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1.
Clin Infect Dis ; 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31796965

RESUMO

BACKGROUND: In adults, anti-tumor-necrosis-factor (TNF)-α therapy is associated with progression of latent tuberculosis infection (LTBI) to tuberculosis (TB) disease. The existing paediatric data are very limited. METHODS: Retrospective multi-centre study within the Paediatric Tuberculosis Network European Trials Group, capturing patients <18 years who developed TB disease during anti-TNF-α therapy. RESULTS: Sixty-six tertiary healthcare institutions providing care for children with TB participated. Nineteen cases were identified; Crohn´s disease (n=8;42%) and juvenile idiopathic arthritis (n=6;32%) were the commonest underlying conditions. Immune-based TB screening (tuberculin skin test and/or interferon-gamma release assay) was performed in 15 patients before commencing anti-TNF-α therapy, but only identified one LTBI case; 13 patients were already receiving immunosuppressants at the time of screening. The median interval between starting anti-TNF-α therapy and TB diagnosis was 13.1 (IQR:7.1-20.3) months. All cases presented with severe disease, predominately miliary TB (n=14;78%). One case was diagnosed post-mortem. TB was microbiologically confirmed in 15 cases (79%). The median duration of anti-TB treatment was 50 (IQR:46-66) weeks. Five of 15 (33%) cases who had completed TB treatment had long-term sequelae. CONCLUSIONS: The data indicate that LTBI screening is frequently false-negative in this patient population, likely due to immunosuppressants impairing test performance. Therefore, patients with immune-mediated diseases should be screened for LTBI at the point of diagnosis, before commencing immunosuppressive medication. Children on anti-TNF-α therapy are prone to severe TB disease, and significant long-term morbidity. Those observations underscore the need for robust LTBI screening programs in this high-risk patient population, even in low TB prevalence settings.

2.
Pediatr Infect Dis J ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31738322

RESUMO

We investigated the impact of baseline tuberculin skin tests (TSTs) and preventive isoniazid chemoprophylaxis on subsequent QuantiFERON-TB Gold In-Tube (QFT-GIT) assays performed after a 10- to 12-week window period in 114 children <5 years of age. Previous TSTs and chemoprophylaxis had no impact on the magnitude of subsequent antigen-induced responses in QFT-GIT. Furthermore, previous TSTs did not induce conversion from a negative to a positive QFT-GIT result.

3.
Pediatr Infect Dis J ; 38(12): 1230-1235, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31738339

RESUMO

BACKGROUND: Congenital cytomegalovirus infection (CMVc) affects 0.7%-6% of recent births. Among its clinical manifestations are low weight and length at birth. OBJECTIVE: Describe the growth patterns of children with CMVc in their early years. METHODS: Observational, multicenter study of patients with CMVc. Anthropometric data were collected during the first 2 years of life and compared with World Health Organization standards. RESULTS: Anthropometric characteristics of 383 children with CMVc were studied, of which 198 (51%) were symptomatic at birth. At birth, 9% were small for gestational age (SGA) in terms of their weight and length and 17% had microcephaly. At 24 ± 3 months, 10% had a weight and length ≤2 SD, and 13% a head circumference ≤2 SD. Of those who were SGA at birth, at 24 ± 3 months >20% remained at ≤2 SD of their weight and length. Conversely, 75% of children with low weight or length at 24 ± 3 had not been SGA at birth. 20% of infants with microcephaly at birth remained with microcephaly, and 10% of those without microcephaly developed it at 24 ± 3 months. The average growth rate in length and weight was normal. Patients who were symptomatic at birth, premature and with motor and neurocognitive impairment had a significantly higher risk of low weight and length at 24 ± 3 months. CONCLUSION: Around 10% of children with CMVc are at ≤2 SD in weight, length and head circumference at 24 ± 3 months. The lack of adequate growth is associated with symptoms at birth, prematurity and motor and neurocognitive impairment. Growth impairment could be incorporated into the symptomatic spectrum of CMVc.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31634404

