Vaccination Ameliorates Cellular Inflammatory Responses in SARS-CoV-2 Breakthrough Infections.

BACKGROUND: Data on cellular immune responses in persons with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection following vaccination are limited. The evaluation of these patients with SARS-CoV-2 breakthrough infections may provide insight into how vaccinations limit the escalation of deleterious host inflammatory responses. METHODS: We conducted a prospective study of peripheral blood cellular immune responses to SARS-CoV-2 infection in 21 vaccinated patients, all with mild disease, and 97 unvaccinated patients stratified based on disease severity. RESULTS: We enrolled 118 persons (aged 50 years [SD 14.5 years], 52 women) with SARS-CoV-2 infection. Compared to unvaccinated patients, vaccinated patients with breakthrough infections had a higher percentage of antigen-presenting monocytes (HLA-DR+), mature monocytes (CD83+), functionally competent T cells (CD127+), and mature neutrophils (CD10+); and lower percentages of activated T cells (CD38+), activated neutrophils (CD64+), and immature B cells (CD127+CD19+). These differences widened with increased disease severity in unvaccinated patients. Longitudinal analysis showed that cellular activation decreased over time but persisted in unvaccinated patients with mild disease at 8-month follow-up. CONCLUSIONS: Patients with SARS-CoV-2 breakthrough infections exhibit cellular immune responses that limit the progression of inflammatory responses and suggest mechanisms by which vaccination limits disease severity. These data may have implications for developing more effective vaccines and therapies. Clinical Trials Registration. NCT04401449.

Long-term evaluation of pulmonary function and survival of patients with interstitial pneumonia with autoimmune features.

OBJECTIVES: Interstitial pneumonia with autoimmune features (IPAF) includes patients with interstitial lung disease with autoimmune features who do not meet criteria for a connective tissue disease (CTD). Previous studies showed a wide variation in the radiologic pattern, pulmonary function and prognosis but there is still limited data on longitudinal outcomes. We aim to describe the long-term pulmonary function, radiological patterns, and survival of IPAF patients and explore a classification based on CTD-like subgroups by using clinical/serologic data. METHODS: Retrospective analysis of IPAF patients who were sub-classified into six CTD-(like) subgroups: systemic lupus erythematosus-like, rheumatoid arthritis-like, Sjögren's syndrome-like, scleroderma, myositis-like, and unclassifiable. Linear mixed-effect models were used to compare the change in percent-predicted forced vital capacity (FVC%), percent-predicted diffusion capacity (DLCO%), and six-minute walk distance (SMWD) over time; and survival in the entire cohort and according to CTD-like subgroups and radiological patterns. RESULTS: Fifty-nine patients fulfilled IPAF criteria. FVC%, DLCO%, and SMWD remained stable over time. There was no difference between usual interstitial pneumonia (UIP) versus non-UIP radiologic patterns. Thirty-five patients were sub-classified into CTD-like subgroups. Survival decreased from 79% at 60 months to 53% at 120 months in the entire cohort but was similar among CTD-like subgroups and radiological patterns. CONCLUSIONS: Long-term pulmonary function and six-minute walk test remained stable over 36 months in our IPAF cohort. Prognosis and pulmonary function in UIP had similar outcomes compared to non-UIP. Although 40% of IPAF patients could not be sub-classified, our exploratory subclassification stratified 60% of patients into a CTD-like subgroup.

A longitudinal cohort study of the anti-synthetase syndrome: increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies.

