Publications by authors named "Nicolas Waespe"

13 Publications

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Cancer predisposition syndromes as a risk factor for early second primary neoplasms after childhood cancer - A national cohort study.

Eur J Cancer 2021 Mar 7;145:71-80. Epub 2021 Jan 7.

Institute of Social and Preventive Medicine, University of Bern, Switzerland; Division of Pediatric Hematology and Oncology, University Children`s Hospital Bern, Switzerland. Electronic address:

Background: Childhood cancer patients are at increased risk of second primary neoplasms (SPNs). We assessed incidence and risk factors for early SPNs with a focus on cancer predisposition syndromes (CPSs).

Patients And Methods: This cohort study used data from the Swiss Childhood Cancer Registry. We included patients with first primary neoplasms (FPNs) diagnosed before age 21 years from 1986 to 2015 and identified SPNs occurring before age 21. We calculated standardised incidence ratios (SIRs) and absolute excess risks (AERs) using Swiss population cancer incidence data, and cumulative incidence of SPNs. We calculated hazard ratios (HRs) of risk factors for SPNs using Fine and Gray competing risk regression.

Results: Among 8074 childhood cancer patients, 304 (4%) were diagnosed with a CPS and 94 (1%) developed early SPNs. The incidence of SPNs was more than 10-fold higher in childhood cancer patients than the incidence of neoplasms in the general population (SIR = 10.6, 95% confidence interval [CI]: 8.7-13.1) and the AER was 179/100,000 person-years (CI: 139-219). Cumulative incidence of SPNs 20 years after FPN diagnosis was 23% in patients with CPSs (CI: 12-41%) and 2.7% in those without (CI: 2.0-3.6%). Risk factors for SPNs were CPSs (HR = 7.8, CI: 4.8-12.7), chemotherapy (HR = 2.2, CI: 1.1-4.6), radiotherapy (HR = 1.9, CI = 1.2-2.9), haematopoietic stem cell transplantation (HR = 1.8, CI: 1-3.3), and older age (15-20 years) at FPN diagnosis (HR = 1.9, CI: 1.1-3.2).

Conclusion: CPSs are associated with a high risk of SPNs before age 21 years. Identification of CPSs is important for appropriate cancer surveillance and targeted screening.
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http://dx.doi.org/10.1016/j.ejca.2020.11.042DOI Listing
March 2021

Post-traumatic stress in parents of long-term childhood cancer survivors compared to parents of the Swiss general population.

J Psychosoc Oncol Res Pract 2020 Oct 28;2(3):e024. Epub 2020 Jul 28.

Department of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland.

Background: We describe post-traumatic stress symptoms (PTSS) and post-traumatic stress disorder (PTSD) in parents of long-term childhood cancer survivors (CCS-parents) and compare them to parents of similar-aged children (comparison-parents) of the Swiss general population (SGP). We compare type of reported stressful event, prevalence of PTSS and PTSD, and psychosocial and cancer-related characteristics associated with PTSS. We further describe the respective normative data for the SGP.

Methods: We conducted a nationwide cross-sectional questionnaire survey in a population-based sample of long-term CCS-parents (survivors aged ≤16 years at diagnosis, ≥20 years at study, >5 years post-diagnosis) and in the SGP. Using the , we measured PTSS regarding the most stressful event experienced, and computed probable cases of PTSD.

Results: Participants included 663 CCS-parents (39.4% fathers) and 1035 individuals of the SGP (40.0% male), of which we identified 391 comparison-parents (41.2% fathers). Illness was most often indicated as stressful event (CCS-parents: 49.5%, comparison-parents: 27.6%, SGP: 25.3%). Prevalence of PTSS and PTSD (CCS-parents: 4.8%, comparison-parents: 6.7%, SGP: 5.6%) did not significantly differ. Lower education was associated with higher intrusion, avoidance, and hyperarousal in all samples (all ≤ .003). Parents of children with a chronic illness reported higher intrusion (all ≤ .004). We found no associations with cancer-related characteristics.

