Governmental Non-Pharmaceutical Interventions during the COVID-19 Pandemic and the COPD Exacerbation and Respiratory Infection Rate in Patients with Alpha-1 Antitrypsin Deficiency.

During the COVID-19 pandemic the number of hospital admissions due to chronic obstructive pulmonary disease (COPD) exacerbations was significantly reduced. The reason for this decline is not fully understood. Governmental non-pharmaceutical interventions (NPI's), an increase in community treated exacerbations, or healthcare avoidance by patients, are potential reasons. For the current study, the impact of Dutch governmental NPI's on the COPD exacerbations and respiratory infections rate in patients with severe alpha-1 antitrypsin deficiency (AATD) was analyzed. The patients participated in the NCT04204252 study, a randomized controlled trial evaluating the efficacy and safety of inhaled alpha-1 antitrypsin. Data collected in the time-period from March 2020 until February 2022 was analyzed. In this period the Dutch government imposed variable NPI's to contain the spread of SARS-CoV-2. Patients were required to document their daily symptoms in an electronic diary. The strictness of the governmental NPI's was measured by the COVID-19 Stringency Index. 19 patients participated in this study during the analysis period. A total of 40 respiratory infections and COPD exacerbations occurred. The Spearman's correlation coefficient of the monthly average COVID-19 Stringency Index and respiratory infections and COPD exacerbations rate was -0.316 (p = 0.132). When months known for a low respiratory infection rate were excluded, the correlation coefficient was -0.625 (p = 0.010). This study showed a significant negative correlation between the COPD exacerbations and respiratory infection rate and the COVID-19 Stringency Index in patients with AATD related COPD in the autumn-winter months.

Distinct anti-inflammatory properties of alpha1-antitrypsin and corticosteroids reveal unique underlying mechanisms of action.

Alpha1-antitrypsin (AAT) is a serum protease inhibitor that rises during inflammation and healthy pregnancies. Plasma-derived AAT, indicated for genetic AAT deficiency, is presently being explored for additional medical indications. Unlike corticosteroids, some anti-inflammatory activities of AAT involve NF-κB-dependent outcomes, e.g., induction of IL-1R antagonist. AAT activities were compared to dexamethasone (DEX), using various in-vitro cells assays, animal studies, and NF-κB-p65 localization and activity studies. Results demonstrate a cytokine shift towards resolution in AAT-treated cells, as opposed to pan-suppression in DEX-treated cells. AAT enhanced, while DEX suppressed LPS-induced IL-1Ra production and re-epithelialization. When drugs were combined, AAT allowed the immunosuppressive DEX activities, while DEX at medium to high levels antagonized beneficial AAT effects. Interestingly, lower levels of DEX maintained the immunosuppressive effect, while allowing upregulation of IL-1Ra. Therefore, AAT may represent a distinct endogenous anti-inflammatory, resolution-promoting agent that may improve tissue well-being while preventing undesired corticostroids side effects.

A Phase II, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Alpha-1 Antitrypsin (AAT) (Glassia®) in the Treatment of Recent-Onset Type 1 Diabetes.

Our aim was to assess the efficacy, safety, and tolerability of alpha-1 antitrypsin (AAT) as a therapeutic modality for ß-cell preservation in patients with recent-onset type 1 diabetes. Seventy type 1 diabetes patients (37 males; mean age 13.1 ± 4.1years) were randomized to treatment with 22 infusions of AAT (Glassia®) (60 or 120 mg/kg) or placebo. The primary outcome was the area under the curve (AUC) of C-peptide from a 2-h mixed-meal tolerance test after 52 weeks. At week 52, C-peptide was 0.9, 0.45, and 0.48 pmol/mL in the AAT-120, AAT-60, and placebo groups (p = 0.170 and p = 0.866 vs. placebo, respectively). The declines in C-peptide glycated hemoglobin (HbA1c) and the total insulin dose (U/kg) were similar across groups. Within the predefined 12-18-years subgroup, the C-peptide AUC decreased significantly in the placebo and AAT-60 groups (-0.34 and -0.54 pmol/mL, respectively, p < 0.01), with a borderline decrease in the AAT-120 group (-0.29 pmol/mL, p = 0.047). The mean HbA1c level was significantly lower in the AAT-120 group compared to the placebo (6.7% ± 0.9% vs. 8.2 ± 1.4%, p = 0.05), and a higher percentage of patients attained HbA1c ≤ 7% (75% vs. 25%, p = 0.05). AAT was tolerated well, with a similar safety profile between groups. The AAT intervention showed promise in the subgroup of adolescents with recent-onset type 1 diabetes. Further studies are warranted to determine the impact and proposed mechanism of action of AAT in ß-cell preservation.

