Lysates and bacterial extracts
Bacterial extracts can be conventionally divided into first-generation extracts containing whole killed bacteria or their lysates, and second-generation extracts containing more immunogenic bacterial components (e.g., ribosomes or proteoglycans) [
37].
Regarding their action, it is believed that bacterial extracts can activate both mechanisms of innate immunity and adaptive immunity.
At the end of the selection process, 19 articles were included, including 5 papers (1 meta-analysis and 4 systematic reviews) assessed using the AMSTAR 2 tool, 3 RCTs and 1 retrospective study assessed using the GRADE method, 9 narrative reviews and 1 prospective observational study.
Among the studies included, there is only one concerning the efficacy of Ribomunyl [
38]; this study shows positive data and is of moderate quality. The data, however, are insufficient to recommend its use.
Only one study, a low-quality meta-analysis [
39], was also included for
polyvalent mechanical bacterial lysate (PMBL), and although it provides encouraging data, they are insufficient to recommend its use.
With regard to D53, only data published in 2013 in the review by Del-Rio-Navarro et al., referring to earlier studies (published between 1995 and 1885) and seeming promising, are available. However, no post-1995 studies were found, and this product is not currently marketed in Italy, so its use is not recommended.
As regards OM-85, several low to moderate-quality studies were found, all produced by the same research group [
40‐
42], along with 4 systematic reviews of low (
n = 2), high (
n = 1), and moderate (
n = 1) quality [
21,
43‐
45], containing some positive data.
In the very low-quality single-blind RCT conducted in 2014, Esposito et al. considered 68 children aged 3 to 5, with RRIs, vaccinated for influenza, and compared the 33 treated with OM-85, at a dosage of 3.5 mg a day for 10 days a month for 3 months, with the 35 untreated children. The authors reported a statistically significant higher incidence of airway infections in the control group than in the treated group; in particular, the proportions of subjects with at least one episode of upper airway infection were 88.6% vs 60.6%, while those with at least one episode of lower airway infection (acute bronchitis, wheezing and pneumonia) were 42.9% vs 15.2% (
p < 0.05) respectively. There was also a statistically significant reduction in the mean number of courses of antibiotics administered to treated versus untreated children (0.49 ± 1.06 vs. 1.76 ± 0.63, respectively) and in the mean number of school days lost in treated versus untreated children (3.16 ± 2.10 vs. 6.55 ± 2.34) [
40].
In 2019, the same research group conducted a further retrospective study of moderate quality including 400 children aged 3 to 6, with RRIs, of whom 200 were treated with OM-85 at a dose of 3.5 mg per day for 10 days a month for 3 months, for 2 consecutive years, compared with a control group of 200 children with similar clinical characteristics who were not treated. The authors reported a statistically significant higher incidence of airway infections in the control group than in the treated group. New episodes of respiratory infection were diagnosed in about two-thirds of the untreated children, and in only about one-third of the children treated with OM-85, with a reduction of about 50% in the risk of new episodes of RRIs. Similar results were obtained considering the total number of respiratory infections, the number of upper and lower airway infections and the number of cases with wheezing. In the first year of treatment, in particular, the proportion of children with at least one episode of respiratory infection was 36% in the treated children vs 64% in the control group (
p < 0.05). Similar values were observed in the second year of treatment (33% vs 60%;
p < 0.05). Eleven children (5.5%) reported mild and transient adverse events to OM-85 during the first year of treatment (5 diarrhoea, 3 vomitings, 2 fever, 1 asthenia) and 9 (4.5%) during the second year (4 diarrhoea, 2 vomiting, 2 headache, 1 asthenia)
. The study also reports a statistically significantly higher proportion of children treated with antibiotics in the control group than in the group treated with OM-85- (
p < 0.05), both in the first and second years of the study [
41].