Conclusions: No increased risk for PTSS or PTSD was found among CCS-parents. Individuals with lower education and those with a chronically ill child might benefit from additional support to help manage and resolve the stress symptoms in the long term.
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http://dx.doi.org/10.1097/OR9.0000000000000024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411524PMC
October 2020

Diagnosing Preclinical Cardiac Dysfunction in Swiss Childhood Cancer Survivors: Protocol for a Single-Center Cohort Study.

JMIR Res Protoc 2020 Jun 10;9(6):e17724. Epub 2020 Jun 10.

Pediatric Oncology/Hematology, University Children's Hospital Basel, University of Basel, Basel, Switzerland.

Background: Cardiovascular disease is the leading nonmalignant cause of late deaths in childhood cancer survivors. Cardiovascular disease and cardiac dysfunction can remain asymptomatic for many years, but eventually lead to progressive disease with high morbidity and mortality. Early detection and intervention are therefore crucial to improve outcomes.

Objective: In our study, we aim to assess the prevalence of preclinical cardiac dysfunction in adult childhood cancer survivors using conventional and speckle tracking echocardiography; determine the association between cardiac dysfunction and treatment-related risk factors (anthracyclines, alkylating agents, steroids, cardiac radiation) and modifiable cardiovascular risk factors (abdominal obesity, hypertension); investigate the development of cardiac dysfunction longitudinally in a defined cohort; study the association between cardiac dysfunction and other health outcomes like pulmonary disease, endocrine disease, renal disease, quality of life, fatigue, strength and endurance, and physical activity; and gain experience conducting a clinical study of childhood cancer survivors that will be extended to a national, multicenter study of cardiac complications.

Methods: For this retrospective cohort study, we will invite ≥5-year childhood cancer survivors who were treated at the University Children's Hospital Bern, Switzerland with any chemotherapy or cardiac radiation since 1976 and who are ≥18 years of age at the time of the study for a cardiac assessment at the University Hospital Bern. This includes 544 childhood cancer survivors, of whom about half were treated with anthracyclines and/or cardiac radiation and half with any other chemotherapy. The standardized cardiac assessment includes a medical history focusing on signs of cardiovascular disease and its risk factors, a physical examination, anthropometry, vital parameters, the 1-minute sit-to-stand test, and echocardiography including 2-dimensional speckle tracking.

Results: We will invite 544 eligible childhood cancer survivors (median age at the time of the study, 32.5 years; median length of time since diagnosis, 25.0 years) for a cardiac assessment. Of these survivors, 300 (55%) are at high risk, and 244 (45%) are at standard risk of cardiac dysfunction.

Conclusions: This study will determine the prevalence of preclinical cardiac dysfunction in Swiss childhood cancer survivors, inform whether speckle tracking echocardiography is more sensitive to cardiac dysfunction than conventional echocardiography, and give a detailed picture of risk factors for cardiac dysfunction. The results will help improve primary treatment and follow-up care of children with cancer.

Trial Registration: ClinicalTrials.gov NCT03790943; https://clinicaltrials.gov/ct2/show/NCT03790943.

International Registered Report Identifier (irrid): DERR1-10.2196/17724.
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http://dx.doi.org/10.2196/17724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315371PMC
June 2020

Primary immunodeficiencies and their associated risk of malignancies in children: an overview.

Eur J Pediatr 2020 May 11;179(5):689-697. Epub 2020 Mar 11.

Division of Haematology/Oncology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G1X8, Canada.

Primary immunodeficiency disorders represent a heterogeneous spectrum of diseases, predisposing to recurrent infections, allergy, and autoimmunity. While an association between primary immunodeficiency disorders and increased risk of cancer has been suggested since the 1970s, renewed attention has been given to this topic in the last decade, largely in light of the availability of large registries as well as advances in next generation sequencing. In this narrative review, we will give an insight of the primary immunodeficiencies that are commonly responsible for the greater number of cancers in the primary immunodeficiency disorders population. We will describe clinical presentations, underlying genetic lesions (if known), molecular mechanisms for carcinogenesis, as well as some management considerations. We will also comment on the future directions and challenges related to this topic.Conclusion: The awareness of the association between several primary immunodeficiencies and cancer is crucial to provide the best care for these patients.What is Known: • Patients with primary immunodeficiency have an increased risk of malignancy. The type of malignancy is highly dependent on the specific primary immunodeficiency disorder.What is New: • Survival in patients with primary immunodeficiency disorders has been improving, and conversely also their lifetime risk of malignancy. • International collaboration and multinational registries are needed to improve our knowledge and therapeutic strategies.
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http://dx.doi.org/10.1007/s00431-020-03619-2DOI Listing
May 2020

