Clinical Outcomes and Predictors of Long-Term Survival in Patients With and Without Previously Known Extracardiac Sarcoidosis Using Machine Learning: A Swedish Multicenter Study.

Background Cardiac involvement can be an initial manifestation in sarcoidosis. However, little is known about the association between various clinical phenotypes of cardiac sarcoidosis (CS) and outcomes. We aimed to analyze the relation of different clinical manifestations with outcomes of CS and to investigate the relative importance of clinical features influencing overall survival. Methods and Results A retrospective cohort of 141 patients with CS enrolled at 2 Swedish university hospitals was studied. Presentation, imaging studies, and outcomes of de novo CS and previously known extracardiac sarcoidosis were compared. Survival free of primary composite outcome (ventricular arrhythmias, heart transplantation, or death) was assessed. Machine learning algorithm was used to study the relative importance of clinical features in predicting outcome. Sixty-two patients with de novo CS and 79 with previously known extracardiac sarcoidosis were included. De novo CS showed more advanced New York Heart Association class (P=0.02), higher circulating levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) (P<0.001), and troponins (P<0.001), as well as a higher prevalence of right ventricular dysfunction (P<0.001). During a median (interquartile range) follow-up of 61 (44-77) months, event-free survival was shorter in patients with de novo CS (P<0.001). The top 5 features predicting worse event-free survival in order of importance were as follows: impaired tricuspid annular plane systolic excursion, de novo CS, reduced right ventricular ejection fraction, absence of ß-blockers, and lower left ventricular ejection fraction. Conclusions Patients with de novo CS displayed more severe disease and worse outcomes compared with patients with previously known extracardiac sarcoidosis. Using machine learning, right ventricular dysfunction and de novo CS stand out as strong overall predictors of impaired survival.

Comparing severe COVID-19 outcomes of first and second/third waves: a prospective single-centre cohort study of health-related quality of life and pulmonary outcomes 6 months after infection.

OBJECTIVE: We aimed to compare long-term outcomes in intensive care unit (ICU) survivors between the first and second/third waves of the COVID-19 pandemic. More specifically, to assess health-related quality of life (HRQL) and respiratory health 6 months post-ICU and to study potential associations between patient characteristic and treatment variables regarding 6-month outcomes. DESIGN: Prospective cohort study. SETTING: Single-centre study of adult COVID-19 patients with respiratory distress admitted to two Swedish ICUs during the first wave (1 March 2020-1 September 2020) and second/third waves (2 September 2020- 1 August 2021) with follow-up approximately 6 months after ICU discharge. PARTICIPANTS: Critically ill COVID-19 patients who survived for at least 90 days. MAIN OUTCOME MEASURES: HRQL, extent of residual changes on chest CT scan and pulmonary function were compared between the waves. General linear regression and multivariable logistic regression were used to present mean score differences (MSD) and ORs with 95% CIs. RESULTS: Of the 456 (67%) critically ill COVID-19 patients who survived at least 90 days, 278 (61%) were included in the study. Six months after ICU discharge, HRQL was similar between survivors in the pandemic waves, except that the second/third wave survivors had better role physical (MSD 20.2, 95% CI 7.3 to 33.1, p<0.01) and general health (MSD 7.2, 95% CI 0.7 to 13.6, p=0.03) and less bodily pain (MSD 12.2, 95% CI 3.6 to 20.8, p<0.01), while first wave survivors had better diffusing capacity of the lungs for carbon monoxide (OR 1.9, 95% CI 1.1 to 3.5, p=0.03). CONCLUSIONS: This study indicates that even though intensive care treatment strategies have changed with time, there are few differences in long-term HRQL and respiratory health seems to remain at 6 months for patients surviving critical COVID-19 in the first and second/third waves of the pandemic.

Peripheral blood lymphopenia in sarcoidosis associates with HLA-DRB1 alleles but not with lung immune cells and organ involvement.

