Path to Diagnosis of Paroxysmal Nocturnal Hemoglobinuria: The Results of an Exploratory Study Conducted By the Aplastic Anemia and Myelodysplastic Syndrome International Foundation and the National Organization for Rare Disorders Utilizing an Internet-Based Survey
Authors: Shammo Jamile M. , Mitchell Rachel L , Ogborn Kylene , Salkeld Ellen , Chisolm Stephanie 
Published: October 2019

Abstract
Introduction:
Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare bone marrow failure disorder characterized by thrombosis and chronic intravascular hemolysis. Symptoms commonly associated with PNH include headaches, fatigue, weakness and back and abdominal pain. PNH has an adverse impact on patient's mortality and quality of life. Little research has been performed to understand and delineate the patients' experiences from onset of symptoms to diagnosis and very few reputable websites are available as resources for both healthcare providers and patients. The purpose of this study was to elucidate the patients' path leading up to diagnosis and impact on quality of life surrounding the diagnosis of PNH in collaboration with the Aplastic Anemia and Myelodysplastic International Foundation (AA&MDSIF) and the National Organization for Rare Disorders (NORD) by utilizing an internet-based survey.
Methods:
The authors initially conducted an open-ended qualitative interview with 12 patients covering topics including history of symptoms, journey through the health care system, experience at diagnosis and strategies for coping with the disease. Utilizing ATLAS.ti software for data management and text searching interview data, the authors identified the most prominent topics for use in creating a 32 question survey representative of key issues related to the path to diagnosis. The survey was distributed to 1066 patients and families identified as having PNH from the databases of the AA&MDSIF and NORD.
Results:
In total, 163 patients with PNH responded to the survey during a one month period. Patients' age ranged from 13-85 years of age. Of those reporting gender (n=158), 70% (110) were female and 30% (48) were male. Patients reported a wide range of symptoms prior to diagnosis and the most common were fatigue (88%), weakness (73%), dyspnea (66%), hemoglobinuria (61%), headaches (59%), bruising or bleeding (58%), back pain (53%) and abdominal pain (52%) (Figure 1). While the average time to diagnosis was reported to be less than 2 years, patients reported a very broad range. Thirty-eight percent (38%) of diagnoses were made within 1 year of symptom onset whereas 24% took between 1-2 years. Thirty-seven percent (37%) reported time to diagnosis greater than 2 years and 24% greater than 5 years. Patients were evaluated by multiple healthcare providers on the path to diagnosis. Seventy-nine percent (79%) of patients reported consulting greater than 1 physician prior to PNH diagnosis; 31% of those patients saw 2 physicians whereas nearly 38% indicated they saw 5 or more physicians prior to diagnosis (Table 1). Interestingly, 82% of patients reported researching PNH online. Patients reported accessing multiple resources they felt were valuable including AA&MDSIF, Paroxysmal Nocturnal Hemoglobinuria Foundation, NORD, Alexion/eculizumab, Mayo Clinic and National Institutes of Health.
Conclusion:
This study was designed to explore pre-diagnosis symptoms and characteristics of patient interface with the healthcare system during the process of diagnosis. The average length of time to diagnosis was less than 2 years but the course remained taxing with multiple physicians consulted along the way. Despite reputable resources being utilized, many patients received outdated information regarding their diagnosis. Raising awareness of symptoms of PNH and approach to diagnosis is important in shortening time to diagnosis and reducing distress associated with the process. Improved resources post-diagnosis as well as increased awareness and understanding of symptomatology may lead to quicker diagnosis in patients with PNH. This study was not designed to capture adverse outcomes related to delayed diagnosis except for impact on patient-reported quality of life however, more research is needed in this area.
Table 1. Order of physicians consulted prior to diagnosis MD n 1st 2nd 3rd 4th 5th Never Cardiologist 114 4 (4%) 3 (3%) 4 (4%) 3 (3%) 5 (5%) 95 (83%) ER MD 124 24 (19%) 27 (22%) 3 (2%) 3 (2%) 5 (2%) 52 (42%) Hematologist 150 19 (13%) 50 (33%) 42 (28%) 17 (11%) 12 (8%) 10 (6%) Nephrologist 102 2 (2%) 7 (7%) 7 (7%) 7 (7%) 3 (3%) 76 (74%) Neurologist 99 0 (0%) 4 (4%) 4 (4%) 2 (2%) 5 (5%) 84 (85%) OB/GYN 82 11 (13%) 10 (12%) 5 (6%) 1 (1%) 1 (1%) 53 (66%) PCP 148 90 (61%) 18 (12%) 4 (3%) 4 (3%) 5 (4%) 19 (13%)
Figure 1. Signs and symptoms experienced by patients leading up to diagnosis of PNH. Figure 1. Signs and symptoms experienced by patients leading up to diagnosis of PNH.

Disclosures
Shammo: Onconova: Research Funding.