Immune signatures underlying post-acute COVID-19 lung sequelae.

Severe coronavirus disease 2019 (COVID-19) pneumonia survivors often exhibit long-term pulmonary sequelae, but the underlying mechanisms or associated local and systemic immune correlates are not known. Here, we have performed high-dimensional characterization of the pathophysiological and immune traits of aged COVID-19 convalescents, and correlated the local and systemic immune profiles with pulmonary function and lung imaging. We found that chronic lung impairment was accompanied by persistent respiratory immune alterations. We showed that functional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)­specific memory T and B cells were enriched at the site of infection compared with those of blood. Detailed evaluation of the lung immune compartment revealed that dysregulated respiratory CD8+ T cell responses were associated with the impaired lung function after acute COVID-19. Single-cell transcriptomic analysis identified the potential pathogenic subsets of respiratory CD8+ T cells contributing to persistent tissue conditions after COVID-19. Our results have revealed pathophysiological and immune traits that may support the development of lung sequelae after SARS-CoV-2 pneumonia in older individuals, with implications for the treatment of chronic COVID-19 symptoms.

Quality control of apheresis platelets: a multicentre study to evaluate factors that can influence pH measurement.

BACKGROUND AND OBJECTIVES: Blood operators routinely monitor the pH of apheresis platelets as a marker of the so-called storage lesion, which can result from manufacturing problems. It is also suspected that some donor characteristics can increase the risk of poor platelet storage. To explore this hypothesis, we analysed a large, multinational data set of quality control (QC) pH test results on apheresis platelets. MATERIALS AND METHODS: For the period between September 2011 and August 2014, seven blood operators in Canada, the USA, the Netherlands, the United Kingdom, France and Australia provided pH QC test results and donor characteristics on a total of 21,671 apheresis platelets. RESULTS: Some variations in pH distribution between blood operators were in part explained by differences in collection, processing and testing methods. Younger age and female gender were significantly associated with a pH value below the 10th percentile. Among donors who had two or more pH measurements (n = 3672), there was a strong correlation between pH results (r = 0·726; P < 0·0001). CONCLUSION: The strong intradonor correlation of pH measurements and the association between donor characteristics and pH results suggest that donor factors play a role in the quality of platelets.

Cigarette smoking and inflammation: cellular and molecular mechanisms.

Cigarette smoke (CS) causes considerable morbidity and mortality by inducing cancer, chronic lung and vascular diseases, and oral disease. Despite the well-recognized risks associated with smoking, the habit remains unacceptably prevalent. Several toxins present in CS have immunomodulatory effects. CS also contains trace amounts of microbial cell components, including bacterial lipopolysaccharide. These and other CS constituents induce chronic inflammation at mucosal surfaces and modify host responses to exogenous antigens. The effects of CS on immunity are far-reaching and complex; both pro-inflammatory and suppressive effects may be induced. The net effect of CS on immunity depends on many variables, including the dose and type of tobacco, the route and chronicity of exposure, and the presence of other factors at the time of immune cell stimulation, such as Toll receptor ligands or other inflammatory mediators. CS impairs innate defenses against pathogens, modulates antigen presentation, and promotes autoimmunity. CS also impairs immunity in the oral cavity and promotes gingival and periodontal disease and oral cancer. The recognition of specific mechanisms by which CS affects host immunity is an important step toward elucidating mechanisms of tobacco-induced disease and may identify novel therapeutic approaches for the management of diseases that afflict smokers.

Coagulation factor content of plasma produced from whole blood stored for 24 hours at ambient temperature: results from an international multicenter BEST Collaborative study.

