Pulmonary Computed Tomography Screening Frequency in Primary Antibody Deficiency.

BACKGROUND: Patients with primary antibody deficiency (PAD) frequently suffer from pulmonary complications, associated with severe morbidity and mortality. Hence, regular pulmonary screening by computed tomography (CT) scanning is advised. However, predictive risk factors for pulmonary morbidity are lacking. OBJECTIVE: To identify patients with PAD at risk for pulmonary complications necessitating regular CT screening. METHODS: A retrospective, longitudinal cohort study of patients with PAD (median follow-up 7.4 [2.3-14.8] years) was performed. CTs were scored using the modified Brody-II scoring system. Clinical and laboratory parameters were retrospectively collected. Potential risk factors were identified by univariate analysis when P < .2 and confirmed by multivariable logistic regression when P < .05. RESULTS: The following independent risk factors for progression of airway disease (AD) were identified: (1) diagnosis of X-linked agammaglobulinemia (XLA), (2) recurrent airway infections (2.5/year), and (3) the presence of AD at baseline. Signs of AD progression were detected in 5 of 11 patients with XLA and in 17 of 80 of the other patients with PAD. Of the 22 patients who progressed, 17 had pre-existent AD scores ≥7.0%. Increased AD scores were related to poorer forced expiratory volume in 1 second values and chronic cough. Common variable immunodeficiency and increased CD4 effector/memory cells were risk factors for an interstitial lung disease (ILD) score ≥13.0%. ILD ≥13.0% occurred in 12 of 80 patients. Signs of ILD progression were detected in 8 of 80 patients, and 4 of 8 patients showing progression had pre-existent ILD scores ≥13.0%. CONCLUSION: We identified risk factors that distinguished patients with PAD at risk for AD and ILD presence and progression, which could guide future screening frequency; however, independent and preferably prospective validation is needed.

Antibody deficiencies in children are associated with prematurity and a family history of infections.

BACKGROUND: Recurrent respiratory tract infections (rRTIs) frequently affect young children and are associated with antibody deficiencies. We investigated the prevalence of and epidemiological risk factors associated with antibody deficiencies in young children with rRTIs and their progression over time, and linked these to prospectively measured RTI symptoms. METHODS: We included children <7 years with rRTIs in a prospective cohort study. Patient characteristics associated with antibody deficiencies were identified using multivariable logistic regression analysis. RESULTS: We included 146 children with a median age of 3.1 years. Daily RTI symptoms were monitored in winter in n = 73 children and repeated immunoglobulin level measurements were performed in n = 45 children. Antibody deficiency was diagnosed in 56% and associated with prematurity (OR 3.17 [1.15-10.29]) and a family history of rRTIs (OR 2.37 [1.11-5.15]). Respiratory symptoms did not differ between children with and without antibody deficiencies. During follow-up, antibody deficiency diagnosis remained unchanged in 67%, while 18% of children progressed to a more severe phenotype. CONCLUSION: Immune maturation and genetic predisposition may lie at the basis of antibody deficiencies commonly observed in early life. Because disease severity did not differ between children with and without antibody deficiency, we suggest symptom management can be similar for all children with rRTIs. IMPACT: An antibody deficiency was present in 56% of children <7 years with recurrent respiratory tract infections (rRTIs) in a Dutch tertiary hospital setting. Prematurity and a family history of rRTIs were associated with antibody deficiencies, suggesting that immune maturation and genetic predisposition may lie at the basis of antibody deficiencies in early life. RTI symptoms did not differ between children with and without antibody deficiency, suggesting that symptom management can be similar for all children with rRTIs, irrespective of humoral immunological deficiencies. During follow-up, 18% of children progressed to a more severe phenotype, emphasizing that early diagnosis is warranted to prevent long-term morbidity and increase quality of life.

16S rRNA-Based Microbiota Profiling Assists Conventional Culture Analysis of Airway Samples from Pediatric Cystic Fibrosis Patients.

