Electronic health record signatures identify undiagnosed patients with common variable immunodeficiency disease.

Human inborn errors of immunity include rare disorders entailing functional and quantitative antibody deficiencies due to impaired B cells called the common variable immunodeficiency (CVID) phenotype. Patients with CVID face delayed diagnoses and treatments for 5 to 15 years after symptom onset because the disorders are rare (prevalence of ~1/25,000), and there is extensive heterogeneity in CVID phenotypes, ranging from infections to autoimmunity to inflammatory conditions, overlapping with other more common disorders. The prolonged diagnostic odyssey drives excessive system-wide costs before diagnosis. Because there is no single causal mechanism, there are no genetic tests to definitively diagnose CVID. Here, we present PheNet, a machine learning algorithm that identifies patients with CVID from their electronic health records (EHRs). PheNet learns phenotypic patterns from verified CVID cases and uses this knowledge to rank patients by likelihood of having CVID. PheNet could have diagnosed more than half of our patients with CVID 1 or more years earlier than they had been diagnosed. When applied to a large EHR dataset, followed by blinded chart review of the top 100 patients ranked by PheNet, we found that 74% were highly probable to have CVID. We externally validated PheNet using >6 million records from disparate medical systems in California and Tennessee. As artificial intelligence and machine learning make their way into health care, we show that algorithms such as PheNet can offer clinical benefits by expediting the diagnosis of rare diseases.

Prevalence of undiagnosed diabetes mellitus and associated factors among adult residents of Mizan Aman town, Southwest Ethiopia: Community-based cross-sectional study.

BACKGROUND: Diabetes mellitus continues to be a significant global public health concern, and it is currently a public health issue in developing nations. In Ethiopia, about three fourth of adult population with diabetes are unaware of their diabetic condition. However, there is a limited research on this specific topic particularly in the study area. OBJECTIVE: To assess prevalence of undiagnosed diabetes mellitus and its associated factor among adult residents of Mizan Aman town, south West Ethiopia. METHODS AND MATERIAL: A community-based cross-sectional study was conducted from May 23 to July 7, 2022, on 627 adult residents of Mizan Aman town. A multi stage sampling technique was used to obtain 646 study units. Interviewer-administered structured questionnaires were employed to gather socio-demographic and behavioral data. Anthropometric measurements were obtained and blood samples were taken from each participants. The fasting blood glucose level was measured after an 8-hour gap following a meal, using a digital glucometer to analyze a blood sample. Data were cleaned and entered into Epi-data v 3.1 and exported to SPSS v. 26 for analysis. Bi-variable analysis was done to select candidate variables and multivariable logistic regression model was fitted to identify independent predictors of undiagnosed diabetes mellitus. Adjusted odds ratio (AOR) with 95% CI was computed and variables with p-value < 0.05 were declared to be predictors of undiagnosed diabetes mellitus. RESULTS: The study revealed that, the overall magnitude of undiagnosed diabetes mellitus was 8.13% (95% CI: 6.1, 10.6). Predictors of undiagnosed diabetes mellitus were; physical activity level less than 600 Metabolic equivalent/min per week (AOR = 3.39, 95%CI 1.08 to 10.66), family history of diabetes mellitus (AOR = 2.87, 95% CI 1.41, 5.85), current hypertension(AOR = 2.9, 95% CI 1.26, 6.69), fruit consumption of fewer than three servings per week(AOR = 2.64, 95% CI 1.18 to 5.92), and sedentary life(AOR = 3.33, 95% CI 1.63 to 6.79). CONCLUSION: The prevalence of undiagnosed diabetes mellitus was 8.13%. Physical inactivity, family history of diabetes mellitus, current hypertension, sedentary life, and fruit servings fewer than three per week were independent predictors of undiagnosed diabetes mellitus.

Prevalence of Diagnosed and Undiagnosed Depression Among US Adults with Human Immunodeficiency Virus: Data from the Medical Monitoring Project.