BACKGROUND: There is increasing international interest in producing components from blood that has been stored at room temperature for 24 hours. The lack of comprehensive data on the quality of plasma produced from blood stored in this way led to this international study. STUDY DESIGN AND METHODS: A total of 128 units of whole blood were pooled in groups of four and split to produce 32 sets of four identical blood units that were processed either within 8 hours of blood collection or after 24-hour storage at 18 to 25°C. RESULTS: Storage of whole blood for 24 hours resulted in a 23% decrease in the activity of Factor (F)VIII, but not significant loss of activity of coagulation factors FV, FVII, FXI, FXII, fibrinogen, antithrombin, or von Willebrand factor. There was a small, but significant decrease in levels of FII, FIX, and FX (all <5%) as well as protein C (6%) and free protein S activity (14%). The ability of plasma to generate thrombin after 24-hour storage as whole blood was unaltered, as assessed by real-time thrombin generation tests as was the rate and strength of clot formation by rotational thombelastometry. Levels of all coagulation factors measured were above 0.50 U/mL in plasma produced from whole blood stored for 24 hours. CONCLUSION: These data show that there is minimal effect of storing whole blood at ambient temperature for 24 hours on the coagulation activity of plasma and that this is an acceptable alternative to producing plasma on the day of blood collection.

Multi-institutional randomized control study of haemolysis in stored red cell units prepared manually or by an automated system.

BACKGROUND: The haemolysis level at the end of storage is a performance parameter for RBC preparations. In the evaluation of new devices or new processes for processing blood, it is relevant to evaluate whether the haemolysis is linked to (1) specific characteristics of the blood donor, or (2) the nature of the blood-processing methodologies. MATERIALS AND METHODS: As part of the validation of a new automated whole blood processing system compared to the current manual methods, randomized, paired crossover studies were conducted evaluating measures of blood component quality, including RBC haemolysis over 42 days of storage. RESULTS: The association between haemolysis and the individual subject was evaluated by modelling haemolysis with independent predictors of treatment (control and test processing) and leucocyte reduction as fixed factors with donor and laboratory as random effects in a mixed-effects ANOVA model. It was found that the day 42 haemolysis values were strongly dependent on the donor subject, with an intraclass correlation coefficient of 0.81. CONCLUSIONS: The data reported in this study suggest a link between the specific whole blood donor and the haemolysis levels observed in red-blood-cell units stored refrigerated for 42 days. Additional research to identify possible donor characteristics associated with haemolysis during storage is warranted.

Recognition and management of antibodies to human platelet antigens in platelet transfusion-refractory patients.

Platelet transfusion refractoriness is a problem for parous and multiply transfused patients, placing them at higher risk for morbidity and mortality when posttransfusion count increments are significantly lower than expected. Although nonimmune causes of transfusion refractoriness are very common, HLA alloantibodies are the most important of the less frequent immune factors responsible for inadequate count increments. As universal leukoreduction decreases the occurrence of HLA antibody formation, antibodies to human platelet antigens (HPAs), an even less common immune factor, may rise proportionately. Carefully matched apheresis platelets can substantially improve platelet count increments in the setting of HLA and HPA alloantibody-mediated transfusion refractoriness. An evidence-based HPA testing strategy is described along with the incidence and specificity of HPA antibodies in platelet transfusion refractoriness. Optimal strategies to manage patients with HPA or combined HPA and HLA antibodies are presented. Ultimately, close cooperation between ordering physicians and the blood provider is critical in choosing the correct tests and assuring platelet availability during intensive support of these challenging patients.

Unique donor-suitability issues.

On occasion, there arise questions or situations involving blood-donor eligibility determination, which are not adequately addressed by the existing regulations and standards. In such instances, even the most experienced blood collector may be uncertain regarding the best course of action and unable to find adequate guidance in the standard blood banking references, regulations and literature. In order to examine this area in greater depth, the American Association of Blood Banks (AABB) sponsored a short topic session on 'Unique Donor Suitability Issues' at their 2004 annual meeting. The invited speakers were four seasoned physician medical directors, with a combined experience of over 40 years in blood collection at both regional and national levels. They were tasked with identifying and researching problematic areas in donor-suitability determination, and suggesting an overall approach to dealing with such issues. They determined that three of the most problematic areas of eligibility evaluation included donors with: (1) disabilities, (2) disorders of haemostasis, and (3) trans-sexual, homosexual and other unusual gender-related issues. Each of these topics was presented in a 10-min lecture, followed by an open format consisting of audience participation and panel discussion by the speakers. The session was additionally enhanced by a representative of the United States Food and Drug Administration (FDA) who participated as a member of the audience. This review presents the contents of the short topic session in an expanded form.

