Multidrug-resistant organisms in paediatric palliative care patients - Prevalence, risk factors and the impact of a liberal hygiene concept.

AIM: Multidrug-resistant organisms (MDRO) deserve special attention in health-care facilities for children with life-limiting conditions because these children have an increased risk for colonisation. To avoid nosocomial transmissions to other inpatients, single-room isolation is usually recommended. In the context of paediatric palliative care (PPC), such isolation counters the aim of participation in social activities for the patients. This study aimed to determine the prevalence of MDRO, the predictive value of risk factors and the incidence of nosocomial infections and nosocomial colonisations on a PPC inpatient unit applying a special hygiene concept that enables participation in social activities through risk-adaption and barrier nursing. METHODS: Two-year surveillance with MDRO screening of all intakes (N = 386) of a PPC unit on the day of admission and discharge. To determine the predictive value of pre-defined risk factors, logistic regression analyses were calculated. Receiver operating characteristic analyses were performed to determine the predictive power of the number of risk factors on the presence of MDRO. RESULTS: The rate of MDRO colonisation at admission was 12.7%; previous positive MDRO screening was the only significant individual risk factor. Over the 2-year period, no MDRO-related nosocomial infections occurred; nosocomial colonisation incidence density was 0.6. CONCLUSION: Results demonstrate that patients with at least one risk factor have to be cared for by barrier nursing until MDRO screening results are negative. Following these guidelines prevents nosocomial MDRO transmission.

Potential Contributing Factors for Irritability of Unknown Origin in Pediatric Palliative Care.

CONTEXT: In pediatric palliative care, irritability of unknown origin (IUO) in children with severe neurological impairment is a peculiarly complex and challenging symptom, yet its etiology remains poorly understood. OBJECTIVES: Presenting a structured IUO diagnostic and therapeutic approach developed in a specialized inpatient pediatric palliative care facility for identifying IUO's potential contributing factors (PCFs). METHODS: Prospective observational study with N = 22 children showing IUO at admission to the inpatient pediatric palliative care facility. Analysis of patient records and participation in ward routine to identify and treat PCFs. Treatment outcome was assessed using a standardized protocol for tracking IUO at 24-hour intervals. RESULTS: Altogether, 136 PCFs were identified (average 6.18 per child) with pain and psycho-social problems being the most common. Two hundred and twenty-two diagnostic measures were initiated of which 159 (71.6%) helped identify a PCF. The majority of PCFs were identified by basic diagnostics (93.7%). Inpatient length of stay and duration of IUO phases correlated significantly. Between baseline (days 3-5; timing at which inpatients experientially show regular behavior) and discharge, patients showed a significant reduction in average 24-hours IUO duration by 1 hour and 26 minutes (Wilcoxon test: Z = -3.29, P < 0.01). CONCLUSION: Results lead to a more thorough understanding of PCFs to IUO. Following a systematic approach such as the one presented, PCFs can be detected even by simple diagnostics. In addition to biological aspects, diagnostics and therapy should address psycho-social aspects of IUO.

The effect of multidrug-resistant organisms on social participation and quality of life in children with life-limiting conditions.

BACKGROUND: Children with life-limiting conditions have a high risk of colonisation with a multidrug-resistant organism (MDRO). To avoid the spread of hospital-aquired infections to other patients, children with a MDRO are moved to an isolated room or ward. However, such isolation prevents social participation, which may reduce the child's quality of life (QoL). To overcome this challenge of conflicting interests on a paediatric palliative care inpatient unit, a hygiene concept for patients colonised with MDRO, called PALLINI, was implemented. PALLINI advises that, instead of isolating the affected children, strict barrier nursing should be used. AIM: To identify the impact of a complex hygiene concept on children's and parents' QoL and social participation. METHODS: Cross-sectional mixed-methods research approach, comprising semi-structured interviews with parents and staff members, and a QoL-questionnaire focusing on the child which was completed by parents. FINDINGS: In paediatric patients with life-limiting conditions who have MDRO colonisation, using a complex hygiene protocol resulted in both benefits and barriers to social participation. However, the child's QoL did not appear to be affected. CONCLUSION: All staff members and families have to be familiar with the hygiene concept and the concept has to be self-explanatory and easy to apply.