The yield of monitoring adenovirus in pediatric hematopoietic stem cell transplant patients.

Pediatr Hematol Oncol 2019 Apr 30;36(3):161-172. Epub 2019 Apr 30.

a Division of Hematology/Oncology/BMT , The Hospital for Sick Children , Toronto , Ontario , Canada.

Human adenovirus (HAdV) is recognized as a serious pathogen after allogeneic hematopoietic stem cell transplantation (HSCT), causing morbidity and mortality. Currently, there is no universal agreement regarding routine HAdV surveillance after HSCT. We assessed the impact of HAdV weekly monitoring by polymerase chain reaction (PCR) on HAdV viremia rates and the risk factors that influence survival. Three-hundred and fifty-six pediatric allogeneic HSCT were done between 2007 and 2015. Until July 2011, HAdV testing was performed based on clinical suspicion (cohort 1,  = 175) and from August 2011, weekly blood-HAdV monitoring was done (cohort 2,  = 181) until day +100. Twenty-three patients (4 [2.3%] from cohort 1 and 19 [10.5%] from cohort 2,  = .001) were found with HAdV viremia and seven of them died. Both cohorts had a similar incidence of HAdV-associated mortality (3/175; 1.7% in cohort 1 and 4/181; 2.2% in cohort 2). Respiratory failure was the cause of death in all patients. Clinical symptoms appeared prior to or within 5 days of HAdV detection in cohort 2. In summary, weekly monitoring was associated with higher detection of HAdV. The study could not assess survival benefit due to small numbers of HAdV-positive cases. In many instances, symptoms occurred with the development of positive HAdV blood PCR results and hence, symptomatology could have triggered the test. Future studies are needed to provide data that help establishing a uniform approach for regular monitoring of HAdV post-transplant.
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http://dx.doi.org/10.1080/08880018.2019.1607961DOI Listing
April 2019

Clinical Impact of Chronic Venous Changes Induced by Central Lines in Children: A Cohort with Abnormal Venograms.

J Vasc Interv Radiol 2019 May 27;30(5):715-723. Epub 2019 Mar 27.

Image Guided Therapy, Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON, M5G 1X8, Canada.

Purpose: To explore the hypothesis that central venous stenosis/obstructions (CVS/O) in children are influenced by prior central venous access devices (CVADs) and are associated with future risk for thromboses.

Material And Methods: A convenience sample of 100 patients with abnormal venography (stenosis, collaterals, occlusions) documented during peripherally inserted central catheter (PICC) placements were identified from consecutive PICC placements (January 2008 to November 2012). The patients (41 males, 59 females, median age 2.7 years, median weight 11 kg) were categorized based on venographic presence (Group A, n = 53) or absence (Group B, n = 47) of visible connection to the superior vena cava. Each patient's CVAD history, before and after venography, was analyzed (until October 2016).

Results: Before venogram, Group B patients were associated with a higher number of previous CVADs, larger diameter devices, greater incidence of malposition, and more use of polyurethane catheters than Group A patients (P < .001). An ipsilateral PICC was successfully placed in 98% of Group A, compared to 32% of Group B (P < .001). After venogram, significantly more Doppler ultrasounds (DUS) were performed and thromboses diagnosed in Group B (57% and 36%) compared to Group A (21% and 8%) (P < .003; P = .001), respectively.

