Surveillance of invasive pneumococcal disease in Spain exploring the impact of the COVID-19 pandemic (2019-2023).

OBJECTIVES: Dynamic trends of invasive pneumococcal disease (IPD) including the evolution of prevalent serotypes are very useful to evaluate the impact of current and future pneumococcal conjugate vaccines (PCVs) and the rise of non-vaccine serotypes. In this study, we include epidemiological patterns of S. pneumoniae before and after COVID-19 pandemic. METHODS: We characterized all national IPD isolates from children and adults received at the Spanish Pneumococcal Reference Laboratory during 2019-2023. RESULTS: In the first pandemic year 2020, we found a general reduction in IPD cases across all age groups, followed by a partial resurgence in children in 2021 but not in adults. By 2022, IPD cases in children had returned to pre-pandemic levels, and partially in adults. In 2023, IPD rates surpassed those of the last pre-pandemic year. Notably, the emergence of serotype 3 is of significant concern, becoming the leading cause of IPD in both pediatric and adult populations over the last two years (2022-2023). Increase of serotype 4 in young adults occurred in the last epidemiological years. CONCLUSIONS: The COVID-19 pandemic led to a temporary decline in all IPD cases during 2020 attributable to non-pharmaceutical interventions followed by a subsequent rise. Employing PCVs with broader coverage and/or enhanced immunogenicity may be critical to mitigate the marked increase of IPD.

Invasive disease caused simultaneously by two different serotypes of Streptococcus pneumoniae: a microbiological appreciation.

We report a clinical case of a child with an invasive pneumococcal disease caused by two different pneumococcal serotypes that belonged to different sequence types. She was a 15-month-old girl with pneumonia and pleural effusion in which S. pneumoniae colonies with different morphologies grew, one from the blood culture (characteristic greyish appearance) and the other from the pleural fluid (mucoid appearance). The isolate from blood was serotype 22 F (ST698/CC698/GPSC61), while the isolate from the pleural fluid was serotype 3 (ST180/CC180/GPSC12). The patient fully recovered after treatment with intravenous ampicillin followed by oral amoxicillin.

Investigating Local Patterns of Mumps Virus Circulation, Using a Combination of Molecular Tools.

Mumps is a vaccine-preventable disease caused by the mumps virus (MuV). However, MuV has re-emerged in many countries with high vaccine coverage. The World Health Organization (WHO) recommends molecular surveillance based on sequencing of the small hydrophobic (SH) gene. Additionally, the combined use of SH and non-coding regions (NCR) has been described in different studies, proving to be a useful complement marker to discriminate general patterns of circulation at national and international levels. The aim of this work is to test local-level usefulness of the combination of SH and MF-NCR sequencing in tracing hidden transmission clusters and chains during the last epidemic wave (2015-2020) in Spain. A database with 903 cases from the Autonomous Community of Madrid was generated by the integration of microbiological and epidemiological data. Of these, 453 representative cases were genotyped. Eight different SH variants and thirty-four SH haplotypes were detected. Local MuV circulation showed the same temporal pattern previously described at a national level. Only two of the thirteen previously identified outbreaks were caused by more than one variant/haplotype. Geographical representation of SH variants allowed the identification of several previously undetected clusters, which were analysed phylogenetically by the combination of SH and MF-NCR, in a total of 90 cases. MF-NCR was not able to improve the discrimination of geographical clusters based on SH sequencing, showing limited resolution for outbreak investigations.

Evolution of Antimicrobial Susceptibility to Penicillin in Invasive Strains of Streptococcus pneumoniae during 2007-2021 in Madrid, Spain.

The use of pneumococcal conjugate vaccines has affected the epidemiology and distribution of Streptococcus pneumoniae serotypes causing Invasive Pneumococcal Disease (IPD). The aim of this study was to analyze the evolution of the phenotypical profiles of antimicrobial susceptibility to penicillin (PEN) in all IPD strains isolated in Madrid, Spain, during 2007-2021. In total, 7133 invasive clinical isolates were characterized between 2007 and 2021. Levels of PENR and PNSSDR were 2.0% and 24.2%, respectively. In addition, 94.4% of all the PENR belonged to four serotypes, including 11A (33.6%), 19A (30.8%), 14 (20.3%) and 9V (9.8%). All the strains of serotype 11A, which is a non-PCV13 serotype, were detected after the year 2011. Serotypes 6C, 15A, 23B, 24F, 35B, 19F, 16F, 6B, 23F, 24B, 24A, 15F and a limited number of strains of serogroups 16 and 24 (non-typed at serotype level) were associated with PNSSDR (p < 0.05). PNSSDR strains of non-PCV13 serotypes 11A, 24F, 23B, 24B, 23A and 16F were more frequent from 2014 to 2021. The changes in S. pneumoniae serotype distribution associated with the use of conjugate vaccines had caused in our region the emergence of non-PCV13 pneumococcal strains with different PENR or PNSSDR patterns. The emergence of serotype 11A resistant to penicillin as the most important non-PCV13 serotype is a worrisome event with marked relevance from the clinical and epidemiological perspective.

