Pneumocystis jirovecii pneumonia in intensive care units: a multicenter study by ESGCIP and EFISG.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic, life-threatening disease commonly affecting immunocompromised patients. The distribution of predisposing diseases or conditions in critically ill patients admitted to intensive care unit (ICU) and subjected to diagnostic work-up for PJP has seldom been explored. MATERIALS AND METHODS: The primary objective of the study was to describe the characteristics of ICU patients subjected to diagnostic workup for PJP. The secondary objectives were: (i) to assess demographic and clinical variables associated with PJP; (ii) to assess the performance of Pneumocystis PCR on respiratory specimens and serum BDG for the diagnosis of PJP; (iii) to describe 30-day and 90-day mortality in the study population. RESULTS: Overall, 600 patients were included in the study, of whom 115 had presumptive/proven PJP (19.2%). Only 8.8% of ICU patients subjected to diagnostic workup for PJP had HIV infection, whereas hematological malignancy, solid tumor, inflammatory diseases, and solid organ transplants were present in 23.2%, 16.2%, 15.5%, and 10.0% of tested patients, respectively. In multivariable analysis, AIDS (odds ratio [OR] 3.31; 95% confidence interval [CI] 1.13-9.64, p = 0.029), non-Hodgkin lymphoma (OR 3.71; 95% CI 1.23-11.18, p = 0.020), vasculitis (OR 5.95; 95% CI 1.07-33.22, p = 0.042), metastatic solid tumor (OR 4.31; 95% CI 1.76-10.53, p = 0.001), and bilateral ground glass on CT scan (OR 2.19; 95% CI 1.01-4.78, p = 0.048) were associated with PJP, whereas an inverse association was observed for increasing lymphocyte cell count (OR 0.64; 95% CI 0.42-1.00, p = 0.049). For the diagnosis of PJP, higher positive predictive value (PPV) was observed when both respiratory Pneumocystis PCR and serum BDG were positive compared to individual assay positivity (72% for the combination vs. 63% for PCR and 39% for BDG). Cumulative 30-day mortality and 90-day mortality in patients with presumptive/proven PJP were 52% and 67%, respectively. CONCLUSION: PJP in critically ill patients admitted to ICU is nowadays most encountered in non-HIV patients. Serum BDG when used in combination with respiratory Pneumocystis PCR could help improve the certainty of PJP diagnosis.

Monkeypox outbreak in Spain: clinical and epidemiological findings in a prospective cross-sectional study of 185 cases.

BACKGROUND: Since May 2022, a new outbreak of monkeypox has been reported in several countries, including Spain. The clinical and epidemiological characteristics of the cases in this outbreak may differ from those in earlier reports. OBJECTIVES: To document the clinical and epidemiological characteristics of cases of monkeypox in the current outbreak. METHODS: We conducted a prospective cross-sectional study in multiple medical facilities in Spain to describe the cases of monkeypox in the 2022 outbreak. RESULTS: In total, 185 patients were included. Most cases started with primarily localized homogeneous papules, not pustules, in the probable area of inoculation, which could be cutaneous or mucous, including single lesions. Generalized small pustules appeared later in some of them. Heterogeneous lesions occurred during this generalized phase. All patients had systemic symptoms. Less common lesions included mucosal ulcers (including pharyngeal ulcers and proctitis) and monkeypox whitlows. Four patients were hospitalized, none died. Smallpox vaccination and well-controlled HIV disease were not associated with markers of severity. Contact during sex is the most likely mechanism of transmission. In this outbreak, cases have been described in men who have sex with men and are strongly associated with high-risk sexual behaviours. Seventy-six per cent of the patients had other sexually transmitted diseases upon screening. CONCLUSIONS: The clinical findings in this outbreak differ from previous findings and highly suggest contact transmission and initiation at the entry site. The characterization of the epidemiology of this outbreak has implications for control. What is already known about this topic? Monkeypox eruption is described as consisting of pustules. The roles of HIV and previous smallpox vaccination in the prognosis are unknown. The transmission route was initially described as respiratory droplets and was later suggested to be via sexual contact. What does this study add? Initial lesions at the probable inoculation area were homogeneous and papular (pseudopustules). Generalized small pustules appeared later in some of them. Heterogeneous lesions occurred during this generalized phase. All patients had systemic symptoms. Less common signs included mucosal ulcers (including pharyngeal ulcers and proctitis) and monkeypox whitlows. Well-controlled HIV and previous smallpox vaccination were not associated with severity. No patient died. The data support the hypothesis of transmission via contact during sex. Although this might change, the outbreak is currently limited mostly to men who have sex with men, with high-risk factors for sexually transmitted diseases.