People with human immunodeficiency virus (PWH) are disproportionately affected by depression, but the recent national estimates for US PWH encompassing both current symptoms and clinical diagnoses to assess missed diagnoses and lack of symptom remission are lacking. We used data from CDC's Medical Monitoring Project (MMP) to report nationally representative estimates of diagnosed and undiagnosed depression among US adult PWH. During June 2021 to May 2022, MMP collected interview data on symptoms consistent with major or other depression and depression diagnoses from medical records of 3928 PWH. We report weighted percentages and prevalence ratios (PRs) to quantify differences between groups on key social and health factors. Overall, 34% of PWH experienced any depression (diagnosis or Patient Health Questionnaire-8); of these, 26% had symptoms but no diagnosis (undiagnosed depression), 19% had both diagnosis and symptoms, and 55% had a diagnosis without symptoms. Among those with depression, persons with a disability (PR: 1.52) and food insecurity (PR: 1.67) were more likely to be undiagnosed. Unemployed persons (PR: 1.62), those experiencing a disability (PR: 2.78), food insecurity (PR: 1.46), or discrimination in human immunodeficiency virus (HIV) care (PR: 1.71) were more likely to have diagnosed depression with symptoms. Those with symptoms (undiagnosed or diagnosed) were less likely to be antiretroviral therapy (ART) dose adherent (PR: 0.88; PR: 0.73) or have sustained viral suppression (PR: 0.62; PR: 0.91) and were more likely to have unmet needs for mental health services (PR: 2.38, PR: 2.03). One-third of PWH experienced depression, of whom nearly half were undiagnosed or still experiencing clinically relevant symptoms. Expanding screening and effective treatment for depression could improve quality of life and HIV outcomes.

Cluster analysis and visualisation of electronic health records data to identify undiagnosed patients with rare genetic diseases.

Rare genetic diseases affect 5-8% of the population but are often undiagnosed or misdiagnosed. Electronic health records (EHR) contain large amounts of data, which provide opportunities for analysing and mining. Data mining, in the form of cluster analysis and visualisation, was performed on a database containing deidentified health records of 1.28 million patients across 3 major hospitals in Singapore, in a bid to improve the diagnostic process for patients who are living with an undiagnosed rare disease, specifically focusing on Fabry Disease and Familial Hypercholesterolaemia (FH). On a baseline of 4 patients, we identified 2 additional patients with potential diagnosis of Fabry disease, suggesting a potential 50% increase in diagnosis. Similarly, we identified > 12,000 individuals who fulfil the clinical and laboratory criteria for FH but had not been diagnosed previously. This proof-of-concept study showed that it is possible to perform mining on EHR data albeit with some challenges and limitations.

Occult liver disease: A multinational perspective.

Occult liver disease refers to the presence of unrecognized chronic liver disease and cirrhosis. Liver disease is currently the eleventh cause of death globally, representing 4% of all deaths in the world. Alcohol consumption is the leading cause of cirrhosis globally, accounting for approximately 60% of cases. The estimated global prevalence of non-alcoholic fatty liver disease (NAFLD) is 32.4% and has been steadily increasing over the last years. Viral hepatitis B and C accounted for 1.3 million deaths in 2020. Several studies in populations at high risk of chronic liver disease (elevated liver enzymes, type 2 diabetes, excessive alcohol consumption) have found an elevated prevalence of occult liver disease. Attempts should be made to assess the prevalence of occult liver disease in Latin America, a region with one of the highest rates of metabolic diseases and excessive alcohol consumption. Screening for NAFLD in high-risk subjects and screening for excessive drinking and alcohol use disorders at every level of medical care is relevant. Efforts should also focus on the early treatment of occult liver disease to try to reduce liver disease burden and, in the case of occult viral hepatitis infection, prevent further spreading.

A qualitative evaluation of patient and parent experiences with an undiagnosed diseases program.