Multidrug-Resistant Organisms in Palliative Care: A Systematic Review.

Background: Multidrug-resistant organisms (MDROs) are an important health care issue. Patients in Western societies often present an increased morbidity of chronic conditions accompanied by poor immune status and the use of devices. In particular, patients in palliative care (PC) are at greater risk of MDRO colonization, due to accompanying special devices and being hospitalized. Objective: To gain an overview of the literature regarding MDROs in PC. Design: Systematic review Data sources: On the 19th of October 2019 the databases " PubMed" and " CINAHL" were used to identify studies reporting on MDROs in PC; the search was updated on 16th of May 2020. Results: Seventeen out of 486 articles were included. Six represent qualitative data, 10 quantitative data, and one a mixed methods approach. Prevalence data range from 4.0% to 18%. MDRO colonization has a negative impact on patients and families. It leads to uncertainties and higher workload by staff members. Strategies for the management of MDROs in the field of PC are predominantly available for methicillin-resistant Staphylococcus aureus. Not even half of institutions utilize existing protocols. Recommendations for dealing with MDROs indicate required staff and time resources as well as information, communication, and specific knowledge. Conclusion: There is a great need for studies examining the prevalence of all MDROs in the PC setting. Additionally, not only patients but also a public enlightenment on MDROs should be provided to decrease knowledge gaps and therefore reduce transmission on MDROs.

Opioid-Induced Respiratory Depression in Pediatric Palliative Care Patients with Severe Neurological Impairment-A Scoping Literature Review and Case Reports.

Pediatric Palliative Care (PPC) addresses children, adolescents, and young adults with a broad spectrum of underlying diseases. A substantial proportion of these patients have irreversible conditions accompanied by Severe Neurological Impairment (SNI). For the treatment of pain and dyspnea, strong opioids are widely used in PPC. Nonetheless, there is considerable uncertainty regarding the opioid-related side effects in pediatric patients with SNI, particularly concerning Opioid-Induced Respiratory Depression (OIRD). Research on pain and OIRD in pediatric patients with SNI is limited. Using scoping review methodology, we performed a systematic literature search for OIRD in pediatric patients with SNI. Out of n = 521 identified articles, n = 6 studies were included in the review. Most studies examined the effects of short-term intravenous opioid therapy. The incidence of OIRD varied between 0.13% and 4.6%; besides SNI, comorbidities, and polypharmacy were the most relevant risk factors. Additionally, three clinical cases of OIRD in PPC patients receiving oral or transdermal opioids are presented and discussed. The case reports indicate that the risk factors identified in the scoping review also apply to adolescents and young adults with SNI receiving low-dose oral or transdermal opioid therapy. However, the risk of OIRD should never be a barrier to adequate symptom relief. We recommend careful consideration and systematic observation of opioid therapy in this population of patients.

[Paediatric palliative care (PPC) - a particular challenge : Tasks, aims and specifics]. / Pädiatrische Palliativversorgung ­ herausfordernd anders : Aufgaben, Ziele und Besonderheiten.

In Germany, there are about 50,000 children, adolescents and young adults with life threatening or life limiting conditions, who will likely die due to their illness before reaching the age of 40. In recent years prevalence has increased significantly.The aim of paediatric palliative care (PPC) is to optimize quality of life for the child, adolescent or young adult and its whole family. Whenever possible the patient should be treated at home.The very complex and rare diseases as well as the patients' wide range of age and developmental stage are particularly challenging within PPC. Many PPC patients have cognitive disabilities and are not able to communicate verbally. In contrast to adult palliative care, PPC is often delivered for many years.To date, families with a child suffering from a life limiting condition have access to several care systems; however most of them are still financed by donations. One of PPC's most important tasks is the implementation of individual case management to find the right mix of care provision, its flexible adaption on changing needs and the appropriate intensity of care.Specific education and training courses in the field of PPC are still rare. There is a single chair for childrens' pain therapy and paediatric palliative care at Witten/Herdecke University in Germany. In addition, quality-checked multiprofessional PPC courses for the additional "palliative health care professional" designation based on the Dattelner Curriculum are offered at several institutions.