Different human leukocyte antigen (HLA) alleles associate with disease phenotypes in sarcoidosis. Peripheral blood (PB) lymphopenia is reported as more common in sarcoidosis patients with worse prognosis. The mechanisms behind are unrecognized but a PB depletion due to lymphocytes migrating to lung and/or extra pulmonary organs has been suggested. Insights into associations between HLA alleles, lung immune cells, clinical phenotype including extra pulmonary manifestations (EPM), and PB lymphopenia may provide mechanistic clues and enable adequate intervention in this patient group. In this situdy,141 treatment naïve, newly diagnosed patients were retrospectively identified in a Swedish cohort of sarcoidosis patients. Data on HLA-DRB1 alleles, lung immune cells from bronchoalveolar lavage fluid (BALF), PB lymphocytes and clinical parameters including treatment and disease course (chronic vs. resolving) were collected. The patients were followed for 2 years. PB lymphopenia associated with male sex, development of non-resolving disease, a need for first- and second-line systemic immunosuppressant treatment and HLA- DRB1*07. No correlation between BALF and PB lymphocytes, and no difference in EPM was detected between patients with and without PB lymphopenia. In conclusion, PB lymphopenia is associated with a more severe disease phenotype and carriage of the HLA-DRB1*07 allele. The results do not lend support to the hypothesis about sarcoidosis PB lymphopenia being due to a migration of PB lymphocytes to other organs. Rather, they provide a basis for future studies on the connection between HLA-DRB1*07 and PB lymphopenia mechanisms.

Sarcoidosis: Epidemiology and clinical insights.

Sarcoidosis is characterized by noncaseating granulomas which form in almost any part of the body, primarily in the lungs and/or thoracic lymph nodes. Environmental exposures in genetically susceptible individuals are believed to cause sarcoidosis. There is variation in incidence and prevalence by region and race. Males and females are almost equally affected, although disease peaks at a later age in females than in males. The heterogeneity of presentation and disease course can make diagnosis and treatment challenging. Diagnosis is suggestive in a patient if one or more of the following is present: radiologic signs of sarcoidosis, evidence of systemic involvement, histologically confirmed noncaseating granulomas, sarcoidosis signs in bronchoalveolar lavage fluid (BALF), and low probability or exclusion of other causes of granulomatous inflammation. No sensitive or specific biomarkers for diagnosis and prognosis exist, but there are several that can be used to support clinical decisions, such as serum angiotensin-converting enzyme levels, human leukocyte antigen types, and CD4 Vα2.3+ T cells in BALF. Corticosteroids remain the mainstay of treatment for symptomatic patients with severely affected or declining organ function. Sarcoidosis is associated with a range of adverse long-term outcomes and complications, and with great variation in prognosis between populations. New data and technologies have moved sarcoidosis research forward, increasing our understanding of the disease. However, there is still much left to be discovered. The pervading challenge is how to account for patient variability. Future studies should focus on how to optimize current tools and develop new approaches so that treatment and follow-up can be targeted to individuals with more precision.

Cognitive Behavioral Therapy and Acceptance and Commitment Therapy (CBT-ACT) vs. Standard Care After Critical Illness Due to COVID-19: Protocol for a Pilot Randomized Controlled Trial.

Background: Post-covid syndrome is an emerging condition involving a wide range of symptoms, including high rates of poor mental health. The diagnostic relevance and clinical severity of these symptoms are largely unknown, and evidence for treatment of post-covid mental health symptoms is lacking. This protocol describes a pilot randomized clinical trial, primarily aiming to assess feasibility, participant adherence and satisfaction in a novel phycho-therapeutic intervention on post-covid anxiety and depression symptoms ≥1 year after critically ill COVID-19. Whether the intervention may generate improvements in post-covid depression, anxiety, post-traumatic stress and health-related quality of life (HRQoL) will be addressed in a following larger trial. Methods: A multicenter, investigator-initiated randomized controlled trial (Clinical Trial Identifier number NCT05119608) including Intensive Care Unit (ICU)-treated COVID-19 survivors, who display symptoms of anxiety and/or depression at follow-up 12 months after hospitalization (Hospital Anxiety and Depression Scale ≥8 for depression or anxiety). Eligible individuals are referred to a psychiatrist for structured diagnostic assessment and inclusion in the trial. Participants will be randomized to either a 10-week cognitive behavioral therapy intervention with added acceptance and commitment therapy (CBT-ACT) or standard care (primary care referral). Primary study outcome measure is feasibility and patient adherence, defined as the proportion of participants who consent to randomization and remain in the study including follow-up. Secondary outcome measures include reduced symptoms in the HADS depression/anxiety subscales, post-traumatic symptoms, HRQoL and user satisfaction at 3 months after the intervention. Discussion: This protocol describes a pilot trial to assess feasibility and preliminary effects of a structured psycho-therapeutic intervention to ameliorate mental health in a population severely affected by COVID-19, where evidence for structured psycho-therapy is lacking.

