Copd_990_braido.indd

Bacterial lysate in the prevention of acute exacerbation of COPD and in respiratory Abstract: Respiratory tract infections (RTIs) represent a serious problem because they are
one of the most common cause of human death by infection. The search for the treatment of those diseases has therefore a great importance. In this study we provide an overview of the currently available treatments for RTIs with particular attention to chronic obstructive pulmonary diseases exacerbations and recurrent respiratory infections therapy and a description of bacterial lysate action, in particular making reference to the medical literature dealing with its clinical effi cacy. Those studies are based on a very large number of clinical trials aimed to evaluate the effects of this drug in maintaining the immune system in a state of alert, and in increasing the defences against microbial infections. From this analysis it comes out that bacterial lysates have a protective effect; which induce a signifi cant reduction of the symptoms related to respiratory infections. Those results could be very interesting also from an economic point of view, because they envisage a reduction in the number of acute exacerbations and a shorter duration of hospitalization. The use of bacterial lysate could therefore represent an important means to achieve an extension of life duration in patients affected by respiratory diseases.
Keywords: bacterial lysate, COPD, respiratory recurrent infections
ound and introduction
Respiratory tract infections (RTIs) represent one of the most common and important causes of human disease in terms of morbidity, mortality, and economic cost to society. RTIs are the most common, and potentially the most severe, infections treated by health care practitioners. Lower RTIs, along with infl uenza, are the most common cause of death by infection in the United States. Risk factors for pneumonia and other respiratory tract infections include: extremes of age (very young and elderly), smok- ing, alcoholism, immunosuppression, and comorbid conditions (File 2000). We can distinguish two main clinical manifestations of relevant impact: acute exacerbations of chronic bronchitis (AECB), and recurrent respiratory infections (RRI).
Recurrent respiratory infections (RRI) are characterized by at least three episodes of fever, locoregional infl ammation, cough, asthma, wheezing without severe impair- ment of respiratory functions. This syndrome is frequent both in pediatric and in adult patients accounting for the principal cause of absence from school and work during winter time. RRI involve both upper and lower respiratory tract and are caused by a wide panel of microorganisms. In particular, viral infections, caused by infl uenza viruses, parainfl uenza viruses, respiratory syncitial virus, adenovirus, rhinoviruses are Allergy and Respiratory Diseases, DIMI, Pad. Maragliano, L.go R. Benzi 10, 16132 the original cause of the disease but recurrences are also caused by bacteria, including Acinetobacter spp., Chlamydia pneumoniae, Enterobatteriacee, Hemophilous infl u- Tel +39 010 555 3524Fax +39 010 353 8904 enzae, Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Nocardia asteroids, Pasturella multocida, Pseudomonas aeruginosa, Staphylococcus International Journal of COPD 2007:2(3) 1–11 2007 Dove Medical Press Limited. All rights reserved aureus, Stenotrophomonas maltophilia, Straphylococcus purulence development (named the “Anthonisen’s aureus, Streptococcus pneumoniae and Streptococcus pyo- criteria”) (Anthonisen NR 1987) There is considerable heterogeneity in the character, frequency, and time course Chronic obstructive pulmonary disease (COPD) is a state of COPD exacerbations, which cannot be accounted for characterized by airfl ow limitation that is not fully reversible. solely on the basis of degrees of airway obstruction or The airfl ow limitation is usually both progressive and associ- ated with an abnormal infl ammatory response of the lungs The lower airways of 25% to 50% of COPD patients are to noxious particles or gases. A diagnosis of COPD should colonized by bacteria, especially noncapsulated Haemophi- be considered in any patient who presents with symptoms of lus infl uenzae, Streptococcus pneumoniae, and Moraxella cough, sputum production, or dyspnoea, and/or has a history catarrhalis (Anthonisen et al 1987) (Cabello 1997).
of exposure to the risk factors for the disease. Clinical symp- The predominant bacteria recovered in the lower air- toms and signs, such as an abnormal shortness of breath and ways of patients with mild exacerbations are H. infl uenzae, increased forced expiratory time, can be used to help with S. pneumoniae and M. catarrhalis, whereas in severe COPD the diagnosis. Chronic cough and sputum production often requiring mechanical ventilation gram negative bacilli, and precede the development of airfl ow limitation by many years; P. aeruginosa are more frequent (Papi et al 2006) Lower although not all individuals with cough and sputum produc- airway bacterial colonization is increasingly recognized as tion go on to develop COPD. The classifi cation of Severity an independent stimulus to airway infl ammation (Sethi et al is shown in Table 2. The pathogenesis of COPD is charac- 2001) It can modulate the character and frequency of COPD terized by chronic infl ammation throughout the airways, parenchyma, and pulmonary vasculature. Macrophages, A signifi cant role in the aetiology of acute exacerbations T lymphocytes (predominately CD8), and neutrophils are of chronic bronchitis seems to be played also by viruses, increased in various parts of the lung. Infl ammation of the responsible of almost 40% of the exacerbations. (Seemungal lungs is caused by exposure to inhaled noxious particles and gases. Cigarette smoke can induce infl ammation and directly damage the lungs. Pathologic changes in the lungs Pharmacological treatments:
lead to corresponding physiologic changes characteristic of systemic overview
the disease, including mucus hypersecretion, ciliary dys- The currently available treatments for COPD therapy function, airfl ow limitation, pulmonary hyperinfl ation, gas exchange abnormalities, pulmonary hypertension, and cor pulmonale. The destruction of alveolar attachments, which inhibits the ability of the small airways to maintain patency, Bronchodilator medications are central to the symptom- plays a smaller role. In advanced COPD, peripheral airways atic management of COPD (Vathenen et al 1998; Gross obstruction, parenchymal destruction, and pulmonary vascu- et al 1989; Chrystyn et al 1988; Higgins et al 1991) lar abnormalities reduce the lung’s capacity for gas exchange, (Evidence A). They are given either on an as-needed basis producing hypoxemia and, later on, hypercapnia. Pulmonary for relief of persistent or worsening symptoms, or on a regu- hypertension, which develops late in the course of COPD lar basis to prevent or reduce symptoms. The side effects (Stage III: Severe COPD), is the major cardiovascular com- of bronchodilator therapy are pharmacologically predict- plication of COPD and is associated with the development able and dose dependent. Adverse effects are less likely, of cor pulmonale and a poor prognosis.
