**6. Conclusion**

inflammation, enhanced inflammatory/oxidative response to leptin and decreased airway eosinophils. The high level of leptin stimulates the synthesis of TNF‐alpha, IL6, and prosta‐ glandins, which is the basis for a low‐grade inflammatory process that leads to the atherogen‐ esis process and early development of metabolic syndrome. The leptin receptors are reduced in the airways but they are represented in the visceral fat, which enables metabolic influence on bronchial hyperreactivity [20, 37]. Increased oxidative stress and decreased physiologic nitric oxide are due to low L‐arginine/asymmetric dimethylarginine ration, which overall contributes to bronchoconstriction [20, 21, 38, 39]. This metabolic function of smooth muscle in the airways contributes to a poor response to bronchodilators, poor asthma control, and low pulmonary function. In the "obese asthma" phenotype, increased airway oxidative stress and systemic inflammation are followed by reduced cycling loading and unloading impulses, the less production of adenosine triphosphate for uncoupling, i.e., unlocking of actin‐myosin latch [19, 20], so that the smooth muscles airways are in a stiff state, the bronchoconstriction is very strong and without bronchodilator response, i.e., the resistance to short‐acting beta‐

Both conditions, asthma and obesity, associated, act to aggravate the degree of bronchodilata‐ tion after a deep inhalation, which is a mechanical airway dysfunction [37]. The mechanical airway dysfunction in an "obese asthma" phenotype is a consequence of restriction or reduced the total lung capacity, decreased expiratory reserve volume and there is a ventilation/per‐ fusion mismatch. In obese asthmatics, it is associated with increased airway inflammation indices. At the same time, body mass index (BMI) more than 30 was associated with a 10‐fold increase in odds for developing methacholine responsiveness [37, 38]. Anyhow, early onset of asthma is a potential risk factor for the weight gain. In the early onset category, BMI increased linearly for every year of having asthma since diagnosis [37]. It is still not clear whether obe‐ sity, preceding or following asthma, influences the severity of asthma and asthma control.

A special problem in the treatment of this asthma phenotype is the steroid resistance. The response to inhaled steroids is different according to BMI categories [39]. The oxidative stress contributes to the activation of MAPK, baseline TNF‐alpha in peripheral blood mononuclear cells and bronchoalveolar lavage cells, so that the response, for example, to dexamethasone is poor or does not exist. The TNF‐alpha is in a positive correlation with the adipocyte diameter, with which metabolism is rich. Doubtless, we can always try to treat this asthma phenotype in the form of fixed combinations of low doses of inhaled steroid and long‐acting beta 2 agonist. The second reason for the steroid resistance in the "obese asthma" phenotype is, often, a low vitamin D level that is inversely related to BMI [40, 41]. Vitamin D performs the upregula‐ tion of IL‐10 by CD4 Treg lymphocytes, thus it exceeds steroid resistance [37] and inhibits the activity of DCs across the decreased LPS activation, inhibits the proliferation and fibro‐ blasts activation and inhibits the inflammatory cytokines and the airway remodeling media‐ tors secretion by the smooth muscle cells in airway, reduces the secretion of extracellular matrix, acts anti‐proliferatively on smooth muscles, improves the immune function in the lungs, upregulates the antimicrobial proteins (cathelicidin, beta‐defensin), acts anti‐inflam‐ matory, reduces the pulmonary hyperplasia, inhibits the eosinophils recruitment, promotes

the immune tolerance [41], and reduces the IL‐17A and IL‐22 cytokine levels [42].

agonists exists.

22 Clinical Trials in Vulnerable Populations

Well‐known and safe recommendations for the "obese asthma" phenotype control are, without doubt, the cutoff of the vicious cycle of childhood obesity/asthma, which should be reached with more physical activity and less desire for food [43, 44]. Afterward, the substitu‐ tion of D3 vitamin may be decisive in the treatment of the asthma with a distinct phenotype "obese asthma." The treatment of this asthma phenotype in children, always, involves an attempt with antileukotriene or/and a fixed combination of low dose of inhaled steroid and long‐acting beta 2 agonist. The current use of some macrolides, as an anti‐inflammatory drug for asthma, is under question now, because it is necessary to make a new assessment of ben‐ efit and harm, or establish a new treatment modality with a combination of macrolides and probiotics/synbiotics.

