Anastassios C. Koumbourlis

Lung Function in Sickle Cell Disease

Although some of the most severe complications of Sickle Cell Disease (SCD) tend to be acute and severe (e.g. acute chest syndrome, stroke etc.), the chronic ones can be equally debilitating. Prominent among them is the effect that the disease has on lung growth and function. For many years the traditional teaching has been that SCD is associated with the development of a restrictive lung defect. However, there is increasing evidence that this is not a universal finding and that at least during childhood and adolescence, the majority of the patients have a normal or obstructive pattern of lung function. The following article reviews the current knowledge on the effects of SCD on lung growth and function. Special emphasis is given to the controversies among the published articles in the literature and discusses possible causes for these discrepancies.

Somatic growth and lung function in sickle cell disease

Somatic growth is a key indicator of overall health and well-being with important prognostic implications in the management of chronic disease. Worldwide studies of growth in children and adults with SCD have predominantly shown delayed growth (especially in terms of body weight) that is gradual and progressive in nature. However, more recent studies have shown that a substantial number of patients with SCD have normal weight gain whereas some are even obese. Height in patients with SCD is not universally affected even among those with suboptimal weight gain, whereas some achieve the same or greater height than healthy controls. The relationship between somatic growth and lung function in SCD is not yet clearly defined. As a group, patients with SCD tend to have lower lung volumes compared with healthy controls. These findings are similar across the age spectrum and across ethnic/racial lines regardless of the differences in body weight. Several mechanisms and risk factors have been proposed to explain these findings. These include malnutrition, racial differences and socioeconomic status. In addition, there are structural changes of the thorax (specifically the anterio-posterior chest diameter and anterio-posterior to lateral chest ratio) specific to sickle cell disease, that potentially interfere with normal lung growth. Although, caloric and protein intake have been shown to improve both height and weight, the composition of an optimal diet remains unclear. The following article reviews the current knowledge and controversies regarding somatic growth and its relationship with lung function in sickle cell disease (SCD) as well as the role of specific deficiencies of certain micronutrients.

Pulmonary Complications of Obesity

There is an increasing prevalence of obesity globally. Implications of the global obesity epidemic are far-reaching and have become a major public health issue. Strikingly, the incidence of obesity is growing fastest among the pediatric population. Complications of childhood obesity are multifactorial with effects on psychosocial, pulmonary, gastrointestinal, renal, musculoskeletal, neurological, cardiovascular, and endocrine systems. The following chapter discusses the pulmonary complications of obesity as body habitus has a significant impact, not only on the mechanics of the respiratory system but by interfering with several immunopathologic and endocrine mechanisms as well.

Pulmonary Complications of Rheumatologic Disorders

Rheumatologic diseases are a heterogeneous group of more than 100 immunologically mediated chronic systemic inflammatory disorders. Although they are not specific to the respiratory system (in fact one of their characteristics is that they affect multiple tissues/organs in the body), these disorders invariably involve the respiratory system, but the extent and severity of the pulmonary complications as well as their onset and clinical course vary significantly among them. The following chapter discusses the pathophysiology of these disorders as they relate to the different components of the respiratory system as well as on the various diagnostic modalities that clinicians should consider in making the diagnosis and monitoring of the disease.

Pulmonary Complications of Cardiovascular Disorders

Although the cardiovascular system and the lungs have different embryologic origins, they are anatomically and functionally completely interconnected in order to achieve the gas exchange that takes place in the alveolar-capillary membrane. As a result any disorder that affects the cardiovascular system is bound to have effects on the lungs and the airways, whereas any acute or chronic lung disease puts a strain on the cardiovascular system. For example, cardiomegaly or abnormal vessels can cause compression of the lungs and of the large airways, and cardiac dysfunction may result in the development of significant pulmonary edema. All these conditions will impede onto lung mechanics, and they will eventually affect the normal gas exchange. Conversely, significant lung disease will affect the cardiovascular function (e.g., development of secondary pulmonary hypertension due to chronic hypoxemia). Dysfunction of both the respiratory and cardiovascular systems often presents with similar clinical signs and symptoms (e.g., dyspnea especially on exertion, wheezing, cough, hypoxemia), and identifying the actual culprit is not always easy. Thus, it is imperative for the pulmonologist who evaluates a patient (especially one with known heart disease) to consider to what extend the respiratory symptoms may be due to abnormalities of the heart and the big vessels.

Antibiotic multidrug resistance in the cystic fibrosis airway microbiome is associated with decreased diversity

Background Cystic fibrosis (CF) is associated with significant morbidity and early mortality due to recurrent acute and chronic lung infections. The chronic use of multiple antibiotics increases the possibility of multidrug resistance (MDR). Antibiotic susceptibility determined by culture-based techniques may not fully represent the resistance profile. The study objective was to detect additional antibiotic resistance using molecular methods and relate the presence of MDR to airway microbiome diversity and pulmonary function. Methods Bacterial DNA was extracted from sputum samples and amplified for the V4 region of the 16S rRNA gene. An qPCR array was used to detect antibiotic resistance genes. Clinical culture results and pulmonary function were also noted for each encounter. Results Six study participants contributed samples from 19 encounters. Those samples with MDR (n = 7) had significantly lower diversity measured by inverse Simpsons index than those without (n = 12) (2.193 ± 0.427 vs 6.023 ± 1.564, p = 0.035). Differential abundance showed that samples with MDR had more Streptococcus (p = 0.002) and Alcaligenaceae_unclassified (p = 0.002). Pulmonary function was also decreased when MDR was present (FEV1, 51 ± 22.9 vs 77 ± 26.7, p = 0.054; FVC, 64.5 ± 22.7 vs 91.6 ± 27.7, p = 0.047). Conclusions The presence of MDR within the CF airway microbiome was associated with decreased microbial diversity, the presence of Alcaligenes, and decreased pulmonary function.

