Micafungin twice-a-week for prophylaxis of invasive Aspergillus infections in children with acute lymphoblastic leukaemia: A controlled cohort study.

OBJECTIVES: Invasive Aspergillus infections during the early phase of childhood acute lymphoblastic leukemia (ALL) treatment come with morbidity and mortality. The interaction with vincristine hampers first-line azole prophylaxis. We describe the efficacy of an alternative twice-a-week micafungin regimen for Aspergillus prophylaxis. METHODS: Newly diagnosed paediatric patients with ALL treated according to the ALL-11 protocol received micafungin twice-a-week (9 mg/kg/dose [max. 300 mg]) during the induction course (first 35 days of treatment) as part of routine care. A historical control cohort without Aspergillus prophylaxis was used. During the first consolidation course (day 36-79), standard itraconazole prophylaxis was used in both groups. The percentage of proven/probable Aspergillus infections during the induction/first consolidation course was compared between the cohorts. The cumulative incidence of proven/probable Aspergillus infections was estimated using a competing risk model. For safety evaluation, liver laboratory chemistry values were analysed. RESULTS: A total of 169 and 643 paediatric patients with ALL were treated in the micafungin cohort (median age: 4 years [range 1-17]) and historical cohort (median age: 5 years [range 1-17]). The percentage of proven/probable Aspergillus infections was 1·2% (2/169) in the micafungin cohort versus 5·8% (37/643) in the historical cohort (p=0.013; Fisher's exact test). The differences in estimated cumulative incidence were assessed (p=0·014; Gray's test). Although significantly higher ALT/AST values were reported in the micafungin cohort, no clinically relevant side effects were observed. CONCLUSIONS: Twice-a-week micafungin prophylaxis during the induction course significantly reduced the occurrence of proven/probable Aspergillus infections in the early phase of childhood ALL treatment.

The Dutch Working Party on Antibiotic Policy (SWAB) Recommendations for the Diagnosis and Management of Febrile Neutropenia in Patients with Cancer.

INTRODUCTION: This guideline was written by a multidisciplinary committee with mandated members of the Dutch Society for Infectious Diseases, Dutch Society for Hematology, Dutch Society for Medical Oncology, Dutch Association of Hospital Pharmacists, Dutch Society for Medical Microbiology, and Dutch Society for Pediatrics. The guideline is written for adults and pediatric patients. METHOD: The recommendations are based on the answers to nine questions formulated by the guideline committee. To provide evidence-based recommendations we used all relevant clinical guidelines published since 2010 as a source, supplemented with systematic searches and evaluation of the recent literature (2010-2020) and, where necessary, supplemented by expert-based advice. RESULTS: For adults the guideline distinguishes between high- and standard-risk neutropenia based on expected duration of neutropenia (> 7 days versus ≤ 7 days). Where possible a distinction has been made between pediatric and adult patients. CONCLUSION: This guideline was written to aid diagnosis and management of patients with febrile neutropenia due to chemotherapy in the Netherlands. The guideline provides recommendation for children and adults. Adults patient are subdivided as having a standard- or high-risk neutropenic episode based on estimated duration of neutropenia. The most important recommendations are as follows. In adults with high-risk neutropenia (duration of neutropenia > 7 days) and in children with neutropenia, ceftazidime, cefepime, and piperacillin-tazobactam are all first-choice options for empirical antibiotic therapy in case of fever. In adults with standard-risk neutropenia (duration of neutropenia ≤ 7 days) the MASCC score can be used to assess the individual risk of infectious complications. For patients with a low risk of infectious complications (high MASCC score) oral antibiotic therapy in an outpatient setting is recommended. For patients with a high risk of infectious complications (low MASCC score) antibiotic therapy per protocol sepsis of unknown origin is recommended.

Comparison of antibiotic dosing recommendations for neonatal sepsis from established reference sources.