Phenotypic and HLA-DRB1 allele characterization of Swedish cardiac sarcoidosis patients.

BACKGROUND: Early detection and initiation of treatment in cardiac sarcoidosis (CS) is believed to be crucial to reduce morbidity and mortality. The diagnosis of CS is challenging, especially in isolated CS (ICS). Certain human leukocyte antigen (HLA-DRB1) alleles associate with different phenotypes of sarcoidosis. Phenotypic and genotypic characterization of patients with CS may improve our ability to identify patients being at risk for developing CS. METHODS: 87 patients with CS, identified at two Swedish university hospitals were included. Phenotypic characteristics were extracted from the medical records and the patients were HLA-DRB1 typed. RESULTS: Median age at diagnosis was 55 years, 37% were women. HLA-DRB1 distribution was similar to a general sarcoidosis population. A majority of patients (51/87) had CS as the first sarcoidosis presentation. They were younger (p = 0.04), more often presenting with ventricular tachycardia (VT) or atrioventricular block (AVB) grade II or III (p < 0.001), had lower left ventricular ejection fraction (LVEF) (p = 0.002), lower serum angiotensin converting enzyme (s-ACE) (p = 0.025), and fewer extra cardiac manifestations (ECM) (p = 0.02) than those presenting with CS later. CONCLUSIONS: Of Swedish CS patients, 59% presented with cardiac involvement as first manifestation. They had more severe cardiac symptoms than patients presenting with CS later. This phenotype disclosed less ECM and lower s-ACE thus diagnosis can be missed or delayed. We did not observe significant differences in HLA-DRB1 allele frequency between patients with CS compared to sarcoidosis in general. Awareness of CS as a primary manifestation can enable early detection and adequate intervention.

The role of ventilatory support for long-term outcomes after critical infection with COVID-19: A prospective cohort study.

OBJECTIVES: The full range of long-term health consequences in intensive care unit (ICU) survivors with COVID-19 is unclear. This study aims to investigate the role of ventilatory support for long-term pulmonary impairment in critically ill patients and further to identify risk factors for prolonged radiological recovery. METHODS: A prospective observational study from a single general hospital, including all with COVID-19 admitted to ICU between March and August 2020, investigating the association between ventilatory support and the extent of residual parenchymal changes on chest computed tomography (CT) scan and measurement of lung volumes at follow-up comparing high-flow nasal oxygen (HFNO) or non-invasive ventilation (NIV) with invasive ventilation. A semi-quantitative score (CT involvement score) based on lobar involvement and a total score for all five lobes was used to estimate residual parenchymal changes. The association was calculated with logistic regression and adjusted for age, sex, smoking, and severity of illness. RESULTS: Among the 187 eligible, 86 had a chest CT scan and 76 a pulmonary function test at the follow-up with a median time of 6 months after ICU discharge. Residual lung changes were seen in 74%. The extent of pulmonary changes was similar regardless of ventilatory support, but patients with invasive ventilation had a lower total lung capacity 84% versus 92% of predicted (p < 0.001). CONCLUSIONS: The majority of ICU-treated patients with COVID-19 had residual lung changes at 6 months of follow-up regardless of ventilator support or not, but the total lung capacity was lower in those treated with invasive ventilation.

Differences in disease presentation between men and women with sarcoidosis: A cohort study.

