Hospital Outcomes in Patients Hospitalized for COVID-19 Pneumonia: The Effect of SARS-CoV-2 Vaccination and Vitamin D Status.

SARS-CoV-2 vaccination promises to improve outcomes for patients with COVID-19 pneumonia (most notably those with advanced age and at high risk for severe disease). Here, we examine serum 25-Hydroxyvitamin D (25(OH)D) status and outcomes in both old (>70 years) and young vaccinated (n = 80) and unvaccinated (n = 91) subjects, who were hospitalized due to COVID-19 pneumonia in a single center (Connolly Hospital Dublin). Outcomes included ICU admission and mortality. Serum 25(OH)D levels were categorized as D30 (<30 nmol/L), D40 (30-49.99 nmol/L) and D50 (≥50 nmol/L). In multivariate analyses, D30 was independently associated with ICU admission (OR: 6.87 (95% CI: 1.13-41.85) (p = 0.036)) and mortality (OR: 24.81 (95% CI: 1.57-392.1) (p = 0.023)) in unvaccinated patients, even after adjustment for major confounders including age, sex, obesity and pre-existing diabetes mellitus. While mortality was consistently higher in all categories of patients over 70 years of age, the highest observed mortality rate of 50%, seen in patients over 70 years with a low vitamin D state (D30), appeared to be almost completely corrected by either vaccination, or having a higher vitamin D state, i.e., mortality was 14% for vaccinated patients over 70 years with D30 and 16% for unvaccinated patients over 70 years with a 25(OH)D level greater than 30 nmol/L. We observe that high mortality from COVID-19 pneumonia occurs in older patients, especially those who are unvaccinated or have a low vitamin D state. Recent vaccination or having a high vitamin D status are both associated with reduced mortality, although these effects do not fully mitigate the mortality risk associated with advanced age.

Vitamin D Status and Mortality from SARS CoV-2: A Prospective Study of Unvaccinated Caucasian Adults.

COVID-19 and a low vitamin D state share common risk factors, which might explain why vitamin D deficiency has been linked with higher COVID-19 mortality. Moreover, measures of serum vitamin D may become lower during systemic inflammatory responses, further confounding the association via reverse causality. In this prospective study (recruited over 12 months), we examined whether the association between a low vitamin D state and in-hospital mortality due to SARS-CoV-2 pneumonia in unvaccinated subjects is explained by (i) the presence of shared risk factors (e.g., obesity, advanced age) or (ii) a reduction in serum 25(OH)D due to COVID-19 (i.e., reverse causality). In this cohort of 232 (mean age = 56 years) patients (all had SARS-CoV-2 diagnosed via PCR AND required supplemental oxygen therapy), we failed to find an association between serum vitamin D and levels of CRP, or other inflammatory markers. However, the hazard ratio for mortality for subjects over 70 years of age (13.2) and for subjects with a serum 25(OH)D level less than 30 nmol·L−1 (4.6) remained significantly elevated even after adjustment for gender, obesity and the presence of diabetes mellitus. Subjects <70 years and >70 years had significantly higher mortality with a serum 25(OH)D less than 30 nmol·L−1 (11.8% and 55%), than with a serum 25(OH)D greater than 30 nmol·L−1 (2.2% and 25%). Unvaccinated Caucasian adults with a low vitamin D state have higher mortality due to SARS CoV-2 pneumonia, which is not explained by confounders and is not closely linked with elevated serum CRP.

Title: Understanding a Low Vitamin D State in the Context of COVID-19.

While a low vitamin D state has been associated with an increased risk of infection by SARS-CoV-2 in addition to an increased severity of COVID-19 disease, a causal role is not yet established. Here, we review the evidence relating to i) vitamin D and its role in SARS-CoV-2 infection and COVID-19 disease ii) the vitamin D status in the Irish adult population iii) the use of supplemental vitamin D to treat a deficient status and iv) the application of the Bradford-Hill causation criteria. We conclude that reverse causality probably makes a minimal contribution to the presence of low vitamin D states in the setting of COVID-19. Applying the Bradford-Hill criteria, however, the collective literature supports a causal association between low vitamin D status, SARS-CoV-2 infection, and severe COVID-19 (respiratory failure, requirement for ventilation and mortality). A biologically plausible rationale exists for these findings, given vitamin D's role in immune regulation. The thresholds which define low, deficient, and replete vitamin D states vary according to the disease studied, underscoring the complexities for determining the goals for supplementation. All are currently unknown in the setting of COVID-19. The design of vitamin D randomised controlled trials is notoriously problematic and these trials commonly fail for a number of behavioural and methodological reasons. In Ireland, as in most other countries, low vitamin D status is common in older adults, adults in institutions, and with obesity, dark skin, low UVB exposure, diabetes and low socio-economic status. Physiological vitamin D levels for optimal immune function are considerably higher than those that can be achieved from food and sunlight exposure alone in Ireland. A window exists in which a significant number of adults could benefit from vitamin D supplementation, not least because of recent data demonstrating an association between vitamin D status and COVID-19. During the COVID pandemic, we believe that supplementation with 20-25ug (800-1000 IU)/day or more may be required for adults with apparently normal immune systems to improve immunity against SARS-CoV-2. We expect that higher monitored doses of 37.5-50 ug (1,500-2,000)/day may be needed for vulnerable groups (e.g., those with obesity, darker skin, diabetes mellitus and older adults). Such doses are within the safe daily intakes cited by international advisory agencies.

