RESPIRE INSPIRE › wp-content › uploads › 2016 › ... · 2017-05-08 · fungal infection. It is one of the most common upper respiratory tract infections, affecting an estimated

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Upper respiratory tract infections (URTI) represent the major cause of general medicine consultations and an important eco-nomic burden in terms of healthcare costs and indirect costs (work absenteeism...). URTI refers to acute infections involving the nose, paranasal sinuses, pharynx, larynx and trachea, but also the ear and eardrum, which have a direct link with the sinuses. URTIs range in seriousness from the common cold to life-threatening illnesses such as epiglottitis. If most of these pathologies are of viral origin, they are frequently overlapped and complicated by a bacterial surinfection that often requires antibiotherapy: acute respiratory infections are responsible for the largest number of antibiotic prescriptions. The principle and modes of action of Polyvalent Mechanical Bacterial Lysates (PMBL) used as oral vaccines indicate that they represent a safe and valuable solution to help prevent the recurrence of URTI, as shown by various clinical studies. These effects appear to be mediated through an activation of both acquire and innate immune response in at risk patients.

The main URTIs: causes and prevalence Viruses cause most URTIs, with rhinovirus, parainfluenza virus, coronavirus, adenovirus, respiratory syncytial virus, coxsackievirus, and influenza virus accounting for most cases (1). However, primary viral infections are frequently overlapped and complicated by a bacterial surinfection (see table 1 for a non-exhaustive list of major pathogens involved in URTI). This phenomenon has been partly explained by the fact that viral infections facilitate bacterial colonisation by modifying the local defence mechanisms of the respiratory tract, and by inducing some changes in the cell membrane that have for effect to facilitate the adhesion of bacteria (2).

OTITISOtitis is a general term for infection or inflammation of the ear, usually bacterial (98%) (3) and occasionally fungal or viral. Ear infections do not spread from person to person and they most commonly occur as a surinfection following a cold. Antibiotics are often used to treat ear infections.

Different forms of otitis can be found :

> Otitis externa (acute, chronic or malignant) which involves the outer ear and ear canal. > Otitis media (acute, chronic, with effusion) which involves the middle ear with a localisation

just behind the eardrum. The usual symptomatic presentation is known as acute otitis media and is often characterised by fever, irritability, otorrhea, letargy, vomiting, diarrhoea and

Oct. 2012

P o l y v a l e n t M e c h a n i c a l B a c t e r i a l L y s a t e

FOCUS ON...RESPIRE INSPIRE

UPPER RESPIRATORY TRACT INFECTIONS

C o n t e n t s

The main URTIs: Causes and prevalence 1Otitis 1Rhino-sinusitis 2Tonsillitis 2Pharyngitis 2Laryngitis 3Epiglottitis 4

Focus on 3 major culprits: S. pneumoniae, S. aureus, H. influenzae 4How bacterial lysates can help? 5

What is PMBL? 5Potential modes of action of PMBL in URTI 5

Clinical efficacy 6

References 9

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hearing loss in some children. Otitis media is the second most common childhood disease and it can occur at any age.

> Otitis interna (Labyrinthitis) is an inflammation of the inner ear when bacteria move from the naso-pharynx to reach the level of the alignment of the ear.

The annual incidence of acute otitis externa is between 1/100 and 1/250 of the general popu-lation (4) and 256/1000 for acute otitis media in European children under 5 years (5).

Rhino-sinusitisRhino-sinusitis (or sinusitis) is an inflammation or infection of the lining of the sinus cavities (fig.1), triggered by a viral, bacterial or fungal infection. It is one of the most common upper respiratory tract infections, affecting an estimated 16% of the US adult popula-tion. In Europe, acute sinusitis affects an estimated 2 %, and chronic rhino-sinusitis 10 % of the adult population (6).

Sinusitis can be:

> Acute, which is usually caused by a bacterial infection in the sinuses that results from an upper respiratory tract infection.

> Sub-acute or chronic, which refers to long-term swelling and inflammation of the sinuses that may be caused by bacteria (such as Staphylococcus aureus; see boxed text) or fungus and may involve allergy, environmental factors (pollution…).

Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the most common organisms that cause the bacterial superinfection of viral acute sinusitis. Acute bacterial sinusitis develops in 0.5% to 2% of cases of viral URIs. Approximately 20 million cases of acute sinusitis occur annually in the United States.

