Introduction
Children, elderly adults, and immunocompromised patients are particularly vulnerable to developing recurrent respiratory tract infections, which can lead to complications and chronic conditions.[1–3] Studies suggest that bacterial lysates stimulate the immune response and can prevent recurrent respiratory infections.[4–6]
The expert panel in this Clinical Forum discussed:
the importance of preventing recurrent viral and bacterial respiratory tract infections
bacterial lysates as preventative therapies; the rationale for using them and their efficacy and safety
which patients could benefit from preventative therapy with bacterial lysates.
What are the consequences of recurrent respiratory infections in children?
Alejandro Jiménez Chobillon (AJC): Recurrent respiratory infections in paediatric patients place a significant economic, emotional, and psychological burden on the child and their family, but my primary concern is their impact on the child's overall immunity. Repeated respiratory infections and repeated antibiotic treatments lower the diversity of the gut and airway microbiome.[7] If the microbiome is damaged irreversibly, the risk of chronic conditions increases, and more invasive treatments may be required. Children who experience frequent, repeated episodes of tonsillitis, for example, undergo a tonsillectomy if they fulfil the Paradise criteria.[8]
Désirée Larenas-Linnemann (DLL): Can recurrent infections lead to chronic changes in the lungs that then predispose a child to developing long-term health problems?
AJC: Yes: recurrent ear infections can cause irreversible ear damage, leading to hypoacusis, or even cholesteatoma. Sleep apnoea can develop due to hypertrophy of the adenoids and tonsils. Early childhood pneumonia is associated with an increased risk of asthma, bronchiectasis, and chronic obstructive pulmonary disease (COPD) later in life.[9]
Elsy Navarrete (EN): Paediatricians must also be vigilant for children who have recurrent infections that are not 'normal' in terms of childhood illness. Children with recurrent respiratory infections who progress quickly to chronic bacterial bronchitis, bronchiectasis, pneumonia, and/or otitis media for example, may need tests to investigate a possible underlying primary immune deficiency.[10]
At the other end of the spectrum, I am concerned that pressure from parents can lead health professionals to overtreat childhood infections with antibiotics, cough medicines, and antiviral medications. Parents with a sick child naturally want them to recover quickly but, in many cases, the infection is benign and self-limiting, and medical intervention is unwarranted.
Rosalaura V. Villarreal González (RVG): Exposure to recurrent viral and bacterial respiratory (and gastrointestinal) infections in infancy and early childhood is associated with the development of chronic respiratory conditions such as asthma.[11]
Which factors put people at a higher risk of recurrent respiratory infections?
DLL: We have already mentioned that infants and young children have an increased risk of recurrent respiratory infections, but which other patient populations experience recurrent respiratory infections more frequently than healthy adults?
AJC: Two important groups are patients who are affected by any immunodeficiency (such as HIV positive patients), and those undergoing treatment for an autoimmune disease. We see many patients with granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis (EGPA), eosinophilic polyposis, neutrophilic polyposis, and so on. All these groups show altered permeability of the respiratory epithelial barrier, making it easier for pathogens to set up an infection. The same is true of elderly people; immune function declines with advancing age, and similar abnormalities in the epithelial barrier may develop.[12,13]
RVG: I see a greater number of respiratory infections in cancer patients, whose immune system is often compromised by either the disease or the treatment, and in patients with rheumatological diseases. Pollution is also a major risk factor; here in Monterrey in the north of Mexico, we see many patients of all ages who have developed inflammatory conditions such as allergic rhinitis and asthma due to exposure to pollutants. Recurrent infections in early childhood can predispose a child to developing respiratory allergies, but it happens the other way round too; changes in the immune system due to allergies increase the risk of frequent respiratory infections.
DLL: It is interesting that some adhesion molecules are upregulated because of an allergic response; one of these, intracellular adhesion molecule-1 (ICAM-1) is the target receptor that allows rhinovirus entry into cells.[14] Children with more target receptors are more likely to become infected when exposed to other children who are sick and shedding rhinovirus.
AJC: Pollution is an important contributory factor in recurrent respiratory infections and allergic respiratory conditions.[15,16] Beyond pollution, we perhaps also need to consider chronic exposure to detergents, food additives, and anything that can lead to the development of chronic inflammation within the body’s epithelial barriers.[17]
EN: I agree that all the factors mentioned are important, but I would also like to add that recurrent infections are also more common in patients with anatomical abnormalities in the respiratory system (for example nasal polyps and deviated septum),[18,19] and in patients with impaired removal of secretions from the airways due to a genetic syndrome, notably cystic fibrosis.[20] More generally, nutritional status can also be a contributory factor, particularly vitamin D deficiency.[21]
DLL: The population in Mexico typically has low levels of vitamin D. Over 60% of people, particularly women and the elderly, have vitamin D deficiency (<20 ng/mL), with around 30% vitamin D insufficient (21–29 ng/mL).[22] Those living in cooler, less sunny climates might be surprised, but the reality is that we avoid the heat and the sun, and if we do venture outside, we apply high factor sunscreen.
