Invasive meningococcal disease in Chile seven years after ACWY conjugate vaccine introduction.

BACKGROUND: A serogroup W (MenW) outbreak in Chile prompted a meningococcal vaccination campaign using tetravalent meningococcal-conjugate vaccines (MCV-ACWY) in children since 2012, followed by its introduction into the National Immunization Program (NIP) in toddlers from 2014. Direct protection was observed, but no indirect effects in other age-groups were evidenced. The aim of this study was to describe invasive meningococcal disease (IMD) cases in Chile between 2009 and 2019, and its trend after the introduction of MCV-ACWYs. METHODS: IMD cases, cumulative incidence per 100,000 inhabitants, CFR, and vaccination uptake were described. Data were obtained from the Public Health Institute and NIP. RESULTS: Overall-IMD cases increased in 2009-2014 period, followed by a decline in 2015-2019, focused in infants, children <5 years and people ≥60 years. Serogroup B (MenB) and MenW alternate its predominance. Median overall incidence was 0.6/100,000, increasing from 0.6/100,000 in 2009 to 0.8/100,000 in 2014, later decreasing to 0.4/100,000 in 2019. Median incidences for MenB, serogroup C (MenC) and Y (MenY) were 0.25/100,000, <0.01/100,000 and <0.01/100,000, respectively. Median MenW incidence was 0.53/100,000, increasing from 0.01/100,000 in 2009 to 0.56/100,000 in 2014, followed by a constant decline to 0.12 in 2019. Infants, children <5 years and adults ≥60 years were affected the most, with median incidences of 9.7, 0.9 and 0.93, decreasing to 1.3, 0.1 and 0.1/100,000 in 2019, respectively. Median overall-CFR was 19%, 7.5% for MenB and 24.5% for MenW. Median MCV-ACWY uptake was 93% CONCLUSION: Overall-IMD, MenW cases and incidence declined since 2015 after the MCV-ACWY introduction, while MenB, MenC and MenY have been stable. MenW incidence declined in all age groups, including non-immunized infants and people >60 years. Further analysis and a longer period of observation are needed to have a more robust conclusion about this epidemiological trend. By 2019, CFR remains high.

Meningococcal invasive disease by serogroup W and use of ACWY conjugate vaccines as control strategy in Chile.

BACKGROUND: Serogroup causing invasive meningococcal disease (IMD) can change abruptly, as it occurred in Chile when serogroup predominance switched from MenB to MenW in 2012. As a response, a national vaccination strategy was implemented since 2012 using tetravalent meningococcal-conjugate vaccines (MCV-ACWY) in children 9 months through 4 years of age. The aim of this study was to describe IMD cases by MenW in Chile 2009-2016, and to analyse its trend after the introduction of MCV-ACWY. METHODS: Descriptive study of IMD cases in Chile, period 2009-2016. Cumulative incidence and mortality rate per 100,000 inhabitants, and case fatality rate (CRF) were used for descriptive analysis. Linear regression was used for post-intervention trend analysis. RESULTS: In 2012, MenW, mainly ST-11 cc, became predominant. MenW incidence rose from 0.01/100,000 inhabitants in 2009 to a maximum of 0.6/100,000 in 2015. Infants and adults 80 years of age and older were mostly affected, with an incidence peak of 9.7/100,000 and 1.6/100,000, respectively, in 2015. In the group of children from 1 to 4 years of age MenW incidence declined from 1.3/100,000 in 2012 to 0.1/100,000 in 2016, a 92.3% reduction after vaccination implementation. In the same period and age-cohort, CFR decreased from 23% to 0%. High mortality rates concentrated in infants and adults 80 years of age and over. CONCLUSION: MenW became predominant in Chile since 2012. IMD cases increased steadily from 2009 to 2016, with higher incidence, CFR and mortality concentrating in infants and people 80 years of age and older. MCV-ACWY provided direct protection against MenW, reducing its incidence after mass meningococcal vaccine implementation. Indirect effects of vaccination are not yet observed.

[From a pathogen's genome to an effective vaccine: the four-component meningococcal serogroup B vaccine]. / Del genoma de un patógeno a una vacuna efectiva: la vacuna de cuatro componentes frente a los meningococos del serogrupo B.

