[Febrile neutropenia in pediatric and adolescent cancer patients]. / Fieber während der Granulozytopenie bei krebskranken Kindern und Jugendlichen.

Febrile neutropenia is the most common potential emergency situation in children and adolescents with cancer. The host response of these patients is severely compromised by treatment-induced immunosuppression resulting in a lack of important defence mechanisms, so that bacterial infections and in certain risk groups also fungal infections can be life threatening. As the clinical course of these infectious complications may be rapid and fatal, early antibiotic treatment can save lives. This article aims to raise awareness to this emergency situation and gives an overview of the management of pediatric cancer patients with febrile neutropenia.

Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.

The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

Micafungin twice weekly as antifungal prophylaxis in paediatric patients at high risk for invasive fungal disease.

BACKGROUND: Current guidelines recommend antifungal prophylaxis for children at high risk for invasive fungal disease (IFD), but the use of polyenes and triazoles may not be feasible in some patients due to toxicities and drug-drug interactions. Micafungin is well tolerated, with intravenous daily dosing being the current standard. Recent reports indicate safety and efficacy of intermittent dosing of micafungin. METHODS: We analysed safety, efficacy and micafungin serum concentrations of children at high risk for IFD receiving prophylactic micafungin between 3 and 4 mg/kg twice weekly. All children were intolerant or had contraindications to polyenes and triazoles. RESULTS: A total of 21 children (median age = 9 years) at high risk for IFD were included in the analysis. No significant clinical adverse event occurred, and end of treatment values of parameters of renal and hepatic function in serum were not different from baseline. Proven or probable breakthrough IFD did not occur in any of the patients. In 9 out of 11 patients in whom plasma micafungin concentrations were assessed, the first trough concentration exceeded 150 ng/mL, a concentration proposed to be effective for prophylaxis. CONCLUSIONS: Our data indicate that micafungin administered twice weekly at a dosage of 3-4 mg/kg of bodyweight could be a convenient, safe and efficient alternative for antifungal prophylaxis in children at high risk for IFD.

Cerebral toxoplasmosis in an adolescent post allogeneic hematopoietic stem cell transplantation: successful outcome by antiprotozoal chemotherapy and CD4+ T-lymphocyte recovery.

Toxoplasmosis is a rare opportunistic infection in pediatric allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients and associated with severe T-cell deficiency. Here, we report the successful management of cerebral toxoplasmosis in a 15-year-old adolescent 4 months post allo-HSCT for non-Hodgkin lymphoma through rapid invasive diagnostics, long-term antiprotozoal chemotherapy, and an hematopoietic stem cell boost for persistently poor graft function. While supportive care and antiprotozoal chemotherapy achieved stabilization, definite improvement only occurred following recovery of CD4(+) T lymphocytes to >100 cells/µL. At 5 years after the diagnosis of toxoplasmosis, the patient is in continuing remission with normalized clinical and imaging findings.

Assessment of Aspergillus-specific PCR as a screening method for invasive aspergillosis in paediatric cancer patients and allogeneic haematopoietic stem cell recipients with suspected infections.

Invasive aspergillosis (IA) remains difficult to diagnose in immunocompromised patients, because diagnostic EORTC/MSG criteria are often not met. As biomarkers might elucidate the pathogen, we analysed the performance of an Aspergillus PCR assay in blood for diagnosis of IA in immunocompromised paediatric patients with suspected infections. Ninety-five haemato-oncological paediatric patients were included over a period of 3 years, the underlying diseases consisting of acute leukaemia, solid tumours, non-malignant immunocompromising disorders and haematopoietic stem cell transplantation recipients. We retrospectively analysed 253 consecutive episodes of suspected infections. Thirty-eight patients had possible IA, none of the patients fulfilled EORTC/MSG criteria of probable/proven IA. PCR positivity was observed in 97/967 analyses. Sensitivity, specificity, positive and negative predictive value of the PCR per episode were 34%, 78%, 31% and 81% using possible IA as endpoint. Taken together, an undirected blood screening by Aspergillus-specific PCR is of little diagnostic value in a heterogenous paediatric patient cohort. Harnessing PCR for diagnosis of IA should thus be focused on blood analyses of more homogenous high-risk patients and/or analyses of bronchoalveolar lavage, tissue or cerebrospinal fluid specimens.

ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: Fusarium spp., Scedosporium spp. and others.