Background Incorrect dosing is the most frequent prescribing error in neonatology, with antibiotics being the most frequently prescribed medicines. Computer physician order entry and clinical decision support systems can create consistency contributing to a reduction of medication errors. Although evidence-based dosing recommendations should be included in such systems, the evidence is not always available and subsequently, dosing recommendations mentioned in guidelines and textbooks are often based on expert opinion. Objective To compare dosage recommendations for antibiotics in neonates with sepsis provided by eight commonly used and well-established international reference sources. Setting An expert team from our Dutch tertiary care neonatal intensive care unit selected eight well-established international reference sources. Method Daily doses of the seven most frequently used antibiotics in the treatment of neonatal sepsis, classified by categories for birth weight and gestational age, were identified from eight well-respected reference sources in neonatology/pediatric infectious diseases. Main outcome measure Standardized average daily dosage. Results A substantial variation in dosage recommendations of antibiotics for neonatal sepsis between the reference sources was shown. Dosage recommendations of ampicillin, ceftazidime, meropenem and vancomycin varied more than recommendations for benzylpenicillin, cefotaxime and gentamicin. One reference source showed a larger variation in dosage recommendations in comparison to the average recommended daily dosage, compared to the other reference sources. Conclusion Antibiotic dosage recommendations for neonates with sepsis can be derived from important reference sources and guidelines. Further exploration to overcome variation in dosage recommendations is necessary to obtain standardized dosage regimens.

[Tularaemia in a boy following participation in a mud race]. / Een jongen met tularemie na een modderrace.

BACKGROUND: Tularaemia is a rare disease. In Europe it mostly occurs in Scandinavia. Since 2011 more cases are being reported in the Netherlands. Tularaemia may manifest itself in various ways. It is important to take strict precautions during biopsy, drainage and biopsy processing in order to prevent transmission. CASE DESCRIPTION: A 10-year-old boy presented to the paediatrician with a left inguinal lymphadenitis. A week before the onset of symptoms he had participated in a children's mud race. Serology and PCR of pus from the lymph node tested positive for Francisella tularensis. Treatment with ciprofloxacin was insufficiently effective, so surgical drainage of the gland was performed under strict isolation conditions. Water from the mud race location contained genetic material from F. tularensis. CONCLUSION: Given the rising incidence of tularaemia in the Netherlands, it is important to consider 'tularaemia' in the differential diagnosis in patients with lymphadenitis and epidemiological clues in their case history. Since 1 November 2016 it has been mandatory to report tularaemia in the Netherlands.

[Cutaneous leishmaniasis in a Syrian refugee]. / Cutane leishmaniasis bij een Syrische vluchteling.

BACKGROUND: Cutaneous leishmaniasis is rare in the Netherlands, but it is endemic to Syria. The disease can manifest itself many years after initial exposure. Given the arrival of Syrian refugees in the Netherlands, awareness of this disease entity is warranted. CASE DESCRIPTION: A 5-year-old boy from Syria had investigations for hepatosplenomegaly. As an incidental finding a solitary, moderately demarcated, erythematous plaque was noted on his right cheek. It measured 4 × 2 cm and had a central haemorrhagic, exudative, honey-yellow slough. Due to the hepatosplenomegaly, as well as cutaneous leishmaniasis we also included its visceral form in the differential diagnosis. Additional investigations confirmed the diagnosis of cutaneous leishmaniasis. CONCLUSION: Given the rising incidence of leishmaniasis in Syria, the diagnosis of cutaneous leishmaniasis should be considered in a Syrian refugee who has an ulcerating nodule or plaque. A timely local treatment may improve long-term cosmetic outcome.

Urine is superior to saliva when screening for postnatal CMV infections in preterm infants.

BACKGROUND: Cytomegalovirus (CMV) is the most frequently contracted virus in preterm infants. Postnatal infection is mostly asymptomatic but is sometimes associated with severe disease. To diagnose an infection, urine or saliva samples can be tested for CMV-DNA by real-time polymerase chain reaction (rtPCR). Although the diagnostic accuracy of testing saliva samples has not been determined in preterm infants, saliva is widely used because it is easier to obtain than urine. OBJECTIVES: To determine whether screening of saliva is equivalent to urine to detect a postnatal CMV infection in preterm infants. STUDY DESIGN: Between 2010 and 2013 saliva and urine samples were collected from infants admitted to the Neonatal Intensive Care Unit of the University Medical Center Utrecht and born with a gestational age (GA) below 32 weeks. Urine samples were obtained within three weeks after birth and urine and saliva samples at term equivalent age (40 weeks GA) and tested for CMV-DNA by rtPCR. Infants with a congenital CMV infection were excluded. RESULTS: Of 261 preterm infants included in the study, CMV-DNA was detected in urine of 47 and in saliva of 43 children. Of 47 infants with postnatal CMV infection, CMV was detected in 42 saliva samples (sensitivity 89.4%; CI 76.9-96.5). Of 214 children without postnatal CMV infection, one saliva sample tested positive for CMV (specificity 99.5%; CI 97.4-99.9). CONCLUSIONS: Screening saliva for CMV-DNA by rtPCR is inferior to urine to diagnose postnatal CMV infections in preterm infants.

