Wheezing in children: approaches to diagnosis and management

Wheezing in early life is a common disorder, with approximately 50% of children having an episode of wheezing in the first year of life [1]. A recurrent wheeze is estimated to occur in one-third of children of preschool age and can cause significant morbidity, decrease quality of life, and increase the frequency of the use of health care services and economic costs [2]. Data have confirmed that wheezing is clinically heterogeneous in early life in terms of its temporal pattern (i.e., age of onset and duration until symptoms disappear) and its risk factors, which include atopy and genetic or environmental factors, and the outcomes are different for such phenotypes [3,4]. Different wheezing phenotypes have been reported in the literature, with the first such report being the Tucson childhood respiratory study of Martinez et al. [5], in which children were classified into four main subtypes, including never wheezing, early transient wheezing, persistent wheezing, and late-onset wheezing; later reports further categorized patients with persistent wheeze as having nonatopic persistent wheezing or atopic/IgE-associated wheezing [6,7]. This became a popular area of research, with a further six subtypes identified through longitudinal studies [8,9] and a further five subtypes reported by similar longitudinal studies [4,[10], [11], [12], [13]]. Regardless of whether five or six different types are included in an assay, it remains difficult to differentiate these phenotypes clinically because the expression of symptoms and risk factors can change over time. Additionally, different factors, including genetic, environmental, and host factors (and interactions among these factors), can impact a child's condition and contribute to the development of wheezing and the progression of a patient's symptoms [14]. Our proposed operational criteria are aimed at simplifying the types of wheezing used to categorize children of preschool age and identifying risk factors for the persistent wheezing subtypes that can impact lung function [15] or lead to the subsequent development of asthma as these conditions should be treated by appropriate medical interventions [16]. Wheeze can be divided according to its pattern and duration: 1. Wheeze subtypes according to pattern (symptomatic classification): a. Episodic wheeze: Wheezing within a discrete period that is often associated with clinical evidence of a viral cold. There is wheezing between episodes [17]. b. Multitrigger wheeze: Wheezing presenting with and apart from an acute viral episode [17,18]. 2. Wheeze according to duration: a. Never or infrequent: Children who never wheeze or have presented with wheezing once in their life. In addition, 51% of patients in the Tucson study [5], 59.9% of the patients in the Avon Longitudinal Study of Parents and Children (ALSPAC) study [8], 75% of the patients in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study [10], and 83% of the patients in the Italian Studies of Respiratory Disorders in Childhood and the Environment (SIDRIA) [13] had a higher forced expiratory volume in the first second and a lower airway responsiveness than unaffected patients who were nonatopic. b. Transient early wheeze: This is a type of wheeze that starts early in the first year of life and then continues through the second year before beginning to subside after the third year. Most of these patients are not atopic and exhibit no evidence of eosinophilia or other markers of inflammation, which are observed in approximately 16% of affected patients [8]. The main risk factors in this group are maternal exposure to smoke, prematurity, low maternal age, low socioeconomic status, low birth weight, attending day-care center at an early age, and more than two siblings at home. Additionally, in these patients, pulmonary function test (PFT) scores are low even before the onset of the wheeze, suggesting that affected individuals may have had smaller airways than were observed in the control group, and remain slightly lower than those reported in their peers in adolescence [5]. c. Intermediate wheeze: This is very rare in the first 18 months (2.7%) according to the ALSPAC study and the PIAMA study (3.1%). This condition presents as wheezing with onset between 18 and 42 months that subsequently persists into later childhood and is strongly associated with atopy, allergic sensitization, hyperresponsiveness, and lower PFT scores [9]. d. Late-onset wheeze: This presents as infrequent wheezing from 6 to 42 months od age that becomes more frequent at 42 months of age and then persists to an age of 6 years (approximately 1.7–6%) [8,10]. A skin allergy test usually produces strong results in this group, and this is known to be a major prognostic factor. Allergies in the nose are also commonly associated with late-onset wheezing, similar to smoke exposure is known to be a risk factor in males [5,8]. e. Persistent wheeze: This is wheeze with onset at 6 months of age or later that occurred in approximately 3.1% of patients in the PIAMA study, 4.1% of patients in SIDRIA, and 8.9% of patients in the ALSPAC study. This subgroup presents with symptoms similar to asthma, and affected patients are further divided into two main subgroups: • Nonatopic persistent wheezing phenotype: This accounts for approximately 40% of patients with persistent wheeze and usually presents as episodic wheezing triggered mainly by viral illness; it is therefore often referred to in the literature as a viral-induced wheeze [5]. Many viruses implicated in this subgroup can also cause new-onset wheeze, and include respiratory syncytial virus (RSV), rhinovirus, parainfluenza virus, and human metapneumovirus. Exacerbations involve RSV, parainfluenza virus, influenza virus, or corona viruses or persistent wheeze, which can be caused by adenovirus, chlamydia, or mycoplasma. RSV causes persistent wheezing in children younger than 2 years, while rhinovirus is the most common cause of recurrent or persistent wheezing in children older than 2 years [6]. • IgE-associated atopic and/or persistent wheezing phenotype: Accounting for 60% of persistent wheezing cases, this type of wheezing usually begins in the second year of life and persists into late childhood [3,6]. The risk factors in this subgroup include male sex, house dust mites, a family history of asthma atopic dermatitis, eosinophilia in the first year of life, and early sensitization to food and aeroallergens [[3], [4], [5],19,20].