Mycoses summarized in the hyalohyphomycosis group are heterogeneous, defined by the presence of hyaline (non-dematiaceous) hyphae. The number of organisms implicated in hyalohyphomycosis is increasing and the most clinically important species belong to the genera Fusarium, Scedosporium, Acremonium, Scopulariopsis, Purpureocillium and Paecilomyces. Severely immunocompromised patients are particularly vulnerable to infection, and clinical manifestations range from colonization to chronic localized lesions to acute invasive and/or disseminated diseases. Diagnosis usually requires isolation and identification of the infecting pathogen. A poor prognosis is associated with fusariosis and early therapy of localized disease is important to prevent progression to a more aggressive or disseminated infection. Therapy should include voriconazole and surgical debridement where possible or posaconazole as salvage treatment. Voriconazole represents the first-line treatment of infections due to members of the genus Scedosporium. For Acremonium spp., Scopulariopsis spp., Purpureocillium spp. and Paecilomyces spp. the optimal antifungal treatment has not been established. Management usually consists of surgery and antifungal treatment, depending on the clinical presentation.

ESCMID and ECMM joint clinical guidelines for the diagnosis and management of systemic phaeohyphomycosis: diseases caused by black fungi.

The aetiological agents of many invasive fungal infections are saprobes and opportunistic pathogens. Some of these fungi are darkly pigmented due to melanin production and traditionally have been named 'dematiaceous'. The melanized fungi cause a wide array of clinical syndromes ranging from superficial to deep-seated infections. Diagnosis relies on histopathological examination of clinical specimens and on examination of cultures. Sequencing is recommended for accurate species identification, especially for unusual or newly described pathogens. In cases of mycetoma and chromoblastomycosis, pathognomonic histological findings are useful and the Fontana-Masson stain, specific for melanin, usually confirms the diagnosis. There are no standardized therapies but voriconazole, posaconazole and itraconazole demonstrate the most consistent in vitro activity against this group of fungi. Oral itraconazole has been considered the drug of choice, given the extensive clinical experience with this drug. However, voriconazole may presumably be superior for central nervous system infections because of its ability to achieve good levels in the cerebrospinal fluid. Posaconazole is a well-tolerated alternative drug, backed by less clinical experience but with excellent salvage treatment results after failure of other antifungals. Amphotericin B has been useful as alternative therapy in some cases. Combination antifungal therapy is recommended for cerebral abscesses when surgery is not possible and for disseminated infections in immunocompromised patients.

ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013.

These European Society for Clinical Microbiology and Infectious Diseases and European Confederation of Medical Mycology Joint Clinical Guidelines focus on the diagnosis and management of mucormycosis. Only a few of the numerous recommendations can be summarized here. To diagnose mucormycosis, direct microscopy preferably using optical brighteners, histopathology and culture are strongly recommended. Pathogen identification to species level by molecular methods and susceptibility testing are strongly recommended to establish epidemiological knowledge. The recommendation for guiding treatment based on MICs is supported only marginally. Imaging is strongly recommended to determine the extent of disease. To differentiate mucormycosis from aspergillosis in haematological malignancy and stem cell transplantation recipients, identification of the reverse halo sign on computed tomography is advised with moderate strength. For adults and children we strongly recommend surgical debridement in addition to immediate first-line antifungal treatment with liposomal or lipid-complex amphotericin B with a minimum dose of 5 mg/kg/day. Amphotericin B deoxycholate is better avoided because of severe adverse effects. For salvage treatment we strongly recommend posaconazole 4×200 mg/day. Reversal of predisposing conditions is strongly recommended, i.e. using granulocyte colony-stimulating factor in haematological patients with ongoing neutropenia, controlling hyperglycaemia and ketoacidosis in diabetic patients, and limiting glucocorticosteroids to the minimum dose required. We recommend against using deferasirox in haematological patients outside clinical trials, and marginally support a recommendation for deferasirox in diabetic patients. Hyperbaric oxygen is supported with marginal strength only. Finally, we strongly recommend continuing treatment until complete response demonstrated on imaging and permanent reversal of predisposing factors.

Fatal human metapneumovirus infection following allogeneic hematopoietic stem cell transplantation.

Respiratory viruses are an important yet underestimated cause of infectious morbidity and mortality in immunocompromised children and adolescents. Here, we report the occurrence of fatal lower respiratory tract disease associated with human metapneumovirus (HMPV) infection in a 10-year-old girl with chronic graft-versus-host disease following allogeneic hematopoietic stem cell transplantation (HSCT) for secondary chronic myeloid leukemia. Symptoms occurred 8 months after HSCT while on immunosuppression with 0.2 mg/kg/day of prednisone, and presented as dry cough, bilateral pneumonitis, and progressive respiratory distress. Non-invasive and invasive microbiological investigations revealed HMPV type B as the sole pathogen. Histopathological findings showed interstitial and intra-alveolar pneumonitis with profound alveolar cell damage. The patient was treated with intravenous and oral ribavirin and polyvalent immunoglobulins, but ultimately died from respiratory failure. The case reflects the potentially fatal impact of infections by respiratory viruses in immunocompromised patients and the need for effective approaches to their prevention and treatment.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: developing European guidelines in clinical microbiology and infectious diseases.

