European Respiratory Society

European Respiratory Society statement on novel nicotine and tobacco products, their role in tobacco control and “harm reduction”

Posted by

0


Novel nicotine and tobacco products and harm reduction

What are novel and emerging nicotine and tobacco products?

A growing number of new tobacco and nicotine products have emerged in recent years and are especially popular among adolescents and young adults. These are collectively known as “novel and emerging nicotine and tobacco products” [1, 2], and include electronic cigarettes, heated tobacco products and nicotine pouches.

Electronic cigarettes (e-cigarettes or vapes), including electronic nicotine delivery systems or electronic non-nicotine delivery systems (ENNDS), utilise a battery to heat an e-liquid solution containing flavourings, additives and, with the exception of ENNDS, nicotine [3]. Notably, disposable e-cigarettes have recently gained significant popularity, especially among adolescents and young adults [4]. The majority of e-cigarettes available on the market contain a high concentration of nicotine which has addictive potency [5]. Consequently, their usage among young people has reached epidemic levels in many countries [3, 4].

Heated tobacco products (HTPs), also known as “heat-not-burn” products, utilise electrical devices to heat tobacco sticks, producing nicotine-containing aerosols without combustion [6]. Unlike e-cigarettes, these products do contain tobacco and exhibit diversity in heating device styles and tobacco types. However, similar to e-cigarettes, HTPs incorporate novel features and designs to attract users, resembling the experience of smoking traditional cigarettes.

Another emerging product is nicotine pouches, originating in Scandinavia but gaining popularity with users in the European region and beyond [7]. These pouches resemble tobacco pouches (snus) used in Sweden and are placed under the upper lip to release nicotine. Unlike snus, which is known to have adverse health impacts, including the development of specific cancers [8], nicotine pouches do not contain tobacco, but nicotine powder, salts, flavourings and sweeteners, making them particularly appealing to younger individuals [9, 10]. It is unknown whether these differences will translate into different risk profiles. Furthermore, nicotine pouches offer discreet usage, attracting non-smokers and youth [9]. Some users turn to nicotine pouches as a way to circumvent smoke-free regulations [10]. Currently, nicotine pouches are not subject to European Union (EU) tobacco product regulations, allowing marketing without packaging regulations or health warnings [7, 10]. Advertisements target younger populations, raising concerns about the popularity of nicotine pouches among the youth [11].

What is the tobacco industry’s so-called “harm reduction” strategy?

The concept of harm reduction originated in drug use [12], recognising that complete abstinence may not always be achievable. Instead, it proposes helping individuals transition to less harmful alternatives [13]. However, the tobacco industry exploited this concept and adopted a strategy of marketing novel nicotine and tobacco products as less harmful than traditional cigarettes [7]. Yet, these products allow the tobacco industry to maintain its profits in a context of declining smoking prevalence [1, 14]. Ongoing scientific and legislative debates centre around concerns regarding the long-term health impacts and safety of these products [7, 14]. Currently, there is insufficient scientific evidence to conclusively establish the reduced risk claimed by the tobacco industry for any of these novel products when compared to conventional cigarettes.

What are the health effects of novel nicotine and tobacco products?

Despite their diverse forms, many novel products contain high levels of nicotine and toxic substances, posing risks and contributing to initiation and dependence of use among young individuals [15]. Exposure to nicotine, which is highly addictive and detrimental to brain development until age 25 years [16], may lead to addiction and dependency-related outcomes in the younger population [17]. While e-cigarettes are devices built predominantly to deliver nicotine, they emit harmful vapour consisting of hundreds of chemicals, including toxins with uncertain effects [17, 18], irrespective of their nicotine content. An Australian toxicological review identified 243 unique chemicals, including known poisons and banned substances, in non-nicotine e-cigarette liquids. Among these, carbonyls such as formaldehyde, acetaldehyde and acrolein, which are linked to adverse health outcomes, have been identified [19]. Furthermore, studies have voiced concerns that e-cigarette use may be associated with increased susceptibility to COPD and lung/cardiovascular diseases, and increased exposure to harmful chemicals and carcinogens [20, 21]. A recent extensive review of studies provides strong evidence demonstrating that vaping e-cigarettes could cause acute (short-term) lung injury, poisoning, burns, seizures and adverse respiratory symptoms, particularly in youths [17, 22]. Recently in the USA, an influx of young patients hospitalised due to e-cigarette- or vaping-associated lung injury [23] has highlighted the potential public health risks.