Previous studies have explored patient experiences before being seen or at the beginning of their evaluation by undiagnosed diseases programs. This study provides additional insight into experiences after participation through in-depth, qualitative evaluation, allowing for reflection of current practice and patient/parent needs. Semi-structured interviews were conducted with patients and parents of patients seen at the University of Alabama at Birmingham (UAB)'s unique, clinically focused Undiagnosed Diseases Program (UDP). Analysis of the interviews was guided by a thematic approach. Participants had undergone a diagnostic odyssey before being evaluated by the UDP and remained hopeful for a diagnosis. They appreciated the opportunity to be seen by the UDP. However, perception of experiences differed based on whether evaluation by the UDP led to a diagnosis. Additionally, while participants were pleased with initial communication, they indicated that there were unmet needs regarding follow-up. Patients and parents of patients believe that participation in an undiagnosed diseases program is the best option for diagnosis. The findings of this study provide a general overview of patient experiences and highlight strengths of the UAB UDP while also emphasizing areas to focus the improvement to optimize the benefit to patients and families with undiagnosed and rare diseases, which could be used helpful in the development of similar clinics.

International Undiagnosed Diseases Programs (UDPs): components and outcomes.

Over the last 15 years, Undiagnosed Diseases Programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases, integrating research and clinical care to optimize diagnostic outcomes. This narrative review summarizes the published literature surrounding Undiagnosed Diseases Programs worldwide, including thirteen studies that evaluate outcomes and two commentary papers. Commonalities in the diagnostic and research process of Undiagnosed Diseases Programs are explored through an appraisal of available literature. This exploration allowed for an assessment of the strengths and limitations of each of the six common steps, namely enrollment, comprehensive clinical phenotyping, research diagnostics, data sharing and matchmaking, results, and follow-up. Current literature highlights the potential utility of Undiagnosed Diseases Programs in research diagnostics. Since participants have often had extensive previous genetic studies, research pipelines allow for diagnostic approaches beyond exome or whole genome sequencing, through reanalysis using research-grade bioinformatics tools and multi-omics technologies. The overall diagnostic yield is presented by study, since different selection criteria at enrollment and reporting processes make comparisons challenging and not particularly informative. Nonetheless, diagnostic yield in an undiagnosed cohort reflects the potential of an Undiagnosed Diseases Program. Further comparisons and exploration of the outcomes of Undiagnosed Diseases Programs worldwide will allow for the development and improvement of the diagnostic and research process and in turn improve the value and utility of an Undiagnosed Diseases Program.

Risks and benefits of anesthesia for combined pediatric procedures in the NIH undiagnosed diseases program.

PURPOSE: The NIH Undiagnosed Diseases Program (UDP) aims to provide diagnoses to patients who have previously received exhaustive evaluations yet remain undiagnosed. Patients undergo procedural anesthesia for deep phenotyping for analysis with genomic testing. METHODS: A retrospective chart review was performed to determine the safety and benefit of procedural anesthesia in pediatric patients in the UDP. Adverse perioperative events were classified as anesthesia-related complications or peri-procedural complications. The contribution of procedures performed under anesthesia to arriving at a diagnosis was also determined. RESULTS: From 2008 to 2020, 249 pediatric patients in the UDP underwent anesthesia for diagnostic procedures. The majority had a severe systemic disease (American Society for Anesthesiology status III, 79%) and/or a neurologic condition (91%). Perioperative events occurred in 45 patients; six of these were attributed to anesthesia. All patients recovered fully without sequelae. Nearly half of the 249 patients (49%) received a diagnosis, and almost all these diagnoses (88%) took advantage of information gleaned from procedures performed under anesthesia. CONCLUSIONS: The benefits of anesthesia involving multiple diagnostic procedures in a well-coordinated, multidisciplinary, research setting, such as in the pediatric UDP, outweigh the risks.

Unmet needs in countries participating in the undiagnosed diseases network international: an international survey considering national health care and economic indicators.