Invasive meningococcal disease (IMD), caused by the bacterium Neisseria meningitidis, entails significant mortality and morbidity. Disease incidence is highest in infants <1 year and young children globally. In Europe, N. meningitidis serogroup B is responsible for over 50% of overall IMD cases, whereas the majority of IMD cases in Latin America is caused either by serogroup B or C. The development of an effective vaccine against serogroup B has challenged the researchers for over half a century. Serogroup B capsular polysaccharide was an inappropriate vaccine antigen, and the success of outer membrane vesicle (OMV) vaccines was restricted to homologous bacterial strains. Reverse vaccinology led to the development of a 4-component meningococcal vaccine including three novel antigens, and OMVs (4CMenB). Each vaccine component has a different target. 4CMenB has been authorised based on its immunogenicity and safety data because the low disease incidence precluded formal clinical efficacy studies. Human serum bactericidal antibody (hSBA) assay tests functional antibodies in the serum of vaccinated individuals (i.e. the vaccine immunogenicity), and is the accepted correlate of protection. Vaccine strain coverage has been assessed both through hSBA assays and a more conservative method named Meningococcal Antigen Typing System (MATS). Effectiveness data of 4CMenB have been collected in the field since 2013. The vaccine proved effective in outbreak control in North America, and recent data from the introduction of the vaccine in the United Kingdom infant national immunisation programme reveal a vaccine effectiveness of 82.9% for the first two doses, with an acceptable safety profile.

Efficacy and safety of withholding antimicrobial treatment in children with cancer, fever and neutropenia, with a demonstrated viral respiratory infection: a randomized clinical trial.

OBJECTIVES: To determine efficacy and safety of withholding antimicrobials in children with cancer, fever and neutropenia (FN) with a demonstrated respiratory viral infection. METHODS: Prospective, multicentre, randomized study in children presenting with FN at five hospitals in Santiago, Chile, evaluated at admission for diagnosis of bacterial and viral pathogens including PCR-microarray for 17 respiratory viruses. Children positive for a respiratory virus, negative for a bacterial pathogen and with a favourable evolution after 48 h of antimicrobial therapy were randomized to either maintain or withhold antimicrobials. Primary endpoint was percentage of episodes with uneventful resolution. Secondary endpoints were days of fever/hospitalization, bacterial infection, sepsis, admission to paediatric intensive care unit (PICU) and death. RESULTS: A total of 319 of 951 children with FN episodes recruited between July 2012 and December 2015 had a respiratory virus as a unique identified microorganism, of which 176 were randomized, 92 to maintain antimicrobials and 84 to withdraw. Median duration of antimicrobial use was 7 days (range 7-9 days) versus 3 days (range 3-4 days), with similar frequency of uneventful resolution (89/92 (97%) and 80/84 (95%), respectively, not significant; OR 1.48; 95% CI 0.32-6.83, p 0.61), and similar number of days of fever (2 versus 1), days of hospitalization (6 versus 6) and bacterial infections throughout the episode (2%-1%), with one case of sepsis requiring admission to PICU in the group that maintained antimicrobials, without any deaths. CONCLUSIONS: The reduction of antimicrobials in children with FN and respiratory viral infections, based on clinical and microbiological/molecular diagnostic criteria, should favour the adoption of evidence-based management strategies in this population.

Meningococcal carriage prevalence in university students, 1824 years of age in Santiago, Chile.

INTRODUCTION: Neisseria meningitidis invasive disease is a major public health problem. Pharyngeal carriage is considered a prerequisite for invasive infection. Prevalence reaches 10% in general population and up to 30% in the 20-24 years age group. The aim of this study was to asses pharyngeal carriage prevalence in healthy subjects aged 18-24 years, and as secondary endpoints evaluate known risk factors, to identify serogroups and sequence in the isolated strains. METHODS: Cross-sectional study in 500 healthy subjects; students from Universidad de Chile aged 18-24 years, Santiago, Chile, October 2012. Each subject underwent a risk factor survey prior to throat culture sampling. Samples were processed in one central Microbiology Laboratory of Hospital Luis Calvo Mackenna and serogrouping and sequencing was performed at Instituto de Salud Pública de Chile. RESULTS: We obtained throat samples from 500 healthy subjects, 20 (4%) positive for N. meningitidis. Of positive strains 20% were serogroup B, 15% W and the rest non groupable. The median age was 20 years, 50% were men. Of the risk factors evaluated, 24% were current smokers, 16% shared a room, 72% had kissed someone during the last month, 64% had gone to pub and 76% had consumed alcohol in the same period of time. DISCUSSION: Literatures meningococcal carriage prevalence reaches up to 30% in people aged 18-24 years. Prevalence in our study was 4%. Different interpretations could be given; one could be the absence of overcrowding in our students because of the lack of dorms in our scholar system and also the characteristics of our enrolled group. CONCLUSIONS: Our results suggest the necessity to extend the study to other age groups and to other cities, to better understand the Chilean reality, as well as others regions of America, considering that these results cannot be extrapolated to another countries.

