Francesco Nieddu

Distribution of invasive meningococcal B disease in Italian pediatric population: Implications for vaccination timing

Neisseria meningitidis group B (MenB) is a leading cause of meningitis and sepsis. A new vaccine has been recently licensed. The aim of the present study was to evaluate the epidemiology of MenB disease in pediatric age and define the optimal age for vaccination. All patients aged 0-18 years admitted with a diagnosis of meningitis or sepsis to the 83 participating Italian pediatric hospitals were included in the study. Blood and/or cerebrospinal fluid (CSF) samples were tested by Realtime-PCR and/or culture. One hundred and thirty-six cases (mean age 5.0 years, median 2.7) of MenB disease were found. Among these, 96/136 (70.6%) were between 0 and 5 years, 61/136 (44.9%) were between 0 and 2 years. Among the latter, 39/61 (63.9%) occurred during the first year of life with highest incidence between 4 and 8 months. A case-fatality rate of 13.2% was found, with 27.8% cases below 12 months. Sepsis lethality was 24.4%. RT-PCR was significantly more sensitive than culture: 82 patients were tested at the same time by both methods, either in blood or in CSF; MenB was found by RT-PCR in blood or CSF in 81/82 cases (98.8%), culture identified 27/82 (32.9%) infections (Cohens Kappa 0.3; McNemars: p<10⁻⁵). The study shows that the highest incidence of disease occurs in the first year of age, with a peak between 4 and 8 months of life; 30% of deaths occur before 12 months. The results suggest that the greatest prevention could be obtained starting MenB vaccination in the first months of life; a catch-up strategy up to the fifth year of life could be considered. Our results also confirm that Realtime PCR is significantly more sensitive than culture. In those countries where only isolate positive infections are counted as cases, the incidence of MenB infection results highly underestimated.

Potential serotype coverage of three pneumococcal conjugate vaccines against invasive pneumococcal infection in Italian children

BACKGROUND AND AIM OF THE WORK Since the introduction of the 7-valent vaccine, invasive pneumococcal disease have greatly decreased; however, changes in the distribution of pneumococcal serotypes have recently highlighted the need for vaccines with wider coverage. The aim of the work was to assess the potential serotype coverage of three pneumococcal conjugate vaccines (7-, 10- and 13-valent) against bacteremic pneumococcal pneumonia and meningitis/sepsis in Italian children. PATIENTS AND METHODS We determined pneumococcal serotypes in immunocompetent patients who had been admitted to hospital with suspicion of invasive bacterial disease and had confirmed bacteremic pneumococcal pneumonia or meningitis/sepsis determined by molecular detection of Streptococcus pneumoniae in a normally sterile site. Positive samples were serotyped using Realtime-PCR. RESULTS Between April 2008 and March 2011, a total of 144 patients (age median 4.1 years; Interquartile range 1.8-5.6) with pneumococcal meningitis/sepsis (n=43) or pneumonia (n=101) from 83 participating centers located in 19 of 20 Italian regions were serotyped. The 10 most prevalent serotypes were 1 (29.9%), 3 (16.0%), 19A (13.2%), 7F (8.3%), 5 (4.2%), 14 (4.2%), 6A (3.5%), 6B (3.5%), 18C (3.5%), 19F (3.5%). Overall, serotype coverage for PCV-7, -10 and -13 were respectively 19.4%, 61.8% and 94.4% with no statistical difference between pneumonia and meningitis/sepsis. Potential coverage was similar for children 0-2 or 2-5 years of age. Cultures resulted positive in 35/99 (35.4%) samples simultaneously obtained for both culture and RT-PCR. CONCLUSION These findings indicate that increasing the potential serotype coverage by introducing PCV13 in the vaccination schedule for infancy could provide substantial added benefit for protection from pneumococcal pneumonia or meningitis/sepsis in Italy in children below 2 years as well in older children. The importance of molecular methods for diagnosis and serotyping of invasive pneumococcal disease was confirmed.

Pneumococcal serotype distribution in adults with invasive disease and in carrier children in Italy: Should we expect herd protection of adults through infants' vaccination?

ABSTRACT The 7-valent pneumococcal conjugate vaccine (PCV7) produced a significant herd protection in unvaccinated adult population mostly because of pneumococcus carriage decrease in vaccinated children. It is not known if the 13-valent pneumococcal vaccine can give similar effect on adults. Aims of the work were to evaluate whether the 6 additional serotypes are present in nasopharynx of children and serotype distribution in invasive pneumococcal infections (IPD) in adults.  Realtime-PCR was used to evaluate pneumococcal serotypes in adults with confirmed IPD and in nasopharyngeal swabs (NP) from 629 children not vaccinated or vaccinated with PCV7 and resident in the same geographical areas. Two hundred twenty-one patients (116 males, median 67.9 years) with IPD were studied (pneumonia n = 103, meningitis n = 61 sepsis n = 50, other n = 7). Two hundred twelve were serotyped. The most frequent serotypes were 3, (31/212; 14.6%), 19A, (19/212; 9.0%), 12 (17/212; 8.0%), 7F, (14/212; 6.6%). In NP of children, the frequency of those serotypes causing over 50% of IPD in adults was very low, ranging from 0.48% for serotype 7F to 7.9% for serotype 19A. On the other side serotype 5, very frequent in NP (18.7%) caused <1% IPD. In conclusion serotypes causing IPD in adults are very rarely found in children NP. We suggest that herd protection obtainable with the additional 6 serotypes included in PCV13 may be more limited than that demonstrated with PCV7 in the past. In order to reduce the burden of disease in adults, adults should be offered a specific vaccination program with highly immunogenic PCV.