and resolve more rapidly after treatment withdrawal. All Patients with chronic obstructive pulmonary disease categories of bronchodilators have been shown to increase (COPD) are prone to exacerbations; which account for sig- exercise capacity in COPD, without necessarily producing nifi cant morbidity and mortality and are a key determinant signifi cant changes in FEV (Ikeda et al 1995; Guyatt et al of health-related quality of life. (Seemungal et al 1998) 1987a; Man et al 2004; O’Donnell et al 2004) (Evidence A). COPD exacerbations are defi ned as a change in the patient’s Regular treatment with long-acting bronchodilators is more chronic respiratory symptoms suffi cient to warrant a change effective and convenient than treatment with short-acting bronchodilators, but also more expensive (Mahler et al The cardinal symptoms of COPD exacerbations 1999; Dahl et al 2001; Oostenbrink et al 2002; Vincken are increase in dyspnoea, sputum volume and sputum bacterial lysate: effects on prevention of respiratory infections a reduction in the frequency of exacerbations. A Cochrane Regular treatment with inhaled glucocorticosteroids does collaborative review performed a meta-analysis of all the not modify the longterm decline of FEV in patients with available data, including those from a number of abstracts COPD (Pauwels et al 1999; Vestbo et al 1999; Burge et (Poole and Black 2003). A statistically signifi cant reduction al 2000; The Lung Health Study Research Group 2000). in the number of episodes of chronic bronchitis was found in However, regular treatment with inhaled glucocorticoste- patients treated with mucolytics compared to those receiving roids is appropriate for symptomatic COPD patients with placebo. However, those data are not easy to interpret, as an FEV <50% predicted (Stage III: Severe COPD and the follow-up ranged from 2 to 6 months and all the patients Stage IV: Very Severe COPD) and repeated exacerbations had an FEV > 50% predicted. Although a few patients with (for example, 3 in the last three years) (Mahler et al 2002; viscous sputum may benefi t from mucolytics (Siafakas et al Szafranski et al 2002; Calverley et al 2003a; Jones et al 1995 American Thoracic Society 1986), the overall benefi ts 2003) (Evidence A). This treatment has been shown to seem to be very small. Therefore, the widespread use of these reduce the frequency of exacerbations and thus to improve agents cannot be recommended on the basis of the present health status (Spencer et al 2004) (Evidence A). Withdrawal from treatment with inhaled glucocorticosteroids can lead to exacerbations in some patients. Inhaled glucocorticosteroid combined with a long-acting β -agonist is more effective Antioxidants, in particular N-acetylcysteine, have been shown than the individual components (Mahler et al 2002; Calver- to reduce the frequency of exacerbations and could have a ley et al 2003; Szafranski et al 2002; Hanania et al 2003; role in the treatment of patients with recurrent exacerbations Calverley et al 2003b) (Evidence A).
(Boman et al 1983; British Thoracic Society Research Com- mittee 1985; Rasmussen and Glennow 1988; Hansen et al 1994) (Evidence B). However, before their routine use can be recommended, the results of ongoing trials have to be carbocysteine, iodinated glycerol)The regular use of mucolytics in COPD has been evaluated in a number of long-term studies with controversial results Cough, although it is sometimes a troublesome symptom in (Allegra et al 1996; Guyatt et al 1987b; Petty 1990). The COPD, has a signifi cant protective role (Irwin et al 1998). Thus majority of the studies showed no effect of mucolytics on the regular use of antitussives is contraindicated in stable COPD lung function or symptoms, although some of them reported (Evidence D). For classifi cation of evidences, see Table 1.
Table 1 Classifi cation of evidence
Evidence
Category
Sources of evidence defi nition
Rich body of data. Evidence is from endpoints of well designed RCTs that provide a consistent pattern of fi ndings in the population for which the recommendation is made. Category A requires substantial numbers of studies involving substantial Limited body of data. Evidence is from endpoints of intervention studies that include only a limited number of patients, post hoc or subgroup analysis of RCTs, or meta-analysis of RCTs. In general, Category B pertains when few randomized trials exist, they are small in size, or they were undertaken in a population that differs from the target population of the recommendation, or the results are Observational studies. Evidence is from outcomes of uncontrolled or non randomized trials or from observational studies.
Consensus Judgment. This category is used only in cases where the provision of some guidance was deemed valuable but the clinical literature addressing the subject was deemed insuffi cient to justify placement in one of the other categories. The Panel Consensus is based on clinical experience or knowledge that does not Table 2 Classifi cation of severity according to GOLD guide-
Innate and adaptive immunity
lines. (http://goldcopd.com/ GOLD Global Iniative for Cronich modulation in preventing and
treating respiratory infection
Stage Characteristics
The potentiation of both specifi c and non specifi c immunere- sponse has been considered a central point in the treatment of recurrences in respiratory tract infections. Specifi c immunity against viruses (such as infl uenza virus) and bacteria (Strep- tococcus pneumoniae) can be raised using specifi c treatment with vaccines. This is the case of: Infl uenza vaccines; that can reduce serious illness (Wongsurakiat et al 2004) and • 50% < or = FEV < 80% predicted.
death in COPD patients by about 50% (Nichol et al 1994; Wongsurakiat et al 2003) (Evidence A). Vaccines containing killed or live, inactivated viruses are recommended (Edwards • 30% < or = FEV < 50% predicted.
et al 1994) as they are more effective in elderly patients with COPD (Hak et al 1998). The strains are adjusted each year for appropriate effectiveness and should be given once (in autumn) or twice (in autumn and winter) each year.