Prospective evaluation of a model of prediction of invasive bacterial infection risk among children with cancer, fever, and neutropenia.

A risk prediction model for invasive bacterial infection (IBI) was prospectively evaluated among children presenting with cancer, fever, and neutropenia. The model incorporated assessment of 5 previously identified risk factors: serum level of C-reactive protein (CRP) >/=90 mg/L, hypotension, identification of relapse of leukemia as the cancer type, platelet count of

Prospective, multicenter evaluation of risk factors associated with invasive bacterial infection in children with cancer, neutropenia, and fever.

PURPOSE: To identify clinical and laboratory parameters present at the time of a first evaluation that could help predict which children with cancer, fever, and neutropenia were at high risk or low risk for an invasive bacterial infection. PATIENTS AND METHODS: Over a 17-month period, all children with cancer, fever, and neutropenia admitted to five hospitals in Santiago, Chile, were enrolled onto a prospective protocol. Associations between admission parameters and risk for invasive bacterial infection were assessed by univariate and logistic regression analyses. RESULTS: A total of 447 febrile neutropenic episodes occurred in 257 children. Five parameters were statistically independent risk factors for an invasive bacterial infection. Ranked by order of significance, they were as follows: C-reactive protein levels of 90 mg/L or higher (relative risk [RR], 4.2; 95% confidence interval [CI], 3.6 to 4.8); presence of hypotension (RR, 2.7; 95% CI, 2.3 to 3.2); relapse of leukemia as cancer type (RR, 1.8, 95% CI, 1.7 to 2.3); platelet count less than or equal to 50,000/mm(3) (RR, 1.7; 95% CI, 1.4 to 2.2); and recent (< or = 7 days) chemotherapy (RR, 1.3; 95% CI, 1.1 to 1.6). Other previously postulated risk factors (magnitude of fever, monocyte count) were not independent risk factors in this study population. CONCLUSION: In a large population of children, common clinical and laboratory admission parameters were identified that can help predict the risk for an invasive bacterial infection. These results encourage the possibility of a more selective management strategy for these children.

Bacterial and viral etiology of acute otitis media in Chilean children.

BACKGROUND: Acute otitis media (AOM) is a main cause for antimicrobial prescription in Latin America. Pathogen diversity in different geographic regions underscores the need for updated knowledge on AOM microbiology. AIM: To prospectively determine the role of bacteria and viruses in Chilean children with AOM. METHODS: Between July, 1998, and June, 1999, children >3 months with a presumptive diagnosis of AOM were referred to the study ear, nose and throat physician. Middle ear fluid and nasopharyngeal aspirates were obtained from children with confirmed AOM and processed for common bacteria, Mycoplasma pneumoniae, Chlamydia pneumoniae and viruses. Antimicrobial susceptibility patterns and serotypes of Streptococcus pneumoniae strains were determined. RESULTS: An ear, nose and throat physician confirmed diagnoses for 222 (42%) of 529 children referred with diagnosis of AOM, and 170 children met eligibility criteria for the study. One or more pathogens were detected in 140 of 170 (82%) children. Predominant bacteria were S. pneumoniae (37%), Haemophilus influenzae (24%) and Streptococcus pyogenes (13%). M. catarrhalis was detected in 2 children, C. pneumoniae was found in 1 and M. pneumoniae was not detected. Viruses were detected in 22 children (13%) from nasopharyngeal aspirates, and in 6 of them the same virus was detected in middle ear fluid. Penicillin-resistant (intermediate and high) S. pneumoniae represented 40% of isolates and 10% of H. influenzae were beta-lactamase producers. All 10 penicillin-resistant S. pneumoniae strains were resistant to cefuroxime. Eighteen S. pneumoniae serotypes were detected and 19F was associated with high level penicillin resistance. CONCLUSION: This study can impact local management of AOM, and it should encourage continuous surveillance of AOM microbiology in Chile and other developing countries.

Search for primary infection by Pneumocystis carinii in a cohort of normal, healthy infants.