Underestimation of Invasive Meningococcal Disease in Italy

Underestimation is attributable to misdiagnosis, especially in fatal cases, and use of insufficiently sensitive laboratory methods.

PCV13 serotype decrease in Italian adolescents and adults in the post-PCV13 era: Herd protection from children or secular trend?

BACKGROUND AND AIM OF THE WORK In 2010 PCV13 replaced PCV7 in the pediatric vaccination schedule for Italian children. While a strong herd effect was demonstrated for PCV7, a possible herd effect due to PCV13 is still under debate. Our aim was to evaluate differences in the distribution of pneumococcal serotypes between the pre and post-PCV13 eras in unvaccinated Italian adolescents and adults with laboratory-confirmed pneumococcal infection from 3 Italian Regions with a high rate of PCV13 vaccination of children. PATIENTS AND METHODS Adolescents and adults admitted with laboratory-confirmed pneumococcal infection in the hospitals of 3 Italian Regions (Friuli-Venezia Giulia, Emilia Romagna, and Tuscany) between April 2006 and June 2016 were included in the study. Diagnosis of pneumococcal infection and serotyping were performed with Real Time PCR directly on normally sterile fluids or on culture isolates. RESULTS 523 patients with laboratory-confirmed pneumococcal infection were enrolled (Male/Female ratio was 300/223, 1.3; median age 67.1, IQR 53.4-74.9). None of the patients had been vaccinated with any pneumococcal vaccine; 96.4% were serotyped. Overall, the most frequent serotypes were 3 (67/504, 13.3%), 8 (43/504, 8.5%), and 19A (38/504, 7.5%). Serotype distribution differed among age classes and clinical presentations. Overall, PCV13 serotypes accounted for 47.6% of cases: 62.3% in the pre-PCV13 era and 45.0% in the post-PCV13 era; (p=0.005 OR=2.03; CL 95%: 1.2-3.3). Serotype 7F accounted for 12/77 (15.6%) of all serotypes in the pre-PCV13 period and for 12/427 (2.8%) in the post-PCV13 period and was the only serotype significantly contributing to the difference in percentage between pre and post-PCV13 eras. CONCLUSION Our study demonstrated a difference in percentage in serotype distribution in adolescents and adults laboratory-confirmed pneumococcal infection between the pre and post-PCV13 eras. This difference is mainly due to the decrease of serotype 7F. Thus, in order to decrease disease burden, adults and in particular the elderly should be offered a specific vaccination program.

Role of Streptococcus pneumoniae infection in chronic obstructive pulmonary disease patients in Italy

Background: The aim of this study was to determine the incidence of exacerbations due to Streptococcus pneumoniae in chronic obstructive pulmonary disease (COPD) patients during stable state. Methods: We conducted a prospective, observational, cohort study including stable COPD patients, who were evaluated at least every 4 months over a 24-month period at the Respiratory Unit of the IRCCS Policlinico Hospital in Milan, Italy, from 2012 to 2015. Sputum samples were collected at enrollment during stable state to evaluate the frequency of S. pneumoniae colonization and in case of an acute exacerbation to evaluate the incidence of pneumococcal infection. Results: A total of 79 stable patients with moderate to very severe COPD were enrolled. A total of 217 samples were collected, and 27% (n = 59) of those were positive for S. pneumoniae. A total of four exacerbations due to S. pneumoniae occurred during follow up (0.31 per 100 person/month). Among positive samples of S. pneumoniae, 109 serotypes were identified. The most frequent serotypes in moderate-to-severe COPD patients during both stable state and exacerbation were 19F (12%), 18 (10%), 19A and 9V (9%) and 35 F (7%). Only 32% of COPD patients were effectively vaccinated for S. pneumoniae with PPV23 vaccine. Conclusion: The most frequent S. pneumoniae serotypes in COPD patients are 19F, 18, 19A, 9V and 35 F, and that almost 50% of S. pneumoniae strains could be covered by PCV13 in adult COPD patients.