We expect that, in the future, the indications for macrolides, as an anti‐inflammatory drug (e.g., for infantile and asthma in childhood), will be accompanied by a recommendation on mandatory, simultaneous, and the concomitant application of probiotics or synbiotics, espe‐ cially in the youngest children (**Figure 1**). The duration of substitution with probiotics or synbiotics during and after discontinuation of macrolides should be determined in future studies. From our current perspective and findings, and bearing in mind the long‐term dis‐ ruption (24 months) of the intestinal microbiota, we suggest a period of, at least, 9 months of probiotics or synbiotics supplementation, which is necessary time for the restitution of immune balance between immunoglobulin A and E, in the youngest children [34, 44]. We join the recommendation, to avoid all antibiotics, in particular macrolides, for the "irresponsible" treatment of viral infections in the youngest children, or several times a year, or longer than the prescribed time and doses for macrolides [45] and penicillin [46]. All antibiotics should be avoided for one more reason—it is the exclusive way to avoid the intestinal microbiota dis‐ ruption, disorder of the genetic material within the intestinal microbial niches (microbiome), metabolic alterations, obesity, immunological imbalance, and early onset of asthma.

We and many other authors worldwide did not end the research for the treatment of asthma in obese children, for the "balanced" treatment of the youngest children during respiratory infections, for the overcoming the side effects of some antibiotics in early childhood, for a new therapeutic modality, especially in children suffering from wheezing/asthma, respira‐ tory infections and obesity, simultaneously, but this is our future research goal.

ICS inhaled steroids

ATP adenosine triphosphate

FVC forced vital capacity

VO2 oxygen consumption LPS lipopolysaccharide

**Author details**

**References**

FRC functional residual capacity

FEV1 forced expiratory volume in 1 second

Andjelka Stojkovic1,2\*, Aleksandra Simovic1,2, Vesna Velickovic2

2 Paediatric Clinic, Clinical Centre Kragujevac, Kragujevac, Serbia

Communications. 2015;**6**:74‐86. DOI: 10.1038/ncomms8486

Communications. 2016;**7**:10410. DOI: 10.1038/ncomms10410

2012;**143**(2):418‐428. DOI: 10.1053/j.gastro.2012.04.017

1 Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

[1] Stojkovic A, Velickovic V. The clinical implications of asthma in obese children: Review.

[2] Papadopoulos NG, Arakawa H, Carlsen K‐H, Custovic A, Gern J, Lemanske R, et al. International consensus on (icon) pediatric asthma. Allergy 2012; DOI: 10.1111/j.

[3] Nobel RY, Cox ML, Kirgin FF, Bokulich AN, Yamanishu S, Teitler I, et al. Metabolic and metagenomic outcomes from early‐life pulsed antibiotic treatment. Nature

[4] Korpela K, Salonen A, Virta LJ, Kekkonen RA, Forslund K, Bork P, de Vos WM. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre‐school children. Nature

[5] Haahtela T, Holgate S, Pawankar R, Akdis CA, Benjaponpitak S, Caraballo L, et al. The biodiversity hypothesis and allergic disease: World allergy organization position state‐ ment. World Allergy Organization Journal. 2013;**6**:3‐41. DOI: 10.1186/1939‐4551‐6‐3 [6] Wingender G, Stepniak D, Krebs P, Lin L, McBrides S, Wei B, et al. Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice. Gastroenterology.

\*Address all correspondence to: andja410@mts.rs

Pediatru.ro. 2015;**39**(3):18‐20

1398‐9995.2012.02865.x

and Katerina Dajic<sup>2</sup>

The "Obese Asthma" in Children as a Distinct Clinical Phenotype: Review

http://dx.doi.org/10.5772/intechopen.70184

25

Vt tidal volume
