Teresa del Rosal

Treatment of symptomatic congenital cytomegalovirus infection beyond the neonatal period

BACKGROUND Congenital cytomegalovirus (CMV) is an important cause of sensorineural hearing loss. Ganciclovir treatment in the neonatal period may prevent hearing deterioration in infants with central nervous system (CNS) involvement. However, there are hardly any data regarding antiviral treatment begun beyond the neonatal period. OBJECTIVES To describe the hearing outcome of infants with congenital CMV infection and CNS involvement treated beyond the neonatal period. To assess the tolerability and toxicity of prolonged valganciclovir treatment in these patients. STUDY DESIGN Retrospective case series of infants with congenital CMV infection and CNS involvement who started antiviral treatment beyond the neonatal period in Spain between 2008 and 2010. Hearing was tested by brainstem-evoked response at the time of diagnosis, 6 and 12 months after the beginning of treatment. RESULTS Thirteen cases were included. All received oral valganciclovir, and 4 also intravenous ganciclovir. Median valganciclovir treatment duration was 6 months and it was well tolerated. Six patients developed neutropenia, none requiring granulocyte colony-stimulating factor. Eleven children (85%) had hearing defects at baseline, compared to 50% at 12 months. By ears, 18 ears showed hearing loss at baseline (7 mild, 3 moderate, 8 severe). At 12 months, 9 remained stable, 7 had improved and none had worsened. In 8 normal ears at baseline, no deterioration was found at 12 months. CONCLUSIONS Valganciclovir treatment is well tolerated. It may improve or preserve the auditory function of congenitally cytomegalovirus-infected patients treated beyond the neonatal period for at least one year after the beginning of antiviral treatment.

Impact of immigration on pulmonary tuberculosis in Spanish children: a three-decade review.

Background: Tuberculosis causes significant morbidity and mortality worldwide. In the last years, international travel and immigration have led to important changes in the epidemiology of this disease. Drug resistance has emerged as an important threat to tuberculosis control. Data regarding the impact of immigration and the incidence of drug-resistant strains in children are lacking. Methods: Retrospective review of patients diagnosed with pulmonary tuberculosis at La Paz Childrens Hospital in a 30-year period. Data were collected with regard to the clinical, radiologic, microbiologic, and demographic characteristics of patients, and data from the 3 decades of the study were compared using &khgr;2 test and Fisher exact test. Results: A total of 507 cases of tuberculosis were identified, 414 of which had pulmonary involvement. During the study, there was a significant decrease in tuberculous meningitis: 10.4% in 1978–1987, 5.6% in 1988–1997, and 2.9% in 1998–2007 (P < 0.05). The most frequent reason for a consultation was case contact investigation. The adult source case was identified in 64% of patients. We observed an increase in extrafamilial contacts (8% in 1978–1987 and 18% in 1998–2007, P < 0.01), including 4 cases of immigrant caretakers. Tuberculosis in immigrant children has increased with time: 2% in the period 1978–1987, 6% in 1988–1997, and 46% in 1998–2007 (P < 0.001). The primary resistance rate to isoniazid in our population was 6.5%. Conclusions: Tuberculosis in our area continues to be a major health problem, especially among foreign-born children. As drug-resistant strains are increasing, initial therapy with 4 drugs is recommended in our population.

Successful treatment of childhood cutaneous leishmaniasis with liposomal amphotericin B: report of two cases.

Treatment of cutaneous leishmaniasis is sometimes difficult. No single ideal therapy has yet been identified and some of the drugs that are currently used are associated with significant toxicity. We present two cases of cutaneous leishmaniasis in children, one caused by Leishmania infantum and the other by Leishmania braziliensis. Both of them were successfully treated with intravenous liposomal amphotericin B.

Pandemic H1N1 influenza-associated hospitalizations in children in Madrid, Spain.

Please cite this paper as: del Rosal et al. (2011) Pandemic H1N1 influenza‐associated hospitalizations in children in Madrid, Spain. Influenza and Other Respiratory Viruses 5(6), e544–e551.

18F-FDG PET/CT in the diagnosis of occult bacterial infections in children

The role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the diagnosis and follow-up of infectious diseases has expanded recently. The aim of this report is to communicate our experience regarding its role in the diagnosis and management of occult bacterial infections in children. We present three pediatric patients with occult bacterial infections and negative conventional studies in whom 18F-FDG PET/CT had a significant effect on clinical management. One patient had streptococcal endocarditis and prolonged fever. 18F-FDG PET/CT identified pneumonia and osteomyelitis, and was also used to monitor therapeutic response. Other patient had a cerebrospinal shunt fluid infection. 18F-FDG PET/CT was used to determine the exact localization of infection and establish the best surgical approach. The last patient had fever of unknown origin. 18F-FDG PET/CT identified splenic abscesses, which were surgically treated. Conclusion: 18F-FDG PET/CT should be considered as a useful diagnostic tool in children with suspected bacterial infections, if conventional diagnostic imaging techniques have failed to yield positive results.

