syndrome (SARS)/Middle Eastern Respiratory Syndrome (MERS)/COVID-19. It was found that most of the studies on SARS and SARS-COV-2 were suspected or supported the diffusion of virus particles through air conditioning systems, and MERS has been confirmed to be infected by viruses in air conditioning systems. Moreover, aerosols often move along with air flow so that the air conditioning system promotes the long-distance transmission of respiratory droplets. Therefore, the air conditioning system may play a key role in promoting the longdistance transmission of aerosol molecules during the transmission of SARS-COV-2.

High-Risk Factors

High-Risk Industries

Health Care: Health care workers have always been on the front lines of the fight against SARS-COV-2 amid the grim global COVID-19 situation. Consequently, they are in more frequent contact with SARS-COV-2 than other industries and the key population at risk of SARS-COV-2 infection. Personal protective equipment, workplace environment, occupation, exposure, and testing are risk factors for health care workers to be infected with SARS-COV-2. (Gómez-Ochoa, et al. [7]) showed that approximately 1 in 10 health care workers in hospitals screened were diagnosed as positive for SARS-CoV-2 infection, half of whom were nurses. Then, compared with nurses and general service workers, physicians exposed to COVID-19- positive patients are at higher risk, primarily including key medical workers in respiratory departments, infection control departments, ICUs, and surgical departments. Based on the current situation, if health care workers fail to protect themselves and become infected, the strength of epidemic prevention and control will be weakened to a certain extent. Therefore, adequate prevention and control measures should be taken to protect them from SARS-COV-2.

Quarantined Hotel: Strict nucleic acid testing and isolation control should be carried out for all passengers regardless of whether they show symptoms at the time of entry to take the initiative for epidemic prevention and control. Centralized quarantine at designated hotels is one of the essential steps to prevent the importation of COVID-19. There are strict requirements on the quarantine facilities and management system. Effective centralized isolation is of great significance to prevent further transmission of SARS-COV-2. The staff of quarantined hotels are mainly responsible for indoor and outdoor disinfection, daily meal delivery, garbage disposal, and other life supplies that may have close contact with quarantined people. Therefore, workers in quarantined hotels are also at high risk for SARS-COV-2 infection (Yue, et al. [8]). Showed that the local outbreak was most likely caused by transmission of SARS-CoV-2 infection through contact with household waste from imported cases based on the results of on-site epidemiological investigation and gene sequencing analysis. Among them, the place where the epidemic occurred is adjacent to the quarantined hotel for inbound people. Additionally, the routine management of quarantined hotels also revealed that the staff did not properly manage the household waste of quarantined staff, which undoubtedly increased the risk of infection.

Clinical Features: Due to differences in sex, blood type, age, race, and behavior habits, people have different susceptibilities to SARS-COV-2.

Men: The risk of SARS-COV-2 infection, disease severity, and death in men is higher than that in women, which is consistent with previous studies that respiratory infections are more severe and will cause greater mortality in men than in women [9]. It has been reported [10] that higher levels of estradiol in women can increase the expression level and activity of a disintegrin and metalloprotease-17 (ADAM17), thereby promoting the shedding of angiotensin converting enzyme 2 (ACE2). Since the ACE2 receptor has been identified as the main functional entry receptor of SARSCOV- 2 [11], decreasing the number of ACE2 receptors in the body may be a critical method to block SARS-CoV-2 entry into cells, which leads to a large difference in susceptibility between males and females to SARS-COV-2.

Type O and RH-Blood: (Zhao, et al. [12]) Demonstrated that ABO blood groups had different associations with SARS-CoV-2 infection risk. In particular, blood type A increases the risk of infection, while blood type O reduces the risk of infection. Similarly, (Ray, et al. [13]). Found that type O and Rh-blood may reduce the risk of SARS-COV-2 infection, severe COVID-19 disease, and death. The reason might be that SARS-COV-2 infections in the population could be prevented by some unspecified characteristics conferred by type O blood. Moreover, anti-A antibodies in the blood specifically inhibit the adhesion of SARS-CoV S protein-expressing cells to ACE2 receptors. SARS-CoV shares a high degree of similarity with SARSCoV- 2 in terms of nucleic acid sequences as well as ACE2 receptor binding sequences [12]. Thus, anti-A antibodies may inhibit the transmission of SARS-CoV-2.

Age: Evidence from around the world [14] showed that aging was a prominent risk factor for severe disease and death from COVID-19, with patients over 70 years of age appearing to have a 65% higher risk of contracting COVID-19 than the rest of the population. This may be related to the different immune responses of T cells to SARS-COV-2, which result from the complex effect of aging on the immune system and the potential impact of taking various drugs while suffering from various diseases. In addition, differences in the severity of symptoms in elderly patients are also associated with the expression of ACE2 and the lymphocyte count [2]. (Hu, et al. [15]). Also believed that older age was an independent risk factor for the severe Delta variation in Guangzhou, especially in those older than 58.5 years. Therefore, aging should be given adequate attention as a risk factor for SARS-CoV-2 infection. Currently, some countries have started to develop protection plans for COVID-19 outbreaks in nursing homes, which play a positive role in preventing SARS-COV-2 transmitted infections for elderly individuals.

Black, Asian, and Minority Ethnic Groups: Human evolution has always been tied to natural pathogens. For long stretches of history, different risk factors for infection among ethnic groups make the immune system gradually adapt to the environment, which eventually leads to great differences in the immune system. Thus, during the transmission of SARS-CoV-2, the organism may undergo a different immune response. A systematic evaluation of the relationship between race and SARS-COV-2 infection by (Daniel, et al. [16]). Showed that black, Asian, and minority ethnic individuals were at increased risk of SARS-COV-2 infection compared with Caucasians. Similarly, (Lusignan, et al. [17]). Found that black patients were more likely to test positive for SARS-COV-2 than other ethnic groups. Individuals of other races may be protected from SARS-COV-2 infection due to their low ACE2 expression level [18]. However, the specific mechanism needs to be further confirmed.