In 2019, the same research group published a randomised phase IV, placebo-controlled, double-blind, single-centre, moderate-quality study. In the study, the efficacy of OM-85 was assessed in 288 children aged 1 to 6, with a history of RRIs (123 treated with OM-85 at a dosage of 3.5 mg a day for 10 days a month for 3 months, 41 children treated with OM-85 at 3.5 mg a day for 10 days a month for 6 months, and 124 children, in the control group, who received placebo for 10 days a month for 6 months). On the day of enrolment, 35.8% of the children in the first group, 34.6% in the second group and 36.5% in the third group were vaccinated for influenza with trivalent inactivated vaccine (Fluarix). The number of respiratory tract infections and the number of children with at least one episode of airway infection were significantly lower in the group of children treated with OM-85 for 3 months than in the placebo group (33% vs 65%;
p < 0.0001). These differences were statistically significant for upper airway infections such as rhinitis, pharyngitis and acute otitis media (
p < 0.0001 and
p = 0.006, respectively). A significant reduction in the administration of antibiotics was also observed in the group of children treated with OM-85 compared to the control group (25% vs 50.5%;
p = 0.0002). The authors also showed a statistically significant reduction (
p = 0.007) in the mean number of school days lost in treated children compared to those who were untreated (5.10 ± 1.33 vs 4.49 ± 1.10) and a statistically significant (
p = 0.004) reduction in the mean number of working days lost by the parents of children who were treated compared to those who were not (2.58 ± 0.73 vs 1.76 ± 0.76) [
42].
In Schaad’s work, which was rated as poor quality according to AMSTAR 2, 8 publications, from 1986 to 2003, in which children with a history of RRIs were monitored for 6 months, comparing OM-85-treated and untreated children, were reviewed. The authors report a statistically significant difference in the incidence of RRIs in the patients treated (32%) compared to the control group (58.2%) [
43].
In a subsequent high-quality review [
44], including 9 studies published from 1984 until 2003, with a total of 852 children with RRIs, comparing OM-85-treated children (437) and placebo-treated children (415), a statistically significant reduction in the number of acute respiratory infections was observed in the group of children treated compared to the control group [MD (
mean difference) -1.20; CI 95% -1.75, − 0.66;
p < 0.0001].
The third and most recent systematic review of 54 studies (4851 children) was published in 2018 and judged to be of moderate quality. The authors, taking data from 44 RCTs, reported a statistically significant association between treatment with OM-85 and a reduction in the frequency of respiratory infections (MD -2.33; 95% CI -2.75, − 1.90;
P < 0.00001). Furthermore, taking data from 15 RCTs, a statistically significant reduction in fever days in the group treated with OM-85 compared to the control group was reported (MD − 2.91 days; 95% CI -3.75, − 2.07;
p < 0.00001), along with a reduction in cough days, (MD − 5.26 days; CI 95%-6.41, − 4.12;
P < 0.00001) and a reduction in days of antibiotic therapy (MD − 4.10 days; CI 95%-4.52, − 3.67;
p < 0.00001) [
45].
The low-quality systematic review by Esposito et al. reports that OM-85 reduced the incidence, prevalence and/or duration of infections in children with a history of RRIs compared to placebo and compared to probiotic therapy [
21].
The safety data collected for OM-85 are reassuring, although the drug’s technical data sheet contraindicates its use in the following cases: hypersensitivity to the active substances or any of the excipients, in children under 1 year of age, with autoimmune diseases or acute intestinal infections. Moreover, an interval of 4 weeks between the end of treatment with OM-85 and the start of vaccine administration is recommended [
46].
As reported in the datasheet of the product sold in Italy with more than 500 million units of OM-85 prescribed for adults and children, one isolated case of toxic necrotic epidermolysis in a child was reported. The relationship with the use of OM-85 has been estimated as possible, considering that other causes may have contributed to this adverse event (e.g.,
Mycoplasma pneumoniae infection). In some cases, asthma attacks have been observed in predisposed patients after taking drugs containing bacterial extracts; in this case, OM-85 is contraindicated [
46].
In general, the frequency of adverse events observed is estimated to be extremely low compared to the high exposure to the product.