Pneumococcal vaccine. A pneumococcal vaccine contain- ing 23 virulent serotypes has been used (Williams and Moser 1986; Davis 1987; Simberkoff et al 1996) (Evidence B). The potentiation of non specifi c and specifi c immunere- sponse against other bacteria (such as the bacteria shown as the cause of recurrent infection of the respiratory tract), can In several large-scale controlled studies (Francis and Spicer be obtained using polyvalent bacterial lysate. This category of 1960; Francis et al 1961; Fletcher et al 1966), the prophy- drugs includes different kinds of bacterial extracts, included lactic, continuous use of antibiotics was shown to have no a different number of bacterial species (polyvalent extracts) effect on the frequency of exacerbations in COPD. Another obtained through different ways of lysis, both chemical or study examined the effi cacy of winter chemoprophylaxis over mechanical (PMBL, PCBL). We will further on discuss the a period of 5 years and concluded that there was no benefi t effects of this kind of drugs, through an analysis of Random- (Johnston et al 1969). Thus, on the present evidence, the use ized Controlled Trials published to date. of antibiotics, other than for treating infectious exacerbations of COPD and other bacterial infections, is not recommended (Isada and Stoller 1994; Siafakas Bouros 1998) (Evidence A). Characteristics of bacterial lysate
In the case of an acute exacerbation, antibiotic therapy Bacterial lysate are constituted by a mixture of bacterial signifi cantly shortens the duration of symptoms and can be antigens derived from different bacterial species, according cost-effective. Over the past 50 years, virtually all classes of to the considered extract. The more often included species antimicrobial agents have been studied in AECB. Important are: Staphylococcus aureus, Streptococcus viridans, Strep- considerations include penetration into respiratory secre- tococcus pneumoniae (6 strains), Streptococcus pyogenes, tions, spectrum of activity and antimicrobial resistance. Klebsiella pneumoniae, Klebsiella ozenae, Moraxella Those factors limit the usefulness of drugs such as amoxi- catarrhalis, Hemophylous infl uenzae. Each extract is pre- cillin, erythromycin and trimethoprim-sulfamethoxazole. pared with billions of these bacteria. Antigens are obtained Extended-spectrum oral cephalosporins, newer macrolides following a mass culture of reference bacterial strains, using and doxycycline have demonstrated effi cacy in clinical tri- a chemical or mechanical lysis of cells and lyophilization. als. Amoxicillin-clavulanate and fl ouoroquinolones should Different antigens are mixed and excipients are added in generally be reserved for patients with more severe disease. A number of investigational agents; including ketolides and Bacterial lysate is both a specific and non specific newer quinolones; hold promise for treatment of AECB. immunostimulating agent, indicated for the prevention and treatment of respiratory infections, including sequelae to bacterial lysate: effects on prevention of respiratory infections common cold and infl uenza. In particular it is useful for the All these fi ndings indicate that the maturation of dendritic treatment of acute and chronic bronchitis, anginas, tonsillitis, cells, the specifi c activation of the T and B cell population of pharyngitis, laryngitis, rhinitis, sinusitis, and otitis. It can also lymphocytes, and the resulting production of IgA in the respira- be used for infections resistant to common antibiotics and tory mucosa specifi cally directed to the antigens administered, for the sequelae to bacterial and viral infections. characterized by the capacity of opsonizing living bacteria thus The more usual treatment schedule for PMBL is the allowing their engulfment and killing in phagocytes, represent the actual pathway for the potentiation of a both non specifi c –acute events: one tablet per day to dissolve under the (dendritic cells and phagocytes) and specifi c (T and B cells) tongue, (for a minimum of ten days) until the symptoms immune-response, resulting in a prophylactic effect on recur- rent infections of the respiratory tract.
–long term treatment: one tablet per day to dissolve under the tongue for 10 consecutive days, followed by 20 days’ rest. Bacterial lysate clinical effi cacy:
The cycle is repeated for three consecutive months.
literature review
The effects of bacterial lysate as an immunostimulatory agent
Mode of action of bacterial lysate
has been debated in many clinical trials.
The capacity of a virtually intact microbe to activate By performing a simple research on PubMed directory resting monocytic-macrophage cells is strictly linked to of the terms “bacterial lysate”, and limiting the search only the presence of structures belonging to the bacterial cell to randomized clinical trials, it is possible to fi nd more than wall (for example, protido-glycane or lipopolysaccharide) thirty papers. The aim of those studies, all published during against which some receptor structures (such as the so the last twenty years, is to evaluate the effects of this class of called toll like receptors -TLR) are specific directed. TLR drugs in maintaining the immune system in a state of alert, are expressed on the surface of monocyte membrane. and in raising a fence against microbial infections, eventually The interaction between bacterial structures and TLR leading to a reduction in their number.
results in the activation of monocytes, their differentiation Those studies are very different and heterogeneous. In to immature dendritic cells and the following maturation fact the populations and samples of those trials are various, to mature dendritic cells, able to be considered a suitable being representative of diverse diseases, such as: recurrent professional antigen presenting cell. The use of bacterial respiratory infections of upper and/or lower airways; chronic antigens obtained by mechanical or chemical lysis is thus bronchitis; rhino-sinusitis and other ENT infections; chronic able to activate monocytic-macrophagic cells of the sub- obstructive pulmonary disease. Even the age of patients mucosa, inducing the differentiation through immature included is different: many trials are conducted on pediatric dendritic cells and their maturation in mature dendritic cells. The activation of such a mechanism results in a We will briefl y discuss the fi ndings of these RCTs, ana- suitable stimulation of the immune-response.