Prevention and treatment of fetal cytomegalovirus infection with cytomegalovirus hyperimmune globulin: a multicenter study in Madrid

Abstract Introduction: Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Data about the management of CMV infection in pregnant women are scarce, and treatment options are very limited. The aim of the study is to investigate the effectiveness of cytomegalovirus hyperimmune globulin (CMV-HIG) for the prevention and treatment of congenital CMV (cCMV) infection. Materials and methods: A retrospective observational study was conducted in three tertiary hospitals in Madrid. In the period 2009–2015, CMV-HIG (Cytotect® CP Biotest, Biotest) treatment was offered to all pregnant women with primary CMV infection and/or detection of CMV-DNA in amniotic fluid in participating centers. Women were divided into prevention and treatment groups (PG and TG, respectively). Those with primary CMV infection who had not undergone amniocentesis comprised the PG and received monthly CMV-HIG (100 UI/kg). If CMV-DNA was subsequently detected in amniotic fluid, one extra dose of CMV-HIG (200 UI/kg) was given 4 weeks after the last dose. Those women were considered to be part of the PG group despite detection of CMV-DNA in amniotic fluid. In the case of a negative result in CMV-DNA detection in amniotic fluid or if amniocentesis was not performed, monthly HIG was given up to the end of the pregnancy. Results: Thirty-six pregnant women were included. Median gestational age at birth was 39 weeks (interquartile range: 38–40) and two children (5.5%) were premature (born at 28 and 34 weeks’ gestation). Amniocentesis was performed in 30/36 (83.4%) pregnancies and CMV PCR was positive in 21 of them (70%). One fetus with a positive PCR in amniotic fluid that received one dose of HIG after amniocentesis presented a negative CMV-PCR in urine at birth, and was asymptomatic at 12 months of age. Twenty-four children were infected at birth, and 16/21 (76.2%) presented no sequelae at 12 months, while two (9.5%) had a mild unilateral hearing loss and three (14.3%) severe hearing loss or neurological sequelae. Seventeen women were included in the PG and 19 in the TG. In the PG 7/17 (41%) fetuses were infected, one pregnancy was terminated due to abnormalities in cordocentesis and one showed a mild hearing loss at 12 months of age. In the TG, 18/19 children (95%) were diagnosed with cCMV, while the remaining neonate had negative urine CMV at birth. Eight out of the 19 fetuses (42.1%) showed CMV related abnormalities in the fetal US before HIG treatment. Complete clinical assessment in the neonatal period and at 12 months of age was available in 16 and 15 children, respectively. At birth 50% were symptomatic and at 12 months of age, 4/15 (26.7%) showed a hearing loss and 3/15 (20%) neurologic impairment. Fetuses with abnormalities in ultrasonography before HIG presented a high risk of sequelae (odds ratios: 60; 95%CI: 3–1185; p = .007). Discussion: Prophylactic HIG administration in pregnant women after CMV primary infection seems not to reduce significantly the rate of congenital infection, but is safe and it could have a favorable effect on the symptoms and sequelae of infected fetuses. The risk of long-term sequelae in fetuses without US abnormalities before HIG is low, so it could be an option in infected fetuses with normal imaging. On the other hand, the risk of sequelae among infected fetuses with abnormalities in fetal ultrasonography before HIG despite treatment is high.

Enterovirus neurological disease and bacterial coinfection in very young infants with fever

BACKGROUND Very little information exists on simultaneous infections by viruses and bacteria in infants with fever without source (FWS). OBJECTIVES To investigate the incidence of bacterial coinfection in infants up to 3 months of age with neurological viral infection. STUDY DESIGN Prospective study performed in infants below 90 days of age attending the emergency room of two public hospitals in Spain for FWS. Those who had viral screening performed in CSF, together with blood, CSF and urine cultures were included. Herpes virus, EV and HPeV detection in CSF was performed by PCR. Coinfections between viruses in CSF and serious bacterial infections were described. RESULTS 119 Infants less than 90 days of age were recruited. Forty-five (38%) had viral infection of the central nervous system, and in 8 of them (17.7%) we found a concurrent bacterial infection: 7 urinary tract infections (UTI) and 1 sepsis. In all cases, the virus identified in CSF was EV. CONCLUSIONS Bacterial infections were frequent in young infants with viral neurological infections associated to EV. Urinary tract infection was the most common bacterial disease.

