Validation of Lung EpiCheck, a novel methylation-based blood assay, for the detection of lung cancer in European and Chinese high-risk individuals.

AIM: Lung cancer screening reduces mortality. We aim to validate the performance of Lung EpiCheck, a six-marker panel methylation-based plasma test, in the detection of lung cancer in European and Chinese samples. METHODS: A case-control European training set (n=102 lung cancer cases, n=265 controls) was used to define the panel and algorithm. Two cut-offs were selected, low cut-off (LCO) for high sensitivity and high cut-off (HCO) for high specificity. The performance was validated in case-control European and Chinese validation sets (cases/controls 179/137 and 30/15, respectively). RESULTS: The European and Chinese validation sets achieved AUCs of 0.882 and 0.899, respectively. The sensitivities/specificities with LCO were 87.2%/64.2% and 76.7%/93.3%, and with HCO they were 74.3%/90.5% and 56.7%/100.0%, respectively. Stage I nonsmall cell lung cancer (NSCLC) sensitivity in European and Chinese samples with LCO was 78.4% and 70.0% and with HCO was 62.2% and 30.0%, respectively. Small cell lung cancer (SCLC) was represented only in the European set and sensitivities with LCO and HCO were 100.0% and 93.3%, respectively. In multivariable analyses of the European validation set, the assay's ability to predict lung cancer was independent of established risk factors (age, smoking, COPD), and overall AUC was 0.942. CONCLUSIONS: Lung EpiCheck demonstrated strong performance in lung cancer prediction in case-control European and Chinese samples, detecting high proportions of early-stage NSCLC and SCLC and significantly improving predictive accuracy when added to established risk factors. Prospective studies are required to confirm these findings. Utilising such a simple and inexpensive blood test has the potential to improve compliance and broaden access to screening for at-risk populations.

[TREATMENT OF A PATIENT IN A TERMINAL CONDITION].

INTRODUCTION: It is generally understood that Jewish law requires every effort to be made to extend the life of a terminally ill patient using routine treatments, whether he is conscious or not, and whether he wants his life prolonged or is opposed to it. The "Law for Patients Wishing to Die" proposes this approach with slight variations. This article discusses the patient who wishes to die from a Jewish viewpoint, illustrating that this is not the only Jewish approach. The role of the doctor is to cure and not to extend a life of suffering in any case. If the doctor cannot cure him, he should respect the wishes of the patient who does not wish to continue to suffer, by stopping life-prolonging treatment and providing only pain-reducing treatment. This law is correct not only in cases where the patient is aware of his situation but also in cases where the patient is comatose and has no realistic chance of returning to life. Ideas from the Talmud, from the Shulchan Aruch, and from the rulings of many poskim (rabbis) confirm that Judaism places great emphasis on personal autonomy and on limiting medical intervention to situations of need. The authors of the article call for the law to be changed in this respect.

[DIAPHRAGMATIC PARALYSIS].

INTRODUCTION: One-sided diaphragmatic paralysis is a common phenomenon which is usually a-symptomatic. In case of acute onset or if there is an underlying lung disease, the phenomenon may be symptomatic and even limiting. In this article, we present a patient who arrived with subacute shortness of breath when lying down. She underwent thorough investigations but, as happens in most cases, the cause of the paralysis was not identified and it remains idiopathic. The authors present an overview of the etiology, differential diagnosis and treatment of diaphragmatic paralysis.

Identification of Asthma-COPD Overlap, Asthma, and Chronic Obstructive Pulmonary Disease Phenotypes in Patients with Airway Obstruction: Influence on Treatment Approach.

