Identifying diagnostic and prognostic factors in cerebral amyloid angiopathy-related inflammation: A systematic analysis of published and seven new cases.

AIMS: Cerebral amyloid angiopathy (CAA)-related inflammation (CAA-RI) is a potentially reversible manifestation of CAA, histopathologically characterised by transmural and/or perivascular inflammatory infiltrates. We aimed to identify clinical, radiological and laboratory variables capable of improving or supporting the diagnosis of or predicting/influencing the prognosis of CAA-RI and to retrospectively evaluate different therapeutic approaches. METHODS: We present clinical and neuroradiological observations in seven unpublished CAA-RI cases, including neuropathological findings in two definite cases. These cases were included in a systematic analysis of probable/definite CAA-RI cases published in the literature up to 31 December 2021. Descriptive and associative analyses were performed, including a set of clinical, radiological and laboratory variables to predict short-term, 6-month and 1-year outcomes and mortality, first on definite and second on an expanded probable/definite CAA-RI cohort. RESULTS: Data on 205 definite and 100 probable cases were analysed. CAA-RI had a younger symptomatic onset than non-inflammatory CAA, without sex preference. Transmural histology was more likely to be associated with the co-localisation of microbleeds with confluent white matter hyperintensities on magnetic resonance imaging (MRI). Incorporating leptomeningeal enhancement and/or sulcal non-nulling on fluid-attenuated inversion recovery (FLAIR) enhanced the sensitivity of the criteria. Cerebrospinal fluid pleocytosis was associated with a decreased probability of clinical improvement and longer term positive outcomes. Future lobar haemorrhage was associated with adverse outcomes, including mortality. Immunosuppression was associated with short-term improvement, with less clear effects on long-term outcomes. The superiority of high-dose over low-dose corticosteroids was not established. CONCLUSIONS: This is the largest retrospective associative analysis of published CAA-RI cases and the first to include an expanded probable/definite cohort to identify diagnostic/prognostic markers. We propose points for further crystallisation of the criteria and directions for future prospective studies.

Peripheral airway dysfunction in prematurity-associated obstructive lung disease identified by oscillometry.

INTRODUCTION: Mechanisms underlying lung dysfunction after preterm birth are poorly understood. Studying phenotypes of prematurity-associated lung disease may aid understanding of underlying mechanisms. Preterm-born children with and without lung dysfunction and term controls were assessed using oscillometry before and after exercise, and after postexercise bronchodilation. METHODS: Preterm-born children, born at gestation of 34 weeks or less, were classified into those with prematurity-associated obstructive lung disease (POLD; FEV1 < LLN, FEV1 /FVC < LLN), prematurity-associated preserved ratio of impaired spirometry (pPRISm; FEV1 < LLN, FEV1 /FVC ≥ LLN) and compared to preterm (FEV1 ≥ LLN) and term controls (%predicted FEV1 > 90%). All children underwent cardiopulmonary exercise, and oscillometry assessment at baseline, postexercise, and after postexercise bronchodilator administration. RESULTS: From 241 participants aged 7-12 years, complete data were available from 179: 15 children with POLD and 11 with pPRISm were compared with 93 preterm and 60 term controls. POLD group, when compared to both control groups, had impaired impedance, greater resistance, more negative (greater magnitude) reactance at low frequencies, and also had decreased compliance. pPRISm group demonstrated impaired reactance and compliance compared to term controls. No differences were noted between the preterm and term controls. Exercise had little impact on oscillometry values, but children with POLD had greatest improvements after postexercise bronchodilator administration, with decreased resistance and decreased magnitude of reactance, particularly at low frequencies. CONCLUSION: Preterm-born children with obstructive airway disease had the greatest oscillometry impairments and the largest improvements after postexercise bronchodilator compared to control groups. Oscillometry can potentially be used to identify preterm-born children with lung disease to institute treatment.

Respiratory Oscillometry in Newborn Infants: Conventional and Intra-Breath Approaches.