Objective: The aim was to study the prevalence, rate of appearance and severity of clinical features in patients with different anti-synthetase syndrome (ASyS) autoantibodies. Methods: All Johns Hopkins Myositis Longitudinal Cohort subjects positive for any ASyS autoantibodies were included. Clinical information, including symptoms, signs, strength, creatine kinase concentrations and pulmonary function tests, were prospectively collected. The standardized mortality and cancer rates and the rate of appearance and intensity of the different organ manifestations were assessed using univariate and multivariate analysis and compared between ASyS autoantibodies. Results: One hundred and twenty-four (73.4%) patients were positive for anti-Jo1, 23 (13.6%) for anti-PL12, 16 for anti-PL7 (9.5%) and 3 (1.8%) for anti-EJ or anti-OJ, respectively. The mean length of follow-up was 4.1 years. Anti-PL12 was more frequent in black subjects. Anti-PL12 and anti-PL7 were associated with more prevalent and severe lung involvement, often without muscle involvement. Anti-Jo1 displayed more severe muscle involvement compared with anti-PL12 patients. Concurrent anti-Ro52 was more prevalent in anti-Jo1 patients and was associated with earlier development of mechanic's hands, DM-specific skin findings and arthritis. Independent of ASyS antibody status, black patients demonstrated more severe lung involvement than white patients. There was no significant increase in mortality or cancer risk in ASyS patients compared with the general US population. Conclusion: Different ASyS autoantibodies are associated with phenotypically distinct subgroups within the ASyS spectrum. Anti-PL7 and anti-PL12 are characterized by more severe lung involvement, whereas anti-Jo1 is associated with more severe muscle involvement. Black race is a major prognostic factor associated with lung disease severity.

Longitudinal analysis of the lung proteome reveals persistent repair months after mild to moderate COVID-19.

In order to assess homeostatic mechanisms in the lung after COVID-19, changes in the protein signature of bronchoalveolar lavage from 45 patients with mild to moderate disease at three phases (acute, recovery, and convalescent) are evaluated over a year. During the acute phase, inflamed and uninflamed phenotypes are characterized by the expression of tissue repair and host defense response molecules. With recovery, inflammatory and fibrogenic mediators decline and clinical symptoms abate. However, at 9 months, quantified radiographic abnormalities resolve in the majority of patients, and yet compared to healthy persons, all showed ongoing activation of cellular repair processes and depression of the renin-kallikrein-kinin, coagulation, and complement systems. This dissociation of prolonged reparative processes from symptom and radiographic resolution suggests that occult ongoing disruption of the lung proteome is underrecognized and may be relevant to recovery from other serious viral pneumonias.

Quantitative CT Metrics Associated with Variability in the Diffusion Capacity of the Lung of Post-COVID-19 Patients with Minimal Residual Lung Lesions.

(1) Background: A reduction in the diffusion capacity of the lung for carbon monoxide is a prevalent longer-term consequence of COVID-19 infection. In patients who have zero or minimal residual radiological abnormalities in the lungs, it has been debated whether the cause was mainly due to a reduced alveolar volume or involved diffuse interstitial or vascular abnormalities. (2) Methods: We performed a cross-sectional study of 45 patients with either zero or minimal residual lesions in the lungs (total volume < 7 cc) at two months to one year post COVID-19 infection. There was considerable variability in the diffusion capacity of the lung for carbon monoxide, with 27% of the patients at less than 80% of the predicted reference. We investigated a set of independent variables that may affect the diffusion capacity of the lung, including demographic, pulmonary physiology and CT (computed tomography)-derived variables of vascular volume, parenchymal density and residual lesion volume. (3) Results: The leading three variables that contributed to the variability in the diffusion capacity of the lung for carbon monoxide were the alveolar volume, determined via pulmonary function tests, the blood vessel volume fraction, determined via CT, and the parenchymal radiodensity, also determined via CT. These factors explained 49% of the variance of the diffusion capacity, with p values of 0.031, 0.005 and 0.018, respectively, after adjusting for confounders. A multiple-regression model combining these three variables fit the measured values of the diffusion capacity, with R = 0.70 and p < 0.001. (4) Conclusions: The results are consistent with the notion that in some post-COVID-19 patients, after their pulmonary lesions resolve, diffuse changes in the vascular and parenchymal structures, in addition to a low alveolar volume, could be contributors to a lingering low diffusion capacity.

Long-Term Treatment With Azathioprine and Mycophenolate Mofetil for Myositis-Related Interstitial Lung Disease.

