Circulating calprotectin levels four months after severe and non-severe COVID-19.

BACKGROUND: Calprotectin is an inflammatory marker mainly released by activated neutrophils that is increased in acute severe COVID-19. After initial recovery, some patients have persistent respiratory impairment with reduced diffusion capacity of the lungs for carbon monoxide (DLCO) months after infection. Underlying causes of this persistent impairment are unclear. We aimed to investigate the correlation between circulating calprotectin, persistent lung functional impairment and intensive care unit (ICU) stay after COVID-19 in two university hospital centres in Switzerland. METHODS: Calprotectin levels were measured in serum from 124 patients (50% male) from the Bern cohort (post-ICU and non-ICU patients) and 68 (76% male) from the Lausanne cohort (only post-ICU patients) four months after COVID-19. Calprotectin was correlated with clinical parameters. Multivariate linear regression (MLR) was performed to evaluate the independent association of calprotectin in different models. RESULTS: Overall, we found that post-ICU patients, compared to non-ICU, were significantly older (age 59.4 ± 13.6 (Bern), 60.5 ± 12.0 (Lausanne) vs. 48.8 ± 13.4 years) and more obese (BMI 28.6 ± 4.5 and 29.1 ± 5.3 vs. 25.2 ± 6.0 kg/m2, respectively). 48% of patients from Lausanne and 44% of the post-ICU Bern cohort had arterial hypertension as a pre-existing comorbidity vs. only 10% in non-ICU patients. Four months after COVID-19 infection, DLCO was lower in post-ICU patients (75.96 ± 19.05% predicted Bern, 71.11 ± 18.50% Lausanne) compared to non-ICU (97.79 ± 21.70% predicted, p < 0.01). The post-ICU cohort in Lausanne had similar calprotectin levels when compared to the cohort in Bern (Bern 2.74 ± 1.15 µg/ml, Lausanne 2.49 ± 1.13 µg/ml vs. non-ICU 1.86 ± 1.02 µg/ml; p-value < 0.01). Calprotectin correlated negatively with DLCO (r= -0.290, p < 0.001) and the forced vital capacity (FVC) (r= -0.311, p < 0.001). CONCLUSIONS: Serum calprotectin is elevated in post-ICU patients in two independent cohorts and higher compared to non-ICU patients four months after COVID-19. In addition, there is a negative correlation between calprotectin levels and DLCO or FVC. The relationship between inflammation and lung functional impairment needs further investigations. TRIAL REGISTRATION: NCT04581135.

Medical and Personal Characteristics Can Predict the Risk of Lung Metastasis.

AIMS: Understanding the correlations between underlying medical and personal characteristics of a patient with cancer and the risk of lung metastasis may improve clinical management and outcomes. We used machine learning methodologies to predict the risk of lung metastasis using readily available predictors. MATERIALS AND METHODS: We retrospectively analysed a cohort of 11 164 oncological patients, with clinical records gathered between 2000 and 2020. The input data consisted of 94 parameters, including age, body mass index (BMI), sex, social history, 81 primary cancer types, underlying lung disease and diabetes mellitus. The strongest underlying predictors were discovered with the analysis of the highest performing method among four distinct machine learning methods. RESULTS: Lung metastasis was present in 958 of 11 164 oncological patients. The median age and BMI of the study population were 63 (±19) and 25.12 (±5.66), respectively. The random forest method had the most robust performance among the machine learning methods. Feature importance analysis revealed high BMI as the strongest predictor. Advanced age, smoking, male gender, alcohol dependence, chronic obstructive pulmonary disease and diabetes were also strongly associated with lung metastasis. Among primary cancers, melanoma and renal cancer had the strongest correlation. CONCLUSIONS: Using a machine learning-based approach, we revealed new correlations between personal and medical characteristics of patients with cancer and lung metastasis. This study highlights the previously unknown impact of predictors such as obesity, advanced age and underlying lung disease on the occurrence of lung metastasis. This prediction model can assist physicians with preventive risk factor control and treatment strategies.