BACKGROUND: Sarcoidosis is an elusive disease due to its heterogeneity. It is well recognized that the clinical picture is dependent on ethnicity, organ involvement and age. However, data on the role of sex is inconsistent. We aimed to study the gender-related differences in disease presentation in Swedish patients with sarcoidosis. SUBJECTS AND METHODS: Clinical data was collected between 1996 and 2020, yielding a register with 1429 cases with sarcoidosis in a pulmonary clinic. The diagnosis was met according to WASOG criteria. Data on age, radiologic stage at the time of disease onset, and potential extra-pulmonary manifestations, was retrieved. Differences between men and women were analyzed with Fisher's Exact Test and t-test where appropriate. RESULTS: In the register there were 61% men and they were approximately three years younger than the women at the time of diagnosis. Men presented with a more advanced radiographic stage on chest imaging compared to women, radiographic stage II (46% vs 36%, p < 0.001), while women compared to men more often had stage 0-I disease on pulmonary x-rays (6% vs 2%, p < 0.001 for stage 0 and 46% vs 38%, p < 0.01 for stage I). Women had more cutaneous involvement (13% vs 8%, p < 0.01) and more often involvement of salivary glands (3% vs 1%, p < 0.05). CONCLUSIONS: In this cohort with sarcoidosis patients, there was a predominance of men. They presented with more severe disease at a younger age, while women more often were found to have involvement of the skin and salivary glands.

Bronchoalveolar lavage fluid cell subsets associate with the disease course in Löfgren's and non-Löfgren's sarcoidosis patients.

BACKGROUND: Sarcoidosis is a multisystem granulomatous inflammatory disorder, that predominantly involves the lungs. Patients with Löfgren's syndrome (LS) are characterized by acute onset and usually have the HLA-DRB1*03 (DR3positive) allele and a good prognosis. Non-LS patients are usually DR3negative and are more likely to develop chronic disease. The study aimed to identify bronchoalveolar lavage fluid (BALF) cells that could associate with disease severity (reduced pulmonary function tests (PFTs), advanced chest radiographs, need for treatment) and/or chronicity (duration >2 years) in newly diagnosed LS and non-LS patients, respectively. METHODS: We retrospectively included data from 955 non-LS patients, 477 LS patients, and 295 healthy controls (HC) in this study. Intra-group comparison of patients with resolving versus chronic disease was performed in LS and non-LS, respectively. Non-LS patients were divided into two subgroups according to the binary BALF cell concentrations for intra-group comparison (i.e. higher or lower than the 95th percentile of the BALF cells references in healthy individuals). RESULTS: LS patients with a non-resolving disease course had higher BALF lymphocytes, neutrophils, and eosinophils than LS with a favourable outcome. In non-LS subjects increased BALF of the same cells and in addition also of basophils and mast cells were more likely associated with more severe disease course. CONCLUSION: Increased BALF cells display prognostic significance in sarcoidosis. Certain BALF profiles should promote the clinician to monitor these patients more closely as they may associate non-resolving disease, in turn, resulting in future irreversible functional impairment.

HLA-DRB1 alleles associate with hypercalcemia in sarcoidosis.

BACKGROUND: The mechanisms behind and which patients are at risk of developing sarcoidosis associated hypercalcemia (SAHC) have not been addressed. Different human leukocyte antigen (HLA) alleles associate with disease phenotypes in sarcoidosis. Insights into associations between HLA alleles, clinical phenotype and calcium levels may provide clues to mechanisms behind SAHC and help monitoring patients at risk for SAHC. AIMS AND OBJECTIVES: To identify any HLA-association with SAHC, and to phenotypically characterize this patient group. METHODS: 66 patients with SAHC (s-Ca2+>1.33 mmol/L) and 150 normocalcemic patients as controls were identified in a cohort of sarcoidosis patients. Data on HLA-DRB1 alleles, sex, angiotensin-converting enzyme (ACE), creatinine, extrapulmonary manifestations (EPM), age at sarcoidosis diagnosis, and how long after diagnosis SAHC emerged, were retrieved. RESULTS: HLA-DRB1*04 was more common in patients with SAHC and the proportion of patients with HLA-DRB1*04 increased the more pronounced hypercalcemia. In patients with s-Ca2+>1.4 mmol/L, 20 out of 30 carried the HLA-DRB1*04 allele (67%, p < 0.01). Patients with SAHC more often disclosed renal insufficiency, elevated ACE, EPM, and a non-resolving disease than controls. The mean duration between sarcoidosis diagnosis and detection of SAHC was 1.39 years. CONCLUSIONS: SAHC is associated with a more severe disease phenotype, particularly patients carrying the HLA-DRB1*04 allele are at higher risk for SAHC. HLA-assessment in the clinic can be a way to identify these patients. The results provide a basis for future studies on the connection between HLA-DRB1*04 and SAHC mechanisms.