BACKGROUND: The efficacy of azathioprine (AZA) and mycophenolate mofetil (MMF) for interstitial lung disease (ILD) has been described, but mainly in connective tissue disease-associated ILD. The objective of this study was to evaluate the effect of AZA and MMF on lung function and prednisone dose in myositis-related ILD (M-ILD). METHODS: In this retrospective study, patients with M-ILD seen at Johns Hopkins and treated with AZA or MMF and no other steroid-sparing agents were included. Linear mixed-effects models adjusted for sex, age, antisynthetase antibody, and smoking status were used to compare the change in FVC % predicted, diffusing capacity of the lungs for carbon monoxide (Dlco) % predicted, and prednisone dose. RESULTS: Sixty-six patients with M-ILD were treated with AZA and 44 with MMF. At treatment initiation, mean FVC % predicted and Dlco % predicted were significantly lower in the AZA group than in the MMF group. In both groups, FVC % predicted improved and the prednisone dose was reduced over 2 to 5 years; however, for Dlco % predicted, only the AZA group improved. The adjusted model showed no significant difference in posttreatment FVC % predicted or Dlco % predicted between groups (mean difference of 1.9 and -8.2, respectively), but a 6.6-mg lower dose of prednisone at 36 months in the AZA group. Adverse events were more frequent with AZA than MMF (33.3% vs 13.6%; P = .04). CONCLUSIONS: In M-ILD, AZA treatment was associated with improved FVC % predicted and Dlco % predicted, and lower prednisone dose. Patients treated with MMF had improved FVC % predicted and lower prednisone dose. After 36 months, patients treated with AZA received a lower prednisone dose than those treated with MMF.

Risk factors for mortality and mortality rates in interstitial lung disease patients in the intensive care unit.

Data on interstitial lung disease (ILD) outcomes in the intensive care unit (ICU) is of limited value due to population heterogeneity. The aim of this study was to examine risk factors for mortality and ILD mortality rates in the ICU.We performed a systematic review using five databases. 50 studies were identified and 34 were included: 17 studies on various aetiologies of ILD (mixed-ILD) and 17 on idiopathic pulmonary fibrosis (IPF). In mixed-ILD, elevated APACHE score, hypoxaemia and mechanical ventilation are risk factors for mortality. No increased mortality was found with steroid use. Evidence is inconclusive on advanced age. In IPF, evidence is inconclusive for all factors except mechanical ventilation and hypoxaemia. The overall in-hospital mortality was available in 15 studies on mixed-ILD (62% in 2001-2009 and 48% in 2010-2017) and 15 studies on IPF (79% in 1993-2004 and 65% in 2005-2017). Follow-up mortality rate at 1 year ranged between 53% and 100%.Irrespective of ILD aetiology, mechanical ventilation is associated with increased mortality. For mixed-ILD, hypoxaemia and APACHE scores are also associated with increased mortality. IPF has the highest mortality rate among ILDs, but since 1993 the rate appears to be declining. Despite improving in-hospital survival, overall mortality remains high.

[Knowledge, practices and attitudes toward volunteer work in an influenza pandemic: cross-sectional study with Peruvian medical students]. / Conocimientos, prácticas y actitudes hacia el voluntariado ante una influenza pandémica: estudio transversal con estudiantes de medicina en Perú.

INTRODUCTION: Reductions in health personnel during disasters or epidemics such as an influenza pandemic may need to include volunteer students. OBJECTIVE: The aim of this article is to determine knowledge and practices about pandemic influenza and the attitudes towards volunteer work in Peruvian medical students. METHODS: We performed a cross-sectional analytic study by simple sampling using a survey regarding “"knowledge and practices"” about pandemic influenza and the attitudes to volunteer work. RESULTS: From the group of 865 students who were surveyed, 848 accepted to participate in the investigation (54% were male and their mean age was 22.1 ± 3.0). Ninety-seven percent correctly identified the spread routes of influenza and 81% knew its treatment. Regarding preventive measures, covering the mouth when coughing/sneezing and hand-washing were the most commonly recognized options (95% y 92%, respectively), and vaccination was the less recognized one (54%). The most common practice, readily acknowledged as preventive, was covering when coughing/sneezing (86%). Regarding volunteer works, students answered that it is a moral/ethical/professional obligation (77%); that a contingency university service needs to be established (88%), that it does not have to substitute for the lack of workers (49%), and that its role should be related to hospital work (83%). Coming from a public university was more associated to the concept that volunteer work was a moral obligation and that the student should be punished if he/she refuses to be a volunteer, whereas being from a private university was more related to a history of been involved in volunteering programs. CONCLUSIONS: In general, medical students have good knowledge and practices toward influenza. There is a good disposition to volunteer their work and skills, recognizing it as a moral/ethical/professional obligation.