Macroscopically Nonlocal Quantum Correlations.

It is usually believed that coarse graining of quantum correlations leads to classical correlations in the macroscopic limit. Such a principle, known as macroscopic locality, has been proved for correlations arising from independent and identically distributed (IID) entangled pairs. In this Letter, we consider the generic (non-IID) scenario. We find that the Hilbert space structure of quantum theory can be preserved in the macroscopic limit. This leads directly to a Bell violation for coarse-grained collective measurements, thus breaking the principle of macroscopic locality.

Inpatient dermatology: Where are we headed? A nationwide population-based study of Spain from 2006 to 2016.

BACKGROUND AND OBJECTIVES: Information about hospital admissions for skin diseases is restricted to studies describing admissions to single centers, to specific wards, or only for a few diagnoses, and there is no information about the outcomes between different wards. The aim of this research is to describe hospital admissions due to dermatological diseases. PATIENTS AND METHODS: Cross-sectional study of hospital discharges at Spanish hospitals. Discharges were assumed to be the same as admissions. RESULTS: 519,440 discharges (1.1 % of total discharges) were identified. Most admissions (60.1 %) were done from emergency departments. Only 7 % of cases were admitted to dermatology wards. The most prevalent group was cellulitis and acute lymphangitis. Median age was 57 years, and men were more common. The median length of hospital stay was four days; 40,823 (7.9 %) cases required readmission. There were 13,558 (2.6 %) hospital deaths. After adjusted analysis (by age, sex and group of diagnosis), the OR of readmission was 1.49 (95 % CI: 1.42-1.57) times higher and length of stay was 0.22 (95 % CI: 0.15-0.29) days longer in non-dermatology wards (P < 0.0001). From 2006-2016, admissions to dermatology wards decreased 38 %, while in non-dermatology wards they increased 8 %. CONCLUSIONS: A non-negligible number of patients require dermatological inpatient management. This is mainly provided by non-dermatologists. Some of our findings may indicate an improved overall care by dermatologists.

Determinants of empirical antipseudomonal antibiotic prescription for adults with pneumonia in the emergency department.

BACKGROUND: Antipseudomonal antibiotics should be restricted to patients at risk of Pseudomonas aeruginosa infection. However, the indications in different guidelines on community-acquired pneumonia (CAP) are discordant. Our objectives were to assess the prevalence of antipseudomonal antibiotic prescriptions and to identify determinants of empirical antibiotic choices in the emergency department. METHODS: Observational, retrospective, one-year cohort study in hospitalized adults with pneumonia. Antibiotic choices and clinical and demographic data were recorded on a standardized form. Antibiotics with antipseudomonal activity were classified into two groups: a) ß-lactam antipseudomonals (ß-APS), including carbapenems, piperacillin / tazobactam or cefepime (in monotherapy or combination) and b) monotherapy with antipseudomonal quinolones. RESULTS: Data were recorded from 549 adults with pneumonia, with Pseudomonas aeruginosa being isolated in only nine (1.6%). Most (85%) prescriptions were compliant with SEPAR guidelines and 207 (37%) patients received antibiotics with antipseudomonal activity (14% ß-APS and 23% levofloxacin). The use of ß-APS was independently associated with ICU admission (OR 8.16 95% CI 3.69-18.06) and prior hospitalization (OR 6.76 95% CI 3.02-15.15), while levofloxacin was associated with negative pneumococcal urine antigen tests (OR 3.41 95% CI 1.70-6.85) but negatively associated with ICU admission (OR 0.26 95% CI 0.08-0.86). None of these factors were associated with P aeruginosa episodes. In univariate analysis, prior P aeruginosa infection/colonization (2/9 vs 6/372, p = 0.013), severe COPD (3/9 vs 26/372, p = 0.024), multilobar involvement (7/9 vs 119/372, p = 0.007) and prior antibiotic (6/9 vs 109/372, p = 0.025) were significantly associated with P aeruginosa episodes. CONCLUSIONS: Antipseudomonal prescriptions were common, in spite of the very low incidence of Pseudomonas aeruginosa. The rationale for prescription was influenced by both severity-of-illness and pneumococcal urine antigen test (levofloxacin) and prior hospitalization and ICU admission (ß-APS). However, these factors were not associated with P aeruginosa episodes. Only prior P aeruginosa infection/colonization and severe COPD seem to be reliable indicators in clinical practice.

