Management of tracheobronchial amyloidosis: a review of the literature.

Introduction: Tracheobronchial amyloidosis is a rare idiopathic disorder characterised by extracellular deposition of misfolded protein fibrils in the tracheobronchial tree. It presents with nonspecific symptoms. Deciding on the best treatment approach can be challenging due to the lack of a treatment guideline. We undertook a review to assess the therapeutic options for tracheobronchial amyloidosis and to highlight gaps within the existing evidence. Methods: We performed a literature search from 1 January 1990 until 1 March 2022 to identify relevant literature regarding patient characteristics, symptoms, management and prognosis for patients with tracheobronchial amyloidosis. Results: 77 studies consisting of 300 patients were included. We found a great heterogeneity in the management of tracheobronchial amyloidosis patients. Although a fifth of the reported patients were managed with a wait-and-see approach, many different treatments were used as a single intervention, or multiple treatments were combined. An interesting finding is the slightly higher percentage of patients with Sjögren syndrome (n=5, 1.7%) and tracheobronchial amyloidosis compared to the normal population (0.5-1.0%). Conclusions: There is a great heterogeneity in the management of tracheobronchial amyloidosis patients. The treatment is still based on expert opinion due to the lack of a treatment guideline. Various treatment approaches include a wait-and-see approach, external beam radiotherapy, therapeutic bronchoscopy, immunosuppressive treatment and surgery.

Focal 18 F-FDG uptake predicts progression of pre-invasive squamous bronchial lesions to invasive cancers.

INTRODUCTION: Pre-invasive squamous lesions of the central airways can progress into invasive lung cancers. Identifying these high-risk patients could enable detection of invasive lung cancers at an early stage. In this study, we investigated the value of 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography (PET) scans in predicting progression in patients with pre-invasive squamous endobronchial lesions. METHODS: In this retrospective study, patients with pre-invasive endobronchial lesions, who underwent an 18 F-FDG PET scan at the VU University Medical Center Amsterdam, between January 2000 and December 2016, were included. Autofluorescence bronchoscopy (AFB) was used for tissue sampling and was repeated every 3 months. The minimum and median follow-up was 3 and 46.5 months. Study endpoints were the occurrence of biopsy proven invasive carcinoma, time-to-progression and overall survival (OS). RESULTS: A total number of 40 of 225 patients met the inclusion criteria of which 17 (42.5%) patients had a positive baseline 18 F-FDG PET scan. A total of 13 of 17 (76.5%) developed invasive lung carcinoma during follow-up, with a median time to progression of 5.0 months (range, 3.0-25.0). In 23 (57.5%) patients with a negative 18 F-FDG PET scan at baseline, 6 (26%) developed lung cancer, with a median time to progression of 34.0 months (range, 14.0-42.0 months, p < 0.002). With a median OS of 56.0 months (range, 9.0-60.0 months) versus 49.0 months (range, 6.0-60.0 months) (p = 0.876) for the 18 F-FDG PET positive and negative groups, respectively. CONCLUSIONS: Patients with pre-invasive endobronchial squamous lesions and a positive baseline 18 F-FDG PET scan were at high-risk for developing lung carcinoma, highlighting that this patient group requires early radical treatment.

Diagnostic yield of a targeted gene panel in primary ciliary dyskinesia patients.

We aimed to determine the diagnostic yield of a targeted-exome panel in a cohort of 74 Dutch primary ciliary dyskinesia (PCD) patients. The panel consisted of 26 PCD-related and 284 candidate genes. To prioritize PCD candidate genes, we investigated the transcriptome of human airway cells of 12 healthy volunteers during in vitro ciliogenesis and hypothesized that PCD-related genes show significant upregulation. We compared gene expression in epithelial precursor cells grown as collagen monolayer and ciliated cells grown in suspension by RNA sequencing. All genes reported as PCD causative, except NME8, showed significant upregulation during in vitro ciliogenesis. We observed 67.6% diagnostic yield when testing the targeted-exome panel in our cohort. There was relatively high percentage of DNAI and HYDIN mutations compared to other countries. The latter may be due to our solution for the problem of the confounding HYDIN2 pseudogene. Candidate genes included two recently published PCD-related genes DNAJB13 and PIH1D3; identification of the latter was a direct result of this study. In conclusion, we demonstrate 67.6% diagnostic yield by targeted exome sequencing in a Dutch PCD population and present a highly sensitive and moderately specific approach for identification of PCD-related genes, based on significant upregulation during in vitro ciliogenesis.

