Diagnostic Delay in PHTN

Diagnostic Delay in Pulmonary Hypertension: Determinants and Impact on Disease Severity at Initial Presentation

Pulmonary hypertension (PH) is a progressive cardiopulmonary condition that may remain undiagnosed for a prolonged period because its initial symptoms are often nonspecific. This study aims to assess the relationship between diagnostic delay and disease severity at the time of initial presentation among adult patients with pulmonary hypertension at Assiut University Heart Hospital. The study will use an observational cross-sectional analytical design with retrospective review of available medical records and prospective data collection. Eligible patients will be consecutively recruited. Data will include demographic and clinical characteristics, duration of symptoms before diagnosis, previous medical consultations and diagnoses, WHO functional class, six-minute walk distance, echocardiographic findings, laboratory investigations, and available right heart catheterization data. The primary outcome is advanced disease at presentation, defined as WHO functional class III-IV. The study will also assess clinical, echocardiographic, functional, and hemodynamic markers of disease severity and potential factors associated with diagnostic delay.

Pulmonary hypertension (PH) is a complex cardiopulmonary syndrome associated with progressive pulmonary vascular disease and right ventricular overload. Its early clinical manifestations, including exertional dyspnea, fatigue, reduced exercise tolerance, chest discomfort, palpitations, presyncope, syncope, and peripheral edema, are often nonspecific and may overlap with common cardiac, respiratory, hematological, and other conditions. This may contribute to delayed recognition and referral for specialist assessment.

The present study aims to assess the relationship between the duration of diagnostic delay and disease severity at the time of initial presentation among adult patients with pulmonary hypertension attending the Pulmonary Hypertension Unit at Assiut University Heart Hospital. The study will also identify potential patient- and healthcare-related factors associated with delayed diagnosis.

This will be an observational cross-sectional analytical study with retrospective chart review and prospective data collection. Consecutive sampling will be used. All eligible adult patients with pulmonary hypertension fulfilling the predefined inclusion criteria will be recruited until the required sample size is reached. Patients identified from previously available medical records may be included when the required clinical and investigation data are available and the patient fulfills the eligibility criteria. Relevant prospective data will be collected during the study period.

Eligible participants will be adults aged 18 years or older with pulmonary hypertension diagnosed by right heart catheterization when available, or based on high echocardiographic probability or clinician diagnosis when right heart catheterization is not available. Participants should have baseline clinical assessment at or near the time of diagnosis or first presentation and should be able to provide an approximate date or month/year of the first PH-related symptom. Patients with unreliable information regarding symptom onset without alternative documentation, incomplete baseline data preventing assessment of disease severity, acute pulmonary embolism as the sole acute cause of transient pulmonary pressure elevation, or inability to complete the required assessment will be excluded.

Data will be collected using a structured case report form, standardized questionnaire, and review of available clinical records and investigations. Information will include demographic characteristics, residence, occupation, education, smoking status, comorbidities, presenting symptoms, date of first PH-related symptom, date of first medical consultation, initially consulted specialty, number of physicians visited, previous diagnoses, date of first echocardiography, date of suspected PH diagnosis, date of confirmed diagnosis, and patient-reported reasons for diagnostic delay.

Clinical assessment will include symptoms and signs of right-sided heart failure, WHO functional class, vital signs, oxygen saturation, relevant comorbidities, and medications. Functional capacity will be assessed using the six-minute walk distance when available. Available laboratory investigations, particularly hemoglobin and serum creatinine, will be recorded.

Available baseline echocardiographic data will be reviewed, including right atrial size, right ventricular basal diameter, RV systolic function, TAPSE, TR velocity, estimated pulmonary artery systolic pressure, IVC diameter and collapsibility, pericardial effusion, LV ejection fraction, LV diastolic function, left atrial size, valvular disease, and congenital shunts when present.

Right heart catheterization data will be recorded when available as part of routine clinical care, including right atrial pressure, right ventricular pressure, pulmonary artery pressures, pulmonary artery wedge pressure, pulmonary vascular resistance, cardiac output, cardiac index, pulmonary artery/mixed venous oxygen saturation, systemic blood pressure, and vasoreactivity testing results. Right heart catheterization will not be performed solely for research purposes.

The primary outcome will be advanced disease at initial presentation, defined as WHO functional class III-IV. Secondary outcomes will include six-minute walk distance below 300 meters, TAPSE below 17 mm, moderate or severe RV systolic dysfunction, moderate or severe right atrial or right ventricular dilatation, moderate or severe tricuspid regurgitation, pericardial effusion, clinical signs of right-heart failure, hospitalization before diagnosis, and high-risk right heart catheterization features such as elevated right atrial pressure, low cardiac index, and high pulmonary vascular resistance.

Exploratory outcomes will include the number of physicians visited before diagnosis, the first specialty consulted, initial misdiagnosis, and patient-reported causes of diagnostic delay.

Data will be analyzed using appropriate statistical methods. Categorical variables will be compared using the Chi-square or Fisher's exact test, while continuous variables will be analyzed using the independent-samples t-test or Mann-Whitney U test according to data distribution. Correlation analysis will assess the relationship between diagnostic delay in months and continuous severity markers. Multivariable logistic regression will be used to identify independent predictors of advanced disease presentation, with WHO functional class III-IV as the dependent variable. Odds ratios with 95% confidence intervals will be reported, and a two-sided p-value <0.05 will be considered statistically significant.

Medical records will be used whenever possible to verify important dates and investigation results in order to reduce recall bias. No additional invasive procedure will be performed solely for research purposes, and all investigations will be recorded only when performed as part of routine clinical care.

Inclusion Criteria:

• 1. Age 18 years or older

  2. Patients with pre-capillary pulmonary hypertension, Group 1 PAH, Group 3 PH associated with lung disease/hypoxia, Group 4 chronic thromboembolic pulmonary hypertension (CTEPH) or other pulmonary artery obstructions, and Group 5 PH with unclear or multifactorial mechanisms.

  3. Diagnosis of pulmonary hypertension based on RHC when available, or high echocardiographic probability/clinician diagnosis of PH when RHC is not available.

  4. Availability of baseline clinical assessment at or near the time of diagnosis or first PH-unit presentation.

  5. Ability to provide an approximate date or month/year of first PH-related symptom.

  6. Willingness to participate and provide informed consent.

Exclusion Criteria:

• 1. Inability to provide reliable information about symptom onset and no alternative documentation in the medical record.

  2. Incomplete baseline data preventing classification of disease severity. 3. Post-capillary pulmonary hypertension due to left heart disease (Group 2 PH).

  4. Acute pulmonary embolism as the sole acute cause of transient pulmonary pressure elevation at presentation.

  5. Severe acute illness, cognitive impairment, or communication barrier preventing questionnaire completion.

  6. Refusal to participate. 7. Optional exclusion according to committee preference: patients with isolated post-capillary PH due to left heart disease may be excluded if the aim is to focus on PAH/pre-capillary PH.