lysing them separately, according to the characteristic of the The presentation of bacterial antigens on mature dendritic cells results in the stimulation of the T cell compartment (with a consequent induction of a powerful helper function) and of the B cell compartment of the immune-response, A pilot study involving 89 children pointed out that the with a following maturation to plasmacells and secretion administration of polivalent mechanical bacterial lysate of antibodies specifi cally directed to the administered. The could lead to a signifi cant decrease in recurrent respiratory administration of bacterial lysate is thus able to induce a T infections in patients treated with this drug, compared to the helper function and a maturation of B specifi c lymphocytes controls on the same children during the previous year; also resulting in the production of IgA salivary antibodies directed phlogosis indexes were signifi cantly lower in the treated to the administered mixture of antigens.
group, and the values of B-lymphocytes were found to be The secretion of antibodies directed to bacterial antigens increased (Rosaschino and Cattaneo 2004). has a positive function only in the case of these antibodies Even in patients from 3 to 6 years of age, affected by having the capability to opsonize living bacterial cells, thus recurrent respiratory infections and IgG defi ciency, a RCT favouring the phagocytosis and the killing mediated by pro- proved the benefi cial effect of bacterial lysate (Del-Rio- fessional phagocytes, such as granulocytes. Another RCT that included 232 children aged 3–5 years, 1997; Rutishauser et al 1998; Tielemans et al 1999; Li et al showed that the treatment with PMBL signifi cantly reduced 2004; Steurer-Stey et al 2004; Tricarico et al 2004; Macchi the rate of upper respiratory tract infections, being this and Vecchia 2005), we will discuss them separately, accord- reduction higher in children affected more frequently by this ing to the disease considered (recurrent respiratory infections, kind of infections; the drug was also safe and well tolerated compared to placebo (Schaad et al 2002).
Another RCT involving 188 pediatric patients and lasting more than one year, put in evidence that the rate of infec- A recent study, a RCT involving 140 patients with a history tion was reduced of 50% in treated patients, and this was of recurrent respiratory infections, compared the effects of sustained for half a year after the end of drug administration; bacterial lysate obtained through mechanical lysis (pts in the drug reactions were few, transient, expected and non serious fi rst group) to the effects of bacterial lysate obtained through chemical lysis (pts in the second group) and to the effects of A RCT lasting one year, including 54 children aged 1–12 no treatment at all (pts in the third group, control); the end years, evaluated for the two groups of patients (active/pla- points were: the number of upper respiratory tract infections, cebo) the number of acute respiratory tract infections and the number of patients free from disease, the duration of their duration, and also the number of antibiotic courses infectious episodes, the number of working days lost because needed. The results showed a reduction in the number of of the disease, the need for antibiotic treatment. The results infections, and a more signifi cant reduction in antibiotic for each one of the end points showed the effi cacy of the two requirements and in the duration of the infection episodes in treatments, but the best results were achieved with the treat- the treated group compared to placebo (Gutierrez-Tarango ment with the bacterial lysate obtained through mechanical lysis, and were signifi cantly superior to those achieved with 56 young patients affected by subacute sinusitis were placebo and also with the bacterial lysate obtained through involved in a RCT lasting 6 months, evaluating the effects of chemical lysis (Macchi and Vecchia 2005).
bacterial lysate added to amoxicillin/clavulanate. The results A particular study evaluated the effi cacy of bacterial pointed out that the cure and improvement of the patients in lysate in preventing upper respiratory tract infections in the active group were faster, and that these patients expe- subjects belonging to a specifi c setting, that is a commu- rienced a lower incidence of respiratory infections (Gomez nity of cloistered nuns. 47 nuns were allocated into two different groups, active treatment and placebo. The results A bigger trial involving 423 children attending day-care showed a signifi cant lower number in respiratory infec- centers (subjects with a higher risk of infection) showed that, tions, and a shorter duration, in the active treatment group; during the period of treatment with bacterial lysate, treated moreover, a signifi cant increase in serum Ig and salivary children had a relative risk of 0.52 to present three or more IgA was recorded in the active treatment group (Tricarico episodes of upper respiratory infections (Collet et al 1993).
A much older study also revealed that, in children with Other trials have shown the effi cacy of bacterial lysate rhinosinusitis, the treatment with bacterial lysate decreases in treating patients with recurrent respiratory infections the incidence and duration of infectious episodes and the (Ahrens and Wiedenbach 1984; Debelic and Eckenberger number and duration of concomitant treatments; moreover, 1992; Rutishauser et al 1998 ), even in group of patients with the clinical response showed a correlation with an increase an increased risk, such as patients in hemodialysis treatment in serum levels of IgA (Zagar and Lofl er-Badzek 1989). (Tielemans 1999). A particular attention was also given to the Quite a big trial involving 825 children in the treatment investigation of the tolerability of such kind of treatments, group and 327 in the placebo one, pointed out that the ad- and the results were excellent (Ahrens and Wiedenbach 1984; ministration of a bacterial lysate applied intranasally for 6 months does not reduce the number of acute respiratory One trial (Heintz et al 1989) was designed to test the diseases compared to placebo (Sramek et al 1986).
effi cacy of bacterial lysate in treating patients suffering from Concerning the studies focused on samples of adult pa- chronic purulent sinusitis. This study, carried over on 284 tients (Ahrens and Wiedenbach 1984; Keller 1984; Heintz patients for a duration of six months, showed the effi cacy of et al 1989; Cvoriscec et al 1989; Debbas and Derenne 1990; treatment in reducing cough, purulent nasal discharge and Debelic and Eckenberger 1992; Orcel et al 1994; Collet et al headache, on the basis of the score of symptoms.
