Eduardo L. Lopez

Multinational study of pneumococcal serotypes causing acute otitis media in children

Background. Streptococcus pneumoniae is a major cause of acute otitis media (AOM) in young children. More than 90 immunologically distinct pneumococcal serotypes have been identified, but limited information is available regarding their relative importance in AOM. Methods. We analyzed nine existing datasets comprising pneumococcal isolates from middle ear fluid samples collected from 1994 through 2000 from 3232 children with AOM from Finland, France, Greece, Israel, several East European countries, the US and Argentina. We examined the distribution of pneumococcal serotypes in relation to several demographic and epidemiologic variables, including gender, age, antibiotic resistance and source of culture material. Results. The major serotypes identified included 19F and 23F, each comprising 13 to 25% of pneumococcal middle ear fluid isolates in most datasets; 14 and 6B, comprising 6 to 18%; whereas 6A, 19A and 9V each comprised 5 to 10%. Despite differences in location, study design and antibiotic susceptibility, each major serotype was prominent in most age groups of each dataset. Serotypes represented in the 7-valent pneumococcal conjugate vaccine (PCV-7, 4, 6B, 9V, 14, 18C, 19F, 23F) accounted for 60 to 70% of all pneumococcal isolates in the 6- to 59-month age range, but only 40 to 50% of isolates in children <6 or ≥60 months old. Serotype 3 and, in certain datasets, serotypes 1 and 5, were more important in the <6- and ≥60-month age groups. In each age group vaccine-related serotypes (mainly 6A and 19A) comprised an additional 10 to 15% of all pneumococcal isolates. Four serotypes (23F, 19F, 14 and 6B) accounted for 83% of all penicillin-resistant observations. Conclusions. This analysis of several geographically diverse datasets indicates that a limited number of serotypes, largely represented in PCV-7, accounted for the majority of episodes of pneumococcal AOM in children between 6 and 59 months of age. Certain serotypes appeared to be relatively more significant in children <6 months or >59 months of age.

Anticytotoxin-neutralizing antibodies in immune globulin preparations: Potential use in hemolytic-uremic syndrome

The pathogenesis of primary (classic) hemolytic-uremic syndrome (HUS) is thought to be related to cytotoxin-producing enteric pathogens such as Shigella dysenteriae serotype 1 and Escherichia coli serotypes O157:H7 and 026:H11. The relevant cytotoxins include Shiga toxin and the closely related Shiga-like toxins (SLTs) produced by some E. coli strains. Intravenously administered immune globulin (IVIG) therapy has been reported to be beneficial in a few children with HUS. We therefore examined commercially available immune globulin preparations for the presence of anticytotoxin-neutralizing antibodies. Cytotoxicity and neutralization of the HUS-associated cytotoxins were quantitatively determined by means of a (3H)thymidine-labeled HeLa cell assay. The immune globulin preparations tested almost completely neutralized Shiga toxin (produced by S. dysenteriae 1) and SLT-I (produced by E. coli serotype 026:H11). Twofold dilutions of the preparations showed significant (p less than 0.01) neutralizing titers of 1:64 to 1:128. No significant neutralization (greater than 20%) of SLT-II (produced by E. coli strain C600 (933W] was noted. The IVIG preparation lost its inhibitory activity when passed through a protein A-Sepharose column, which bound immune globulin, indicating that its neutralizing effect is related to the antibody content. We also examined sera from 30 children without diarrhea or HUS; only one child had neutralizing titers against Shiga toxin (1:64) and SLT-I (1:128). Immune globulin preparations contain anticytotoxin-neutralizing antibodies, a finding that warrants further investigation of the therapeutic role of these preparations in early treatment of children with HUS related to Shiga toxin and SLT-I.

Incomplete hemolytic-uremic syndrome in Argentinean children with bloody diarrhea☆☆☆★★★

Argentina has an exceptionally high frequency of hemolytic-uremic syndrome (HUS). We sought to define prospectively the role of verocytotoxins (Shiga-like toxins [SLTs]) in 254 Argentinean children with grossly bloody diarrhea during spring and summer. Free fecal SLTs (I/II) and/or DNA probe-positive isolates were found in 99 (39%) of the children. During the follow-up period, HUS developed in 6 patients (4 with evidence of recent SLT infection based on stool studies); another 14 patients had some, but not all, of the abnormalities seen in typical HUS. The development of HUS or incomplete HUS in these children was significantly associated with recent SLT-Escherichia coli infection (p = 0.024). The high incidence of SLT-associated bloody diarrhea in Argentina explains, at least partially, the unusually high frequency of HUS. Our data indicate that incomplete forms of HUS may be common in patients with SLT-associated bloody diarrhea.