RESUMO

BACKGROUND: Neisseria meningitidis serogroup B (MenB) is the most frequent cause of invasive meningococcal disease (IMD) in Spain. The multicomponent vaccine against MenB (4CMenB) was approved in Spain in January 2014. METHODS: We present 4 cases of children who developed MenB-associated IMD despite previous vaccination with 4CMenB. Extensive immunologic diagnostic work-up was performed in order to rule out any immunodeficiency. Also, molecular characterization of the MenB strain was conducted to determine whether bacterial antigens matched vaccine antigens. RESULTS: Among the 4 patients (2 girls), 2 had previous risk factors for IMD (recurrent bacterial meningitis of unknown origin and treatment with eculizumab). All patients developed meningitis, but only 2 developed septic shock; they were all cured without sequelae. No other primary or secondary immunodeficiencies were detected. MenB sequence type 213 was identified in 3 cases. With the exception of neisserial heparin-binding antigen peptide 465 present in 1 isolate, the rest of the isolated strains harbored vaccine antigen variants that did not match antigen variants included in the vaccine. CONCLUSIONS: We present 4 children who developed MenB-associated IMD despite previous vaccination with 4CMenB. In 2 cases, the antibodies induced by 4CMenB likely were not effective against the isolated strains. A high level of suspicion for IMD seems advisable regardless of the patient's vaccination history.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30929024

RESUMO

Data for a total of 57 patients vertically coinfected with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) and 365 HIV-monoinfected patients were compared until their transition to adult care. No differences regarding the dynamics of CD4 and/or CD8 T-cell counts during childhood were found. The coexistence of HCV does not increase the risk of disease progression in vertically HIV-infected patients.

7.
J Microbiol Methods ; 161: 8-11, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30986431

RESUMO

We assessed the capacity of Kingella kingae to grow in blood culture bottles (BCB), taking into account the concentrations of the microorganism and blood in the culture medium. An initial suspension (McFarland 0.5) of 32 strains of K. kingae was serially diluted. One mL of the initial suspension and 1 mL of the subsequent dilutions were inoculated in two BCB, together with 1 mL of human blood in the 2nd BCB. Also, 1mL serial dilutions of human blood were added to BCBs previously inoculated with 1 mL of K. kingae dilution 1/104. In non-blood-supplemented BCB, 23 strains grew with the initial suspension and only one with the first processed dilution, as compared to all strains with the initial suspension and the 3 first dilutions, 22 with the 4th dilution, and one with the 5th dilution in blood-supplemented BCB. In BCB inoculated with K. kingae dilution 1/104 and decreasing concentrations of human blood, all strains grew with blood dilutions 1/2 and 1/4, 26 with dilution 1/8, 19 with dilution 1/16, 10 with dilution 1/32, and none with dilution 1/64. Increasing time to positivity was observed with both decreasing bacterial (p = .001) and blood concentrations (r = -0.632, p < .0001). The addition of human blood was essential to boost the growth of K. kingae in BCB. If replicated in vivo, these findings would increase the isolation of fastidious K. kingae organisms from pediatric osteoarticular exudates.

10.
Pediatr Infect Dis J ; 37(12): 1235-1241, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30408005

RESUMO

BACKGROUND: Available data to assess the optimal diagnostic approach in infants and preschool children at risk of tuberculosis (TB) are limited. METHODS: We conducted a prospective observational study in children younger than 5 years undergoing assessment with both tuberculin skin tests (TST) and QuantiFERON-TB Gold In-Tube (QFT-GIT) assays at 2 tertiary TB units in Barcelona, Spain. RESULTS: A total of 383 children were included. One of 304 participants considered uninfected developed active TB during follow-up {median [interquartile range (IQR)]: 47 [30; 48] months}, compared with none of 40 participants with latent TB infection [follow-up since completion of anti-TB treatment: 42 (32; 45) months]. Overall test agreement between TST and QFT-GIT was moderate (κ = 0.551), but very good in children screened after TB contact (κ = 0.801) and in Bacillus Calmette-Guérin (BCG)-unvaccinated children (κ = 0.816). Discordant results (16.8%, all TST+/QFT-GIT-) were mainly observed in new-entrant screening and in BCG-vaccinated children. Children with indeterminate QFT-GIT results were on average younger than those with determinate results (median age: 12 vs. 30 months; P < 0.001). The sensitivity of TSTs and QFT-GIT assays in children with confirmed active TB was 100% (95% confidence interval: 79.4%-100%) and 93.7% (95% confidence interval: 69.8%-99.8%), respectively. In patients with latent TB infection or active TB, there was no correlation between age and antigen-stimulated interferon-γ responses (r = -0.044; P = 0.714). CONCLUSIONS: In young BCG-unvaccinated children with recent TB contact, a dual testing strategy using TST and QFT-GIT in parallel may not be necessary. However, TST+/QFT-GIT- discordance is common, and it remains uncertain if this constellation indicates TB infection or not. In active TB, QFT-GIT assays do not perform better than TSTs.