16S-based sequencing provides broader information on the respiratory microbial community than conventional culturing. However, it (often) lacks species- and strain-level information. To overcome this issue, we used 16S rRNA-based sequencing results from 246 nasopharyngeal samples obtained from 20 infants with cystic fibrosis (CF) and 43 healthy infants, which were all 0 to 6 months old, and compared them to both standard (blind) diagnostic culturing and a 16S-sequencing-informed "targeted" reculturing approach. Using routine culturing, we almost uniquely detected Moraxella catarrhalis, Staphylococcus aureus, and Haemophilus influenzae (42%, 38%, and 33% of samples, respectively). Using the targeted reculturing approach, we were able to reculture 47% of the top-5 operational taxonomical units (OTUs) in the sequencing profiles. In total, we identified 60 species from 30 genera with a median of 3 species per sample (range, 1 to 8). We also identified up to 10 species per identified genus. The success of reculturing the top-5 genera present from the sequencing profile depended on the genus. In the case of Corynebacterium being in the top 5, we recultured them in 79% of samples, whereas for Staphylococcus, this value was only 25%. The success of reculturing was also correlated with the relative abundance of those genera in the corresponding sequencing profile. In conclusion, revisiting samples using 16S-based sequencing profiles to guide a targeted culturing approach led to the detection of more potential pathogens per sample than conventional culturing and may therefore be useful in the identification and, consequently, treatment of bacteria considered relevant for the deterioration or exacerbation of disease in patients like those with CF. IMPORTANCE Early and effective treatment of pulmonary infections in cystic fibrosis is vital to prevent chronic lung damage. Although microbial diagnostics and treatment decisions are still based on conventional culture methods, research is gradually focusing more on microbiome and metagenomic-based approaches. This study compared the results of both methods and proposed a way to combine the best of both worlds. Many species can relatively easily be recultured based on the 16S-based sequencing profile, and it provides more in-depth information about the microbial composition of a sample than that obtained through routine (blind) diagnostic culturing. Still, well-known pathogens can be missed by both routine diagnostic culture methods as well as by targeted reculture methods, sometimes even when they are highly abundant, which may be a consequence of either sample storage conditions or antibiotic treatment at the time of sampling.

Analysing the protection from respiratory tract infections and allergic diseases early in life by human milk components: the PRIMA birth cohort.

BACKGROUND: Many studies support the protective effect of breastfeeding on respiratory tract infections. Although infant formulas have been developed to provide adequate nutritional solutions, many components in human milk contributing to the protection of newborns and aiding immune development still need to be identified. In this paper we present the methodology of the "Protecting against Respiratory tract lnfections through human Milk Analysis" (PRIMA) cohort, which is an observational, prospective and multi-centre birth cohort aiming to identify novel functions of components in human milk that are protective against respiratory tract infections and allergic diseases early in life. METHODS: For the PRIMA human milk cohort we aim to recruit 1000 mother-child pairs in the first month postpartum. At one week, one, three, and six months after birth, fresh human milk samples will be collected and processed. In order to identify protective components, the level of pathogen specific antibodies, T cell composition, Human milk oligosaccharides, as well as extracellular vesicles (EVs) will be analysed, in the milk samples in relation to clinical data which are collected using two-weekly parental questionnaires. The primary outcome of this study is the number of parent-reported medically attended respiratory infections. Secondary outcomes that will be measured are physician diagnosed (respiratory) infections and allergies during the first year of life. DISCUSSION: The PRIMA human milk cohort will be a large prospective healthy birth cohort in which we will use an integrated, multidisciplinary approach to identify the longitudinal effect human milk components that play a role in preventing (respiratory) infections and allergies during the first year of life. Ultimately, we believe that this study will provide novel insights into immunomodulatory components in human milk. This may allow for optimizing formula feeding for all non-breastfed infants.

Treatment Strategies for GLILD in Common Variable Immunodeficiency: A Systematic Review.