Efficacy and safety of inhaled α1-antitrypsin in patients with severe α1-antitrypsin deficiency and frequent exacerbations of COPD.

Patients with inherited α1-antitrypsin (AAT) deficiency (ZZ-AATD) and severe chronic obstructive pulmonary disease (COPD) frequently experience exacerbations. We postulated that inhalation of nebulised AAT would be an effective treatment.We randomly assigned 168 patients to receive twice-daily inhalations of 80 mg AAT solution or placebo for 50 weeks. Patients used an electronic diary to capture exacerbations. The primary endpoint was time from randomisation to the first event-based exacerbation. Secondary endpoints included change in the nature of the exacerbation as defined by the Anthonisen criteria. Safety was also assessed.Time to first moderate or severe exacerbation was a median of 112 days (interquartile range (IQR) 40-211 days) for AAT and 140 days (IQR 72-142 days) for placebo (p=0.0952). The mean yearly rate of all exacerbations was 3.12 in the AAT-treated group and 2.67 in the placebo group (p=0.31). More patients receiving AAT reported treatment-related treatment-emergent adverse events compared to placebo (57.5% versus 46.9%, respectively) and they were more likely to withdraw from the study. After the first year of the study, when modifications to the handling of the nebuliser were introduced, the rate of safety events in the AAT-treated group dropped to that of the placebo group.We conclude that in AATD patients with severe COPD and frequent exacerbations, AAT inhalation for 50 weeks showed no effect on time to first exacerbation but may have changed the pattern of the episodes.

[ALPHA-1-ANTITRYPSIN ACTIVITY IN PATIENTS HOSPITALIZED FOR CELLULITIS].

INTRODUCTION: Deficiency or impaired activity of alpha-1-antitrypsin (AAT), which neutralizes multiple proteolytic enzymes, such as collagenases and elastases may result in significant tissue autodigestion. Hence, AAT may have a role in the healing process in chronic and acute inflammation including skin infection, such as cellulitis. AIM: The aim of this study was to evaluate the role of AAT activity and inflammatory markers in patients with cellulitis. METHODS: The study included eleven consecutive patients (6 males and 5 females, mean age 68.5 ± 4.5 years) who were hospitalized for cellulitis between 09/2009-02/2010. We analyzed tests results for C reactive protein (CRP), AAT level and activity that were obtained on admission (T1), 2 days after admission (T2) and 2 weeks after admission (T3). RESULTS: AAT levels were found to be within the normal range. AAT activity values were found to be within or above the normal range. The highest activity values were measured after 2 days of treatment and the lowest values were measured after 2 weeks of treatment. CRP values were highest on admission and lowest, as expected, after the end of treatment 2 weeks later. AAT activity values were significantly lower statistically in patients with unresolved cellulitis 2 weeks after treatment began. SUMMARY: AAT activity was significantly lower statistically in patients who suffered from slow resolving cellulitis 14 days after hospitalization. This possibly suggests a role AAT activity may have in the inflammation cascade in patients with cellulitis. Further studies are needed to evaluate the role of AAT activity in the inflammatory process.

[Electrical stimulation of the genioglossus to improve pharyngeal patency in obstructive sleep apnea: comparison of results obtained during sleep and anesthesia].