Sentinel lymph node biopsy versus observation in thick melanoma: A multicenter propensity score matching study.

The clinical value of sentinel lymph node (SLN) biopsy in thick melanoma patients (Breslow >4 mm) has not been sufficiently studied. The aim of the study is to evaluate whether SLN biopsy increases survival in patients with thick cutaneous melanoma, and, as a secondary objective, to investigate correlations between survival and lymph node status. We included 1,211 consecutive patients with thick melanomas (>4 mm) registered in the participating hospitals' melanoma databases between 1997 and 2015. Median follow-up was 40 months. Of these patients, 752 were matched into pairs by propensity scores based on sex, age, tumor location, histologic features of melanoma, year of diagnosis, hospital and adjuvant interferon therapy. The SLN biopsy vs. observation was associated with better DFS [adjusted hazard ratio (AHR), 0.74; 95% confidence interval (CI) 0.61-0.90); p = 0.002] and OS (AHR, 0.75; 95% CI, 0.60-0.94; p = 0.013) but not MSS (AHR, 0.84; 95% CI, 0.65-1.08; p = 0.165). SLN-negative patients had better 5- and 10-year MSS compared with SLN-positive patients (65.4 vs. 51.9% and 48.3 vs. 38.8%; p = 0.01, respectively). As a conclusion, SLN biopsy was associated with better DFS but not MSS in thick melanoma patients after adjustment for classic prognostic factors. SLN biopsy is useful for stratifying these patients into different prognostic groups.

Severity-related changes of bronchial microbiome in chronic obstructive pulmonary disease.

Bronchial colonization by potentially pathogenic microorganisms (PPMs) is often demonstrated in chronic obstructive pulmonary disease (COPD), but culture-based techniques identify only a portion of the bacteria in mucosal surfaces. The aim of the study was to determine changes in the bronchial microbiome of COPD associated with the severity of the disease. The bronchial microbiome of COPD patients was analyzed by 16S rRNA gene amplification and pyrosequencing in sputum samples obtained during stable disease. Seventeen COPD patients were studied (forced expiratory volume in the first second expressed as a percentage of the forced vital capacity [FEV1%] median, 35.0%; interquartile range [IQR], 31.5 to 52.0), providing a mean of 4,493 (standard deviation [SD], 2,598) sequences corresponding to 47 operational taxonomic units (OTUs) (SD, 17) at a 97% identity level. Patients were dichotomized according to their lung function as moderate to severe when their FEV1% values were over the median and as advanced when FEV1% values were lower. The most prevalent phyla in sputum were Proteobacteria (44%) and Firmicutes (16%), followed by Actinobacteria (13%). A greater microbial diversity was found in patients with moderate-to-severe disease, and alpha diversity showed a statistically significant decrease in patients with advanced disease when assessed by Shannon (ρ = 0.528; P = 0.029, Spearman correlation coefficient) and Chao1 (ρ = 0.53; P = 0.028, Spearman correlation coefficient) alpha-diversity indexes. The higher severity that characterizes advanced COPD is paralleled by a decrease in the diversity of the bronchial microbiome, with a loss of part of the resident flora that is replaced by a more restricted microbiota that includes PPMs.

Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary disease: characterization and risk factors.