Smoking: Whether smoking increases the risk of SARS-COV-2 infection has become a hot research topic in recent years (Lee, et al. [19]). Studied and analyzed three independent RNA expression databases of smokers to explore the potential connection between smoking and biological behavior associated with COVID-19. This study revealed that smoking may exacerbate COVID-19-related inflammation and increase susceptibility to COVID-19. Further research suggested that inflammation and the upregulation of ACE2 may be the molecular mechanisms that increase susceptibility to COVID-19. Tobacco has elevated ACE2 activity, while e-cigarettes without flavoring and nicotine lack a correlation with ACE2 activity. Furthermore, in addition to the upregulation of ACE2 in smokers [11], the host proteases TMPRSS2 and furin are also upregulated, which increases the affinity of SARS-CoV-2 for ACE2 by modifying spike proteins. However. Showed the opposite result through epidemiological investigation, suggesting that smoking status was negatively correlated with positive SARS-COV-2 infection [20]. Nicotine may increase the number of receptors on the cell surface of the lungs and protect tissue from damage caused by SARS-COV-2 infection. Nevertheless, the claim that smoking protects against SARS-COV-2 infection is not supported by further evidence, so smoking is more likely to increase susceptibility to SARS-COV-2.

Basic Diseases: Population-based diseases often have a subtle impact on the risk of SARS-COV-2 infection. The Centers for Disease Control and Prevention stated that people of any age with certain underlying medical conditions were at increased risk of severe COVID-19 [21].

Cancer

(Lee, et al. [22]) that individuals with cancer had a 60% increased risk of testing positive for SARS-CoV-2 compared to those without cancer. In particular, the association between cancer and SARS-CoV-2 infection was stronger in men over 65 years of age than in women. Among cancer patients, current chemotherapy or immunotherapy doubled the risk of testing positive for SARS-COV-2. For example, the use of corticosteroids and other immunosuppressants can reduce the ability of the body’s immune system to fight infection, thus making patients more susceptible to infection in the face of various foreign invasions [23]. Moreover, a high proportion of stage IV cancer patients were infected with SARS-CoV-2, suggesting that patients with advanced cancer may be more susceptible to SARS-COV-2 infection.

Asthma

(Sunjaya, et al. [24]) conducted a systematic evaluation of the relationship between asthma and SARS-CoV-2 infection, demonstrating that the risk of COVID-19 infection was reduced by approximately 14% in asthmatic patients compared to those without asthma. On the one hand, downregulation of ACE-2 receptors has been observed in patients with high T2 asthma. On the other hand, patients treated with corticosteroids are less susceptible to COVID-19 because of the decreased expression of ACE2 [23]. In addition, behavioral aspects may also play a vital role in reducing asthma patients’ susceptibility to COVID-19 due to their better compliance during the SARS-COV-2 pandemic.

Obesity

Obesity has been identified as an independent susceptibility factor for severe cases of SARS and MERS infections [25]. The genetic similarity of SARS-CoV-2 has been 80% with SARS-CoV-2 and 50% with MERS. Moreover, obesity is very common among hospitalized COVID-19 patients, which not only increases the risk of SARS-COV2 infection but also exacerbates the severity of COVID-19 [26]. Further research showed that severe obesity (BMI≥ 35) was independently associated with the risk of acquiring COVID-19, with an odds ratio greater than 1.05. Obesity may increase susceptibility to SARSCoV- 2 for the following three reasons: First, obesity disrupts the immune system, limiting its ability to respond to new viruses such as SARS-CoV-2. Second, the expression of ACE2 is increased among obese patients, which makes them more susceptible to SARS-CoV-2. Third, the body’s adipose tissue may create space for viral retention, which may slow viral clearance and exacerbate infection [27].

Rheumatic Diseases

Rheumatic diseases are also closely associated with the risk of SARS-COV-2 infection. Patients with rheumatic diseases have higher rates of SARS-COV-2 infection and mortality than the general population. Further studies by (Wang, et al. [28]). Showed that patients with rheumatic diseases had a 53% increased risk of sarS-COV-2 infection compared with the general population. The main reason may be that long-term use of glucocorticoids and immunosuppressants in patients with rheumatic diseases destroys their own immune system, resulting in reduced resistance to SARSCOV- 2 [23].

Other Common Diseases

In addition to the above representative diseases associated with SARS-COV-2 infection risk, the virus may be related to the renin-angiotensin-aldosterone system (RAAS), which is closely connected with the ACE2 receptor, thus significantly increasing the risk of SARS-CoV-2 infection in the population with hypertension. Furthermore, the susceptibility to SARSCOV-2 in patients with cardiovascular disease may be increased through increased expression of ACE2 in muscle cells and vascular fibroblasts [29].