TonsillitisTonsillitis is an inflammation of the glands of the throat. It is mostly caused by viruses, and, in 10 to 30 % of cases, by bacteria. The tonsils are two glands located in the back of the throat that help to protect the body from upper respiratory infections. In Europe, the prevalence in community studies is estimated to 2-4 % (20 000 - 40 000 individuals per million population) (7).

Tonsillitis is mainly transmitted from one person to another by social contact, by droplets in the air from sneezing. The symptoms of tonsillitis are essentially fever, sore throat, pain when swallowing, headache. In some cases, complications are possible, they include cervical adenitis and tonsil abscess.

PharyngitisPharyngitis is defined as an infection or irritation of the pharynx and/or tonsils.

Most cases are of viral origin, and with few exceptions these illnesses are both benign and self-limited. The most important bacterial cause is the beta-hemolytic group A Streptococcus (GABHS) that causes 5% to 10% of cases of pharyngitis in adults (8). Other less common causes of bacterial pharyngitis include group C beta-hemolytic Streptococci, Corynebacte-rium diphtheriae, Neisseria gonorrhoeae, Arcanobacterium haemolyticum, Chlamydia pneu-moniae, Mycoplasma pneumoniae, and herpes simplex virus. Other causes include allergy, trauma, toxins, and neoplasia

Acute pharyngitis is one of the most common illnesses for which patients visit primary care physicians. Acute pharyngitis accounts for 1% to 2% of all visits to outpatient and emergency departments, resulting in 7 million annual visits by adults alone (1). Pharyngitis occurs with much greater frequency in the pediatric population. Approximately 15-30% of pharyngitis cases among school-aged children in the cooler months are due to GAS. Only 10% of adult cases of pharyngitis are due to GAS (9).


URTI

Figure 1: The sinuses.

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LaryngitisLaryngitis (10) is an inflammation and swelling of the larynx, characterized by voice loss and irritation of the vocal cords.

There are two types of laryngitis : acute or chronic.

> Acute laryngitis is usually caused by an infection that inflames the vocal cords, but may also be caused by voice overuse with excess talking, singing or shouting. It usually lasts for less than 7 days.

> Chronic laryngitis lasts over a week and comes back over time. It can be caused by : - Acid reflux, which leads to laryngeal inflammation and chronic cough (known as Gas-troesophageal reflux disease). - Irritation, due for example to allergies, smoke, prolonged alcohol use or excess coughing.

Rarely, chronic laryngitis can provoke cancer of the throat and tumor on the vocal cords.

The most common cause of laryngitis is an infection, which could be either viral (the main virus being Rhinovirus), bacterial and rarely of fungal origin.

OTI

TIS

MAIN PATHOGENS

BACTERIA VIRUSES FUNGI

Pseudomonas aeruginosa Staphylococcus aureus Streptococcus pneumo-niae Haemophilus influenzae Moraxella catarrhalis Mycoplasma pulmonis Streptobacillus moniliformis

Candida

RHIN

O-S

INU

SITI

S

Streptococcus pneumo-niae (30-35%), Haemophilus influenzae (20-25 %) Moraxella catarrhalis (20%) Staphylococcus aureus

Rhinovirus Influenza A and B Parainfluenza Coronavirus (primary pathogens) Respiratory Syncytial Virus Adenovirus Enterovirus

Aspergillus Alternaria Bipolaris Curvularia species

TON

SILL

ITIS

Staphylococcus aureus Streptococcus pyogenes Staphylococcus pneumoniae Mycoplasma pneumoniae Chlamydophila pneumoniae

Adenovirus Rhinovirus Influenza Coronavirus Respiratory Syncytial Virus Epstein-Barr Virus Herpes Simplex Virus Cytomegalovirus, or HIV

LARY

NG

ITIS Moraxella catarrhalis

Haemophilus influenzae Streptococcus pneumonia Staphylococcus aureus Klebsiella pneumoniae

Rhinovirus Parainfluenza Virus Respiratory Syncytial Virus Influenza Adenoviruses

Candida species Histoplasma capsulatum Blastomyces dermatitis Cryptococcus neoformans.

EPIG

LOTT

ITIS Haemophilus influenzae

Streptococcus pneumo-niae Staphylococcus aureus

Herpes Simplex virus type 1 Parainfluenza virus

Candida Aspergillus

Table 1: Main causative agents of upper respiratory tract infections .

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EpiglottitisEpiglottitis is an inflammation of the epiglottis. When it becomes infected and inflamed, it can swell and obstruct or close off the windpipe, which may be fatal unless promptly treated.

Conditions that cause epiglottitis include infectious, chemical and traumatic agents :

> Infectious causes are the most common, classically with Haemophilus influenzae, but also from other potential pathogens.