The process to develop a guideline in a European setting remains a challenge. The ESCMID Fungal Infection Study Group (EFISG) successfully achieved this endeavour. After two face-to-face meetings, numerous telephone conferences, and email correspondence, an ESCMID task force (basically composed of members of the Society's Fungal Infection Study Group, EFISG) finalized the ESCMID diagnostic and management/therapeutic guideline for Candida diseases. By appreciating various patient populations at risk for Candida diseases, four subgroups were predefined, mainly ICU patients, paediatric, HIV/AIDS and patients with malignancies including haematopoietic stem cell transplantation. Besides treatment recommendations, the ESCMID guidelines provide guidance for diagnostic procedures. For the guidelines, questions were formulated to phrase the intention of a given recommendation, for example, outcome. The recommendation was the clinical intervention, which was graded by a score of A-D for the 'Strength of a recommendation'. The 'level of evidence' received a score of I-III. The author panel was approved by ESCMID, European Organisation for Research and Treatment of Cancer, European Group for Blood and Marrow Transplantation, European Society of Intensive Care Medicine and the European Confederation of Medical Mycology. The guidelines followed the framework of GRADE and Appraisal of Guidelines, Research, and Evaluation. The drafted guideline was presented at ECCMID 2011 and points of discussion occurring during that meeting were incorporated into the manuscripts. These ESCMID guidelines for the diagnosis and management of Candida diseases provide guidance for clinicians in their daily decision-making process.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.

This part of the EFISG guidelines focuses on non-neutropenic adult patients. Only a few of the numerous recommendations can be summarized in the abstract. Prophylactic usage of fluconazole is supported in patients with recent abdominal surgery and recurrent gastrointestinal perforations or anastomotic leakages. Candida isolation from respiratory secretions alone should never prompt treatment. For the targeted initial treatment of candidaemia, echinocandins are strongly recommended while liposomal amphotericin B and voriconazole are supported with moderate, and fluconazole with marginal strength. Treatment duration for candidaemia should be a minimum of 14 days after the end of candidaemia, which can be determined by one blood culture per day until negativity. Switching to oral treatment after 10 days of intravenous therapy has been safe in stable patients with susceptible Candida species. In candidaemia, removal of indwelling catheters is strongly recommended. If catheters cannot be removed, lipid-based amphotericin B or echinocandins should be preferred over azoles. Transoesophageal echocardiography and fundoscopy should be performed to detect organ involvement. Native valve endocarditis requires surgery within a week, while in prosthetic valve endocarditis, earlier surgery may be beneficial. The antifungal regimen of choice is liposomal amphotericin B +/- flucytosine. In ocular candidiasis, liposomal amphotericin B +/- flucytosine is recommended when the susceptibility of the isolate is unknown, and in susceptible isolates, fluconazole and voriconazole are alternatives. Amphotericin B deoxycholate is not recommended for any indication due to severe side effects.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT).

Fungal diseases still play a major role in morbidity and mortality in patients with haematological malignancies, including those undergoing haematopoietic stem cell transplantation. Although Aspergillus and other filamentous fungal diseases remain a major concern, Candida infections are still a major cause of mortality. This part of the ESCMID guidelines focuses on this patient population and reviews pertaining to prophylaxis, empirical/pre-emptive and targeted therapy of Candida diseases. Anti-Candida prophylaxis is only recommended for patients receiving allogeneic stem cell transplantation. The authors recognize that the recommendations would have most likely been different if the purpose would have been prevention of all fungal infections (e.g. aspergillosis). In targeted treatment of candidaemia, recommendations for treatment are available for all echinocandins, that is anidulafungin (AI), caspofungin (AI) and micafungin (AI), although a warning for resistance is expressed. Liposomal amphotericin B received a BI recommendation due to higher number of reported adverse events in the trials. Amphotericin B deoxycholate should not be used (DII); and fluconazole was rated CI because of a change in epidemiology in some areas in Europe. Removal of central venous catheters is recommended during candidaemia but if catheter retention is a clinical necessity, treatment with an echinocandin is an option (CII(t) ). In chronic disseminated candidiasis therapy, recommendations are liposomal amphotericin B for 8 weeks (AIII), fluconazole for >3 months or other azoles (BIII). Granulocyte transfusions are only an option in desperate cases of patients with Candida disease and neutropenia (CIII).

