RESPIRE INSPIRE FOCUS ON... SUMMER RESPIRATORY INFECTIONS. Polyvalent Mechanical Bacterial Lysate. June 2017

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1 FOCUS ON... SUMMER RESPIRATORY INFECTIONS June 17 Polyvalent Mechanical Bacterial Lysate Risks of respiratory tract infections are not limited to wintertime Seasonality is a well-known phenomenon in public health. Climatic changes (temperature, humidity, precipitation) can affect the development and transmission of certain pathogens and influence life style and behaviors, which can also play a role in the transmission of certain diseases. This is particularly true in the summer, often associated with specific respiratory tract infections in children and adults. Respiratory tract infections are not limited to winter because: > > Important temperatures variations (air-conditioning) can be associated to rhinitis, throat infections etc. > > Streptococcus pneumonia is more contagious in summer than in winter > > Frequentation of swimming pools increases the risks of otitis externa (according to WHO, Staphylococcus aureus is frequent in recreational waters, especially when there is a high density of bathers) > > Rhinoviruses are the most frequently isolated viruses in the summer > > Most viruses thrive under warm, humid conditions, while they can be dormant in winter (e.g. rhinoviruses, influenza, enteroviruses etc.) > > In COPD patients, there is a second peak of acute exacerbation episodes in summer > > Seasonal rhinitis have soared in recent decades and could affect today as much as % of the adult population in industrialized countries % carriage of bacteria and viruses in healthy populations LALLEMAND PHARMA 1 /FOCUS LETTER (Adapted from Coughtrie et al., 17) Summer (N = 115) Winter (N = 75) Figure 1 : Carriage of bacteria and viruses in nose swabs detected by real-time PCR in both children & adults (%) (from Coughtrie et al. 17)

2 Bacterial infections in the summer Bacteria account for up to 25% of upper respiratory tract infections, they are also responsible for otitis. If bacteria of the upper respiratory tract are usually more common in the winter, their presence in summer should not be neglected, and certain bacteria have shown increased spreading rate in the summer (1) (Fig. 1): > > Streptococcus pneumoniae is the etiology of many diseases including pneumonia, meningitis, otitis media, and sinusitis. In a study in children attending a daycare unit, it was shown that, even though S. pneumonia was more frequent in winter, its spreading rate was the highest during the summer. The strains isolated in summer differed from the winter strains, with more transmitting characteristics. The authors concluded that to prevent infections in closed crowded areas, the summer months should not be overlooked (2). > > Staphylococcus aureus, responsible for numerous infections, including otitis externa, is found in recreational waters, especially when there is a high density of bathers. This also explains its occurrence in the summer, especially in children (3). > > Haemophilus influenzae is one of the major bacterial pathogens colonising the nasopharynx and it often causes acute otitis media and sinusitis. A community study (children in day-care centers) showed a carriage rate of 38% in the summer, with nearly half of the carrier infected by an antibiotic resistant strain (4). Common summer viruses Viruses are often associated with acute respiratory infections, for example, in the summer rhinoviruses are the most common causes of acute respiratory infections. A comprehensive review of epidemiology studies on rhinovirus seasonality shows that they are the most frequently isolated viruses during the summer months (5). Since respiratory viruses are generally transmitted through inhalation or direct contact with respiratory aerosols or secretions, the environment (temperature, humidity, UV) plays a crucial role on their survival and transmission. This would be the case of rhinoviruses, but also respiratory non polio enteroviruses, influenza A etc. > > Respiratory non polio enteroviruses are responsible for what are known as summer colds. In the Northern hemisphere, they thrive between June and October (1, 6). They spread in aerosols, through coughing and sneezing. Respiratory infections with enteroviruses cause mild upper respiratory symptoms, sore throats, rashes and other symptoms beyond the common cold s typical headache, hacking cough, congestion and low fever. Summer colds often last longer and have a higher chance of recurring as compared to winter colds, mostly caused by rhinoviruses. > > Influenza A appears to be both more prominent and more virulent in summer. Epidemiology studies under sub-tropical climates (7) show two seasonal peaks, one in winter/ spring and one in summer in most years. They suggested that hot and humid conditions were associated with a higher activity of influenza. > > Adenoviruses are responsible for many infections, including respiratory, ocular and enteric infections or pneumonia. An extensive review of recreational water-borne viral outbreaks from reported adenovirus as the second leading cause of waterborne virus outbreaks, present in 24% of these outbreaks, essentially in pools (8). Summer COPD exacerbations In patients with Chronic Obstructive Pulmonary disease (COPD), it is known that acute exacerbation episodes (AECOPD), which contribute to the disease progression and morbidity, follow a seasonal pattern, with peaks in winter but also in summer. Indeed, exacerbations are mainly linked to infections and as we have seen, many respiratory tract pathogens show 2 /FOCUS LETTER