INTRODUCCIÓN : La reducción crítica en el personal de salud ante situaciones de desastre o epidemia como una pandemia de influenza podría requerir la necesidad de incluir estudiantes voluntarios. OBJETIVO: El objetivo del artículo es determinar los conocimientos y prácticas sobre influenza pandémica y la actitud hacia el voluntariado en estudiantes de medicina peruanos. MÉTODOS: Estudio transversal analítico por muestreo simple utilizando una encuesta. RESULTADOS: De los 865 estudiantes, 848 aceptaron participar en el estudio (54% varones, edad promedio 22,1 ± 3,03). El 97% identificó de manera correcta las vías de propagación de la influenza y el 81% conocía su tratamiento. Sobre medidas preventivas correctas, cubrirse al toser o estornudar y lavado de manos fueron las respuestas mejores reconocidas (95% y 92%, respectivamente) y la vacunación fue la menor (54%). La práctica más frecuentemente realizada fue cubrirse al toser o estornudar (86%). Al respecto del voluntariado los participantes respondieron que es un deber moral/ético/profesional (77%), que se debe instituir un servicio universitario de contingencia (88%), que no debe suplir la falencia de trabajadores (49%) y que debe radicar en atención médica hospitalaria (83%). El pertenecer a universidades estatales estuvo más asociado a pensar que el voluntariado es una obligación moral y que el estudiante debe ser castigado en caso se niegue a ser voluntario, mientras que el pertenecer a universidades particulares estuvo más asociado con el antecedente de haber participado en un programa de voluntariado. CONCLUSIONES: En general, los estudiantes poseen un buen nivel de conocimientos y prácticas sobre influenza. Hay una buena disposición hacia el voluntariado reconociéndolo como una obligación moral/ética/profesional.

Validation of the salivary urea test as a method to diagnose chronic kidney disease.

BACKGROUND: Serum urea correlates very well to salivary urea, which can be used as a low-cost, easily accessible and noninvasive diagnostic method for screening patients in early stages of kidney disease, especially in developing countries where resources are limited, giving the possibility of establishing secondary prevention programs later. METHODS: One hundred and one people were enrolled: 11 with creatinine clearance (CrCl) less than 10 ml/min per 1.73 m(2); 10 with CrCl of 11-20 ml/min per 1.73 m(2); 12 with CrCl of 21-50 ml/min per 1.73 m(2); 26 with CrCl of 51-80 ml/min per 1.73 m(2) and 42 with CrCl of 81-170 ml/min per 1.73 m(2), to analyze salivary urea test accuracy through construction of a receiver operating characteristic curve. RESULTS: Salivary urea cutoff point of 20 mg/dL and a CrCl of 80 ml/min per 1.73 m(2) showed sensitivity (S) of 0.98, specificity (SP) of 0.29, pretest probability (PPT) of 0.58, positive predictive value (PPV) of 0.66, negative predictive value (NPV) of 0.92, posttest positive probability (PTPP) of 0.66 and posttest negative probability (PTNP) of 0.09. A cutoff point of 40 mg/dL and a CrCl of 80 ml/min per 1.73 m(2) showed S=0.80, SP=0.71, PPT=0.58, PPV=0.80, NPV=0.71, PTPP=0.79 and PTNP=0.28. A cutoff point of 100 mg/dL and a CrCl of 80 ml/min per 1.73 m(2) showed S=0.22, SP=1, PPT=0.58, PPV=1, NPV=0.48, PTPP=1 and PTNP=0.52. Receiver operating characteristic curve analysis showed that the best cutoff point for salivary urea was 40 mg/dL. CONCLUSION: The salivary urea test has a great capacity to discriminate patients with chronic kidney disease from healthy people, and it was shown that the best cutoff point is 40 mg/dL.