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
lead to corresponding physiologic changes characteristic of
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
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,
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.
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LUNDBECK AND CHEMICAL PRODUCT INVENTIONS Martin J. Adelma The English courts in Generics (UK) Ltd. v. H. Lundbeck A/S arguably decided each of the two issues raised in the case incorrectly, but the end result demonstrates that two wrongs do make a right. At its core Lundbeck raises an old but perplexing conundrum. When should an inventor of a new chemical product receive full prod
RESEARCH CONDUCTED BY THE SOUTH STAFFORDSHIRE SEXUAL HEALTH SERVICE ORAL PRESENTATION Is the Mirena suitable at any age? Moss EL, Pryce A, Kundu A. Annual Scientific Meeting of the Faculty of Family Planning and Reproductive Health Care, Newcastle, May 2006 PUBLISHED MEETING ABSTRACTS Patterns of Emergency Contraception use in Women Attending South Staffordshire Sexual Heal