Candidaemia in a European Paediatric University Hospital: a 10-year observational study.

In this retrospective observational study covering 1998 to 2008, 32 patients (mean age: 7.50 years) were identified that had 35 episodes of candidaemia (0.47 cases/1000 hospital discharges). Cancer/allogeneic haematopoietic stem cell transplantation (43%) and congenital malformations/syndromes (21%) were the predominant underlying conditions. Central venous catheterization (90%), a history of antibacterial therapy (69%) and previous bacteraemia (54%) were frequent comorbidities. Candida albicans (46%) was most common, followed by Candida parapsilosis (17%) and Candida glabrata (14%). Resistance was infrequent and limited to non-albicans Candida spp. The 30-day and 100-day mortality rates were 11.4%.

Use of linezolid in neonatal and pediatric inpatient facilities--results of a retrospective multicenter survey.

The purpose of this investigation was to describe the use of linezolid in pediatric inpatient facilities. A retrospective multicenter survey including data from nine participating tertiary care pediatric inpatient facilities in Germany and Austria was undertaken. Data on 126 off-label linezolid treatment courses administered to 108 patients were documented. The survey comprises linezolid treatment in a broad spectrum of clinical indications to children of all age groups; the median age was 6.8 years (interquartile range 0.6-15.5 years; range 0.1-21.2 years; ten patients were older than 18 years of age but were treated in pediatric inpatient units). Of the 126 treatment courses, 27 (21%) were administered to preterm infants, 64 (51%) to pediatric oncology patients, and 5% to patients soon after liver transplantation. In 25%, the infection was related to a medical device. Linezolid iv treatment was started after intensive pre-treatment (up to 11 other antibiotics for a median duration of 14 days) and changed to enteral administration in only 4% of all iv courses. In 39 (53%) of 74 courses administered to children older than 1 week and younger than 12 years of age, the dose was not adjusted to age-related pharmacokinetic parameters. In only 17 courses (13%) was a pediatric infectious disease consultant involved in the clinical decision algorithm. Linezolid seemed to have contributed to a favorable outcome in 70% of all treatment courses in this survey. Although retrospective, this survey generates interesting data on the off-label use of linezolid and highlights several important clinical aspects in which the use of this rescue antibiotic in children might be improved.

Phase II dose escalation study of caspofungin for invasive Aspergillosis.

Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥ 4 in 2 of 8 patients or ≥ 3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin.

Liposomal amphotericin B twice weekly as antifungal prophylaxis in paediatric haematological malignancy patients.

Data on antifungal prophylaxis in paediatric cancer patients at high risk for invasive fungal disease (IFD) are scant. Intermittent administration of liposomal amphotericin B (LAMB) has been shown to be safe and effective in adult patients with haematological malignancies. We prospectively evaluated the safety and efficacy of prophylactic LAMB at a dosage of 2.5 mg/kg twice weekly in children at high risk for IFD. Efficacy was compared with that in a historical control group of patients with similar demographic characteristics not receiving LAMB prophylaxis. A total of 46 high-risk patients (24 boys; mean age, 7.7 years) with 187 episodes of antifungal prophylaxis were analysed. The median duration of neutropenia (<500/µL) was 10 days. LAMB was discontinued in four patients because of acute allergic reactions. Median values for creatinine and liver enzymes at end of treatment did not differ significantly from those at baseline. Hypokalaemia (<3.0 mmol/L) occurred with 13.5% of the prophylactic episodes, but was usually mild and always reversible. No proven/probable IFD occurred in patients receiving LAMB prophylaxis. In comparison, five proven and two probable IFDs were observed in 45 historical controls not receiving LAMB prophylaxis (p 0.01). LAMB prophylaxis had no impact on the use of empirical antifungal therapy. Systemic antifungal prophylaxis with LAMB 2.5 mg/kg twice weekly is feasible and safe, and seems to be an effective approach for antifungal prophylaxis in high-risk paediatric cancer patients.

Catheter-associated aspergillosis of the chest wall following allogeneic hematopoietic stem cell transplantation.