In 2018, an AIFA document on safety and efficacy data and claims on the use of bacterial lysates was published (
https://www.ema.europa.eu/en/documents/referral/bacterial-lysate-medicines-article-31-referral-notification_en.pdf). The authors of the document were called for the EU to take a stance regarding indications on the use of bacterial lysates. On June 27, 2019 EMA recommended the use of medicines containing bacterial lysate only for the prevention of RRIs, with the exception of pneumonia. The EMA’s recommendation followed a review that concluded the absence of reliable data to show that these medicines are effective in treating respiratory infections or preventing pneumonia and should not be used for these purposes. In the review, the EMA’s
Committee for Medicinal Products for Human Use (CHMP) looked at the results of clinical trials, data on side effects and advice from a panel of experts on infectious diseases. Although the data were limited, the review found some evidence of the efficacy of these products in preventing RRIs, and the safety profile was in line with that expected for this type of product. The CHMP therefore recommended the use of these medicines for the prevention of RRIs, but pharmaceutical companies must provide additional safety and efficacy data with new clinical studies by 2026.
In conclusion, although the data in the majority of cases suggest the efficacy of OM-85 in the prevention of RRIs, only 2 RCTs, of low to moderate quality, have been conducted in limited numbers of children, and they were produced by one research group only. Consequently, the evidence currently available does not allow us to recommend the routine use of OM-85 for the prevention of RRIs, but it can be recommended in selected populations of children, particularly in children with higher number of RRIs/year, always considering the cost-benefit ratio.
Vitamins and trace elements
Vitamins are multifunctional compounds belonging to the category of micronutrients. They carry out biological activities that are essential for the completion of enzymatic processes and the health of the human body. Some of them can modulate the functions of the immune system.
Trace elements, which are present in very small quantities in the body, play a fundamental role in the metabolism and proper functioning of the immune system. The increased risk of infection in deficient states has led to the hypothesis that dietary supplements of trace elements can improve the immune response [
47]. Zinc, copper and iron are the trace elements involved in the development of the immune response.
At the end of the selection process, 20 full-texts were included, including 5 RCTs [
48‐
52] and 8 observational studies [
53‐
60] of low or very low quality, assessed using the GRADE method, and 7 systematic reviews assessed with the AMSTAR 2 tool, 4 of which were of high quality [
61‐
64], 1 of moderate quality [
65], and 2 of very low quality [
66,
67].
As regards the efficacy of trace elements in the prevention of RRIs, we have a few low-quality intervention studies available, including 3 RCTs [
49,
50,
52], 1 observational study [
60], 1 systematic review [
62] and 1 meta-analysis [
68]. The studies currently available in the literature are burdened by a lack of reproducibility, methodological imprecision, low population size and the heterogeneity of the population studied and of the results obtained, so it is not possible to recommend the use of trace elements in the prevention of RRIs. In response to the outcome about the possible relationship between reduced serum levels of vitamin D/ vitamin A/ vitamin E and increased risk of RRIs in children, 7 observational studies of very low methodological quality and with very heterogeneous results were included [
53‐
56,
58,
59,
69]. The outcomes are different: 3 studies [
54,
56,
59] enrolled subjects with RRIs, 1 study [
55] selected subjects with AOM, 1 study [
53] with recurrent tonsillitis, and, lastly, Shokrollahi’s study assessed subjects with lower respiratory tract infections. The studies by Cayir, Ingham, Zhang and Science show significantly lower vitamin D serum levels in children with RRIs, while the studies by Aydin and Shokrollah show no significant difference in vitamin D serum levels, which are low in both children with RRIs and controls. No studies are currently available in the literature showing that low levels of vitamin A and E create a predisposition for respiratory infections in children, so their use cannot be recommended in the prevention of RRIs.
