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.

Genomic features of predominant non-PCV13 serotypes responsible for adult invasive pneumococcal disease in Spain.

BACKGROUND: Although pneumococcal conjugate vaccines (PCVs) effectively prevent invasive pneumococcal disease (IPD), serotype replacement has occurred. OBJECTIVES: We studied the pangenome, antibiotic resistance mechanisms and presence of mobile elements in predominant non-PCV13 serotypes causing adult IPD after PCV13 vaccine introduction in Spain. METHODS: We conducted a multicentre study comparing three periods in six Spanish hospitals and analysed through whole genome sequencing representative strains collected in the pre-PCV13, early-PCV13 and late-PCV13 periods. RESULTS: Among 2197 cases of adult IPD identified, 110 pneumococci expressing non-PCV13 capsules were sequenced. Seven predominant serotypes accounted for 42.6% of IPD episodes in the late-PCV13 period: serotypes 8 (14.4%), 12F (7.5%), 9N (5.2%), 11A (4.1%), 22F (3.9%), 24F (3.9%) and 16F (3.6%). All predominant non-PCV13 serotypes were highly clonal, comprising one or two clonal complexes (CC). In general, CC538, CC4048, CC3016F, CC43322F and CC669N, related to predominant non-PCV13 serotypes, were antibiotic susceptible. CC15611A was associated with resistance to co-trimoxazole, penicillin and amoxicillin. CC23024F was non-susceptible to penicillin and resistant to erythromycin, clindamycin, and tetracycline. Six composite transposon structures of the Tn5252-family were found in CC23024F, CC98912F and CC3016F carrying different combinations of erm(B), tet(M), and cat. Pangenome analysis revealed differences in accessory genomes among the different CC, with most variety in CC3016F (23.9%) and more conservation in CC15611A (8.5%). CONCLUSIONS: We identified highly clonal predominant serotypes responsible for IPD in adults. The detection of not only conjugative elements carrying resistance determinants but also clones previously associated with vaccine serotypes (CC15611A and CC23024F) highlights the importance of the accessory genome.

Efficacy of Low-Dose versus High-Dose Continuous Cyclic Azithromycin Therapy for Preventing Acute Exacerbations of COPD.

BACKGROUND: Long-term azithromycin therapy significantly reduces the frequency of COPD exacerbations (ECOPD). However, previous studies have used different dosing regimens, and the efficacy of these regimens has not been compared. OBJECTIVE: Compare the efficacy of low-dose with high-dose continuous cyclic azithromycin (CC-A) in severe COPD. METHODS: Patients with severe COPD and repeated exacerbations (ECOPD ≥4 or ≥3 with at least 1 hospital admission in the previous year) were prospectively recruited (January 2017 to December 2019) as a multicenter cohort (from 3 university hospitals in the Barcelona area) and treated with low-dose CC-A: 250 mg 3 times per week (250-CC-A group). This cohort was compared with a historical (January 2007 to December 2013) single-center cohort of severe COPD with frequent ECOPD treated with high-dose CC-A: 500 mg 3 times per week (500-CC-A group). To assess differences in ECOPD prevention according to the administration of low-dose or high-dose CC-A, moderate-to-severe ECOPD was evaluated during the 12-month period before and after starting CC-A therapy. RESULTS: Fifty-eight patients with severe COPD were evaluated: 37 in the low-dose group and 21 in the high-dose group. The 250-CC-A therapy group achieved a mean reduction in moderate-to-severe ECOPD of 65.6% at 12 months after starting CC-A therapy (with a 61.5% reduction in hospitalizations), while the 500-CC-A group achieved a reduction of 60.5% (with a 44.8% reduction in hospitalizations). No significant differences between 250-CC-A and 500-CC-A dosages were observed in the mean annual reduction of moderate-to-severe ECOPD (p = 0.55) or hospitalizations (p = 0.07) with respect to the year prior to starting CC-A. CONCLUSIONS: Low-dose 250-CC-A therapy over a 1-year period is similar to high-dose 500-CC-A in reducing exacerbation frequency in severe COPD patients with frequent ECOPD despite maximal medical therapy.

Evolution of invasive pneumococcal disease by serotype 3 in adults: a Spanish three-decade retrospective study.

Background: Invasive pneumococcal disease due to serotype 3 (S3-IPD) is associated with high mortality rates and long-term adverse effects. The introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) into the Spanish paediatric immunisation programme has not led to a decrease in the adult S3-IPD. We aimed to analyse the incidence, clinical characteristics and genomics of S3-IPD in adults in Spain. Methods: Adult IPD episodes hospitalized in a Southern Barcelona hospital were prospectively collected (1994-2020). For genomic comparison, S3-IPD isolates from six Spanish hospitals (2008-2020) and historical isolates (1989-1993) were analysed by WGS (Illumina and/or MinION). Findings: From 1994 to 2020, 270 S3-IPD episodes were detected. When comparing pre-PCV (1994-2001) and late-PCV13 (2016-2020) periods, only modest changes in S3-IPD were observed (from 1.58 to 1.28 episodes per 100,000 inhabitants year). In this period, the incidence of the two main lineages shifted from 0.38 to 0.67 (CC180-GPSC12) and from 1.18 to 0.55 (CC260-GPSC83). The overall 30-day mortality remained high (24.1%), though a decrease was observed between the pre-PCV (32.4%; 95.0% CI, 22.0-45.0) and the late-PCV13 period (16.7%; 95.0% CI, 7.5-32.0) (p = 0.06). At the same time, comorbidities increased from 77.3% (95.0% CI, 65.0-86.0) to 85.7% (95.0% CI, 71.0-94.0) (p = 0.69). There were no differences in clinical characteristics or 30-day mortality between the two S3 lineages. Although both lineages were genetically homogeneous, the CC180-GPSC12 lineage presented a higher SNP density, a more open pan-genome, and a major presence of prophages and mobile genetic elements carrying resistance genes. Interpretation: Adult S3-IPD remained stable in our area over the study period despite PCV13 introduction in children. However, a clonal shift was observed. The decrease in mortality rates and the increase in comorbidities suggest a change in clinical management and overall population characteristics. The low genetic variability and absence of clinical differences between lineages highlight the role of the S3 capsule in the disease severity. Funding: This study has been funded by Instituto de Salud Carlos III (ISCIII) "PI18/00339", "PI21/01000", "INT22/00096", "FI22/00279", CIBER "CIBERES-CB06/06/0037", "CIBERINFEC-CB21/13/00009" and MSD grant "IISP 60168".