Introduction: Besides recurrent infections, a proportion of patients with Common Variable Immunodeficiency Disorders (CVID) may suffer from immune dysregulation such as granulomatous-lymphocytic interstitial lung disease (GLILD). The optimal treatment of this complication is currently unknown. Experienced-based expert opinions have been produced, but a systematic review of published treatment studies is lacking. Goals: To summarize and synthesize the published literature on the efficacy of treatments for GLILD in CVID. Methods: We performed a systematic review using the PRISMA guidelines. Papers describing treatment and outcomes in CVID patients with radiographic and/or histologic evidence of GLILD were included. Treatment regimens and outcomes of treatment were summarized. Results: 6124 papers were identified and 42, reporting information about 233 patients in total, were included for review. These papers described case series or small, uncontrolled studies of monotherapy with glucocorticoids or other immunosuppressants, rituximab monotherapy or rituximab plus azathioprine, abatacept, or hematopoietic stem cell transplantation (HSCT). Treatment response rates varied widely. Cross-study comparisons were complicated because different treatment regimens, follow-up periods, and outcome measures were used. There was a trend towards more frequent GLILD relapses in patients treated with corticosteroid monotherapy when compared to rituximab-containing treatment regimens based on qualitative endpoints. HSCT is a promising alternative to pharmacological treatment of GLILD, because it has the potential to not only contain symptoms, but also to resolve the underlying pathology. However, mortality, especially among immunocompromised patients, is high. Conclusions: We could not draw definitive conclusions regarding optimal pharmacological treatment for GLILD in CVID from the current literature since quantitative, well-controlled evidence was lacking. While HSCT might be considered a treatment option for GLILD in CVID, the risks related to the procedure are high. Our findings highlight the need for further research with uniform, objective and quantifiable endpoints. This should include international registries with standardized data collection including regular pulmonary function tests (with carbon monoxide-diffusion), uniform high-resolution chest CT radiographic scoring, and uniform treatment regimens, to facilitate comparison of treatment outcomes and ultimately randomized clinical trials.

Risk factors for atopic diseases and recurrent respiratory tract infections in children.

INTRODUCTION: The simultaneously increased prevalence of atopic diseases and decreased prevalence of infectious diseases might point to a link between the two entities. Past work mainly focused on either atopic diseases or recurrent infections. We aim to investigate whether risk factors for atopic diseases (ie, asthma, allergic rhinitis, atopic dermatitis, and/or food allergy) differ from risk factors for recurrent respiratory tract infections (RRTIs) in children. METHODS: Cross-sectional data were used from 5517 children aged 1 to 18 years who participated in an Electronic Portal for children between 2011 and 2019. Univariable/multivariable logistic regression analyses were performed to determine risk factors for any atopic disease and RRTIs. RESULTS: Children aged ≥5 years were more likely to have any atopic disease (adjusted odds ratio [OR]: 1.50-2.77) and less likely to have RRTIs (OR: 0.68-0.84) compared to children aged less than 5 years. Female sex (OR: 0.72; 95% confidence interval [CI]: 0.63-0.81), low birth weight (OR: 0.74; 95% CI: 0.57-0.97) and dog ownership (OR: 0.79; 95% CI: 0.66-0.95) reduced the odds of any atopic disease, but not of RRTIs. Daycare attendance (OR: 1.22; 95% CI: 1.02-1.47) was associated with RRTIs, but not with atopic diseases. A family history of asthma, allergic rhinitis, atopic dermatitis, and RRTIs was significantly associated with the same entity in children, with OR varying from 1.58 (95% CI: 1.35-1.85) in allergic rhinitis to 2.20 (95% CI: 1.85-2.61) in asthma. CONCLUSION: Risk factors for atopic diseases are distinct from risk factors for RRTIs, suggesting that the changing prevalence of both entities is not related to shared risk factors.

Development of the gut microbiota in early life: The impact of cystic fibrosis and antibiotic treatment.