BACKGROUND: Many studies have described asthma-COPD overlap (ACO) among patients diagnosed with asthma or chronic obstructive pulmonary disease (COPD), but less so in broad populations of patients with chronic airway obstruction. OBJECTIVE: This study aimed to (i) examine the prevalence of ACO, asthma, and COPD phenotypes among subjects referred for pulmonary function testing (PFT), who had airway obstruction in spirometry (forced expiratory volume in 1 s [FEV1]/forced vital capacity [FVC] <0.7); and (ii) delineate the therapeutic approach of each group. METHODS: Cross-sectional study of patients who were referred for PFT at the Rokach Institute, in Jerusalem. Working definitions were as follows: (a) COPD: post-bronchodilator (BD) FEV1/FVC <0.70; (b) asthma: physician-diagnosed asthma before age 40 and/or minimum post-BD increase in FEV1 or FVC of 12% and 200 mL; and (c) ACO: the combination of the 2. Demographics, smoking habits, episodes of exacerbation, health-related quality of life (HRQL), and respiratory medication utilization were analyzed. RESULTS: Of 3,669 referrals from January 1 to April 30, 2017, 1,220 had airway obstruction of which 215 were included. Of these, 82 (38.1%) had ACO, 49 (22.8%) asthma, and 84 (39.1%) COPD. ACO subjects tended to (a) be predominantly female; (b) be older than asthmatics, (c) be smokers; (d) have worse HRQL in the activity domain; and (d) have more exacerbations. Treatment of ACO and COPD patients differed from that of asthmatics, but not from each other, in the proportion of subjects on maintenance treatment, use of LABA, LAMA, and ICS, alone or in combination, and in the number of inhaler devices used by patients. CONCLUSION: ACO represented >1/3 of patients referred for PFT. Despite a clearly identifiable phenotype, ACO patients received treatment similar to COPD patients, suggesting poor ACO identification. Our data emphasize the need to raise the awareness of ACO among clinicians, in order to guide better recognition and appropriate treatment in individual patients.

To Fly Or Not To Fly? Aviation and Respiratory Diseases.

BACKGROUND: For most passengers, even those with respiratory disease, air travel is safe and comfortable. Some travelers may experience hypoxia at sea level but may not need supplemental oxygen during air travel in a hypobaric hypoxic environment. For some individuals compensatory pulmonary mechanisms may be inadequate, causing profound hypoxia. In addition, venous thromboembolism/pulmonary emboli may occur, especially during long haul flights. With adequate screening, patients at risk can be identified, therapeutic solutions can be proposed for the flight, and most can travel can continue safely with supplemental oxygen and other preventive measures.

Medical Cannabis in Asthmatic Patients.

BACKGROUND: With the increased use of cannabis in the medicinal and recreational domains, it is becoming more important for physicians to better understand its harmful and beneficial effects. Although medical cannabis comes in several forms, the preferred route of administration is smoking or inhalation. After caring for three asthmatic patients who were treated with medical cannabis and who reported improvement in their symptoms, we decided to review the available data on the effects of medical cannabis on asthmatic patients. OBJECTIVES: To review the known effects of medical cannabis on asthmatic patients. METHODS: A thorough search was conducted of the MEDLINE and PubMed databases as well as the internet for publications about the effects of medical cannabis on asthmatic patients. RESULTS: Cannabis has a bronchodilator effect on the airways and might have an anti-inflammatory effect on asthmatic patients. However, harmful effects on the lungs are mainly attributed to smoking and include airway irritation and the development of chronic bronchitis symptoms. CONCLUSIONS: Cannabis has some benefit, yet there are many harmful effects on the lungs. Additional research is needed to determine the harmful effects of vaporizers as well as inhalers.

The Effect of Pulmonary Rehabilitation on Non-chronic Obstructive Pulmonary Disease Patients.

BACKGROUND: Pulmonary rehabilitation has shown significant benefit for patients with chronic obstructive pulmonary disease (COPD). The effect on non-COPD pulmonary patients is less well established. OBJECTIVES: To determine whether pulmonary rehabilitation is also beneficial for non-COPD pulmonary patients. METHODS: Clinical and demographic data on non-COPD pulmonary patients who participated in our institutional pulmonary rehabilitation program between January 2009 and December 2016 were collected. Participants engaged in a 60-minute, twice-weekly, ambulatory hospital-based program lasting 12 to 24 sessions. Sessions included both endurance and muscle training as well as healthy lifestyle educational activities. The six-minute walk test (6MWT) and the St. George's Respiratory Questionnaire (SGRQ) were conducted before and after the rehabilitation program. RESULTS: We recruited 214 non-COPD patients, of whom 153 completed at least 12 sessions. Of these, 59 presented with interstitial lung disease (ILD), 18 with non-ILD restrictive lung defects, 25 with asthma, 30 with lung cancer, and 21 with other conditions (e.g., pulmonary hypertension, bronchiectasis) The groups demonstrated significant improvement in 6MWT and in SGRQ scores. Non-COPD patients gained a 61.9 meter (19%) improvement in the 6MWT (P < 0.0001) and 8.3 point reduction in their SGRQ score (P < 0.0001). CONCLUSIONS: Pulmonary rehabilitation is effective in non-COPD pulmonary patients. As such, it should be an integral part of the treatment armament provided to the vast majority of those suffering from chronic respiratory disease.