Background: Patients, families, the healthcare system, and society as a whole are all significantly impacted by rare diseases (RDs). According to various classifications, there are currently up to 9,000 different rare diseases that have been recognized, and new diseases are discovered every month. Although very few people are affected by each uncommon disease individually, millions of people are thought to be impacted globally when all these conditions are considered. Therefore, RDs represent an important public health concern. Although crucial for clinical care, early and correct diagnosis is still difficult to achieve in many nations, especially those with low and middle incomes. Consequently, a sizeable amount of the overall burden of RD is attributable to undiagnosed RD (URD). Existing barriers and policy aspects impacting the care of patients with RD and URD remain to be investigated. Methods: To identify unmet needs and opportunities for patients with URD, the Developing Nations Working Group of the Undiagnosed Diseases Network International (DNWG-UDNI) conducted a survey among its members, who were from 20 different nations. The survey used a mix of multiple choice and dedicated open questions covering a variety of topics. To explore reported needs and analyze them in relation to national healthcare economical aspects, publicly available data on (a) World Bank ranking; (b) Current health expenditure per capita; (c) GDP per capita; (d) Domestic general government health expenditure (% of GDP); and (e) Life expectancy at birth, total (years) were incorporated in our study. Results: This study provides an in-depth evaluation of the unmet needs for 20 countries: low-income (3), middle-income (10), and high-income (7). When analyzing reported unmet needs, almost all countries (N = 19) indicated that major barriers still exist when attempting to improve the care of patients with UR and/or URD; most countries report unmet needs related to the availability of specialized care and dedicated facilities. However, while the countries ranked as low income by the World Bank showed the highest prevalence of referred unmet needs across the different domains, no specific trend appeared when comparing the high, upper, and low-middle income nations. No overt trend was observed when separating countries by current health expenditure per capita, GDP per capita, domestic general government health expenditure (% of GDP) and life expectancy at birth, total (years). Conversely, both the GDP and domestic general government health expenditure for each country impacted the presence of ongoing research. Conclusion: We found that policy characteristics varied greatly with the type of health system and country. No overall pattern in terms of referral for unmet needs when separating countries by main economic or health indicators were observed. Our findings highlight the importance of identifying actionable points (e.g., implemented orphan drug acts or registries where not available) in order to improve the care and diagnosis of RDs and URDs on a global scale.

[Rare diseases and undiagnosed diseases: advances in neurodevelopment]. / Enfermedades sin diagnóstico y enfermedades raras: avances en neurodesarrollo.

Rare diseases and undiagnosed diseases have recently positioned themselves as clinical entities that provide important opportunities to advance our understanding of gene functions and the impact of them in the individual development. In this review, we present how efforts made over years to understand common diseases, rare diseases and even undiagnosed diseases come together today to cooperatively advances scientific knowledge. These advance in science and new acquired knowledge, make possible to apply the advances obtained in a group of clinical conditions to others with similar phenotypic characteristics or vice versa. The cooperative work of multidisciplinary teams and the communication between clinicians and researchers have and will provide opportunities for better treatments for patients and families across multiple common and rare diseases.

Las enfermedades raras y enfermedades sin diagnóstico se han posicionado en los últimos años como condiciones clínicas que han permitido avanzar el entendimiento de las funciones de los genes y el impacto en el desarrollo del individuo. En esta revisión, presentamos como los esfuerzos individuales hechos por muchos años para entender la fisiopatología de enfermedades comunes, enfermedades raras y otras aún más raras, como las enfermedades sin diagnóstico, que se unen hoy para, de manera cooperativa, avanzar en el conocimiento científico. Estos avances en el conocimiento permiten aplicar los avances obtenidos en un grupo de condiciones clínicas a otras con características fenotípicas similares o viceversa. El trabajo conjunto de equipos multidisciplinarios y la comunicación entre clínicos e investigadores proporcionarán oportunidades para proveer mejores oportunidades de tratamiento para pacientes y familias a lo largo de múltiples diagnósticos comunes o raros.

