Upper and lower airway interactions in children.

PURPOSE OF REVIEW: The aim of the present review was to highlight the interactions between rhinitis, rhinosinusitis and asthma in children and to discuss the most relevant scientific progresses in the pathophysiology and treatment of these combined conditions. RECENT FINDINGS: Advances in understanding the mechanisms underlying the relationship between upper and lower airways have provided valuable insights into the role of eosinophils in the pathophysiology of inflammatory events and have further delineated the concept of united airway disease. Studies addressed to evaluate the burden of sinonasal system on asthma outcomes showed a parallel severity of upper and lower airway diseases. Histopathology of sinonasal tissue in patients with chronic rhinosinusitis is different in adults and children. Targeted administration of biological agents represents an effective treatment in patients with severe uncontrolled asthma, but specific trials are awaited in children with chronic sinonasal disease. SUMMARY: Allergic rhinitis and rhinosinusitis are important comorbidities in patients with asthma. Improved knowledge of pathogenic mechanisms of inflammation and remodelling in the sinonasal system and the lung has led to new therapeutic approaches in patients with united airway disease and opened interesting perspectives for personalized drug therapies.

Necrotizing pneumonia among Italian children in the pneumococcal conjugate vaccine era.

BACKGROUND: Necrotizing pneumonia (NP) is a severe complication of community-acquired pneumonia. The impact of 13-valent pneumococcal conjugate vaccine (PCV13) on the epidemiology of NP in children has not been assessed. PATIENTS AND METHODS: Medical records of children less than 18 years admitted with NP to two pediatric hospitals in Italy between 2005 and 2019 were reviewed. The following four periods were defined: 2005-2010 (pre-PCV13), 2011-2013 (early post-PCV13), 2014-2016 (intermediate post-PCV13), and 2017-2019 (late post-PCV13). RESULTS: Forty-three children (median age, 44 months) were included. Most of them (93%) were previously healthy. No differences in age, sex, season of admission, comorbidity, clinical presentation, or hospital course were identified between pre-PCV13 and post-PCV13 periods. A significant decrease in the rate of NP-associated hospitalizations was found between the early (1.5/1000 admissions/year) and the intermediate (0.35/1000 admissions/year) post-PCV13 period (p = .001). An increased trend in admissions was found thereafter. Streptococcus pneumoniae was the most common agent detected in both periods (pre-PCV13: 11/18, 61%; post-PCV13: 13/25, 52%). Serotype 3 was the most common strain in both periods (pre-PCV13: 3/11, 27%; post-PCV13; 4/13, 31%). There were no changes in the etiology over time, but most patients with Streptococcus pyogenes or Staphylococcus aureus infection were admitted during the post-PCV13 period. CONCLUSIONS: The hospitalization rate for NP in children decreased a few years after the implementation of PCV13 immunization in Italy. However, an increased trend in admissions was found thereafter. S. pneumoniae was the most frequent causal agent in both pre- and post-PCV13 periods. Pneumococcal serotypes were mainly represented by Strain 3.

Complicated pneumonia in children.

Complicated community-acquired pneumonia in a previously well child is a severe illness characterised by combinations of local complications (eg, parapneumonic effusion, empyema, necrotising pneumonia, and lung abscess) and systemic complications (eg, bacteraemia, metastatic infection, multiorgan failure, acute respiratory distress syndrome, disseminated intravascular coagulation, and, rarely, death). Complicated community-acquired pneumonia should be suspected in any child with pneumonia not responding to appropriate antibiotic treatment within 48-72 h. Common causative organisms are Streptococcus pneumoniae and Staphylococcus aureus. Patients have initial imaging with chest radiography and ultrasound, which can also be used to assess the lung parenchyma, to identify pleural fluid; CT scanning is not usually indicated. Complicated pneumonia is treated with a prolonged course of intravenous antibiotics, and then oral antibiotics. The initial choice of antibiotic is guided by local microbiological knowledge and by subsequent positive cultures and molecular testing, including on pleural fluid if a drainage procedure is done. Information from pleural space imaging and drainage should guide the decision on whether to administer intrapleural fibrinolytics. Most patients are treated by drainage and more extensive surgery is rarely needed; in any event, in low-income and middle-income countries, resources for extensive surgeries are scarce. The clinical course of complicated community-acquired pneumonia can be prolonged, especially when patients have necrotising pneumonia, but complete recovery is the usual outcome.

