Luisa Galli

Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis.

BACKGROUND Data on the short-term risk of disease progression in HIV-1-infected children are needed to address the question of when to begin combination antiretroviral therapy. We estimated 12-month risks of progression to AIDS and death, by age and most recent measurement of CD4 T-cell percentage (CD4%) or viral load, in children receiving no antiretroviral therapy or zidovudine monotherapy only. METHODS We undertook a meta-analysis of individual longitudinal data for 3941 children from eight cohort studies and nine randomised trials in Europe and the USA. Estimates of risk were derived from parametric survival models. FINDINGS 997 AIDS-defining events were recorded over 7297 person-years of follow-up in the analysis of CD4%, and 284 events over 2282 person-years in the viral load analysis, corresponding to 568 deaths (9087 person-years) and 129 deaths (2816 person-years), respectively. In children older than 2 years, risk of death increased sharply when CD4% was less than about 10%, or 15% for risk of AIDS, with a low and fairly stable risk at greater CD4%. Children younger than 2 years had worse outlook than older children with the same CD4%. Risk of progression increased when viral load exceeded about 10(5) copies per mL, although this association was more gradual compared with CD4%. Both markers had independent predictive value for disease progression; CD4% was the stronger predictor. INTERPRETATION This information is important for paediatricians making decisions, and for researchers designing trials, about when to initiate or restart antiretroviral therapy.

Response to combination antiretroviral therapy: variation by age.

Objective:To provide information on responses to combination antiretroviral therapy in children, adolescents and older HIV-infected persons. Design and setting:Multicohort collaboration of 33 European cohorts. Subjects:Forty-nine thousand nine hundred and twenty-one antiretroviral-naive individuals starting combination antiretroviral therapy from 1998 to 2006. Outcome measures:Time from combination antiretroviral therapy initiation to HIV RNA less than 50 copies/ml (virological response), CD4 increase of more than 100 cells/μl (immunological response) and new AIDS/death were analysed using survival methods. Ten age strata were chosen: less than 2, 2–5, 6–12, 13–17, 18–29, 30–39 (reference group), 40–49, 50–54, 55–59 and 60 years or older; those aged 6 years or more were included in multivariable analyses. Results:The four youngest age groups had 223, 184, 219 and 201 individuals and the three oldest age groups had 2693, 1656 and 1613 individuals. Precombination antiretroviral therapy CD4 cell counts were highest in young children and declined with age. By 12 months, 53.7% (95% confidence interval: 53.2–54.1%) and 59.2% (58.7–59.6%) had experienced a virological and immunological response. The probability of virological response was lower in those aged 6–12 (adjusted hazard ratio: 0.87) and 13–17 (0.78) years, but was higher in those aged 50–54 (1.24), 55–59 (1.24) and at least 60 (1.18) years. The probability of immunological response was higher in children and younger adults and reduced in those 60 years or older. Those aged 55–59 and 60 years or older had poorer clinical outcomes after adjusting for the latest CD4 cell count. Conclusion:Better virological responses but poorer immunological responses in older individuals, together with low precombination antiretroviral therapy CD4 cell counts, may place this group at increased clinical risk. The poorer virological responses in children may increase the likelihood of emergence of resistance.

Maternal Drug Use Is a Preeminent Risk Factor for Mother-to-Child Hepatitis C Virus Transmission: Results from a Multicenter Study of 1372 Mother-Infant Pairs

This prospective multicenter study evaluated separately the significance of maternal injection drug use (IDU) and human immunodeficiency virus type 1 (HIV-1) coinfection in vertical transmission of hepatitis C virus (HCV). In all, 1372 consecutive, unselected HCV antibody-positive mothers and their infants were studied. Maternal HIV-1 coinfection (crude odds ratios [OR], 1.41; 95% confidence interval [CI], 1.16-1.66; P =.007) and IDU (OR, 1.58; 95% CI, 1.37-1.78; P <.00001) were linked to mother-to-child HCV transmission in unadjusted analysis when all anti-HCV-positive mothers were evaluated. When only HCV RNA-positive mothers were evaluated, maternal IDU, but not maternal HIV-1 coinfection, was significantly associated with mother-to-child HCV transmission. Multivariable analysis confirmed the link between maternal IDU and HCV transmission (adjusted OR [AOR], 1.51; 95% CI, 1.19-1.92; P =.0006), but no association was found with HIV-1 coinfection (AOR, 0.98; 95% CI, 0.73-1.33; P =.93). IDU, but not HIV-1 coinfection, seems to be a preeminent risk factor for vertical HCV transmission.