Conclusions: Previous catheter characteristics influenced the severity of venographic changes of CVS/O (Group B). Group B was associated with more subsequent symptomatic thromboses. This information may assist parents and referring physicians to anticipate potential adverse sequelae from CVS/O on the child's venous health.
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http://dx.doi.org/10.1016/j.jvir.2018.08.034DOI Listing
May 2019

Sirolimus Treatment of an Infant With Intrathoracic Kaposiform Hemangioendothelioma Complicated by Life-threatening Pleural and Pericardial Effusions.

J Pediatr Hematol Oncol 2020 01;42(1):74-78

Paediatrics, Division of Haematology/Oncology.

Kaposiform hemangioendothelioma (KHE) is a rare infiltrative vascular tumor that may be associated with Kasabach-Merritt Phenomenon (KMP), which is a consumptive coagulopathy with potentially life-threatening thrombocytopenia. Management of KHE and KMP is challenging, and currently, there are no standardized validated treatment protocols. Mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of KHE. We describe a term male who presented as a diagnostic dilemma with life-threatening pleural and pericardial effusions and severe thrombocytopenia. After extensive work-up the etiology for his condition was determined to be KHE with KMP. The patient was commenced on sirolimus and responded well to therapy with resolution of KMP.
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http://dx.doi.org/10.1097/MPH.0000000000001268DOI Listing
January 2020

Monitoring pulmonary health in Swiss childhood cancer survivors.

Pediatr Blood Cancer 2018 10 15;65(10):e27255. Epub 2018 Jun 15.

Swiss Childhood Cancer Registry, Institute of Social and Preventive Medicine, University of Bern, Switzerland.

Background: Childhood cancer survivors are at increased risk for pulmonary morbidity and mortality. International guidelines recommend pulmonary function tests (PFT) during follow-up care. This nationwide study assessed how many children received PFT within 5 years after pulmotoxic treatment in Switzerland, types of tests, and predictors for testing.

Methods: We included all children from the Swiss Childhood Cancer Registry who were diagnosed with cancer from 1990 to 2013 at age 0-16 years, survived for ≥2 years from diagnosis, and had pulmotoxic chemotherapy with bleomycin, busulfan, nitrosoureas, and/or chest radiotherapy. We searched medical records in all Swiss pediatric oncology clinics for PFT (spirometry, plethysmography, diffusion capacity of carbon monoxide [DLCO]) and treatment details.

Results: We found medical records for 372 children, of whom 147 had pulmotoxic chemotherapy and 323 chest radiotherapy. Only 185 had plethysmography and/or spirometry (50%), 122 had DLCO (33%). Testing varied by cancer center from 3% to 79% (P = 0.001). Central nervous system tumor survivors and those not treated according to study protocols had less plethysmography and/or spirometry (odds ratio (OR) 0.3 and 0.3), lymphoma survivors and those who were symptomatic had more PFT (plethysmography and/or spirometry: OR 5.9 and 8.7; DLCO: OR 3.4 and 2.3). Cumulative incidence (CuI) of PFT was 52% in the first 5 years after pulmotoxic treatment; most of the tests were done in the first 2 years after treatment (CuI 44%).

Conclusion: Only half of the survivors exposed to pulmotoxic treatment have been followed up with PFT in Switzerland. We need to optimize, update, and implement monitoring guidelines.
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http://dx.doi.org/10.1002/pbc.27255DOI Listing
October 2018

Increased risk of symptomatic upper-extremity venous thrombosis with multiple peripherally inserted central catheter insertions in pediatric patients.

Pediatr Radiol 2018 07 27;48(7):1013-1020. Epub 2018 Feb 27.

Image Guided Therapy, Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Background: Peripherally inserted central catheters (PICCs) are associated with superficial and deep venous thrombosis of the arm.

Objective: The purpose of this study was to analyze the sequelae of repeated upper limb PICC insertions in children, in terms of the frequency of upper limb thrombosis in this patient group.

Materials And Methods: The study population included all children who underwent their first successful arm PICC insertion between January 2010 and December 2015. We included subsequent ipsilateral arm PICCs in the analysis. Patients were followed until March 2016 or until any alternative central venous line insertion. For each PICC insertion, we collected demographic variables and line characteristics. We correlated all symptomatic deep and superficial thromboses of the arm with the PICC database.

