Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology.

BACKGROUND AND PURPOSE: Among post-COVID-19 symptoms, fatigue is reported as one of the most common, even after mild acute infection, and as the cause of fatigue, myopathy diagnosed by electromyography has been proposed in previous reports. This study aimed to explore the histopathological changes in patients with post-COVID-19 fatigue. METHODS: Sixteen patients (mean age = 46 years) with post-COVID-19 complaints of fatigue, myalgia, or weakness persisting for up to 14 months were included. In all patients, quantitative electromyography and muscle biopsies analyzed with light and electron microscopy were taken. RESULTS: Muscle weakness was present in 50% and myopathic electromyography in 75%, and in all patients there were histological changes. Muscle fiber atrophy was found in 38%, and 56% showed indications of fiber regeneration. Mitochondrial changes, comprising loss of cytochrome c oxidase activity, subsarcollemmal accumulation, and/or abnormal cristae, were present in 62%. Inflammation was found in 62%, seen as T lymphocytes and/or muscle fiber human leukocyte antigen ABC expression. In 75%, capillaries were affected, involving basal lamina and cells. In two patients, uncommon amounts of basal lamina were found, not only surrounding muscle fibers but also around nerves and capillaries. CONCLUSIONS: The wide variety of histological changes in this study suggests that skeletal muscles may be a major target of SARS-CoV-2, causing muscular post-COVID-19 symptoms. The mitochondrial changes, inflammation, and capillary injury in muscle biopsies can cause fatigue in part due to reduced energy supply. Because most patients had mild-moderate acute affection, the new variants that might cause less severe acute disease could still have the ability to cause long-term myopathy.

Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case-cohort study.

BACKGROUND: Diffuse parenchymal lung disease represents a diverse and challenging group of pulmonary disorders. A consistent diagnostic approach to diffuse parenchymal lung disease is crucial if clinical trial data are to be applied to individual patients. We aimed to evaluate inter-multidisciplinary team agreement for the diagnosis of diffuse parenchymal lung disease. METHODS: We did a multicentre evaluation of clinical data of patients who presented to the interstitial lung disease unit of the Royal Brompton and Harefield NHS Foundation Trust (London, UK; host institution) and required multidisciplinary team meeting (MDTM) characterisation between March 1, 2010, and Aug 31, 2010. Only patients whose baseline clinical, radiological, and, if biopsy was taken, pathological data were undertaken at the host institution were included. Seven MDTMs, consisting of at least one clinician, radiologist, and pathologist, from seven countries (Denmark, France, Italy, Japan, Netherlands, Portugal, and the UK) evaluated cases of diffuse parenchymal lung disease in a two-stage process between Jan 1, and Oct 15, 2015. First, the clinician, radiologist, and pathologist (if lung biopsy was completed) independently evaluated each case, selected up to five differential diagnoses from a choice of diffuse lung diseases, and chose likelihoods (censored at 5% and summing to 100% in each case) for each of their differential diagnoses, without inter-disciplinary consultation. Second, these specialists convened at an MDTM and reviewed all data, selected up to five differential diagnoses, and chose diagnosis likelihoods. We compared inter-observer and inter-MDTM agreements on patient first-choice diagnoses using Cohen's kappa coefficient (κ). We then estimated inter-observer and inter-MDTM agreement on the probability of diagnosis using weighted kappa coefficient (κw). We compared inter-observer and inter-MDTM confidence of patient first-choice diagnosis. Finally, we evaluated the prognostic significance of a first-choice diagnosis of idiopathic pulmonary fibrosis (IPF) versus not IPF for MDTMs, clinicians, and radiologists, using univariate Cox regression analysis. FINDINGS: 70 patients were included in the final study cohort. Clinicians, radiologists, pathologists, and the MDTMs assigned their patient diagnoses between Jan 1, and Oct 15, 2015. IPF made up 88 (18%) of all 490 MDTM first-choice diagnoses. Inter-MDTM agreement for first-choice diagnoses overall was moderate (κ=0·50). Inter-MDTM agreement on diagnostic likelihoods was good for IPF (κw=0·71 [IQR 0·64-0·77]) and connective tissue disease-related interstitial lung disease (κw=0·73 [0·68-0·78]); moderate for non-specific interstitial pneumonia (NSIP; κw=0·42 [0·37-0·49]); and fair for hypersensitivity pneumonitis (κw=0·29 [0·24-0·40]). High-confidence diagnoses (>65% likelihood) of IPF were given in 68 (77%) of 88 cases by MDTMs, 62 (65%) of 96 cases by clinicians, and in 57 (66%) of 86 cases by radiologists. Greater prognostic separation was shown for an MDTM diagnosis of IPF than compared with individual clinician's diagnosis of this disease in five of seven MDTMs, and radiologist's diagnosis of IPF in four of seven MDTMs. INTERPRETATION: Agreement between MDTMs for diagnosis in diffuse lung disease is acceptable and good for a diagnosis of IPF, as validated by the non-significant greater prognostic separation of an IPF diagnosis made by MDTMs than the separation of a diagnosis made by individual clinicians or radiologists. Furthermore, MDTMs made the diagnosis of IPF with higher confidence and more frequently than did clinicians or radiologists. This difference is of particular importance, because accurate and consistent diagnoses of IPF are needed if clinical outcomes are to be optimised. Inter-multidisciplinary team agreement for a diagnosis of hypersensitivity pneumonitis is low, highlighting an urgent need for standardised diagnostic guidelines for this disease. FUNDING: National Institute of Health Research, Imperial College London.