To determine whether Pneumocystis carinii is associated with clinical illness in the competent host, 107 normal, healthy infants were enrolled in a 2-year prospective cohort study in Chile. P. carinii was identified by specific stains and nested--deoxyribonucleic acid (DNA) amplification of the large subunit mitochondrial ribosomal ribonucleic acid gene of P. carinii f. sp. hominis, and seroconversion was assessed by enzyme-linked immunosorbent assay of serum samples drawn every 2 months. P. carinii DNA was identified in nasopharyngeal aspirates obtained during episodes of mild respiratory infection in 24 (32%) of 74 infants from whom specimens were available for testing. Three (12.5%) of those 24 infants versus 0 of 50 infants who tested negative for P. carinii had apnea episodes. Seroconversion developed in 67 (85%) of 79 infants who remained in the study by 20 months of age and occurred in the absence of any symptoms of disease in 14 (20.8%). The study indicates that P. carinii DNA can be frequently detected in healthy infants, and it raises the hypothesis that they may be an infectious reservoir of P. carinii in the community. Further investigation is needed to identify whether P. carinii causes overt respiratory disease in infants.

[Febrile neutropenia in the child with cancer. Current concepts about risk assessment and selective management]. / Neutropenia febril en el niño con cáncer. Conceptos actuales sobre criterios de riesgo y manejo selectivo.

The risk for invasive bacterial infection (IBI) in cancer pediatric patients with febrile neutropenia, is variable. Clinicians worldwide are increasingly considering selective strategies for children at low risk for IBI, including shortened antimicrobial course, early hospital discharge, oral antimicrobial treatment, and management as outpatients. These strategies would significantly benefit these children and health care systems. The critical issue is to identify the most reliable risk factors useful for selection of those individuals who are at low risk for IBI. In Chile, during the past 10 years, a group of physicians from the Subcommittee of Infectious Diseases of the National Child Program of Antineoplastic Drugs and the University of Chile have worked to develop more selective strategies for pediatric patients with cancer, fever and neutropenia. During 1996-1997 we identified risk factors of IBI in a group of 447 febrile neutropenic episodes. During 1999-2000 we validated these risk factors in a prospective study that included 263 febrile neutropenic episodes. A model of risk prediction was developed and is currently being evaluated for the selection of low risk patients who are treated as inpatients for 24 hours, followed by outpatient treatment.

[Causative agents of bloodstream infections in children with neoplasm, in 5 hospitals of Santiago (1994-1998)]. / Agentes causantes de infecciones del torrente circulatorio en niños con cáncer, en cinco hospitales de Santiago (1994-1998).

BACKGROUND: Pediatric patients in treatment for cancer can have fatal bacterial infections. Thus, in the presence of fever or other signs infection, antimicrobials have to be prescribed empirically. AIM: To know the causative agents of bacteremia in children with cancer, their changes with time and between different hospitals and their patterns of susceptibility. MATERIAL AND METHODS: We reviewed the blood cultores of children with cancer in five hospitals of Santiago, from 1994 at 1998. RESULTS: During the study period, 707 agents were isolated. The most frequently isolated species or genus were coagulase negative Staphylococcus (43%), Staphylococcus aureus (16%), Escherichia coli (9%), Klebsiella spp. (8%), Pseudomonas spp. (5%) and Candida spp. (4%). Coagulase negative Staphylococcus was 55% resistant to meticilin and S. aureus was 44% resistant. Enterobacteriaceae had 15% resistance to gentamicin and amikacin, 2% to imipenem, 26% to ceftriaxone, 21% to cefotaxime and 20% to ceftazidime. Among non fermenting agents resistance was 6% for imipenem, 9% for amikacin 10% for ciprofloxacin, 19% for ceftazidime and 22% for cefoperazone. The resistance of Streptococcus spp. (non pneumoniae) to penicillin reached 50% and that of Enterococcus spp. was of 33%. CONCLUSIONS: Treatment for pediatric patients with cancer must be modified and new guidelines including more active medications for patients at risk for bacteremia, should be devised.

Antipyretic effects of dipyrone versus ibuprofen versus acetaminophen in children: results of a multinational, randomized, modified double-blind study.

This study compared the antipyretic effectiveness of acetaminophen, ibuprofen, and dipyrone in young children with fever. The results were based on a modified double-blind, randomized, multinational trial that evaluated 628 febrile children, aged 6 months to 6 years. All three drugs lowered temperature in the 555 patients completing the study. Temperature normalization rates in the ibuprofen and dipyrone groups (78% and 82%, respectively) were significantly higher than the acetaminophen group (68%, P = 0.004). After 4 to 6 hours, mean temperature in the dipyrone group was significantly lower than the other groups, demonstrating longer temperature normalization with dipyrone. All three drugs showed comparable tolerability profiles.