> Other types of epiglottitis that are environmental and not caused by infection include heat damage that may injure the epiglottis, called thermal epiglottitis and in rare instance, epi-glottitis may be caused by allergic reactions to food.

Focus on 3 major culprits…Streptococcus pneumoniaeThis Gram positive anaerobic encapsulated bacteria is a major human pathogen implicated in RTI (pneumonia, otitis media, acute sinusitis), but also other infections.

The external capsular polysaccharide of the bacterium is the primary factor of virulence. S. pneumoniae serotyping is based on the nature of these polysaccharides: 91 serotypes have been defined. The distribution of disease-causing serotypes varies between geo-graphic regions and by age and disease within regions. Approximately 90% of the most frequent isolates belong to 23 serotypes and have been included in the 23-valent pneumococcal vaccine.

The only natural reservoir of S pneumoniae is the human nasopharynx, from which it can be transmitted through respiratory droplets to other individuals. Virtually every child in the world is colonised with one or more strains of S pneumonia, and becomes a carrier during his first years of life. According to WHO, In some developing countries, as for example Southern India, 50% of infants have been colonised by S . pneumoniae by 2 months of age and 80% are carriers by the age of 6 months. In industrialised countries, carriage occurs on average at about six months of age. In most cases carriage is asymptomatic. Infection occurs when the bacteria translocate from the nasopharynx to other organs. Based on the fact that most infections do not occur after pro-longed carriage but follow the colonisation by new serotypes, it seems that its pathogenicity depends on the host immune status at the moment of colonisation, and the virulence of the particular strain (11).

Although all age groups may be affected, the highest rate of pneumo-coccal diseases occurs in young children and in the elderly population.

Staphylococcus aureus This facultative anaerobic Gram-positive coccal bacterium is the most common species of staphylococcus to cause infections. S. aureus can cause a range of illnesses, from minor skin infections, to life-threate-ning diseases such as pneumonia, meningitis, osteomyelitis, endocardi-tis, toxic shock syndrome (TSS), bacteremia, and sepsis.

S. aureus is frequently found as part of the normal skin flora on the skin and nasal passages: an estimated 20% of the human population are long-term carriers of S. aureus, while around 60% are designated

as intermittent carriers (12). Its virulence is linked to a combination of bacterial immuno-evasive strategies. One of these strategies is the production of carotenoid pigment staphyloxanthin, which is responsible for the characteristic golden colour of S. aureus colonies. This pigment acts as a virulence factor, primarily by being a bacterial antioxidant which helps the microbe evade the reactive oxygen species which the host immune system uses to kill pathogens (13,14)

S. aureus is still one of the five most common causes of nosocomial infections and is often the cause of postsurgical wound infections. Methicillin-resistant S. aureus, or MRSA, is one of a number of greatly feared strains of S. aureus which have become resistant to most antibiotics. MRSA strains are most often found associated with insti-tutions such as hospitals, but are becoming increasingly prevalent in community-acquired infections. It is also a common cause of the main URTIs: otitis, rhino-sinusitis, laryngitis etc.

Haemophilus influenzae Haemophilus influenzae is a gram negative coccibacillus that affects only humans. Two main categories of H. influenzae are defined by the presence of external capsule. There are six generally recognised types of encapsulated H. influenzae, called serotypes: a, b, c, d, e, and f. Serious infections are usually caused by the capsulated forms. The capsule is recognised as a major factor of virulence: it allows resis-ting phagocytosis and complement-mediated lysis in the non-immune host. The unencapsulated strains are almost always less invasive, but can however produce an inflammatory response. Unencapsulated H. influenzae causes ear infections (otitis media), and sinusitis in children, and is associated with pneumonia.

Most strains of H. influenzae are opportunistic pathogens. In infants and young children, H. influenzae type b (Hib) causes bacteremia, pneu-monia, and acute bacterial meningitis. On occasion, it causes cellulitis, osteomyelitis, epiglottitis, and infectious arthritis. Haemophilus influen-zae is the most common etiologic agent associated with epiglottitis. Hib remains a major cause of lower respiratory tract infections in infants and children in developing countries where the vaccine is not widely used. Moreover, the Hib vaccines, which has been initially developed to protect children from meningitis, does not provide protection against the unencapsulated forms which cause ear infections and sinusitis.