Predictors of invasive fungal infection in pediatric allogeneic hematopoietic SCT recipients.

This study was aimed at finding predictors of invasive fungal infection (IFI) after pediatric allogeneic hematopoietic SCT (HSCT). All children who received allogeneic HSCT in the Wilhelmina Children's Hospital Utrecht between 2004 and 2012 were included. HSCT data were prospectively collected. Patients were retrospectively classified into high- or low-risk groups for developing IFI using criteria based on available literature. Predictors for the occurrence of IFI were analyzed using Cox regression models. We used logistic regression models to analyze the association between other HSCT-related complications and IFI. Secondary outcomes were overall survival and treatment-related mortality (TRM). Two-hundred nine patients were included in the analysis; median age was 6.6 years. The cumulative incidence of IFI was 12%. In patients classified as 'low risk' (n=75), only 5.3% developed IFI (odds ratio (OR): 0.325; P=0.047). In multivariate analysis, a predictor for the occurrence of IFI was an a priori determined HSCT TRM risk >20% (based on EBMT-risk score). Post-HSCT, the administration of high-dose steroids was associated with IFI (OR: 4.458; P=0.010). Patients who developed IFI showed an increased risk of TRM (OR: 3.773; P=0.004). These results confirm that risk group stratification should guide intensity of monitoring for IFI and use of antifungal prophylaxis.

Initial Pseudomonas aeruginosa infection in patients with cystic fibrosis: characteristics of eradicated and persistent isolates.

Despite intensive eradication therapy, some CF patients with early Pseudomonas aeruginosa infection rapidly develop a chronic infection. To elucidate factors associated with this persistence, bacterial characteristics of early P. aeruginosa isolates were analysed that were either eradicated rapidly or persisted despite multiple antimicrobial treatments. Eighty-six early infection episodes were studied. First P. aeruginosa isolates from patients with eradication (36) or persistent infection (16) were included; isolates from patients with intermittent infection (34) were omitted from the study. Virulence assays, antimicrobial resistance, cytotoxicity and mutation frequencies were analysed in vitro. P. aeruginosa was genotyped by SNP-array. Transcriptomic profiles of two eradicated and two persistent strains were compared. Nineteen per cent of patients developed persistent infection; 42% achieved eradication. Secretion of virulence factors and mutation frequencies were highly variable among both eradicated and persistent isolates and were not different between the groups. Cytotoxicity was present in 57% of eradicated vs. 100% of persistent isolates (p <0.01). None of the isolates were resistant to antibiotics. The isolates were genotypically highly diverse. Multivariate analysis showed that in vitro determined bacterial characteristics could not predict persistence after first P. aeruginosa infection. Preliminary transcriptomic data showed increased expression of some genes related to a metabolic pathway. The early onset of chronic infection was not associated with (in vitro determined) bacterial characteristics only. Although the persistent isolates were more often cytotoxic, for the individual patient it was not possible to predict the risk of persistence based on bacterial characteristics. Unknown factors such as host-pathogen and pathogen-pathogen interactions should be further explored.

Bordetella species in children with cystic fibrosis: what do we know? The role in acute exacerbations and chronic course.

Despite vaccination, pertussis is still endemic in the Netherlands. A literature search was performed to verify what is known about the role of Bordetella species in children with cystic fibrosis, with regard to the incidence of Bordetella infections, the involvement in pulmonary exacerbations and the influence on chronic course. Little is known about the frequency of Bordetella infections and the involvement of Bordetella species both in relation to the chronic course of cystic fibrosis and to pulmonary exacerbations. Since it is difficult to detect Bordetella species in cultures and few sputum cultures investigated have been obtained during an exacerbation, it is likely that the frequency of Bordetella species in CF patients is underestimated. Identification of Bordetella species in these patients may have serious consequences for the treatment of exacerbations in CF. Future research investigating the role of Bordetella species in cystic fibrosis should use specific techniques to detect Bordetella in cultures.

Clinical impact of a highly prevalent Pseudomonas aeruginosa clone in Dutch cystic fibrosis patients.