11.
J Acquir Immune Defic Syndr ; 79(2): 269-276, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30211778

RESUMO

BACKGROUND: Future strategies aiming to achieve HIV-1 remission are likely to target individuals with small reservoir size. SETTING: We retrospectively investigated factors associated with HIV-1 DNA levels in European, perinatally HIV-infected children starting antiretroviral therapy (ART) <6 months of age. METHODS: Total HIV-1 DNA was measured from 51 long-term suppressed children aged 6.3 years (median) after initial viral suppression. Factors associated with log10 total HIV-1 DNA were analyzed using linear regression. RESULTS: At ART initiation, children were aged median [IQR] 2.3 [1.2-4.1] months, CD4% 37 [24-45] %, CD8% 28 [18-36] %, log10 plasma viral load (VL) 5.4 [4.4-5.9] copies per milliliter. Time to viral suppression was 7.98 [4.6-19.3] months. After suppression, 13 (25%) children had suboptimal response [≥2 consecutive VL 50-400 followed by VL <50] and/or experienced periods of virological failure [≥2 consecutive VL ≥400 followed by VL <50]. Median total HIV-1 DNA was 43 [6195] copies/10 PBMC. Younger age at therapy initiation was associated with lower total HIV-1 DNA (adjusted coefficient [AC] 0.12 per month older, P = 0.0091), with a month increase in age at ART start being associated with a 13% increase in HIV DNA. Similarly, a higher proportion of time spent virally suppressed (AC 0.10 per 10% higher, P = 0.0022) and the absence of viral failure/suboptimal response (AC 0.34 for those with fail/suboptimal response, P = 0.0483) were associated with lower total HIV-1 DNA. CONCLUSIONS: Early ART initiation and a higher proportion of time suppressed are linked with lower total HIV-1 DNA. Early ART start and improving adherence in perinatally HIV-1-infected children minimize the size of viral reservoir.

12.
Pediatr Infect Dis J ; 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30199483

RESUMO

BACKGROUND: Detection of cytomegalovirus (CMV) DNA by real-time polymerase chain reaction (rt-PCR) in dried blood spots (DBS) collected for newborn screening has been assessed for retrospective diagnosis of congenital CMV (cCMV) infection, with variable results (sensitivities ranging from 34% to 100%). We aimed to assess the accuracy of this technique in Spain in a large patient series. METHODS: Ambispective, multicenter study including patients with confirmed cCMV from the Spanish Registry of cCMV patients (REDICCMV). cCMV was established on the presence of CMV DNA in any body fluid, by positive culture findings, or by molecular techniques during the first 2 weeks of life. Children in whom cCMV had been excluded were used as negative controls. Neonatal DBS samples were collected from both groups. The presence of CMV DNA was assessed by rt-PCR (RealStar CMV, Altona, Hamburg, Germany) in a central laboratory. RESULTS: One-hundred and three patients and 81 controls from 10 hospitals were included. The performance of CMV DNA determination in DBS for the diagnosis of cCMV was as follows (95% CI): sensitivity 0.56 (0.47-0.65), specificity 0.98 (0.91-0.99), positive likelihood ratio 22.81 (5.74-90.58), negative likelihood ratio 0.45 (0.36-0.56). Sensitivity increased with the birth viral load (bVL) log category. In cCMV patients, lower bVL was the single variable associated with a negative DBS rt-PCR result (p=0.017). CONCLUSION: The sensitivity of CMV rt-PCR in DBS in our series was low and correlated with the bVL. Thus, a negative DBS result would not rule out cCMV infection, especially in patients with a low viremia level at birth.