HTPs heat tobacco instead of burning it, which is claimed by the tobacco industry to reduce levels of the harmful substances typically formed during tobacco combustion [24]. However, similar to vaping e-cigarettes, users of HTPs can still be exposed to other potentially harmful substances [1, 25]. Lower exposure levels to harmful substances in these products do not necessarily translate to lower risk of cardiovascular diseases [26]. This is due to the non-linear relationship between exposure and effects, where the duration and level of exposure play significant roles [27]. For instance, despite reduced emissions compared to traditional cigarettes, HTPs have been associated with elevated heart rate, increased blood pressure, arterial stiffness, vascular endothelial dysfunction and lung dysfunction [28, 29], which may suggest deteriorating cardiovascular and lung health [30]. Furthermore, as HTPs are relatively new to the market, their long-term health effects and risks remain unclear [31]. Although marketed as safer alternatives to traditional smoking, HTPs are not risk-free and pose an emerging public health concern.

Nicotine pouches are also marketed by the tobacco industry as harm reduction alternatives for cigarette and oral tobacco product users [9, 15]. These pouches contain nicotine salts, resulting in higher nicotine levels compared to most smokeless tobacco products [32]. However, the safety of these new products remains unclear due to limited published research. Concerns arise from emerging evidence that highlights alarmingly high nicotine contents in certain pouches, particularly regarding their potential impact on oral health [33, 34]. Additionally, carcinogenic substances in nicotine pouches have been shown to have genotoxic effects, which may contribute to tumour growth [33].

In summary, e-cigarettes, HTPs and nicotine pouches are relatively new to the market compared to conventional cigarettes. However, with the exception of ENNDS, they are addictive due to their nicotine content and, although the long-term health effects of these products are not fully understood, emerging literature suggests potential health risks for all of them.

Evidence-based positions on novel products and their role on tobacco “harm reduction”

Based on the latest evidence, the European Respiratory Society (ERS)’s positions on novel products and their role in tobacco “harm reduction” are discussed in the light of:

  • reduction of harm,
  • effects on public health, and
  • smoking cessation.

Table 1 presents a point-by-point comparison between the current statement and the previous (2019) statement [35] on tobacco harm reduction.

TABLE 1

Update of the current 2024 statement relative to the 2019 statement on tobacco harm reduction

Reduction of harm

Position 1: Despite the tobacco industry’s claims of so called “harm-reduction”, there is legitimate concern regarding the potential long-term health risks of novel products. The ERS maintains its stance that the claim that novel products are less harmful lacks robust independent scientific support and is instead simply exploited and misused by the tobacco industry for commercial gain [1, 14]. As noted above, these products are relatively new compared to conventional cigarettes, and our understanding of their long-term health effects remains limited. However, since the 2019 ERS statement was published [35], new evidence has accumulated, indicating potential adverse effects on respiratory and cardiovascular function contributing to the development of chronic respiratory and cardiovascular diseases in humans [17, 20, 36]. Given there is no safe level of exposure to these substances, the ERS position remains that all nicotine or tobacco products inherently carry risks, particularly considering their uncertain long-term health impact.

Position 2: Much of the evidence about harm reduction comes from the cigarette industry itself, which has a track record of manipulating science to further its financial interests. Driven by commercial objectives, the tobacco industry has a vested interest in claiming that novel products have reduced risks. The tobacco industry has a well-documented history of deception, exemplified by a series of deliberate actions since the 1950s: denial of the smoking–lung cancer link [37], followed by claims of reduced harm from filter cigarettes [38], then promoting “healthier” alternatives such as “light” and “mild” cigarettes despite contradicting evidence [39]. This pattern highlights the industry’s consistent prioritisation of profits over public health concerns.