Two of the intervention studies selected concern the efficacy of vitamin D in the prevention of RRIs, 1 RCT [
48] and 1 observational study [
57] of low quality, characterised by different outcomes and significant heterogeneity of the populations studied, with non-homogeneous results. The effects of the administration of vitamin D in the prevention of RRIs have also been the subject of systematic reviews and meta-analyses, 5 of which considered eligible [
63‐
67]. Assessment with the AMSTAR 2 tool found 2 of these to be very low quality [
66,
67], 2 to be of high quality [
63,
64] and 1 to be of moderate quality [
65]. Three of them included studies in adults [
64,
66,
67]; 1 included only studies carried out in children under the age of 5 and considered the effects of vitamin D supplementation in the prevention of infections in general, including gastrointestinal infections [
63]. The majority of them also included patients with asthma, COPD (Chronic Obstructive Pulmonary Disease) or influenza [
64‐
67]. Twenty-five RCTs were included in the most recent meta-analysis [
64], only 10 of which were studied in children or adolescents that also included asthma exacerbations or influenza prevention as an outcome
. The authors concluded the efficacy of vitamin D in preventing infections [adjusted odds ratio (AOR) 0.88, CI 95% 0.81–0.96, heterogeneity
p < 0.001] with an effect detectable only through daily or weekly administrations but not in a bolus. Furthermore, the effects were greater in subjects with vitamin D values < 25 nmol/l.
The high quality meta-analysis of Yakoob et al. showed no benefit of the administration of vitamin D in the prevention of pneumonia [
63]. The authors of the other meta-analysis of moderate quality [
65] concluded that there is no evidence to justify the routine use of vitamin D in the prevention of RRIs; however, potential benefits in children with asthma were highlighted. Limited evidences indicate some benefits of vitamin D supplementation in the prevention of recurrent acute otitis media [
70].
The reviews assessed as low, moderate and high-quality show different results, with non-homogeneous study populations. It is therefore not possible to recommend the routine use of vitamin D in the prophylaxis of RRIs unless a condition of vitamin D insufficiency or higher risk of low vitamin D levels exist.
As reported in the Italian Consensus on vitamin D in paediatric age published on 2015, the available epidemiological studies show a high prevalence of hypovitaminosis D (above 50%) throughout Italy. Vitamin D status of newborns is influenced by ethnicity, season of birth, and maternal vitamin D status during pregnancy; vitamin D status of children and adolescents is influenced by sun exposure, seasonality, ethnicity, and body mass index. The vitamin D supplementation should be recommended in all infants in the first year of life, independently of the type of feeding. Supplementation should be subsequently individualized in terms of regimen and duration on the basis of the presence of risk factors for vitamin D deficiency. Non-Caucasian ethnicity with dark skin pigmentation, reduced sunlight exposure and/or constant use of sunscreens, international adoption, obesity, inadequate diets (i.e. vegan diet), chronic kidney disease, hepatic failure and/or cholestasis, malabsorption syndromes (i.e. cystic fibrosis, inflammatory bowel diseases, celiac disease at diagnosis, etc.) and chronic therapies (anticonvulsants, systemic glucocorticoids, antiretroviral therapy, systemic antifungals) are the most important risk factors for vitamin D deficiency between 1 and 18 years of age. In the presence of risk factors for vitamin D deficiency the supplementation is recommended according to the dosages reported in the Consensus [
71].
The studies currently present in the literature on vitamin C supplementation in the prevention of RRIs, an RCT [
51] of very low quality and a systematic review of high methodological quality [
61], are burdened by the heterogeneity and a low number of populations studied and the diversity of treatments used, and so do not allow the recommendation of its routine use in the prevention of these episodes. The authors conclude that regular vitamin C supplementation does not reduce the incidence of the common cold in the general population. Although regular supplementation can reduce the duration and severity of episodes, this was not reproducible in the few therapeutic trials performed. Further data are therefore needed.
Complementary/alternative medicines
Medicines other than official medicine have been given different names over the years: Non-Conventional Medicines, Alternative Medicines, Complementary and Alternative Medicines (CAM), up to the recent proposal of the term Complementary and Integrative Medicines (CIM).