Results: Applying inclusion and exclusion criteria, 2,180 PICCs remained for analysis. We identified first, second, third and fourth PICC insertions in the same arm in 1,955, 181, 38 and 6 patients, respectively. In total there were 57 upper body deep symptomatic thrombotic events. An increasing odds ratio was seen with higher numbers of PICC insertions, which was significant when comparing the first with the third and fourth PICC insertions in the same arm (odds ratio [OR] 6.00, 95% confidence interval [CI] 2.25-16.04, P=0.0004). Double-lumen PICCs were associated with a significantly higher risk of thrombosis than single lumen (OR 2.77, 95% CI 1.72-4.47, P=0.0003).

Conclusion: Repetitive PICC insertions in the same arm are associated with an increased risk of symptomatic thrombosis. Double-lumen PICCs are associated with a higher risk of thrombosis compared to single-lumen lines.
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http://dx.doi.org/10.1007/s00247-018-4096-xDOI Listing
July 2018

The clinical impact of copy number variants in inherited bone marrow failure syndromes.

NPJ Genom Med 2017 May;2

Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.

Inherited bone marrow failure syndromes (IBMFSs) comprise a genetically heterogeneous group of diseases with hematopoietic failure and a wide array of physical malformations. Copy number variants (CNVs) were reported in some IBMFSs. It is unclear what impact CNVs play in patients evaluated for a suspected diagnosis of IBMFS. Clinical and genetic data of 323 patients from the Canadian Inherited Marrow Failure Registry from 2001 to 2014, who had a documented genetic work-up, were analyzed. Cases with pathogenic CNVs (at least 1 kilobasepairs) were compared to cases with other mutations. Genotype-phenotype correlations were performed to assess the impact of CNVs. Pathogenic nucleotide-level mutations were found in 157 of 303 tested patients (51.8%). Genome-wide CNV analysis by single nucleotide polymorphism arrays or comparative genomic hybridization arrays revealed pathogenic CNVs in 11 of 67 patients tested (16.4%). In four of these patients, identification of CNV was crucial for establishing the correct diagnosis as their clinical presentation was ambiguous. Eight additional patients were identified to harbor pathogenic CNVs by other methods. Of the 19 patients with pathogenic CNVs, four had compound-heterozygosity of a CNV with a nucleotide-level mutation. Pathogenic CNVs were associated with more extensive non-hematological organ system involvement (=0.0006), developmental delay (=0.006) and short stature (=0.04) compared to nucleotide-level mutations. In conclusion, a significant proportion of patients with IBMFSs harbor pathogenic CNVs which were associated with a more extensive non-hematological phenotype in this cohort. Patients with a phenotype suggestive of IBMFSs but without identification of pathogenic nucleotide-level mutations should undergo specific testing for CNVs.
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http://dx.doi.org/10.1038/s41525-017-0019-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498150PMC
May 2017

Response to treatment with azacitidine in children with advanced myelodysplastic syndrome prior to hematopoietic stem cell transplantation.

Haematologica 2016 12 18;101(12):1508-1515. Epub 2016 Aug 18.

Marrow Failure and Myelodysplasia Program, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Canada

Advanced myelodysplastic syndrome harbors a high risk of progression to acute myeloid leukemia and poor prognosis. In children, there is no established treatment to prevent or delay progression to leukemia prior to hematopoietic stem cell transplantation. Azacitidine is a hypomethylating agent, which was shown to slow progression to leukemia in adults with myelodysplastic syndrome. There is little data on the efficacy of azacitidine in children. We reviewed 22 pediatric patients with advanced myelodysplastic syndrome from a single center, diagnosed between January 2000 and December 2015. Of those, eight patients received off-label azacitidine before hematopoietic stem cell transplantation. A total of 31 cycles were administered and modification or delay occurred in four of them due to cytopenias, infection, nausea/vomiting, and transient renal impairment. Bone marrow blast percentages in azacitidine-treated patients decreased significantly from a median of 15% (range 9-31%) at the start of treatment to 5.5% (0-12%, P=0.02) before hematopoietic stem cell transplantation. Following azacitidine treatment, four patients (50%) achieved marrow remission, and none progressed. In contrast, three untreated patients (21.4%) had progressive disease characterized by >50% increase in blast counts or progression to leukemia. Azacitidine-treated patients had significantly increased 4-year event-free survival (P=0.04); predicted 4-year overall survival was 100% versus 69.3% in untreated patients (P=0.1). In summary, azacitidine treatment prior to hematopoietic stem cell transplantation was well tolerated in pediatric patients with advanced myelodysplastic syndrome, led to partial or complete bone marrow response in seven of eight patients (87.5%), and correlated with superior event-free survival in this cohort.
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http://dx.doi.org/10.3324/haematol.2016.145821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479623PMC
December 2016