[Initiative on Rare and Undiagnosed Diseases: Achievements and Future Prospects].

The Initiative on Rare and Undiagnosed Diseases (IRUD) was a project for patients who remain undiagnosed after undergoing various clinical tests. This project includes both the clinical aspect of diagnosing rare diseases and the research aspect of identifying new diseases. Since 2015, the diagnosis rate for undiagnosed patients has been 40-50%. From a clinical perspective, this project demonstrated how genome analysis has become indispensable in rare diseases, especially in pediatrics. From a research standpoint, over 30 diseases have been identified through this project. This project was coordinated with a similar undiagnosed disease program from outside the country, and we strongly believe that much success has been achieved. Future challenges include examining which approaches (e.g., long-read genome analysis, transcriptome analysis, and methylation analysis) would be effective for undiagnosed patients after exome analysis, and developing therapeutic drugs for rare diseases. Future challenges include addressing the approximately 50% of patients whose undiagnosed diseases cannot be diagnosed even after exome analysis and developing therapeutic agents for the rare diseases that have been diagnosed.

Neighborhood-Level Risk Factors for Severe Hyperglycemia among Emergency Department Patients without a Prior Diabetes Diagnosis.

A person's place of residence is a strong risk factor for important diagnosed chronic diseases such as diabetes. It is unclear whether neighborhood-level risk factors also predict the probability of undiagnosed disease. The objective of this study was to identify neighborhood-level variables associated with severe hyperglycemia among emergency department (ED) patients without a history of diabetes. We analyzed patients without previously diagnosed diabetes for whom a random serum glucose value was obtained in the ED. We defined random glucose values ≥ 200 mg/dL as severe hyperglycemia, indicating probable undiagnosed diabetes. Patient addresses were geocoded and matched with neighborhood-level socioeconomic measures from the American Community Survey and claims-based surveillance estimates of diabetes prevalence. Neighborhood-level exposure variables were standardized based on z-scores, and a series of logistic regression models were used to assess the association of selected exposures and hyperglycemia adjusting for biological and social individual-level risk factors for diabetes. Of 77,882 ED patients without a history of diabetes presenting in 2021, 1,715 (2.2%) had severe hyperglycemia. Many geospatial exposures were associated with uncontrolled hyperglycemia, even after controlling for individual-level risk factors. The most strongly associated neighborhood-level variables included lower markers of educational attainment, higher percentage of households where limited English is spoken, lower rates of white-collar employment, and higher rates of Medicaid insurance. Including these geospatial factors in risk assessment models may help identify important subgroups of patients with undiagnosed disease.

Assessment of whole-exome sequencing results in neurogenetic diseases.

Neurogenetic diseases are rare genetic diseases in which neurological findings are prominent. Whole exome sequencing (WES) has led to great advances in the understanding of the causes of neurogenetic diseases. Etiological research ends with the WES method in many patients. This etiological research is called a "diagnostic odyssey" for many families. Here, we present the results of 168 patients who were previously undiagnosed and underwent WES with the suspicion of neurogenetic disease. A total of 168 cases, 94 males and 74 females, with suspected undiagnosed neurogenetic disease were included in the study. We presented the WES results of the patients. The mean age of patients at the time of WES request was 11 years (range 0.25-68 years). Seventy percent (n = 117) of the patients were born from consanguineous marriage. Most of the patients were children (n = 145). Patients were grouped according to age at the time of examination. Patients younger than 18 years of age at the time of examination were classified as children, otherwise adults. Seventy-eight patients had either a pathogenic variant or a likely pathogenic variant so the diagnostic rate for WES in our cohort was %46. Our experience showing the high diagnostic rate of WES, supports its use in undiagnosed neurogenetic diseases. It also affects medical treatment, prognosis and family planning by enabling early diagnosis in patients.