Cytomegalovirus DNA Detection by Polymerase Chain Reaction in Cerebrospinal Fluid of Infants With Congenital Infection: Associations With Clinical Evaluation at Birth and Implications for Follow-up

Background DNA detection of human cytomegalovirus (hCMV) in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) is a marker of central nervous system (CNS) involvement in congenital hCMV infection (cCMV), but its prognostic value is unknown. Methods A multicenter, retrospective study was performed using the Spanish Congenital Cytomegalovirus Infection Database (REDICCMV; http://www.cmvcongenito.es). Newborns with cCMV and a lumbar puncture performed were included and classified according to their hCMV-PCR in CSF result (positive/negative). Clinical characteristics, neuroimaging abnormalities, plasma viral load, and audiological and neurological outcomes of both groups were compared. Results A total of 136 neonates were included in the study: 21 (15.4%) with positive CSF hCMV-PCR and 115 (84.6%) with negative results. Seventeen patients (81%) in the positive group were symptomatic at birth compared with 52.2% of infants in the negative group (odds ratio [OR], 3.86; 95% confidence interval [CI], 1.28-14.1; P = .01). Only 4 asymptomatic newborns (6.8%) had a positive CSF hCMV-PCR. There were no differences between groups regarding the rate of microcephaly, neuroimaging abnormalities, neurological sequelae at 6 months of age, or plasma viral load. Sensorineural hearing loss (SNHL) at birth was associated with a positive CSF hCMV-PCR result (OR, 3.49; 95% CI, 1.08-11.27; P = .04), although no association was found at 6 months of age. Conclusions A positive hCMV-PCR result in CSF is associated with symptomatic cCMV and SNHL at birth. However, no differences in neuroimaging studies, plasma viral load, or outcomes at 6 months were found. These results suggest that hCMV-PCR in CSF may not be a useful prognostic marker in cCMV.

18F-FDG PET/CT monitoring of non-tuberculous mycobacterial infection in a child with interleukin-12 receptor β-1 deficiency

We report a 6-year-old girl with interleukin-12 receptor β-1 (IL-12Rβ1) deficiency due to a homozygous deletion (g.1019_1020delAC) affecting codon His-339 in exon nine [1], and a mycobacterial infection by M.genavense with intestinal and mesenteric involvement, diagnosed by PCR in small bowel biopsy, with negative cultures and no antimicrobial susceptibility data. She received empirical treatment with oral rifampicin, ethambutol, clarithromycin and levofloxacin for 4 months, which was later modified to oral rifampicin and clarithromycin plus intravenous ciprofloxacin and amikacin for 9 months, combined with IFN-gamma-1b (Imukin®, Boehringer Ingelheim, Austria; initial dose of 50 mcg/m2 three times/week subcutaneously, which was later increased to 80 mcg/m2), with partial improvement. Persistence of active infection was confirmed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) (Fig. 1). Treatment was changed to intravenous clarithromycin, amikacin, ciprofloxacin, linezolid and cefoxitin and IFN-gamma-1b dose was progressively increased (up to 250mcg/m2 three times/ week), with significant clinical improvement after 3 months, confirmed by18F-FDG-PET/CT (Fig. 2). During the following 24 months, treatment response was assessed using 18F-FDG-PET/CT. PET/CT (Fig. 3), showing ongoing improvement that led to the progressive discontinuation of antimicrobial therapy after 36 months, with no further relapses reported in 18F-FDG-PET/CT performed 7 months after finishing therapy (Fig. 4). IL-12Rβ1 deficiency predisposes to severe mycobacterial infections, with a mortality rate of up to 52% [2]. 18F-FDG PET/CT is a useful tool for monitoring therapeutic response in mycobacterial infections, especially in immunocompromised patients, disseminated disease, drugresistant strains and unknown antimicrobial susceptibility. Serial 18F-FDG PET/CT allows evaluation of disease activity and extent of the infection, facilitates adjustment of potentially toxic therapies and guides therapeutic decisions, especially when other clinical markers are suboptimal to assess disease activity [3–5].

Clinical Features Before Hematopoietic Stem Cell Transplantation or Enzyme Replacement Therapy of Children With Combined Immunodeficiency.

Background: Survival of children with combined immunodeficiency is strongly related to patient’s age and clinical situation at the time of hematopoietic stem cell transplantation (HSCT). We describe the clinical features before HSCT or enzyme replacement therapy (ERT) in a cohort of children treated in a National Reference Unit. Methods: A retrospective study of children with CIDs treated in our Hospital during a 20-year period (1995–2014) was performed, analyzing their clinical situation before HSCT/ERT. Results: Thirty-one children were included. Risk factors such as family history or consanguinity were present in 35% of cases, but only 3 children (9%) were initially studied because of family history. Median ages at clinical onset, diagnosis and HSCT/ERT were 3.3, 5.6 and 8.1 months, respectively. All patients had lymphopenia before HSCT/ERT. At the time of admission to our unit, 68% of cases had abnormal lung auscultation, 72% were malnourished, 45% reported chronic gastroenteritis and 35% had hepatosplenomegaly. Before HSCT/ERT, respiratory infections and sepsis episodes were documented in 80% and 42% of cases, respectively. In 23% of children, a viral systemic infection was confirmed. The mortality rate was 35%, and 72% of children who died had Gram-negative bacterial sepsis or a viral infection. Conclusions: The present study shows the characteristics and outcome of children with CIDs in the absence of neonatal screening. Although all our patients had lymphopenia and most of them had suffered relevant infections or had a positive family history, these factors were not identified early. Respiratory and systemic viral infections were the main source of infection with important implications in clinical outcome. Our results highlight the importance of the implementation of neonatal screening, to improve survival rates.