Treat Respir Med 2006; 5 (5): 317-324 1176-3450/06/0005-0317/$39.95/0

REVIEW ARTICLE

© 2006 Adis Data Information BV. All rights reserved.

Role of Ribomunyl® in the Prevention of Recurrent Respiratory Tract Infections in Adults Overview of Clinical Results Jean Bousquet1 and Dario Oliveri2 1 2

Respiratory Diseases Department, A. de Villeneuve Hospital, Montpellier, France Respiratory Diseases Department, Rasori Hospital, University of Parma, Parma, Italy

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 1. Incidence of Recurrent Respiratory Tract Infections (RRTIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 2. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 4. Clinical Overview of Immunostimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 5. Immuno-Pharmacology of Ribomunyl® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319 5.1 Specific Immune Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319 5.2 Nonspecific Immune Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319 6. Clinical Efficacy of Ribomunyl® in Adults with RRTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319 6.1 Clinical Studies in the International Registration File for the Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 6.2 Meta-Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 6.3 Efficacy Studied with a Clinical Score Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 6.4 Efficacy in Chronic Bronchitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 6.5 Efficacy in Infectious Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 6.6 Efficacy of Ribomunyl® in Combination with Influenza Virus Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322

Abstract

Recurrent respiratory tract infections (RRTIs) in adults are the result of an imbalance between lung defense mechanisms, and bacterial burden. Antibacterial treatments can temporarily restore the equilibrium between host and bacterial load, but do not prevent recurrence of infection. An alternative approach to prevent recurrence of infection is treatment with an immunostimulant, which provides immune protection against repeated bacterial and viral infection. All immunostimulant products are bacterial in origin: lysates (first generation immunostimulants), or bacterial extracts, like bacterial ribosomes, or membrane proteoglycans. This review highlights the current state of knowledge regarding the use of immunostimulants in adults with RRTIs, taking the ribosomal immunostimulant Ribomunyl® as an example. Many studies are available on the mechanism of action and clinical efficacy in prevention of RRTIs in adults treated with Ribomunyl®. The effect of this immunostimulant on anti-infectious responses is explained by a stimulation of both nonspecific (innate) and specific (adaptive) immunity. In order to obtain a global overview of the therapeutic efficacy of Ribomunyl® the most pertinent trials were selected from the literature based on adequate patient numbers and good methodology. Results of double-blind placebo-controlled trials using Ribomunyl® for the treatment of different upper or lower RRTIs have demonstrated a statistically significant reduction in the number of infectious episodes and as a consequence, a decrease in antibacterial consumption, after 3 and 6 months of treatment. The tolerance profile of Ribomunyl® was good in all studies. Economic evaluations suggest that savings can be made in healthcare expenditure, in patients with recurrent episodes of infection.

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It is concluded that Ribomunyl® is effective in preventing and reducing upper and lower respiratory tract infections in adults. The product may also have an impact on reducing the development of bacterial resistance, as a result of fewer courses of antibacterials required to treat patients with RRTIs.

1. Incidence of Recurrent Respiratory Tract Infections (RRTIs) Because of their high incidence, recurrent ear, nose and throat (ENT) and bronchopulmonary infections in adults constitute a major public health problem.[1] In adults, ENT infections are common,[2] and exacerbations of COPD or chronic bronchitis are frequent; patients with chronic bronchitis experience episodes of fever, increased cough, expectoration and shortness of breath, sometimes associated with loss of days at work and social incapacity.[3] COPD is a major cause of chronic morbidity and mortality and is currently the fourth leading cause of death in the world, and further increases in its prevalence and mortality can be predicted in the coming decades.[4,5] There are different published statistics: for example, national statistics in the UK showed that in 1997 the prevalence of COPD was 1.7% among men and 1.4% among women. Between 1990 and 1997 the prevalence increased by 25% in men and 69% in women.[6] The worldwide prevalence of COPD in 1990 was estimated at 9.34/1000 in men and 7.33/1000 in women. However, these estimates include all ages and underestimate the true prevalence of COPD in older adults.[7] 2. Pathogenesis Respiratory infections in adults, in the majority of cases, are the result of an imbalance between lung defense mechanisms and bacterial load. Impaired lung defenses are usually required at first for bacterial colonization of the respiratory mucosa, but these bacteria subsequently produce factors which facilitate their persistence and spread through the bronchial tree. In healthy individuals, the host remains intact and the bacterial load remains low. However, in the event of bronchial or pulmonary epithelial damage accompanied by impaired immunity, acute infection sets in; there are sufficient bacterial numbers to overcome local host defenses which fail to cope leading to acute respiratory tract infection.[8,9] Deficits in host defense are mainly ciliary or mucociliary clearance dysfunction, epithelial damage, mucus hyper-secretion, secretory IgA deficiency, and impaired phagocytosis. After the period of acute bacterial infection and colonization, chronic infection sets in characterized by excess mucus production, fever and decreased respiratory capacity. This host inflammatory response[10] causes structural damage, which further compromises the host defense. © 2006 Adis Data Information BV. All rights reserved.