An arteriovenous fistula increases exercise capacity in patients with COPD.

BACKGROUND: Supplemental oxygen usually increases exercise capacity in hypoxemic COPD, but some patients are refractory because of venous admixture. An arteriovenous fistula (AVF) with left-to-right shunt increases mixed venous oxygen content and cardiac output; therefore, this might improve arterial oxygen delivery. We hypothesized that creation of an AVF would therefore increase exercise capacity in severe COPD. METHODS: We created an AVF in 12 patients with severe hypoxemic COPD: mean (SD) age, 66 (6) years; Pao(2), 57.5 (3.0) mm Hg, and FEV(1), 19% (8%) predicted. We measured 6-min walk distance (6MWD) while the subjects were breathing room air and again while they were breathing portable supplemental oxygen at baseline, 6 weeks, and 12 weeks after creation of an AVF in the iliofemoral region. RESULTS: After surgery, the mean (SEM) 6MWD increased from 217 (63) m at baseline to 272 (18) m and 276 (25) m, 6 weeks and 12 weeks after surgery, respectively. Patients who walked > 54 m further while breathing supplemental oxygen at baseline (n = 5) increased 6MWD while breathing room air by 129 (34) m after 6 weeks (P = .02) and by 124 (29) m after 12 weeks (P = .004). Walking distance did not change in patients who did not have a clinically meaningful response to oxygen at baseline. CONCLUSIONS: An iliofemoral AVF increased 6MWD patients with severe COPD, matching the improvement seen with supplemental oxygen. An initial response to supplemental oxygen predicted a therapeutic response to the AVF.

The effect of an inhaled corticosteroid on glucose control in type 2 diabetes.

OBJECTIVE: To determine the effect of inhaled corticosteroid (ICS) therapy on glucose control in adults with type 2 diabetes mellitus and coexisting asthma or chronic obstructive pulmonary disease (COPD). DESIGN: A prospective randomized, double-blind, double-dummy placebo-controlled, crossover investigation of inhaled steroids and oral leukotriene blockers. SETTING: A United States Department of Veterans Affairs Health Care System outpatient setting. PARTICIPANTS: Adults with type 2 diabetes and asthma or COPD. METHODS: Subjects (n=12) were randomized to receive either inhaled fluticasone propionate (440 microg twice daily) and oral placebo, or inhaled placebo and oral montelukast (10 mg/day). After 6 weeks, subjects were switched to the opposite therapy for 6 weeks. The primary outcome measure was the change in the percentage of glycosylated hemoglobin (%HbA1c) at 6 weeks relative to the baseline value. RESULTS: Ten patients completed the study. The difference between the mean within-subject changes in %HbA1c associated with 6-week periods of fluticasone and the mean changes associated with montelukast therapy was small but statistically significant (mean difference=0.25; P<0.025). Neither fluticasone nor oral montelukast therapy for 6 weeks led to a significantly different mean % HbA1c compared with the relevant baseline (mean differences=0.11 and -0.14, respectively). CONCLUSION: The absence of a clinically significant within-subject difference in the changes in %HbA1c associated with fluticasone versus oral montelukast therapy, or between either therapy or baseline does not warrant recommending changes in therapy for asthma or diabetes in patients with these co-morbid conditions. However, we suggest that clinicians carefully monitor blood glucose control when diabetic patients initiate ICS, especially with higher dosages.

Current therapies for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature, characterized by relentless deterioration and death. Patients with PAH are known to be at increased risk for anesthetic complications and surgical morbidity and mortality. However, outcomes in patients have improved with the recent development of new drug therapies. The 3 major drug classes for treatment of PAH are prostanoids, endothelin-receptor antagonists, and phosphodiesterase-5 inhibitors. In this review, the authors provide an overview of each drug class, its mechanism of action, indications, and current supportive literature. Surgical and interventional treatments of PAH, including atrial septostomy, pulmonary thromboendarterectomy, and transplantation, are briefly reviewed, and the rationale, indications, and selection criteria for each are discussed. Although available medical and surgical therapies for PAH have improved patient outcomes, acute decompensated right heart failure (RHF) remains a common and challenging complication of PAH. The authors review this topic and provide an outline of the general pathophysiology of RHF and an approach to its management.

CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma.

BACKGROUND: Bronchial asthma is associated with an inflammatory process that is characterized by the presence in the airways of large numbers of CD4+ T cells producing interleukin-4 and interleukin-13. However, the CD4 antigen is expressed not only by class II major histocompatibility complex (MHC)-restricted CD4+ T cells, but also by a newly identified subgroup of T cells, CD1d-restricted natural killer T cells. These cells express a conserved (invariant) T-cell receptor and have a potent immunoregulatory function. Because mouse models of allergic asthma indicate that natural killer T cells are required for the development of allergen-induced airway hyperreactivity, we hypothesized that natural killer T cells play an important role in human asthma. METHODS: We used CD1d-tetramers, antibodies specific for natural killer T cells, as well as reverse-transcriptase-polymerase-chain-reaction analysis of the invariant T-cell receptor of natural killer T cells to assess the frequency and distribution of natural killer T cells in the lungs and in the circulating blood of 14 patients with asthma. RESULTS: About 60 percent of the pulmonary CD4+CD3+ cells in patients with moderate-to-severe persistent asthma were not class II MHC-restricted CD4+ T cells but, rather, natural killer T cells. The natural killer T cells expressed an invariant T-cell receptor and produced type 2 helper cytokines. In contrast, the CD4+ T cells found in the lungs of patients with sarcoidosis were conventional CD4+CD3+ T cells, not natural killer T cells. CONCLUSIONS: Together with studies in mice indicating a requirement for natural killer T cells in the development of allergen-induced airway hyperreactivity, our results strongly suggest that CD4+ natural killer T cells play a prominent pathogenic role in human asthma.

Transcutaneous electrical nerve stimulation for severe gastroparesis after lung transplantation.

Gastroparesis is a serious complication of lung transplantation that can lead to weight loss, gastroesophageal reflux disease, and recurrent aspiration pneumonia. We present 2 lung allograft recipients in whom gastroparesis resolved with the use of transcutaneous electrical nerve stimulation (TENS). In both patients, severe symptoms of gastroparesis refractory to medical therapy were completely ablated after 20 and 30 days of therapy. Both patients are currently asymptomatic with a normal diet, without the use of promotility agents. Lung transplant recipients with severe gastroparesis can derive significant benefit from TENS.

Lymphocytic myocarditis after lung transplantation.

This study reports the development of lymphocytic myocarditis in a bilateral lung allograft recipient. A 23-year-old woman developed congestive heart failure and severe left ventricular dysfunction 32 months after a bilateral lung allograft for cystic fibrosis. She had taken oral acyclovir for infectious mononucleosis that was diagnosed 11 months previously. Her viral load for Epstein-Barr virus (EBV) increased, and an echocardiogram revealed a left ventricular ejection fraction of 25% and endomyocardial biopsy revealed lymphocytic myocarditis. She received valacyclovir (1 g x 3 times daily) and made a full recovery 6 months later.

Thoracic lymphatic disorders.

Thoracic complications of lymphatic disorders can culminate in respiratory failure and death and should be considered in any patient with a lymphatic disease and clinical or radiographic evidence of chest disease. Congenital lymphatic disorders are being increasingly recognized in the adult population. The spectrum of thoracic manifestations of lymphatic disorders ranges from incidental radiographic findings to diffuse lymphatic disease with respiratory failure. This article serves to review some recent advances that allow improved diagnosis and management of thoracic lymphatic disorders. Herein, we describe their anatomical and physiologic effects, the time course of their progression, and the therapies that are currently available. The management of malignant (cancerous) lymphatic disorders of the thorax is beyond the scope of this paper.

Chylothorax after heart/lung transplantation.

Chylothorax is a potentially serious complication of lung and heart-lung transplantation. This article describes the clinical course of chylothorax in 3 heart-lung allograft recipients. We discuss management options, including dietary modifications, octreotide infusion, thoracic duct ligation and embolization, and surgical pleurodesis. In addition, we describe the novel use of aminocaproic acid to reduce lymph flow. We propose a multidisciplinary approach for the management of chylothorax that includes both medical and surgical options.

Longitudinal transcriptional analysis of developing neointimal vascular occlusion and pulmonary hypertension in rats.