Lung stereotactic radiation therapy: Intercomparison of irradiation devices in terms of outcome and predictive factors.

PURPOSE: To compare three different radiotherapy devices able to perform pulmonary stereotactic radiotherapy: CyberKnife® (CK), Helical Tomotherapy® (HT), and volumetric modulated arc therapy (VMAT). This study aims to define the patients' outcome in terms of SBRT efficacy and toxicities depending of the device choice. MATERIALS AND METHODS: We retrospectively analyzed the clinical, radiological, and dosimetric data of patients treated with lung SBRT between 2016 and 2020 at Lausanne University Hospital, using the Chi2 test for proportions, the t-test for means comparisons, the Kaplan-Meier method for survival, and the Log-rank test and Cox-regression for intergroups comparisons. RESULTS: We identified 111 patients treated by either CK (59.9%), VMAT (38.0%), or HT (2.1%). Compared to other techniques, CK treated comparable gross tumor volume (GTV; 2.1 vs. 1.4cm3, P=0.84) with smaller planning treatment volume (PTV; 12.3 vs. 21.9cm3, P=0.013) and lower V5 (13.5 vs. 19.9cm3, P=0.002). Local control rates at 2years were not different whatever the irradiation device, respectively of 96.2% (range, 90.8-100) and 98.1% (range, 94.4-100), P=0.68. Toxicity incidence significantly increased with V5 value>17.2% (56.0 vs. 77.4%, P=0.021). CONCLUSION: Compared to other SBRT techniques, CK treatments permitted to treat comparable GTV with reduced PTV and V5. Toxicity incidence was less frequent when reducing the V5. CK is particularly attractive in case of multiple courses of lung SBRT or lung reirradiation.

Pulmonary embolism in patients with COVID-19: Time to change the paradigm of computed tomography.

OBJECTIVE: To raise awareness for possible benefits of examining known COVID-19 patients presenting sudden clinical worsening with CT pulmonary angiography instead of standard non-contrast chest CT.

Early detection of lung cancer: a statement from an expert panel of the Swiss university hospitals on lung cancer screening.

The discussion about setting up a program for lung cancer screening was launched with the publication of the results of the National Lung Screening Trial, which suggested reduced mortality in high-risk subjects undergoing CT screening. However, important questions about the benefit-harm balance and the details of a screening program and its cost-effectiveness remain unanswered. A panel of specialists in chest radiology, respiratory medicine, epidemiology, and thoracic surgery representing all Swiss university hospitals prepared this joint statement following several meetings. The panel argues that premature and uncontrolled introduction of a lung cancer screening program may cause substantial harm that may remain undetected without rigorous quality control. This position paper focuses on the requirements of running such a program with the objective of harmonizing efforts across the involved specialties and institutions and defining quality standards. The underlying statement includes information on current evidence for a reduction in mortality with lung cancer screening and the potential epidemiologic implications of such a program in Switzerland. Furthermore, requirements for lung cancer screening centers are defined, and recommendations for both the CT technique and the algorithm for lung nodule assessment are provided. In addition, related issues such as patient management, registry, and funding are addressed. Based on the current state of the knowledge, the panel concludes that lung cancer screening in Switzerland should be undertaken exclusively within a national observational study in order to provide answers to several critical questions before considering broad population-based screening for lung cancer.

Update in clinical allergy and immunology.

In the recent years, a tremendous body of studies has addressed a broad variety of distinct topics in clinical allergy and immunology. In this update, we discuss selected recent data that provide clinically and pathogenetically relevant insights or identify potential novel targets and strategies for therapy. The role of the microbiome in shaping allergic immune responses and molecular, as well as cellular mechanisms of disease, is discussed separately and in the context of atopic dermatitis, as an allergic model disease. Besides summarizing novel evidence, this update highlights current areas of uncertainties and debates that, as we hope, shall stimulate scientific discussions and research activities in the field.

Quantitative PCR to diagnose Pneumocystis pneumonia in immunocompromised non-HIV patients.