Sex differences in pain intensity in adolescents suffering from cancer: differences in pain memories?

UNLABELLED: Although sex differences have been investigated in chronic pain populations, little is known about sex differences in the pain experience of paediatric oncology patients and also whether their parents rate the pain experience differently for boys and girls. The aim of the present study was to determine if (1) boys and girls with cancer differ in current perception and past recollection of cancer-related pain and (2) if adolescents' and parents' pain ratings differ in relation to the sex of the adolescent. One hundred twelve adolescents with malignant diagnoses (12 to 18 years) and their parents participated in the study. Girls reported higher pain intensity within the last 7 days and 4 weeks despite similar diagnosis, physical status, duration of diagnoses, and main pain causes. When asked for pain intensity that dated back in time, parent and adolescent ratings diverged, with a trend for parents to reporting higher pain intensity in boys and lower pain intensity in girls, particularly for pain in the preceding 7 days. The present study provides preliminary evidence for sex differences in the recalled pain experience of adolescents with malignant diagnoses. Although boys and girls experience present pain similarly and hence should be treated similarly, girls recall higher pain intensity than boys. Future studies should address whether negative memories in girls play a significant role and may have an impact on girls' well-being and pain-related distress. Additionally, psychosocial factors such as gender role expectations may need to be investigated. Parental variables and their impact on parents' pain ratings, especially for ratings of precedent pain, warrants further investigation. PERSPECTIVE: Girls with malignant diagnoses differ from boys in their recalled pain intensity ratings, with girls reporting higher pain intensity. Additional pain management strategies referring to the memory of pain may need to be implemented.

Stop the pain! A nation-wide quality improvement programme in paediatric oncology pain control.

INTRODUCTION: Little is known about the impact of translation of pain management clinical practice guidelines on pain control in paediatrics. In an effort to overcome this, a longitudinal, nation-wide, multi-centre paediatric quality improvement (QI) study was initiated by the German Society of Pediatric Haematology and Oncology (GPOH) entitled Schmerz-Therapie in der Onkologischen Paediatrie (STOP). OBJECTIVE: The project's primary major aims were to improve paediatric oncology pain control in Germany, and to evaluate the project's impact on the pain management quality. To achieve these aims, STOP encompassed six sequential phases to evaluate present practice, develop recommendations for practical pain control, actively engage participants in improvement strategies, and assess change. The purpose of this paper is to briefly describe STOP in its entirety, report on comparisons between active quality management (QM) departments that actively participated in the project and non-active QM departments regarding differences in pain control, patients' and parents' perspectives on pain control and health professionals' knowledge, and to discuss the impact of STOP as a whole. METHODS: Four hypotheses were examined: (1) changes in health care professionals' knowledge on pain in paediatric oncology and pain management after a three-year period (2) impact of active participation in the STOP-project; (3) differences in patients' and parents' perspective in active QM versus non-active QM departments; (4) impact of the STOP-project on the health care professionals' knowledge in active QM versus non-active QM departments. Data included surveys, interviews, and standardised pre-/post-intervention documentation of pain control. All German paediatric oncology departments were invited to participate. The prime means of intervention was education (printed material, passive participation; additional lectures and feed-back, active participation). Quality indicators were defined and compared with regards to the four hypotheses. RESULTS: Sixty-eight departments participated passively. Eight departments participated actively, enrolling 224 patients (median age, 9 years) and documenting a total of 2265 treatment days. In the areas addressed, all health professionals demonstrated increases in knowledge on pain and pain control after a three-year period. STOP objectively improved pain control in the actively participating departments. Painful modes of drug administration were used less frequently; the usage of mixed opioid agonists-antagonists was reduced; the physicians' knowledge of the treatment of neuropathic pain increased; pain ratings significantly decreased, and less episodes of strong pain were observed. There was a significant increase in the proportion of health-care professionals who post-interventionally judged that pain therapy had been initiated earlier and at exactly the right time. Neither patients nor parents felt, however, that there was any quality improvement. According to participants' self-assessment, STOP improved practical pain management in actively participating departments, while in passively participating departments the change to the better was negligible. CONCLUSION: STOP predominantly aimed at and succeeded in the improvement of structure, process and outcome quality. With regard to patients' and parents' opinions, the interview tools might have been unsuited to measure the quality of pain control, or STOP was insufficient to improve pain control to a magnitude significant to the patient.

