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.

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.

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.

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.

[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.

[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.

[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.

Detection of Pseudomonas aeruginosa in patients with cystic fibrosis.

Chronic pulmonary colonisation with Pseudomonas aeruginosa (PA) in patients with CF is associated with a high morbidity and mortality. Adequate treatment of first acquisition of PA might prevent or postpone chronic colonisation. Early detection of PA is therefore of major importance. Currently, cultures of oropharynx or sputum are most commonly practised. However, oropharyngeal culture has limitations both in the positive and negative predictive value for the presence of PA in the lower respiratory tract. Induction of sputum has little benefit in detection of PA. Serology might have additional value in early detection, when bacterial density is too low to be detected by culture. Molecular techniques are not yet widespread used for detection of PA, but have in general a high sensitivity. In this review, we describe the value of different diagnostic techniques for detecting PA.

[Agranulocytosis induced by an antithyroid drug in a 14-year-old girl]. / Thyreostaticumgeïnduceerde agranulocytose bij een 14-jarig meisje.

A 14-year-old girl with Graves' disease developed a fever, sore throat and a severe systemic infection after being treated with antithyroid drugs for 1 year. Agranulocytosis was diagnosed. After long-term antibiotic treatment and supportive therapy she recovered. Agranulocytosis is a known side-effect of antithyroid drugs and is seen in 0.2 to 0.5% of the patients. It usually occurs within the first 3 months of treatment. Patients above the age of 40 seem to be more susceptible. Since the onset of agranulocytosis is relatively acute, routine blood monitoring is not very useful. It is more important to instruct patients who use a thyreostatic to contact their physician in case of unexplained fever or a sore throat.

[Three toddlers with a swelling in the neck]. / Drie peuters met een zwelling in de hals.

Three children, a girl aged 2.5 years and two boys aged 2 and 3 years respectively, presented with unilateral cervical lymphadenitis. The first patient had acute bacterial lymphadenitis due to group A Streptococcus, characterised by a painful cervical swelling of acute onset. The second patient had painless cervical lymphadenitis caused by Mycobacterium avium-intracellulare, which drained spontaneously. The third patient developed a non-tender, cervical swelling within a day. He too was systemically ill with fever and a headache. The lymphadenitis was caused by Bartonella henselae. After drainage, dissection and/or antibiotic therapy, all three recovered. A cervical mass in a young child is most frequently caused by an infectious lymphadenopathy. It rarely represents a malignant or other systemic disease. In many cases the diagnosis of infectious lymphadenitis can be made on the basis of the case history and clinical characteristics. However, when malignancy cannot be excluded tissue examination is always indicated.

[Serious invasive pneumococcal disease in young children: the importance of vaccination]. / Ernstige pneumokokkeninfecties bij jonge kinderen: het belang van vaccinatie.

In three children with fever, two girls aged 8 and almost 10 months and one boy aged 5 months, invasive pneumococcal disease was present. The youngest girl presented with pneumococcal sepsis which was complicated by haemolytic uraemic syndrome--she recovered--and the boy developed fulminant fatal pneumococcal sepsis/meningitis. The oldest girl was admitted for pneumococcal cellulitis and recovered. More than 80% of the cases of childhood invasive pneumococcal disease occur in children less than 2 years of age. However, the long available 23-valent pneumococcal polysaccharide vaccine is not effective in this age group. Recently, a 7-valent pneumococcal conjugate vaccine was registered in the Netherlands. This conjugate vaccine is effective in protecting infants and children from invasive pneumococcal disease. The Health Council of the Netherlands has recommended inclusion of the conjugate vaccine in the standard vaccine schedule. In the absence of a universal vaccination, the 7-valent pneumococcal conjugate vaccine is recommended for children at high risk of invasive disease.

[Fulminating pneumococcal septicemia in a 2 year old child with sickle cell anemia]. / Fulminant verlopende pneumokokkensepsis bij een 2-jarig kind met sikkelcelanemie.