What options are available for preventing recurrent respiratory infections?
RVG: If possible, the first step is to diagnose and then to treat, or at least ameliorate, the underlying cause. So, for example, a child with allergic rhinitis or asthma should receive control therapy with antihistamines, intranasal steroids, inhalers with bronchodilators and corticosteroids, and leukotriene modifiers as necessary. A child with a primary immunodeficiency might require prophylactic antivirals, antibiotics, and antifungals as well as intravenous or subcutaneous gamma globulin.
EN: Modification of risk factors can also be considered at an early stage. Some, such as urban pollution, cannot be avoided easily, but minimising exposure to smoke, detergents, and mould is a good idea.
It is also essential to stress that early adenectomy or tonsillectomy to prevent recurrent respiratory infections often carries a strong negative recommendation,[1] and must be avoided.
AJC: I agree. As an ENT surgeon, I approach the care for each patient systematically, starting with necessary medical therapies to treat the underlying cause, but keeping antibiotic use to a minimum. It is important to make sure all available vaccinations are up to date, particularly the pneumococcal vaccine. This has a general immunostimulatory effect as well as protecting specifically against pneumococcal pneumonia.
I then educate the patient/their family on improving nutritional status by eating a diet high in unprocessed and preferably organic foods, high in fibre, and mostly plant based. I advise avoiding detergents and practicing nasal lavage to reduce antigenic load and to reduce exposure to environmental pollutants. I also recommend probiotics and prebiotics to restore the gut microbiome, bacterial lysates to boost antibacterial immune response and, in selected cases, I prescribe pidotimod to boost innate and adaptive immunity.[23,24]
Surgery is reserved for patients still experiencing regular bouts of tonsillitis after several months (if they meet the Paradise criteria),[8] or if they have sleep apnoea syndrome related to adenoid hypertrophy.[25]
EN: Probiotics, prebiotics, symbiotics, and vitamin D are readily available, well tolerated, and with few contraindications, but high quality clinical evidence for their activity and efficacy is lacking.[1] Bacterial lysates were viewed in a similar way until recently but they are now supported by a growing body of evidence; in 2019, the European Medicines Agency (EMA) recommended the use of bacterial extracts and bacterial lysates as immunomodulators to prevent recurrent upper respiratory infections.[26,27]
Bacterial lysates: how can they be used to prevent recurrent respiratory infections?
| Box 1: What are bacterial lysates? |
|---|
| Lysates contain a mixture of antigens extracted from inactivated bacterial pathogens that often cause respiratory infections.[28] Extraction methods vary but the different preparations comprise mixtures of bacterial extracts from species of Staphylococcus (S. aureus, S. pneumoniae, S. pyogenes, S. viridans), Mycobacterium catarrhalis, Klebsiella pneumoniae and Haemophilus influenzae, and others.[6,28] Bacterial lysates can be administered orally, sublingually, intranasally (via a nasal spray), or subcutaneously.[26,29] |
What evidence supports the efficacy and safety profile of bacterial lysates?
RVG: Many recent systematic reviews and meta-analyses provide good evidence of the beneficial impact of bacterial lysate therapy in many clinical scenarios:
Reducing the frequency of recurrent respiratory infections caused by bacterial and viral pathogens in children and adults[6,30]
Preventing recurrent respiratory infections in adults and children with allergic rhinitis[31]
Improvement of asthma symptom control in adults and more prominent effects in children[32]
one study showed that antibiotic use and duration of wheezing episodes were reduced[33]
Preventing symptoms of allergic rhinitis in children sensitive to grass pollen[34,35]
Preventing exacerbations of symptoms in adults with COPD[36,37]
Bacterial lysate therapy has also been shown to be cost effective with potential savings for healthcare systems.[38,39]
EN: In addition, the EMA produced an extensive section on efficacy data in their assessment of bacterial lysates as part of their approval process.[27]
DLL: In terms of the safety profile and adverse events, do you know of anything to suggest that bacterial lysates are problematic?
RVG: My search of the recent literature, including several reviews and meta-analyses, suggests that the safety profile is excellent; the most common adverse events were mild (rash, vomiting, nausea, abdominal pain, diarrhoea, common cold) and occurred in treatment groups at the same frequency as placebo groups.[31–33,40]
EN: The EMA identified five individual reports of serious adverse effects but noted that causality was unclear. As a condition of marketing authorisation, the EMA have requested submission of the results of a placebo-controlled double-blind multicentre randomised controlled trial for each medicinal product based on bacterial lysates by March 2026.[27]
What is the mechanism of action of bacterial lysates?
RVG: The underlying mechanism is complex[29,41] but, as an overview, antigens within the bacterial lysate bind to dendritic cells that stimulate an adaptive and an innate immune response. The innate immune response is activated via immune cascades that restore the balance between Th1 and Th2 cells.