13.
J Clin Immunol ; 38(6): 712-716, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30039354

RESUMO

PURPOSE: Mendelian suceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing to severe disease caused by mycobacteria and other intracellular pathogens. Delay in diagnosis can have an impact on the patient's prognosis. METHODS: We evaluated the IFN-γ circuit by studying IFN-γ production after mycobacterial challenge as well as IL-12Rß1 expression and STAT4 phosphorylation in response to IL-12p70 stimulation in whole blood of a 6-year-old Peruvian girl with disseminated recurrent mycobacterial infection diagnosed as multidrug-resistant tuberculosis. Genetic studies with Sanger sequencing were used to identify the causative mutation. Microbiological studies based on PCR reactions were used to diagnose the specific mycobacterial species. RESULTS: We identified a homozygous mutation in the IL12RB1 gene (p. Arg211*) causing abolished expression of IL-12Rß1 and IL-12 response. MSMD diagnosis led to a microbiological reevaluation of the patient, revealing a BCG vaccine-related infection instead of tuberculosis. Treatment was then adjusted, with good response. CONCLUSIONS: We report the first Peruvian patient with IL-12Rß1 deficiency. Specific mycobacterial species diagnosis within Mycobacterium tuberculosis complex is still challenging in countries with limited access to PCR-based microbiological diagnostic techniques. Awareness of MSMD warning signs and accurate microbiological diagnosis of mycobacterial infections are of the utmost importance for optimal diagnosis and management of affected patients.

14.
Artigo em Inglês | MEDLINE | ID: mdl-29957674

RESUMO

BACKGROUND: Future strategies aiming to achieve HIV-1 remission are likely to target individuals with small reservoir size. SETTING: We retrospectively investigated factors associated with HIV-1 DNA levels in European, perinatally HIV-infected children starting ART <6 months of age. METHODS: Total HIV-1 DNA was measured from 51 long-term suppressed children 6.3 years (median) after initial viral suppression. Factors associated with log10 total HIV-1 DNA were analyzed using linear regression. RESULTS: At ART initiation, children were aged median [IQR] 2.3 [1.2,4.1] months, CD4% 37 [24,45] %, CD8% 28 [18,36] %, log10 plasma viral load (VL) 5.4 [4.4,5.9] copies/ml. Time to viral suppression was 7.98 [4.6,19.3] months. Following suppression, 13 (25%) children had suboptimal response [≥2 consecutive VL50-400 followed by VL<50] and/or experienced periods of virological failure [≥2 consecutive VL≥400 followed by VL<50]. Median total HIV-1 DNA was 43 [6,195] copies/10 PBMC.Younger age at therapy initiation was associated with lower total HIV-1 DNA (adjusted coefficient [AC] 0.12 per month older, p=0.0091), with a month increase in age at ART start being associated with a 13% increase in HIV DNA. Similarly, a higher proportion of time spent virally suppressed (AC 0.10 per 10% higher, p=0.0022) and absence of viral failure/suboptimal response (AC 0.34 for those with fail/ suboptimal response, p=0.0483) were associated with lower total HIV-1 DNA. CONCLUSION: Early ART initiation and a higher proportion of time suppressed are linked with lower total HIV-1 DNA. Early ART start and improving adherence in perinatally HIV-1 infected children minimize the size of viral reservoir.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