Emerging evidence underscores the necessity to scrutinise the industry’s novel product science, notably their attempts to influence the scientific debate in favour of novel products and “harm reduction”. Recent reviews of these products revealed that many pro-harm reduction studies were industry-funded and exhibit substantial risk of bias [36, 40]. Independent research is crucial for obtaining reliable information on the safety and risks of these products, enabling a more unbiased understanding of their “harm reduction” potential and impact on public health [17, 36].

Effects on public health

Position 3: Even assuming that novel nicotine and tobacco products may present lower risks for individual users than smoked tobacco, they can cause net harm at a population level. While evidence suggests that some novel products could potentially lower individual risks for heavy smokers who have been unsuccessful in quitting using other evidence-based methods [36, 41, 42], it is crucial to consider the potential harm they may pose at the population level, especially among nicotine- or tobacco-naïve individuals and the younger population.

Without strong regulation, the availability and promotion of novel and emerging products may lead to initiation of tobacco use among non-smokers. Similarly, it could prevent smokers from quitting completely, or lead to dual or poly product use, significantly contributing to the global burden of tobacco [43, 44].

The ERS emphasises the importance of carefully assessing the use of novel tobacco products in tobacco control, considering potential risks and their long-term “net” impact on population health. As a result, the ERS maintains a cautious stance and does not recommend the use of novel products.

Position 4: Increasing evidence shows that novel tobacco and nicotine products constitute gateways towards nicotine addiction and the initiation of smoking among youth. The emergence of novel nicotine and tobacco products raises concerns about addiction and health risks among young people [15]. Evidence suggests that non-smoking youths who use e-cigarettes could increase their chance of using cigarettes in later life [45, 46]. Furthermore, the appealing flavours and advertisements associated with these products play a significant role in steering adolescents towards nicotine addiction. A recent review of 189 studies on vaping e-cigarettes also concluded that non-smoking youths who use e-cigarettes have substantially higher likelihood of starting smoking [17]. Although gathering evidence on the causal nature of this association is challenging, the ERS recognises the harmful health effects and gateway potential of e-cigarettes towards cigarette smoking, particularly among young people [18].

Position 5: Failure to consider contextual factors may result in population-wide harm from novel nicotine and tobacco products. Harm reduction at the population level should consider contextual variations in tobacco control across countries, taking into account factors such as product accessibility, legislation and policies, user profiles, and the stages of the tobacco epidemic [47].

Under specific controlled circumstances, such as in countries with low smoking prevalence and in clinical settings, some of these products may offer potential risk reduction for heavy smokers who would not otherwise quit smoking [48]. However, the regulatory landscape for these products, as well as the broader context, varies from country to country. This heterogeneity introduces potential adverse effects at the population level. Novel products, if not regulated effectively, could renormalise tobacco and nicotine use, impede smoking cessation initiatives and attract new generations of nicotine consumers, leading to addiction and the normalisation of smoking.

In light of these complexities, adherence to the “precautionary principle” is crucial for the tobacco control community. This principle emphasises proactive measures in the face of potential harm to human health or the environment, even when causative relationships lack full scientific consensus [49]. By embracing this principle, the tobacco control community ensures vigilant regulation of these products, prioritising public health while minimising potential harm.

Smoking cessation

Position 6: Quitting smoking entirely is the best option. Recent research has examined the use of e-cigarettes to aid heavy smokers in quitting in clinical settings [41, 42]. While some instances show their effectiveness, particularly in high-income countries such as the UK [48], uncertainties persist regarding their effectiveness outside clinical settings, the overall balance of risks and benefits, and the long-term health impact of novel products for those who continue using them after they have quit smoking.

The ERS maintains a firm position that all nicotine and tobacco products are highly addictive and harmful. For current smokers, complete cessation of all nicotine products is the recommended goal to achieve freedom from addiction and reduce tobacco-related diseases [1, 35]. Furthermore, promoting complete cessation is the optimal public health strategy for increasing quit rates and reducing smoking consumption. Consequently, the ERS does not support the use of these devices as replacement therapy for current smokers; when cessation aids are required, it is preferable to use evidence-based interventions, such as nicotine replacement therapy (NRT) or tobacco cessation medications [50].