bacterial lysate: effects on prevention of respiratory infections Another, more recent, RCT (Li et al 2004) included 90 Since acute bronchitis is a major source of morbidity in patients. The considered endpoints were: the frequency of elderly patients, a RCT involving 354 patients living in acute exacerbations, symptom scores, lung function, all institutions for elderly was designed, in order to assess the recorded for one year after the end of the treatment. The effects of treatment with bacterial lysate on the incidence of results showed, in the group treated with bacterial lysate lower respiratory tract infections. A reduction of 28% was compared to the placebo group: a decrease in incidence, observed, and this was due to a 40% reduction in episodes of duration, and severity of acute exacerbation; a reduction in acute bronchitis, with no differences in the incidence of pneu- the course of antibiotics; an improvement in symptom scored monia in the two groups. During the 6 months of duration of and a higher bacterial clearance rate in sputum cultures. the trial, a larger number of patients in the active treatment Recently, a systematic review and metanalysis was pub- group didn’t experience any episode of acute bronchitis, and lished (Steurer-Stey et al 2004), investigating the use of oral a reduction in antibiotic prescription in the same group was purifi ed bacterial extracts in the treatment of patients affected by COPD. An extensive and systematic search for random- Another 104 patients affected by chronic bronchitis were ized clinical trials in all the electronic databases, biographies, involved in a RCT comparing bacterial lysate to placebo and data from manufacturers was performed. Eventually, a over a period of 6 months. The results showed a signifi cant total of 13 studies, corresponding to almost two thousands reduction of the duration of acute episodes and fever in the patients, were included in the analysis. Concerning the pre- treatment group, with a concomitant sparing-effect on the vention of exacerbations, the results showed that the main use of antibiotics, an increase in serum IgA levels and in treatment effect was found in the smaller studies, the ones T-lymphocyte counts (Cvoriscec et al 1989).
with lower quality score. As a consequence, the combination A previous, much older study (Keller 1984), evalu- of all the data results in high heterogeneity; and the difference ated the effect of bacterial lysate in patients with chronic between active extracts and placebo does not reach statistical bronchitis. The conclusions on the effects of this treatment signifi cance. The metanalysis also showed a shorter duration on clinical symptoms didn’t reach a statistically signifi cant of exacerbations in the active treatment groups. The improve- benefi t compared to placebo, and the authors advocated for ment of symptoms, as assessed both by the patients and the further studies, with more patients, and with a longer period observers; was in favour of bacterial extracts. Hospitalization admission resulted lower in the bacterial extracts group (but data were drawn only from one study) (Collet et al 1997). This systematic review clearly points out that a strong evidence One of the fi rst RCT on the use of bacterial lysate in COPD for the prevention of exacerbation in COPD patients through patients (Debbas and Derenne 1990), lasting 6 months and the use of bacterial extracts is still missing; nonetheless, an involving 265 patients, demonstrated a statistically signifi cant improvement in symptoms has been underlined, as well as reduction of infectious events, and a concomitant reduction a shorter duration of exacerbation, and a reduction of hospi- talization. Anyway, those conclusions are relevant as there A well-built RCT (Collet et al 1997) recruited 381 patients could be some important economic consequences if a reduc- with COPD and followed them for 6 months. This trial pointed tion of hospitalization can be prospected by the use of those out that the risk of having at least one exacerbation during the relatively cheap drugs, which can be applied intermittently. 6 months was similar in both groups. The most signifi cant Also a benefi t on symptoms, as perceived by the patients, is result showed a clear reduction in the total number of days of important, as a refl ection of a better quality of life.
hospitalization for respiratory problems in the group treated with bacterial lysate compared to the placebo group (642). Discussion and conclusions
Also the risk of being hospitalized was reduced for the same As we have previously reported, bacterial lysates are pow- patients group (16.2% vs 23.2%). Moreover, the number of erful inducers of a specifi c locoregional immune response deaths observed was reduced in the treatment group (2 vs 6), that signifi cantly enhance the concentration of antibodies but without statistical signifi cance. These results showed that directed to antigenic structures of bacteria most commonly immunostimulating agents could be useful for treating patients observed during infections of the upper respiratory tract. with COPD, being able to reduce the likelihood of severe Those antibodies have the capability of opsonizing living respiratory events possibly responsible for hospitalization. bacteria, thus allowing the engulfment and killing mediated Table 3 Paediatric trials
Paediatric trials
Author Year
Patients
Preparation
Table 4 Adult trials
Adult trials
Author Year
Patients
Preparation
bacterial lysate: effects on prevention of respiratory infections by human phagocytes, such as granulocytes. This activity is Acknowledgment
linked to the capacity of inducing a signifi cant reduction (or Authors thank ARMIA (Associazione Ricerca Malattie a complete disappearance) of signs and symptoms related to Immunologiche e Allergiche) for supporting the literature This effect comes out also from the systematic analysis A special mention to Dr Silvia Raco for the linguistic of medical literature, and is refl ected in the results of the randomized clinical trials. Those results underline an over- all protective effect, with a different level of signifi cance, References
depending on the study design, the disease considered, and Ahrens J, Wiedenbach M. 1984. [Effi cacy of the immunostimulant Broncho- the type of patients involved. Both in pediatric and adult tri- Vaxom] Schweiz Med Wochenschr, 114(25):932–4.
als, as reported in the Tables 3 and 4, we can fi nd a positive Allegra L, Cordaro CI, Grassi C. 1996. Prevention of acute exacerba- tions of chronic obstructive bronchitis with carbocysteine lysine salt trend in the results: a general reduction of infection rates, a monohydrate: a multicenter, double-blind, placebo-controlled trial. reduction of their duration, a benefi cial effect on symptoms, American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Those effects also have, as a direct consequence, impor- Adopted by the ATS Board of Directors, November 1986. Am Rev tant economic implications. In the case of COPD, a reduction Respir Dis, 1987, 136:225–44.
Anthonisen NR, Manfreda J, Warren CP, et al. 1987. Antibiotic therapy in the number of acute exacerbations, or a shorter duration of in exacerbations of chronic obstructive pulmonary disease. Ann Intern hospitalization, could represent an actual opportunity for cur- tailing costs of management of such patients. In fact, patients Boman G, Backer U, Larsson S, et al. 1983. Oral acetylcysteine reduces exacerbation rate in chronic bronchitis: report of a trial organized with a moderate-severe COPD can experience a mean of at by the Swedish Society for Pulmonary Diseases. Eur J Respir Dis, least 2 AECB/year (Miravitlles et al 1999). The most serious British Thoracic Society Research Committee. 1985. Oral Nacetylcysteine patients, besides experiencing more frequent exacerbations, and exacerbation rates in patients with chronic bronchitis and severe are more frequently hospitalized, and for longer periods airways obstruction. Thorax, 40:832–5.