Pertussis re-emergence in the post-vaccination era

BackgroundResurgence of pertussis in the post-vaccination era has been reported in Western countries. A shift of cases from school-age children to adolescents, adults and children under 1 year of age has been described in the last decade, and mortality rates in infants are still sustained. We aimed to review and discuss the possible vaccination strategies which can be adopted in order to improve the pertussis control, by searches of Pubmed, and websites of US and European Centers for Disease Control and Prevention, between 1st January 2002, and 1st March 2013.DiscussionThe following vaccination strategies have been retrieved and analysed: the cocooning strategy, the immunization of pregnant women and newborns, vaccination programs for preschool children, adolescents, adults and health-care workers. Cost-effectiveness studies provide some contrasting data, mainly supporting both maternal vaccination and cocooning. Adolescent and/or adult vaccination seems to be cost-effective, however data from observational studies suggest that this vaccination strategy, used alone, leads to a reduced pertussis burden globally, but does not affect the disease incidence in infants. Moreover, substantial logistical and economic difficulties have to be overcome to vaccinate the largest number of individuals.SummaryThe simultaneous use of more than one strategy, including cocooning strategy plus vaccination of adolescents and adults, seems to be the most reasonable preventive measure. The development of new highly immunogenic and efficacious pertussis vaccines continues to be a primary objective for the control of pertussis.

Interferon-Gamma Release Assay Improves the Diagnosis of Tuberculosis in Children

Background: Interferon-&ggr; release assays (IGRAs) have been recently developed for the diagnosis of tuberculosis (TB) infection. The aim of the present study was to evaluate the performance of an enzyme-linked immunosorbent assay (ELISA)-based IGRA for detecting TB in children. Methods: A prospective study in 336 children at risk for TB infection was carried out. All children were tested with tuberculin skin test (TST) and a commercial ELISA-based IGRA [QuantiFERON-TB Gold In-Tube (Cellestis)]. Results: TST were positive in 58 of 336 (17.3%) and IGRA in 60 of 336 (17.9%) children. Two (0.6%) IGRA results were indeterminate. The overall agreement between the 2 tests was intermediate (86.2%, κ = 0.533). IGRA was positive in 15 of 16 (93.8%) children with active pulmonary TB. The discordant pattern IGRA−/TST+ was significantly associated with Bacille Calmette-Guérin (BCG) vaccination. Among IGRA+ children (excluding cases of TB disease), TST− were significantly younger than TST+ children. Conclusions: The good agreement between positive IGRA and active TB disease suggests a good sensitivity of IGRA. Discrepancies between IGRA and TST can be a result of higher specificity of IGRA that is not influenced by previous BCG vaccination. IGRA may be more sensitive in children younger than 48 months.

Allergy to different fish species in cod-allergic children: In vivo and in vitro studies

The presence of a positive clinical history and skin test (ST) results for 17 fish species (anchovy, bass, carp, dogfish, eel, gilthead, mackerel, mullet, perch, red mullet, salmon, sardine, sole, tench, toothed gilthead, trout, and tuna) were investigated in 20 children with cod-positive clinical history, ST, and RAST, and in 40 children positive to one or more foods different from cod (cows milk, chicken egg white, peanut, and tomato). In cod-positive children, positive clinical history (60%) and ST (85%) to fish species were more frequent than in cod-negative children (7.5% and 10% respectively). In cod-positive children, a high frequency of positive STs to eel (85%) and to bass, dentex, sole, and tuna (55%) was observed. Positivity to dogfish (10%) was the least frequent. RAST-inhibition experiments suggested the presence of cross-reacting antigen(s) in cod, bass, dentex, eel, sole, and tuna. Results of this study demonstrate that cod allergy might be, on the whole, a reliable index of fish allergy, but cod-positive children may perhaps tolerate some other species, which will have to be tested for possible inclusion in their diet.

HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding.

ObjectivesTo estimate the risk of HIV-1 transmission through breast-milk in children born to infected mothers, and to determine the relationship between duration of breast-feeding and risk. Design and methodsThe study population included 168 breast-fed and 793 bottle-fed children born to seropositive mothers. All subjects were enrolled and followed-up in the Italian Register for HIV Infection in Children; HIV serostatus was defined in all children. Multivariate analysis was performed using a logistic regression model. Independent variables included biological factors (duration of breast-feeding, gestational age, clinical condition of mother at delivery, mode of delivery, birth-weight and sex). Year of birth and age when HIV infection was diagnosed were also considered in the analysis attempting to control for possible selection biases. ResultsBreast-feeding increased the risk of HIV-1 transmission. The estimated adjusted odds ratio for 1 day of breast- versus bottle-feeding was 1.19 (95% confidence interval, 1.10–1.28). The infection odds ratio of breast- versus bottle-feeding increased with the natural logarithm of the duration of practice. ConclusionsThese results are the first to provide an appraisal of the additional risk of HIV-1 transmission associated with a seropositive mother breast-feeding her child. Biological significance of this route of transmission was supported by demonstration of a relationship between duration of breast-feeding and risk of HIV-1 transmission.

Definitive Results of a Phase II Trial of Cisplatin, Epirubicin, Continuous-Infusion Fluorouracil, and Gemcitabine in Stage IV Pancreatic Adenocarcinoma

PURPOSE To evaluate the efficacy and toxicity of a cisplatin, epirubicin, gemcitabine, and fluorouracil (PEF-G) schedule on stage IV pancreatic adenocarcinoma. PATIENTS AND METHODS Patients < or = 70 years, with no prior chemotherapy and with bidimensionally measurable stage IV pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status < or = 2, and adequate bone marrow, kidney, and liver function were eligible for this trial. Eligibility criteria for clinical benefit assessment were pain with at least a daily analgesic consumption of two nonsteroidal anti-inflammatory drugs or Karnofsky performance status between 50 and 70. Treatment consisted of 40 mg/m2 each of cisplatin and epirubicin day 1, gemcitabine 600 mg/m2 on days 1 and 8 every 4 weeks, and fluorouracil 200 mg/m2/d as a protracted venous infusion. RESULTS Between April 1997 and April 1999, 49 patients from a single institution were eligible for the study. Altogether, 203 cycles (median, four cycles) of PEF-G were delivered. The objective response rate was 58% in 43 assessable patients and 51% in the intent-to-treat population. Fourteen patients had stable disease. Grade 3 or 4 World Health Organization neutropenia occurred in 51% of cycles, thrombocytopenia in 28%, anemia in 7%, stomatitis in 5%, and diarrhea, and nausea, and vomiting in 2%. The median duration of response was 8.5 months. The median time to tumor progression was 7.5 months. The median survival was 11 months in the assessable population and 10 months in the intent-to-treat population. Clinical benefit was achieved in 22 (78%) of 28 assessable patients. CONCLUSION PEF-G is a well-tolerated and safe regimen; it obtained a very high rate of durable responses and deserves further evaluation in a phase III trial.