3 a peak in summer. Moreover the environment plays an important role on acute exacerbations and air pollution is another important factor. It has been estimated that up to 9% of admissions with AECOPD may be due to atmospheric pollution during the summer months (9). A European study focusing on virus-induced AECOPD also indicate strong seasonality. They showed that summer was the second season (after winter) with 25.7% of infections in summer and that most of rhinovirus infections occurred in July (). A study carried out in Hong Kong (11) has also noticed two peaks of viral infections in AECOPD patient, during spring and summer (Figure 2). Total samples Influenza A Influenza B % of positive samples No. of samples of PCR 45 Coronavirus CC43 Rhinovirus Respiratory Syncitial Virus Parainfluenza Adenovirus Metapneumovirus 5 Jan Feb Mar Apr May Jun Jul Aug Sept Oct Nov Dec Figure 2 : Viruses seasonal pattern for patients admitted with acute exacerbation of COPD (from Ko et al., Chest 7). Seasonal rhinitis Seasonal rhinitis, or hay fever, an allergic reaction triggered by pollens, is one of the most common chronic diseases in the industrialized world, and its prevalence has soared in the last decades. In adults, it is estimated to %. It is clinically defined as an IgE-mediated inflammatory response to allergens in the nasal mucosa involving a type 2 helper T cell (TH2) pathway. Symptoms include rhinorrhea, nasal obstruction, nasal itching, and sneezing. It is often associated with ocular symptoms (12). Allergic rhinitis can affect people s quality of life and can trigger asthma in certain patints. Long-term symptomatic treatments (anti-histaminic) are often necessary, linked to the duration of the pollen season. 3 /FOCUS LETTER Month

4 How PMBL can help? What is PMBL? Bacterial lysates are mixtures of bacterial antigens derived from different inactivated pathogenic bacteria. The principle of bacterial lysates is to trigger immune surveillance and to up-regulate immune defences to prevent and help fight infections. According to the method used to inactivate the bacteria, two distinct types of bacterial lysates are defined: chemical lysates and mechanical lysates. Polyvalent mechanical bacterial lysate (PMBL *) is a blend of the most common pathogens of the upper and lower respiratory tract (13 strains), obtained by mechanical lysis (Fig. 3). It has been shown that PMBL, thanks to its conserved antigenic structures, is - times more effective to trigger an immune response than polyvalent chemical lysates (13). PMBL active pharmaceutical ingredients are produced in France by Lallemand. PMBL is formulated as sublingual Figure 3: LEFT: bacterial bodies are clearly visible with mechanical lysis (particulate antigens) while chemical lysis leads to soluble tablets, easy to administer at any time and place, without the antigens (RIGHT). need for water or swallowing. As a registered drug, PMBL sublingual tablet benefits from stringent clinical evidences, together with the high safety and quality standards of the pharmaceutical industry. PMBL sublingual tablet has been marketed for close to twenty years in Europe and benefits from strict safety data monitoring. Today, it is present in more than twenty five countries worldwide. Sub-lingual route One of the advantages of PMBL resides in its mode of administration. The sub-lingual route favours the contact of the antigens with the oral mucosa (part of respiratory mucosa), and allows an effective sampling of these antigens by the dendritic cells which are numerous in this area, allowing an effective mucosal immune response. It has been shown that PMBL is able to stimulate mucosal defences (14) and increase specific salivary IgAs. PMBL is also able to stimulate the systemic immune response, increasing the levels of immune-competent cells and immunoglobulins (IgA, IgG, IgM) circulating in the blood. This systemic action allows to relay action all along the mucosa of the upper and lower respiratory tract (15). A documented mode of action Numerous post-market clinical and pre-clinical studies have been conducted to demonstrate PMBL efficacy and try to elucidate its modes of action in the prevention of respiratory diseases. One of the key words of its efficacy appears to be immunomodulation. Research has shown that PMBL is able to stimulate both types of immune response: innate and acquired. This explains its large array of applications: PMBL is effective to prevent specifically infections by common pathogenic bacteria whose antigens are included in its formulation. Moreover, thanks to its ability to illicit immunomodulation, it may also be able to prevent other pathogens, including viruses or immune disequilibrium such as allergic rhinitis. 4 /FOCUS LETTER *Ismigen, Immubron, Respibron, Provax, PIR-5