Bacteria are mainly implicated in adults with recurrent respiratory tract infections.[9] Streptococcus pneumoniae and Haemophilus influenzae are the major bacterial species involved, followed by Legionella pneumoniae, Chlamydia pneumoniae, Klebsiella pneumoniae and Moraxella catarrhalis. Studies on viruses seem to limit their importance as causative agents in respiratory infections in adults. 3. Treatment The standard therapeutic strategy for bacterial episodes (and often, sadly, for viral episodes) is the repeated use of antibacterial therapy. They restore a temporary balance between the bacterial load and host defense. However, although these antibacterials are curative in the short-term, they do not prevent recurrences or the onset of complications. There are several guidelines in this field,[11] but it is noteworthy that generally antibacterials are overprescribed to patients with upper respiratory tract infections. Indeed, the multiplicity of antibacterial prescriptions plays an unquestionable role in the growing incidence of bacterial resistance to antibacterials.[12-14] In the US the Center for Disease Control (CDC) estimates that between 20% and 50% of antibacterial prescriptions are inappropriate.[15] In this context, bacterial immunostimulants may have a role to play in the treatment of recurrent respiratory tract infections.[16] Both the high incidence of these infections, and the sustained increase in healthcare resource utilization, justify preventive treatment measures directed at environmental factors and the host immune system. Although immunostimulants have no effect in the very short-term on acute infections, they provide immune protection against infections caused by viruses or bacteria and help the host to better fight against infection and acute exacerbations. The Global initiative for Obstructive Lung Diseases (GOLD) guidelines for the treatment of COPD has recommended immunostimulants for preventing acute COPD exacerbations on the basis of clinical studies, with B level of evidence.[17] 4. Clinical Overview of Immunostimulants What constitutes immunostimulation is a matter of debate. Several products are available in the class of immunostimulants all of which are bacterial in origin. The first generation of immunostimulants consisted of bacterial lysates (entire bacteria), ribosomal immunostimulants consisted of bacterial extracts made of the most Treat Respir Med 2006; 5 (5)

Ribomunyl® in Prevention of Recurrent Respiratory Tract Infections in Adults

immunogenic bacterial components i.e. ribosomes and membrane proteoglycans from bacteria causing recurrent respiratory tract infections. The objective of this review is to provide an overview of the mechanism of action, clinical efficacy, and cost impact of the immunostimulant Ribomunyl® (Immucytal®, Biomunil® and Ribovac®),1 which is currently approved in more than 50 countries (including several European countries) for the prevention of recurrent ENT and bronchial infections in children and adults. 5. Immuno-Pharmacology of Ribomunyl® Ribomunyl® belongs to the class of bacterial immunostimulants. The product is composed of immunogenic components of the following bacteria:[18] a ribosomal fraction which includes the ribosomes of K. pneumoniae, Streptococcus pneumoniae, S. pyogenes and H. influenzae, and a membrane fraction of K. pneumoniae. These bacteria were selected because of their involvement in upper and lower respiratory tract infections. The immunologic premise for the development of Ribomunyl® arose from animal studies. Later, studies in humans using modern immunologic techniques have demonstrated the specific and nonspecific stimulant action of this product on the immune system, and particularly on mucus-associated lymphoid tissue (MALT). These studies have been the subject of numerous publications.[18-64]

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treatment with Ribomunyl® is recommended for 3–6 months (depending on the length of the winter period), conferring protection for a further 3–6 months. 5.2 Nonspecific Immune Stimulation