Analysis of Different Recommendations From International Guidelines for the Management of Acute Pharyngitis in Adults and Children

BACKGROUND Streptococcal pharyngitis is a frequently observed condition, but its optimal management continues to be debated. OBJECTIVE The goal of this study was to evaluate the available guidelines, developed at the national level, for the management of streptococcal pharyngitis in Western countries, with a focus on their differences. METHODS A literature search was conducted of the Cochrane Library, EMBASE, TRIP, and MEDLINE databases from their inception (1993 for the Cochrane Library, 1980 for EMBASE, 1997 for TRIP, and 1966 for MEDLINE) through April 25, 2010. The following search terms were used: pharyngitis, sore throat, tonsillitis, pharyngotonsillitis, Streptococcus pyogenes, Group A β-haemolytic Streptococcus pyogenes, and streptococcal pharyngitis. Searches were limited to type of article or document (practice guideline or guideline) with no language restrictions or language limits. RESULTS Twelve national guidelines were identified: 6 from European countries (France, United Kingdom, Finland, Holland, Scotland, and Belgium), 5 from the United States, and 1 from Canada. Recommendations differ substantially with regard to the use of a rapid antigen diagnostic test or throat culture and the indications for antibiotic treatment. The North American, Finnish, and French guidelines recommend performing one timely microbiologic investigation in suspected cases, and prescribing antibiotics in confirmed cases to prevent suppurative complications and acute rheumatic fever. According to the remaining European guidelines, however, acute sore throat is considered a benign, self-limiting disease. Microbiologic tests are not routinely recommended by these latter guidelines, and antibiotic treatment is reserved for well-selected cases. The use of the Centor score, for evaluation of the risk of streptococcal infection, is recommended by several guidelines, but subsequent decisions on the basis of the results differ in terms of which subjects should undergo microbiologic investigation. All guidelines agree that narrow-spectrum penicillin is the first choice of antibiotic for the treatment of streptococcal pharyngitis and that treatment should last for 10 days to eradicate the microorganism. Once-daily amoxicillin was recommended by 2 US guidelines as equally effective. CONCLUSION The present review found substantial discrepancies in the recommendations for the management of pharyngitis among national guidelines in Europe and North America.

Onset of clinical signs in children with HIV-1 perinatal infection

Objective: To investigate the timing of onset of each clinical sign in infants and children with HIV‐1 perinatal infection. Design and methods: A total of 200 HIV‐1‐infected children followed‐up from birth were studied. Failure and conditional probabilities were estimated by the Kaplan‐Meier product‐limit method. Cox proportional hazard analysis was used to evaluate independently associated factors. Results of 934 seroreverters were used to calculate reference values of CD4+ cell counts and predictivity of early signs. Results: Median age at the onset of any sign was 5.2 months (range, 0.03‐56 months). The probability of remaining asymptomatic was 19% [95% confidence interval (CI), 14‐25.1] at 12 months and 6.1% (95% Cl, 2.6‐11.7) at 5 years. Lymphadenopathy (69.5%), splenomegaly (62.4%) and hepatomegaly (58.4%) were the most common signs in the first year of life. Peculiar to the first year of life (compared with subsequent ages) was the onset of primary HIV‐1 hepatitis and diarrhoea (rate ratios, 23.3 and 15.2, respectively). When CD4+ cell counts in the asymptomatic stage (age, 2 months; range, 0.03‐5.9 months) were below rather than above the fifth percentile in seroreverters, onset of signs was earlier [3 (range, 0.03‐19) versus 5 (range, 0.03‐56) months]. Children manifesting signs before the 5.2‐month breakpoint had a lower survival rate [74% (range, 65.9‐82%) at 12 months and 45% (range, 32.9‐57%) at 5 years] than children manifesting signs later 198% (range, 92.2‐100%) at 12 months and 74% (range, 60.3‐87.7%) at 5 years]. Children whose birthweight was ≤2400g had an earlier onset (24 months; range, 1‐57 months) of severe conditions than children with higher birthweight (71 months; range, 1‐71 months). Development of lymphadenopathy or hepatosplenomegaly within 3 months of life were reliable indicators of infection. Conclusions: This study describes the sequence of onset of signs in perinatal HIV‐1 infection. Infection is shown to progress faster than in adults and in a different manner. Low birthweight, early decreased CD4+ cell counts, and early onset of signs are predictive of rapid progression. AIDS 1995, 9:455‐461