Contraction of the geniogtossus (GG) has been shown to improve upper airway patency in patients with sleep apnea during sleep and anesthesia. However, a large variability in response exists, requiring selection of adequate patients if GG stimulation should be used as a treatment modality. In the present study, we compared responses in upper airway pressure-flow relationships to electrical stimulation of the GG in patients with obstructive sleep apnea during sleep and mild anesthesia. Nine patients studied during sleep were matched with 9 patients evaluated during propofol anesthesia. Stimulation was performed with fine wire electrodes inserted near the mandibular insertion of the GG. Airflow was measured at muLtiple levels of CPAP, and upper airway collapsibility was defined by the pressure below which airflow ceased (the "critical" pressure, Pcrit). ELectrical stimulation shifted the pressure-flow reLationships toward higher flow Levels in all patients over the entire range of CPAP applied. Pcrit decreased significantly during stimulation-induced contraction of the GG, and similarly in the patients evaluated during sleep and during anesthesia (from 1.6 +/- 2.0 to -1.6 +/- 2.5, and from 1.8 +/- 1.8 to -0.2 +/- 1.8 cmH2O, during steep and anesthesia, respectively, p < 0.01, without a significant change in upstream resistance. Our findings imply that responses in Pcrit to electrical stimulation of the main tongue protrusor during propofoL anesthesia may reflect those observed during sleep, and evaluation of the response of sleep apnea patients to GG stimulation can be evaluated during short anesthesia.

Interacting effects of genioglossus stimulation and mandibular advancement in sleep apnea.

Both mandibular advancement (MA) and stimulation of the genioglossus (GG) have been shown to improve upper airway patency, but neither one achieves the effect of continuous positive airway pressure (CPAP) treatment. In the present study we assessed the combined effect of MA and GG stimulation on the relaxed pharynx in patients with obstructive sleep apnea (OSA). We evaluated responses of upper airway pressure-flow relationships and endoscopically determined pharyngeal cross-sectional area to MA and electrical stimulation of the GG in 14 propofol-anesthetized OSA patients. Measurements were undertaken at multiple levels of CPAP, enabling calculation of the critical closing pressure (Pcrit), upstream resistance (Rus), and pharyngeal compliance. GG stimulation, MA, and the combination of both shifted the pressure:flow relationships toward higher flow levels, resulting in progressively lower Pcrit (from baseline of 2.9 +/- 2.2 to 0.9 +/- 2.5, -1.4 +/- 2.9, and -4.2 +/- 3.3 cmH(2)O, respectively), without significant change in Rus. DeltaPcrit during GG stimulation was significantly larger during MA than under baseline conditions (-2.8 +/- 1.4 vs. -2.0 +/- 1.4 cmH(2)O, P = 0.011). Combining the effect of GG stimulation with MA lowered Pcrit below 0 in all patients and restored pharyngeal patency to a level that enabled flow above the hypopnea level in 10/14 of the patients. Velopharyngeal compliance was not affected by either manipulation. We conclude that the combined effect of MA and GG stimulation is additive and may act in synergy, preventing substantial flow limitation of the relaxed pharynx in most OSA patients.

Long-lasting sleep patterns of adult patients with minor traumatic brain injury (mTBI) and non-mTBI subjects.

BACKGROUND: Sleep disturbance is a common subjective complaint of minor traumatic brain-injured (mTBI) patients, but little is known about the characteristics of sleep disturbance in adults years after the injury. METHODS: Polysomnographic (PSG) and multiple sleep latency test (MSLT) records of 26 mTBI adult patients with normal brain computerized tomography and negative encephalographic studies, no past history of CNS pathology, no premorbid or present major psychiatric diagnosis, and no sleep apnea syndrome were compared to a matched group of apparently healthy individuals (controls). RESULTS: Sleep patterns were disturbed in the mTBI patients. Their sleep architecture was altered, with significantly higher light-sleep non-rapid eye movement (NREM) stage 2 scores compared to controls (54.5+/-13.4% vs. 46.6+/-10.4%, respectively, p=0.03) and significantly lower REM sleep scores (21.2+/-8.4% vs. 25.4+/-4.5%, respectively, p=0.05). The MSLT findings documented significant excessive daytime episodes of falling asleep. CONCLUSIONS: Sleep disturbances of adult patients with chronic mTBI may manifest characteristic alterations in both timing and architecture of their sleep patterns. Sleep lab evaluations may help identify subgroups of mTBI patients who would probably benefit from treatment.

Computerized acoustic assessment of treatment efficacy of nebulized epinephrine and albuterol in RSV bronchiolitis.