The nonspecific stimulation of the immune system is based on the properties of membrane proteoglycans of K. pneumoniae. Ribomunyl® has demonstrated stimulation of natural killer cells, increased production of interferon alpha,[22,26,58] polyclonal stimulation of B and T lymphocytes,[24,60,62] activation of neutrophils (particularly their adhesion and chemotaxis),[33,35,36,45] stimulation of dendritic cells and macrophages, and an increase in phagocytosis[57,61,62,64] and in the production of cytokines interleukin (IL) IL1, IL6 and IL8.[25,27,30-32,59] This nonspecific activity enables a broad stimulation of immune system factors and, particularly, defense mechanisms against viruses.[33,38,53] These immunologic results provide evidence of the ‘immunostimulating’ basis for Ribomunyl®, and are consistent with the clinical efficacy of the product in preventing recurrent ENT and bronchopulmonary infections. 6. Clinical Efficacy of Ribomunyl® in Adults with RRTIs

5.1 Specific Immune Stimulation

The mechanism of action of an immunostimulant is a process of maintaining the immune system in a state of alert and is capable of efficiently handling microbial or viral infections. The specific stimulation of the immune system is linked to the immunogenic properties of ribosomes, which has been widely validated. Ribomunyl® was shown to increase the number of specific secretory plasmocytes in adults and children following oral therapy for 3 weeks.[28,37] The number of plasmocyte cells secreting antibodies specific to the ribosomal antigens in the immunostimulant was increased both in the tonsils and peripheral blood in children after oral treatment with bacterial ribosomes, thus emphasizing stimulation of the mucous immune system (MALT) following oral administration.[40,43] Furthermore, a marked elevation of salivary IgA specific to the four strains of bacteria in the immunostimulant Ribomunyl® was observed in saliva from volunteers after treatment for 3 months.[44,45] Thus, the ribosomes in Ribomunyl® induce the production of specific humoral and secretory antibodies, and stimulate the mucous immune system, by the oral route, via the Peyer plaques.[47,50] Usually, 1

Screening of the published literature was carried out using the search terms ‘immunostimmulant’, ‘Ribomunyl’, ‘RRTIs’, and ‘prevention of RRTIs’ on the electronic databases MEDLINE and PubMed. The manufacturer, P. Fabre, also provided information from their research database. The claimed indications for Ribomunyl® have been the object of a large number of clinical trials in children and adults. In the present review, we examined only studies in prevention of RRTIs in adults,[65-82] and we eliminated all studies in children. We also excluded studies conducted outside official indications (prevention of recurrent upper and lower respiratory infections in children and adults) or approved dosage (1 tablet or sachet per day for the first month then 4 days per week for 3 weeks, then boosters; 4 days per month for the 2–5 following months), open-label studies, and all trials and publications based on pharmacodynamic and not clinical parameters. We selected the most pertinent studies for their methodology complying with modern good clinical practice standards, large number of patients, or specific patient populations (rhinitis for example), in order to quantify the efficacy of the product and to generate a global overview.

The use of trade names is for product identification purposes only and does not imply endorsement.

© 2006 Adis Data Information BV. All rights reserved.

Treat Respir Med 2006; 5 (5)

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6.1 Clinical Studies in the International Registration File for the Product

The most important publication[82] involving a large number of patients included 19 double-blind randomized clinical trials, with an adequate level of good clinical practice and statistical power to be included in the international registration file of the product. The studies were conducted with children and adults, but our aim was to focus only on results in adults, which were analyzed separately. All studies dealt with the official indication of prevention of recurrent upper or lower respiratory infections in patients prone to develop RRTIs, and used the recommended dosage of Ribomunyl® with follow-up periods of 3 and 6 months. Nine randomized controlled studies were conducted in adults, and included 902 patients with recurrences of ENT and bronchopulmonary infections. Diagnoses in these populations were established based on past history and clinical and radiologic examinations, including blood gas determination and respiratory function tests for patients with COPD. These objective parameters provided homogeneous populations. In all studies, the principal evaluation focus was the frequency of recurrent episodes over a period of 3 or 6 months. The efficacy of Ribomunyl® in patients with ENT infections was demonstrated in a study conducted over a period of 6 months and enrolled 328 patients, 168 of whom received ribosomal immunostimulant and 160 placebo. Two other studies compared smaller groups of patients. Ribosomal immunostimulant was significantly more effective than placebo in reducing the mean number of recurrences of ENT infectious episodes by 38% after 3 months (p = 0.003), and by 33% after 6 months (p = 0.001). As a consequence, the mean number of courses of antibacterial therapy and the mean number of days of treatment with antibacterials was significantly reduced by 38% (p = 0.002). Results from studies in small groups of patients were consistent with the findings from this first study. In patients with mixed ENT and acute bronchopulmonary infections or superinfections of the upper or lower respiratory tract, the preventive effect of ribosomal immunostimulant on recurrence was shown in six controlled clinical trials, and involving a total of 544 patients, 271 of whom received the treatment and 273 placebo. Two of these six studies compared small groups of patients and should be considered as supportive. Results indicated that in patients with various types of respiratory infections, ribosomal immunostimulant produced a significant reduction versus placebo in the mean number of recurrences per patient (54–78% reduction in the different trials; p < 0.05 and < 0.01, respectively) and the mean duration of infection per patient (42–79% reduction depending on the study) after 3 months’ treatment. In two 6-month studies © 2006 Adis Data Information BV. All rights reserved.