111In-pentetreotide scintigraphy in medulloblastoma: a comparison with magnetic resonance imaging.

Medulloblastoma (MB) is a primitive neuroectodermal tumour constituting a grade IV brain malignancy. Early and correct detection of recurrence or metastasis is desirable for follow-up of patients in this entity. Frequent expression of somatostatin receptors by MB lesions facilitates functional tumour imaging by somatostatin receptor scintigraphy (SRS). To investigate the value of SRS in the follow-up of MB, the results of ten consecutive patients (seven children and three adults) undergoing additional imaging with 111In-pentetreotide were reviewed. Four, 24 and 48 h p.i. planar and whole body images as well as a SPECT study at 4 h p.i. were acquired after intravenous injection of 109 +/- 35 MBq 111In-pentetreotide (Octreoscan). SRS yielded 11 positive and ten negative imaging results, compared to 17 positive and four negative in magnetic resonance imaging (MRI). The lesion-by-lesion analysis with a total of 44 lesions revealed a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 42%, 83%, 94%, 18% for SRS and 89.5%, 50%, 92%, 43% for MRI. Based on a per-patient analysis, considering the patient as to be either tumour-free or tumour-positive by one imaging modality, the following values for sensitivity, specificity, PPV and NPV were obtained: 61%, 100%, 100%, 30% for SRS and 94%, 67%, 94%, 67% for MRI. MRI remains the first step imaging technique in medulloblastoma patients before and after surgery and during the follow-up providing the highest sensitivity. However, to improve specificity and contribute to correct diagnosis in MB 111In-pentetreotide scintigraphy should be considered as a confirmatory second step imaging tool, especially in case of equivocal MRI results. Moreover, a positive SRS scan might serve as a reference before and after somatostatin receptor targeted radiotherapy.

Itraconazole prophylaxis in pediatric cancer patients receiving conventional chemotherapy or autologous stem cell transplants.

GOAL OF WORK: During the renovation works at our institution, the incidence density for invasive aspergillosis (IA) increased from <0.5 to 0.99/1,000 inpatient days in 2001. As a direct response to this increased environmental risk, itraconazole (ITC) was administered for primary prophylaxis in pediatric cancer patients for whom a particular high risk of IA was anticipated due to prolonged severe neutropenia (>10 days), autologous stem cell transplantation, acute myeloblastic leukemia or relapsed acute lymphoblastic leukemia, or high-dose steroids >3 weeks. MATERIALS AND METHODS: In this open-label, prospective observational study, ITC was given in ITC solution or capsule. Trough concentrations were measured in plasma with high-performance liquid chromatography after at least 7 days of treatment. Doses were adjusted to target plasma trough ITC concentrations > or =0.5 mg/l. RESULTS: From 2001 to 2005, 39 pediatric cancer patients received 44 prophylactic ITC cycles; 102 trough plasma concentrations were measured after oral administration. Plasma target concentrations >0.5 mg/l were achieved with both formulations. A median dose of 8 mg kg(-1) day(-1) (3.5-16.0 mg kg(-1) day(-1)) was necessary in pediatric oncology patients. The bioavailability of the liquid formulation was significantly lower when the solution was given by a feeding tube. Adverse effects (gastrointestinal, elevated transaminases, and one hemolysis) which led to the cessation of the ITC prophylaxis were reported in 11% of all courses. No breakthrough infection was seen in this pediatric population. CONCLUSION: Oral ITC offers a feasible and inexpensive option for antifungal prophylaxis in selected pediatric cancer patients. Drug monitoring and meticulous consideration of possible interactions and adverse effects are mandatory.