SHIGELLA AND SHIGA TOXIN-PRODUCING ESCHERICHIA COLI CAUSING BLOODY DIARRHEA IN LATIN AMERICA

In Latin America, Shigella and shiga toxin-producing Escherichia coli are the two leading agents in the cause of bloody diarrhea. The already high and increasing antimicrobial resistance of Shigella also is a significant problem. Shiga toxin-producing E. coli is an emerging disease with life-threatening complications: hemolytic uremic syndrome. Although E. coli O157:H7 remains the most commonly recognized serotype, recently emerging, non-O157 bacteria may be the cause of a similar spectrum of disease in humans.

Safety and immunogenicity of a pediatric formulation of inactivated hepatitis A vaccine in Argentinean children.

BACKGROUNDnChildren are a reservoir of hepatitis A virus and must be considered as primary targets of any immunization strategy. The safety and immunogenicity were evaluated for a new formulation of an inactivated hepatitis A vaccine, Avaxim 80 units, containing one-half the antigen dose of the adult formulation.nnnMETHODSnThe safety of two doses of this vaccine given 6 months apart was evaluated in an open study in 537 Argentinean children 12 months to 15 years old. Immunogenicity was evaluated at Weeks 0, 2, 24 and 27 in a subgroup of 120 subjects.nnnRESULTSnTwo weeks after the first vaccine dose, >99% of initially seronegative children had seroconverted (titers > or =20 mIU/ml), with a geometric mean titer of 98.5 mIU/ml. Before booster at 24 weeks all subjects had seroconverted. A strong anamnestic response was observed after the second dose at which time the geometric mean titer had increased >35-fold, and antibody titers were consistent with long term protection. Immediate adverse reactions were observed in 3 of 537 (0.6%) subjects after the first dose. Local reactions were mild and transient and did not increase with subsequent doses. Among the systemic events reported during the 7-day follow-up period, 37 cases of fever after the first dose and 22 cases after the second dose were reported. Only 3 cases of fever were clearly related to vaccination (< or =38.2 degrees C) after the first injection, all of which subsided in less than 1 day.nnnCONCLUSIONSnThis study demonstrated the safety and immunogenicity of a pediatric formulation of hepatitis A vaccine in children ages 12 months to 15 years in healthy children ages 12 to 47 months.

Association between severity of gastrointestinal prodrome and long-term prognosis in classic hemolytic-uremic syndrome.

To determine whether severity of the prodromal gastrointestinal illness is associated with the course and complications of the extraintestinal manifestations of hemolytic-uremic syndrome, we conducted a retrospective review of children (n = 509) hospitalized with hemolytic-uremic syndrome. Those who came to the hospital with colitis and rectal prolapse associated with hemolytic-uremic syndrome (group I, n = 40) were compared with an equal number of time-matched children with hemolytic-uremic syndrome but without prolapse (group II). Children in group I had evidence of more severe colitis than children in group II had, as indicated by increased frequency of bloody diarrhea (p less than 0.001) and longer duration of diarrhea (p less than 0.001). However, they also had more severe extraintestinal manifestations during hemolytic-uremic syndrome, including edema (p less than 0.0001), severe thrombocytopenia (p less than 0.0001), prolonged anuria (p less than 0.001), and seizures (p = 0.036). Long-term prognosis for recovery of renal function was worse for group I than group II. Within group II, patients with bloody diarrhea had milder extraintestinal illness than those with prolapse but more severe extraintestinal illness than those with watery diarrhea. Analysis of Kaplan-Meier survival curves demonstrated a better prognosis for return of normal renal function in the children with watery diarrhea but without prolapse (p = 0.009) than in children with bloody diarrhea or prolapse. These data demonstrate that the severity of the gastrointestinal prodrome reflects the severity of the extraintestinal acute microangiopathic process and the resulting long-term outcome. Widespread vascular damage, often followed by permanent sequelae, is characteristic of patients with the most severe colitis.

Multiply resistant nontyphoidal Salmonella gastroenteritis in children.

From January, 1990, to December 31, 1990, 75 children with multiply resistant Salmonella gastroenteritis were studied at the Childrens Hospital Ricardo Gutierrez of Buenos Aires. These children ranged from 1 month to 15 years of age. Infection was community-acquired in 20 (26.6%), nosocomially acquired in 50 (66.7%) and undetermined in 5. Thirty-nine (52%) had grossly bloody stools. Fever occurred at some point in the clinical course in 61 children (81.3%) with a duration of 1 to 33 days (mean, 6.7 days). The duration of diarrhea (1 to 69 days) was longer in those who developed complications (P < 0.001). Six (8%) developed enterocolitis (2 with bowel perforation), 1 had a pulmonary abscess and 8 (11.4%) had bacteremia; 4 children died (5.3%). Salmonella typhimurium was the most common serovar (85.3%). Ninety percent minimum inhibitory concentration studies demonstrated that all strains were resistant to ampicillin (> 128 micrograms/ml), cephalothin (> 128 micrograms/ml), cefuroxime (> 128 micrograms/ml), nalidixic acid (> 256 micrograms/ml), rifampin (> 256 micrograms/ml), gentamicin (> 256 micrograms/ml) and tobramycin (256 micrograms/ml); 77.3% of strains were resistant to ceftazidime (32 micrograms/ml), 97.6% to netilmicin (> 256 micrograms/ml), 92.8% to amikacin (256 micrograms/ml), 24.4% to isepamicin (32 micrograms/ml), 5.3% to chloramphenicol (4 micrograms/ml) and 2.7% to cefoxitin (2 micrograms/ml). The 90% minimum inhibitory concentration of cefotaxime and ceftazidime was reduced by the addition of clavulanate. Aggressive multiply resistant Salmonella strains are a major pediatric problem in Buenos Aires.