Studies suggest that infection with highly prevalent Pseudomonas aeruginosa clones in cystic fibrosis (CF) is associated with an unfavourable clinical outcome. We studied the clinical characteristics of patients infected with a recently described, highly prevalent P. aeruginosa clone (ST406) in two CF centres in The Netherlands. Multilocus sequence typing data were available for 219 patients, of whom 40 (18.3%) were infected with ST406 and 179 with other sequence types. ST406 infection was independently associated with age, having a sibling with ST406 infection and use of inhaled antibiotics, but not with unfavourable clinical outcome, suggesting that high transmissibility is not necessarily associated with high virulence.

Aspergillus fumigatus colonization in cystic fibrosis: implications for lung function?

Aspergillus fumigatus is commonly found in the respiratory secretions of patients with cystic fibrosis (CF). Although allergic bronchopulmonary aspergillosis (ABPA) is associated with deterioration of lung function, the effects of A. fumigatus colonization on lung function in the absence of ABPA are not clear. This study was performed in 259 adults and children with CF, without ABPA. A. fumigatus colonization was defined as positivity of >50% of respiratory cultures in a given year. A cross-sectional analysis was performed to study clinical characteristics associated with A. fumigatus colonization. A retrospective cohort analysis was performed to study the effect of A. fumigatus colonization on lung function observed between 2002 and 2007. Longitudinal data were analysed with a linear mixed model. Sixty-one of 259 patients were at least intermittently colonized with A. fumigatus. An association was found between A. fumigatus colonization and increased age and use of inhaled antibiotics. In the longitudinal analysis, 163 patients were grouped according to duration of colonization. After adjustment for confounders, there was no significant difference in lung function between patients colonized for 0 or 1 year and patients with 2-3 or more than 3 years of colonization (p 0.40 and p 0.64) throughout the study. There was no significant difference in lung function decline between groups. Although colonization with A. fumigatus is more commonly found in patients with more severe lung disease and increased treatment burden, it is not independently associated with lower lung function or more severe lung function decline over a 5-year period.

Challenging and emerging pathogens in cystic fibrosis.

Cystic fibrosis (CF) lung disease is characterised by chronic inflammation and infection. Patients are predominantly infected by specific pathogens, of which Staphylococcus aureus and Pseudomonas aeruginosa are the most important. In recent years however there has been an increasing number of reports on potentially emerging and challenging pathogens like Stenotrophomonas maltophilia, Non-tuberculous mycobacteria, highly prevalent P. aeruginosa clones, methicillin resistant Staphylococcus aureus and Burkholderia cepacia. Also, a role for viral infections in the pathogenesis of CF lung disease has increasingly been recognised. It is not always clear whether or how these pathogens influence the progression of CF lung disease and how they should be treated. In this review, the epidemiology and clinical impact of these pathogens is discussed. Furthermore, treatment strategies of these pathogens in a CF setting are reviewed.

Transmission of respiratory syncytial virus at the paediatric intensive-care unit: a prospective study using real-time PCR.

Transmission of respiratory syncytial virus (RSV) from children with lower respiratory tract infection (LRTI) at a paediatric intensive-care unit (PICU) was examined using a highly sensitive real-time PCR. Twenty-four children with RSV LRTI were admitted during the study period (total days of potential transmission: 239). Forty-eight RSV-negative patients were followed up for RSV acquisition every 5 days (total days of exposure: 683). No single RSV transmission was documented with this highly sensitive diagnostic method. Therefore, routine infection control measures of LRTI patients seem to be adequate to prevent RSV transmission at the PICU.

Pseudomonas aeruginosa diversity in distinct paediatric patient groups.

Pseudomonas aeruginosa is a pathogen that often infects patients who are either immunocompromised or have local defects in host defences. It is known that cystic fibrosis (CF) patients are sometimes infected with certain clonal isolates. It is not clear whether these clonal isolates also infect non-CF patients and whether clonality of isolates occurs in other patient groups. The aim of this study was to investigate P. aeruginosa diversity and the occurrence of clones within five distinct paediatric patient groups susceptible to P. aeruginosa infection. P. aeruginosa isolates were cultured from 157 patients (CF first infection (CF-1 group) (29); CF chronic infection (CF-chronic group) (27); urinary tract infection (34); chronic suppurative otitis media (43); and intensive-care hospitalization/immunodeficiency (24)). All 202 phenotypically different isolates were tested for antimicrobial resistance and further typed by pulsed-field gel electrophoresis. Simpson's diversity index was calculated for the five groups. CF-chronic patients carried the highest number of distinct P. aeruginosa phenotypes and genotypes per culture. Isolates from the CF-chronic group were significantly less diverse than those from the other groups. A group of clonal isolates was observed among patients from the CF-chronic and CF-1 groups. These or different clonal isolates were not encountered among the three other patient groups. No characteristic resistance pattern could be identified among isolates from the distinct patient groups and among the clonal isolates. In conclusion, isolates of the CF-chronic group were less diverse than those in the other patient groups with P. aeruginosa infection; clonal isolates were not encountered in non-CF patients. Transmission of clonal CF isolates to other patient groups was not observed.