Effectiveness and persistence of a topical treatment for cervical ectropion with deoxyribonucleic acid.

AIM: The aim of this study was to estimate short and long term effectiveness of a topical treatment for cervical ectropion with 5 mg of deoxyribonucleic acid (DRNA). METHODS: A randomized case-control study was carried out. Two-hundred and twenty patients, colposcopically diagnosed with cervical ectropion, were consecutively enrolled and randomly divided into 2 groups: treated (group 1) and controls (group 2). The therapeutic plan consisted of DRNA 5 mg vaginal suppositories, administered for 15 days monthly; subsequently posology was reduced gradually. Both groups underwent a clinical and colposcopical follow-up on the 1st, 4th, 10th and 22nd months after the first examination. At the end of the study, the size of ectropion was considered a parameter of re-epithelialization and provided a criterion of treatment effectiveness. According to this protocol, subjects were defined improved, stable or worsened. Statistical analysis including Pearson chi2 tests, Fisher's exact tests, Yate's corrected chi2 and relative-risk (95% CI) was performed. RESULTS: Of the 220 enrolled patients, 140 completed the study protocol: 76 treated and 64 controls. Outcomes after treatment and follow-up consisted of: 74 (97.4%) improved in group 1, against 2 cases (3.1%) in group 2. High statistical significance was reported comparing outcome frequencies in the 2 groups (P<0.0001). CONCLUSIONS: This study shows a significant reduction (P<0.0001) in cervical ectropion size between cases (topical treatment with DRNA 5 mg) and controls. A follow-up of 22 months confirmed the persistence and effectiveness of this medical approach.

Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products.

Despite yielding a definitive diagnosis in fewer than 20 percent of anaphylactic transfusion reactions, investigation for IgA deficiency and the presence of presumably pathogenic IgG anti-IgA is useful in patient management. Individuals with demonstrated anti-IgA are thereafter committed to receiving IgA-depleted cellular products or IgA-deficient plasma and derivatives to prevent recurrent severe reactions. Unfortunately, in populations of IgA-deficient individuals screened for anti-IgA, the predictive value of the test in the absence of a prior reaction is quite low. Anti-IgA testing is complex and limited to a few reference laboratories, many of which still employ a labor-intensive hemagglutination assay developed in the late 1960s. Timely decisions regarding further transfusion management of patients experiencing anaphylaxis often rely upon more rapidly obtained assays of the IgA concentration as an indicator of the likelihood of subsequent demonstration of anti-IgA. The scarcity of IgA-deficient banked plasma products and dedicated plateletpheresis donors has led to the development of American Rare Donor Program policies designed to appropriately allocate these precious resources. The test methods used to establish the diagnosis of IgA deficiency and identify the approximately one third of these individuals with anti-IgA are discussed, along with the incidence of abnormal tests in various populations. Also presented are testing recommendations for the identification of an IgA-mediated mechanism for transfusion-associated anaphylaxis and qualification of patients to receive rare IgA-deficient plasma-containing products.

[Evaluation of the results after 5 year from a vertical banded gastroplasty: our experience]. / Risultati a 5 anni della gastroplastica verticale secondo MacLean: nostra esperienza.

BACKGROUND AND AIMS: vertical banded gastroplasty (GPV) is the most frequently performed restrictive procedure for morbid obesity, but long-term follow-up is almost nonexistent. A poor outcome after GPV and a low quality of life has been reported. The aim of the study was to determine long-term outcome after 5 years follow-up. METHODS: 225 GPV were performed from 1995 to 2002. Patients were followed every month in the first three months, after 6 and 12 months, and subsequently every year. RESULTS: No mortality was observed. One gastric fistula, treated with medical therapy, was the single related complication observed. Vomiting occurred in 21.2% of patients. After 2 years 74.5% of patients had a BMI < 35, with a decrease of IEW = 50% (IEW% L 54.1%, 56.4%, and 57.1% after 12, 24 and 60 months, respectively). After 5 years, the results were unsatisfactory in 17.1% of patients; 8 patients underwent bariatric re-operation with good results. CONCLUSIONS: GPV represents a safe procedure with a low incidence of complications, with poor results in 17.1% of patients. Pre-operative identification of non responders is achievable with "BIB test". In the responders significant dietary changes are complained.