Bousquet & Oliveri

in patients with mixed infection, the preventive effect of Ribomunyl® was confirmed with significant reductions in the frequency (47% and 55%, respectively) and duration (43% and 47%) of episodes (p < 0.05). A month-by-month report of frequency scores collected in two major studies (137 and 177 patients, respectively) showed that ribosomal immunostimulant was consistently and significantly (p < 0.05) superior to placebo from the second month up to the sixth month of treatment. The mean number of courses of antibacterials and the number of days of antibacterial therapy were also markedly reduced, after 3 and 6 months of treatment with ribosomal immunostimulant. These favorable, statistically and clinically significant results demonstrate that ribosomal immunostimulant treatment diminishes the frequency of recurrences of acute respiratory tract infections and reduces, as a consequence, the need for antibacterials. The two studies involving the largest numbers of patients showed that the clinical benefits of ribosomal immunostimulant was evident from the second month of treatment, and benefits were sustained during the 6 months’ treatment period. 6.2 Meta-Analysis

Boyle et al.[77] conducted a large meta-analysis, of all clinical trial data published worldwide on Ribomunyl® during the period 1985–99, including 28 clinical studies conducted in 11 countries, and involving a total of more than 14 000 patients. The efficacy of ribosomal immunostimulant was tested on 14 213 patients (adults and children) with recurrent ENT and bronchopulmonary tract infections in 12 randomized double-blind placebo-controlled trials, and 16 non-blind studies with Ribomunyl® alone, used only as supportive evidence. The meta-analysis was performed on all patients (adults + children) taken together and focussed on the number of infectious episodes and number of courses of antibacterials. The results showed that the mean number of recurrent infections per patient, at the time of inclusion in the studies, was 5.5. During the treatment periods, this mean number of infections per patient fell to 2.39 in the placebo group and to 0.97 in the Ribomunyl® group, after 3 months of treatment (–59%, p < 0.001). The number of antibacterial treatments per patient decreased from 2.09 in the placebo group to 1.45 in the ribosomal immunostimulant group (–31%, p = 0.002). Similar findings were reported at 6 months. 6.3 Efficacy Studied with a Clinical Score Method

A recent multicenter double-blind study[78] is interesting because it was based on the clinical score method.[79] To study efficacy and tolerance of ribosomal immunostimulant in prevenTreat Respir Med 2006; 5 (5)

Ribomunyl® in Prevention of Recurrent Respiratory Tract Infections in Adults

tion of RRTS, this trial included 180 adult patients (44% smokers) with infections of the respiratory tract, of at least 2 years’ duration and including at least three acute infections during the previous winter. The two comparative groups – Ribomunyl® tablets versus placebo – were homogenous and received the recommended treatment for 6 months. The main criterion was the clinical score. The results showed a reduction in the incidence of ENT episodes from the second month (0.50 vs 0.67, –25%, p < 0.02) and a lower incidence of bronchopulmonary infections from the third month (0.03 vs 0.17, –82%, p < 0.02). Noticeably, from month four onwards, there were no further cases of lower respiratory tract infections in the ribosomal immunostimulant group. Other significant improvements versus placebo noticed on the score parameters were fever, duration of infection, concomitant therapies, absence from work (from month one, p < 0.05); medical consultations decreased in both groups. Concerning secondary criteria, serum concentrations of immunoglobulins were increased in the ribosomal immunostimulant group compared with the placebo group on day 21 (IgG and IgA, p < 0.05, but not IgM) and at the end of the trial. Ventilatory functions were also improved in the ribosomal immunostimulant group versus placebo at the end of treatment (vital capacity [p < 0.05] and FEV1 [p < 0.05]). 6.4 Efficacy in Chronic Bronchitis