Janus looks both ways: How do the upper and lower airways interact?

Our understanding of the relationship between the upper and lower airways has greatly increased as a consequence of epidemiologic and pharmacologic studies. A consistent body of scientific evidence supports the concept that rhinitis, rhinosinusitis and asthma may be the expression of a common inflammatory process, which manifests at different sites of the respiratory tract, at different times. This paradigm states that allergic reactions may begin at the local mucosa, but tend to propagate along the airway. Central to the allergic diathesis is the eosinophil and its interaction with the airway epithelium. The implications of the interplay between upper and lower airway are not only academic, but also important for diagnostic and therapeutic reasons. Furthermore, there is significant overlap in symptomatology and pathophysiology for childhood sleep disordered breathing (SDB) and asthma. Recent evidence supports an association between these two conditions, but causality has not been demonstrated. Regardless, it is important to recognize the overlap and evaluate for the other condition when one is present. In children with poorly controlled asthma, the presence of SDB may significantly contribute to asthma morbidity and, as such, should be actively excluded. On the other hand, clinical evaluation for asthma should be considered in children with SDB. Future robust longitudinal research is needed to explore the association between upper and lower airway diseases using objective measures in children.

Question 4: Is there a role for antibiotics in infantile wheeze?

Acute wheezing episodes are frequent in young children and are associated with high morbidity and healthcare utilization. The role of respiratory viruses in triggering acute wheezing is well known. There is also accumulating evidence that airway bacteria, either alone or as part of bacteria-virus interaction, are important determinants of acute asthma exacerbations. Targeting airway bacteria with antibiotics to reduce the severity of acute wheezing episodes and prevent recurrent wheezing among preschool children has been recently evaluated in three randomized, double-blind, placebo-controlled trials. The results of these studies are controversial. An interventional approach with azithromycin in young children during acute wheezing episodes cannot be generically incorporated into clinical practice, due to the potential consequences of widespread use of antibiotics in such a common clinical setting. This intervention may be reserved for children with really severe, recurrent wheezing episodes. Future research should focus on risk factors that facilitate acquisition of bacterial airway infection in young children and better understanding how virus and bacteria interact with each other during wheezing attacks. Identifying objective biomarkers that may direct the treatment to specific groups of children may represent a significant step forward in the clinical approach of acute wheezing.

Significant impact of pneumococcal conjugate vaccination on pediatric parapneumonic effusion: Italy 2006-2018.

Etiology and serotyping of parapneumonic effusion (PPE) and the impact of vaccination was evaluated over a 12-year period, before and after the PCV13 introduction (2011) for Italian children From 0 to 16 years of age. Five hundred and two children were evaluated; 226 blood and 356 pleural fluid samples were obtained and tested using Realtime-PCR and culture. In the pre-PCV13 era S. pneumoniae was the most frequent pathogen identified (64/90; 71.1%) with a large predominance of serotypes 1 (42.4%), 3 (23.7%), 7F (5.1%) and 19A (11.9%). The impact of vaccination, calculated on children 0-8 years of age, demonstrated a significant reduction of PPE: with an incidence rate of 2.82 (95%CL 2.32-3.41) in the pre-PCV13 era and an age-standardized rate (ASR) of 0.66 (95% CL 0.37-1.99) in the post-PCV13 era, p < 0.0001. No increase in non-PCV13 serotypes was recorded. S. pneumoniae remained the most frequent pathogen identified in the post-PCV13 era in unvaccinated children with an unchanged serotype distribution: respectively 26/66 (39.4%), 25/66 (37.9%), 5/66 (7.6%), and 4/66 (6.1%) for 1, 3, 7F and 19A. On the other hand 7F and 19A disappeared in vaccinated children and serotype 1 and 3 decreased by 91.8% and 31.5%, respectively. Realtime PCR was significantly more sensitive than culture both in pleural fluid (79.7% vs 12.5%) and in blood (17.8% vs 7.4%). In conclusion, our findings indicate that routine immunization with PCV13 has significantly reduced the burden of childhood PPE in vaccinated children, without increasing PPE due to other bacteria and without serotype shift. Moreover, the impact of PCV13 may be underestimated due to the increase in pneumococcal surveillance in Italy. Data has also shown that Real-time PCR is an essential tool to better define the etiology of PPE and to monitor vaccination plans. Longer studies will be necessary to evaluate the role of herd protection in PPE prevention.