Distribution of Multidrug-Resistant Invasive Serotypes of Streptococcus pneumoniae during the Period 2007-2021 in Madrid, Spain.

After the systematic use of conjugate vaccines, the invasive pneumococcal disease (IPD) was included into the Madrid Notifiable Diseases Surveillance System through an Epidemiological Surveillance Network. Furthermore, Streptococcus pneumoniae was included in the Spanish Plan of Antibiotic Resistance. The aim of this study was to analyse the multidrug-resistant (MDR) phenotype distribution among invasive strains of Streptococcus pneumoniae isolated during 2007-2021 from usually sterile clinical samples in Madrid, Spain. A total number of 7133 invasive pneumococcal isolates were studied during the period from February 2007 to December 2021. Serotyping was characterised using the Pneumotest-Latex and by the Quellung reaction. Antibiotic susceptibility testing to penicillin (PEN), erythromycin (ERY), and levofloxacin (LVX) was performed using the E-test according to the EUCAST guidelines and breakpoints. Combination of non-susceptibility to PEN at standard dosing regimen (PNSSDR), resistance to ERY (ERYR) and to LVX (LVXR) was considered to be multidrug-resistant at standard dosing regimen of penicillin (MRPSDR), whereas the combination of resistance to PEN (PENR), ERYR, and LVXR was considered multidrug-resistant (MDR). The number of MDRPSDR and or MDR strains in the entire population (n = 7133) during the complete period (2007-2021) were 51 (0.7%) and 6 (0.1%), respectively. All MDRPSDR and/or MDR strains belonged to nine serotypes: 19A (n = 13), 15A (n = 12), 9V (n = 12), 14 (n = 7), 24F (n = 3), 15F (n = 1), 19F (n = 1), 6B (n = 1) and 6C (n = 1). Only two serotypes (9V and 19A) were found among MDR strains, and most of them (5/6) belonged to serotype 9V. Only 12.4% of the strains typified as serotype 9V were MDRPSDR and only 5.2% as MDR. The levels of pneumococcal MDRPSDR and/or MDR in this study were low and all six MDR strains were isolated between 2014 and 2018. These results reinforce the importance of monitoring the evolution of non-susceptible serotypes including those with MDR in the coming years, especially after the introduction of new conjugate vaccines of a broader spectrum.

Cross-Sectional Analysis of Risk Factors for Outbreak of COVID-19 in Nursing Homes for Older Adults in the Community of Madrid.

INTRODUCTION: Nursing homes for older adults have been hot spots for SARS-CoV-2 infections and mortality. Factors that facilitate COVID-19 outbreaks in these settings need to be assessed. METHODS: A retrospective cross-sectional study of a cohort of residents and workers in nursing homes taking occasion of a point seroprevalence survey was done in the Community of Madrid. Factors related to outbreaks in these facilities were analyzed. RESULTS: A total of 369 nursing homes for older adults, making a population of 23,756 residents and 20,795 staff members, were followed from July to December 2020. There were 54.2% SARS-CoV-2 IgG+ results in residents and in 32.2% of workers. Sixty-two nursing homes (16.8%) had an outbreak during the follow-up. Nursing homes with outbreaks had more residents than those without (median number of 81 [IQR, 74] vs. 50 [IQR, 56], p < 0.001). Seropositivity for SARS-CoV-2 was lower in facilities with versus without outbreaks, for residents (42.2% [IQR, 55.7] vs. 58.7% [IQR, 43.4], p = 0.002) and for workers (23.9% [IQR, 26.4] vs. 32.8% [IQR, 26.3], p = 0.01). For both residents and staff, the number of infections in outbreaks was larger in centers with lower, as compared with intermediate or high seroprevalence. The size of the facility did not correlate with the number of cases in the outbreak. Taking the incidence of cases in the community as a time-dependent variable (p = 0.03), a Cox analysis (HR [95% CI], p) showed that intermediate or high seroprevalence among residents in the facility was related to a reduction of 55% (0.45 [0.25-0.80], p = 0.007) and 78% (0.22 [0.10-0.48], p < 0.001) in the risk of outbreaks, respectively, as compared with low sero-prevalence. Also, as compared with smaller, medium (1.91 [1.00-3.65], p = 0.05) or large centers (4.57 [2.38-8.75], p < 0.001) had more respective risk of outbreaks. CONCLUSIONS: The size of the facility and the seroprevalence among residents in nursing homes, and the incidence of infections in the community, are associated with the risk of outbreaks of COVID-19. Facilities with greater proportion of seropositives had smaller number of cases. Monitoring of immunity in nursing homes may help detect those at a greater risk of future cases.