Perspectives on Shiga-like toxin infections in Argentina

Argentina has the highest frequency of hemolytic uremic syndrome (HUS) in the world (300 cases/year). The risk of HUS in children from 6 to 48 months old is approximately 22/100,000 in Buenos Aires. In Argentina, HUS is the most frequent cause of acute renal damage and the second cause of chronic renal injury in children. We have shown that during the spring/summer season, the incidence of Shiga-like toxin (SLT)-associated bloody diarrhea in children less than 5 years old is 30 to 39%. The risk of HUS in SLT-associated bloody diarrhea is about 4 to 5%; 14% of children with SLT diarrhea developed incomplete HUS. Household contacts of children with HUS are commonly colonized with SLT-producing Escherichia coli (39%), and seroconversion occurs in 42% of these. No evidence of free fecal SLTs was observed in healthy children. In Argentina E. coli serotype O157:H7 has been associated with only 2 to 18% of HUS patients and in 4.5 to 7% of children with bloody diarrhea. Other serotypes were also recognized. About 20% of Argentine children start to eat meat at 5 months old, and 80% of them have meat in their diets at least three times a week. Eighty percent of the meat consumed is undercooked. Few data about the incidence of SLT-producing E. coli in cows in our country are available. E. coli O157:H7 was isolated in only 7.7% of calves aged 1 to 3 weeks with E. coli bacillosis from different farms in Argentina. Preliminary data show that SLT-producing E. coli were also present in stools from healthy animals and in fresh retail ground beef, determined by polymerase chain reaction.

First case of human infection due to Pseudomonas fulva, an environmental bacterium isolated from cerebrospinal fluid.

ABSTRACT We report the first case of human infection due to Pseudomonas fulva. P. fulva caused acute meningitis following the placement of a drainage system in a 2-year-old female. Additionally, the isolate displayed a VIM-2 carbapenemase in a class 1 integron context.

Clinical and epidemiologic aspects of human immunodeficiency virus-1-infected children in Buenos Aires, Argentina.

BACKGROUNDnArgentina has the sixth largest number of cumulative pediatric cases of acquired immunodeficiency syndrome (AIDS) in the Americas; therefore, this study was designed to characterize human immunodeficiency virus-1 (HIV-1) infection in children in Buenos Aires, Argentina.nnnMATERIALS AND METHODSnMedical records of 389 children at risk and infected with HIV-1, an urban population followed by the AIDS Reference Center at the Hospital de Niños Dr. Ricardo Gutiérrez of Buenos Aires, from February 1990 to June 1997, were retrospectively reviewed. Mother-infant pairs were analyzed according to clinical and epidemiologic patterns.nnnRESULTSnPerinatal transmission occurred in 94.9% of the 389 cases classified as seroreverter (n=104, 26.7%), exposed (n=64, 16.4%), asymptomatic (n=13, 3.4%), and symptomatic patients (n=208, 53.5%); 132 patients met the Centers for Disease Control and Prevention (CDC) criteria for AIDS. The main maternal risk factor was sexual transmission 58.9% (73.4% of their sexual partners were injection drug users [IDU]). Among the AIDS patients, the most common AIDS-defining condition and death-related disease were severe bacterial infection and Pneumocystis carinii pneumonia, respectively. Death occurred in 51 of 221 HIV-infected children. Low CD4 was related to death (P < 0.001). Mortality was estimated for two periods: January 1990 to December 1995 (G1) and January 1996 to May 1997 (G2). In G1, 37 of 127 (29.1%) died compared with 14 of 154 (9.1%) in G2 (P=0.001). The median age of death was 10 months for G1 and 29 months for G2 (P=0.01). The 3-year survival rate was 72% for G1 and 87% for G2 (log rank P=0.06).nnnCONCLUSIONSnIntravenous drug use is the leading risk factor among parents of children exposed to HIV. Infant mortality was related to age less than 12 months, low CD4 count, severe bacterial infection and P. carinii pneumonia. In this study, P. carinii pneumonia prophylaxis and combined antiretroviral therapy routinely implemented since 1996 has demonstrated a trend toward increased survival rates (P=0.06) and a lower mortality rate (P=0.001).