Association between retinal neovascularization and serial weight measurements in murine and human newborns.

INTRODUCTION: Retinopathy of prematurity (ROP) is a leading cause of preventable blindness throughout the world. Several risk factors have been studied, but most studies remain inconclusive. Evidence is accumulating that one of the strongest predictors of ROP, in addition to oxygen use and low gestational age, is poor weight gain during the first postnatal weeks.
 METHODS: In a prospective study, we sought to determine the importance of serial weight measurements to help predict neovascularization (NV). In a first stage, a summary of the response in each case is identified and calculated as area under the curve (AUC). In a second stage, these different AUCs are analyzed by nonparametric Mann-Whitney U test. For the murine study, pups were redistributed in smaller and larger litters. On postnatal day (P)7-12, the oxygen-induced retinopathy (OIR) model was applied. Body weight was measured on P7, P14, and P17. Retinal NV was assessed on P17. For the human study, the subjects were part of the control arm of the NIRTURE trial. Ophthalmologists screened for ROP. Birthweight was recorded. Weekly weight measurements were performed for the first 4 weeks.
 RESULTS: The AUC of serial weight (gain) measurements was significantly lower in murine (14 vs 17 g; p = 0.01) and human (140 g/wk vs 240 g/wk; p = 0.0001) newborns developing retinal NV.
 CONCLUSION: This prospective study supports previous findings, using a new way of statistical analysis, that early postnatal weight gain is an important indicator in the development of neovascular disease.

Continuous glucose monitoring and retinopathy of prematurity.

PURPOSE: To use the continuous glucose monitoring system (CGMS) in very low birthweight (VLBW) infants to further explore the association between elevated glucose levels and retinopathy of prematurity (ROP) and to find new preventive strategies for ROP. METHODS: A secondary analysis of risk factors for ROP in VLBW infants was performed in the neonatal intensive care units of University Hospital Leuven and ZOL Genk, Belgium. The subjects were part of the NIRTURE trial (ISRCTN78428828). Only control subjects with conclusive ROP assessments who received standard clinical care were included in this analysis. A total of 100 VLBW infants (birthweight = 1500 g) were included. Twenty-three (23%) infants developed ROP; 77 (77%) did not. RESULTS: Development of ROP was linked to the known classic risk factors. In addition, ROP was associated with higher glycemia levels across the first week (p between 0.01 and <0.0001). Across the first week, glycemia predicted ROP with receiver operating characteristic (ROC) scores between 0.67 and 0.80, and with a median glycemia cutoff of 6.7 mmol/L. Comparison of ROC curves revealed first-week glycemia as an important variable in the development of ROP with a predictive power as high as the classic risk factors. CONCLUSIONS: Moderately elevated glucose levels in the first week of life are associated with the development of ROP. They contribute to this multifactorial disease in a way equal to the known classical risk factors for ROP. Therefore, careful monitoring of glucose levels by CGMS can be helpful in the prevention of ROP.

Heart rate variability during REM and non-REM sleep in preterm neonates with and without abnormal cardiorespiratory events.

AIM: Analyse heart rate variability (HRV) of preterm neonates undergoing a polysomnography in relation to the occurrence of abnormal cardiorespiratory events on one hand and the type of sleep states on the other hand. METHODS: To quantify nonlinear HRV, the numerical noise titration technique is used, adapted to neonatal heart rate data. HRV is calculated for 30 preterm neonates with mean post-conceptional age of 36.4weeks, divided into three groups according to the occurrence of abnormal events during the polysomnographies and the eventual home monitoring. RESULTS: Periods of non-REM sleep have lower noise limit values and can be distinguished significantly from periods of REM sleep and from the total recording period. The presence of abnormal events does not influence this finding. Significant differences between groups are only found during non-REM segments by means of the noise limit value computed via numerical noise titration while the linear HRV parameters were not able to discriminate. CONCLUSION: ECG measurement of a relatively short non-REM sleep period without specific abnormal events is sufficient to define a mature cardiorespiratory pattern in preterm infants.