Ultra-micro samples can be used for mRNA quantification of lung cancer biomarkers.

BACKGROUND: Isolating sufficient material for molecular testing remains challenging in non-small cell lung cancer (NSCLC). The use of new ultra-microsamples (uMS) is proven sufficient for DNA and mRNA detection, but whether uMS are useful for quantifying mRNA expression is unknown. We investigated if uMS from lung cancer patients can be used to generate quantitative data on mRNA expression. METHODS: uMS were collected from primary tumors and lymph nodes from patients suspected of having lung cancer. mRNA was isolated, reverse-transcribed into cDNA and quantified with quantitative PCR assays for hepatocyte growth factor receptor (MET), hepatocyte growth factor (HGF), epidermal growth factor receptor (EGFR) and amphiregulin (AREG) mRNA. The fraction of tumor cells to normal cells was estimated in each sample. RESULTS: MET, HGF, EGFR, and AREG expression were evaluated in 90 samples (30 containing cancer cells and 60 without cancer cells). MET and EGFR expression were negligible in samples without cancer cells. In samples containing cancer cells, MET and EGFR could be quantified in 13 samples each. Adjustment for tumor-cell fraction made it possible to obtain a quantitative result for the tumor-cell mRNA expression of MET and EGFR. In contrast, AREG and HGF were expressed in samples without tumor cells. These samples were used to establish the AREG and HGF mRNA expression in normal cells. Seven out of 14 AR-positive and two out of eight HGF-positive samples with tumor cells were above a cut-off of the mean + 2SD established in samples without tumor cells. CONCLUSION: We demonstrate that uMS contain high-quality mRNA, and quantitative studies can be performed when the tumor-cell fraction is considered.

Health-related quality of life (SF-36) during telemonitoring of home blood pressure in hypertensive patients: a randomized, controlled study.

Telemonitoring of home blood pressure (BP) is a new advance in home BP monitoring (HBPM) and has proved effective in improving BP control. The impact of telemedical HBPM on health-related quality of life (HRQOL) has not yet been studied. The purpose of this study is to compare HRQOL using a generic scale (SF-36) in patients with antihypertensive treatment based on telemedical HBPM and in patients with antihypertensive treatment based on conventional monitoring of office BP. Hypertensive patients (n = 223) recruited by general practitioners participated in the study. In the intervention group, antihypertensive treatment was based on telemedical HBPM. In the control group, patients (n = 118) received usual care with office visits to monitor BP. After 6 months, participants filled out SF-36 questionnaires. Patients in the telemonitoring group (T) had higher mean scores in the bodily pain domain than patients in the control group (C), indicating less pain and interference with activities among telemonitored patients [T: 85.3(20.2), C: 78.3(26.4), p = 0.026)]. Patients were more likely to feel their general health had worsened during the last year if antihypertensive treatment was based on conventional office measurements. In the bodily pain domain and health transition scale, scores were slightly better among telemonitored patients compared with control patients.

Heart rate variability in white-coat hypertension.

OBJECTIVES: The objective of this study was to compare heart rate variability (HRV) in patients with essential hypertension, in patients with white-coat hypertension and in normotensive control individuals, and to investigate a possible relation between HRV and vasoactive hormones. METHODS: Patients with essential hypertension (n=19, 61 years, median and interquartile range: 40-66 years), patients with white-coat hypertension (n=8, 52 years, median and interquartile range: 41-64 years) and normotensive participants (n=13, 50 years, median and interquartile range: 39-57 years) participated in the study. HRV was measured at rest in the supine position, during standing and during controlled forced breathing (respiration frequency >20/min). Power spectral density was calculated using Fourier transformation. RESULTS: Controlled breathing caused a decrease in low frequency (LF) variation and LF/high frequency variation (LF/HF) in all blood pressure groups. The decrease in LF was smaller in the hypertensive group (-60 ms2) than in the normotensive group (-139 ms2) (P=0.03; hypertensive group vs. normotensive group). The decrease in LF/HF induced by controlled breathing was -0.9 ms in the hypertensive group, -2.0 ms2 in the white-coat hypertensive group and -2.8 ms2 in the normotensive group, (P=0.037; hypertensive group vs. normotensive group). We found a positive correlation between baseline plasma renin concentration and LF (r=0.330, P=0.037) and LF/HF (r=0.378, P=0.016) at rest. CONCLUSION: The observed differences in HRV might reflect the impaired responsiveness to autonomic challenge in hypertensive patients. We did not find the HRV spectrum in white-coat hypertension different from the HRV spectrum in hypertension or normotension.