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Chandigarh, India
Dr. Jindal is the Professor and Head, Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh.
Correspondence to: Surinder K. Jindal, MD, FCCP, Professor and Head, Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India 160012
What constitutes immunostimulation is a matter of debate. Immunity is a highly complex mechanism with multiple functions. Activation of macrophages, enhanced antigen presentation, and increased lymphocyte responses are some of the functions of immune cells likely to promote phagocytic activity. Correction of an aberration in immunity is a function-directed rather than a general phenomenon. Immunostimulation therefore is a confusing nomenclature. Immunoregulation or immunomodulation are other terms used for the same phenomenon, which are as poorly defined as immunostimulation. It is perhaps better understood as the process of maintaining the immune system in a "state of alert" that is capable of efficiently handling microbial infections.1 This is precisely the objective that is desired to handle the invading organisms.
Immunostimulation has been advocated as a management strategy in COPD for the purposes of preventing acute exacerbations. Exacerbations are most commonly caused by infections, and prevention of infections is likely to prevent most of the acute exacerbations. Undoubtedly, acute exacerbations of COPD characterized by aggravation of respiratory symptoms and decline of function significantly add to the disease morbidity and mortality.2 Reduction in the number of acute exacerbations does improve the quality of life, decrease the overall morbidity, and lessen the costs of disease management. Several therapeutic and preventive strategies have been adopted for this purpose from time to time.2345 Long-term inhaled corticosteroids, mucolytic agents, and antioxidants have been employed in different studies with limited benefits. Use of immunostimulation agents is one such option included in the management recommendation of the Global Initiative of Chronic Obstructive Lung Disease (GOLD), as well as some other guidelines, including those from this country.67 But the evidence in favor of their use is available only from a limited body of data.
Oral purified lyophilized extracts such as OM 85-BV of bacteria that are commonly responsible for respiratory infections in COPD have been employed as immunomodulating agents in some European countries for over 2 decades.89 Several other reports101112 were published in the following years. But their role was not clearly established. Now, after the publication of the Prevention of Acute Respiratory Infection by an Immuno-stimulant (PARI-IS) study and its incorporation in the GOLD document, there is a rejuvenated interest in the subject and a search is on to find a clear answer.16 Steurer-Stay and colleagues in this issue (see page 1645) have systematically reviewed the available evidence and presented important findings. The authors have reviewed 13 trials on two commercially available agents: OM 85-BV, LW50020, or SL-04. They had retrieved "seventy one potentially relevant reports," of which 58 were excluded. A meticulous meta-analysis was performed using fixed and random effect models, which concluded that although the evidence is not enough to suggest the role of immunostimulators in prevention of exacerbations, they do improve symptoms in patients of COPD. This in itself is an important conclusion to keep the interest in the subject alive.
Incidentally, there were very few trials with high global score of quality assessment, ie, only one trial with a score of 6 and two trials with scores of 4 each. This is a great limitation to reach any final conclusion. For this very reason, the authors have recommended further research on the subject. The PARI-IS study, which was a large, double-blind, placebo-controlled, randomized trial and scored the best quality global scores by the authors of this article, suggested the beneficial effect of the immunostimulation in COPD by reducing the likelihood of severe respiratory events to hospitalization.1 The average duration of an exacerbation was shown to be reduced in three other trials,131415 while prevention of exacerbations was reported in one large trial15 of acceptable quality and another small trial of low quality.16 An important advantage of preventive treatment with immunostimulation has been shown in another study17 on cost-effectiveness analysis in Switzerland. Incidentally, immunotherapy with OM-85 BV was found to be useful also in prevention of respiratory tract infections (RTIs) in children, as well as in adults employed in a car factory who were highly susceptible to acute RTIs.1819
While the search to find answers to this riddle will continue, the question a clinician faces is whether to use the drug or wait until we accumulate more clinical experience and know the immunologic pathway that is effectively stimulated, useful to prevent, and fight infection in these patients. The use of immunostimulators is clearly an option that a clinician can exercise as per the needs of his patient.20 The cutaneous eruptions and urologic problems seen in up to 3 to 8% of patients in some trials would limit the use of immunostimulation on a large scale. But the additional benefit of symptomatic relief and reduction in the hospitalization period, however small these may be, would be difficult to deny to a patient who has no other option.
References
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