BACKGROUND: Patients with severe chronic obstructive pulmonary disease (COPD) are at increased risk of infection by P. aeruginosa. The specific role of bronchiectasis in both infection and chronic colonization by this microorganism in COPD, however, remains ill defined.To evaluate the prevalence and risk factors for P. aeruginosa recovery from sputum in outpatients with severe COPD, characterizing P. aeruginosa isolates by pulsed-field gel electrophoresis (PFGE) and focusing on the influence of bronchiectasis on chronic colonization in these patients. METHODS: A case-cohort study of 118 patients with severe COPD attended at a Respiratory Day Unit for an acute infectious exacerbation and followed up over one year. High-resolution CT scans were performed during stability for bronchiectasis assessment and sputum cultures were obtained during exacerbation and stability in all patients. P. aeruginosa isolates were genotyped by PFGE. Determinants of the recovery of P. aeruginosa in sputum and chronic colonization by this microorganism were assessed by multivariate analysis. RESULTS: P. aeruginosa was isolated from 41 of the 118 patients studied (34.7%). Five of these 41 patients (12.2%) with P. aeruginosa recovery fulfilled criteria for chronic colonization. In the multivariate analysis, the extent of bronchiectasis (OR 9.8, 95% CI: 1.7 to 54.8) and the number of antibiotic courses (OR 1.7, 95% CI: 1.1 to 2.5) were independently associated with an increased risk of P. aeruginosa isolation. Chronic colonization was unrelated to the presence of bronchiectasis (p=0.75). In patients with chronic colonization the isolates of P. aeruginosa retrieved corresponded to the same clones during the follow-up, and most of the multidrug resistant isolates (19/21) were harbored by these patients. CONCLUSIONS: The main risk factors for P. aeruginosa isolation in severe COPD were the extent of bronchiectasis and exposure to antibiotics. Over 10% of these patients fulfilled criteria for chronic colonization by P. aeruginosa and showed clonal persistence, independently of the presence of bronchiectasis.

Renal flagellate infections in reptiles: 29 cases.

Renal infection with flagellated protozoa was retrospectively evaluated in 29 reptiles, including 12 turtles, 7 tortoises, and 6 chameleons; overall, 20 species of reptiles were represented. Most cases presented with nonspecific clinical signs or a combination of several concurrent diseases. Nineteen of 29 reptiles had tubulointerstitial nephritis associated with flagellates, and this lesion was considered contributory to death in 15 cases, although concurrent diseases were frequent. Infection was invasive into the renal interstitium in three reptiles due to tubular rupture and in one chameleon also spread to adjacent tissues, coelomic cavity, and blood vessels due to renal rupture. Cytologic or ultrastructural evaluation of trophozoites in two cases was consistent with diplomonad flagellates. Renal disease was often complicated with soft-tissue mineralization and/or gout. Gastrointestinal and cloacal infection with flagellates and inflammation were frequent in reptiles in which the digestive tract was available for histopathologic examination, and this supports the possibility of infections ascending the urinary tract from the cloaca. Renal disease associated with flagellate protozoa is rare in vertebrates but appears to be relevant in reptiles, particularly chelonians and chameleons.

Trends in Faecal Zonulin Concentrations in Paediatric Patients with Celiac Disease at Baseline and on a Gluten-Free Diet: Exploring Correlations with Other Faecal Biomarkers.