AIM: We evaluated the use of computerized quantification of wheezing and crackles compared to a clinical score in assessing the effect of inhaled albuterol or inhaled epinephrine in infants with RSV bronchiolitis. METHODS: Computerized lung sounds analysis with quantification of wheezing and crackles and a clinical score were used during a double blind, randomized, controlled nebulized treatment pilot study. Infants were randomized to receive a single dose of 1 mgr nebulized l-epinephrine or 2.5 mgr nebulized albuterol. Computerized quantification of wheezing and crackles (PulmoTrack) and a clinical score were performed prior to, 10 minutes post and 30 minutes post treatment. Results were analyzed with Student's t-test for independent samples, Mann-Whitney U test and Wilcoxon test. RESULTS: 15 children received albuterol, 12 received epinephrine. The groups were identical at baseline. Satisfactory lung sounds recording and analysis was achieved in all subjects. There was no significant change in objective quantification of wheezes and crackles or in the total clinical scores either within the groups or between the groups. There was also no difference in oxygen saturation and respiratory distress. CONCLUSION: Computerized lung sound analysis is feasible in young infants with RSV bronchiolitis and provides a non-invasive, quantitative measure of wheezing and crackles in these infants.

Pregnancy exacerbating hepatopulmonary syndrome.

BACKGROUND: Hepatopulmonary syndrome is an uncommon complication of liver cirrhosis. The natural history of this condition and its optimal management during pregnancy are not yet known. CASE: We present the case of a 35-year-old woman with liver cirrhosis who developed severe dyspnea in the 25th week of gestation and was diagnosed as suffering from hepatopulmonary syndrome. She was managed conservatively until 35 weeks of gestation, when she was delivered by cesarean. CONCLUSION: The natural history, in this case, indicates that pregnancy may induce hepatopulmonary syndrome in an otherwise asymptomatic cirrhotic patient. Oxygen supplementation was the cornerstone of treatment and resulted in a favorable outcome.

Pulmonary calcification in hemodialysis patients: correlation with pulmonary artery pressure values.

BACKGROUND: End-stage renal disease (ESRD) patients receiving chronic hemodialysis (HD) via an arteriovenous (A-V) access often develop unexplained pulmonary hypertension (PHT). This study evaluated the role of pulmonary calcification (PC) in this phenomenon. METHODS: The clinical manifestations, systolic pulmonary artery pressure (PAP) values measured by Doppler echocardiography and the presence and the extent of PC expressed by lung uptake of 99mTc-MDP bone scintigraphy, were studied in 49 patients with ESRD receiving chronic HD therapy via A-V access. The correlation between PC and PHT was investigated. RESULTS: There were 36 men and 13 women with a mean age of 61.7 +/- 13.2 years receiving HD therapy for 38.2 +/- 43.7 months. Twenty (40.8%) patients had PC expressed by increased lung uptake of 99mTc- MDP and 28 (57.1%) patients had PHT with a mean systolic PAP of 46 +/- 11 mm Hg. No correlation was found between PC and PHT. CONCLUSION: The data suggest that PC expressed by lung uptake of 99mTc-MDP has no role in the pathogenesis of PHT among ESRD patients undergoing HD therapy via A-V access.

Pulmonary hypertension in patients with end-stage renal disease.

BACKGROUND: The aims of this study were to evaluate the incidence of unexplained pulmonary hypertension (PH) among patients with end-stage renal disease (ESRD) and to suggest possible etiologic factors. METHODS: The incidence of PH was prospectively estimated by Doppler echocardiography in 58 patients with ESRD receiving long-term hemodialysis via arteriovenous access, and in control groups of 5 patients receiving peritoneal dialysis (PD) and 12 predialysis patients without a known other cause to suggest the presence of PH. Clinical variables were compared between patients with and without PH receiving hemodialysis. Changes in pulmonary artery pressure (PAP) values before and after onset of hemodialysis via arteriovenous access, arteriovenous access compression, and successful kidney transplantation were recorded. RESULTS: PH > 35 mm Hg was found in 39.7% of patients receiving hemodialysis (mean +/- SD, 44 +/- 7 mm Hg; range, 37 to 65 mm Hg), in none of the patients receiving PD, and in 1 of 12 predialysis patients. Patients with PH receiving hemodialysis had a significantly higher cardiac output (6.9 L/min vs 5.5 L/min, p = 0.017). PH developed in four of six patients with normal PAP after onset of hemodialysis therapy via arteriovenous access. One-minute arteriovenous access compression in four patients decreased the mean systolic PAP from 52 +/- 7 to 41 +/- 4 mm Hg (p = 0.024). PH normalized in four of five patients receiving hemodialysis following kidney transplantation. Kaplan-Meier survival analysis according to PAP values revealed significant survival differences (p < 0.024). CONCLUSIONS: This study demonstrates a surprisingly high incidence of PH among patients with ESRD receiving long-term hemodialysis with surgical arteriovenous access. Both ESRD and long-term hemodialysis via arteriovenous access may be involved in the pathogenesis of PH by affecting pulmonary vascular resistance and cardiac output.