Position 7: Evidence suggests novel tobacco and nicotine product users often engage in dual or poly tobacco product use, instead of fully replacing conventional cigarettes for harm reduction or cessation. The tobacco industry’s claim of “harm reduction” is based on the unfounded assumption that smokers will replace conventional cigarettes completely with novel products. However, many continue to smoke or use cigarettes concurrently as dual or poly users [44, 51], risking higher exposure to toxicants and nicotine dependence [52]. This trend is evident from population-based studies, which highlighted a large proportion of novel product users who were also concurrent cigarette smokers (dual or poly users) [51, 53, 54].

Position 8: There is no evidence of hardening (high dependence and low motivation to quit) among the smoking population over time, and the tobacco industry’s claim that existing tobacco control measures are ineffective is misleading. The tobacco industry has misleadingly exploited the concept of “harm reduction”, suggesting that complete nicotine and tobacco cessation is not always possible or desired by the users [35]. However, recent evidence has shown that there is no hardening of smoking populations, and instead indicates a shift towards lighter smoking patterns over time [55–57]. The 2020 Eurobarometer data revealed that over 51% of current smokers in the EU had attempted to quit, with the majority of users doing so without aids [51]. Furthermore, smoking prevalence in EU member states has declined over the last decade, leading to a reduction in daily smokers [58]. These findings challenge the industry’s claims and highlight the effectiveness of tobacco control policies in reducing tobacco use and promoting smoking cessation worldwide.

Conclusions

The ERS Tobacco Control Committee draws the conclusion that we still lack sufficient independent evidence to support the tobacco industry’s so-called “harm reduction” claims. All these nicotine products remain highly addictive and harmful. We must not allow the industry to exploit these products and undermine the existing implementation of the Framework Convention on Tobacco Control at any level. Reducing tobacco use and protecting youth from addiction to emerging products that may normalise tobacco use should be a top priority.

The EU prioritises tobacco control for disease prevention and aims for a “tobacco-free generation” by 2040. Consequently, the ERS does not recommend any lung-damaging products and cannot recommend harm reduction as a population-based strategy to reduce smoking and aid quitting.

Novartis data presented at ERS showcases once-daily COPD portfolio and further demonstrates efficacy of Ultibro® Breezhaler® (QVA149) .

Posted by

0


 

  • BLAZE study also demonstrated significant improvements in shortness of breath with QVA149 compared to tiotropium 18 mcg in patients with moderate-to-severe COPD[3]

 

  • SPARK study showed similar rates of reduction in exacerbations with once-daily Seebri® Breezhaler®(glycopyrronium bromide) and open-label tiotropium 18 mcg in patients with severe-to-very severe COPD[4],[5]

 

Novartis announced today new analyses of data for once-daily Ultibro® Breezhaler®(investigational QVA149 – indacaterol 85 mcg/glycopyrronium 43 mcg delivered dose, equivalent to 110 mcg/50 mcg metered dose per capsule), which showed significant improvements in lung function, shortness of breath and health-related quality of life for chronic obstructive pulmonary disease (COPD) patients versus all comparators[1],[2].These data were part of 39 respiratory abstracts presented at the European Respiratory Society (ERS) Annual Congress in Barcelona, Spain.

 

First results from a pooled analysis of 4,891 COPD patients in the IGNITE clinical trial program (SHINE, ILLUMINATE and SPARK studies) showed that QVA149 provided superior, rapid and sustained improvements in lung function, and significantly reduced shortness of breath, compared to placebo, once-daily indacaterol maleate 150 mcg,glycopyrronium 50 mcg, open-label (OL) tiotropium 18 mcg and twice-daily salmeterol/fluticasone fixed dose combination (FDC SFC) 50 mcg/500 mcg[1],[2]. These improvements were maintained throughout the duration of the trials[1],[2].