Discussion

Despite the extensive isolation control and health protection measures taken by governments and health care institutions at all levels based on the main modes of transmission of SARS-CoV-2, the epidemic trend of COVID-19 has still not been controlled in all aspects. Aerosol transmission is another important route of SARS-COV-2 transmission in addition to close contact and droplet transmission, which plays a vital role in the prevention of SARSCOV- 2 transmission. Among them, the air conditioning system may promote the long-distance diffusion of aerosol molecules. At the same time, health care and quarantine hotel control are key industries and external risk factors related to the spread of SARSCOV- 2. Therefore, while preventing and controlling the spread of the epidemic, it is necessary to make strict requirements on SARS-COV-2 protection. Except for focusing on external factors, it is also essential to keep an eye on internal factors. Men, aging, along with black, Asian, and minority individuals and smoking behavior can increase the risk of SARS-COV-2 infection. In addition, cancer, obesity, and rheumatic diseases increase the susceptibility of the population to SARS-COV-2, while individuals with type O and Rh-blood groups and with asthma may be at reduced risk. By exploring the mechanism of population risk factors, we found that there are two main reasons for population susceptibility to SARSCOV- 2. First, the ACE2 receptor is the key structure for SARSCOV-2 to enter cells [12], which affects the expression and affinity of the ACE2 receptor. Second, the use of corticosteroids and other immunosuppressants will reduce the ability of the body’s immune system to fight infection, thus making patients more susceptible to infection in the face of various foreign invasions [24].

Therefore, understanding the transmission characteristics and mechanism of SARS-COV-2 and the causes of the widespread epidemic from the perspective of genetics and molecular biology will help researchers develop an effective vaccine against the novel coronavirus as soon as possible and control the epidemic. In addition, clinicians and community health workers should also focus on the prevention of SARS-COV-2 transmission among patients with underlying diseases. When conducting COVID-19 screening, medical prevention and vaccine research and development, governments at all levels and medical and health institutions should be conscious of the risk factors and transmission routes of SARS-COV-2 infection in advance. Through targeted scientific research and prevention as well as relevant knowledge dissemination among high-risk groups, the self-prevention awareness of the public in preventing novel coronavirus can be strengthened. In addition, professional guidance for all epidemic prevention and control personnel will be beneficial to epidemic prevention and control, allocation of medical resources, and control of key groups.

Conclusion

When preventing the spread of SARS-COV-2, we should not only consider aerosols as an important route of transmission and external infection risk factors, such as high-risk industries related to COVID-19 but also pay attention to the influence of internal factors, such as high-risk populations and basic diseases. Comprehensive assessment of SARS-COV-2 infection risk and identification of high-risk individuals play a certain guiding significance for the prevention and control of SARS-COV-2 and lay a certain foundation for the elimination of SARS-COV-2 in the future.

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Neuroanatomy of Affective Touch Sensation

Introduction

Touch is central to interpersonal interactions and is one of the four main modalities of somatic sensation. Each relay either touch, heat, pain or pruritic (itch) information to the central nervous system. Apart from localized discrimination in space and time, touch also provides the subjective experience of affiliative or emotional somatic pleasure (McGlone, et al. [1]). Affective processing in skin-brain pathways has wider implications for the exchange of social information (Morrison, et al. [2]) and behavioral development (Bales, et al. [3]). Affective or pleasant touch such as stroking, caressing or hugging is an essential part of human behaviour. Complex molecules acting as neurotransmitters are involved including some that act as hormones such as oxytocin. The latter is well known for its role in generating feelings of attachment and affection (Shen, 2015) Interpersonal affective touch has an important role in mental health and plays a crucial part in social interactions including human development (Cascio, et al. [4]). Pleasant touch seems to provide emotional and psychological support that helps mitigate social isolation and stress (Chen [5]). However, the way in which pleasant touch information is encoded and transmitted from sensory neurons to the spinal cord - and the brain, remains somewhat uncertain.

Spinal Circuitry

Liu and colleagues (Bao, et al. [6]) identified interneurons in the spinal cord dorsal horn that express prokineticin receptor 2, as well as sensory neurons that express a binding molecule, or ligand, the neuropeptide prokineticin 2. These are involved in the encoding and transmission of pleasant touch. Chen showed that genetic ablation of these neurons in mice selectively abolished the pleasant touch-conditioned place preference test whilst preserving other sensations. These mutant mice display profound impairment in stress response and prosocial behaviour (Chen, et al. [7]). The subjective experience of emotional pleasure of touch seems to be mediated by a class of slow, unmyelinated peripheral nerve fibres with specific neurobiological and electrophysiological properties (McGlone, et al. [1]) that synapse in the spinal cord to produce this ligand or neuropeptide.

Mammalian and Primate Brain Pathways

Hang Yu and colleagues showed that social touch- like stimulation enhanced the firing of oxytocin neurons in the mouse paraventricular hypothalamus (Yu, et al. [8]). This pleasant sensory experience promoted social interactions and social behaviour with positive reinforcement of place preference. In primates, presumably including humans, social grooming (affective touching) clearly plays a particularly important role in social bonding. This has a major impact on social development and an individual’s lifetime reproductive fitness. There is strong evidence from comparative brain analysis that primates have social relationships of a qualitatively different kind to those found in other animal species (Panksepp [9] and Hertenstein, et al. [10]) with social grooming acquiring a new function. Dunbar has reviewed the evidence for a neuropeptide basis for social bonding (Dunbar [11]) with the neuroendocrine pathways involved demonstrating the central importance of oxytocin and endorphins. These two neuropeptides may play different roles however in the processes of social bonding in both primates and non-primates. The rewarding properties of social interaction in mice require the coordinating activity of oxytocin and the serotonin receptor 5HT in the nucleus accumbens (Dolen, et al. [12]). This has implications for understanding the pathogenesis of social dysfunction in neuropsychiatric disorders such as autism, discussed below.