Wet Cough and Nasal Symptoms in Children: Can We Do Better?

The causes of chronic cough in children are mainly dependent on the setting and age of the child. Protracted bacterial bronchitis is a frequent cause of morbidity in childhood, and antibiotic treatment is beneficial. Prompt recognition and early treatment is important both to prevent inappropriate use of asthma medications and also progression to bronchiectasis, but the diagnosis should not be made uncritically, because chronic wet cough is not necessarily due to lower airway disease. Upper Airway Cough Syndrome (UACS) is considered by some to cause chronic cough in childhood. Underlying UACS are many common conditions, including allergic rhinitis, adenoiditis and rhinosinusitis. Diagnosis relies on a combination of clinical criteria that are relatively sensitive but non-specific. The role of nasal endoscopy in children with chronic cough and signs suggesting UACS is unclear. Nasal saline solution irrigation is commonly used in UACS, but most studies have methodological biases, and efficacy data are scanty. Randomized controlled trials are urgently required. However, if saline washes, rather than oral antibiotics, can effectively treat some children with wet cough associated with upper airway conditions, antibiotic resistance could potentially be reduced. There is a need to further study wet cough and not to assume it to be equivalent to lower airway infection in all children.

Prospective evaluation of lung function in children with parapneumonic empyema.

RATIONALE: Prospective studies that evaluated the outcome of childhood empyema are limited. OBJECTIVE: To compare the outcome of pulmonary function in children with empyema. PATIENTS AND METHODS: Children discharged with a diagnosis of empyema underwent a longitudinal study including measurement of pulmonary function and radiographic imaging. RESULTS: The population consisted of 39 patients, 24 males, and 15 females; with a median age of 4.6 years. Etiology was defined in 20/39 patients, and predominant microorganism was Streptococcus pneumoniae (19/20 isolates). Chest tube drainage with or without fibrinolytic agents was the primary intervention in 25 children. Video-assisted thoracoscopic surgery was performed in 14 and 5 children as primary and secondary intervention, respectively. Thirty-five children completed the lung function follow-up. At first follow-up visit, 5 out of 17 children able to perform spirometry (initially collaborating children) had normal tests, and 12 had mild-to-moderate defects of lung function that returned to normal over 2-57 months. Eighteen children unable to perform spirometry at first follow-up visit (initially non-collaborating children) had normal tests when they were evaluated 5-78 months postdischarge. At the end of the follow-up, all patients had normal lung function. Time to normalize did not differ between groups receiving different treatments (initially collaborating children, P = 0.064; initially non-collaborating children P = 0.223). Three previously healthy children had recurrent cough, and all children had normal chest radiographs aside from pleural thickening. CONCLUSIONS: The respiratory outcome in children with empyema is generally good and is not influenced by the type of intervention.

GPs Meet Rare Lung Disorders Task Force factsheet: primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive disease of abnormalities of ciliary structure and function. The result is impaired mucociliary clearance, causing a variety of respiratory symptoms, and likely progression to bronchiectasis in most cases. Situs anomalies are present in nearly 50% of cases.

Middle lobe syndrome in children today.

Middle lobe syndrome in children is a distinct clinical and radiographic entity that has been well described in the pediatric literature. However, issues regarding its etiology, clinical presentation, and management continue to puzzle the clinical practitioner. Pathophysiologically, there are two forms of middle lobe syndrome, namely obstructive and nonobstructive. Middle lobe syndrome may present as symptomatic or asymptomatic, as persistent or recurrent atelectasis, or as pneumonitis or bronchiectasis of the middle lobe and/or lingula. A lower threshold of performing a chest radiograph is warranted in children with persistent or recurrent nonspecific respiratory symptoms, particularly if there is clinical deterioration, in order to detect middle lobe syndrome and to initiate a further diagnostic and therapeutic workup.

Th17/Treg imbalance in murine cystic fibrosis is linked to indoleamine 2,3-dioxygenase deficiency but corrected by kynurenines.