Celiac disease (CeD) is an autoimmune condition triggered by gluten in genetically predisposed individuals, affecting all ages. Intestinal permeability (IP) is crucial in the pathogenesis of CeD and it is primarily governed by tight junctions (TJs) that uphold the intestinal barrier's integrity. The protein zonulin plays a critical role in modulating the permeability of TJs having emerged as a potential non-invasive biomarker to study IP. The importance of this study lies in providing evidence for the usefulness of a non-invasive tool in the study of IP both at baseline and in the follow-up of paediatric patients with CeD. In this single-centre prospective observational study, we explored the correlation between faecal zonulin levels and others faecal and serum biomarkers for monitoring IP in CeD within the paediatric population. We also aimed to establish reference values for faecal zonulin in the paediatric population. We found that faecal zonulin and calprotectin values are higher at the onset of CeD compared with the control population. Specifically, the zonulin levels were 347.5 ng/mL as opposed to 177.7 ng/mL in the control population (p = 0.001), while calprotectin levels were 29.8 µg/g stool compared to 13.9 µg/g stool (p = 0.029). As the duration without gluten consumption increased, a significant reduction in faecal zonulin levels was observed in patients with CeD (348.5 ng/mL vs. 157.1 ng/mL; p = 0.002), along with a decrease in the prevalence of patients with vitamin D insufficiency (88.9% vs. 77.8%). We conclude that faecal zonulin concentrations were higher in the patients with active CeD compared with healthy individuals or those following a gluten-free diet (GFD). The significant decrease in their values over the duration of the GFD suggests the potential use of zonulin as an additional tool in monitoring adherence to a GFD.

Molecular diagnosis of cystic fibrosis by RNA obtained from nasal epithelial cells.

BACKGROUND: The diagnosis of cystic fibrosis (CF) is established when characteristic clinical signs are coupled with biallelic CFTR pathogenic variants. No previously reported non-canonical splice site variants have to be considered as variants of uncertain significance unless their effect on splicing has been validated. METHODS: Two variants identified by next-generation sequencing were evaluated. We assayed their effects on splicing employing RNA analysis and real-time expression quantification from RNA obtained from the nasal epithelial cells of a patient with clinically suspected CF and of two patients with milder phenotypes (CFTR-related disorders). RESULTS: The variant c.164+2dup causes skipping of exon 2 (p.(Ser18_Glu54del)) and exon 2 plus 3 (p.(Ser18Argfs*16)) in CFTR mRNA. Exon 2 expression in the patient heterozygous for c.164+2dup was decreased to 7 % of the exon 2 expression in the controls. The synonymous variant c.1584G>A causes a partial skipping of exon 11. The exon 11 expression in the two patients heterozygous for this variant was 22 % and 42 % of that of the controls, respectively. CONCLUSION: We conclude that variant c.164+2dup affects mRNA processing and can be considered a CF-causing variant. The results of the functional assay also showed that the p.(Glu528=) variant, usually categorized as a neutral variant based on epidemiological data, partially affects mRNA processing in our patients. This finding would allow us to reclassify the variant as a CFTR-related variant with incomplete penetrance. RNA obtained from nasal epithelial cells is an easy and accurate tool for CFTR functional studies in patients with unclassified splice variants.

Effects of immunocompromise and comorbidities on pneumococcal serotypes causing invasive respiratory infection in adults: implications for vaccine strategies.

BACKGROUND: The 13-valent pneumococcal conjugate vaccine (PCV13) has recently been approved for use in immunocompromised adults. However, it is unclear whether there is an association between specific underlying conditions and infection by individual serotypes. The objective was to determine the prevalence of serotypes covered by PCV13 in a cohort of patients with invasive pneumococcal disease of respiratory origin and to determine whether there are specific risk factors for each serotype. METHODS: An observational study of adults hospitalized with invasive pneumococcal disease in 2 Spanish hospitals was conducted during the period 1996-2011. A multinomial regression analysis was performed to identify conditions associated with infection by specific serotypes (grouped according their formulation in vaccines and individually). RESULTS: A total of 1094 patients were enrolled; the infecting serotype was determined in 993. In immunocompromised patients, 64% of infecting serotypes were covered by PCV13. After adjusting for age, smoking, alcohol abuse, and nonimmunocompromising comorbidities, the group of serotypes not included in either PCV13 or PPV23 were more frequently isolated in patients with immunocompromising conditions and cardiopulmonary comorbidities. Regarding individual serotypes, 6A, 23F, 11A, and 33F were isolated more frequently in patients with immunocompromise and specifically in some of their subgroups. The subgroup analysis showed that serotype10A was also associated with HIV infection. CONCLUSIONS: Specific factors related to immunocompromise seem to determine the appearance of invasive infection by specific pneumococcal serotypes. Although the coverage of serotypes in the 13-valent conjugate pneumococcal vaccine (PCV13) was high, some non-PCV13-emergent serotypes are more prevalent in immunocompromised patients.