Human Studies

Functional magnetic resonance imaging (fMRI) studies have been used to elucidate the unique different cortical signals in response to passive touch, both active and slow (Ackerley, et al. [13,14]) examined the relationship between the neural response and individuals’ social abilities in 19 healthy adults. Connectivity analysis revealed co-activation of the medial prefrontal cortex, orbitofrontal cortex, amygdala and insular cortex during slow touch. However, in participants with autistic traits, there was negative correlation to slow touch in some of these regions. The Voos study supports previous findings of the involvement of a network of “social brain regions” that process slow, unmyelinated afferent peripheral nerve fibres mediating affective touch (C tactile or CT system) as well as highlighting the multimodal nature of this system. The variability in the brain response to affective touch also illustrates a tight coupling of social behaviour and social brain function in a cohort of typical adults. In (Kirsch, et al. [15]) and colleagues reported studies addressing neurophysiological specificity in the communication of emotions by touch.

Blindfolded participants were touched without any contextual cues, and asked to identify the touch provider’s emotion and intention. Affiliative emotions such as love, or social support were reliably elicited by gentle, soft touch whether delivered by CT optimal velocities (3cm/s) or CT suboptimal velocities (18cm/s). However the CT optimal velocity gentle touch participants were significantly more likely to report arousal, lust or desire. This suggests that other “top-down” factors contribute to these aspects of tactile social communication. The posterior insular cortex is considered the primary cortical target of CT afferents and temporal cortex involvement has been linked to more affiliative aspects of CT optimal touch. This paradigm was tested by Kirsch in a stroke patient with right perisylvian damage including the insular cortex but excluding temporal cortex on MRI studies. He showed impairment in “reading” emotions based on CT optimal (3cm/s) touch. This study by Kirsch and colleagues suggest that the CT system can add specificity to emotional and social communication, particularly with regards to feelings of desire and arousal. On the basis of these findings they speculate that its primary functional role may be to enhance the “sensual salience” of tactile interactions in humans.

Touch and Human Development

Interpersonal touch influences neural and behavioral development throughout life (Bales, et al. [3]). Mental retardation in infants emanating from the notorious charity orphanages of Romania in the Soviet era (Nelson, et al. [16]) demonstrates the powerful force of touch in human development. The children in the orphanage were deprived of human touch and it is clear that disruption in early social-sensory input during infancy has severe developmental consequences throughout the life span. Social touch is important for cognition, attachment, communication and emotional regulation from infancy (Cascio, et al. [4]). The quality of touch matters with gentle stroking touch generating increased smiling, a lowered heart rate and increased engagement in infants. The pattern of neural responses to CT targeted touch appears similar in school age children as in adults, namely the posterior insular and posterior superior temporal sulcal regions. This circuitry for social touch continues to mature as the brain develops (Bjornsdotter, et al. [17]).

Cascio and colleagues reviewed the role of social touch in disordered development using as an example the autism spectrum disorder. Avoidance of social touch in infancy is a predictor of autism spectrum in older children (Mammen, et al. [18]). It seems clear that social touch plays a critical role in the neural, behavioural and physiological growth and advancement of infants and young children through to adolescence and adulthood. Far reaching epigenetically mediated effects on development have been broadly studied in the context of critical windows in the social and physical environments in humans (Szyf [19]). Parental touch is linked to oxytocin levels in parents (Feldman, et al. [20]) and this has effects on later social-emotional behavioural issues in children that are associated with maternal anxiety (Pickles, et al. [21]).

Social Touch in the Covid-19 Pandemic

Social distancing regulations and lockdowns during the pandemic reduced the ability to engage in personal touch. Meijer and colleagues conducted an online survey of nearly 2000 people in regard to the effect of these regulations. Participants reported feelings of longing for touch which increased with the duration and severity of the COVID-19 restrictions. There was also an associated increase in the perceived pleasantness of observing touch. Stress also seems to respond in a positive fashion to social touch and assists with adaptation to adversity (Dagnino Subiabre [22]) as witnessed in the COVID-19 pandemic. Whilst there are several factors affecting stress resilience, social behaviour inclusive of social touch seems vital. It may be possible in the future to modulate stress resilience through the stimulation of low threshold CT-fiber mechanoreceptors. This technology may have a role in the prevention of stress related neuropsychiatric disorders including social avoidance, acute anxiety and major depression [23-29].

Conclusion

The ligand prokineticin 2 has now been identified as the neuropeptide that encodes and transmits social or pleasant touch to the equivalent, appropriate spinal neurons. These findings have important implications for elucidating mechanisms by which pleasant touch deprivation contributes to brain development and mental disorders. Social touch in infancy has far reaching sequelae throughout the developing brain and it continues to influence brain development beyond infancy. Furthermore, it appears that this somatosensory system plays a key role in translating the socioemotional information of social touch into active coping with stress and building stress resilience in the longer term.

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Over-Prescription of Short-Acting β2-Agonists in Mexico: Results from the SABINA III Stud

Introduction

Asthma is a chronic disease of the airways that imposes a significant social and economic burden on patients and healthcare systems, affecting approximately 339 million people worldwide [1]. Despite significant advances in asthma care and the availability of updated international and national guidelines on asthma treatment and prevention [2], many patients worldwide may not have benefited from these efforts, especially those living in lowand middle-income countries where access to essential asthma medications remains a challenge [1]. As an upper middle-income country [3], Mexico has an estimated asthma prevalence of 5% [4] that continues to increase, with both underdiagnosis and poor disease control contributing to its impact [1,5]. Studies have shown that asthma in Mexico is associated with a number of factors, such as exposure to traffic-related pollution [6] and an urban lifestyle [7] accompanied by the consumption of a westernized, fat-rich diet [8] and limited physical activity [9]. Notably, the segmentation of the Mexican healthcare system continues to restrict public investment and expenditure and has failed to substantially reduce outof-pocket expenditure [3].