Pneumonectomized rats injected with the alkaloid toxin, monocrotaline, develop progressive neointimal pulmonary vascular obliteration and pulmonary hypertension resulting in right ventricular failure and death. The antiproliferative immunosuppressant, triptolide, attenuates neointimal formation and pulmonary hypertension in this disease model (Faul JL, Nishimura T, Berry GJ, Benson GV, Pearl RG, and Kao PN. Am J Respir Crit Care Med 162: 2252-2258, 2000). Pneumonectomized rats, injected with monocrotaline on day 7, were killed at days 14, 21, 28, and 35 for measurements of physiology and gene expression patterns. These data were compared with pneumonectomized, monocrotaline-injected animals that received triptolide from day 5 to day 35. The hypothesis was tested that a group of functionally related genes would be significantly coexpressed during the development of disease and downregulated in response to treatment. Transcriptional analysis using total lung RNA was performed on replicate animals for each experimental time point with exploratory data analysis followed by statistical significance analysis. Marked, statistically significant increases in proteases (particularly derived from mast cells) were noted that parallel the development of vascular obliteration and pulmonary hypertension. Mast-cell-derived proteases may play a role in regulating the development of neointimal pulmonary vascular occlusion and pulmonary hypertension in response to injury.

Gastric pacing for severe gastroparesis in a heart-lung transplant recipient.

Gastroparesis is a serious complication of lung and heart-lung transplantation that can lead to malnutrition, gastroesophageal reflux, aspiration pneumonia and deteriorating lung function. Some patients with severe gastroparesis have symptoms that are refractory to dietary modifications and gastric promotility agents and require surgery. We describe the successful use of gastric pacing for the management of intractable gastroparesis, malnutrition and recurrent aspiration in a heart-lung allograft recipient. Lung transplant recipients with severe gastroparesis may benefit from gastric pacing.

Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells.

BACKGROUND: Pulmonary vascular injury by toxins can induce neointimal formation, pulmonary arterial hypertension (PAH), right ventricular failure, and death. We showed previously that simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in pneumonectomized rats injected with the alkaloid toxin monocrotaline. The present study was undertaken to investigate the efficacy of simvastatin and its mechanism of reversing established neointimal vascular occlusion and pulmonary hypertension. METHODS AND RESULTS: Pneumonectomized rats injected with monocrotaline at 4 weeks demonstrated severe PAH at 11 weeks (mean pulmonary artery pressure [mPAP]=42 versus 17 mm Hg in normal rats) and death by 15 weeks. When rats with severe PAH received simvastatin (2 mg x kg(-1) x d(-1) by gavage) from week 11, there was 100% survival and reversal of PAH after 2 weeks (mPAP=36 mm Hg) and 6 weeks (mPAP=24 mm Hg) of therapy. Simvastatin treatment reduced right ventricular hypertrophy and reduced proliferation and increased apoptosis of pathological smooth muscle cells in the neointima and medial walls of pulmonary arteries. Longitudinal transcriptional profiling revealed that simvastatin downregulated the inflammatory genes fos, jun, and tumor necrosis factor-alpha and upregulated the cell cycle inhibitor p27Kip1, endothelial nitric oxide synthase, and bone morphogenetic protein receptor type 1a. CONCLUSIONS: Simvastatin reverses pulmonary arterial neointimal formation and PAH after toxic injury.

Effect of a surgical aortocaval fistula on monocrotaline-induced pulmonary hypertension.

OBJECTIVE: Increased pulmonary blood flow is believed to contribute to the development of pulmonary hypertension. We investigated the effect of overcirculation via an aortocaval fistula, on the development of monocrotaline-induced pulmonary hypertension in rats. Monocrotaline was administered 1 wk after the creation of an aortocaval fistula. DESIGN: Randomized, controlled study. SETTING: Research laboratory of an academic institution. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Overcirculation was induced by pneumonectomy and by surgical creation of aortocaval fistula. Pulmonary artery hypertension was induced by administration of monocrotaline. MEASUREMENTS AND MAIN RESULTS: Aortic blood flow, Pao(2), and pulmonary arterial pressure were measured 4 wks later. A blinded investigator quantified pulmonary arterial neointimal formation in small pulmonary arteries. Compared with animals that received monocrotaline and/or underwent pneumonectomy but did not undergo aortocaval fistula, the presence of a surgical aortocaval fistula was associated with increased aortic blood flow (p <.001), increased Pao(2) (p <.001), and lower mean pulmonary arterial pressure (p <.001). In addition, rats with aortocaval fistula had less pulmonary arterial neointimal formation than matched animals without an aortocaval fistula (p =.034). CONCLUSIONS: The presence of a surgical aortocaval fistula attenuates, rather than worsens, the development of monocrotaline-induced pulmonary hypertension in rats.