Photo provided by CD

C-C

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Photo provided by CD

C- C

redit: J. H. Carr

Figure 2 : Correlation between clinical response and significant increase of specific IgA, IgG and IgM directed

against PMBL antigens in patients following PMBL treatment. (Braido et al. 2011)

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How bacterial lysates 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 lysates* (PMBL) is a blend of the most common pathogens involved in infections of the upper and lower respiratory tract (13 strains), obtained by mechanical lysis. It has recently been shown that PMBL, thanks to their preserved antigenic structures are 10-100 times more effective to trigger an immune response than polyvalent chemical lysates (15).

The advantage of PMBL also resides in its mode of administration. PMBL is formulated in sublingual tablets. The sublingual route of administration of bacterial lysates has been pro-posed as a safer and effective immunotherapy to stimulate strong and long-lasting systemic and mucosal antigen-specific humoral and cell-mediated immunity. Sublingual route of administration induces as well a satisfactory antibody barrier of mucosal IgA, this is impor-tant as it allows acting as first line of defence in preventing infections (16).

Potential modes of action of PMBL in URTIURTI prevention certainly represents one of the primary targets of PMBL which contains the main bacterial pathogens involved in URTI, including 6 different serotypes of S. pneumoniae:

> Staphylococcus aureus, > Streptococcus pyogenes, > Streprococcus oralis (viridans), > Streprococcus pneumoniae (6 different serotypes), > Klebsiella pneumoniae, > Klebsiella ozaenae, > Haemophilus influenzae serotype B, > Neisseria (Moraxella) catharralis.

There is a strong body of evidence in favour of its clinical efficacy in patients with recurrent URTI, or RURTI (see section 4), and several studies have been conducted to illustrate their potential modes of action. These studies indicate that PMBL is able to modulate both arms of the immune response: the specific, antibody mediated and cellular immune responses.

In 2006, after a previous in vitro study showing PMBL efficacy to acti-vate immune cells (17), Lanzilli et al. published a human study aimed at investigating PMBL mode of action in URTI in vivo (18). This study was performed in a group of patients with a medical history of RURTI. They received the standard PMBL treatment for three months and the study included a further three months follow-up period.

Immunological parameters were followed to be correlated with cli-nical outcome:

> Level of memory B lymphocytes, > Activated IL2 receptor-expressing lymphocytes (CD25+) in blood.

IL2 is important in the survival, growth and development of the immune response, cells involved in both specific and non specific response are sensitive to IL2 ad express IL2 receptors.

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It was found that positive clinical outcome (significant reduction of acute and recurrent URTI) in patients was correlated with the activation and enhancement of IgM memory B lymphocytes and CD25+ B cells and mononuclear cells, involved in both specific and innate immunity.

Moreover, these immunostimulating effects were persistent during the 3 months following the treatment period, indicating a vaccination-like effect. This was consistent with the obser-ved clinical outcome in URTI and confirmed the PMBL course of administration (3 months cure, once or twice a year).

In a more recent clinical study in URTI patients, immunology expert F. Braido has shown a strict correlation between clinical outcome and the induction by PMBL of a specific locore-gional (salivary) functional immune response in at risk patients (19). In this study, the level of salivary IgG and/or IgA and /or IgM directed against pathogens present in the PMBL prepara-tion was increased in 82% of responsive patients who received PMBL. Salivary IgAs represent the most important Immunoglobulins class involved in the defence against the infections of the upper respiratory tract, especially as they act as a first barrier of defense (Fig. 2).

In the responsive patients, it was also shown that the locoregional Ig had the capacity of effectively opsonizing live pathogens.

This study showed that PMBL treatment was able to trigger an efficient and well-targeted immune-response resulting in positive clinical outcome in UTRTI patients. Braido et al. argue that patients with RURTI are usually characterized by a selective defect of IgA specifically directed to the surface molecules of bacteria frequently involved in URTI.

In 2004, Tricarico et al. showed the same impact on both circulating Ig (IgG +35%; IgM +86%; IgA +80 %) and salivary IgA (+110%) (20).

In another study conducted in healthy volunteers (21), Rossi et al. showed that ten days administration of PMBL was followed in the majority of subjects (8/10) by an increased titre of specific salivary IgAs.

Clinical efficacyURTI are one of the main targets of PMBL. Since the drug has been launched on the market about 20 years ago, numerous clinical studies have been published, evaluating its efficacy in the prophylaxis of lower and upper respiratory tract diseases, (see 22 for recent meta-analysis). Concerning URTI in particular, we will highlight three randomized placebo control studies conducted in adults with recurrent URTI.