Avoiding Routine Chest Radiography after Transbronchial Biopsy Is Safe.

BACKGROUND: Fiberoptic bronchoscopy (FOB) with transbronchial biopsy (TBB) is complicated by a pneumothorax in 1-4% of cases. Performance of routine post-TBB chest radiography (CXR) results in an extremely low diagnostic yield but nevertheless is the common clinical practice prevailing today. It has previously been suggested that routine post-TBB CXR could be avoided in asymptomatic patients. OBJECTIVE: The objective of this study was to prospectively assess the feasibility and safety of this approach. METHODS: The study group included 201 consecutive patients who underwent FOB with TBB at our institution between January 2009 and September 2014. All subjects completed a preprocedural, a 2-hour postprocedural, and a 24- to 48-hour postprocedural symptom questionnaire (chest pain, dyspnea, and cough). Post-TBB CXR was ordered by the treating physician only if indicated. All cases of pneumothorax were documented. Additionally, the following information was recorded: sex, age, immune status, indication for FOB, total number of biopsies done, lobe sampled, and pulse oxygen saturation. RESULTS: Sixteen CXRs were ordered by the treating physician due to suspected pneumothorax (8%). Early-onset pneumothorax (i.e. within 2 h of TBB) was diagnosed radiologically in 6 patients (3%). Two late-onset pneumothoraxes (1%) were diagnosed more than 24 h after TBB. No pneumothoraxes of clinical significance were diagnosed among asymptomatic patients without significant oxygen desaturation events. CONCLUSIONS: Among asymptomatic patients without significant desaturation events, pneumothorax is rare and usually of negligible clinical significance. Therefore, performance of routine CXR after TBB is not necessary and can be safely avoided in this category of patients.

[Going forward--five years experience in pulmonary rehabilitation].

INTRODUCTION: Pulmonary rehabilitation is regarded as a crucial component of the therapeutic armamentarium in chronic lung disease. Ten years ago the Pulmonary Rehabilitation Service at the Shaare Zedek Medical Center (SZMC) was established as part of the Cardiac Rehabilitation Center. Over the last six years this service operates independently within the physiotherapy center under the supervision of the Pulmonary Institute, in collaboration with the social and nutritional services. AIMS: To evaluate the efficacy of pulmonary rehabilitation in improving the patients' quality of life and functional capacity. METHODS: Prospective follow-up of patients referred for pulmonary rehabilitation at the SZMC between the years 2009-2013. The participants were required to complete a pulmonary function test, a 6 minute walk test (6MWT) and a quality of life questionnaire, the Saint George Respiratory Questionnaire (SGRQ). The SGRQ and the 6MWT were readministered after completion of the program. RESULTS: During the follow-up period 415 patients underwent pulmonary rehabilitation at SZMC, of them 330 completed a series of at least 12 sessions. Complete data pertaining to the 6MWTwas obtained for 276 subjects. Participation in the program led to an improvement of 57.5 meters (p < 0.001) in the walking distance. Complete data regarding the SGRQ were available for 94 patients. Completion of the pulmonary rehabilitation program led to a decrease of 8.9 points in the SGRQ (p < 0.001). CONCLUSIONS: Our results indicate that pulmonary rehabilitation was clinically useful as well as statistically significant in improving the functional capacity and quality of life among patients with chronic lung diseases.

Association of the risk of obstructive sleep apnoea with the severity of COVID-19.