AJC: This rebalance between Th1 and Th2 is something that has also been indirectly observed in the immune response generated to the BCG vaccine. With allergic disorders being related to a Th2 skewed immune reaction, the tuberculosis vaccine elicits a strong Th1-based response that can protect against recurrent infections, irrespective of the individual causative pathogens.[42–44]
DLL: I agree, and I am convinced that the response to bacterial lysates involves the non-specific trained innate immunity causing a boost in the innate arm of our immune response, this concept is becoming more widely recognised since the pioneering works of Netea and colleagues.[45]
How do you recommend that bacterial lysates are administered?
Prescribers should refer to the individual summaries of product characteristics for further information and recommendations regarding the use of pharmacological therapies. For off-licence use of medicines, the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented.
AJC: In terms of frequency and age groups targeted, I recommend a full cycle of three months per year of oral bacterial lysate therapy every year (usually at the start of winter) for children aged 3–12 years. After 12 years of age, when the immune system has matured, I would reserve treatment only for adolescents and adults with recurrent respiratory infections.
EN: For prevention in children prone to recurrent respiratory infections, I would recommend oral bacterial lysate therapy at the start of winter, in either October or November.
RVG: I also recommend treatment for winter and daily treatment for around 2 months. I am interested in alternatives to oral administration. Intranasal preparations have produced some promising results in mouse models.[46] It makes sense to deliver the lysate directly to the mucosa, avoiding transit through the digestive system.
DLL: I often prefer the sublingual administration route and recommend preparations of bacterial extracts, a few drops of which are added under the tongue daily every day for as long as 6 months.
AJC: Sublingual and intranasal administration could offer advantages over oral delivery of bacterial lysates because of the high dose of antigens going directly to the adenoids. This lymphoid tissue, which lies at the back of the nose/throat, contributes significantly to an early immune response to a pathogenic assault.
Which patients might benefit from preventative therapy with bacterial lysates? Are there any contraindications?
DLL: It is clear from the studies discussed that bacterial lysates prevent recurrent respiratory infections in children with deficits in respiratory function that range from wheezing or allergic rhinitis, through diagnosable asthma, to those who are already experiencing recurrent respiratory infections.[6,27,30–39]
EN: Children need an immune boost now more than ever. The restrictions that reduced exposure to SARS-CoV-2 also limited exposure to other pathogens, creating an immunological debt. Currently, in the post-COVID era, we are seeing that immunological debt being paid; the rate of respiratory infections is particularly high. Using bacterial lysates over the next 2–3 years to stimulate the immune system in young children could prevent respiratory infections, and reduce the risk of recurrent, chronic, and long-term problems.
AJC: I agree, bacterial lysates are a preventative therapy that has the greatest utility in children. Adults who are experiencing recurrent infections can also receive treatment with bacterial lysates, but it is not justifiable in terms of cost purely as a preventative therapy in older, healthy adults. Adults in some vulnerable groups, for example, those with COPD, should certainly be considered for bacterial lysate therapy.
EN: In my practice, I see parents of children who are regularly infected by the different pathogens their children bring home; preventative, immune boosting therapy with bacterial lysates could certainly help them.
DLL: It is also important to recognise when bacterial lysates are inappropriate; I would never use them in a patient with an active autoimmune disease, such as rheumatoid arthritis or lupus, that is not well controlled.
EN: I would not give a bacterial lysate to a patient with an autoimmune disease, but I would consider it in a patient with atopic dermatitis undergoing treatment with immunosuppressants.
AJC: I would not systematically recommend bacterial lysates for patients undergoing long-term steroid treatment because it would, in my opinion, be a waste of medication as the immune response is being actively suppressed in that patient. They are also not suitable in patients with a flare in urticaria (acute or chronic).
When recommending bacterial lysates as preventative therapy, what else needs to be considered?
DLL: First, be aware and alert when there are too many severe infections, that this is not an immunodeficiency. In this case, the patient must be referred.
EN: Bacterial lysates are valuable immunomodulators, but we must not forget how lifestyle modifications such as better nutrition, reducing exposure to detergents, and using probiotics all have a role to play. A holistic, multifaceted approach combining all of these can reduce recurrent infections in patients while reducing healthcare costs, patient/family anxiety, and antibiotic usage.
RVG: I agree, and it follows that the ideal scenario is to put in place a multidisciplinary team that includes an allergist, an immunologist, and a paediatrician, so that assessment, diagnosis, and treatment is individualised and coordinated for each patient.
AJC: The economic burden on families with a child with recurrent infections is substantial in Mexico, and there are cost implications for the public healthcare system, here and around the world. Studies performed so far on the cost effectiveness of bacterial lysates are encouraging;[38,39] manufacturers of bacterial lysate preparations could consider their own studies to demonstrate the potential cost savings that are possible if a substantial number of recurrent infections can be prevented.
Acknowledgement
Dr Kathryn Senior, independent medical writer, helped draft this article.
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Cite this: Prevention of Respiratory Infections in Vulnerable Populations - Medscape - Mar 07, 2024.
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