Restricted use of glycopeptides in paediatric cancer patients with fever and neutropenia.

Until now, studies confirming the safety of glycopeptide restriction in the empirical treatment of prolonged fever and neutropenia included only nine children. In an open-label observational study, the use of teicoplanin in paediatric oncology patients was investigated. A period of unrestricted use (2001-2003) was compared with a second period (2004) following implementation of a restrictive treatment guideline. Empirical first-line treatment consisted of piperacillin/tazobactam; in 2004, fosfomycin was added after 72 h as the second-line combination instead of teicoplanin. In total, 213 episodes (n=163 in 2001-2003; n=50 in 2004) managed with teicoplanin or fosfomycin (only 2004) were eligible. Empirical treatment of fever of unknown origin with teicoplanin was reduced by 97%. In 2004, the mean length of stay was 0.4 days shorter, no infection-related death occurred and no vancomycin-resistant enterococci were detected. Restriction of empirical glycopeptides is safe in paediatric cancer patients after first-line treatment with piperacillin/tazobactam. Fosfomycin appears to offer a feasible and cost-saving alternative in second-line combination therapy.

Norovirus outbreak in a pediatric oncology unit.

OBJECTIVE: Norovirus (NV) is an etiologic agent of outstanding importance that can cause severe epidemic gastroenteritis in day-care centers, schools, nursing homes, and hospitals. Therefore NV requires foremost attention as a pathogen responsible for epidemics of gastroenteritis in immunocompromised inpatients. In this study, a NV outbreak in a pediatric oncology unit is described and the consequences for this high-risk population are discussed. MATERIAL AND METHODS: Stool and vomitus samples from 11 patients were tested for NV and other relevant viruses during the outbreak by reverse transcriptase-polymerase chain reaction (RT-PCR) and/or enzyme-linked immunosorbent assay (ELISA) (whenever an appropriate ELISA was available). Norwalk virus PCR amplifications were sequenced and phylogenetic analysis was performed. RESULTS: The index patient and the chain of infection were identified. Follow-up investigation surprisingly demonstrated viral shedding for a maximum of 140 days (median 23 days). Three patients experienced severe or life-threatening symptoms, probably related to NV infection. CONCLUSIONS: In the event of an outbreak of gastroenteritis (involving two or more symptomatic patients) in a pediatric oncology unit, the search for NV in stool or vomitus specimens should be initiated in good time. As long as the data are limited regarding whether a detectable viral antigen or RNA in stools represents an infectious virus, patients have to be isolated as long as the diagnostic assays remain positive. During the acute phase of the illness, health-care workers should wear masks in addition to practicing meticulous hand hygiene with a disinfectant of proven activity against NV. Pediatric oncology patients must be closely monitored during follow-up investigations as they may shed the virus for months. There is some evidence from the outbreak described here that those patients face a greater risk of severe NV-related complications.

Acupuncture against chemotherapy-induced nausea and vomiting in pediatric oncology. Interim results of a multicenter crossover study.

GOALS: In this multicenter crossover study, our aim was to evaluate the efficacy and acceptance of acupuncture as a supportive antiemetic approach during highly emetogenic chemotherapy in pediatric oncology. PATIENTS AND METHODS: Eleven children receiving several courses of highly emetogenic chemotherapy for treatment of solid tumors were included. Randomization allocated patients to start chemotherapy either with antiemetic medication plus acupuncture or antiemetic medication alone. During all study courses, patients continued to receive their programmed and additional antiemetic medication as needed. Acupuncture was given at day 1 of chemotherapy and at subsequent days on patient's demand. The amount of baseline and additional antiemetic medication during chemotherapy was documented. Patients maintained a daily diary of vomiting episodes and completed an evaluated nausea score at the end of every course. Their body weight was taken before and after a chemotherapy course. MAIN RESULTS: Twenty-two courses with or without acupuncture were compared. The benefits of acupuncture in adolescents with respect to the reduction of additional antiemetic medication were observed. Acupuncture enabled patients to experience higher levels of alertness during chemotherapy and reduced nausea and vomiting. Except for needle pain, no side effects were noted. Patient's acceptance of acupuncture was high. CONCLUSION: Our data indicate that acupuncture might reduce antiemetic medication and episodes of vomiting in pediatric oncology.