In a double-blind multicenter study versus placebo,[69] 118 chronic bronchitic patients were studied. The aim of this work was to further examine the effect of ribosomal immunostimulant on the frequency of acute infections in patients prone to recurrent exacerbations of chronic bronchitis. Patients with severe disease were chosen, because winter exacerbations in these patients were often a key factor for decompensation. These patients on average had 13 years of chronic disease and showed at least three acute bronchial infections during the past winter. Patients were included in two comparative groups – Ribomunyl® tablets versus placebo – and received treatment for a period of 6 months. The results showed a significantly lower number of exacerbations in the treated group. The number of acute exacerbation during the 6-month period decreased from 1.55 in the placebo group to 0.82 in the ribosomal immunostimulant group (–47%, p = 0.01). In addition, the duration of infectious episodes reached 20 days in the placebo group versus 10 days in the ribosomal immunostimulant group (–50%, p = 0.01), and the number of antibacterial treatments 1.26 in the placebo group versus 0.67 in the treated group (–47%, p = 0.01). Tolerance to treatment was good, with an absence of adverse effects. The authors concluded that ribosomal immunostimulant is able to reduce the number of acute infections in patients with chronic bronchitis and might be a useful supplement in preventing acute exacerbations in this category of patients. © 2006 Adis Data Information BV. All rights reserved.

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6.5 Efficacy in Infectious Rhinitis

There are only a few efficacious treatments for chronic bronchitis where patients are immunologically compromised and superinfection can lead to hospitalization. Serrano et al.[75] investigated the efficacy of Ribomunyl® in preventing recurrences of infectious rhinitis. This well designed multicenter, double-blind, placebo-controlled study investigated the efficacy of ribosomal immunostimulant in the prevention of infectious rhinitis, and included 327 adult patients. The two comparative groups received either Ribomunyl® tablets or placebo for 6 months. The primary endpoint was the cumulative number of recurrences of episodes of infectious rhinitis. On average, during the year preceding the trial patients had 4.3 ± 1.8 episodes of infectious rhinitis. Results showed a significant reduction of infectious rhinitis episodes, with one-third fewer episodes in the ribosomal immunostimulant group compared with placebo, starting from the first month (–40%, p < 0.05 ), and maintained until the end of the study. Additionally, a 38.5% reduction in the number of antibacterial courses required per patient was observed between treatment groups: 0.8 for ribosomal immunostimulant and 1.3 for placebo (p = 0.002). 6.6 Efficacy of Ribomunyl® in Combination with Influenza Virus Vaccine

Centanni et al.[73] investigated the efficacy of a vaccine-immunostimulant combination. Influenza is a leading cause of morbidity and mortality in patients with chronic respiratory diseases. The objective was to evaluate the efficacy of a combination of Ribomunyl® plus influenza virus vaccine in adult patients with COPD or asthma. The trial involved 66 patients with COPD (mean age 68 years) or chronic asthma (mean age 45 years), divided into two groups, receiving influenza vaccine alone (32 patients) or influenza virus vaccine plus ribosomal immunostimulant (34 patients). Hemagglutinin antibody titers were measured on day 0, day 30, and day 90. The primary endpoint was the rate of influenza episodes during the follow-up period of 3 months: among recipients of vaccine alone, 31.3% of patients had influenza versus only 8.8% of patients treated with vaccine plus ribosomal immunostimulant (–70%, p < 0.05). Between group difference for hemagglutinin antibody titers for vaccines strains H1N1, H3N2, did not reach statistical significance on days 0 and 30 but on day 90 the geometric mean antibody titers for strains H1N1 (p = 0.07) and H3N2 (p = 0.08) were higher in recipients of vaccine plus immunostimulant. The authors concluded that bacterial immunostimulants acted as possible adjuvants in the prevention of influenza virus episodes, and most likely prolonged post-vaccination immunity. Treat Respir Med 2006; 5 (5)

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Table I. Reductions in the number of recurrent respiratory tract infections (RRTIs) after 3 months in adults treated with ribosomal immunostimulant in double-blind placebo-controlled studies Main indication

Number of patients

Registration file: ENT infections[82] Registration file: BP and ENT

infections[82]

Global meta-analysis: ENT and BP[77] Score: BP and ENT

infections[78]

Chronic bronchitis[69]a Infectious

rhinitis[75]

Ribosomal immunostimulant in combination with influenza virus vaccine [73] a

% Reduction RRTI relative to placebo

p-Value

358

–38

544

–54 and –78

<0.05 and <0.01

–59

<0.001

180

–82 and –25

<0.02

118

–47

0.01

327

–40

<0.05

66

–72

<0.05

14 213

0.003

Evaluation after 6 months.