Clinical presentation and outcome of twenty cases of Invasive Meningococcal Disease due to Serogroup C – Clonal complex 11 in the Florence province, Italy, 2015–2016

We read with interest the paper by Lucidarme et al. about geo-temporal localization of Invasive Meningococcal Diseases (IMD) cases due to hyperinvasive ST-11 clonal complex (cc11). In Tuscany, Central Italy, 58 IMD cases, of which 12 deaths, occurred from January 2015 to November 2016, following the emergence of cc-11 Neisseria meningitidis Serogroup C. We analyze 20 cases from this outbreak managed in 3 tertiary hospitals in Florence area (S. Maria Annunziata in Bagno a Ripoli, S. Maria Nuova in Florence, and S. Giuseppe in Empoli), in order to describe clinical presentation and outcome determinants. These hospitals have Emergency Departments (EDs) operating on 24-hbasis. All data derived from the retrospective analysis of electronic clinical charts, and from the laboratory electronic database. All patients consecutively referring to the EDs of these hospitals in the period January 2015eJune 2016, and confirmed positive for IMD, were included. A diagnosis of laboratory-confirmed IMD was made, according to National Guidelines, if a patient’s samples (blood and/ or cerebrospinal fluid) were culture-positive for N. meningitidis, or Real Time-PCR (RT-PCR) positive for the ctrA gene, or both. All samples in which the ctrA gene was detected by RT-PCR were included in a serogrouping analysis. The

OL-EDA-ID Syndrome: a Novel Hypomorphic NEMO Mutation Associated with a Severe Clinical Presentation and Transient HLH

Abbreviations NF-kB Nuclear factor kappa-light-chain-enhancer of activated B cells NEMO NF-kappa B Essential Modulator IKBKG Inhibitor of kappa light polypeptide gene enhancer in B cells, kinase gamma OL-EDA-ID Osteopetrosis and lymphedema-anhidrotic ectodermal dysplasia with immunodeficiency HLH Hemophagocytic Lymphohistiocytosis IL Interleukin TLR Toll like receptor VEGFR-3 Vascular endothelial growth factor receptor-3 RANK Receptor activator of NF-κB CRP C-Reactive protein PCR Polymerase chain reaction HSCT Hematopoietic stem cell transplantation CADD Combined annotation dependent depletion TREC T cell receptor excision circle LPS Lipopolysaccharide SAC Staphylococcus aureus Cowan I TNF-α Tumor necrosis factor-α PMA Phorbol myristate acetate GVHD Graft versus host disease

Factors That Negatively Affect the Prognosis of Pediatric Community-Acquired Pneumonia in District Hospital in Tanzania

Community-acquired pneumonia (CAP) is still the most important cause of death in countries with scarce resources. All children (33 months ± 35 DS) discharged from the Pediatric Unit of Itigi Hospital, Tanzania, with a diagnosis of CAP from August 2014 to April 2015 were enrolled. Clinical data were gathered. Dried blood spot (DBS) samples for quantitative real-time polymerase chain reaction (PCR) for bacterial detection were collected in all 100 children included. Twenty-four percent of patients were identified with severe CAP and 11% died. Surprisingly, 54% of patients were admitted with a wrong diagnosis, which increased complications, the need for antibiotics and chest X-rays, and the length of hospitalization. Comorbidity, found in 32% of children, significantly increased severity, complications, deaths, need for chest X-rays, and oxygen therapy. Malnourished children (29%) required more antibiotics. Microbiologically, Streptococcus pneumonia (S. p.), Haemophilus influenza type b (Hib) and Staphylococcus aureus (S. a.) were the bacteria more frequently isolated. Seventy-five percent of patients had mono-infection. Etiology was not correlated with severity, complications, deaths, oxygen demand, or duration of hospitalization. Our study highlights that difficult diagnoses and comorbidities negatively affect clinical evolution. S. p. and Hib still play a large role; thus, implementation of current vaccine strategies is needed. DBS is a simple and efficient diagnostic method for bacterial identification in countries with scarce resources.

Serotypes and antibiotic susceptibility of Streptococcus pneumoniae isolated from hospitalized patients with community-acquired pneumonia in Italy

Background: Pneumonia remain an important public health problem. The primary objective was to determine the proportion of community-acquired pneumonia that is attributable to Streptococcus pneumoniae infection; secondary objectives were the description of community-acquired pneumonia attributable to Streptococcus pneumoniae according to socio-demographic and clinical variables, the clinical evolution of community-acquired pneumonia and the description of the serotype distribution of vaccine-preventable disease and antibiotic resistance rate of pneumococcal infections. Methods: An observational, prospective study was conducted on consecutive patients coming from the community, who were hospitalized with pneumonia. Data on admission, at discharge and 30 days after discharge were collected. Logistic regression models were used to evaluate the risk factors independently associated with pneumococcal pneumonia. Results: Among the 193 patients enrolled in the study, the etiology of community-acquired pneumonia was identified in 60 patients (33%) and 35 (18%) of evaluable patients had community-acquired pneumonia due to Streptococcus pneumoniae. Of all clinical characteristics, if no previous antibiotic treatment was performed, there was a 13-fold higher risk of presenting community-acquired pneumonia due to Streptococcus pneumoniae (odds ratio, 12.9; 95% confidence interval, 1.42–117.9). Moreover, the most frequent isolated serotypes were 35F, 3 and 24 (29%, 23% and 16%, respectively). Conclusion: The most frequent serotypes in pneumococcal community-acquired pneumonia are 35F, 3, 24, 6 and 7A, and thus almost 50% of Streptococcus pneumoniae strains could be covered by pneumococcal conjugate vaccine 13 in adult patients with risk factors for pneumococcal infections.