Effectiveness of 10 and 13-valent pneumococcal conjugate vaccines against invasive pneumococcal disease in European children: SpIDnet observational multicentre study.

BACKGROUND: Pneumococcal conjugate vaccines covering 10 (PCV10) and 13 (PCV13) serotypes have been introduced in the infant immunization schedule of most European countries in 2010-11. To provide additional real-life data, we measured the effectiveness of PCV10 and PCV13 against invasive pneumococcal disease (IPD) in children of 12 European sites (SpIDnet). METHODS: We compared the vaccination status of PCV10 and PCV13 serotype IPD (cases) to that of nonPCV13 serotype IPD (controls) reported in 2012-2018. We calculated pooled effectiveness as (1-vaccination odds ratio)*100, and measured effectiveness over time since booster dose. RESULTS: The PCV13 and PCV10 studies included 2522 IPD cases from ten sites and 486 cases from four sites, respectively. The effectiveness of ≥ 1 PCV13 dose was 84.2% (95 %CI: 79.0-88.1) against PCV13 serotypes (n = 2353) and decreased from 93.1% (87.8-96.1) < 12 months to 85.1% (72.0-92.1) ≥ 24 months after booster dose. PCV13 effectiveness of ≥ 1 dose was 84.7% (55.7-94.7) against fatal PCV13 IPD, 64.5% (43.7-77.6), 83.2% (73.7-89.3) and 85.1% (67.6-93.1) against top serotypes 3, 19A and 1, respectively, and 85.4% (62.3-94.4) against 6C. Serotype 3 and 19A effectiveness declined more rapidly. PCV10 effectiveness of ≥ 1 dose was 84.8% (69.4-92.5) against PCV10 serotypes (n = 370), 27.2% (-187.6 to 81.6) and 85.3% (35.2-96.7) against top serotypes 1 and 7F, 32.5% (-28.3 to 64.5) and -14.4% (-526.5 to 79.1) against vaccine-related serotypes 19A and 6C, respectively. CONCLUSIONS: PCV10 and PCV13 provide similar protection against IPD due to the respective vaccine serotype groups but serotype-specific effectiveness varies by serotype and vaccine. PCV13 provided individual protection against serotype 3 and vaccine-related serotype 6C IPD. PCV10 effectiveness was not significant against vaccine-related serotypes 19A and 6C. PCV13 effectiveness declined with time after booster vaccination. This multinational study enabled measuring serotype-specific vaccine effectiveness with a precision rarely possible at the national level. Such large networks are crucial for the post-licensure evaluation of vaccines.

Humoral and Cellular Response after mRNA Vaccination in Nursing Homes: Influence of Age and of History of COVID-19.

Background: Most residents and staff in nursing homes have received full vaccination. Factors related to the immune response to vaccination might be related to the risk of future severe COVID-19 and may guide the need for vaccine boosters. Design: Nursing homes that were tested in a point survey in July-October 2020 were again analyzed after a vaccination campaign in June-July 2021. Immune responses according to IgG against nucleocapsid and spike antigens, and CD4 and CD8 interferon-gamma release assay against spike antigens, were evaluated. Results: A total of 1973 subjects were tested (61.7% residents, 48.3% staff), with a mean (SD) follow-up of 46.4 (3.6) weeks between assessments. More than half of residents and more than a third of staff had evidence of COVID-19 before vaccination; 26.9% and 22.7% had seroreversion of IgG-N, and 8.9% and 4.6% had IgG-N seroconversion at second assessment, respectively. Up to 96.8% of residents and 98.1% of workers had positive IgG-S after a mean of 19.9 (2.1) weeks after vaccination. In residents with vs without a history of COVID-19, IgG-S titers were 4.11 (0.54) vs. 2.73 (0.74) logAU/mL (p < 0.001); in workers these titers were 3.89 (0.61) vs. 3.15 (0.64) logAU/mL (p < 0.001). Linear regression analysis showed that younger age (OR: −0.03 per 10 years-older [95% CI, −0.04 to −0.02], p < 0.001) and evidence of COVID-19 (OR: 1.14 [95% CI, 1.08 to 1.20], p < 0.001) are associated with greater IgG-S titers after vaccination. A direct association was found between IgG-S titers and the intensity of IFN-gamma response against spike antigens. Conclusions: Waning of humoral response and reinfection seems to be more frequent in older as compared to younger adults, although cellular responses shortly after vaccination are comparable between these groups. Younger age and prior COVID-19 are related to greater humoral response after vaccination against SARS-CoV-2.