5 Clinical Results Numerous clinical studies have been published using PMBL in the prophylaxis of various lower and upper respiratory tract diseases. A meta-analysis has compiled these trials (16). We detail below (Study 1) a study conducted in a community of cloistered nuns with recurrent upper respiratory tract infections (RURTI), showing a significant effect of PMBL on ear symptoms in particular, during the 3 months of the study. At the end of the study, 43% of subjects suffered from otidinia in the placebo group vs. 8% in the PMBL group (17) (Fig. 4). In the case of COPD exacerbations (AECOPD), which show a secondary peak in the summer, it is well documented that PMBL is effective to reduce COPD exacerbations (18). This outcome leads Prof. Cazzola to suggest two annual courses of treatments in COPD patients, in winter and in summer to prevent acute exacerbations (Study 2). A pilot study was conducted in patients with % of patients suffering from the symptoms Nasal obstruction Rhynorrhea Otidinia Pharyngodinia Cough Symptoms Placebo PMBL Total nbr of infections * P<.5; P<.1 Figure 4 : Effect of a 3-month PMBL treatment on the reduction of symptoms and infection rate in patients with RURTI (Tricarico et al., 4). * Number of infections STUDY 1 PREVENTION OF RECURRENT UPPER RESPIRATORY TRACT INFECTIONS (Tricarico, 4) 5 /FOCUS LETTER STUDY DESIGN RESULTS CONCLUSION Placebo controlled randomized trial. Study duration: 6 months in total. 47 patients (cloistered nuns, aged 25-8), randomized in 2 groups. Reccurent respiratory tract infections (RURTI). Treatment regimen: daily administration of PMBL for consecutive days X 3 months. 3 months follow-up. Significantly less episodes of RURTI in PMBL group during and at the end of treatment (Fig. 4). Marked reduction in the number of patients showing symptoms of infection. 79 % of the patients showed an improvement of one or more of the evaluated symptoms. The results of this study demonstrate that PMBL is an efficacious and safe therapeutic option for the treatment and prevention of recurrent upper respiratory tract infections and that its use is recommended in subjects with a possible immune disequilibrium. Distributors are responsible for regulatory compliance in their jurisdiction.

6 allergic rhinitis (19) (Study 3). It was shown that symptoms decreased or even disappeared in the majority of patients (Fig. 5). Blood IgE levels were not affected by the treatment; the authors suggested that PMBL effect could be linked to locoregional immunomodulation of T cell response, rather than a peripheral response (mucosal Ig were not measured). Moreover, Il-4 expression decreased in some patients. The authors concluded that the great improvement of clinical conditions observed in allergic rhinitis patients following a 3 month PMBL therapy, in some patients may be accompanied by a potential immunomodulating activity by decreasing IL-4 cytokine expression. % of patients according to evolution of symptoms % 9% 8% 7% 6% % % % % % % Unchanged Improved PMBL Worsened Unchanged Improved Placebo Figure 5 : Clinical evaluation of allergic rhinitis symptoms in patients following 3 months treatment with PMBL vs. placebo (Banche et al., 7). STUDY 2 REDUCTION OF INFECTIOUS EXACERBATION IN MODERATE TO VERY SEVERE COPD (Cazzola, 6) STUDY 3 IMPROVEMENT OF CLINICAL RESPONSE IN ALLERGIC RHINITIS PATIENTS (Banche, 7) STUDY DESIGN RESULTS CONCLUSION Placebo controlled randomized trial. Study duration: 12 months. 178 patients, randomized in 2 groups. Moderate- very severe COPD. Treatment regimen: daily administration of PMBL for consecutive days X 3 months. 9 months follow-up. Significant reduction of the frequency of acute exacerbation: 215 vs. 248 cases. Significant reduction of the duration of exacerbation s (.6 vs days). Significant reduction of antibiotherapy (-27 doses used with COPD). % reduction of total hospitalization time: lower hospitalization rate (31 vs. 56 cases) and shorter hospitalization duration (8.9 vs..5 days, P<.5). No adverse effect reported. " On the basis of the important clinical results of this trial, i.e. lower incidence of exacerbations and greater efficacy of antibiotic treatment in patients immunized with bacterial lysates, it is possible to state that this therapeutic approach should always be considered in patients suffering from moderate to very severe COPD. " STUDY DESIGN RESULTS CONCLUSION Study duration: 6 months. 41 allergic rhinitis patients, randomized in 2 groups: PMBL (26 patients) and Placebo (15). Treatment regimen: daily administration of PMBL for consecutive days/month. 3 months follow-up. Significant and clinically relevant improvement in 61.5% of patients with PMBL (Fig. 5). Relevant decrease in nasal blockage and rhinorrea in 53.8% of patients; ocular symptoms almost disappeared in % of patients. Large improvement in asthmatic symptoms in 38.4% of patients. Improvement started 2-3 weeks or later after beginning of treatment for all symptoms and persisted in the follow-up period. Decreased IL-4 expression in some patients. The results of our study indicate that PMBL is effective in the treatment of allergic rhinitis ( ). The clinical data recorded during PMBL treatment probably correlate with its efficacy as both an immunostimulant agent and a vaccine capable of directly activating effector cells, hence inducing an innate protective immune response. 6 /FOCUS LETTER