15.
J Adv Nurs ; 2018 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-29726024

RESUMO

AIM: To evaluate the association of a new nursing intervention on the adherence to antituberculosis treatment in a paediatric cohort (<18 years). BACKGROUND: Tuberculosis remains a public health problem worldwide. The risk of developing tuberculosis after primary infection and its severity are higher in children. Proper adherence to antituberculosis treatment is critical for disease control. DESIGN: Nonrandomized controlled trial; Phase 1, retrospective (2011-2013), compared with Phase 2, prospective with intervention (2015-2016), in a referral centre for paediatric tuberculosis in Spain (NCT03230409). METHODS: A total of 359 patients who received antituberculosis drugs after close contact with a smear-positive patient (primary chemoprophylaxis) or were treated for latent tuberculosis infection or tuberculosis disease were included, 261 in Phase 1 and 98 in Phase 2. In Phase 2, a new nurse-led intervention was implemented in all patients and included two educational steps (written information in the child's native language and follow-up telephone calls) and two monitoring steps (Eidus-Hamilton test and follow-up questionnaire) that were exclusively carried out by nurses. RESULTS: Adherence to antituberculosis treatment increased from 74.7% in Phase 1% to 87.8% in Phase 2 (p = 0.014; Chi-square test), after the implementation of the nurse-led intervention. In Phase 2, nonadherence was only associated with being born abroad (28.6% vs. 7.8%; p = 0.019; Chi-square test) and with foreign origin families (27.3% vs. 0%; p < 0.0001; Chi-square test). CONCLUSION: The nurse-led intervention was associated to an increase in adherence to antituberculosis treatment. Immigrant-related variables remained major risk factors for sub-optimal adherence in a low-endemic setting.

19.
PLoS Med ; 15(1): e1002491, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29381702

RESUMO

BACKGROUND: Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand. METHODS AND FINDINGS: Children with perinatal HIV aged <18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. Rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for early/late (≤/>6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4-9.3) years; 35% of children aged <5 years had a CD4 lymphocyte percentage <15% in 1997-2003, which fell to 15% of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of children ≥5 years had a CD4 count <200 cells/mm3 in 1997-2003 and in 2011 onwards, respectively (p < 0.001). Median follow-up was 5.6 (2.9-8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43 (46%) and 100 (42%) were within 6 months of initiating cART, respectively. Multivariable predictors of early death were: being in the first year of life; residence in Russia, Ukraine, or Thailand; AIDS at cART start; initiating cART on a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen; severe immune suppression; and low BMI-for-age z-score. Current severe immune suppression, low current BMI-for-age z-score, and current viral load >400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time. CONCLUSIONS: In our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred ≤6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.

20.
Eur J Pediatr ; 177(9): 1377-1381, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29374831

RESUMO

Normal procalcitonin (PCT) levels have been reported in adult pulmonary tuberculosis (TB) but have not been previously investigated in children. We aimed to assess PCT levels at diagnosis of TB in young children in a low-burden setting. In a cross-sectional observational study in a referral pediatric center in Barcelona (Spain), we assessed the value of PCT and other inflammatory markers (leucocyte counts, C-reactive protein, and erythrocyte sedimentation rate) in the diagnosis of TB in pre-school children (< 6 years at diagnosis, n = 45), as compared with two control groups (pneumococcal pneumonia, n = 25; and healthy controls, n = 49). Normal PCT levels were observed at diagnosis of TB in most cases, while C-reactive protein values and leucocyte counts were slightly elevated when compared to healthy controls. All three inflammatory biomarkers were significantly higher in children with pneumococcal pneumonia. CONCLUSIONS: In our study, PCT was not a useful diagnostic test for TB in young children. In a low-burden TB setting, PCT may be of some value in distinguishing pulmonary TB from pneumococcal pneumonia. What is Known: • Diagnosis of pediatric tuberculosis on clinical evidence is difficult, particularly in infants and small children. • Studies in adults with tuberculosis have mostly reported normal procalcitonin levels at diagnosis. What is New: • In pre-scholars with tuberculosis, erythrocyte sedimentation rate and white blood cell counts were higher than in healthy controls, but procalcitonin was not. • Procalcitonin may be useful in the differential diagnosis of intrathoracic tuberculosis and pneumococcal pneumonia.


Assuntos
Calcitonina/sangue , Tuberculose Pulmonar/diagnóstico , Biomarcadores/sangue , Proteína C-Reativa , Pré-Escolar , Estudos Transversais , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Contagem de Leucócitos , Masculino , Espanha
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