A 2-year-old boy known with homozygous sickle cell anaemia became acutely ill at home. Despite intensive care, he died a few hours later due to pneumococcal septicaemia. In young children with homozygous sickle cell anaemia, spleen function is already severely impaired in childhood due to haemolysis and frequent vaso-occlusive episodes. These children therefore have an elevated susceptibility to severe invasive infections with encapsulated bacteria. Vaccination against pneumococci at-2 years of age, re-vaccination every 3-5 years, and antibiotic prophylaxis until 5 years of age, and thereafter with possible infections, are therefore necessary.

[Reduction of vertical transmission by means of perinatal prophylaxis in the case of children exposed to HIV-1 and born in the Netherlands during the period 1995-1999]. / Reductie van verticale transmissie door perinatale profylaxe bij aan HIV-1 geëxposeerde in Nederland geboren kinderen in de periode 1995-1999.

OBJECTIVE: Registration of the number of children born to HIV-infected mothers diagnosed prepartum and analysis of the efficacy of the policy for preventing mother-to-child transmission of HIV-1 in the period 1995 to 1999. DESIGN: Prospective. METHOD: On a monthly basis, Dutch paediatricians reported HIV-1 exposed children to the Dutch Paediatric Surveillance Unit. All reports were followed up with standard questionnaires. An additional retrospective study was performed because of incomplete registration. Paediatricians in centres for the care of HIV-infected patients were requested to retrospectively report HIV-exposed children. The standard questionnaires were submitted to these paediatricians. Data were collected during the period 1 January 1995-31 December 1999. RESULTS: The number of children known to be exposed to HIV-1 and for whom the mother was diagnosed prepartum, increased from 5 to 25 per year. The percentage of HIV-1 infected children decreased from 20% (1/5) to 4% (1/25). The number of pregnant HIV-1 infected women using highly active antiretroviral therapy increased during the study period from 0% (0/5) to 72% (18/25). Antiretroviral therapy was administered to 92% (23/25) of HIV-1 exposed children. In total 2% of the children received breastfeeding. CONCLUSION: Despite an increase in the number of children known to be exposed to HIV-1, a decrease in the percentage of HIV-1-infected children was observed. Of the children born in 1999 and known to be exposed to HIV-1, 4% were infected. Measures taken in the Netherlands to prevent mother-to-child transmission of HIV-1 infection are effective.

[Tetanus in a young unvaccinated girl after a fall in the street]. / Tetanus bij een jong ongevaccineerd meisje na een val op straat.

A 4-year-old girl developed tetanus after she had fallen on the street a week before. She had never been vaccinated and despite pressure from the family practitioner, the parents refused to allow her to be given human anti-tetanus immunoglobulin as a matter of principle after the wound had been stitched. Seven days later she was admitted to hospital with trismus and risus sardonicus. Upon initial treatment with human anti-tetanus immunoglobulin and penicillin, and subsequently metronidazole, her clinical condition deteriorated with opisthotonus and life-threatening respiratory insufficiency, upon which she was moved to the intensive-care department where she was intubated and mechanically ventilated for two weeks. Finally she made a complete clinical recovery. Thanks to the extensive national vaccination program, tetanus has become a rare disease in the Netherlands. However, the very serious course and possible fatal outcome warrant a keen attitude and adequate treatment.

[Pneumonia due to Legionella pneumophila in an immunocompromised child]. / Pneumonie bij een immuungecompromitteerd kind, veroorzaakt door Legionella pneumophila.

A one-year-and-seven-months-old boy was hospitalised because of fever, cough and general malaise. A diagnosed tonsillitis and pneumonia were treated with intravenous antibiotics. His clinical condition worsened despite antibiotic therapy. After immunologic investigations revealed both a cellular and a humoral immune disorder, a broncho-alveolar lavage was performed. The culture revealed Legionella pneumophila. Antibiotic treatment was then changed to erythromycin in combination with rifampicin, with a good response. Although rarely described in childhood, one should consider L. pneumophila as a possible pathogen in immunocompromised children presenting with pneumonia.

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.