Orphanet Journal of Rare Diseases | Real-World Data from the Heidelberg Registry of Chronic Singultus (HeReChroS) Reveals Disease Burden and Comorbidity Profiles

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This study reveals the extremely high comorbidity rates and psychological burden in patients with chronic singultus, suggesting that the construction of multi-system disease models and the assessment of psychobehavioral indicators must be prioritized in experimental design.

 

Overview

This article, "Real world data from the Heidelberg Registry of Chronic Singultus (HeReChroS)," published in the "Orphanet Journal of Rare Diseases," systematically explores the initial cohort characteristics of the Chronic Singultus Registry (HeReChroS) established at Heidelberg University in Germany. It aims to fill knowledge gaps in epidemiology, symptomatology, and comorbidity management for this rare disease through real-world data.

Background

Chronic singultus (persisting for more than one month) is a rare disease that severely impacts quality of life, with pathophysiological mechanisms involving abnormalities in the reflex arc formed by the vagus and phrenic nerves. A major clinical challenge is the lack of systematic epidemiological data, leading to difficulties in etiological diagnosis and often accompanied by a severe comorbidity burden. Existing studies focus mainly on case reports, lacking quantitative analysis of multi-system disease associations. This study leverages large registry data to quantify disease burden and mental health status, particularly the high prevalence of depression and anxiety in chronic singultus patients, providing key evidence for understanding the neurological mechanisms and formulating comprehensive treatment strategies.

 

Diseases Comparison: Analyze the intrinsic links between chronic singultus and multi-system comorbidities at the gene and pathway levels, assisting researchers in deep mining of cross-disease mechanisms.

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Methods and Core Experiments

This study employed a retrospective single-center real-world data analysis approach, enrolling 131 patients who were first seen at the Heidelberg Chronic Singultus Center between October 2022 and March 2025. The research team used standardized Case Report Forms (CRFs) to collect data on demographics, medical history, comorbidities, medication use, and Patient-Reported Outcomes (PROs). Key evidence was presented through descriptive statistics, including the use of the DASS-21 scale to assess psychological status and recording comorbidity frequencies in systems such as gastrointestinal, vascular, and pulmonary.

Key Conclusions and Perspectives

• Data Findings: 79% of the 131 patients were male, with a median symptom duration of 19 months; the comorbidity burden was extremely heavy, with a median of 3 organ system diseases, where gastrointestinal diseases accounted for 75% and vascular diseases for 52%.
• Data Findings: Patient quality of life was significantly impaired, with an average well-being score of only 35.3/100; psychological screening showed 42% of patients had depression, and 15% reported suicidal ideation.
• Data Findings: Associated symptoms were prevalent, with 90% of patients experiencing fatigue, 80% having sleep disorders, and 70% reporting attention difficulties, suggesting that singultus is not merely a local reflex abnormality but a manifestation of systemic multi-system disorder.
• Data Findings: 64% of patients experienced singultus attacks during sleep, refuting the traditional view that "cessation at night implies a psychological cause" and supporting an organic neurological mechanism basis.

Significance and Outlook

These findings offer significant guidance for drug development, suggesting that treatment for chronic singultus should not be limited to antiemetics or muscle relaxants but must include comprehensive intervention strategies targeting anxiety, depression, and sleep disorders. In terms of clinical monitoring, establishing standardized multi-center registries will help identify potential biomarkers and optimize treatment pathways. Furthermore, this study provides real-world data support for building more precise disease models in the future, particularly for the analysis of complex cases involving multi-system comorbidities.

 

Signal Path: Input genes related to the vagus or phrenic nerves to quickly view their associated signaling pathways and upstream/downstream molecules, aiding in the analysis of the molecular mechanisms of the singultus reflex arc.

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Conclusion

The initial data analysis from the Heidelberg Registry of Chronic Singultus (HeReChroS) not only quantified the devastating impact of chronic singultus on patients' physiological, psychological, and social functions but also revealed its close association with multi-system diseases and mental health issues. The study confirms that a depression prevalence rate of up to 42% and a 15% suicide risk indicate that the clinical care system must shift from simple neurological reflex treatment to a multidisciplinary comprehensive management model. This finding points the way for future drug development, indicating the need to develop new therapies that can simultaneously alleviate somatic symptoms and psychological burdens. At the same time, the establishment of this registry provides valuable resources for disease modeling and long-term follow-up, promoting the translation from laboratory mechanism research to clinical precision medicine, ultimately improving the quality of life for rare disease patients.

 

Claudia Busch, Marco Richard Zugaj, Nelly Zental, and Jens Keßler. Real world data from the Heidelberg Registry of Chronic Singultus (HeReChroS). Orphanet Journal of Rare Diseases.