At the end of the selection process, 18 full-texts were included, including 9 systematic reviews assessed using the 16-item AMSTAR questionnaire, and 9 studies assessed with the GRADE method (4 RCTs, 1 randomised open-label study, 2 uncontrolled clinical studies, 1 cohort study and 1 retrospective study).
As regards the effectiveness of homeopathy in reducing the number of RRIs episodes, 2 moderate-quality RCTs [
72,
73] and 1 low-quality retrospective observational study [
74] were included. The first 2 studies demonstrated no significant effect on reducing the number of episodes; 1 reported effects on symptom severity, appetite and vitality status. The retrospective observational study reporting a reduction in the number of episodes in the group treated with the homoeopathic product is of low quality, both because of the observational nature of the design and because of the absence of a control group treated with placebo. On the other hand, concerning the efficacy of homoeopathy in reducing the use of antibiotics to treat episodes of RRIs, the same 2 moderate-quality RCTs and 1 very low-quality observational study [
75] were included; the results of the studies are heterogeneous and, also given their low numbers, it is not possible to provide recommendations regarding the routine use of homoeopathy in this area. Only 2 of the studies included [
76,
77], low-quality unblinded RCTs, investigated the efficacy of homeopathy in reducing the intensity and duration of symptoms in episodes of respiratory infection, both reporting a positive result.
Due to the small number of studies currently available on Beta Glucan in the prevention of RRIs episodes, it is not possible to make recommendations in this sense.
In the field of phytotherapy, the effectiveness of
Echinacea in reducing the number of episodes of RRIs has been assessed; only one non-randomised intervention study [
78] is available; it is of very low quality since it lacks a control group, is of low generalisability as it concerns children with otitis or tonsillitis and is imprecise with regard to the number of episodes considered. The Cochrane systematic review [
79] included does not show significant efficacy of
Echinacea preparations in the prevention of common colds. Moreover, it is worth bearing in mind that there is a significant risk of allergic reaction when using
Echinacea in children under the age of 12. Studies in literature on the use of herbal extracts based on
Pelargonium sidoides are scarce and of low quality, so there is currently no evidence to support the use of such products in the prevention of RRIs. Regarding the efficacy of
Yupingfen (a preparation used in Chinese Traditional Medicine) only one study [
80], a meta-analysis of moderate quality, was included, as well as for Oscillococcinum only one Cochrane systematic review [
81], also of moderate quality, is available. Further studies are therefore needed to provide recommendations.
Vaccinations
Regarding the role of pneumococcal and influenza vaccinations in the prevention of RRIs, there are few studies currently available in literature; the panel identified only 2 studies, 1 RCT and 1 observational study of low to moderate quality.
In the randomised, double-blind, moderate-quality study by Esposito et al. children with RRIs aged between 6 months and 9 years were given either trivalent inactivated virosomal influenza vaccine (
n = 64) or placebo (
n = 63) to assess the number of upper and lower airway infections. The study showed vaccine efficacy in the prevention of upper airway infections of 27% (
p < 0.0001) and 33% (
p = 0.03) in the prevention of lower airway infections. Influenza vaccination seems, therefore, to be effective in reducing RRIs in children. Parallel to the significant reduction in infections, an equally significant reduction in the loss of school days (61% efficacy;
p < 0.0001) and days with fever (23% efficacy;
p = 0.02) is reported, while the effect on the rate of hospitalisations remains unchanged (1.31 ± 1.33 vs
2.35 ± 1.59: 44%;
p < 0
.0001) [
82].
Estrada et al. in a very low-quality retrospective observational study of 72 patients aged 2–25 years, with RRIs, who underwent PCV23 vaccination, assessed the efficacy of vaccination at 1, 3 and 6 months. Clinical response was present in 96% of children with a 50% reduction in episodes or resolution of episodes after 3 months [
83].
In conclusion, considering the general safety and benefits of these vaccinations, the panel believes that the general advantages of their use in paediatrics may support their administration, although the strength of the recommendation remains weak due to the limited amount of literature available on RRIs prevention.