The utility of quantitative Pneumocystis jirovecii PCR in clinical routine for diagnosing Pneumocystis pneumonia (PCP) in immunocompromised non-HIV patients is unknown. We analysed bronchoalveolar lavage fluid with real-time quantitative P. jirovecii PCR in 71 cases with definitive PCP defined by positive immunofluorescence (IF) tests and in 171 randomly selected patients with acute lung disease. In those patients, possible PCP cases were identified by using a novel standardised PCP probability algorithm and chart review. PCR performance was compared with IF testing, clinical judgment and the PCP probability algorithm. Quantitative P. jirovecii PCR values >1,450 pathogens·mL(-1) had a positive predictive value of 98.0% (95% CI 89.6-100.0%) for diagnosing definitive PCP. PCR values of between 1 and 1,450 pathogens·mL(-1) were associated with both colonisation and infection; thus, a cut-off between the two conditions could not be identified and diagnosis of PCP in this setting relied on IF and clinical assessment. Clinical PCP could be ruled out in 99.3% of 153 patients with negative PCR results. Quantitative PCR is useful for diagnosing PCP and is complementary to IF. PCR values of >1,450 pathogens·mL(-1) allow reliable diagnosis, whereas negative PCR results virtually exclude PCP. Intermediate values require additional clinical assessment and IF testing. On the basis of our data and for economic and logistical limitations, we propose a clinical algorithm in which IF remains the preferred first test in most cases, followed by PCR in those patients with a negative IF and strong clinical suspicion for PCP.

[Smoking behaviour and willingness to stop smoking in patients admitted in an internal medicine ward]. / Untersuchung der Rauchgewohnheiten und der Bereitschaft zum Rauchstopp bei Patienten einer internistischen Abteilung.

Smoking is one of the leading preventable risk factors for the development of lung-, cardio-vascular diseases and cancer. We report results of a prospective survey regarding smoking behaviour and willingness to stop smoking in patients of an internal medicine clinic. Twenty percent of participants admitted smoking cigarettes in the previous 7 days. Smokers were more often males and were younger than non- or ex-smokers. Every second smoker reported being told to stop smoking by a physician before but only about a third was offered active support in doing so. About half of the smoking participants were interested to quit smoking and to participate in a hospital-based smoking cessation program. In patients admitted to the hospital, smoking behaviour and willingness to quit smoking should be recorded and help in quitting smoking should be offered actively. Beside recording smoking behaviour and willingness to quit, patients who are admitted in the hospital should be offered help to quit smoking or to join a proactive structured smoking cessation program.

[Resistant anemia in resistant patients]. / Resistente Anämie bei resistentem Patienten.

A 93 year old man with a severe anaemia with possible origin in the gastrointestinal tract refused any clarifying examinations except palliative blood transfusions. Within half a year, he received 48 red blood cell transfusions without any diagnostic or other therapeutically steps. To further decide on treatment strategies, we discussed this problematic case with our local ethic committee and found a reasonable treatment solution

[A 81-year-old patient with physiotherapy-resistant upper limb tenderness]. / 81-jährige Patientin mit bewegungstherapieresistenten Schmerzen der oberen Extremitäten.

A 81-year-old patient with a six month history of upper extremity tenderness, most likely due to an atypical presentation of a polymyalgia rheumatica, responded well to a course of systemic steroids. A good clinical assessment is of primary importance to distinguish polymyalgia rheumatica from giant cell arteritis and other possible differential diagnoses, and constitutes the basis of a controlled therapy with steroids.

In vivo kinetics of the immunoglobulin E response to allergen: bystander effect of coimmunization and relationship with anaphylaxis.