Oxygen-induced retinopathy in mice: amplification by neonatal IGF-I deficit and attenuation by IGF-I administration.

In preterms, low serum levels of IGF (IGF-I) correlate with retinopathy of prematurity (ROP). In mice, IGF-I is a prerequisite for normal retinal development. We further explored the link between IGF-I and oxygen-induced retinopathy (OIR). To assess the role of endogenous IGF-I, pups were redistributed into smaller versus larger litters at birth; in one subgroup, we measured body weight and circulating IGF-I; in another, we applied hyperoxia and assessed retinal neovascularization (NV). To screen for the potential role of exogenous IGF-I, we administered a single bolus of rhIGF-I on postnatal day (P) 4 to pups in normal litters, and applied hyperoxia; body weight and IGF-I were measured; maturation and NV were assessed. Neonatal mice in larger litters had a lower body weight than mice in smaller litters; they had lower levels of circulating IGF-I, and developed more OIR (p = 0.002). Mice who had received rhIGF-I, weighed more and had higher endogenous IGF-I levels; they matured faster and developed less OIR (p = 0.00001). These findings in mice are the first to support the notion that higher availability of endogenous or exogenous IGF-I reduces OIR risk, and thus sharpen the perspective that ROP may be preventable by briefly up-regulating IGF-I after birth.

Renal outcome of children with one functioning kidney from birth. A study of 99 patients and a review of the literature.

In patients with a single functioning kidney, renal function was assessed at regular intervals over a period of 10 years. Serum creatinine, glomerular filtration rate (GFR), blood pressure, and urinary protein-creatinine ratio were assessed at the age of 2, 5 and 10 years. Between January 1980 and December 2005, 99 such patients were diagnosed in the first year of life. They were divided into three groups: A, patients with multicystic kidney disease and a normal contralateral kidney (n = 36); B, patients with a normal solitary kidney without uropathy (n = 20); and C, patients with obstructive uropathy and one nonfunctioning kidney (n = 43). Serum creatinine levels increased significantly with increasing age in every group. In group C, serum creatinine was significantly elevated compared with group A in all age categories (p = 0.043, p = 0.019, p = 0.001 respectively). Median figures of GFR remained within normal limits over the 10-year period. GFR was significantly lower in group C compared with group A (p = 0.001, p = 0.009, p = 0.019 respectively) and B in all age categories (p = 0.013, p = 0.002, p = 0.016 respectively). There were no changes in blood pressure over time and no differences among the three groups were observed. At the age of 10 years, the patients in group C had a significantly higher median urinary protein-creatinine ratio (p = 0.022) than those in groups A and B. There was also an increasing level of proteinuria with increasing age in group C (p = 0.002). In conclusion, renal function was stable over time in all patients, but children with obstructive uropathy have a lower median GFR and higher serum creatinine level for the whole study period. Hypertension was exceptionally observed in group C, with obstructive uropathy, as was an elevated urinary protein-creatinine ratio.

Characterization of CD4+ memory T cell responses directed against common respiratory pathogens in peripheral blood and lung.

BACKGROUND: We investigated CD4(+) memory T cell responses to influenza virus (FLU), respiratory syncytial virus (RSV), and nontypeable Haemophilus influenzae (NTHi). METHODS: The precursor frequencies of antigen-specific CD4(+) cells were determined by in vitro expansion of peripheral blood mononuclear cells from healthy individuals (n=9) and patients with chronic obstructive pulmonary disease (COPD; n=16). The expression of CD27 and CCR7 and the production of interferon (IFN)- gamma and interleukin-2 was measured directly ex vivo. Furthermore, the phenotypic and functional properties of CD4(+) T cells residing in the lung were analyzed and compared with those of circulating CD4(+)memory cells from the same donors (n=8). RESULTS: FLU-, RSV-, and NTHi-specific CD4(+) memory T cells circulated at low frequencies in the peripheral blood of healthy individuals and patients. RSV- and NTHi-specific CD4(+) T cells had a memory phenotype with moderate to high CD27 and CCR7 expression. In contrast to the low frequencies of circulating FLU-specific CD4(+) T cells, we found an enrichment of differentiated CD4(+) FLU-specific cells and high IFN- gamma expression in CD4(+) memory cells in lung tissue. CONCLUSION: No gross defects were found in circulating CD4(+) memory cells specific for pathogens associated with COPD. However, the large differentiated CD4(+) memory T cell pool residing in the lung may contribute to a large extent to local antiviral immunological protection.

