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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
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. ( 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
Table 4 Adult trials
Adult trials
Author Year
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
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Disclosure of interest
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