BACKGROUND: Murine models of hypersensitivity to allergens are useful tools for the evaluation of preclinical strategies to down-regulate the IgE response. OBJECTIVE: To monitor the long-term kinetics of T and B cell responses to allergen as a function of allergen dosage and to investigate the effect of parallel immunization with a second antigen; to correlate B cell response with anaphylaxis. METHODS: CBA/J mice were sensitized every other week by subcutaneous injections of phospholipase A2 (PLA2) and/or ovalbumin (OVA) adsorbed to alum. Specific antibody isotype responses, T cell proliferation, T cell cytokine production and anaphylaxis were assessed throughout the sensitization phase. RESULTS: Low-dose immunization with PLA2 (0.1 microg) favoured a long-term, specific T helper (Th)2 response with high IgE and IL-4 production in contrast to high-dose PLA2 (10 microg) immunization, which biased the immune response towards a Th1 response with high IgG2a and low IL-4 production. Parallel immunization with an unrelated antigen (ovalbumin) had a significant bystander effect on the immunization with PLA2, which was also dose-dependent. Finally, although anaphylaxis as measured by rectal temperature drop was allergen-specific, it could be induced in the high- and low-dose immunization groups, and was not solely dependent on IgE levels. CONCLUSION: Though low-dose allergen immunization appears to induce an efficient IgE response, the intensity and quality of this response may be modulated by bystander effects of parallel immunization and does not correlate strictly with anaphylaxis. This observation has relevance to the design of clinical immunotherapy protocols using murine model-based data.

Inducing tolerance by intranasal administration of long peptides in naive and primed CBA/J mice.

To assess the capacity of a peptide-based immunotherapy to induce systemic tolerance via the nasal route, we designed three long overlapping peptides of 44-60 aa covering the entire sequence of phospholipase A2 (PLA2), a major bee venom allergen. Both prophylactic and therapeutic intranasal administrations of long peptides to PLA2-hypersensitive CBA/J mice induced specific T cell tolerance to the native allergen. In prophylactic conditions, this tolerance was marked by a suppression of subsequent specific IgE response, whereas the therapeutic approach in presensitized mice induced a more than 60% decrease in PLA2-specific IgE. This decline was associated with a shift in the cytokine response toward a Th1 profile, as demonstrated by decreased PLA2-specific IgG1 and enhanced IgG2a levels, and by a decline in the specific IL-4/IFN-gamma ratios. T cell transfer from long peptide-tolerized mice to naive animals abrogated the expected anti-PLA2 IgE and IgG1 Ab response, as well as specific T cell proliferation, but enhanced specific IgG2a response upon sensitization with PLA2. These events were strongly suggestive of a clonal anergy affecting more profoundly Th2 than the Th1 subsets. In conclusion, these results demonstrate that allergen-derived long peptides delivered via the nasal mucosa may offer an alternative to immunotherapy with native allergens without the inherent risk of systemic anaphylactic reactions. Moreover, long peptides, in contrast to immunotherapy strategies based on short peptides, have the advantage of covering all potential T cell epitopes, and may represent novel and safe tools for the therapy of allergic diseases.

Allergen-derived long peptide immunotherapy down-regulates specific IgE response and protects from anaphylaxis.

To evaluate a long peptide-based allergy vaccine in a murine model, CBA/J mice were sensitized with low dose alum-adsorbed phospholipase A2 (PLA2), a major bee venom allergen. Presensitized mice were treated by daily i.p. injections of a mixture of three long overlapping peptides (44- to 60-mer) spanning the entire PLA2 molecule (100 microg/peptide) for 6 consecutive days. This therapeutic approach induced a sharp drop in PLA2-specific IgE, an increase in specific IgG2a, and a marked T cell hyporesponsiveness. T cell cytokine secretion was characterized by a shift from a Th2 to a Th1 profile. Prophylactic treatment of naive mice with long peptides prior to sensitization with PLA2 induced a comparable modulation of B and T cell responses. Upon i.p. challenge with native PLA2, presensitized mice treated with the long peptide mixture were fully protected from anaphylaxis. This indicated that allergen-derived long overlapping peptides were safe and able to modulate an established Th2 response or to prevent its development. Furthermore, long peptide-based immunotherapy provided clinical protection against anaphylaxis, thus appearing as a promising approach of the therapy of allergic diseases.