Patients with coronavirus 2019 (COVID-19) and obstructive sleep apnoea (OSA) have a worse prognosis than COVID-19 patients without OSA. This study aimed to examine the relationship between OSA risk and the severity of COVID-19 in patients undiagnosed with OSA. Patients diagnosed with COVID-19 and hospitalized or admitted to a community hotel were recruited for the study after recovery during a clinic check-up visit 6-8 weeks after discharge. At this visit, they answered the Epworth Sleeping Scale (ESS) and Berlin questionnaire. Demographic and clinical details were collected from electronic medical records. OSA risk was observed in 37 of 119 included patients (31.1%). Patients with high OSA risk were male, significantly older, had a higher body mass index (BMI), and had higher rates of hypertension and snoring than patients with low OSA risk. Moreover, OSA risk was associated with COVID-19 severity; 48.6% of patients with high risk for OSA suffered from severe COVID-19 compared to 22% of patients with low risk for OSA (p = 0.007). The duration of hospitalization for patients with a high OSA risk was 10.97±9.43 days, while that for those with a low OSA risk was 4.71±6.86 days (p = 0.001). After adjusting for BMI, age, hypertension, and chronic disease, the odds ratio was 4.3 (95%CI, 1.2-16, p = 0.029). A high OSA risk was associated with severe COVID-19 and longer hospitalization. Thus, we recommend that the Berlin and ESS questionnaires be completed for every COVID-19-infected patient at hospitalization, especially in the presence of comorbidities.

Clinical Use of an Exposure, Symptom, and Spirometry Algorithm to Stratify Smokers into COPD Risk Phenotypes: A Case Finding Study Combined with Smoking Cessation Counseling.

Background: Chronic obstructive pulmonary disease (COPD) case-finding aims to detect airflow obstruction in symptomatic smokers and ex-smokers. We used a clinical algorithm including smoking, symptoms, and spirometry to classify smokers into COPD risk phenotypes. In addition, we evaluated the acceptability and effectiveness of including smoking cessation advice in the case-finding intervention. Methods: Smoking, symptoms, and spirometry abnormalities (airflow obstruction: forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC] <0.7 or preserved-ratio spirometry (FEV1<80% of predicted value and FEV1/FVC ratio ≥ 0.7)] were assessed in a group of 864 smokers aged ≥ 30 years. The combination of these parameters allowed the identification of 4 phenotypes: Phenotype A (no symptoms, normal spirometry; reference), Phenotype B (symptoms; normal spirometry; possible COPD), Phenotype C (no symptoms; abnormal spirometry; possible COPD), and Phenotype D (symptoms; abnormal spirometry; probable COPD). We assessed phenotype differences in clinical variables and modeled the trend from phenotype A to phenotype D. Smoking cessation advice based on spirometry was provided. Follow-up was done by telephone 3 months later. Results: Using smokers without symptoms or abnormal spirometry (phenotype A; n=212 [24.5%]) as a reference, smokers were classified into possible COPD (phenotype B;n=332 [38.4%]; and C: n=81 [9.4%]) and probable COPD (phenotype D: n=239 [27.2%]). The trend from baseline phenotype A to probable COPD phenotype D was significant for the number of cigarettes/day and the number of years of smoking (p=0.0001). At follow-up, 58 (7.7%) of the respondents (n=749) reported that they had quit smoking. Conclusions: Our clinical algorithm allowed us to classify smokers into COPD phenotypes whose manifestations were associated with smoking intensity and to significantly increase the number of smokers screened for COPD. Smoking cessation advice was well accepted, resulting in a low but clinically significant quit rate.

Seasonal effect on exercise challenge tests for the diagnosis of exercise-induced bronchoconstriction.