Pharmacodynamics of chloral hydrate in former preterm infants.

UNLABELLED: The aim of this study was to document the pharmacodynamics of chloral hydrate in former preterm infants at term post-conception age. The degree of sedation (COMFORT), feeding behaviour and cardiorespiratory events (bradycardic events, apnoeas) before and after administration of chloral hydrate (oral, 30 mg/kg) were prospectively evaluated in former preterm infants during procedural sedation. Characteristics at birth, during neonatal stay and at inclusion were collected. Paired Wilcoxon and McNemar tests were used to study the impact of chloral hydrate. Characteristics of infants who displayed severe bradycardic events were compared to infants in whom no bradycardic events were recorded (Mann Whitney U, Fischer's exact). A significant increase in sedation (decrease COMFORT scale) was observed up to 12 h after administration. There was a minor but significant decrease in oral intake (161 to 156 ml/kg/day, P < 0.01). A significant increase in the number of bradycardic events (<80/min: 38 to 82 events, of which < 70/min: 30 to 79 of which < 60/min: 15 to 45; at least P < 0.01) and in the duration of the most severe bradycardic event (8-12.5 s) was observed. Therefore, further inclusion was stopped when 26 neonates were included. Infants who displayed severe bradycardic (< 60/min) events ( n = 13) after administration of chloral hydrate had a lower gestational age at birth without difference in post-conception age at inclusion. CONCLUSION: Chloral hydrate was associated with an increase in unintended side-effects in former preterm infants, likely reflecting population specific pharmacodynamics and kinetics of chloral hydrate.

Sensitivity of detrended fluctuation analysis applied to heart rate variability of preterm newborns.

Detrended fluctuation analysis (DFA), a fractal analysis method which is widely used in heart rate variability (HRV) studies, is used to analyze the scaling behaviour of RR interval series of preterm neonates. The average scaling behaviour, calculated using 30000 RR intervals (3 - 4 hours), is characterized by a scaling exponent of 1.4 ± 0.1 at small scales (n ≤ 20) and a smaller exponent of 1.0 ± 0.1 at larger scales. It is shown that the scaling behaviour is not constant over such long segments and how heart rate patterns, associated with specific physiological mechanisms, contribute to the observed variation of the scaling exponents. The effect of the two most important patterns, spikes (either due to faulty peak detection or true decelerations in heart rate) and periodic fluctuations, on the scaling behaviour is investigated.

Nonlinear analysis of heart rate variability in infants with apparent life-threatening events.

Some studies have shown that neonates having experienced an Apparent Life-Threatening Event (ALTE) have an increased risk of dying of the Sudden Infant Death Syndrome (SIDS). In this study the heart rate variability in neonates has been analyzed through a study of the long range correlations and scale invariance (self-similarity) in their cardiac rhythm. The goal is to see whether it is possible to distinguish normal infants from infants with ALTEs using the previously mentioned nonlinear measures of the heart rate variability. Twelve ALTE infants are included in this study. To determine the degree to which these neonates suffer from ALTEs two examinations are performed: a polysomnography and home monitoring. Using the nonlinear measures obtained from the nonlinear analysis of the heart rate variability, the group suffering most from ALTEs can clearly be separated from the other neonates.

Postnatal cranial ultrasonographic findings in feto-fetal transfusion syndrome.

Our objective was a retrospective evaluation of cranial US in survivors of twin pregnancy with feto-fetal transfusion syndrome (FFTS), with knowledge of prenatal treatment and neonatal/postnatal clinical data. In 18 pregnancies with FFTS (January 1996 to May 2000), pregnancy management and outcome, and neonatal clinical/neurological data and follow-up (age of 3-7 months) were documented when available. Postnatal cranial US abnormalities were differentiated in prenatal and peri/postnatal lesions, respectively, in "donor" and "recipient." The statistical analysis used was Mann Whitney U test and Fisher's exact test. Overall pregnancy survival rate was 19 of 36 (53%); mors in utero occurred in five twin members. Gestational age at birth was significantly lower in FFTS after laser coagulation (13 of 18; p<0.05). Initial (