Antonio Arbo

Adjuvant Glycerol and/or Dexamethasone to Improve the Outcomes of Childhood Bacterial Meningitis: A Prospective, Randomized, Double- Blind, Placebo-Controlled Trial

BACKGROUND Despite favorable meta-analyses, no study involving third-generation cephalosporins for the treatment of childhood bacterial meningitis has documented a benefit of adjuvant dexamethasone therapy if the outcomes are examined individually. METHODS We conducted a prospective, randomized, double-blind trial comparing adjuvant dexamethasone or glycerol with placebo in children aged from 2 months through 16 years in Latin America. Ceftriaxone was administered to all children; children were randomized to also receive dexamethasone intravenously, glycerol orally, both agents, or neither agent. Primary end points were death, severe neurological sequelae, or deafness, with the first 2 end points forming a composite end point. A subgroup analysis for Haemophilus influenzae type b meningitis was undertaken. Intention-to-treat analysis was performed using binary logistic regression models. RESULTS H. influenzae type b, pneumococci, and meningococci were the main agents found among 654 patients; dexamethasone was given to 166, dexamethasone and glycerol were given to 159, glycerol was given to 166, and placebo was given to 163. No adjuvant therapy significantly affected death or deafness. In contrast, glycerol and dexamethasone plus glycerol reduced severe neurological sequelae, compared with placebo; the odds ratios were 0.31 (95% confidence interval [95% CI], 0.13-0.76; P=.010) and 0.39 (95% CI, 0.17-0.93; P=.033), respectively. For neurological sequelae and death, the odds ratios were 0.44 (95% CI, 0.25-0.76; P=.003) and 0.55 (95% CI, 0.32-0.93; P=.027), respectively. Dexamethasone therapy prevented deafness in patients with H. influenzae type b meningitis only if patients were divided grossly into dexamethasone recipients and nonrecipients and if timing between dexamethasone and ceftriaxone administration was not taken into account (odds ratio, 0.27; 95% CI, 0.09-0.77; P=.014). CONCLUSION Oral glycerol therapy prevents severe neurological sequelae in patients with childhood meningitis. Safety, availability, low cost, and oral administration also add to its usefulness, especially in resource-limited settings.

Influence of Admission Findings on Death and Neurological Outcome from Childhood Bacterial Meningitis

A post hoc analysis of 654 children with bacterial meningitis showed that the level of consciousness is the most important predictor of death and/or neurological sequelae, more than is etiology per se. This finding emphasizes the need of including a measurement of the presenting status in all studies examining treatment efficacy.

Hearing Impairment in Childhood Bacterial Meningitis Is Little Relieved by Dexamethasone or Glycerol

OBJECTIVE. Several studies have evaluated dexamethasone for prevention of hearing loss in childhood bacterial meningitis, but results have varied. We compared dexamethasone and/or glycerol recipients with placebo recipients, and measured hearing at 3 threshold levels. METHODS. Children aged 2 months to 16 years with meningitis were treated with ceftriaxone but were double-blindly randomly assigned to receive adjuvant dexamethasone intravenously, glycerol orally, both agents, or neither agent. We used the Glasgow coma scale to grade the presenting status. The end points were the better ears ability to detect sounds of >40 dB, ≥60 dB, and ≥80 dB, with these thresholds indicating any, moderate-to-severe, or severe impairment, respectively. All tests were interpreted by an external audiologist. Influence of covariates in the treatment groups was examined by binary logistic regression. RESULTS: Of the 383 children, mostly with meningitis caused by Haemophilus influenzae type b or Streptococcus pneumoniae, 101 received dexamethasone, 95 received dexamethasone and glycerol, 92 received glycerol, and 95 received placebo. Only the presenting condition and young age predicted impairment independently through all threshold levels. Each lowering point in the Glasgow scale increased the risk by 15% to 21% (odds ratio: 1.20, 1.21, and 1.15 [95% confidence interval: 1.06–1.35, 1.07–1.37, and 1.01–1.31]; P = .005, .003, and .039) for any, moderate-to-severe, or severe impairment, respectively. Each increasing month of age decreased the risk by 2% to 6% (P = .0001, .0007, and .041, respectively). Neither dexamethasone nor glycerol prevented hearing loss at these levels regardless of the causative agent or timing of antimicrobial agent. CONCLUSIONS: With bacterial meningitis, the childs presenting status and young age are the most important predictors of hearing impairment. Little relief is obtained from current adjuvant medications.

Risk factors for mortality in Paraguayan children with pneumococcal bacterial meningitis

Background  Over the last decade Streptococcus pneumoniae has emerged as the most common bacterial pathogen for meningitis in all age groups, beyond the neonatal period.