Undiagnosed Rare Genetic Disorders: Importance of Functional Characterization of Variants.

Rare Genetic Disorders (RGDs) are defined as disorders that affect less than 1 in 2000 people, and collectively affect more than 300 million people worldwide [...].

Success and Pitfalls of Genetic Testing in Undiagnosed Diseases: Whole Exome Sequencing and Beyond.

Novel approaches to uncover the molecular etiology of neurodevelopmental disorders (NDD) are highly needed. Even using a powerful tool such as whole exome sequencing (WES), the diagnostic process may still prove long and arduous due to the high clinical and genetic heterogeneity of these conditions. The main strategies to improve the diagnostic rate are based on family segregation, re-evaluation of the clinical features by reverse-phenotyping, re-analysis of unsolved NGS-based cases and epigenetic functional studies. In this article, we described three selected cases from a cohort of patients with NDD in which trio WES was applied, in order to underline the typical challenges encountered during the diagnostic process: (1) an ultra-rare condition caused by a missense variant in MEIS2, identified through the updated Solve-RD re-analysis; (2) a patient with Noonan-like features in which the NGS analysis revealed a novel variant in NIPBL causing Cornelia de Lange syndrome; and (3) a case with de novo variants in genes involved in the chromatin-remodeling complex, for which the study of the epigenetic signature excluded a pathogenic role. In this perspective, we aimed to (i) provide an example of the relevance of the genetic re-analysis of all unsolved cases through network projects on rare diseases; (ii) point out the role and the uncertainties of the reverse phenotyping in the interpretation of the genetic results; and (iii) describe the use of methylation signatures in neurodevelopmental syndromes for the validation of the variants of uncertain significance.

Suspected Undiagnosed ADRD Among Middle Eastern and North African Americans.

ADRD underdiagnosis among minority populations is well-established and known to be more prevalent among women. Yet, it remains unclear if these patterns exist among adults of Middle Eastern and North African (MENA) descent. We estimated ADRD underdiagnosis among adults of MENA descent and other US- and foreign-born non-Hispanic Whites and compared sex-stratified results. We linked 2000-2017 National Health Interview Survey and 2001-2018 Medical Expenditure Panel Survey data (ages > = 65 years, n = 23,981). Undiagnosed ADRD was suspected if participants reported cognitive limitations without corresponding ADRD diagnosis. Undiagnosed ADRD was highest among adults of MENA descent (15.8%) compared to non-Hispanic Whites (US-born = 8.1%; foreign-born = 11.8%). Women of MENA descent had 2.52 times greater odds (95% CI = 1.31-4.84) of undiagnosed ADRD compared to US-born White women after adjusting for risk factors. This study contributes the first national estimates of undiagnosed ADRD among adults of MENA descent. Continued research is needed to facilitate policy changes that more comprehensively address health disparities and related resource allocation.

Implementation of genomic medicine for rare disease in a tertiary healthcare system: Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD).

BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

Severe SARS-CoV-2 infection as a marker of undiagnosed cancer: a population-based study.

No study has yet investigated if a severe SARS-CoV-2 infection represents a marker of an undiagnosed cancer. This population-based study, using the SNDS database, identified from 02/15/2020 to 08/31/2021, 41,302 individuals hospitalized in intensive care unit due to SARS-CoV-2 (ICU-gr) and 713,670 control individuals not hospitalized for SARS-CoV-2 (C-gr). Individuals were matched according to year of birth, sex and French department. The cancer incidence was compared in the two groups during the follow-up period (index date-12/31/2021), using Cox proportional hazards models adjusted on matching variables, socioeconomic characteristics and comorbidities. In the ICU-gr, 2.2% (n = 897) was diagnosed with a cancer in the following months, compared to 1.5% (n = 10,944) in the C-gr. The ICU-gr had a 1.31 higher risk of being diagnosed with a cancer following hospital discharge compared to the C-gr (aHR 1.31, 95% CI 1.22-1.41). A global similar trend was found when competing risk of death was taken into account (aHR 1.25, 95% CI 1.16-1.34). A significant higher risk was found concerning renal (aHR 3.16, 95% CI 2.33-4.27), hematological (aHR 2.54, 95% CI 2.07-3.12), colon (aHR 1.72, 95% CI 1.34-2.21), and lung (aHR 1.70, 95% CI 1.39-2.08) cancers. This suggests that a severe SARS-CoV-2 infection may represent a marker of an undiagnosed cancer.