The first study, directed by Macchi in 2002 (23), involved 69 at-risk subjects in total and compared sub-lingual to orally administered chemical lysates (CL). This study showed that PMBL was helpful to significantly prevent infections (see Study 1), both after the 3-month treatment and 3 month follow-up period. For all para-meters observed, PMBL had a superior efficacy to CL (fig. 3). It is noteworthy to mention that in the PMBL group there was no resort to antibiotics at all, contrarily to the other groups (fig. 4). This pilot study lead the investigators to conclude that “the new product undoubtedly represents a further means of prevention of infectious pathologies of the upper airways thanks to its ability to reduce the number of infectious processes and improve their course in subjects at risk. A more rapid resolution of the episode of infection and/or its prevention proves to be highly advantageous also in terms of pharmacoeconomics repercussions.”

The same team published in 2005 another similar study involving

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Figure 3: Effect of the different treatments (PMBL= polyvalent mechanical bacterial lysates : CL= polyvalent

chemical bacterial lysates) on the duration of URTI episodes in patients (Macchi et al. 2002).

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a larger number of patients (24), that confirm their initial conclusions (Study 2): again, PMBL showed a significant effect on URTI prevention, reducing both the number (fig. 5) and duration (fig. 6) of infectious episodes, as well as their severity and socioe-conomic impact as shown by a reduction of work absenteeism and antibiotic use. These effects persisted during a three month fol-low-up period and was significantly superior to those of chemical lysates administered orally.

In the meantime, another placebo controlled study conducted in a confined community population with recurrent URTI (20) showed a significant effect of PMBL on the rate of infectious episodes (pri-mary end-point) and their duration both during and at the end of the 3-month treatment (Study 3). In addition, the severity of symptoms was also reduced for the main symptoms: there was a marked reduction inthe number of patients showing symptoms of infection (fig. 7) : nasal obstruction, rhynorrhea, otodinia, pharyngodinia and cough, as compared to the placebo group.

Approximately 79% of the patients showed an improvement of one

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• Randomized trial, PMBL vs. non treated control and oral chemical lysates.

• Study duration: 6 months: 3 months treatment + 3 months follow up.

• 69 patients with a history of 4 URTI episodes/year, randomized in 3 groups (non treated control, PMBL, PCBL).

• Treatment regimen: daily administration of PMBL (sublingual administration) or PCBL(orally) for 10 consecutive days X 3 months.

• Primary end-points: frequency of episodes during treatment period and follow-up.

• Secondary end-points: severity of episodes, quality of life (QOL), pharmacoeconomic impact (antibiotherapy, days off work, need for other therapy).

• Primary endpoint: significant reduction of the number of infectious episodes vs. control, and a trend towards reduction vs. chemical lysates (NS), both at the end of treatment and of the follow-up period.

• The duration of episodes was significantly shorter with PMBL, as compared to control and CL, both after the treatment and follow-up period.

• Work absenteeism was also significantly lower with the lysates as compared to control.

• No patients required antibiotic treatment with PMBL, while in the control and Chemical lysates groups there was respectively 13 and 6 patients out of 23 who needed antibiotherapy.

• No side-effects reported; excellent compliance.

“The results obtained demonstrated that although chemical lysates has prophylactic efficacy against episodes of URTI in subjects at risk, the overall analysis of the data indicate that PMBL exerts a more effective protective action...it can be hypothesized taht this difference of efficacy could be related to the greater specificity of action of PMBL as compared to PCBL, due in turn to the difference in the techniques used for their preparation”.

STUDY 1EFFICACY AND TOLERABILITY OF BACTERIAL LYSATES BY MECHANICAL LYSIS IN THE PROPHYLAXIS OF EPISODES OF INFECTION OF THE RESPIRATORY TRACT(MACCHI 2002)

STUDY DESIGN

RESULTS

CONCLUSION

• Randomized trial, PMBL vs. non treated control and oral chemical lysates (CL)


• 114 patients with a history of 4 URTI episodes/year, randomized in 3 groups (non treated control, PMBL, CL).

• Treatment regimen: daily administration of PMBL(sublingual administration) or CL (orally) for 10 consecutive days X 3 months.

• Primary objective: number of acute episodes during treatment + follow-up period.

• Secondary objectives: number of patients free from disease, duration of infectious episodes, number of working days lost, need for antibiotics, safety.

• During the treatment and follow-up period: significantly less URTI episodes with PMBL vs. Control and CL. CL effect was not significant.

• The number of patients free from any URTI was also significantly lower with PMBL as compared to the 2 other groups.

• Duration of episodes was significantly reduced with PMBL vs. CL and Control during the whole trial period.