Nasal therapies with hyaluronic acid, thermal waters and resveratrol
To investigate the role of nasal and thermal treatments in the prevention of RRIs, 8 papers were selected, 4 of which were systematic reviews assessed with the AMSTAR II questionnaire [
84‐
87]. The first 3 were of very low quality, while the last was of high quality. The other 4 papers were clinical studies, 3 RCTs [
88‐
90] of low, moderate and low quality respectively, and 1 observational study of moderate quality [
91].
Hyaluronic acid is one of the most widely represented components in the extracellular matrix and plays a role in regulating vasomotor tone and mucous gland secretions and in inflammatory processes in the upper and lower airways; consequently, it plays a major role in the effectiveness of mucociliary clearance, which is known to be reduced in patients with rhinitis and chronic rhinosinusitis [
92,
93].
As regards the efficacy of nasal therapy with hyaluronic acid in the prevention of RRIs, 5 papers were included, 2 low-quality RCTs [
88,
90], 2 very low-quality systematic reviews [
84,
85] and 1 more recent good-quality Cochrane review from 2015. The latter assesses the efficacy of nasal irrigation with a saline solution, identifying 3 randomised trials with a total of 544 children. The studies all compared routine care with saline irrigation or other nasal sprays, or otherwise placebo. Most results showed no difference between saline nasal treatment and control. However, the biggest study, conducted in an exclusively paediatric population (aged 6 to 10), showed a significant reduction in nasal secretion score [MD (mean difference) -0.31, CI 95%-0.48, − 0.14], and in nasal obstruction (MD -0.33, CI 95% -0.47, − 0.19) in the group treated with nasal saline. However, an MD − 0.33 on a 4 point symptomatic scale may have minimal clinical significance. The trial also showed a significant reduction in the use of decongestants in the group treated with nasal saline [
87].
It has been hypothesised that crenotherapy (inhalation treatment with thermal water) with sodium sulphate-chloride water may modulate the expression of pro-inflammatory cytokines and immunoregulatory and antimicrobial peptides such as
TNF-α (Tumor Necrosis Factor-α), human β-defensin 2 and calprotectin in the nasal secretions of children with chronic rhinosinusitis. Moreover, the therapeutic activity of thermal water could depend on its mechanical cleansing function and its physical and chemical composition, acting on those alterations of the nasal mucosa typical of inflammatory diseases [
94].
As regards the use of crenotherapy in the prevention of RRIs, 2 studies are available, a moderate-quality RCT [
89] and a very low-quality systematic review [
86]; the studies included showed that, overall, children treated with thermal saline-sulphurous water had a lower number of RRIs than children in the control group, a significant reduction in nasal obstruction, in the degree of turbinate hypertrophy and adenoid hypertrophy, and in the number of neutrophils and bacteria (and biofilms) in the nasal mucosa, as well as a statistically significant improvement in ciliary mucus clearance time.
Resveratrol (R) is a natural non-flavonoid polyphenol belonging to a subclass of stilbenes that has been studied for its possible immunomodulatory action. There is currently only one open-label study, of moderate quality, that has assessed the effect of resveratrol combined with carboxymethyl-β-glucan administered by inhalation in the prevention of RRIs in children. In the group treated, nasal symptoms (obstruction - rhinorrhoea - sneezing) decreased significantly and persistently over time, as did the number of days with cough and fever, the use of medication and the number of school days lost [
91].
In conclusion, although the studies available in the literature on the use of nasal therapies with hyaluronic acid, thermal waters and resveratrol in the prevention of RRIs show promising results, they are few in number and of low to moderate quality. For this reason, based on the evidence currently available, the panel does not consider it possible to recommend the use of nasal therapies for the prevention of RRIs.
Modification of risk factors, antibiotic prophylaxis and adeno/tonsillectomy
Historically, risk factors for the development of RRIs have been divided into modifiable and non-modifiable.