In addition, human resources and physical infrastructure are in relatively low supply and unequally distributed across the country [3]. Furthermore, the healthcare system faces challenges associated with chronic diseases, such as obesity and diabetes, as well as health inequity[3]. In addition to socioeconomic factors, treatmentrelated factors, such as overuse of short-acting β2-agonists (SABAs), often at the expense of regular maintenance therapy with inhaled corticosteroids (ICS), have been associated with poor asthma control across Latin America, including Mexico [10,11]. However, the Global Initiative for Asthma (GINA) no longer recommends as-needed SABAs without concomitant ICSs for patients aged ≥12 years [12].

Considering that medications rank as an important cost driver in asthma management [13], a greater understanding of prescription patterns is an area of growing interest, especially in low- and middle-income countries where improving access to affordable medications represents an unmet need [1]. Therefore, a detailed assessment of both SABA prescription patterns and over-the-counter (OTC) SABA purchases is required to provide clinicians, researchers, and healthcare policymakers with a better understanding on the extent of SABA use to ensure that treatment practices align with the latest evidence-based treatment recommendations, to prioritize healthcare resource expenditure, and to devise public health strategies to improve the quality of care for all patients with asthma.

The SABA use IN Asthma (SABINA) series of studies were undertaken to describe the global extent of SABA use through a series of large observational cohort studies applying a harmonized approach to data collection, evaluation, and interpretation [14]. Findings from SABINA III, conducted across 23 countries in the Asia-Pacific, Africa, the Middle East, Latin America, and in Russia, demonstrated that SABA over-prescription (≥3 canisters) in the previous 12 months was common, occurring in 38.0% of patients, and was associated with poor asthma-related outcomes [15]. Here, we report the results from the Mexican cohort of SABINA to provide real-world evidence on SABA prescriptions and asthma treatment practices in this country. The objectives of this study were to describe the demographics and clinical features of the asthma population by asthma severity, estimate prescriptions of SABA (canisters/year) and ICS (by average daily dose—low, medium, or high) per patient, and describe patients within the different treatment groups.

Methods

Study Design

The detailed methodology for SABINA III [15] has been published previously. In this observational, cross-sectional study conducted at four sites in Mexico, patients were recruited from August 2019 to January 2020. Retrospective data were obtained from existing medical records, and patient data were collected during a study visit and entered into an electronic case report form (eCRF). The study was conducted in accordance with the study protocol, the Declaration of Helsinki, and local ethics committees, and signed informed consent was obtained from all patients or their legal guardians.

Study Population

Patients aged ≥12 years with a documented diagnosis of asthma, ≥3 consultations with their healthcare practitioner (HCP), and medical records containing data for ≥12 months prior to the study visit were enrolled. Patients with a diagnosis of other chronic respiratory diseases, such as chronic obstructive pulmonary disease, or with an acute or chronic condition that, in the opinion of the investigator, would limit their ability to participate in the study were excluded. Study sites were selected using purposive sampling with the aim of obtaining a sample representative of asthma management within Mexico.

Study Variables

Each patient was categorized by their SABA and ICS prescriptions in the 12 months before the study visit. SABA prescriptions were categorized as 0, 1–2, 3–5, 6–9, 10–12, and ≥13 canisters, with prescription of ≥3 SABA canisters/year being defined as over-prescription [14]. ICS canister prescriptions in the previous 12 months were recorded and categorized according to the prescribed average daily dose (low, medium, or high) [16].

Secondary variables included practice type (primary or specialist care), investigator-classified asthma severity (guided by the GINA 2017 treatment steps: steps 1–2, mild asthma; steps 3–5, moderate-to-severe asthma) [16], time since asthma diagnosis, and prescriptions for asthma medications in the preceding 12 months (SABA monotherapy, SABA in addition to maintenance therapy, ICS, fixed-dose combinations of ICS with long-acting β2-agonists [LABAs], oral corticosteroid [OCS] burst treatment [defined as a short course of intravenous corticosteroids or OCS administered for 3–10 days or a single dose of an intramuscular corticosteroid to treat an exacerbation], long-term OCS [defined as any OCS treatment for >10 days], and antibiotics). Patients were also asked about pharmacy purchases of OTC SABA without a prescription at the pharmacy in the 12 months prior. Other variables included medication reimbursement status (not reimbursed, partially reimbursed, or fully reimbursed), educational level (primary or secondary school, high school, or university and/or post-graduate), body mass index (BMI), number of comorbid conditions, and smoking status.

Outcomes

Asthma symptom control was evaluated using the GINA 2017 assessment for asthma control [16] and categorized as well controlled, partly controlled, or uncontrolled. Severe exacerbations in the 12 months before the study visit were based on the American Thoracic Society/European Respiratory Society recommendations [17] and defined as a worsening of asthma symptoms requiring hospitalization, an emergency room visit, or the need for intravenous corticosteroids or OCS for ≥3 days or a single dose of an intramuscular corticosteroid.

Statistical Analysis

Descriptive analyses were used to characterize patients according to baseline demographics and clinical characteristics. Continuous variables were summarized by the number of nonmissing values, mean, standard deviation (SD), median, and range, whereas categorical variables were summarized by frequency counts and percentages.

Results

Patient Disposition

Of the 150 patients enrolled, one patient was excluded due to an asthma duration of <12 months; therefore, 149 patients were included in the analysis (Supplementary Figure 1). Although the intention was to recruit patients treated in both primary- and specialist-care settings, all patients were recruited by specialists, with most being treated by pulmonologists (94.6%; n=141). However, two patients were erroneously allocated to “primary care.” Therefore, data on overall disease characteristics and treatment patterns are reported for 149 patients, whereas data on asthma severity (“mild” vs. “moderate-to-severe”) are reported for 147 patients.