Empiric treatment for persistent fever from suspected autoinflammatory disease: Experience from an undiagnosed diseases program.

BACKGROUND: Patients with persistent fevers of undetermined etiology often undergo extensive evaluation without a diagnosis. Autoinflammatory syndromes may not always be considered in the differential, as these are rare entities, there are no consensus clinical criteria and genetic testing can only capture a few of these diseases. We aimed to describe the experience and value of an undiagnosed diseases program in the evaluation and management of patients who present with persistent fevers. METHODS: A retrospective analysis was performed on eleven patients who presented with persistent fevers to the Undiagnosed Diseases Program (UDP) at University of Alabama at Birmingham. All patients received extensive testing prior to referral and were seen by multiple subspecialists. The primary outcome of complete remission was resolution of episodes of fever and malaise in response to empiric biological anti-inflammatory treatment. RESULTS: All patients received genetic testing and further diagnostic evaluation by the UDP. Even without confirmed genetic testing, they were empirically started on anti-inflammatory therapies (including colchicine, IL-1 inhibitors, IL-6 inhibitors). Ten patients have achieved complete remission on empiric treatment. Three patients were given formal diagnoses. No patients have had any major adverse events from therapy. CONCLUSIONS: This is a pilot study suggesting the role for empiric treatment trials of biologics for patients with suspected autoinflammatory diseases. As the differential diagnosis of patients with persistent fevers is broad, and the diagnosis of autoinflammatory diseases often comes with some degree of uncertainty, evaluation by a center with expertise in diagnosing these conditions can help determine which patients should have empiric trials of biologics.

Psychological distress of adult patients consulting a center for rare and undiagnosed diseases: a cross-sectional study.

BACKGROUND: Centers for rare diseases serve as contact points for patients with complex, often undiagnosed complaints and persistent somatic symptoms of heterogeneous origin. Little is known about psychological distress of patients consulting these centers. OBJECTIVES: To better understand psychological distress of adult patients presenting at a center for rare diseases by determining the proportion of patients screening positive for depressive, anxiety, and somatic symptom disorders (SSD) and to identify factors associated with increased psychopathology. METHODS: Cross-sectional data from the routine care registry of the Martin Zeitz Center for Rare Diseases (MZCSE) at the University Medical Center Hamburg-Eppendorf in Germany was retrieved and analyzed. We included all adult patients presenting between October 01,2020 and September 30,2021, who gave written informed consent. MEASURES: Sociodemographic variables, medical history and healthcare utilization, as well as validated measures to screen for a depressive disorder (PHQ-8), an anxiety disorder (GAD-7), and SSD (PHQ-15, SSD-12). RESULTS: N = 167 patients were included (age 44.5 ± 14.3 years, 64.7% female). A total of 40.7% of the patients screened positive for a depressive disorder (PHQ-8 ≥ 10), 27.5% for an anxiety disorder (GAD-7 ≥ 10) and 45.0% screened positive for SSD (PHQ-15 ≥ 9 & SSD-12 ≥ 23). Factors associated with increased psychopathology included the number of symptoms, the number of different specialties consulted before and past psychotherapy. CONCLUSIONS: Patients presenting at centers for rare diseases are likely to experience high rates of psychological distress. Systematically screening patients with rare and undiagnosed diseases for mental disorders can help to detect those at risk at an early stage and initiate adequate psychological care.