Concerning modifiable factors, the examination of literature led to the inclusion of 15 full texts in the final assessments, 12 of which assessed using the GRADE method and 1 with the AMSTAR 2 tool.
The good-quality review in 2013 by Sauni et al. [
95], takes into account 2 environmental factors - damp and mould - and finds that building improvements are associated with a decrease in the number of paediatric visits for acute pathology (mean difference (MD) -0.45; CI 95% -0.76, − 0.14).
Among the modifiable risk factors, diet and food pollution also play an important role; in the studies included, the low-quality study by Calatayud et al. [
96] showed an important reduction in episodes of upper respiratory tract infection, in antibiotic use by 87% and in symptomatic treatments by 57% in children with a Mediterranean diet.
The very low-quality observational study by Stølevik et al. assesses the association between prenatal maternal dietary exposure to toxic polychlorinated biphenyls (PCBs) and dioxins and the development of immune-related diseases in children [
97].
As regards indoor pollution, 3 low-quality studies are available, 2 of which are observational [
98,
99] and 1 cross-sectional [
100].
Norbäck et al. [
98] conclude that indoor mould, water damage, window condensation, cockroaches and keeping dogs or cats as pets may be risk factors for the common cold while daily cleaning may be a protective factor (OR = 0.89; CI 95% 0.81–0.97).
In the study by Casas et al., the authors conclude that passive exposure to bleach, used for cleaning in the home, can have negative effects on the health of school-age children by increasing the risk of respiratory infections. The high frequency of use of irritating disinfectants for cleaning may be a public health concern [
99].
The study by Simoni et al. [
100] analysed the relationship between CO
2 and PM10 concentrations in classrooms and the frequency of respiratory symptoms and diseases (wheezing, night cough and rhinitis).
Only one very low-quality observational study on outdoor pollution was included [
101]; the study suggests that prenatal exposure to PM2.5 increases susceptibility to respiratory infections and may influence respiratory morbidity in early childhood.
Regarding the role of smoking, 3 very low-quality studies are available, 1 observational and 2 cross-sectional. The main outcome of the observational study by Marseglia et al. was to assess whether exposure to second-hand smoke altered the immune response and increased the risk of RRIs in children subject to adenoidectomy; children exposed to smoke had more infectious episodes and more courses of antibiotic therapy than children who were not exposed [
102].
In an observational study [
103] of 64 children, 70.3% of whom were exposed to smoke, Inci et al. showed that, in those exposed, urinary cotinine levels were significantly increased (
p = 0.011), as was the frequency of acute respiratory infection (
p = 0.047).
El-Hodhod’s study considered healthy children exposed to smoke and those not exposed, with the former showing a higher frequency of acute bronchitis, dyslipidaemia and significantly higher early lymphocyte apoptosis [
104].
Clinicians should always address the emerging problem of the “third-hand smoke” (THS); this term refers to the residue of tobacco smoke that clings to skin, hair clothing, carpets, bags and furniture. Because of their developmental behaviours and their immature immune system infants and children are more prone to the risks related to THS exposure than adults.
Regarding attendance of day-care/preschool, the literature contains data on the association between community placement and environmental exposure to potential pathogens and increased risk of RRIs [
105,
106]. However, the panel did not identify studies with the specific outcome of interest.
In conclusion, although some studies support interventions to eliminate certain risk factors in order to prevent RRIs, such as reducing exposure to second-hand smoke, reducing exposure to indoor and outdoor pollutants, such evidence is scarce and obtained from low or very low-quality studies, except for exposure to damp and moulds, for which a good-quality systematic review that supports the elimination of this risk factor is available. However, even on the basis of more general considerations of promoting the general well-being of children, the panel agrees that it is necessary to discourage exposure to second and third-hand smoke and pollutants in general, in addition to improve hand washing as one of the best methods to reduce respiratory infections.
Based current literature review antibiotic prophylaxis and adeno/tonsillectomy are not recommended (Table
2).