Benchmark Evaluation of True Single Molecular Sequencing to Determine Cystic Fibrosis Airway Microbiome Diversity

Cystic fibrosis (CF) is an autosomal recessive disease associated with recurrent lung infections that can lead to morbidity and mortality. The impact of antibiotics for treatment of acute pulmonary exacerbations on the CF airway microbiome remains unclear with prior studies giving conflicting results and being limited by their use of 16S ribosomal RNA sequencing. Our primary objective was to validate the use of true single molecular sequencing (tSMS) and PathoScope in the analysis of the CF airway microbiome. Three control samples were created with differing amounts of Burkholderia cepacia, Pseudomonas aeruginosa, and Prevotella melaninogenica, three common bacteria found in cystic fibrosis lungs. Paired sputa were also obtained from three study participants with CF before and >6 days after initiation of antibiotics. Antibiotic resistant B. cepacia and P. aeruginosa were identified in concurrently obtained respiratory cultures. Direct sequencing was performed using tSMS, and filtered reads were aligned to reference genomes from NCBI using PathoScope and Kraken and unique clade-specific marker genes using MetaPhlAn. A total of 180–518 K of 6–12 million filtered reads were aligned for each sample. Detection of known pathogens in control samples was most successful using PathoScope. In the CF sputa, alpha diversity measures varied based on the alignment method used, but similar trends were found between pre- and post-antibiotic samples. PathoScope outperformed Kraken and MetaPhlAn in our validation study of artificial bacterial community controls and also has advantages over Kraken and MetaPhlAn of being able to determine bacterial strains and the presence of fungal organisms. PathoScope can be confidently used when evaluating metagenomic data to determine CF airway microbiome diversity.

Lung function in sickle cell disease: An elusive relationship

Sickle cell disease (SCD) has been known as a distinct entity for over 100 years, but its effects on lung function especially in children had not attracted attention until very recently (there had been only 3 published studies on lung function in children with SCD before the year 2000). Despite a growing interest and research on the subject the number of publications is still lagging far behind the numbers on diseases such as Cystic Fibrosis or asthma. Thus, any new published study on SCD is an event worth mentioning. The current consensus in the pediatric literature is that SCD does affect the lung function, that its effects may start early in life (even during infancy), and that changes do occur as the patients grow older. However, there is still no consensus on whether SCD is causing a specific lung function abnormality. Several mechanisms have been implicated in the pathogenesis of the pulmonary complications including airway reactivity and asthma but the exact timing and mechanism(s) involved remain unclear. In this issue of the Journal, Lunt and colleagues present a study of longitudinal follow-up of lung function in 2 cohorts of children with SCD. Both cohorts were tested twice with standard techniques (spirometry before and after administration of bronchodilator and measurement of lung volumes by body plethysmography). The first group (cohort 1) consisted of relatively young children (median age 8.8 years at baseline) who were tested at baseline and approximately 2 years later. The secondgroup (cohort 2) consisted of slightly older children at baseline (median age 10.2 years) who were tested approximately 10 years apart. The main objective of the study was to “examine the rate of decline in lung function in children with SCD in comparison to age and ethnic matched controls” and more specifically to test the hypothesis that younger patients (cohort 1) will have a greater rate of decline in lung function compared with older patients (cohort 2) due to the higher occurrence of acute chest syndrome (ACS) among them. Two additional hypotheses were also examined, a) that obstructive abnormalities will be replaced by restrictive abnormalities overtime, and (b) that the pattern of lung function abnormalities aswell as the presence of asthma may be risk factors for ACS episodes. The analysis of the data seemed to confirm the hypotheses showing a) that the parameters of lung function indeed declined in both groups over time, and that the rate of decline was faster among the younger group; b) that the prevalence of obstructive pattern decreased overtime, whereas the prevalence of the restrictive pattern increased; c) that there was a significant association between the presence of obstructive pattern of lung function and ACS; and d) that the obstructive pattern was predictive of the development of ACS. The study confirms the findings of several previously published studies, i.e. that SCD is not associated with a specific pattern of lung function; that the majority of children and adolescents with SCD have actually normal pattern of lung function; that the most common lung function abnormality is lower airway obstruction and that the restrictive pattern tends to develop gradually from late childhood to adulthood. Compared with the older studies thatwere retrospective and ofmuch shorter follow-up, the study by Lunt et al. carries extra credibility because of its 10 year prospective longitudinal follow-up. However, due to its design and the way the data were analyzed and presented, the study misses the opportunity to provide certain very important pieces of information. For example, one of the most important elements of the current study is the comparison of changes in lung function over time between “younger” and “older” patients. However,

Interpretation of Pulmonary Function Tests in Clinical Practice

Pulmonary function tests (PFTs) are diagnostic modalities that evaluate qualitatively and quantitatively the size and function of the lungs. The most common areas of evaluation in clinical practice are: (a) the measurement of the lung volume, (b) the assessment and measurement of the airway function (upper and lower), and (c) the ability of the lung to diffuse oxygen. Several other tests can be performed to evaluate specific aspects of the lung function such as lung or respiratory system compliance and resistance, airway hyperreactivity/hyperresponsiveness, airway inflammation. This chapter focuses on the principles of interpretation (and its pitfalls) of the most commonly used tests that are commercially available for use in children and adolescents in an inpatient or outpatient setting.