In vitro activity of delafloxacin against highly levofloxacin-resistant invasive isolates of Streptococcus pneumoniae.

INTRODUCTION: We report the activity of delafloxacin, a new fluoroquinolone with high affinity for both topoisomerase IV and DNA gyrase, against highly-levofloxacin-resistant invasive strains of Streptococcus pneumoniae. METHODS: A total of 173 highly-levofloxacin-resistant (MIC>32mg/L) S. pneumoniae invasive isolates were studied. The strains were isolated from blood (n=162) and other sterile fluids (n=11). Serotyping was performed by the Pneumotest-Latex and Quellung reaction. Delafloxacin, levofloxacin, penicillin, cefotaxime, erythromycin and vancomycin MICs were determined by the gradient diffusion method following EUCAST guidelines and breakpoints. RESULTS: Among the isolates, 32.9% were penicillin non-susceptible, 19.7% cefotaxime non-susceptible, and 76.9% erythromycin resistant. All were susceptible to vancomycin. Delafloxacin MIC50 and MIC90 (mg/L) values were 0.064 and 0.12, respectively; 60% (15/25) of serotype 9V isolates showed delafloxacin MICs≥0.12mg/L. CONCLUSIONS: Delafloxacin was very active against highly-levofloxacin-resistant invasive isolates of S. pneumoniae. Isolates belonging to serotype 9V showed higher delafloxacin MIC values.

A Pilot Study for the Evaluation of an Interferon Gamma Release Assay (IGRA) To Measure T-Cell Immune Responses after SARS-CoV-2 Infection or Vaccination in a Unique Cloistered Cohort.

Assessment of T-cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens may be of value to determine long-lasting protection to breakthrough infections or reinfections. Interferon gamma release assay is a validated method to test cellular immunity in mycobacterial infections and has been proposed for patients with SARS-CoV-2 infection or vaccination. Quantitative IgG to spike and qualitative IgG to nucleocapsid antigens were determined by chemiluminescence microparticle immunoassay using the Architect platform (Abbott), and interferon gamma release assays against two Qiagen proprietary mixes of SARS-CoV-2 spike protein (antigen 1 and antigen 2) were performed for a selected group of subjects. A total of 121 subjects in a cloistered institution after a COVID-19 outbreak was studied. IgG spike levels and interferon gamma concentrations were highest among subjects after two doses of vaccine, followed by patients with a longer history of past COVID-19 and no vaccination. The best cutoff for the interferon gamma assay was 25 IU/L for all subgroups of individuals and the two sets of SARS-CoV-2 antigens studied. Testing T-cell response may be of clinical utility to determine immunity after exposure to SARS-CoV-2 antigens, with the interferon gamma concentration of 25 IU/L as the best cutoff either after infection or vaccination.

Comparative evaluation of assays for IgM detection of rubella and measles infections.

BACKGROUND: Serological diagnosis of infections due to measles and rubella viruses is done by IgM detection. The aim of this study was to comparatively evaluate commercial systems for detecting IgM against both viruses, including those of ELISA, in indirect and capture formats, chemiluminescence and electrochemiluminescence. METHODS: Seven (for rubella) and six (for measles) assays were studied. One hundred and sixty two samples were included in the study (from 90 rubella and 72 measles cases), and all were analyzed in all the assays. RESULTS: The ranges of sensitivity, specificity and agreement for rubella were 94.8-100%, 52.4-100% and 75.5-98.1%, respectively. The corresponding ranges for measles assays were 87.0-100%, 53.3-100%, and 73.0-99.4%. CONCLUSION: The best-performing assays were chemiluminescence (for measles and rubella IgM), and electrochemiluminescence (for rubella IgM).

Serotype Replacement after Introduction of 10-Valent and 13-Valent Pneumococcal Conjugate Vaccines in 10 Countries, Europe.