Diagnosis of Streptococcus pneumoniae and Haemophilus influenzae type b meningitis by identifying DNA from cerebrospinal fluid-impregnated filter paper strips.

Background: Bacterial meningitis remains often etiologically unconfirmed, especially in resource-poor settings. We tested the potential of real-time polymerase chain reaction to identify Streptococcus pneumoniae (Pnc) and Haemophilus influenzae type b (Hib) from cerebrospinal fluid impregnated on filter paper strips. Methods: Pnc and Hib genome equivalents were blindly quantified by polymerase chain reaction from 129 liquid cerebrospinal fluid (CSF) samples–the standard–and strips stored at room temperature for months. Genome counts were compared by simple regression. Results: The strips showed a sensitivity and specificity of 92% and 99% for Pnc, and of 70% and 100% for Hib, respectively. The positive and negative predictive values were 94% and 97% for Pnc, and 100% and 89% for Hib, respectively. For Pnc, the positive and negative likelihood ratio was 92 and 0.08, and the overall accuracy 98%, whereas for Hib they were 70 and 0.30, and 91%, respectively. Genome counting showed good correlation between the filter paper and liquid CSF samples, r2 being 0.87 for Pnc and 0.68 for Hib (P < 0.0001 for both). Conclusion: Although not replacing bacterial culture, filter paper strips offer an easy way to collect and store CSF samples for later bacteriology. They can also be transported in standard envelops by regular mail.

Clinical Characteristics and Risk Factors of Dengue Shock Syndrome in Children.

Background: Dengue shock syndrome (DSS) represents one of the most severe manifestations of dengue virus infection. The objective of the present study was to analyze the clinical and laboratory characteristics, risk factors and outcome of DSS in children. Methods: Patients <15 years old admitted with DSS during the 2012 and 2013 outbreak of serotype 2 of dengue virus in Paraguay were included. Demographic, clinical and laboratory data of patients with/without DSS were analyzed. Results: Of 471 children hospitalized with dengue, 354 patients (75%) presented with shock at admission or developed later. The mean age of patients with DSS was 10.2 ± 4 years (no difference with patients without shock), without gender preference. Rash (50% vs. 56%), myalgias (45% vs. 40%), vomiting (66% vs. 68%) and bleeding manifestations (24% vs. 21.2%) were similar for 2 groups. Similarly, there was no difference in the frequency of DSS between primary versus secondary infection cases (76.2% vs. 71.6%, P = 0.3). Age group >5 years [odds ratio (OR) 1.6, 95% confidence interval (CI): 1–2.8, P < 0.05), presence of abdominal pain (OR 2.5, 95% CI: 1.3–4.9, P = 0.006), an activated partial thromboplastin time prolonged (OR 4; 95% CI: 1.6–10, P < 0.001) and low fibrinogen level (OR 2.5; 95% CI: 1–5.9, P = 0.02) were found significantly associated with DSS. About 12% of patients required intensive care unit admission, and 2 patients died (lethality 0.35%). Conclusions: This study validated most of the clinical variables present in the current WHO guidelines as markers of severe disease and add additional variables that can help to predict the risk of progression to shock.

Application of a Prognostic Scale to Estimate the Mortality of Children Hospitalized with Community-acquired Pneumonia.

Background: Pneumonia is a major cause of mortality in children. The objective of this study was to construct a prognostic scale for estimation of mortality applicable to children with community-acquired pneumonia (CAP). Methods: This observational study included patients younger than 15 years with a diagnosis of CAP who were hospitalized between 2004 and 2013. A point-based scoring system based on the modification of the PIRO scale used in adults with pneumonia was applied to each child hospitalized with CAP. It included the following variables: predisposition (age <6 months, comorbidity), insult [hypoxia (O2 saturation < 90), hypotension (according to age) and bacteremia], response (multilobar or complicated pneumonia) and organ dysfunction (kidney failure, liver failure and acute respiratory distress syndrome). One point was given for each feature that was present (range, 0–10 points). The association between the modified PIRO score and mortality was assessed by stratifying patients into 4 levels of risk: low (0–2 points), moderate (3–4 points), high (5–6 points) and very high risk (7–10 points). Results: Eight hundred sixty children hospitalized with CAP were eligible for study. The mean age was 2.8 ± 3.2 years. The observed mortality was 6.5% (56/860). Mortality ranged from 0% for a low PIRO score (0/708 pts), 18% (20/112 pts) for a moderate score, 83% (25/30 pts) for a high score and 100% (10/10 pts) for a very high modified PIRO score (P < 0.001). Conclusion: The present score accurately discriminated the probability of death in children hospitalized with CAP, and it could be a useful tool to select candidates for admission to intensive care unit and for adjunctive therapy in clinical trials.