• Work absenteeism was significantly lower with PMBL during both periods.

• No patients had the need for antibiotics in the PMBL group vs. 23,7% with CL during the whole study.

• Patients compliance was optimal with PMBL.• No adverse effects reported.

“These results confirm the importance of PMBL for an effective prevention of respiratory infections in patients at risk, and this is associated with an improvement in their quality of life and a reduced economic impact on the community”.

STUDY 2OPEN COMPARATIVE RANDOMIZED CONTROLLED CLINICAL STUDY OF A NEW IMMUNOSTIMULATING BACTERIAL LYSATE IN THE PROPHYLAXIS OF URTIS. (MACCHI 2005)

STUDY DESIGN

RESULTS

CONCLUSION

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bacterial lysates) on the number of patients who needed antibiotic treatment during the study (Macchi et al. 2002).

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or more of the evaluated symptoms. The same study also indicated that this prophylaxis effect is linked to a raise in immunosurveillance: a statis-tically significant increase of serum immunoglo-bulin and salivary IgA was observed in the PMBL treated subjects as compared to baseline; on the contrary no significant differences were obser-ved in the placebo group. Again, these effects were maintained in the three-month follow-up.

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Figure 6 : Effect of PMBL and chemical lysates on the duration of URTI episodes in patients (Macchi et al. 2005).

• Placebo controlled randomized trial.• Study duration: 6 months in total: 3 months trial

+ 3 months follow-up.• 47 patients (cloistered nuns, aged 25-80),

randomized in 2 groups.• 2 groups: 23 PMBL, 24 Placebo• Treatment regimen: daily administration of

PMBL for 10 consecutive days X 3 months.• Primary objective: number of infections• Secondary objective: duration of episodes• Significantly less episodes of RURTI in PMBL

group both during (after 1 month) and at the end of treatment (Fig. 7).

• Duration of episodes decreased in PMBL group both during (after 1 month) and at the end of treatment

• 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 at risk subjects“.

STUDY 3PREVENTION OF RURTI IN A COMMUNITY OF CLOISTERED NUNS USING A NEW IMMUNOSTIMULATING BACTERIAL LYSATE

(TRICARICO 2004 )

STUDY DESIGN

RESULTS

CONCLUSION

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Figure 5: Effect of PMBL & chemical lysates on the mean number of URTI episodes per patient (Macchi et al. 2005).