Supplementary Figure 1: Patient disposition in the SABINA III Mexico cohort (N=149) by investigator-classified asthma severity.

*Two patients were erroneously classified under primary care.

SABA: short-acting β2-agonist; SABINA: SABA use IN Asthma.

Patient Characteristics

Overall, the mean (SD) age of patients was 49.1 (16.3) years, with most patients (55%; n=82) aged 18–54 years (Table 1). Patients with mild asthma were younger than those with moderatetosevere asthma (mean age, 41.6 years vs. 51.2 years). The majority of patients were female (79.2%; n=118) and had never smoked (79.2%; n=118). The mean (SD) BMI of patients was 28.2 (6.3) kg/ m2, with most (64.4%; n=96) being overweight or obese (BMI ≥25 kg/m2). The proportion of patients with BMI ≥25 kg/m2 was higher among those with moderatetosevere asthma than among those with mild asthma (71.1% [n=81] vs. 42.4% [n=14]). More than onequarter of patients (28.9%; n=43) had received secondary or high school education, while 53% (n=79) had obtained a university and/ or post-graduate education. Overall, 55.7% of patients (n=83) had full healthcare reimbursement, while 35.6% of patients (n=53) had no healthcare reimbursement.

Table 1: Sociodemographics of the SABINA III Mexico cohort by investigator-classified asthma severity.

*Two patients were erroneously classified under primary care.

Data are presented as n (%) unless otherwise specified.

BMI: body mass index; max: maximum; min: minimum; SABA: short-acting β2-agonist; SABINA: SABA use IN Asthma; SD: standard deviation

Disease Characteristics

Patients had a mean (SD) asthma duration of 13.9 (15.1) years (Table 2). Overall, 22.8% of patients (n=34) had investigatorclassified mild asthma (GINA steps 1–2) and 77.2% (n=115) had moderate-to-severe asthma (GINA steps 3–5); the majority of patients were at GINA step 4 (51.0%; n=76). A comparable proportion of patients reported having no comorbidities and ≥1 comorbidity (48.3% [n=72] and 51.7% [n=77], respectively). However, a higher proportion of patients with moderate-to-severe asthma reported having ≥1 comorbidity compared with those with mild asthma (54.4% [n=62] vs. 39.4% [n=13]). Patients reported a mean (SD) of 1.3 (1.7) severe exacerbations in the previous 12 months, with 63.1% (n=94) and 15.4% (n=23) of patients experiencing ≥1 and ≥3 severe exacerbations, respectively. The level of asthma control was assessed as well-controlled in 40.3% of patients (n=60), partly controlled in 25.5% of patients (n=38), and uncontrolled in 34.2% of patients (n=51). More patients with mild asthma reported having well-controlled asthma compared with those with moderate-to-severe asthma (54.5% [n=18] vs. 36.0% [n=41]), whereas a higher proportion of patients with moderateto- severe asthma reported having uncontrolled asthma compared with those with mild asthma (37.7% [n=43] vs. 24.2% [n=8]).

Table 2: Sociodemographics of the SABINA III Mexico cohort by investigator-classified asthma severity.

*Two patients were erroneously classified under primary care.

Data are presented as n (%) unless otherwise specified.

BMI: body mass index; max: maximum; min: minimum; SABA: short-acting β2-agonist; SABINA: SABA use IN Asthma; SD: standard deviation

Asthma Treatment in the 12 Months before the Study Visit

Overall, 51.7% of patients (n=77) were prescribed ≥3 SABA canisters, defined as overprescription, and 41.6% of patients (n=62) were prescribed ≥10 SABA canisters in the preceding 12 months (Figure 1). Approximately one-third of all patients (32.2%; n=48) were prescribed 0 SABA canisters.

Figure 1: Proportion of patients receiving SABA prescriptions in the 12 months before the study visit according to investigator classified asthma severity in the SABINA III Mexico cohort (N=149).

*Patients without SABA prescriptions did not report what reliever they were using.

SABA: short-acting β2-agonist; SABINA: SABA use IN Asthma

A comparable proportion of patients with mild asthma and moderate-to-severe asthma were prescribed ≥3 SABA canisters in the previous 12 months (52.9% [n=18] and 51.3% [n=59], respectively). However, a higher proportion of patients with moderate-to-severe asthma were prescribed ≥10 SABA canisters 12 months prior (44.3% [n=51] vs. 32.4% [n=11]).

Prescriptions and Purchase of SABA

SABA Monotherapy: Overall, 8.7% of patients (n=13), all of whom were categorized with mild asthma, were prescribed SABA monotherapy in the previous 12 months, with a mean (SD) of 7.0 (4.7) canisters (Table 3A). Of these patients, 69.2% (n=9) were prescribed ≥3 SABA canisters in the 12 months prior. Moreover, 46.2% (n=6) were prescribed ≥10 SABA canisters in the previous 12 months.

Saba in Addition to Maintenance Therapy: Overall, 59.1% of patients (n=88) were prescribed SABA in addition to any maintenance therapy, with a mean (SD) of 8.7 (4.8) canisters in the previous 12 months (Table 3B). Among these patients, 77.3% (n=68) and 63.6% (n=56) were prescribed ≥3 and ≥10 SABA canisters, respectively, in the preceding 12 months. Compared with patients with mild asthma, a higher proportion of patients with moderate-to-severe asthma were prescribed ≥3 (82.9% [n=58] vs. 50.0% [n=8]) and ≥10 (72.9% [n=51] vs. 25.0% [n=4]) SABA canisters.