 

“COPD is known to affect an estimated 210 million people worldwide[6] and is projected to be the third leading cause of death by 2020[7].Many patients find COPD symptoms really tough to cope with – even if they’re already taking treatment,” said Tim Wright, Head of Development, Novartis Pharmaceuticals. “Novartis is pleased that these new analyses further support that the efficacy of dual therapy, which has the potential to make a real difference to peoples’ lives.”

 

Currently being assessed in a clinical trial program involving over 10,000 patients[8]-[18], investigational QVA149 is a Fixed-Dose Combination (FDC) of two bronchodilators, Onbrez® Breezhaler® (indacaterol maleate), a long-acting beta2-adrenergic agonist (LABA) and Seebri® Breezhaler® (glycopyrronium bromide), a long-acting muscarinic antagonist (LAMA). Both are currently used by healthcare professionals as individual therapies to treat COPD.

 

QVA149 recentlyreceived a positive opinion for approval from the European Medicine Agency’s (EMA) Committee for the Human use of Medicinal Products (CHMP) in July 2013 as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.

 

About additional data presented at ERS

A new evaluation of patients with moderate-to-severe COPD from the BLAZE study showed that QVA149 provided significant improvements in patient-reported shortness of breath compared to tiotropium 18 mcg[3].

 

Clinical data for Seebri® Breezhaler® (glycopyrronium bromide) presented at ERS included efficacy and safety results from the SPARK study[4],[5]. At Week 64, once-daily glycopyrronium 50 mcg showed similar efficacy to OL tiotropium 18 mcg in reducing the rate of exacerbations, improving lung function and health-related quality of life, and reducing rescue medication use in patients with severe-to-very severe COPD[4].

 

In analyses from the SPARK study, glycopyrronium 50 mcg (via Breezhaler®) showed a safety profile in patients with severe-to-very severe COPD that was similar to OL tiotropium 18 mcg (via HandiHaler®)[5].

 

These results build upon the data previously presented from the glycopyrronium bromide Phase III GLOW trials and provide further evidence for Seebri® Breezhaler® as a once-daily LAMA option for COPD patients.

 

About the IGNITE clinical trial program

In the Phase III IGNITE clinical trial program, QVA149 is being investigated for the treatment of COPD patients as aninhaled, once-daily, FDC of indacaterol maleate and glycopyrronium bromide. IGNITE is one of the largest international clinical trial programs in COPD comprising 11 studies in total (ILLUMINATE, SHINE, BRIGHT, ENLIGHTEN, SPARK, BLAZE, ARISE, BEACON, RADIATE, LANTERN, FLAME) with more than 10,000* patients across 52 countries[8]-[20]. The first eight studies (ILLUMINATE, SHINE, BRIGHT, ENLIGHTEN, SPARK, BLAZE, ARISE, BEACON) completed in 2012. The studies are designed to investigate the efficacy, safety and tolerability, lung function, exercise endurance, exacerbations, shortness of breath and quality of life in patients treated with QVA149.

 

Results from the Phase III IGNITE trials[8]-[18]demonstrated statistically significant improvements in bronchodilation with QVA149 versus comparator treatments widely used as current standards of care[21]. Data showed that QVA149 significantly improved bronchodilation compared to OL tiotropium 18 mcg, SFC 50 mcg/500 mcg, indacaterol maleate 150 mcg, glycopyrronium 50 mcg and placebo providing a rapid onset within five minutes, and sustained bronchodilation during a 24 hour period which was maintained for up to 26 weeks[22]. In the IGNITE Phase III trial program, QVA149 also showed symptomatic improvements versus placebo in COPD patients[8],[9],[11],[21]. These symptomatic improvements included shortness of breath, exercise tolerance, rescue medication use and health-related quality of life[8],[9],[11],[21].

 

In clinical studies, QVA149 demonstrated an acceptable safety profile with no meaningful differences between the treatment groups (placebo, indacaterol 150 mcg, glycopyrronium 50 mcg, OL tiotropium 18 mcg, SFC 50 mcg/500 mcg) in the incidence of adverse and serious adverse events[8],[9],[10],[11],[22].