[The role of superantigens in infectious diseases]. / Superantígenos y su rol en las enfermedades infecciosas.

Exogenous antigens are presented to T lymphocytes through mechanisms that ensure high recognition specificity. Recently described superantigens in contrast to conventional antigens are particles that follow a different processing and presentation route not binding to a specific region of T lymphocyte receptors. These particles bind to a large number of T lymphocytes, generating a disproportionate and non-specific immune response. Two types of superantigens have been described. Endogenous superantigens, transported in the host genoma, have been involved in clonal depletion and immunological tolerance phenomena. Exogenous superantigens, mainly bacterial toxins, have been involved in several diseases. There is evidence that these antigens participate in diseases such as Kawasaki disease, toxic shock caused by Staphylococcus aureus, rheumatoid arthritis, HIV infection and Streptococcus pyogenes infections.

Discontinuation of antimicrobial therapy for febrile, neutropenic children with cancer: a prospective study.

During a 2-year period, all children with cancer, neutropenia, and fever who were admitted to Hospital de Niños Luis Calvo Mackenna (Santiago, Chile) were enrolled in a study of the safety of stopping antibiotic therapy on day 3 of treatment. Children who met predefined criteria for nonbacterial fever were randomized on day 3 to stop (group A) or continue (group B) antibiotic therapy. A total of 220 children with cancer had 238 episodes of fever and neutropenia; 68 children with 75 episodes met entry criteria for nonbacterial fever (group A, 36; group B, 39). Both groups were comparable in terms of age, gender, oncological disease, chemotherapy status, and initial neutrophil count. Resolution of symptoms occurred in 34 of 36 episodes in group A and 36 of 39 episodes in group B (P > .05). No deaths occurred, and bacterial superinfections were uncommon. For children with cancer as well as episodes of fever and neutropenia without an identifiable bacterial etiology at admission, stopping antibiotic therapy on day 3 was safe and not associated with a higher risk of bacterial superinfections.

C-reactive protein: a valuable aid for the management of febrile children with cancer and neutropenia.

The usefulness of determining serum levels of C-reactive protein (CRP) for the identification of bacterial infections in febrile neutropenic patients with cancer was evaluated. Two hundred children with cancer were monitored prospectively for the occurrence of neutropenia and fever; serum was collected from these children for determining baseline levels of CRP. Of these 200 children, 75 had 85 febrile neutropenic episodes; serum was collected daily from these 75 children for CRP analysis by nephelometry. Children were included into one of the three following groups by physicians blinded to results of CRP analysis: group I, demonstrated bacterial infection (24 episodes); group II, probable bacterial infection (31 episodes); and group III, viral infection or no infection (30 episodes). Baseline CRP values were low (mean, 9 mg/L; range, 0-35 mg/L) irrespective of tumor type or stage of therapy. Mean CRP values on day 1 for children in groups I and II (194 and 143 mg/L, respectively) were higher than those for children in group III (29 mg/L) (P < .001). A CRP value of > 40 mg/L discriminated children with a demonstrated bacterial infection (sensitivity, 100%; specificity, 76.6%). Children with an unfavorable outcome had persistently high levels of serum CRP. For children with cancer, neutropenia, and fever, determination of the serum CRP level is useful for early diagnosis of bacterial infections and for monitoring the course of infection.

[Fatal adenovirus pneumonia]. / Neumonía fatal por adenovirus.

Adenoviruses are well known and ubiquitous causes of respiratory illness in children. Serious long-term sequelae and even fatalities have been described in young children affected by adenoviral infections of the respiratory tract. This is a report on clinical and histopathological features of 25 infants dying from acute lower respiratory tract infections apparently caused by adenoviruses, from January 1st 1983 through December 31st 1986. The diagnosis was based on the finding of distinctive intranuclear inclusions in the pulmonary lesions that were present in all 25 cases at necropsy. Necrotizing bronchiolitis was found in 24 patients (96%). Nineteen patients (76%) were younger than 1 year of age and 15 (60%) had underlying malnutrition. In 17 instances (68%) the respiratory illness was nosocomial in origin. A specific etiologic diagnosis was not made in any of the 25 patients during the course of the illness, twenty four of them (96%) received various antimicrobial drugs without success.