A New Integrative and Mobilizable Element Is a Major Contributor to Tetracycline Resistance in Streptococcus dysgalactiae subsp. equisimilis.

Tetracycline resistance in streptococci is mainly due to ribosomal protection mediated by the tet(M) gene that is usually located in the integrative and conjugative elements (ICEs) of the Tn916-family. In this study, we analyzed the genes involved in tetracycline resistance and the associated mobile genetic elements (MGEs) in Streptococcus dysgalactiae subsp. equisimilis (SDSE) causing invasive disease. SDSE resistant to tetracycline collected from 2012 to 2019 in a single hospital and from 2018 in three other hospitals were analyzed by whole genome sequencing. Out of a total of 84 SDSE isolates, 24 (28.5%) were resistant to tetracycline due to the presence of tet(M) (n = 22), tet(W) (n = 1), or tet(L) plus tet(W) (n = 1). The tet(M) genes were found in the ICEs of the Tn916-family (n = 10) and in a new integrative and mobilizable element (IME; n = 12). Phylogenetic analysis showed a higher genetic diversity among the strains carrying Tn916 than those having the new IME, which were closely related, and all belonged to CC15. In conclusion, tetracycline resistance in SDSE is mostly due to the tet(M) gene associated with ICEs belonging to the Tn916-family and a new IME. This new IME is a major cause of tetracycline resistance in invasive Streptococcus dysgalactiae subsp. equisimilis in our settings.

SARS-CoV-2 Spike Protein Vaccine-Induced Immune Imprinting Reduces Nucleocapsid Protein Antibody Response in SARS-CoV-2 Infection.

Immune imprinting or original antigenic sin (OAS) is the process by which the humoral memory response to an antigen can inhibit the response to new epitopes of that antigen originating from a second encounter with the pathogen. Given the situation of the COVID-19 pandemic, multiple vaccines have been developed against SARS-CoV-2 infection. These vaccines are directed to the spike protein (S protein) of the original variant of Wuhan D614G. Vaccine memory immune response against S protein in noninfected subjects could inhibit, through the OAS mechanism, the response to new epitopes of SARS-CoV-2 after infection. The present study analyzes whether the memory antibody B cell response generated by mRNA vaccines against S protein can inhibit the primary antibody immune response to other SARS-CoV-2 antigens, such as nucleocapsid protein (N protein). SARS-CoV-2 primary infection in vaccinated healthcare workers (HCWs) produced significantly lower titers of anti-N antibodies than that in nonvaccinated HCWs: 5.7 (IQR 2.3-15.2) versus 12.2 (IQR 4.2-32.0), respectively (p = 0.005). Therefore, spike protein vaccine-induced immune imprinting (original antigenic sin) reduces N protein antibody response.

Nebulized Colistin And Continuous Cyclic Azithromycin In Severe COPD Patients With Chronic Bronchial Infection Due To Pseudomonas aeruginosa: A Retrospective Cohort Study.

Introduction: Long-term use of nebulized or oral antibiotics is common in the treatment of cystic fibrosis and non-cystic fibrosis bronchiectasis. To date, however, few studies have focused on the use of nebulized antibiotics in COPD patients. The aims of this study are: to establish whether a combination of nebulized colistin plus continuous cyclic azithromycin in severe COPD patients with chronic bronchial infection due to Pseudomonas aeruginosa reduces the frequency of exacerbations, and to assess the effect of this treatment on microbiological sputum isolates. Material and methods: A retrospective cohort was created for the analysis of patients with severe COPD and chronic bronchial infection due to P. aeruginosa treated with nebulized colistin at the Respiratory Day Care Unit between 2005 and 2015. The number and characteristics of COPD exacerbations (ECOPD) before and up to two years after the introduction of nebulized colistin treatment were recorded. Results: We analyzed 32 severe COPD patients who received nebulized colistin for at least three months (median 17 months [IQR 7-24]). All patients but one received combination therapy with continuous cyclic azithromycin (median 24 months [IQR 11-30]). A significant reduction in the number of ECOPD from baseline of 38.3% at two years of follow-up was observed, with a clear decrease in P. aeruginosa ECOPD (from 59.5% to 24.6%) and a P. aeruginosa eradication rate of 28% over the two-year follow-up. Conclusion: In patients with severe COPD and chronic bronchial infection due to P. aeruginosa, combination therapy with nebulized colistin and continuous cyclic azithromycin significantly reduced the number of ECOPD, with a marked decrease in P. aeruginosa sputum isolates.