Prospective applicability study of the new dengue classification system for clinical management in children.

Background: To evaluate the efficacy of the 2009 revised dengue classification system proposed by the World Health Organization (WHO) for early detection of dengue cases requiring intervention. Methods: Children <15 years of age with dengue [confirmed by laboratory testing (IgM enzyme-linked immunosorbent assay, NS1 Ag or reverse transcriptase polymerase chain reaction) or by epidemiologic link] who were admitted to the Institute of Tropical Medicine during the 2011 dengue outbreak in Paraguay were prospectively included. Each case was classified according to the 1997 WHO dengue criteria and by the 2009 WHO revised criteria, which categorize dengue patients using a set of clinical finding into dengue with/without warning signs and severe dengue. The management of all cases followed the new recommendations. Results: During the 2011 dengue outbreak, 123 children were admitted with a mean age of 11 ± 3 years. By the 2009 classification system, 119 cases (97%) were classified as dengue requiring intervention [89 patients (75%) with warning signs and 30 patients (25%) with severe signs], whereas by the old system 67 patients (54%) were classified as dengue requiring intervention (P < 0.001). Further, by the 1997 classification, only 13 patients (10%) were classified as dengue hemorrhagic fever III/IV (severe cases), whereas with the 2009 classification 30 patients (24%) were considered as having severe dengue infection (P < 0.05) Conclusions: This study confirms that the 2009 WHO dengue classification provides better detection of severe cases of dengue than the earlier 1997 WHO dengue system.

Consideraciones referente a la posibilidad de introducir la dosis fraccionada de la vacuna antipoliomielitis inactivada en el calendario de Inmunizaciones del Niño Latinoamericano

As last notified case of poliomyelitis due to wild poliovirus type 2 was 1999, in 2012, the Strategic Advisory Group of Experts on Immunization (SAGE) of the World Health Organization (WHO) recommended the withdrawal of the type 2 component of oral polio vaccine (OPV) and the introduction of bivalent OPV (bOPV) in all countries by 2016. WHO recommended also that the withdrawal should be preceded by the introduction of at least one dose of inactivated poliovirus vaccine (IPV) in routine immunization schedules. The introduction of IPV prior to the change of the bOPV in 2016 to trivalent OPV (tOPV) was based on the concept of ensuring that a substantial proportion of the population would be protected against type 2 polio after the removal of the type 2 OPV. However, the worlds two producers of IPV (Bilthoven Biologicals and Sanofi) have faced problems in the production of this vaccine and therefore reported reduction in IPV global supply. In response to the possible shortage of IPV, the SAGE and Technical Adviser Group (TAG) of the Pan American Health Organization (PAHO), in the meeting of March 10, 2017, has urged that countries in the Latinamerican region should replace the routine administration of the full doses of polio inactivated vaccine (IPV-C) in the immunization schedule (administered by intramuscular route) by the administration of a fraction of the full dose in two shots by intradermal route (IPV-f). The possibility of this strategy was analyzed by leaders of opinions gathered by the call of the Paraguayan Pediatric Society with the support of the Latin American Society of Pediatric Infectious Diseases (SLIPE) and Latin American Association of Pediatrics (ALAPE). The results of the discussion are presented in this document.

Characterization of type I interferon responses in dengue and severe dengue in children in Paraguay

BACKGROUND Infection with dengue virus (DENV) produces a wide spectrum of clinical illness ranging from asymptomatic infection to mild febrile illness, and to severe forms of the disease. Type I interferons (IFNs) represent an initial and essential host defense response against viruses. DENV has been reported to trigger a robust type I IFN response; however, IFN-α/β profile in the progression of disease is not well characterized. OBJECTIVES AND STUDY DESIGN In this context, we conducted a retrospective study assessing the circulating serum levels of type I IFNs and related cytokines at different phases of illness in children during the 2011 outbreak of DENV in Paraguay. Demographic, clinical, laboratory and virological data were analyzed. RESULTS During defervescence, significantly higher levels of IFN-β, IL-6 and MIP-1β, were detected in severe vs. non-severe dengue patients. Additionally, a significant positive correlation between INF-α and viremia was detected in children with severe dengue. A significant positive correlation was also observed between IFN-β serum levels and hematocrit during the febrile phase, whereas IFN-α levels negatively correlated with white blood cells during defervescence in severe dengue patients. Furthermore, previous serologic status of patients to DENV did not influence type I IFN production. CONCLUSIONS The distinct type I IFN profile in children with dengue and severe dengue, as well as its association with viral load, cytokine production and laboratory manifestations indicate differences in innate and adaptive immune responses that should be investigated further in order to unveil the association of immunological and physiological pathways that underlie in DENV infection.