 

*Total refers to all 11 IGNITE studies.

 

About the Novartis COPD portfolio

Novartis is committed to addressing the unmet medical needs of COPD patients and improving their quality of life by providing innovative medicines and devices.

 

Onbrez® Breezhaler® (indacaterol maleate) is a long-acting beta2-adrenergic agonist (LABA) that offers clinically relevant 24 hour bronchodilation combined with a rapid onset of action within five minutes at first dose, as demonstrated in the INERGIZE Phase III trial program[23]-[27]. Onbrez® Breezhaler® 150 mcg once-daily provided greater clinical benefit in terms of reduced shortness of breath, lower use of rescue medication and improved health status, compared with blinded tiotropium bromide 18 mcg in patients with moderate-to-severe COPD[34]. Onbrez®Breezhaler®is approved in approximately 100 countries around the world for maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD[38]. It was first launched in the EU (150 mcg and 300 mcg once-daily doses) and has since received approvals in markets worldwide including Japan (Onbrez® Inhalation Capsules 150 mcg once-daily) and US (ArcaptaTM NeohalerTM 75 mcg once-daily).

 

Once-daily Seebri® Breezhaler® (glycopyrronium bromide) is a novel inhaled long-acting muscarinic antagonist (LAMA; also referred to as a long-acting anticholinergic) indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD[39]. Glycopyrronium bromide was exclusively licensed to Novartis in April 2005 by Vectura and its co-development partner Sosei. Phase III data from the GLOW 1, 2 and 3 studies demonstrated that glycopyrronium 50 mcg delivered rapid and significant sustained improvements in lung function (measured by mean FEV1) from Day 1 compared with placebo and sustained this for 24 hours over 52 weeks, and significantly improved exercise endurance versus placebo[40]-[42]. Seebri® Breezhaler® is approved in the EU/EEA, Japan, Switzerland, Canada, Australia and a number of other countries.

 

Novartis continues development of respiratory products for delivery via a single-dose dry powder inhaler (SDDPI) called the Breezhaler® device which has low air flow resistance, making it suitable for patients with different severity of airflow limitation[43]. The Breezhaler® device allows patients to hear, feel and see that they have taken the full dose correctly[39].

 

Novartis is committed to addressing the unmet medical needs of COPD patients and improving their quality of life by providing innovative medicines and devices.

 

About COPD

COPD is a progressive life-threatening disease that makes it hard to breathe, with symptoms that have a destructive impact on patients’ function and quality of life[7],[44]. It affects an estimated 210 million people worldwide[7] and is projected to be the third leading cause of death by 2020[6]. COPD is often considered to be a disease of later years, but estimates suggest that 50% of those with COPD are now less than 65 years old, resulting in increases in absenteeism, premature retirement and reductions in workforce participation

Source: Novartis Newsletter.

Mannose-binding lectin and innate immunity in bronchiectasis.

Posted by

0


Pathogenic microorganisms often thrive in the inflammatory milieu of the bronchiectatic airway where innate and adaptive defence mechanisms can be impaired. Although genetic defects of the adaptive immune system causing immunodeficiency syndromes are well characterised, genetic defects that impair the recognition of microbes by the innate immune system have only recently been identified.1 For example, polymorphisms in the gene for mannose-binding lectin (MBL), a receptor of the innate immune system that recognises microbial carbohydrates, can lead to deficiency of MBL and increased susceptibility to infection.