We evaluated invasive pneumococcal disease (IPD) during 8 years of infant pneumococcal conjugate vaccine (PCV) programs using 10-valent (PCV10) and 13-valent (PCV13) vaccines in 10 countries in Europe. IPD incidence declined during 2011-2014 but increased during 2015-2018 in all age groups. From the 7-valent PCV period to 2018, IPD incidence declined by 42% in children <5 years of age, 32% in persons 5-64 years of age, and 7% in persons >65 years of age; non-PCV13 serotype incidence increased by 111%, 63%, and 84%, respectively, for these groups. Trends were similar in countries using PCV13 or PCV10, despite different serotype distribution. In 2018, serotypes in the 15-valent and 20-valent PCVs represented one third of cases in children <5 years of age and two thirds of cases in persons >65 years of age. Non-PCV13 serotype increases reduced the overall effect of childhood PCV10/PCV13 programs on IPD. New vaccines providing broader serotype protection are needed.

Age-Dependent Serotype-Associated Case-Fatality Rate in Invasive Pneumococcal Disease in the Autonomous Community of Madrid between 2007 and 2020.

The aim of this study was to investigate the serotype-associated fatality rate in cases of invasive pneumococcal disease (IPD) in the Spanish region of Madrid between 2007 and 2020. Serotyping was performed by Pneumotest Latex and the Quellung reaction using commercial antisera. Case-fatality rate was estimated as the ratio between the number of deaths at hospital discharge and the number of cases attributable to each serotype. To evaluate the association measures, the odds ratios with a 95% confidence interval were calculated. Twenty five pneumococcal serotypes were associated to mortality and comprised 87.8% of the total number of isolates characterized. Serotypes 8, 3, 19A, 1, 7F, 22F, 12F, and 11A were the most prevalent (≥3% each). Serotypes 31, 11A, and 19F were significantly associated to high case-fatality rates (>20% each). The lower significantly associated case-fatality rate (<10% each) was found in serotypes 5, 1, 12B, 7F, 12F, 8, 33, and 10A. The serotypes with higher mortality levels (≥0.04 per 100,000 population) were 11A (fatality 24.0%), 3 (fatality 18.7%), 19A (fatality 12.5%), and 8 (fatality 7.2%). Serotype 3 was worrisome because it is associated with important fatality levels combined with very high incidence and mortality rates. Serotype 11A also showed a high fatality with marked incidence and mortality levels. Some few frequent serotypes as 31, 19F, and 15A despite its high fatality had low levels of mortality. By contrast other serotypes as 8 showing low fatality had high mortality ranges because it shows a wide extended distribution. Finally, common serotypes, such as 1 and 5, presented small mortality length, due to their low case-fatality rates.

Mumps virus outbreak related to a water pipe (narghile) shared smoking.

INTRODUCTION: This study describes a mumps outbreak among a group of young people who shared a same narghile to smoking. Saliva and blood samples were obtained from 3 cases for RT-PCR and serology respectively. METHODS: The notification of a mumps case started an epidemiological investigation. Information of other 6 additional symptomatic persons who had gathered with the case in a discotheque where they smoking in a same narghile was achieved. RT-PCR positive samples were genotyped by sequencing. RESULTS: The 7 patients resided in 3 different municipalities, and they do not have get together for more than a month until the meeting in the discotheque. Four cases were confirmed by RT-PCR and/or IgM determinations. The genomic investigation showed identical nucleic sequences. CONCLUSIONS: This outbreak is consequence of the common use of a narghile to smoking. The public usage of these water pipes should be regulated.

Virological Correlates of IgM-IgG Patterns of Response to SARS-CoV-2 Infection According to Targeted Antigens.

The virological meaning of the different patterns of serology in COVID-19 has been little examined in clinical settings. Asymptomatic subjects with IgM-spike (S) and IgG-nucleocapsid (N) determinations by chemiluminescence were studied for SARS-CoV-2 shedding in respiratory secretions by transcription-mediated amplification (TMA). In subjects showing IgM-S positive and IgG-N negative, IgG-S was determined by lateral flow assay. A total of 712 individuals were tested: 30.0% presented IgM-S(+)/IgG-N(-), 25.8% had IgM-S(+)/IgG-N(+) and 44.2% had IgM-S(-)/IgG-N(+); the proportion with TMA(+) were comparable in these three groups: 12.1, 8.7 and 10.5%, respectively. In individuals with IgM-S(+)/IgG-N(-), IgG-S(+) was detected in 66.5%. The frequency of IgM-S(+)/IgG-S(-) in the total population was 10.0%, of whom 24.1% had TMA(+); the chances for TMA(+) in subjects with an IgM-S(+) alone pattern were 2.4%. Targeting of the same SARS-CoV-2 antigen seems to be better for the characterization of IgM/IgG patterns of response. IgM-S(+) alone reactivity is rare, and a small proportion is associated with viral shedding.