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URTI

References1 Cooper RJ, Hoffman JR, Bartlett JG, et al: Principles of appropriate antibiotic use for acute pharyngitis in adults: Background. Ann Intern Med. 2001, 134: 509-517.2 Palmieri G.. Prophylaxis of airways viral infections: role of the enhancement of the immune defences. GIORN. IT.MAL. TOR., 57, 1, 46-51, 20033 Alter S. J., Vidwan N. K., Sobande P. O., Omoloja A. , and Bennett J. S. Common childhood bacterial infection Curr Probl Pediatr Adolesc Health Care 2011;41:256-2834 Rosenfeld R.M., Brown L., Cannon C. R.et al. Clinical practice guideline: Acute otitis externa Otolaryngology–Head and Neck Surgery (2006) 134, S4-S235 Liese J. & al. Incidence of acute otitis media in European children under 5 years: results of a prospective observational cohort study 2009 6 Fokkens W., LundV., Mullol J. European Position Paper on Rhinosinusitis and Nasal Polyps 2007. Rhinology 45; suppl. 20: 1-139.7 Fox K. Et al. The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology Guidelines on the management of stable angina pectoris : full text- ESC Guidelines 2006 European Heart Journal doi:10.1093/eurheartj/ehl0028 Poole MD, Portugal LG. Treatment of rhinosinusitis in the outpatient setting. Am J Med. 2005, 118: 45S-50S.9 Alcaide ML, Bisno AL. Pharyngitis and epiglottitis. Infect Dis Clin North Am. 2007 Jun;21(2):449-69, vii.10 Dworkin JP. Laryngitis: types, causes, and treatments. Otolaryngol Clin North Am. 2008 Apr;41(2):419-36, ix.11 de Velasco E. A. , Verheul A. F. M., Verhoef J., and Snippe H. Streptococcus pneumoniae: Virulence Factors, Pathogenesis, and Vaccines. Microbiological Reviews, Dec. 1995, p. 591–60312 Kluytmans J., Van Belkum A., Verbrugh H. Nasal Carriage of Staphylococcus aureus: Epidemiology, Underlying Mechanisms, and Associated Risks. Clin. Microbiol. Rev. 1997, 10(3):505.13 Clauditz A., Resch A., Wieland K. P., et al. Staphyloxanthin Plays a Role in the Fitness of Staphylococcus aureus and Its Ability To Cope with Oxidative Stress. Infect. Immun. 2006, 74(8):495014 Liu GY, Essex A, Buchanan JT, Datta V et al. (2005). Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity. J Exp Med 202 (2): 209–15. 15 Morandi B, Agazzi A, D’Agostino A, Antonini F, Costa G, Sabatini F, Ferlazzo G, Melioli G.. 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. 2011 Jul;138(1):86-9116 Cazzola M, Capuano A, Rogliani P, Matera MG. Bacterial lysates as a potentially effective approach in preventing acute exacerbation of COPD. Curr Opin Pharmacol. 2012 Jun;12(3):300-8. 17 Lanzilli G, Falchetti R, Tricarico M, Ungheri D, Fuggetta MP. In vitro effects of an immunostimulating bacterial lysate on human lymphocyte function. Int J Immunopathol Pharmacol. 2005 Apr-Jun;18(2):245-54.18 Lanzilli G, Falchetti R, Cottarelli A, Macchi A, Ungheri D, Fuggetta MP. In vivo effect of an immunostimulating bacterial lysate on human B lymphocytes. Int J Immunopathol Pharmacol. 2006 Jul-Sep;19(3):551-9.19 Braido F, Schenone G, Pallestrini E, Reggiardo G, Cangemi G, Canonica GW, Melioli G. The relationship between mucosal immunoresponse and clinical outcome in patients with recurrent upper respiratory tract infections treated with a mechanical bacterial lysate. J Biol Regul Homeost Agents. 2011 Jul-Sep;25(3):477-85.20 Tricarico D. et al. Prevention of Recurrent Upper Respiratory Tract Infections in a Community of cloistered Nuns Using a New Immunostimulating Bacterial Lysate Arzneimittelforschung 2004; 54(1) :57-63.21 Rossi GA, Peri C, Raynal ME, Defilippi AC, Risso FM, Schenone G, Pallestrini E, Melioli G. Naturally occurring immune response against bacteria commonly involved in upper respiratory tract infections: analysis of the antigen-specific salivary IgA levels. Immunol Lett 2003; 86:85-91.22 Cazzola M, Anapurapu S, Page CP. Polyvalent mechanical bacterial lysate for the prevention of recurrent respiratory infections: a meta-analysis. Pulm Pharmacol Ther. 2012 Feb;25(1):62-8.23 Macchi A., Spriano G.. Efficacy and tolerability of bacterial lysates by mechanical lysis in the prophylaxis of episodes of infection of the respiratory tract. Open, randomised, pilot clinical study versus bacterial lysates by chemical lysis and control group (non treated). 2002- internal report.24 Macchi A, Vecchia LD. Open comparative, randomized controlled clinical study of a new immunostimulating bacterial lysate in the prophylaxis of upper respiratory tract infections. 2005 Arzneimittelforschung;55(5):276-81.

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• Randomized trial, PMBL vs. non treated control and oral chemical lysates.


• 69 patients with a history of 4 URTI episodes/year, randomized in 3 groups (non treated control, PMBL, PCBL).

• Treatment regimen: daily administration of PMBL (sublingual administration) or PCBL(orally) for 10 consecutive days X 3 months.

• Primary end-points: frequency of episodes during treatment period and follow-up.

• Secondary end-points: severity of episodes, quality of life (QOL), pharmacoeconomic impact (antibiotherapy, days off work, need for other therapy).

• Primary endpoint: significant reduction of the number of infectious episodes vs. control, and a trend towards reduction vs. chemical lysates (NS), both at the end of treatment and of the follow-up period.

• The duration of episodes was significantly shorter with PMBL, as compared to control and CL, both after the treatment and follow-up period (Fig. 1).

• Work absenteeism was also significantly lower with the lysates as compared to control.

• No patients required antibiotic treatment with PMBL, while in the control and Chemical lysates groups there was respectively 13 and 6 patients out of 23 who needed antibiotherapy (Fig. 2).

• No side-effects reported; excellent compliance.“The results obtained demonstrated that although chemical lysates has prophylactic efficacy against episodes of URTI in subjects at risk, the overall analysis of the data indicate that PMBL exerts a more effective protective action...it can be hypothesized taht this difference of efficacy could be related to the greater specificity of action of PMBL as compared to PCBL, due in turn to the difference in the techniques used for their preparation”.

