BackgroundWorldwide approximately 7,000 rare diseases have been identified. Accordingly, 4 million individuals live with a rare disease in Germany. The mean time to diagnosis is about 6 years and patients receive several incorrect diagnoses during this time. A multiplicity of factors renders diagnosing a rare disease extremely difficult. Detection of shared phenomena among individuals with different rare diseases could assist the diagnostic process. In order to explore the demand for diagnostic support and to obtain the commonalities among patients, a nationwide Delphi survey of centers for rare diseases and patient groups was conducted.MethodsA two-step Delphi survey was conducted using web-based technologies in all centers for rare diseases in Germany. Moreover, the leading patient support group, the German foundation for rare diseases (ACHSE), was contacted to involve patients as experts in their disease. In the survey the experts were invited to name rare diseases with special need for diagnostic improvement. Secondly, communal experiences of affected individuals were collected.Results166 of 474 contacted experts (35%) participated in the first round of the Delphi process and 95 of 166 (57%) participated in the second round. Metabolic (n = 74) and autoimmune diseases (n = 39) were ranked the highest for need for diagnostic support. For three diseases (i.e. scleroderma, Pompe’s disease, and pulmonary arterial hypertension), a crucial need for diagnostic support was explicitly stated. A typical experience of individuals with a rare disease was stigmatization of having psychological or psychosomatic problems. In addition, most experts endured an ‘odyssey’ of seeing many different medical specialists before a correct diagnosis (n = 38) was confirmed.ConclusionThere is need for improving the diagnostic process in individuals with rare diseases. Shared experiences in individuals with a rare disease were observed, which could possibly be utilized for diagnostic support in the future.

Background Invasive mold disease (IMD) is a severe infectious complication in immunocompromised patients. The outcome of central nervous system (CNS) IMD is poor, but contemporary data, in particular in the pediatric setting, are lacking. Procedure For this retrospective multicenter analysis, pediatric patients < 18 years with proven or probable CNS IMD receiving chemotherapy or undergoing allogeneic HSCT were reported by the local investigator. CNS IMD had to be diagnosed between 2007 and 2016. Proven CNS IMD was defined as compatible CNS imaging or macroscopic autopsy findings in conjunction with a positive microscopic or microbiological result in the brain tissue or cerebrospinal fluid. Probable CNS IMD was defined as compatible CNS imaging findings in combination with proven or probable IMD at a site outside the CNS. Results and conclusions A total of 29 patients (median age, 14 years; 14 allogeneic HSCT recipients) were diagnosed with proven (n = 12) or probable (n = 17) CNS IMD. Aspergillus spp. was the most common fungal pathogen. All but one patient had IMD sites outside the CNS and eight patients (27.6%) were neurologically asymptomatic at diagnosis of CNS IMD. Forty‐nine percent of the patients survived CNS IMD; however, 46.7% of the survivors suffered from severe long‐term neurological sequelae. Our data suggest that (1) outcome of CNS IMD has improved in children as compared with previous series, (2) half of surviving patients suffer from severe neurological sequelae, and (3) imaging of the CNS should be performed in all children with IMD irrespective of neurological symptoms.

Background: Due to the difficulties in the definite diagnosis, data on brain imaging in pediatric patients with central nervous system (CNS)-invasive mold infection (IMD) are scarce. Our aim was to describe brain imaging abnormalities seen in immunocompromised children with CNS-IMD, and to analyze retrospectively whether specific imaging findings and sequences have a prognostic value. Methods: In a retrospective study of 19 pediatric patients with proven or probable CNS-IMD, magnetic resonance imaging (MRI)-findings were described and analyzed. The results were correlated with outcome, namely death, severe sequelae, or no neurological sequelae. Results: 11 children and 8 adolescents (11/8 with proven/probable CNS-IMD) were included. Seven of the patients died and 12/19 children survived (63%): seven without major neurological sequelae and five with major neurological sequelae. Multifocal ring enhancement and diffusion restriction were the most common brain MRI changes. Diffusion restriction was mostly seen at the core of the lesion. No patient with disease limited to one lobe died. Perivascular microbleeding seen on susceptibility weighted imaging (SWI) and/or gradient-echo/T2* images, as well as infarction, were associated with poor prognosis. Conclusions: The presence of infarction was related to poor outcome. As early microbleeding seems to be associated with poor prognosis, we suggest including SWI in routine diagnostic evaluation of immunocompromised children with suspected CNS-IMD.

BackgroundRare diseases (RD) result in a wide variety of clinical presentations, and this creates a significant diagnostic challenge for health care professionals. We hypothesized that there exist a set of consistent and shared phenomena among all individuals affected by (different) RD during the time before diagnosis is established.ObjectiveWe aimed to identify commonalities between different RD and developed a machine learning diagnostic support tool for RD.Methods20 interviews with affected individuals with different RD, focusing on the time period before their diagnosis, were performed and qualitatively analyzed. Out of these pre-diagnostic experiences, we distilled key phenomena and created a questionnaire which was then distributed among individuals with the established diagnosis of i.) RD, ii.) other common non-rare diseases (NRO) iii.) common chronic diseases (CD), iv.), or psychosomatic/somatoform disorders (PSY). Finally, four combined single machine learning methods and a fusion algorithm were used to distinguish the different answer patterns of the questionnaires.ResultsThe questionnaire contained 53 questions. A total sum of 1763 questionnaires (758 RD, 149 CD, 48 PSY, 200 NRO, 34 healthy individuals and 574 not evaluable questionnaires) were collected. Based on 3 independent data sets the 10-fold stratified cross-validation method for the answer-pattern recognition resulted in sensitivity values of 88.9% to detect the answer pattern of a RD, 86.6% for NRO, 87.7% for CD and 84.2% for PSY.ConclusionDespite the great diversity in presentation and pathogenesis of each RD, patients with RD share surprisingly similar pre-diagnosis experiences. Our questionnaire and data-mining based approach successfully detected unique patterns in groups of individuals affected by a broad range of different rare diseases. Therefore, these results indicate distinct patterns that may be used for diagnostic support in RD.

Invasive mold disease (IMD) of the central nervous system (CNS) is a severe infectious complication in immunocompromised patients, but early microbiological diagnosis is difficult. As data on the value of biomarkers in the CNS are scarce, in particular in children, we retrospectively analyzed the performance of galactomannan (GM) and PCR assays in CNS samples of 15 children with proven and probable CNS IMD and of 32 immunocompromised children without fungal infection. Galactomannan in the cerebrospinal fluid (CSF) was assessed in nine of the 15 pediatric patients and was positive in five of them. Polymerase chain reaction (PCR) was performed in eight of the 15 patients and detected nucleic acids from molds in six patients. Galactomannan and PCR in CNS samples were the only positive microbiologic parameter in the CNS in three and two patients, respectively. In four patients, PCR specified the pathogen detected in microscopy. Galactomannan and PCR results remained negative in the CSF of all immunocompromised children without evidence for CNS IMD. Our data suggest that GM and PCR in CNS specimens are valuable additional tools in diagnosing CNS IMD and should be included in the work up of all pediatric patients with suspected mold disease of the CNS.