Difficult-to-control asthma and obstructive sleep apnea.

This study tested the hypothesis that asthma can promote obstructive sleep apnea (OSA) by looking at the prevalence of OSA among patients with difficult-to-control asthma receiving long-term oral corticosteroid (CS) therapy and examined some possible etiological factors. The study design was a prospective cohort study and was conducted in the pulmonary outpatient clinic of a tertiary care center in Haifa, Israel. Twenty-two consecutive patients with severe unstable asthma, 14 on continuous and 8 on bursts of oral CS, in addition to their standard therapy for a mean of 8.9 +/- 3.3 years, underwent a night polysomnography in a sleep laboratory regardless of sleep complaints. A standard questionnaire was completed upon attending the sleep laboratory. The OSA was defined as respiratory disturbance index (RDI) of > or = 5 and typical complaints. The correlation between RDI to asthma and morphometric parameters was tested. All but one patient had OSA [95.5% prevalence], with mean RDI of 17.7 +/- 2.5. The RDI values were significantly higher in the continuous CS therapy subgroup (21.4 +/- 3.4 vs. 11.1 +/- 1.6, p < 0.05]. The study group had above normal neck circumferences and body mass index. The former increased by 12.1% +/- 3.1% % to 29.8% +/- 1% during the oral CS therapy interval but had no significant effect on RDI as a covariant. This study showed an unexpectedly high prevalence of OSA among patients with unstable asthma receiving long-term chronic or frequent burst of oral CS therapy. It may be assumed that prolonged and especially continuous oral CS therapy in asthma increases airway collapsibility.

Value of a negative aeroallergen skin-prick test result in the diagnosis of asthma in young adults: correlative study with methacholine challenge testing.

BACKGROUND: None of the existing tests for the diagnosis of asthma are considered to be definitive. Certain circumstances require prompt diagnosis, and a test able to predict the absence of asthma would be very useful. OBJECTIVE: To evaluate the contribution of a skin-prick test (SPT) to the diagnostic workup of subjects with suspected asthma. PATIENTS AND METHODS: The study included three groups of subjects aged 18 to 24 years: group A, asthmatic patients (n = 175); group B, control subjects (n = 100); and group C, subjects with suspected asthma (n = 150) with normal spirometry findings and a negative exercise challenge test result. All underwent an SPT to a battery of common aeroallergens, and group C underwent a methacholine challenge test (MCT) in addition. The sensitivity, specificity, positive predictive value, and negative predictive values (NPV) of the SPT were calculated using provocative concentrations of methacholine causing a 20% fall in FEV(1) (PC(20)) of < 4 mg/mL and < 8 mg/mL as diagnostic cutoff values for asthma in the MCT. Bayes' formula was used to determine posttest probabilities of having asthma, both for positive and negative SPT results. RESULTS: A positive SPT result to at least one allergen was found in 95.5%, 54%, and 69% of patients in the three groups, respectively. The sensitivity, specificity, and NPV of the SPT were 90.7%, 52.0%, and 84.8%, respectively, with a cutoff value of PC(20) < 8 mg/mL. The lower cutoff, PC(20) < 4 mg/mL, increased the sensitivity and NPV to 98.2% and 97.8%, respectively. A negative SPT result decreased the probability of having asthma by 10-fold to 20-fold in subjects whose pretest probability was low to moderate. CONCLUSIONS: Incorporating an SPT into the workup of subjects with suspected asthma can reduce the cost of this process significantly. The SPT may be used as a simple, fast, safe, inexpensive, and reliable method to predict the absence of asthma in young adults.