Invasive aspergillosis (IA) at the insertion site of central venous catheters is a rare event. Here we report the occurrence of chest wall aspergillosis at the insertion site of a Broviac catheter in a 5-year-old child undergoing allogeneic hematopoietic stem cell transplantation. The infection arose during profound granulocytopenia under conditions of reverse isolation with laminar air flow and high efficiency particulate air filtration and was successfully managed with repeat surgical debridement, voriconazole/caspofungin combination therapy guided by therapeutic drug monitoring, and adjunctive use of granulocyte colony-stimulating factor. The case reflects the occurrence of IA despite reverse isolation and air decontamination, the principles of treatment of Aspergillus soft tissue infections in granulocytopenic patients, and the need for therapeutic drug monitoring of voriconazole particularly in young children.

Trends in the postmortem epidemiology of invasive fungal infections at a university hospital.

BACKGROUND: Due to the continuing lack of sensitive and specific diagnostic tools, clinical data on opportunistic invasive fungal infections (IFIs) remain difficult to assess and postmortem data are indispensable to monitor trends in frequency and disease patterns. METHODS: Following-up on our previous report covering the period between 1978 and 1992, all protocols of postmortems performed between 1993 and 2005 at the University Hospital of Frankfurt/Main were retrospectively screened for the presence of IFIs. RESULTS: The analysis of 2707 consecutive autopsies identified 221 patients with IFIs (mean age, 52 years; range, 10 days-94 years). The prevalence of IFIs at autopsy steadily increased over the analyzed time periods (from 6.6% in 1993-1996 to 10.4% in 2001-2005), continuing the trend that was observed at our institution before. The increasing prevalence of IFIs was mainly due to an increase in Candida infections; rates of infections caused by Aspergillus, Cryptococcus, Zygomycetes and Pneumocystis remained constant. However, Aspergillus remained the leading pathogen. Patients with hematologic malignancies had the highest frequency of IFIs at postmortem. Candida most commonly affected the gastrointestinal tract, whereas Aspergillus most commonly affected the lung. CONCLUSIONS: The results of this analysis show continuing and relevant changes in the epidemiology of IFIs over time. Despite the expanding antifungal armamentarium, IFIs infections remain an important cause of morbidity and mortality in severely ill hospitalized patients.

Hyperbaric oxygen therapy and other adjunctive treatments for zygomycosis.

Zygomycetes are increasingly reported as a cause of life-threatening invasive fungal infections in profoundly immunocompromised patients and in those with diabetic ketoacidosis. Zygomycosis, typically presents as soft tissue, rhino-orbitocerebral, pulmonary or disseminated disease and is characterized by rapid clinical progression and high mortality rates. Treatment with amphotericin B lipid formulations in combination with surgery and, perhaps, the addition of caspofungin offers the best chance for survival; posaconazole, a new antifungal triazole, is increasingly used for consolidation or maintenance therapy. Because of the poor prognosis of zygomycosis, particularly in immunocompromised cancer patients, adjunctive treatments such as hyperbaric oxygen therapy, use of immunomodulatory cytokines, and in vivo iron starvation continue to be explored. However, although each of these modalities is based on a plausible scientific rationale and has been helpful in the management of individual patients, there is no clinical evidence for their general effectiveness as adjunctive treatments in patients with zygomycosis. Further experimental and clinical investigations are necessary to determine whether and how these treatments can impact on outcome and to determine which patients and which types of infection may benefit from them.

Delay in B-lymphocyte recovery and function following rituximab for EBV-associated lymphoproliferative disease early post-allogeneic hematopoietic SCT.

Treatment with rituximab is highly effective for EBV-associated post transplant lymphoproliferative disease. However, little is known about its immunological sequelae in pediatric allogeneic hematopoietic SCT (HSCT). Time to normal CD19+ B-lymphocyte values in blood and intravenous immunoglobulin (IVIG) substitution needed to maintain an IgG>400 mg per 100 ml in six consecutive pediatric allogeneic HSCT patients treated with rituximab for symptomatic EBV reactivation were compared with a matched cohort of non-rituximab-treated patients. Follow-up of the six patients ranged from 149 to 1546 days; all but one survived. The mean (+/-s.d.) time to recovery of CD19+ B-lymphocytes was 353+/-142 days as compared with 139+/-42 in the controls (P<0.01). Similarly, substitution of IVIG as a measure of functional B-cell recovery was extended from a mean of 122+/-45 to a mean of 647+/-320 days, and the cumulative dose of IVIG increased from a mean of 1.86+/-0.51 to 4.4+/-0.97 g/kg, respectively (P<0.05). One patient had functional B-lymphocyte deficiency for >3 years and ultimately required two stem cell boosts. Rituximab is a live-saving treatment for pediatric HSCT patients but may lead to prolonged and even persistent B-cell deficiency.