Vitronectin and fibronectin function as glucan binding proteins augmenting macrophage responses to Pneumocystis carinii.

beta-glucans represent major structural components of fungal cell walls. We recently reported that Pneumocystis carinii beta-glucans stimulate alveolar macrophages to release proinflammatory cytokines. Macrophage activation by beta-glucan is augmented by serum, implying the presence of circulating factors that interact with beta-glucans and enhance their ability to stimulate macrophages. Using beta-glucan-enriched cell wall fractions from P. carinii and Saccharomyces cerevisiae, two prominent proteins were precipitated from serum and demonstrated to be vitronectin (VN) and fibronectin (FN) by immune analysis. Preincubation of beta-glucan with VN or FN enhanced macrophage activation in response to this cell wall component. Because VN and FN accumulate in the lungs during P. carinii pneumonia, we further investigated hepatic and pulmonary expression of VN and FN messenger RNA during infection. P. carinii pneumonia in rodents is associated with increased hepatic expression of VN and FN as well as increased local expression of FN in the lung. Because interleukin (IL)-6 represents the major regulator of VN and FN expression during inflammatory conditions, we measured macrophage IL-6 release in response to stimulation with P. carinii beta-glucan. Stimulation of macrophages with P. carinii beta-glucan induced significant release of IL-6. Elevated concentrations of IL-6 were noted in the blood of infected animals compared with uninfected control animals. These studies indicate that VN and FN bind to beta-glucan components of P. carinii and augment macrophage inflammatory responses. P. carinii cell wall beta-glucan stimulates secretion of IL-6 by macrophages, thereby enhancing hepatic synthesis of both VN and FN, and lung synthesis of FN during pneumonia.

Smoking-related interstitial lung diseases: a concise review.

Interstitial lung diseases (also known as diffuse infiltrative lung diseases) are a heterogeneous group of parenchymal lung disorders of known or unknown cause. These disorders are usually associated with dyspnoea, diffuse lung infiltrates, and impaired gas exchange. The majority of interstitial lung diseases are of unknown cause. Known causes of interstitial lung disease include inhalation of organic and inorganic dusts as well as gases or fumes, drugs, radiation, and infections. This review summarizes the clinical, radiological, and histopathological features of four interstitial lung disorders that have been linked to smoking. These disorders include desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, pulmonary Langerhans' cell histiocytosis, and idiopathic pulmonary fibrosis. Available evidence suggests most cases of desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, and pulmonary Langerhans' cell histiocytosis are caused by cigarette smoking in susceptible individuals. Smoking cessation should be a main component in the initial therapeutic approach to smokers with these interstitial lung diseases. In addition, smoking appears to be a risk factor for the development of idiopathic pulmonary fibrosis.

Mechanisms of defence in the lung: lessons from Pneumocystis carinii pneumonia.

Pneumocystis carinii continues to represent an important complication of individuals with compromised immunity. P. carinii interacts with immune and non-immune cells in the lung and mediates lung injury through a variety of mechanisms. CD4+ T lymphocytes are the cornerstone in defence against P. carinii. Recent studies indicate that alveolar macrophages provide essential functions that significantly enhance clearance of P. carinii infection. P. carinii also attaches to alveolar epithelial cells, causing inhibition of epithelial growth and replication. In addition to cellular interactions, P. carinii organisms bind to a variety of host adhesive proteins present in the lower respiratory tract. Binding of these proteins to P. carinii modulates host cell recognition and immune responses to the parasite. During the course of P. carinii pneumonia, several inflammatory mediators are produced in the lung. Although necessary for control of infection, exuberant inflammatory responses also predispose the host to the development of acute lung injury. Thus, host defences against P. carinii depend on complex interactions between immune and non-immune cells as well as several mediators that facilitate host recognition and eventual elimination of infection. Understanding these complex processes may enable development of novel therapeutic approaches for management of this important infection.