STUDY 1EFFICACY AND TOLERABILITY OF BACTERIAL LYSATES BY MECHANICAL LYSIS IN THE PROPHYLAXIS OF EPISODES OF INFECTION OF THE RESPIRATORY TRACT(MACCHI 2002)

STUDY DESIGN

RESULTS

CONCLUSION

0

5

10

15

20

25

Treatment Follow -up

Tota

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RTI (

days

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Control

CL

PMBL

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*

(3 months)(3 months)

- 52%

- 65%

- 26%

- 48%



bacterial lysates) on the duration of URTI episodes .

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PMBL

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6

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bacterial lysates) on the number of patients who needed antibiotic treatment during the whole study

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• Randomized trial, PMBL vs. non treated control and oral chemical lysates (CL).


• 114 patients with a history of 4 URTI episodes/year, randomized in 3 groups (non treated control, PMBL, CL).

• Treatment regimen: daily administration of PMBL (sublingual administration) or CL (orally) for 10 consecutive days X 3 months.

• Primary objective: number of acute episodes during treatment + follow-up period.

• Secondary objectives: number of patients free from disease, duration of infectious episodes, number of working days lost, need for antibiotics, safety.

• During the treatment and follow-up period: significantly less URTI episodes with PMBL vs. Control and CL (Fig. 1). CL effect was not significant.

• The number of patients free from any URTI was also significantly lower with PMBL as compared to the 2 other groups.

• Duration of episodes was significantly reduced with PMBL vs. CL and Control during the whole trial period (Fig. 2).

• Work absenteeism was significantly lower with PMBL during both periods.

• No patients had the need for antibiotics in the PMBL group vs. 23,7% with CL during the whole study.

• Patients compliance was optimal with PMBL.

• No adverse effects reported.

“These results confirm the importance of PMBL for an effective prevention of respiratory infections in patients at risk, and this is associated with an improvement in their quality of life and a reduced economic impact on the community”.

STUDY 2OPEN COMPARATIVE RANDOMIZED CONTROLLED CLINICAL STUDY OF A NEW IMMUNOSTIMULATING BACTERIAL LYSATE IN THE PROPHYLAXIS OF URTIS.(MACCHI 2005)

STUDY DESIGN

RESULTS

CONCLUSION

Control

CL

PMBL

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5

10

15

20

25

30

35

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Dur

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URT

I (to

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umbe

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- 17%

- 57%


*

- 18%

- 56%

Figure 2 : Effect of PMBL and chemical lysates on the dura-tion of URTI episodes in patients (Macchi et al. 2005).

Control

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0,4

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0,8

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1,2

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1,6

1,8


Mea

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r of U

RTI/

pati

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- 19%


* *

- 72%

- 41%

- 73%

Figure 1: Effect of PMBL & chemical lysates on the mean number of URTI episodes per patient (Macchi et al. 2005).

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• Placebo controlled randomized trial.• Study duration: 6 months in total: 3 months trial

+ 3 months follow-up.• 47 patients (cloistered nuns, aged 25-80),

randomized in 2 groups.• 2 groups: 23 PMBL, 24 Placebo• Treatment regimen: daily administration of PMBL

for 10 consecutive days X 3 months.• Primary objective: number of infections• Secondary objective: duration of episodes• Significantly less episodes of RURTI in PMBL

group both during (after 1 month) and at the end of treatment (Fig. 1).

• Duration of episodes decreased in PMBL group both during (after 1 month) and at the end of treatment

• Marked reduction in the number of patients showing symptoms of infection (Fig. 1).

• 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 at risk subjects“.

STUDY 3REVENTION OF RURTI IN A COMMUNITY OF CLOISTERED NUNS USING A NEW IMMUNOSTIMULATING BACTERIAL LYSATE (TRICARICO 2004 )

STUDY DESIGN

RESULTS

CONCLUSION

% o

f pat

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s su

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th

e sy

mpt

oms

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10

20

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Nasal obstruction

Rhynorrhea Otidinia Pharyngodinia Cough

Symptoms

Placebo

PMBL

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4

6

8

10

12

14

16

18

Total nbr of infections

Num

ber of infections

**

* P< 0.05; ** P< 0.001

*****

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Figure 1: Effect of a 3-month PMBL treatment on the reduction of symptoms and infection rate in patients with RURTI (Tricarico et al., 2004).

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RESPIRE INSPIRE › wp-content › uploads › 2016 › ... · 2017-05-08 · fungal infection. It is one of the most common upper respiratory tract infections, affecting an estimated