Paediatric cancer pain management using the WHO analgesic ladder--results of a prospective analysis from 2265 treatment days during a quality improvement study.

OBJECTIVE: To collect data on pain management in paediatric oncology with respect to the WHO ladder approach. SETTING, DESIGN, PATIENTS AND METHODS: Eight German tertiary care paediatric oncology centres prospectively documented all their in-patient pain treatment courses from June 1999 to December 2000. Pain was scored using a 1-6 faces scale. RESULTS: Two hundred and twenty four patients (median age, 9 years; range 0.2-32.1) were enrolled. Three hundred and thirty three pain episodes comprising a total of 2265 treatment days were documented. Pain was mostly therapy associated. The most frequently administered non-opioid analgesics were dipyrone and paracetamol. On WHO step 2, tramadol was almost the only opioid used. During tramadol monotherapy average daily pain scores were lower than with a combination of tramadol and non-opioid analgesics. On WHO step 3, morphine was at least part of the analgesic regimen on most treatment days. Strong opioids were combined with a non-opioid analgesic on 41% of the treatment days. The mean intravenous morphine equivalence dose was 0.034 mg/kg/h. During opioid and non-opioid combination therapy, adverse effects were more frequent, and average pain scored higher than on opioid monotherapy. CONCLUSIONS: WHO-guidelines were closely followed in Germany and seem to provide effective analgesia for children with cancer pain. In our patient group there is no evidence that a combination of an opioid with a non-opioid is more effective than opioid therapy alone in in-patient paediatric oncology pain treatment.

Pain in pediatric oncology--children's and parents' perspectives.

There is a lack of valid epidemiological data on malignancy-associated pain in modern pediatric oncology. Pediatric oncology patients (self-assessment) and their parents from 28 hospitals were questioned using age-adapted, structured interviews and validated pain assessment tools. Pain intensity was measured by the NRS and Bieri faces scale. We conducted 363 interviews with patients and their parents, and 46 with the parents alone (if patients <2.5 years). Pain was reported at the time of the interview or within the last 24 h, 7 d, or 4 weeks in 15%, 28%, 50% and 58% of cases, respectively. The proportion of patients suffering severe to maximal pain (NRS>3; Bieri>2) increased significantly (p=0.001, chi2 test). The median pain intensity for the most severe pain episode within the last 4 weeks was 6.7 (NRS 0-10). Adverse effects of anti-tumor therapy were the most frequent cause of pain. Multivariate analyses depicted general physical condition either "severely reduced" (ASA status 3) (OR 4.0, 95% CI 1.1-14.7, p=0.037) or "moderately reduced" (ASA status 2) (OR 1.8, 95% CI 1.1-2.9, p=0.018), "in-patient status" (OR 1.8, 95% CI 1.2-2.9, p=0.010), and "co-morbidity present" (OR 3.5, 95% CI 1.1-10.7, p=0.030) as risk factors for severe to maximal pain. General anesthesia was the only factor significantly (OR 0.14, 95% CI 0.05-0.39, p<0.01) associated with a reduction in the proportion of patients suffering severe to maximal pain during bone marrow aspiration. Our data emphasize both the importance of in-house acute pain control and the need for general anesthesia during painful procedures in pediatric oncology.

The role of complete surgical resection in stage IV neuroblastoma.