Long-term consequences in critically ill COVID-19 patients: A prospective cohort study.

BACKGROUND: COVID-19 can cause severe disease with need of treatment in the intensive care unit (ICU) for several weeks. Increased knowledge is needed about the long-term consequences. METHODS: This is a single-center prospective follow-up study of COVID-19 patients admitted to the ICU for respiratory organ support between March and July 2020. Patients with invasive ventilation were compared with those with high-flow nasal oxygen (HFNO) or non-invasive ventilation (NIV) regarding functional outcome and health-related qualify of life. The mean follow-up time was 5 months after ICU discharge and included clinical history, three well-validated questionnaires about health-related quality of life and psychological health, pulmonary function test, 6-minute walk test (6MWT) and work ability. Data were analyzed with multivariable general linear and logistic regression models with 95% confidence intervals. RESULTS: Among 248 ICU patients, 200 patients survived. Of these, 113 patients came for follow-up. Seventy patients (62%) had received invasive ventilation. Most patients reported impaired health-related quality of life. Approximately one-third suffered from post-traumatic stress, anxiety and depression. Twenty-six percent had reduced total lung capacity, 34% had reduced 6MWT and 50% worked fulltime. The outcomes were similar regardless of ventilatory support, but invasive ventilation was associated with more bodily pain (MSD -19, 95% CI: -32 to -5) and <80% total lung capacity (OR 4.1, 95% CI: 1.3-16.5). CONCLUSION: Among survivors of COVID-19 who required respiratory organ support, outcomes 5 months after discharge from ICU were largely similar among those requiring invasive compared to non-invasive ventilation.

Lung CD4+ Vα2.3+ T-cells in sarcoidosis cohorts with Löfgren's syndrome.

BACKGROUND: Sarcoidosis is diagnosed by a combination of typical clinical and radiological findings together with biopsy proof of non-caseating epithelioid cell granulomas in affected tissues and/or the cell distribution in bronchoalveolar lavage fluid (BALF). We aimed at investigating the usefulness of measuring the proportion of T-cell receptor (TCR) CD4+ Vα2.3+ T-cells in BALF as an additive marker to CD4/CD8-ratio to confirm the diagnosis. METHODS: From a register consisting of 749 sarcoidosis patients [Löfgren's syndrome (LS) n = 274, non-LS n = 475] with information on Vα2.3+ T-cells, an expansion of CD4+ Vα2.3+ T-cells (CD4+ Vα2.3+ T cells > 10.5% in BALF) was seen in 268 (36%). Controls were healthy volunteers (n = 69) and patients with other pulmonary conditions (n = 39), investigated because of suspicion of sarcoidosis. RESULTS: A proportion of CD4+ Vα2.3+ T-cells in BALF > 10.5% was highly specific for sarcoidosis, with a specificity of 97% and with a sensitivity of 36% (p < 0.0001). Receiver operating characteristic (ROC) curves show that testing for CD4+ Vα2.3+ T-cells in BALF was a more useable test in individuals with LS [area under the curve (AUC) 0.82, p < 0.0001] compared to the whole patient group (AUC 0.64, p < 0.0001). CONCLUSION: In this study, we show that an increased proportion of CD4+ Vα2.3+ T-cells in BALF is highly specific for sarcoidosis. This suggests that this T-cell subset could be used as an additional tool to the CD4/CD8-ratio to support the sarcoidosis diagnosis, particularly in patients with LS but also in patients with non-LS.

Diagnostic approach for cardiac involvement in sarcoidosis.