(Donaldson et al 2002). We also have to consider that AECB Burge PS, Calverley PM, Jones PW, et al. 2000. Randomised, double blind, placebo controlled study of fl uticasone propionate in patients represent an important cause of death. A trial reported that, with moderate to severe chronic obstructive pulmonary disease: the in a sample of 1000 hospitalized patients affected by severe ISOLDE trial. BMJ, 320:1297–303.
Cabello H, Torres A, Celis R, et al. 1997. Bacterial colonization of distal COPD, when dismissed, 20% of them die within two months, airways in healthy subjects and chronic lung disease: a bronchoscopic 33% within six years, and 43% within one year. (Hilleman study. Eur Respir J, 10:1137–44.
et al 2000) The risk of death in COPD patients is strictly Calverley P, Pauwels R, Vestbo J, et al. 2003. Combined salmeterol and fl uticasone in the treatment of chronic obstructive pulmonary disease: correlated with the frequency and gravity of exacerbations. a randomised controlled trial. Lancet, 361:449–56(a).
As a consequence, it would be extremely useful to obtain a Calverley PM, Boonsawat W, Cseke Z, et al. 2003. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary reduction of exacerbations, in order to extend the life dura- disease. Eur Respir J, 22(6):912–9 (b).
tion of this kind of patients. Therefore, the use of bacterial Celli BR, MacNee W. 2004. Standards for the diagnosis and treatment of lysate could represent an important means to achieve this patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J, 23:932–46.
Chrystyn H, Mulley BA, Peake MD. 1988. Dose response relation to oral In conclusion, even though the results of the analyzed theophylline in severe chronic obstructive airways disease. BMJ, 297:1506–10.
studies are encouraging, it would be worthwhile to build up Collet JP, Ducruet T, Kramer MS, et al. 1993. Stimulation of nonspecifi c new trials. Those new trials should include a higher number immunity to reduce the risk of recurrent infections in children attend- of patients, selected according to the disease and its severity, ing day-care centers. The Epicreche Research Group. Pediatr Infect Dis J, 12(8):648–52.
and should be well-designed trials in term of blinding and Collet JP, Shapiro P, Ernst P, et al. 1997. Effects of an immunostimulat- randomization procedures. This could permit to get even ing agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease. The PARI-IS Study Steer- stronger evidence of their benefi cial effect, both on symptoms ing Committee and Research Group. Prevention of Acute Respira- tory Infection by an Immunostimulant. Am J Respir Crit Care Med, 156(6):1719–24.
Disclosure of interest
Cvoriscec B, Ustar M, Pardon R, et al. 1989. Oral immunotherapy of chronic bronchitis: a double-blind placebo-controlled multicentre study. The authors do not have any confl ict of interest related to Dahl R, Greefhorst LA, Nowak D, et al. 2001. Inhaled formoterol dry powder the pharmaceutical companies whose drugs are cited in this versus ipratropium bromide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 164:778–84.
Davis AL, Aranda CP, Schiffman G, et al. 1987. Pneumococcal infection and Heintz B, Schlenter WW, Kirsten R, et al. 1989. Clinical effi cacy of immunologic response to pneumococcal vaccine in chronic obstructive Broncho-Vaxom in adult patients with chronic purulent sinusitis — a pulmonary disease. A pilot study. Chest, 92:204–12.
multi-centric, placebo-controlled, double-blind study. Int J Clin Phar- Debbas N, Derenne JP. 1990. Preventive effects of an immunostimulating macol Ther Toxicol, 27(11):530–4.
product on recurrent infections of chronic bronchitis in the elderly. Higgins BG, Powell RM, Cooper S, et al. 1991. Effect of salbutamol and ipratropium bromide on airway calibre and bronchial reactivity in Del-Rio-Navarro BE, Luis Sienra-Monge JJ, Berber A, et al. 2003. Use asthma and chronic bronchitis. Eur Respir J, 4:415–20.
of OM-85 BV in children suffering from recurrent respiratory tract Hilleman DE, Dewan N, Maleskar M, et al. 2000. Pharmacoeconomic infections and subnormal IgG subclass levels. Allergol Immunopathol evaluation of COPD. Chest, 118:1278–85.
Ikeda A, Nishimura K, Koyama H, et al. 1995. Bronchodilating effects of Debelic M, Eckenberger HP. 1992. [Prevention of recurrent infection of the combined therapy with clinical dosages of ipratropium bromide and upper and lower airways. Multicenter, open study over three months] salbutamol for stable COPD: comparison with ipratropium bromide Fortschr Med, 110(30):565–70.
Dever LL, Shashikumar K, Johanson WG Jr. 2002. Antibiotics in the treat- Irwin RS, Boulet LP, Cloutier MM, et al. 1998. Managing cough as a ment of acute exacerbations of chronic bronchitis. Expert Opin Investig defense mechanism and as a symptom. A consensus panel report of the American College of Chest Physicians. Chest, 114:133S–181S.
Donaldson GC, Seemungal TAR, Bhowmik A, et al. 2002. Relationship Isada CM, Stoller JK. 1994. Chronic bronchitis: the role of antibiot- between exacerbation frequency and lung function decline in chronic ics. In: Niederman MS, Sarosi GA, Glassroth J, eds. Respiratory obstructive pulmonary disease. Thorax, 57:847–52.
infections: a scientifi c basis for management. London: WB Saunders, Edwards KM, Dupont WD, Westrich MK, et al. 1994. A randomized controlled trial of cold-adapted and inactivated vaccines for the preven- Johnston RN, McNeill RS, Smith DH, et al. 1969. Five-year winter chemo- tion of infl uenza A disease. J Infect Dis, 169:68–76.
prophylaxis for chronic bronchitis. Br Med J, 4:265–9.