OTC SABA Purchase: Approximately one-fifth of all patients (20.8%; n=31) purchased SABA OTC, of whom 71% (n=22) purchased 1-2 canisters and 29.0% (n=9) purchased ≥3 canisters (Table 3C).

Table 3: Patients in the SABINA III Mexico cohort who (A) received prescriptions for SABA monotherapy, (B) received prescriptions for SABA in addition to maintenance therapy, and (C) purchased SABA without a prescription in the 12 months before the study visit.

*Two patients were erroneously classified under primary care.

**“NA” could be selected in the eCRF when patients purchased non-canister forms of SABA (e.g., oral or nebulized SABA) without a prescription.

Data are presented as n (%) unless otherwise specified.

eCRF: electronic case report form; max: maximum; min: minimum; NA: not applicable; OTC: over-the-counter; SABA: short-acting β2-agonist; SABINA: SABA use IN Asthma; SD: standard deviation.

Prescriptions for other Asthma Treatments

Overall, 17.4% of all patients (n=26) were prescribed maintenance therapy in the form of ICS, with a mean (SD) of 9.6 (4.1) canisters in the previous 12 months (Table 4A). Two-thirds of these patients (66.7%; n=16) were prescribed medium-dose ICS. Most patients (77.9%; n=116) were prescribed an ICS/LABA fixeddose combination as maintenance therapy, with 63.8% (n=74) prescribed medium-dose ICS (Table 4B). The majority of patients with moderatetosevere asthma (99.1%; n=113) were prescribed ICS/LABA fixed-dose combination. Overall, in the preceding 12 months, 39.6% of patients (n=59) were prescribed an OCS burst (Table 4C). Compared with patients with mild asthma, a higher proportion of patients with moderatetosevere asthma were prescribed an OCS burst (44.7% [n=51] vs. 21.2% [n=7]). A small percentage of patients (4.7%; n=7), all of whom had moderate-tosevere asthma, were prescribed antibiotics (Table 4D).

Table 4: Patients in the SABINA III Mexico cohort who received prescriptions for (A) ICS, (B) ICS/LABA (fixed-dose combination), (C) OCS burst/short course, and (D) antibiotics in the 12 months before the study visit.

*Two patients were erroneously classified under primary care.

Data are presented as n (%) unless otherwise specified.

ICS: inhaled corticosteroid; LABA: long-acting β2-agonist; max: maximum; min: minimum; OCS: oral corticosteroid; SABA: shortacting β2-agonist; SABINA: SABA use IN Asthma; SD: standard deviation.

Discussion

The findings from the Mexican cohort of the SABINA III study highlight that asthma continues to impose a considerable healthcare and socioeconomic burden on this patient population. Although most patients were prescribed maintenance therapy (ICS and ICS/LABA fixed-dose combinations), more than half of all patients (51.7%) received ≥3 SABA canister prescriptions in the previous 12 months.

In general, the overall demographic and lifestyle characteristics of the SABINA Mexico population were comparable with that of the SABINA III [15] population, although 79.2% of patients in the Mexican cohort were female, which was higher than that observed in the SABINA III [15] population. Notably, approximately twothirds of patients in the Mexican cohort (64.4%) were classified as overweight or obese (BMI ≥25 kg/m2); this finding is not entirely unexpected as the rates of obesity in Mexico have increased dramatically over the past 30 years, with Mexico now ranking second in the world for the overall prevalence of obesity, second only to the United States [3]. Even though all study sites were intended to be representative of healthcare practices across Mexico, their selection was likely restricted due to inherent challenges commonly encountered in conducting clinical trials at a primary care level [18]. Therefore, all patients were treated by specialists, with the majority having moderate-to-severe asthma (77.2%). Consequently, this cohort of patients from Mexico likely represents a “better case scenario,” given that all patients received specialist care.

Over-prescription of SABA medication was common in the Mexican cohort, with 69.2% and 77.3% of patients prescribed ≥3 SABA canisters as monotherapy or in addition to maintenance therapy, respectively, in the preceding 12 months. Therefore, a higher proportion of patients from Mexico were prescribed ≥3 SABA canisters as monotherapy and in addition to maintenance therapy compared with the overall SABINA III population, where this was reported in 53.6% and 61.7% of patients, respectively [15]. Moreover, SABA over-prescription might have been higher if primary care physicians, who may be less familiar with treatment recommendations, had participated in this study. Although findings from this study are based on a small number of patients, they are consistent with those of previous studies from Latin America, including Mexico, that have reported an over-reliance on SABAs among patients with asthma [10,11], reinforcing the urgent need for routine monitoring of SABA prescription patterns to promptly identify patients at increased risk of exacerbations [19]. The SABA prescription patterns observed in this patient cohort from Mexico may also be attributed to prescribing habits, such as automatic prescription refills, which may have resulted in a high and unnecessary number of dispensed canisters. This clearly demonstrates the need to reduce inappropriate prescribing of SABA; in this regard, it has been suggested that the use of electronic alerts integrated within electronic health records and delivered as part of a multicomponent intervention may prove to be a useful tool to reduce SABA over-prescription [20].