When the lungs are exposed to a new pathogen, the first line of defence is the innate immune system, which results in a swift and semi-specific response. Cells of the innate immune system, which include dendritic cells and macrophages, recognise highly conserved structures called pathogen-associated molecular patterns (PAMPs) that are shared by large groups of microorganisms. PAMPs are recognised by pattern-recognition receptors, which activate the cells of the innate immune system to rapidly attack and kill microbes.2

MBL is a soluble pattern-recognition receptor that is synthesised in the liver and is released into the systemic circulation as a component of the acute-phase response. It is not produced locally in the lungs and is thought to leak into the airways and alveoli from the systemic circulation, particularly in the presence of inflammation.3 MBL binds to various respiratory pathogens including Haemophilus influenzae and Pseudomonas aeruginosa, which are commonly identified in the airways of patients with bronchiectasis, and enhances the killing of these organisms by activation of the lectin complement pathway and by facilitating phagocytosis by opsonisation.4

In The Lancet Respiratory Medicine, James Chalmers and colleagues report a large, prospective study5 assessing the relation between MBL deficiency and clinical outcomes during a 4 year follow-up of patients with non-cystic fibrosis bronchiectasis. 55 (12%) of 470 patients with bronchiectasis had genotypes associated with MBL deficiency. These patients had more frequent exacerbations and were more likely to be chronically colonised with bacteria, particularly by P aeruginosa, than were patients with genotypes not associated with MBL deficiency. One strength of the study was the measurement of both MBL deficient genotypes and serum concentrations, which were strongly correlated. Serum MBL deficiency (<200 ng/mL) was also associated with increased exacerbation frequency.

The results of Chalmers and colleagues’ study5 are consistent with the findings from studies of patients with cystic fibrosis in which MBL deficiency has been associated with increased severity of disease. In patients with cystic fibrosis, MBL deficiency results in earlier acquisition of P aeruginosa, reduced pulmonary function, and increased mortality.6 However, a retrospective study7 of patients with non-cystic fibrosis bronchiectasis reported no association between low MBL concentrations and exacerbation frequency. Several conflicting results have also been published from studies8 assessing the association between low levels of MBL and acute exacerbations of chronic obstructive pulmonary disease.

What are the clinical implications of Chalmers and colleagues’ study? The study provides evidence that MBL deficiency is a new risk factor for infection and acute exacerbations in patients with non-cystic fibrosis bronchiectasis. Identification of patients at high risk of development of severe disease could direct clinicians to undertake more intensive management and follow-up of these patients with a view to reducing rates of hospital admission and mortality. Such stratification is increasingly relevant because of the growing range of treatments that is emerging for bronchiectasis. These treatments include long-term azithromycin, nebulised gentamicin, inhaled mannitol, inhaled dry powder ciprofloxacin, and nebulised liposomal ciprofloxacin. Recombinant human MBL might also become a treatment option, after it was reported in a phase 1 study9 to be safe, well tolerated, and able to restore activity of the lectin pathway of complement.

A standard definition of clinically significant MBL deficiency is not presently available but a diagnostic approach that incorporates both serum concentrations and genotyping seems sensible. Some patients with genotypes that are not associated with deficiency can still have very low MBL serum concentrations and, alternatively, serum concentrations can increase with the acute-phase response. One pragmatic approach analogous to that recommended by the American Thoracic Society and European Respiratory Society for α1-antitrypsin deficiency might be for clinicians to initially measure the serum concentration of MBL in patients with bronchiectasis. If the serum level is low, genotyping could then be undertaken. A cutoff of 200 ng/mL, as used in the study by Chalmers and colleagues, classified 19% of patients with bronchiectasis as MBL deficient. Better access to testing facilities and further studies are required to confirm the findings of the present study5before testing for MBL deficiency becomes routine practice in non-cystic fibrosis bronchiectasis. The present findings also raise some interesting questions for future research. MBL deficiency is relatively common in the general population and does not seem to predispose to an increased risk of infection in the absence of other predisposing factors. How do other predisposing factors interact with MBL deficiency to increase the risk of infection and cause severe disease or poor longitudinal outcomes in bronchiectasis? Could serial MBL concentrations in serum and sputum be used as markers for early detection of exacerbations or determination of the duration of antibiotic treatment? Does azithromycin interact with MBL to improve phagocytic activity in macrophages? Although some evidence suggests that azithromycin increases mannose receptor (a pattern-recognition receptor in the same family as MBL) expression and phagocytic activity in alveolar macrophages, the effect of azithromycin on MBL expression is unclear.

Source: lancet

bronchie