File TM. 2000. The epidemiology of respiratory tract infections. Semin Jones PW, Willits LR, Burge PS, et al. 2003. Disease severity and the effect Respir Infect, 15(3):184–94.
of fl uticasone propionate on chronic obstructive pulmonary disease Fletcher CM, Ball JD, Carstairs LW, et al. 1966. Value of chemoprophylaxis exacerbations. Eur Respir J, 21:68–73.
and chemotherapy in early chronic bronchitis. A report to the Medical Keller R. 1984. [Multicenter double-blind study of the action of Bron- Research Council by their Working Party on trials of chemotherpay in cho-Vaxom in chronic bronchitis] Schweiz Med Wochenschr, early chronic bronchitis. BMJ, 1(5499):1317–22.
Francis RS, Spicer CC. 1960. Chemotherapy in chronic bronchitis: infl uence The Lung Health Study Research Group. 2000. Effect of inhaled of daily penicillin and teracycline on exacerbations and their cost. A triamcinolone on the decline in pulmonary function in chronic report to the research committee of the British Tuberculosis Assoication obstructive pulmonary disease: Lung Health Study II. N Engl J Med, by their Chronic Bronchitis subcommittee. BMJ, 1:297–303.
Francis RS, May JR, Spicer CC. 1961. Chemotherapy of bronchitis: infl u- Li J, Zheng JP, Yuan JP, et al. 2004. Protective effect of a bacterial extract against ence of penicillin and tetracylcline administered daily, or intermittently acute exacerbation in patients with chronic bronchitis accompanied by chron- for exacerbations. BMJ, 2:979–85.
ic obstructive pulmonary disease. Chin Med J (Engl), 117(6):828–34.
Global Initiative for Chronic Obstructive Lung Disease. Update 1 July 2005. Macchi A, Vecchia LD. 2005. Open comparative, randomized control- A collaborative project of the National Health L, and Blood Institute, led clinical study of a new immunostimulating bacterial lysate in the NIH and the World Health Organisation., ed. www.goldcopd.com: prophylaxis of upper respiratory tract infections. Arzneimittelforschung, National Institutes of Health, National Heart Lund and Blood Institute, Mahler DA, Donohue JF, Barbee RA, et al. 1999. Effi cacy of salmeterol Gomez Barreto D, De la Torre C, Alvarez A, et al.1998. [Safety and effi cacy xinafoate in the treatment of COPD. Chest, 115:957–65.
of OM-85-BV plus amoxicillin/clavulanate in the treatment of subacute Mahler DA, Wire P, Horstman D, et al. 2002. Effectiveness of fl uticasone sinusitis and the prevention of recurrent infections in children] Allergol propionate and salmeterol combination delivered via the Diskus device Immunopathol (Madr), 26(1):17–22. in the treatment of chronic obstructive pulmonary disease. Am J Respir Gross NJ, Petty TL, Friedman M, et al. 1989. Dose response to Crit Care Med, 166(8):1084–91.
ipratropium as a nebulized solution in patients with chronic Man WD, Mustfa N, Nikoletou D, et al. 2004. Effect of salmeterol on obstructive pulmonary disease. A three-center study. Am Rev Respir respiratory muscle activity during exercise in poorly reversible COPD. Gutierrez-Tarango MD, Berber A. 2001. Safety and effi cacy of two courses Miravitlles M, Mayordomo C, Artés M, et al. 1999. Treatment of chronic of OM-85 BV in the prevention of respiratory tract infections in children obstructive pulmonary disease and its exacerbations in general practice. during 12 months. Chest, 119(6):1742–8. Guyatt GH, Townsend M, Pugsley SO, et al. 1987. Bronchodilators in chron- Nichol KL, Margolis KL, Wuorenma J, et al. 1994. The effi cacy and cost ic air-fl ow limitation. Effects on airway function, exercise capacity, and effectiveness of vaccination against infl uenza among elderly persons quality of life. Am Rev Respir Dis, 135:1069–74(a).
living in the community. N Engl J Med, 331:778–84.
Guyatt GH, Townsend M, Kazim F, et al. 1987. A controlled trial of O’Donnell DE, Fluge T, Gerken F, et al. 2004. Effects of tiotropium on ambroxol in chronic bronchitis. Chest, 92:618–20(b).
lung hyperinfl ation, dyspnoea and exercise tolerance in COPD. Eur Hak E, van Essen GA, Buskens E, et al. 1998. Is immunising all patients Respir J, Jun; 23(6):832–40.
with chronic lung disease in the community against infl uenza cost Oostenbrink JB, Rutten-van Molken MP, Al MJ, et al. 2004. One-year effective? Evidence from a general practice based clinical prospective cost-effectiveness of tiotropium versus ipratropium to treat chronic cohort study in Utrecht, The Netherlands. J Epidemiol Community obstructive pulmonary disease. Eur Respir J, 23(2):241–9.
Orcel B, Delclaux B, Baud M, et al. Oral immunization with bacterial Hanania NA, Darken P, Horstman D, et al. 2003. The effi cacy and safety of extracts for protection against acute bronchitis in elderly fl uticasone propionate( 250microg)/salmeterol(50microg) combined in institutionalized patients with chronic bronchitis. Eur Respir J, the Diskus inhaler for the treatment of COPD. Chest, 124(3):834–43.
Hansen NC, Skriver A, Brorsen-Riis L, et al. 1994. Orally administered Papi A, Luppi F, Franco F, et al. 2006. Pathophysiology of exacerbations N-acetylcysteine may improve general well-being in patients with mild of chronic obstructive pulmonary disease. Proc Am Thorac Soc, chronic bronchitis. Respir Med, 88:531–5.
bacterial lysate: effects on prevention of respiratory infections Patel IS, Seemungal TAR, Wilks M, Lloy, et al. 2002. Relationship between Simberkoff MS, Cross AP, Al-Ibrahim M, et al. 1986. Effi cacy of pneumo- bacterial colonisation and the frequency, character and severity of coccal vaccine in high-risk patients. Results of a Veterans Administra- COPD exacerbations. Thorax, 57:759–64.
tion Cooperative Study. N Engl J Med, 315:1318–27.