BP = bronchopulmonary; ENT = ear, nose, throat.

7. Conclusion It can be concluded that Ribomunyl® is effective in the prevention of recurrences of upper and lower respiratory tract infections or superinfections in adults. The clinical efficacy of ribosomal immunostimulant is consistent with its specific and nonspecific immunostimulating properties. The efficacy of the product is primarily reflected by significant reductions in the number of recurrent infectious episodes (table I), and consequently the need for prescribing antibacterials. Therapeutic benefits are generally observed after 3 months’ treatment and maintained for a further 6 months. This enables a reduction in the use of concomitant medications (antitussives, antipyretics, etc.) less work absenteeism as well as other risks related to chronic disorders (e.g. loss of hearing), and also enables potential avoidance of hospitalization. The fact that treatment with Ribomunyl® is associated with reduced antibacterial consumption may also have a positive impact on the development of bacterial resistance. Ribomunyl® is well tolerated. In controlled clinical trials adverse events were mild or rare, with a similar incidence between active treatment and placebo groups. Adverse effects listed in prescribing information for the product include mild ENT symptoms, fever, cutaneous reactions, and nausea; overall, in more than 900 adults treated with ribosomal immunostimulant in controlled clinical trials, the percentage of adverse events was 2.5% compared with 3.5% in the placebo group.[82] RRTIs impose a significant financial burden on society. The therapeutic benefits provided by Ribomunyl® suggest that savings can be made in healthcare expenditure. This has been confirmed by economic evaluations of ribosomal immunostimulant versus no prophylaxis in patients with chronic ENT and bronchopulmonary infections in France, Italy, and Austria over the winter months.[8385] The threshold incremental efficacy of immunoprophylaxis ver© 2006 Adis Data Information BV. All rights reserved.

sus no prophylaxis for cost equivalence ranged from 2% to 20%, depending on the type of infection. Such cost efficacy was largely reported in controlled clinical trials. Thus, even when clearly lower incremental efficacy rates than those reported in controlled clinical trials (approximately 40–60%) are assumed, ribosomal immunotherapy can still be expected to be cost effective. Economic study results have thus shown that the cost of one full preventive treatment is slightly lower than the cost of treating one infectious episode, depending on the type of infection (e.g. exacerbations of chronic bronchitis). Thus, prevention of infection generates savings in patients who have two or more infectious episodes per winter. In patients with recurrent respiratory tract infections, treatment with ribosomal immunostimulant was associated with direct cost savings of $US145 (rhinopharyngitis) to $US647 (chronic bronchitis exacerbations) per patient, depending on the type of infection and patient.[83] Collet et al.[86] showed that both direct and indirect costs were reduced in patients with COPD using an immunostimulating agent to prevent severe acute exacerbations and concluded that given the high prevalence of COPD worldwide and the high cost of acute exacerbations, immunostimulants may become a key element in the improved control of this condition. The current managemnt of RRTIs is based on curative measures, antibacterials and symptomatic therapies. These treatments, however, do not prevent the recurrence, and have drawbacks, like development of antibacterial resistance, and a significant impact on healthcare resource utilization. Ribosomal immunostimulant is designed to stimulate both specific and nonspecific immunity, to prevent and reduce RRTIs. In this review, we saw that the efficacy of Ribomunyl® in preventing recurrent ENT and bronchopulmonary infections in adults or elderly patients has been demonstrated in multicenter, randomized, double-blind, placebo-controlled studies and meta-analyses. On the basis of demonstrated therapeutic benefits and limited risks, relative to placebo, treatment with Treat Respir Med 2006; 5 (5)

Ribomunyl® in Prevention of Recurrent Respiratory Tract Infections in Adults

ribosomal immunostimulant may be a valid alternative approach to overcome recurrent respiratory tract infections. Acknowledgments The authors would like to thank Pierre Fabre Medicament and M. Leuwers for assistance in supplying documentation, and A.M. Thomas for assistance in coordination. No sources of funding were sought to assist in the preparation of this article and the authors have no conflicts of interest that are directly relevant to the content of this review.

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Correspondence and offprints: Prof. Jean Bousquet, D´epartement des Maladies Respiratoires, Hopital Arnaud de Villeneuve, Montpellier, 34000, France. Treat Respir Med 2006; 5 (5)