Loss of antibodies and response to (re-)vaccination in children after treatment for acute lymphocytic leukemia: a systematic review.

Intensified chemotherapy regimens resulting in improved survival of children with acute lymphocytic leukemia (ALL) lead to concerns about therapy-induced immune damage reflected by the loss of protection of previous immunizations and the efficacy of (re-)vaccination. The severity of secondary immunodeficiency, however, is not clear and knowledge is based on a limited number of studies. We performed a systematic review on literature concerning vaccination data of children with ALL published since 1980. Eight studies fulfilled the inclusion criteria. Regarding antibody titers after treatment, the number of children who had preserved the defined protection level for antibodies differed widely, ranging from 17 to 98% for diphtheria, 27 to 82% for Bordetella pertussis, 20 to 98% for tetanus, 62 to 100% for poliomyelitis, 35 to 100% for Haemophilus influenzae type B (HiB), 29 to 92% for mumps, 29 to 60% for measles and 72 to 92% for rubella. Most patients however responded to revaccination, demonstrating immunological recovery. Although the designs and results of the included studies varied widely, it can be concluded that cytostatic therapy for ALL in children results in a temporarily reduction of specific antibody levels. Memory is preserved but revaccination may be warranted. This is the first systematic review and the best possible current approximation of chemotherapy-induced immune damage in children after ALL treatment.

Diagnostic value of serological tests against Pseudomonas aeruginosa in a large cystic fibrosis population.

BACKGROUND: Serological methods to monitor Pseudomonas aeruginosa colonisation in patients with cystic fibrosis (CF) are advocated but the diagnostic value of a commercially available P aeruginosa antibody test to detect early and chronic P aeruginosa colonisation in a non-research setting has not been assessed. METHODS: Colonisation with P aeruginosa was estimated by regular culture of sputum or oropharyngeal swabs during three consecutive years in 220 patients with CF aged 0-65 years. Commercially available ELISA tests with three P aeruginosa antigens (elastase, exotoxin A, alkaline protease) were performed at the end of the study period. In a subgroup of 57 patients (aged 4-14 years) serological tests were performed annually. RESULTS: Using culture as the reference standard, the ELISA tests using the advised cut off values had a sensitivity of 79% and a specificity of 89% for chronic colonisation. Receiver-operator characteristic curves were created to optimise cut off values. Applying these new cut off values resulted in a sensitivity of 96% and a specificity of 79%. All three individual serological tests discriminated well between the absence and presence of chronic P aeruginosa colonisation. The sensitivity of the individual antibody test was 87% for elastase, 79% for exotoxin A, and 76% for alkaline protease. First colonisation was preceded by positive serological results in only five of 13 patients (38%). CONCLUSION: In patients with CF, serological tests using specific antigens are sensitive for diagnosing chronic P aeruginosa colonisation. However, the failure of serological tests to detect early colonisation in young patients emphasises the need for continued reliance on cultures.

[Three children with recurrent meningitis as the result of an anatomical defect]. / Drie kinderen met recidiverende meningitis als gevolg van een anatomische afwijking.

Three children, a 12-year-old girl, a 5-year-old boy and a 5-year-old girl, were referred with recurrent episodes of meningitis. After an immunological defect had been ruled out early in the diagnostic work-up, the cause appeared to be an anatomical defect. After surgical treatment, no further meningitis occurred. Recurrent meningitis in children is rare. Anatomical defects, congenital or acquired, in the otorhinolaryngological area are the main cause. Conscientious history taking, careful physical examination and imaging using high-definition cranial computed tomography are important in establishing the diagnosis. In order to minimise the risk of another episode of meningitis, the otorhinolaryngologist should be consulted immediately in the diagnostic and therapeutic process and this process should be completed as soon as possible.