Exercise challenge test (ECT) may help in the diagnosis of asthma. Asthma is season dependent (relative summer nadir).This study was designed to prospectively show that ECT sensitivity decreases when performed in summer and/or out of personal asthma season. We performed two ECTs in 49 patients with suspected asthma, at baseline and at least 6 months later. Test positivity was defined as a ≥10% drop of forced expiratory volume in 1 second after exercise. Patients were defined as having exercise-induced bronchoconstriction (EIB) if at least one of the two tests was positive. We analyzed the impact of season and of patient-reported asthma season on ECT sensitivity. We performed 21 ECTs in the summer and 77 in other seasons. Summer tests were positive in 14.3% of patients versus 33.8% in other seasons (p = 0.11). In patients with confirmed EIB, the sensitivity (95% CI) of a summer test was 0.25 (0.007-0.57), compared with 0.76 (0.58-0.89) in other seasons. Tests performed out of personal asthma season were positive in 10.0% of tests compared with 37.1% of tests during personal asthma season (p = 0.007). In patients with confirmed EIB, the sensitivity (95% CI) of a test performed out of asthma season was 0.27 (0.07-0.61), compared with 0.74 (0.55-0.87) during season. The sensitivity of ECT performed in the summer or outside of the personal asthma season is about one-third of ECT performed not in the summer or during personal asthma season. We suggest performing ECTs during personal asthma season and not in the summer if there is no asthma season known.

National asthma observational survey of severe asthmatics in Israel: the no-air study.

BACKGROUND: Asthma is considered a global public health issue requiring a significant medical expenditure as a result of its high prevalence and the low rate of disease control. OBJECTIVE: This is the first nationwide survey of severe asthma patients carried out in Israel. In this study we aimed to assess health resources utilization, compliance with treatment and disease-control in a subgroup of patients with severe asthma in Israel. MATERIAL AND METHOD: One hundred and twenty-three patients with a diagnosis of asthma for more then one year, as well as a hospitalization during the last 12 months due to asthma exacerbation or maintenance systemic steroids therapy, were included in this non-interventional observational study. RESULTS: Asthma was uncontrolled in 43.9%, partly controlled in 50.4% and well controlled in only 5.7%. The majority of the patients (83%) were compliant with drug treatment. CONCLUSION: The fact that 83% of the asthma patients included in this study were compliant with their asthma therapy was not manifested in asthma control. Therefore concrete tools are required for achieving and maintaining asthma control, especially in the treatment of the most severe asthmatic patients.

Homeopathic Treatment for COVID-19-Related Symptoms: A Case Series.

BACKGROUND: Severe acute respiratory syndrome due to coronavirus 2 (SARS CoV-2) is a novel infectious disease, which has quickly developed into a pandemic. The spectrum of COVID-19 symptoms is broad, ranging from a mild, self-limiting respiratory tract illness to severe progressive pneumonia, multi-organ failure and possible death. Despite much effort and multiple clinical trials, there are, to date, no specific therapeutic agents to treat or cure the coronavirus infection. CASE REPORTS: The present paper presents 5 cases of patients with moderate to severe COVID-19 infections, 2 of them hospitalized in the intensive care unit, who were successfully treated with homeopathy. RESULTS: All 5 patients responded to homeopathic treatment in an unexpectedly short time span, improving both physically and mentally. CONCLUSION: The present case series emphasizes the rapidity of response among moderate to severely ill patients to homeopathic treatment, when conventional medical options have been unable to relieve or shorten the disease. The observations described should encourage use of homeopathy in treating patients with COVID-19 during the acute phase of the disease.

Varenicline for Gradual Versus Abrupt Smoking Cessation in Poorly Motivated Smokers With COPD: A Prematurely Terminated Randomized Controlled Trial.

