Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.

BACKGROUND: HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. OBJECTIVE: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. METHODS: The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. RESULTS: The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

Rapid alveolar epithelial fluid clearance following lung lavage in pulmonary alveolar proteinosis.

STUDY OBJECTIVE: To measure the in vivo rate of alveolar epithelial fluid clearance of the human lung in patients with pulmonary alveolar phospholipoproteinosis (PAP). DESIGN: Prospective clinical study. SETTING: The medical-surgical ICUs of a university teaching hospital. PATIENTS: Four patients with idiopathic PAP requiring therapeutic lung lavage. INTERVENTIONS: Large-volume lung lavage with isotonic saline solution using fiberoptic bronchoscopy followed by serial sampling of alveolar fluid using a wedged bronchial catheter. MEASUREMENTS AND RESULTS: The rate of alveolar epithelial fluid clearance was calculated by measuring the concentration of protein in sequential samples. Alveolar epithelial fluid clearance over the first hour after lung lavage was 53 +/- 14% (mean +/- SD). Sequential samples in two patients indicated a sustained high rate of clearance over several hours. Plasma and alveolar fluid epinephrine levels were in the normal range in two patients. CONCLUSIONS AND SIGNIFICANCE: Alveolar fluid clearance is rapid after lung lavage in patients with PAP and appears to be driven by catecholamine-independent mechanisms. The rapid rate of alveolar epithelial fluid transport explains why patients with PAP tolerate large-volume lung lavage.

Nephritogenic cytokines and disease in MRL-Fas(lpr) kidneys are dependent on multiple T-cell subsets.

BACKGROUND: Renal parenchymal cells produce cytokines, colony-stimulating factor-1 (CSF-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha), which recruit autoreactive T cells and, in turn, elicit renal injury in MRL-Fas(lpr) mice. METHODS: To determine whether select T-cell populations regulate intrarenal nephritogenic cytokines (CSF-1, GM-CSF, and TNF-alpha) and renal disease, we compared MRL-Fas(lpr) mice that are genetically deficient in T-cell receptor (TCR) alpha beta T cells, CD4 T cells, and major histocompatibility complex class I (MHC class I), lacking CD8 and double negative (DN) T cells, with wild-type mice. To identify the T cells instrumental in downstream (effector) events, we delivered CSF-1 or GM-CSF into the kidney via gene transfer in these select T-cell-deficient and wild-type strains. RESULTS: Intrarenal CSF-1, GM-CSF, and TNF-alpha were absent or dramatically reduced in TCR alpha beta, CD4, and class I-deficient MRL-Fas(lpr) strains as compared with wild-type mice. In addition, the decrease in CSF-1, GM-CSF, and TNF-alpha was associated with a reduced kidney leukocytic infiltrates and spontaneous autoimmune nephritis. Intrarenal ex vivo retroviral gene transfer of CSF-1 and GM-CSF failed to elicit nephritis in these T-cell-deficient MRL strains (TCR alpha beta, CD4, CD8/DN) as compared with wild-type mice. CONCLUSIONS: Multiple T-cell populations initiate renal disease by increasing intrarenal nephritogenic cytokines, CSF-1, GM-CSF, and TNF-alpha. CSF-1 and GM-CSF recruit additional CD4 and CD8 and DN T cells, which augment downstream events, resulting in progressive autoimmune renal disease. We suggest that MRL-Fas(lpr) kidney disease is driven by a T-cell amplification feedback loop dependent on multiple T-cell populations.

The effect on immunoglobulin glycosylation of altering in vivo production of immunoglobulin G.

The effect on murine immunoglobulin G (IgG) glycosylation of altering IgG production in vivo was assessed in interleukin (IL)-6 transgenic and CD4 knockout mice. C57BL/6 mice carrying the IL-6 transgene showed increased levels of circulating IgG. This was associated with decreased levels of galactose on the IgG oligosaccharides. No decrease in beta4-galactosyltransferase mRNA or in enzyme activity was seen in IL-6 transgenic mice. MRL-lpr/lpr mice normally have elevated levels of circulating IgG, again accompanied by decreased levels of IgG galactose. Disruption of the CD4 gene in MRL-lpr/lpr mice led to a substantial decrease in the concentration of circulating IgG, but IgG galactose levels remained low. Thus, an enforced decrease in IgG levels in the lymphoproliferative MRL-lpr/lpr mice did not alter the percentage of agalactosyl IgG in these mice, suggesting that agalactosyl IgG production is not simply caused by excessive IgG synthesis leading to an insufficient transit time in the trans-Golgi, but rather to a molecular defect in the interaction between galactosyltransferase and the immunoglobulin heavy chain.

Enhanced lymphoproliferation and diminished autoimmunity in CD4-deficient MRL/lpr mice.

MRL/lpr mice spontaneously develop an autoimmune disease with features of systemic lupus erythematosus. They also develop a lymphoproliferative disorder characterized by a massive accumulation of double-negative (DN) T cells that lack both CD4 and CD8. To clarify the role of CD4 in autoimmunity and lymphoproliferation in these mice, CD4-deficient MRL/lpr mice were generated. CD4-deficient MRL/lpr mice developed massive expansion of DN T cells in the blood, spleen, and lymph nodes, which significantly exceeded the degree of lymphoproliferation in CD4-expressing control MRL/lpr mice. Despite this lymphoproliferation, CD4-deficient MRL/lpr mice produced little, if any, antibodies to double-stranded DNA, and they had prolonged survival relative to CD4-expressing littermates. However, they eventually developed moderately severe nephritis, characterized by immunoglobulin and complement deposition in glomeruli, vasculitis, and renal infiltration by CD8+ T cells. These findings indicate that (1) lymphoproliferation in MRL/lpr mice does not require the expression of CD4; (2) autoantibody production in MRL/lpr mice is dependent on the expression of CD4 and not on the accumulation of DN T cells; and (3) the development of nephritis in MRL/lpr mice involves both CD4-dependent and CD4-independent mechanisms.

Management of asthma exacerbations.

The 1997 Expert Panel Report 2 from the National Asthma Education and Prevention Program details principles and goals for managing asthma exacerbations, based on scientific literature and the opinion of the panel. The panel's recommendations are summarized here, along with approaches to the evaluation and management of patients with asthma exacerbations. Methods to assess and classify the severity of asthma exacerbations are discussed, and treatment objectives for mild, moderate, and severe exacerbations are presented, along with a discussion of postinfectious acute airway hyperresponsiveness. A review of pharmacologic agents used in the treatment of asthma exacerbations is also included. Key points in the management of asthma exacerbations include the notion that early treatment is the best strategy for management. Important elements of early treatment include recognition of early signs of worsening asthma, a written action plan to guide patient self-management, appropriate intensification of therapy, and prompt communication between patient and provider about deterioration in asthma control. Other key points include the use of inhaled beta 2-adrenergic agonists to provide prompt relief of airflow obstruction, the early use of systemic corticosteroids for patients with moderate to severe exacerbations or for patients who fail to respond promptly and completely to an inhaled beta 2-adrenergic agonist, and monitoring response to therapy with serial measurements of lung function.