OBJECTIVES: Patients with Cystic Fibrosis (CF) suffer from pancreatic insufficiency, lipid malabsorption and gastrointestinal complaints, next to progressive pulmonary disease. Altered mucosal homoeostasis due to malfunctioning chloride channels results in an adapted microbial composition of the gastrointestinal and the respiratory tract. Additionally, antibiotic treatment has the potential to distort resident microbial communities dramatically. This study aims to investigate early life development of the gut microbial community composition of children with CF compared to healthy infants and to study the independent effects of antibiotics taking into account other clinical and lifestyle factors. STUDY DESIGN: Faecal samples from 20 infants with CF and 45 healthy infants were collected regularly during the first 18 months of life and microbial composition was determined using 16S rRNA based sequencing. RESULTS: We observed significant differences in the overall microbiota composition between infants with CF and healthy infants (p<0.001). Akkermansia and Anaerostipes were significantly more abundant in control infants, whereas Streptococci and E. coli were significantly more abundant in infants with CF, also after correction for several clinical factors (p<0.05). Antibiotic use in infants with CF was associated with a lower alpha diversity, a reduced abundance of Bifidobacterium and Bacteroides, and a higher abundance of Enterococcus. CONCLUSION: Microbial development of the gut is different in infants with CF compared to healthy infants from the first months of life on, and further deviates over time, in part as a result of antibiotic treatment. The resulting dysbiosis may have significant functional consequences for the microbial ecosystem in CF patients.

Concordance between upper and lower airway microbiota in infants with cystic fibrosis.

Nasopharyngeal and oropharyngeal samples are commonly used to direct therapy for lower respiratory tract infections in non-expectorating infants with cystic fibrosis (CF).We aimed to investigate the concordance between the bacterial community compositions of 25 sets of nasopharyngeal, oropharyngeal and bronchoalveolar lavage (BAL) samples from 17 infants with CF aged ∼5 months (n=13) and ∼12 months (n=12) using conventional culturing and 16S-rRNA sequencing.Clustering analyses demonstrated that BAL microbiota profiles were in general characterised by a mixture of oral and nasopharyngeal bacteria, including commensals like Streptococcus, Neisseria, Veillonella and Rothia spp. and potential pathogens like Staphylococcus aureus, Haemophilus influenzae and Moraxella spp. Within each individual, however, the degree of concordance differed between microbiota of both upper respiratory tract niches and the corresponding BAL.The inconsistent intra-individual concordance between microbiota of the upper and lower respiratory niches suggests that the lungs of infants with CF may have their own microbiome that seems seeded by, but is not identical to, the upper respiratory tract microbiome.

Development of the Nasopharyngeal Microbiota in Infants with Cystic Fibrosis.

RATIONALE: Cystic fibrosis (CF) is characterized by early structural lung disease caused by pulmonary infections. The nasopharynx of infants is a major ecological reservoir of potential respiratory pathogens. OBJECTIVES: To investigate the development of nasopharyngeal microbiota profiles in infants with CF compared with those of healthy control subjects during the first 6 months of life. METHODS: We conducted a prospective cohort study, from the time of diagnosis onward, in which we collected questionnaires and 324 nasopharynx samples from 20 infants with CF and 45 age-matched healthy control subjects. Microbiota profiles were characterized by 16S ribosomal RNA-based sequencing. MEASUREMENTS AND MAIN RESULTS: We observed significant differences in microbial community composition (P < 0.0002 by permutational multivariate analysis of variance) and development between groups. In infants with CF, early Staphylococcus aureus and, to a lesser extent, Corynebacterium spp. and Moraxella spp. dominance were followed by a switch to Streptococcus mitis predominance after 3 months of age. In control subjects, Moraxella spp. enrichment occurred throughout the first 6 months of life. In a multivariate analysis, S. aureus, S. mitis, Corynebacterium accolens, and bacilli were significantly more abundant in infants with CF, whereas Moraxella spp., Corynebacterium pseudodiphtericum and Corynebacterium propinquum and Haemophilus influenzae were significantly more abundant in control subjects, after correction for age, antibiotic use, and respiratory symptoms. Antibiotic use was independently associated with increased colonization of gram-negative bacteria such as Burkholderia spp. and members of the Enterobacteriaceae bacteria family and reduced colonization of potential beneficial commensals. CONCLUSIONS: From diagnosis onward, we observed distinct patterns of nasopharyngeal microbiota development in infants with CF under 6 months of age compared with control subjects and a marked effect of antibiotic therapy leading toward a gram-negative microbial composition.