7 References 1- Coughtrie AL et al., Epidemiological and ecological modelling reveal diversity in microbial population structures from a cross-sectional community swabbing study. Preprint article Jan 17 doi: 2- Abut LI et al. The characteristics of nasopharyngeal Streptococcus pneumoniae in children attending a daycare unit. New Microbiol. 8 Jul;31(3): WHO- Microbial Hazards, guidelines for safe recreational water environments-chapter 3 4- Hashida K. et al. Nasopharyngeal Haemophilus influenzae Day-Care Centers Carriage in Japanese Children Attending J. Clin. Microbiol. 8, 46(3): Monto AS. The seasonality of rhinovirus infections and its implications for clinical recognition. Clin Ther. 2 Dec;24(12): Meneghetti A. Upper Respiratory Tract Infection Medscape, Chan PK et al. Seasonal influenza activity in Hong Kong and its association with meteorological variations. J Med Virol. 9 Oct;81(): Sinclair R.G., Jones E.L. and Gerba C.P.. Viruses in recreational water-borne disease outbreaks: a review. Journal of Applied Microbiology 7 (9) Sunyer J et al. Air pollution and emergency room admissions for chronic obstructive pulmonary disease: a 5-year study. Am J Epidemiol Apr 1;137(7): Djamin RS, Uzun S, Snelders E, Kluytmans JJ, Hoogsteden HC, Aerts JG, Van Der Eerden MM. Occurrence of virusinduced COPD exacerbations during four seasons. Infect Dis (Lond). 15 Feb;47(2): Ko F. W. S. et al. Viral Etiology of Acute Exacerbations of COPD in Hong Kong. Chest 7;132; Rondón C et al. Local Allergic Rhinitis: Concept, Clinical Manifestations, and Diagnostic Approach. J Investig Allergol Clin Immunol ; Vol. (5): Morandi B et al.. A mixture of bacterial mechanical lysates is more efficient than single strain lysate and of bacterial-derived soluble products for the induction of an activating phenotype in human dendritic cells. Immunol Lett. 11 Jul;138(1): Cazzola M, Capuano A, Rogliani P, Matera MG. Bacterial lysates as a potentially effective approach in preventing acute exacerbation of COPD. Curr Opin Pharmacol. 12 Jun;12(3): Czerkinsky C et al., Sublingual vaccination, Human vaccines, Cazzola M, Anapurapu S, Page CP. Polyvalent mechanical bacterial lysate for the prevention of recurrent respiratory infections: a meta-analysis. Pulm Pharmacol Ther. 12 Feb;25(1): Tricarico D. et al. Prevention of Recurrent Upper Respiratory Tract Infections in a Community of cloistered Nuns Using a New Immunostimulating Bacterial Lysate Arzneimittelforschung 4; 54(1) : Cazzola M, et al.. Bacterial lysates as a potentially effective approach in preventing acute exacerbation of COPD, Curr Opin Pharmacol (12), doi:.16/ j.coph (in press) 19- Banche G. et al. Improvement of clinical response in allergic rhinitis patients treated with an oral immunostimulating bacterial lysate: in vivo immunological effects. Int J Immunopathol Pharmacol. 7 Jan- Mar;(1): /FOCUS LETTER Distributors For professional are responsible use only. Not for intended regulatory for compliance consumers. in Distributors their jurisdiction. are responsible for regulatory compliance in their jurisdiction.