Background: Oscillometry has been employed widely as a non-invasive and standardized measurement of respiratory function in children and adults; however, limited information is available on infants. Aims: To establish the within-session variability of respiratory impedance (Zrs), to characterize the degree and profile of intra-breath changes in Zrs and to assess their impact on conventional oscillometry in newborns. Methods: 109 healthy newborns were enrolled in the study conducted in the first 5 postpartum days during natural sleep. A custom-made wave-tube oscillometry setup was used, with an 8-48 Hz pseudorandom and a 16 Hz sinusoidal signal used for spectral and intra-breath oscillometry, respectively. A resistance-compliance-inertance (R-C-L) model was fitted to average Zrs spectra obtained from successive 30-s recordings. Intra-breath measures, such as resistance (Rrs) and reactance (Xrs) at the end-expiratory, end-inspiratory and maximum-flow points were estimated from three 90-s recordings. All natural and artifact-free breaths were included in the analysis. Results: Within-session changes in the mean R, C and L values, respectively, were large (mean coefficients of variation: 10.3, 20.3, and 26.6%); the fluctuations of the intra-breath measures were of similar degree (20-24%). Intra-breath analysis also revealed large swings in Rrs and Xrs within the breathing cycle: the peak-to-peak changes amounted to 93% (range: 32-218%) and 41% (9-212%), respectively, of the zero-flow Zrs magnitude. Discussion: Intra-breath tracking of Zrs provides new insight into the determinants of the dynamics of respiratory system, and highlights the biasing effects of mechanical non-linearities on the average Zrs data obtained from the conventional spectral oscillometry.

Effect of nasal airway nonlinearities on oscillometric resistance measurements in infants.

Oscillometric measurements of respiratory system resistance (Rrs) in infants are usually made via the nasal pathways, which not only significantly contribute to overall Rrs but also introduce marked flow (V')-dependent changes. We employed intrabreath oscillometry in casts of the upper airways constructed from head CT images of 46 infants. We examined oscillometric nasal resistance (Rn) in upper airway casts with no respiratory flow (R0) and the effect of varying V' on Rn by simulating tidal breathing. A characteristic nonlinear relationship was found between Rn and V', exhibiting segmental linearity and a prominent breakpoint (V'bp) after log-log transformation. V'bp was linearly related to the preceding value of end-expiratory volume acceleration (V″eE; on average r2 = 0.96, P < 0.001). Rn depended on V', and R at end-expiration (ReE) showed a strong dependence on V″eE in every cast (r2 = 0.994, P < 001) with considerable interindividual variability. The intercept of the linear regression of ReE versus V″eE was found to be a close estimate of R0. These findings were utilized in reanalyzed Rrs data acquired in vivo in a small group of infants (n = 15). Using a graphical method to estimate R0 from ReE, we found a relative contribution of V'-dependent nonlinearity to total resistance of up to 33%. In conclusion, we propose a method for correcting the acceleration-dependent nonlinearity error in ReE. This correction can be adapted to estimate R0 from a single intrabreath oscillometric measurement, which would reduce the masking effects of the upper airways on the changes in the intrathoracic resistance.NEW & NOTEWORTHY Oscillometric measurements of respiratory system resistance (Rrs) in infants are usually made via the nasal pathways, which not only significantly contribute to overall Rrs but also introduce marked flow acceleration-dependent distortions. Here, we propose a method for correcting flow acceleration-dependent nonlinearity error based on in vitro measurements in 3D-printed upper airway casts of infants as well as in vivo measurements. This correction can be adapted to estimate Rrs from a single intrabreath oscillometric measurement.

Intra-breath measures of respiratory mechanics in healthy African infants detect risk of respiratory illness in early life.

Lower respiratory tract illness (LRTI) is a leading cause of mortality and morbidity in children. Sensitive and noninvasive infant lung function techniques are needed to measure risk for and impact of LRTI on lung health. The objective of this study was to investigate whether lung function derived from the intra-breath forced oscillation technique (FOT) was able to identify healthy infants at risk of LRTI in the first year of life.Lung function was measured with the novel intra-breath FOT, in 6-week-old infants in a South African birth cohort (Drakenstein Child Health Study). LRTI during the first year was confirmed by study staff. The association between baseline lung function and LRTI was assessed with logistic regression and odds ratios determined using optimal cut-off values.Of the 627 healthy infants with successful lung function testing, 161 (24%) had 238 LRTI episodes subsequently during the first year. Volume dependence of respiratory resistance (ΔR) and reactance (ΔX) was associated with LRTI. The predictive value was stronger if LRTI was recurrent (n=50 (31%): OR 2.5, ΔX), required hospitalisation (n=38 (16%): OR 5.4, ΔR) or was associated with wheeze (n=87 (37%): OR 3.9, ΔX).Intra-breath FOT can identify healthy infants at risk of developing LRTI, wheezing or severe illness in the first year of life.