The purpose of this study was to examine the outcome of attempted radical surgical resection in patients with stage IV neuroblastoma. Between 1989 and 2003, 20 (median age 2.4 years, range 0.5-8.7 years) children with stage IV neuroblastoma were treated at the Department of Pediatrics. Surgery was performed in 7 consecutive children (6 male and 1 female) between July 1997 and February 2002 at the Department of Urology in Bonn. Mean age at diagnosis was 57 months (21-104 months). Mean age at the time of surgery was 54 months (8-390 months). Follow-up was available for all patients (100%) and mean follow-up after the operation was 32.5 months (4-56 months). Primary localization of the tumor was retroperitoneal in all cases; 4 out of 7 patients (57%) also had additional adrenal, 3 out of 7 (42%) paraganglion and 1 out of 7 (14%) thoracic primaries. Bone marrow and lymph node metastases were found in all patients (100%). Surgery led to complete tumor resection in 6 out of 7 patients (85%). Surgical approach was abdominal (chevron incision) in 6 out of 7 (85%) of the patients, in one patient the approach was thoraco-abdominal. After induction chemotherapy and delayed surgery, 6 out of 7 (86%) patients showed a complete remission (CR) and the mean CR lasted for about 27.7 months (range 3.1-55.4 months). At the last time of follow-up 5 out of 7 (71%) patients were alive, 2 had died due to recurrent disease. Mean time to recurrent disease was 24 and 51 months, respectively. Mean overall survival time since diagnosis was 38.3 months (11-64 months) and mean event-free survival was 34.5 months (11-60.3 months). The final outcome, overall survival and event-free survival time was influenced by metastatic or local relapse. Tumor resection is beneficial but the value of surgery can only be judged when we are able to control metastatic disease in stage IV neuroblastoma. The final outcome may rely on the extent of complete surgical resection, but is also related to treatment of metastases. A longer follow-up period is indicated to detect long term outcome.

Identification of a novel mutation in the coding region of the grey-lethal gene OSTM1 in human malignant infantile osteopetrosis.

Autosomal recessive malignant infantile osteopetrosis (ARO) is characterized by severe osteosclerosis, pathologic fractures, hepatosplenomegaly, and pancytopenia. The pathophysiological basis is inadequate bone resorption due to osteoclast dysfunction. In the majority of cases, mutations in either of two human genes cause this fatal disorder: TCIRG1, encoding a subunit of the osteoclast H(+)-ATPase, and the voltage-gated chloride channel gene CLCN7. We excluded both genes in a small inbred family with malignant infantile osteopetrosis and undertook linkage analysis of several candidate loci that are involved in murine osteopetrosis. A region spanning more than 20 cM between the markers D6S1717 and D6S1608 on chromosome 6q21 was found to be homozygous in the affected child. This locus is syntenic to the genomic region harboring the gene for the osteopetrotic mutant mouse grey-lethal (gl). Recently, mutations in a novel gene of unknown function were described in the grey-lethal mouse and in one human patient. Mutation screening of the grey-lethal gene (OSTM1), revealed a homozygous 2-bp deletion in exon 2 (c.415_416delAG) in the affected child. No mutations could be found in six independent ARO patients who had tested negative for mutations in TCIRG1 and CLCN7. In summary, we describe the identification of a novel mutation in the coding sequence of the human grey-lethal gene, which is the second OSTM1 mutation found in human ARO, confirming the involvement of this gene in the pathogenesis of this severe bone disease.

Acute liver disease and aplastic anemia associated with the persistence of B19 DNA in liver and bone marrow.

We observed a 12-year-old boy with acute hepatitis and associated aplastic anemia (AA), where parvovirus B19 genome was repeatedly detected in liver and bone marrow biopsies, but not in blood samples. We conclude that: (1) B19 infection may be underdiagnosed as the causative agent responsible for acute hepatitis and associated AA if no organ-specific diagnostic tests are applied; (2) B19 deoxyribonucleic acid (DNA) can persist in the liver; (3) during the acute phase of hepatitis, extramedullary hematopoiesis may be involved in the susceptibility for hepatic B19 infection.