Long-term effects of pneumococcal conjugate vaccine on nasopharyngeal carriage of S. pneumoniae, S. aureus, H. influenzae and M. catarrhalis.

BACKGROUND: Shifts in pneumococcal serotypes following introduction of 7-valent pneumococcal conjugate vaccine (PCV-7) may alter the presence of other bacterial pathogens co-inhabiting the same nasopharyngeal niche. METHODOLOGY/PRINCIPAL FINDINGS: Nasopharyngeal prevalence rates of S. pneumoniae, S. aureus, H. influenzae and M. catarrhalis were investigated before, 3 and 4.5 years after introduction of PCV-7 in the national immunisation program in children at 11 and 24 months of age, and parents of 24-month-old children (n≈330/group) using conventional culture methods. Despite a virtual disappearance of PCV-7 serotypes over time, similar overall pneumococcal rates were observed in all age groups, except for a significant reduction in the 11-month-old group (adjusted Odds Ratio after 4.5 years 0.48, 95% Confidence Interval 0.34-0.67). Before, 3 and 4.5 years after PCV-7 implementation, prevalence rates of S. aureus were 5%, 9% and 14% at 11 months of age (3.59, 1.90-6.79) and 20%, 32% and 34% in parents (1.96, 1.36-2.83), but remained similar at 24 months of age, respectively. Prevalence rates of H. influenzae were 46%, 65% and 65% at 11 months (2.22, 1.58-3.13), 52%, 73% and 76% at 24 months of age (2.68, 1.88-3.82) and 23%, 30% and 40% in parents (2.26, 1.58-3.33), respectively. No consistent changes in M. catarrhalis carriage rates were observed over time. CONCLUSIONS/SIGNIFICANCE: In addition to large shifts in pneumococcal serotypes, persistently higher nasopharyngeal prevalence rates of S. aureus and H. influenzae were observed among young children and their parents after PCV-7 implementation. These findings may have implications for disease incidence and antibiotic treatment in the post-PCV era.

Nasopharyngeal colonization elicits antibody responses to staphylococcal and pneumococcal proteins that are not associated with a reduced risk of subsequent carriage.

Knowledge of the immunological correlates of Staphylococcus aureus and Streptococcus pneumoniae colonization is required for the search for future protein vaccines. We evaluated natural antibody levels against pneumococcal and staphylococcal proteins in relation to previous bacterial colonization with both pathogens. In a randomized controlled trial, nasopharyngeal samples were obtained from children at 1.5, 6, 12, 18, and 24 months and cultured for S. aureus and S. pneumoniae. Approximately 50% of the children were PCV7 vaccinated. Serum IgG against 18 pneumococcal and 40 staphylococcal proteins was semiquantified by Luminex technology from 111 12 month olds and 158 24 month olds. Previous culture-proven S. aureus colonization was associated with higher IgG levels against 6/40 staphylococcal proteins (ClfB, ClfA, Efb, CHIPS, LukD, and LukF [P ≤ 0.001]) compared to noncarriers. Previous pneumococcal colonization was associated with increased IgG levels against 12/18 pneumococcal proteins compared to noncarriers (P ≤ 0.003). Increasing age was associated with higher levels of antibodies to most pneumococcal proteins and lower levels of antibodies to over half the staphylococcal proteins, reflecting natural colonization dynamics. Anti-S. pneumoniae and anti-S. aureus protein antibodies at the age of 12 months were not negatively correlated with subsequent colonization with the homologous species in the following year and did not differ between PCV7-vaccinated and nonvaccinated children. Colonization with S. aureus and S. pneumoniae induces serum IgG against many proteins, predominantly proteins with immune-modulating functions, irrespective of PCV7 vaccination. None of them appeared to be protective against new acquisition with both pathogens, possibly due to the polymorphic nature of those proteins in the circulating bacterial population.