Pleural mesothelioma in relation to meteorological conditions and residential distance from an industrial source of asbestos.

OBJECTIVES: Few studies have focused on pleural mesothelioma and environmental exposure in individuals residing around an industrial source of asbestos. The aim of this study is to determine whether residential distance and wind conditions are related to the risk of developing pleural mesothelioma. METHODS: In this retrospective cohort study carried out in an area of Barcelona province (Catalonia, Spain), 24 environmental pleural mesothelioma cases were diagnosed between 2000 and 2009. We calculated the age-standardised incidence rate ratios of developing this disease in the population studied, taking into account the residential distance from the plant. For cases living within a 500-m radius of the plant, the geographical location in relation to the factory was also assessed. RESULTS: The incidence rate of environmental pleural mesothelioma was higher in the population living within 500 m of the plant than in those living in a radius of 500-2000 m and much higher than those living at 2000-10 000 m. The highest incidence rate ratio for pleural mesothelioma (161.9) was found in the southeast quadrant of the 500-m area, coinciding with the predominant wind direction. CONCLUSIONS: Residential distance from an industrial source of asbestos and local wind conditions have a considerable impact on the risk of developing environmental pleural mesothelioma.

Drug survival and safety of biosimilars and originator adalimumab in the treatment of psoriasis: a multinational cohort study.

INTRODUCTION: Psoriasis is a chronic inflammatory skin disease. Adalimumab is an effective but previously expensive biological treatment for psoriasis. The introduction of biosimilars following the patent expiry of the originator adalimumab Humira has reduced the unit cost of treatment. However, the long-term effectiveness and safety of adalimumab biosimilars for treating psoriasis in real-world settings are uncertain and may be a barrier to widespread usage. METHODS AND ANALYSIS: This study aims to compare the drug survival and safety of adalimumab biosimilars to adalimumab originator for the treatment of psoriasis. We will use both routinely collected healthcare databases and dedicated pharmacovigilance registries from the PsoNet initiative, including data from the UK, France and Spain. We will conduct a cohort study using a prevalent new user design. We will match patients on previous adalimumab exposure time to create two equal-sized cohorts of biosimilar and originator users. The coprimary outcomes are drug survival, defined by the time from cohort entry to discontinuation of the drug of interest; and risk of serious adverse events, defined by adverse events leading to hospitalisation or death. Cox proportional hazards models will be fitted to calculate HRs as the effect estimate for the outcomes. ETHICS AND DISSEMINATION: The participating registries agree with the Declaration of Helsinki and received approval from local ethics committees. The results of the study will be published in scientific journals and presented at international dermatology conferences by the end of 2023.

Critical appraisal of international adult bronchiectasis guidelines using the AGREE II tool.

BACKGROUND: Guidelines aim to standardize and optimize diagnosis and management. We evaluated the quality of evidence supporting recommendations from different international adult guidelines on bronchiectasis, and classified with the GRADE system. METHODS: Quality of eligible clinical practice guidelines was assessed for six domains using the AGREE II tool, with ≥ 80% rating as excellent. RESULTS: Seven guidelines (283 recommendations) were analyzed, and four of them were considered "recommended for use" (three reported after 2017 as excellent). Overall, 144 (50.9%) recommendations were based on low-quality evidence, representing 81.5% in diagnosis and 36.2% in therapy. In contrast, 5/92 (5.4%) and 40/191 (20.9%) recommendations regarding diagnostic and treatment (respectively) were based on high-quality evidence. Quality agreement ratings were significantly (p< 0.05) higher for guidelines delivered after 2015, progressing from 27.7% to 58.3%, qualifying as excellent. Highest scores were documented in the domains of "scope and purpose" followed by "clarifying of presentation" and "editorial independence". CONCLUSION: Updated guidelines reported after 2017 improved quality, although well-designed randomized clinical trials remain an unmet need. AGREE II quality assessment identified four guidelines qualified as recommended for use. Improvements are required in stakeholder involvement and applicability.