Treatment-refractory multi-lineage autoimmune cytopenia after unrelated cord blood transplantation: remission after combined bortezomib and vincristine treatment.

Pediatr Blood Cancer 2014 Nov 29;61(11):2112-4. Epub 2014 Jun 29.

Division of Stem Cell Transplantation (SCT), University Children's Hospital, Zurich, Switzerland.

Autoimmune cytopenias (AC) after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with a dismal prognosis. We describe a 1-year-old female with multi-lineage AC occurring on day +43 after HSCT. Multi-agent treatment with high-dose prednisolone, intravenous immunoglobulins, cyclosporine A, mycophenolate mofetil, sirolimus, and rituximab was unsuccessful. Combined treatment with bortezomib and vincristine in addition to ongoing immunosuppressive therapy was started on day +414 with transfusion-independence after day +444. Immunosuppressants were tapered until day +638. On day +1,121 the patient remained in remission. Bortezomib with vincristine may be a promising treatment modality for refractory AC after HSCT that requires further study.
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http://dx.doi.org/10.1002/pbc.25122DOI Listing
November 2014

Etiology of aseptic meningitis, peripheral facial nerve palsy, and a combination of both in children.

Pediatr Infect Dis J 2010 May;29(5):453-6

Division of Pediatric Infectious Diseases, University Children's Hospital Basel, Basel, Switzerland.

Background: A variety of microorganisms have been shown to cause peripheral facial nerve palsy (PFNP) and/or aseptic meningitis in children. Clinical findings and history may help to predict the specific etiology of these entities.

Method: Children > or =12 months old hospitalized at the University Children's Hospital Basel, Switzerland, from 2000 to 2005 with clinical signs of PFNP and/or aseptic meningitis were studied retrospectively. History, clinical, and laboratory findings were evaluated using analysis of variance with Bonferroni (Dunn) correction.

Results: Of 181 patients, 123 (68%) had aseptic meningitis, 28 (15%) had PFNP, and 30 (17%) had a combination of both. PFNP with aseptic meningitis was associated with Borrelia burgdorferi (Bb) infection in the majority of patients (73%) compared with 11% and 9% of patients with PFNP or aseptic meningitis, respectively. The majority of patients with aseptic meningitis without PFNP had enterovirus infection (63%). In patients with aseptic meningitis, mean leukocyte counts in cerebrospinal fluid (CSF) were higher with enterovirus (565/microL) compared with Bb infection (191/microL; P < 0.01) or unknown causes (258/microL; P < 0.01). Further, CSF mean mononuclear cell proportion was higher in patients with Bb (89%) than in those with enterovirus infection (51%; P < 0.01) or unknown causes (60%; P < 0.01). Mean time interval between onset of disease and admission to hospital showed significant differences between Bb (7.6 days) and enterovirus infection (2.8 days; P < 0.01) or unknown causes (2.0 days; P < 0.01).

Conclusions: Time interval between onset of disease and hospital admission and CSF characteristics can contribute to distinguishing the etiology of aseptic meningitis with or without PFNP. As expected, the most common etiology for aseptic meningitis with PFNP was Bb infection whereas enterovirus infection was the predominant cause for aseptic meningitis alone.
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http://dx.doi.org/10.1097/INF.0b013e3181c3cae6DOI Listing
May 2010