Background: Although smoking is the leading cause of chronic obstructive pulmonary disease (COPD), many patients with COPD smoke, highlighting the need for effective smoking cessation interventions in this population. This study examined the efficacy and safety of varenicline in increasing smoking cessation rates through "gradual" versus "abrupt" cessation in COPD patients with low motivation to quit smoking. Methods: A randomized, open label, 30-week, controlled trial (ClinicalTrials.gov identifier: NCT02894957) was conducted between January 2019 and October 2020 at a center in Israel. Smokers with COPD, poorly motivated to quit, were randomized to 6 weeks of varenicline for smoking reduction and a target quit day (TQD) at the end of week 6 (gradual cessation group) or ad libitum smoking for 5 weeks, 1 week of varenicline, and a TQD at the end of week 6 (abrupt cessation group). After the pre-quit phase, both groups received 12-week regular varenicline treatment and 12-week follow-up. Primary outcome was biochemically-validated continuous abstinence for weeks 6-30. Secondary outcomes were: (1) biochemically-confirmed7-day point prevalence abstinence for weeks 4-30, (2) efficient smoking reduction (≥50% in number of cigarettes/day) in the pre-quit phase; and (3) number of cigarettes/day, motivation to quit, and changes in respiratory symptoms and spirometry from baseline through week 30. Results: A drug recall issued by the study sponsor stopped the study after 70/242 (28.9%) patients had been enrolled. The gradual cessation group (n=29) had significantly higher continuous abstinence rates from TQD through week 30 versus the abrupt cessation group (n=41): 20.7% versus 4.9% (odds ratio [OR]=5.09; 95% confidence interval [CI] 0.89-29.17; p=0.048) and higher 7-day point prevalence abstinence levels at all time points but week 18 (p=0.027 at week 6, 0.056 at week 7, and 0.096 at week 9). Motivation to quit increased (p=0.002) and the number of cigarettes/day decreased (p=0.002) over time in both groups. Respiratory symptoms, but not spirometry, improved in both groups at week 30. Treatment was safe and well tolerated. Conclusion: In poorly motivated smokers with COPD, using varenicline for a 6-week gradual smoking cessation before TQD, compared with abrupt cessation, significantly increased quit rates up to 6 months. Results were not affected by the smaller-than-expected sample size. Further studies are needed to confirm these data.

Prevalence and Persistence of Symptoms in Adult COVID-19 Survivors 3 and 18 Months after Discharge from Hospital or Corona Hotels.

COVID-19 is characterized by persistent symptoms beyond acute illness. In this prospective cohort study of patients with COVID-19, we sought to characterize the prevalence and persistence of symptoms up to 18 months after diagnosis. We followed 166 patients and assessed their symptoms during acute illness, and at 3 and 18 months after disease onset. The mean number of symptoms per patient during acute disease was 2.3 (SD:1.2), dropping to 1.8 (SD:1.1) at 3 months after recovery and to 0.6 (SD:0.9) at 18 months after recovery. However, this decrease was not unidirectional. Between acute illness and 3 months, the frequency of symptoms decreased for cough (64.5%→24.7%), ageusia (21.7% to6%), anosmia (17.5%→5.4%), and generalized pain (10.8% to 5.4%) but increased for dyspnea (53%→57.2%) weakness (47%→54.8%), and brain fog (3%→8.4%). Between 3 and 18 months, the frequency of symptoms decreased for all symptoms but remained relatively high for dyspnea (15.8%), weakness (21.2%), and brain fog (7.3%). Symptoms may persist for at least 18 months after acute COVID-19 infection. During the medium- to long-term recovery period, the prevalence of some symptoms may decrease or remain stable, and the prevalence of others may increase before slowly decreasing thereafter. These data should be considered when planning post-acute care for these patients.

Absence of leukocytosis in bacteraemic pneumococcal pneumonia.

BACKGROUND: Evaluation of patients with respiratory symptoms in primary care medicine is often based on peripheral WBC count that dictates the extent of diagnostic investigation. A normal WBC count may result in a limited investigation, often omitting chest radiography. AIMS: To determine the extent to which patients hospitalised with bacteraemic pneumococcal pneumonia have no leukocytosis at presentation. METHODS: A retrospective analysis was performed of patients with bacteraemic community-acquired pneumococcal pneumonia from 2000 to 2007 in a community care academic medical centre. Records were reviewed for symptoms, signs, and laboratory data including pneumococcal serotypes, chest radiographs on admission, and outcome. RESULTS: 21% of the patients presented with a normal WBC count (16.7% of the children and 25.6% of the adults). Among this population with a normal WBC count at presentation, 90% of the adults and 70% of the children developed leukocytosis within a few days after admission. CONCLUSIONS: In this study, in as many as one-fifth of all the patients with bacteraemic pneumococcal pneumonia, there was no leukocytosis at presentation. We therefore suggest that every patient with clinically suspected pneumonia should undergo chest radiography even if the WBC count is normal.