Unregulated access to SABAs was also common, with more than one-fifth of patients (20.8%) purchasing SABA OTC; this was comparable with the SABINA III study (18.0%). Among patients who purchased SABA OTC, 29.0% purchased ≥3 SABA canisters in the previous 12 months. These findings, although based on small patient numbers, are concerning because many patients who purchased SABA OTC likely did so in addition to their SABA prescriptions. However, these data provide valuable insights into patients’ beliefs and attitudes toward asthma management and are in alignment with previous research from Latin America, including Mexico, which reported that approximately half of the patients with asthma use quick-relief medication daily, believing that it is acceptable to do so [11]. As SABA purchases have been associated with infrequent physician consultations and undertreatment of asthma [21], these findings emphasize the urgent need for policymakers to regulate the availability of SABAs without prescription, while ensuring improved access to affordable medications to improve overall asthma management.

In general, most patients (77.9%) were prescribed maintenance medication in the form of a fixed-dose combination of ICS/LABA, which was in alignment with the fact that 77.2% of patients had moderate-to-severe asthma (GINA steps 3–5). However, patients were prescribed a mean of 9.6 ICS canisters in the preceding 12 months. This quantity suggests underuse, as one canister per month is considered good clinical practice, although in some cases, a single ICS inhaler provides a 2-month supply. The observation that prescriptions for maintenance medication did not conform to internationally recommended guidelines may also potentially indicate the risk of polypharmacy among patients in Mexico. Indeed, polypharmacy, or the use of multiple medications to treat patients with multimorbidities, or one or more medicinal agents to treat a single condition, is a common practice in Mexico and an area of concern as it is associated with chronic disease, suboptimal treatment outcomes, and increased adverse events due to drugdrug interactions [22,23].

Despite all patients being treated by specialists, the level of asthma control in SABINA Mexico was poor, with 59.7% of patients having partly controlled/uncontrolled asthma, which translated to a high disease burden, with 63.1% of patients experiencing ≥1 severe exacerbation in the preceding 12 months. In line with other studies [11,24], our findings may be attributed to SABA over-reliance and ICS underuse, particularly as previous research has demonstrated that patients from Latin American countries, including Mexico, have concerns about ICS use, do not have a clear understanding of adequate asthma control or how to measure control, and have low expectations on the benefits of successful asthma management, all of which translate to low treatment adherence [11].

The high disease burden observed in this Mexican cohort may also be explained by a lack of healthcare insurance and access to essential medications. Indeed, inadequate healthcare insurance coverage in patients with asthma has been associated with increased emergency room visits [25] and poor quality of care, including a lower likelihood of receiving ICS [26]. In line with estimates that more than half of the Mexican population is not covered by healthcare insurance [27], only 62.4% of patients from this Mexican cohort received partial or full healthcare reimbursement, while 35.6% received no healthcare reimbursement. Given that poor asthma control remains a major clinical challenge in Mexico, asthma advocacy programs can impact asthma care positively by improving access to treatment, raising awareness of disease and its effective management, and ensuring integration of the patient perspective into policy decisions [1].

In 2017, asthma experts from Mexico presented at the Senators’ Chamber of the Mexican Republic and underscored the importance of asthma as a public health concern, which necessitates a wider basic catalog of asthma medications and well-trained physicians [1]. The findings from this Mexican cohort further emphasize this point and highlight the need for political commitment supported by appropriate policies to improve overall disease management by establishing educational programs targeted at both patients and HCPs; providing additional education for specialists; regulating SABA OTC purchase while ensuring access to quality care and affordable medications, including adequate provision for ICScontaining medications; and prioritizing the implementation of current evidencebased recommendations. Following the historic 2019 updates in the GINA report on asthma management and prevention [12], a panel of experts in Mexico have now recommended that all patients with asthma receive anti-inflammatory treatment [28]. An effective strategy proposed by these experts was the use of low-dose ICS with a fast-acting β2-agonist as the preferred reliever for patients with intermittent symptoms and for those with persistent symptoms as a daily controller treatment and asneeded reliever medication [28]. This anti-inflammatory reliever approach represents a viable asthma management strategy, as ICS and fast-acting β2-agonists are available across most low-income settings [29]. However, as the current Mexican asthma guidelines [30] have not adopted these updated treatment recommendations, immediate action should be taken to ensure alignment with GINA.

Limitations

This study has several limitations. Prescription data were considered a surrogate for medication usage and do not reflect actual SABA administration or provide information on medication adherence, potentially contributing to an under-estimation or over-estimation of SABA use. As this analysis was limited to 149 patients, all of whom were recruited by specialists, the study population is not representative of the overall national asthma population and does not reflect the way asthma is managed presently in Mexico. Therefore, additional studies are required to gain a more comprehensive understanding of treatment patterns in both primary and specialist care. Moreover, the greater number of patients with moderate-to-severe asthma recruited into the study may influence the generalizability of the results.

Nevertheless, to the best of our knowledge, this is the first study specifically designed to examine the extent of SABA prescriptions and asthma treatment practices in Mexico, which may have important public health and policy implications. Moreover, centralized eCRFs can be a reliable source of real-world data, allowing policymakers and clinicians to consider the necessary targeted changes in clinical practice to improve outcomes for patients with asthma in Mexico.

Conclusion

Results from the Mexican cohort of SABINA III reveal concerning SABA prescription practices; despite specialist care, approximately one in every two patients were over-prescribed SABAs (≥3 canisters) and approximately four in every 10 patients were prescribed ≥10 canisters in the preceding 12 months. In addition, unregulated access to SABA was common, with 20.8% of patients purchasing SABAs OTC, of whom 29.0% purchased ≥3 SABA canisters in the previous 12 months. Taken together, these findings highlight that SABA over-prescription is a major public health concern in Mexico, requiring HCPs and policymakers to prioritize the alignment of clinical practices with the latest evidence-based recommendations to improve longterm treatment outcomes for patients with asthma.

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