RATIONALE: Mutations in the cystic fibrosis (CF) transmembrane conductance regulator affect the innate epithelial immune function of the lung, resulting in exaggerated and ineffective airway inflammation that fails to eradicate pathogenic fungi. The appreciation of whether such fungi are primarily responsible for or a consequence of ineffective airway inflammation is important for future therapeutics development. OBJECTIVES: To characterize the impact of the tryptophan/kynurenine pathway on pathogenic airway inflammation preventing effective fungal clearance in CF. METHODS: We studied the expression of indoleamine 2,3-dioxygenase (IDO), the first enzyme in the kynurenine pathway of tryptophan degradation, in human and murine CF, the impact of IDO on lung inflammation and immunity in murine CF, and the potential role of tryptophan catabolism in pathogenesis and therapy of fungus-associated lung inflammation. MEASUREMENTS AND MAIN RESULTS: IDO was defective in murine and human CF. Genetic and transcriptional regulatory mechanisms contributed to dysfunctional IDO activity that, in turn, correlated with imbalanced Th17/Treg-cell responses to Aspergillus fumigatus in murine CF. Treatments enhancing IDO function or preventing pathogenic Th17-cell activation restored protective immunity to the fungus and improved lung inflammation in murine CF. CONCLUSIONS: This study provides a link between tryptophan catabolism and lung immune homeostasis in murine CF, representing a proof-of-concept that targeting pathogenic inflammation via IDO-mimetic drugs may benefit patients with CF.

Corticosteroids in respiratory diseases in children.

We review recent advances in the use of corticosteroids (CS) in pediatric lung disease. CS are frequently used, systemically or by inhalation. Their mechanisms of action in pulmonary diseases are ill defined. CS exert direct inhibitory effects on many inflammatory cells through genomic mechanisms. There is a time lag before clinical response, and the washout of effects is also prolonged. Prompt relief in some conditions, such as croup, may be related to airway mucosal vasoconstriction through a nongenomic mechanism. CS have proven beneficial roles in the treatment of asthma, croup, allergic bronchopulmonary aspergillosis, and subglottic hemangioma. In some conditions, such as bronchiolitis, cystic fibrosis, and bronchopulmonary dysplasia, their use is controversial and is not recommended routinely. In other conditions, such as tuberculosis, interstitial lung disease, acute lung aspiration, and acute respiratory distress syndrome, CS are often used empirically despite the lack of clear evidence of their benefit. New drug regimens, including the more flexible use of inhaled corticosteroids and long-acting ß-agonists in asthma, the lack of efficacy of oral corticosteroids in preschool children with acute wheeze, the severe complications of systemic dexamethasone used to prevent bronchopulmonary dysplasia and thus more restricted use, and the beneficial effect of pulse high-dose intravenous methylprednisolone in patients with allergic bronchopulmonary aspergillosis or cystic fibrosis are among the major recent developments. There is concern about adverse effects, especially growth and adrenal suppression, induced by systemic CS in children. These have been reduced, but not eliminated, with the use of the inhaled route. The benefits must be weighed against the potential detrimental effects.

Exhaled nitric oxide measurements in the first 2 years of life: methodological issues, clinical and epidemiological applications.

Fractional exhaled nitric oxide (FeNO) is a useful tool to diagnose and monitor eosinophilic bronchial inflammation in asthmatic children and adults. In children younger than 2 years of age FeNO has been successfully measured both with the tidal breathing and with the single breath techniques. However, there are a number of methodological issues that need to be addressed in order to increase the reproducibility of the FeNO measurements within and between infants. Indeed, a standardized method to measure FeNO in the first 2 years of life would be extremely useful in order to meaningfully interpret FeNO values in this age group. Several factors related to the measurement conditions have been found to influence FeNO, such as expiratory flow, ambient NO and nasal contamination. Furthermore, the exposure to pre- and postnatal risk factors for respiratory morbidity has been shown to influence FeNO values. Therefore, these factors should always be assessed and their association with FeNO values in the specific study population should be evaluated and, eventually, controlled for.There is evidence consistently suggesting that FeNO is increased in infants with family history of atopy/atopic diseases and in infants with recurrent wheezing. These findings could support the hypothesis that eosinophilic bronchial inflammation is present at an early stage in those infants at increased risk of developing persistent respiratory symptoms and asthma. Furthermore, it has been shown that FeNO measurements could represent a useful tool to assess bronchial inflammation in other airways diseases, such as primary ciliary dyskinesia, bronchopulmonary dysplasia and cystic fibrosis. Further studies are needed in order to improve the reproducibility of the measurements, and large prospective studies are warranted in order to evaluate whether FeNO values measured in the first years of life can predict the future development of asthma or other respiratory diseases.