Pauwels RA, Lofdahl CG, Laitinen LA, et al. 1999. Long-term treatment Spencer S, Calverley PM, Burge PS, et al. 2004. Impact of preventing with inhaled budesonide in persons with mild chronic obstructive exacerbations on deterioration of health status in COPD. Eur Respir pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N Engl J Sramek J, Josifko M, Helcl J, et al. 1986. Bacterial lysate (I.R.S. 19) applied intranasally in the prevention of acute respiratory diseases in children: a Petty TL. 1990. The National Mucolytic Study. Results of a randomized, randomized double-blind study. J Hyg Epidemiol Microbiol Immunol, double-blind, placebo-controlled study of iodinated glycerol in chronic obstructive bronchitis. Chest, 97:75–83.
Steurer-Stey C, Bachmann LM, Steurer, et al. 2004. Oral purifi ed bacterial Poole PJ, Black PN. 2003. Mucolytic agents for chronic bronchitis or extracts inchronic bronchitis and COPD: Systematic Review. Chest, chronic obstructive pulmonary disease. Cochrane Database Syst Rev, Szafranski W, Cukier A, Ramirez A, et al. 2002. Effi cacy and safety of Rasmussen JB, Glennow C. 1988. Reduction in days of illness after long- budesonide/formoterol in the management of chronic obstructive term treatment with N-acetylcysteine controlledrelease tablets in pulmonary disease. Eur Respir J, 21:74–81.
patients with chronic bronchitis. Eur Respir J, 1:351–5.
Tielemans C, Gastaldello K, Husson C, et al. 1999. Efficacy of oral Rosaschino F, Cattaneo L. 2004. Strategies for optimizing compliance of immunotherapy on respiratory infections in hemodialysis patients: paediatric patients for seasonal antibacterial vaccination with sublin- a double-blind, placebo-controlled study. Clin Nephrol, 51(3):153–60.
gually administered polyvalent mechanical bacterial lysates (PMBL).
Tricarico D, Varricchio A, D’Ambrosio S, Ascione E, Motta G. 2004. Acta Biomed Ateneo Parmense, 75(3):171–8.
Prevention of recurrent upper respiratory tract infections in a community Ruah SB, Ruah C, van Aubel A, et al. 2001. Effi cacy of a polyvalent of cloistered nuns using a new immunostimulating bacterial lysate. bacterial lysate in children with recurrent respiratory tract infections. A randomized, double-blind clinical trial. Arzneimittelforschung, Rutishauser M, Pitzke P, Grevers G, et al. 1998. Use of a polyvalent bacterial Vathenen AS, Britton JR, Ebden P, et al. 1998. High-dose inhaled albuterol lysate in patients with recurrent respiratory tract infections: results of a in severe chronic airfl ow limitation. Am Rev Respir Dis, 138:850–5.
prospective, placebo-controlled, randomized, double-blind study. Adv Vestbo J, Sorensen T, Lange P, et al. 1999. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary Schaad UB, Mutterlein R, Goffi n H; BV-Child Study Group. 2002. Immu- disease: a randomised controlled trial. Lancet, 353:1819–23.
nostimulation with OM-85 in children with recurrent infections of the Vincken W, van Noord JA, Greefhorst AP, et al. 2002. Improved health upper respiratory tract: a double-blind, placebo-controlled multicenter outcomes in patients with COPD during 1 yr’s treatment with tiotro- study. Chest, 122(6):2042–9.
pium. Eur Respir J, 19:209–16.
Seemungal TAR, Donaldson GC, Paul EA, et al. 1998. Effect of exacerba- Wongsurakiat P, Lertakyamanee J, Maranetra KN, et al. 2003. Economic tion on quality of life in patients with chronic obstructive pulmonary evaluation of infl uenza vaccination in Thai chronic obstructive pulmo- disease. Am J Respir Crit Care Med, 157:1418–22. nary disease patients. J Med Assoc Thai, 86(6):497–508.
Seemungal T, Harper-Owen R, Bhowmik A, et al. 2001. Respiratory viruses, Wongsurakiat P, Maranetra KN, Wasi C, et al. 2004. Acute respiratory illness symptoms, and infl ammatory markers in acute exacerbations and stable in patients with COPD and the effectiveness of infl uenza vaccination: chronic obstructive pulmonary disease. Am J Respir Crit Care Med, a randomized controlled study. Chest, 125(6):2011–20.
Williams JH, J., Moser KM. 1986. Pneumococcal vaccine and patients with Sethi S, Murphy TF. 2001. Bacterial infection in chronic obstructive chronic lung disease. Ann Intern Med, 104:106–9.
pulmonary disease in 2000: a state of the art review. Clin Microbiol Zagar S, Lofler-Badzek D. 1989. Broncho-Vaxom in children with rhinosinusitis: a double-blind clinical trial. ORL J Otorhinolaryngol Siafakas NM, Vermeire P, Pride NB, et al. 1995. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). The European Respiratory Society Task Force. Eur Respir J, 8:1398–420.
Siafakas NM, Bouros D. 1998. Management of acute exacerbation of chronic obstructive pulmonary disease. In: Postma DS, Siafakas NM, eds. Management of chronic obstructive pulmonary disease. Sheffi eld: ERS Monograph, p.264–77.

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DESIGNS ACT, 1993 DESIGNS REGULATIONS, 1999 These regulations were published under : Government Notice R843 in Government Gazette 20256 of 2 July 1999 as amended by: Government Notice R602 in Government Gazette 27713 of 1 July 2005Government Notice R988 in Government Gazette 28104 of 10 October 2005Government Notice R1182 in Government Gazette 29413 of 1 December 2006--------------

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