AIMS: Cardiac sarcoidosis (CS) is a potentially life-threatening condition. Early detection of CS is therefore important. The aim of this study was to eludicate the usefulness of different investigations in a subgroup of patients with sarcoidosis regarded as having an increased risk for cardiac involvement. METHODS: 42 sarcoidosis patients, who had an abnormal resting electrocardiogram (ECG) and/or symptoms indicating possible cardiac involvement (i.e. palpitations, pre-syncope or syncope), were included in the study. They were identified in a consecutive manner among patients followed-up at outpatient clinics for respiratory disorders. Holter monitoring, exercise test, transthoracic echocardiogram (TTE), cardiovascular magnetic resonance (CMR) and analysis of N-terminal pro B-type natriuretic peptide (NT-pro-BNP) in serum were performed. Note, that the role of FDG-PET was not investigated in this study. RESULTS: In the group with a pathologic ECG 11/25 (44%) were ultimately diagnosed with CS (all with pathologic CMR). However, in the group with only symptoms but a normal ECG just 1/17 got the diagnosis CS (p<0.05). This patient had a pathologic Holter monitoring. The risk for CS was increased if serum NT-pro-BNP was elevated (i.e. NT-pro-BNP>125 ng/L), sensitivity 78% (p<0.05), specificity 67%. By adding a pathologic ECG to an elevated NT-pro-BNP increased specificity to 93% and sensitivity remained at 78%. CONCLUSION: Our findings indicate that CMR should be performed at an early stage in sarcoidosis patients with an abnormal resting ECG. Holter monitoring and elevated levels of NT-pro-BNP may enhance the diagnostic accuracy whereas exercise testing and TTE in this study had less impact on the identification of CS.

Cardiac involvement in Caucasian patients with pulmonary sarcoidosis.

BACKGROUND: Cardiac sarcoidosis (CS) is a potentially life-threatening condition. At present, there is no consensus with regard to the optimal non-invasive clinical evaluation and diagnostic procedures of cardiac involvement in patients with sarcoidosis. The aim of this study in a large homogenous Scandinavian sarcoidosis cohort was therefore to identify risk factors of cardiac involvement in patients with sarcoidosis, and the value of initial routine investigation with ECG and cardiac related symptoms in screening for CS. METHODS: In this retrospective study a cohort of 1017 Caucasian patients with sarcoidosis were included. They were all screened with ECG at disease onset and investigated for CS according to clinical routine. RESULTS: An abnormal ECG was recorded in 166 (16.3%) of the 1017 patients and CS was later diagnosed in 22 (13.2%) of them, compared to in one (0.1%) of the 851 sarcoidosis patients with a normal ECG (p < 0.0001). The risk for CS was higher in patients with a pathologic ECG combined with cardiac related symptoms (11/40) (27.5%) compared to those with pathologic ECG changes without symptoms (11/126) (8.7%) (p < 0.01). Furthermore, patients with Löfgren's syndrome had a reduced risk for CS compared to those without (p < 0.05) the syndrome. CONCLUSIONS: This study on an unusually large and homogenous sarcoidosis population demonstrate the importance of an abnormal ECG and cardiac related symptoms at disease onset as powerful predictors of a later diagnosis of cardiac sarcoidosis. In contrast, CS is very rare in subjects without symptoms and with a normal ECG. This knowledge is of importance, and may be used in a clinical algorithm, in identifying patients that should be followed and investigated extensively for the presence of CS.

Different HLA-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients.

BACKGROUND: A strong genetic influence by the MHC class II region has been reported in sarcoidosis, however in many studies with different results. This may possibly be caused by actual differences between distinct ethnic groups, too small sample sizes, or because of lack of accurate clinical subgrouping. SUBJECTS AND METHODS: In this study we HLA typed a large patient population (n = 754) recruited from one single centre. Patients were sub-grouped into those with Löfgren's syndrome (LS) (n = 302) and those without (non-Löfgren's) (n = 452), and the majority of them were clinically classified into those with recovery within two years (resolving) and those with signs of disease for more than two years (non-resolving). PCR was used for determination of HLA-DRB1 alleles. Swedish healthy blood donors (n = 1366) served as controls. RESULTS: There was a dramatic difference in the distribution of HLA alleles in LS compared to non-LS patients (p = 4 x 10(-36)). Most notably, DRB1*01, DRB1*03 and DRB1*14, clearly differed in LS and non-LS patients. In relation to disease course, DRB1*07, DRB1*14 and DRB1*15 generally associated with, while DRB1*01 and DRB1*03 protected against, a non-resolving disease. Interestingly, the clinical influence of DRB1*03 (good prognosis) dominated over that of DRB1*15 (bad prognosis). CONCLUSIONS: We found several significant differences between LS and non-LS patients and we therefore suggest that genetic association studies in sarcoidosis should include a careful clinical characterisation and sub-grouping of patients, in order to reveal true genetic associations. This may be particularly accurate to do in the heterogeneous non-LS group of patients.