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How to cite this article Mitchell R, Salkeld E, Chisolm S, Clark M and Shammo JM. Path to Diagnosis of Paroxysmal Nocturnal Hemoglobinuria: The Results of an Exploratory Study Conducted by the

Aplastic Anemia and MDS International Foundation and the National Organization for Rare Disorders Utilizing an Internet-Based Survey. SM Clin Med Oncol. 2017; 1(1): 1001.

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IntroductionParoxysmal Nocturnal Hemoglobinuria (PNH) is an ultra-rare bone marrow failure state

characterized by hemolytic anemia, cytopenias, and serious thrombohemorrhagic complications, resulting in significant comorbidities and shorter survival compared with that of the general population [1-3]. The prevalence of PNH worldwide, regardless of ethnicity, is estimated at 1-5 cases per million [4]. PNH occasionally occurs in conjunction with other bone marrow failure states such as Aplastic Anemia (AA) and Myelodysplastic Syndromes (MDS). Symptoms of PNH can be non-specific and quite variable among individuals and can pose diagnostic and therapeutic challenges for healthcare providers, often resulting in missed or delayed diagnoses. Although often times non-specific, symptoms have been associated with serious consequences and can significantly impact patient’s quality of life and survival [5].

Currently, treatment for PNH includes supportive measures such as anticoagulation to prevent or treat thrombosis, red blood cell and platelet transfusions and antibiotics to treat infections [6]. The only FDA-approved treatment is eculizumab, a humanized monoclonal antibody that binds C5 complement protein. The only curative treatment option is allogeneic hematopoietic stem cell transplantation [7,8]. Determining which patients with PNH may benefit from allogeneic stem cell transplantation is challenging, and is dependent upon age, performance status, availability of suitable donor and certain disease characteristics including presence of thromboembolism [9].

Given the rarity of PNH and reported lag in making the diagnosis, very little data exists in the literature regarding the patients’ path to diagnosis including experience within the healthcare system, impact of reported delay of diagnosis, and emotional well-being during “time to diagnosis” period. We, along with the Aplastic Anemia and MDS International Foundation (AA&MDSIF)

Research Article

Path to Diagnosis of Paroxysmal Nocturnal Hemoglobinuria: The Results of an Exploratory Study Conducted by the Aplastic Anemia and MDS International Foundation and the National Organization for Rare Disorders Utilizing an Internet-Based SurveyRachel Mitchell1, Ellen Salkeld2, Stephanie Chisolm2, Melanie Clark1 and Jamile M Shammo1*1Section of Hematology, Rush University Medical Center, Chicago, IL2Department of Oncology, Aplastic Anemia and Myelodysplastic Syndrome International Foundation, Bethesda, MD

Article Information

Received date: May 22, 2017 Accepted date: Jun 15, 2017 Published date: Jun 29, 2017

*Corresponding author

Jamile M Shammo, section of Hematology, Rush University Medical Center, 1725 West Harrison Street, Suite 809, Chicago, IL 60612, United States, Tel: 312-942-5157; Fax: 312-563-4144; Email: jamile_shammo@rush.edu

Distributed under Creative Commons CC-BY 4.0

Keywords PNH; QoL; Diagnosis; Patient survey; Patient experience

Abstract

Paroxysmal Nocturnal Hemoglobinuria has an adverse impact on patients’morbidity and mortality, however, little research has been performed to understand their experiences from onset of symptoms to diagnosis. The purpose of this study was to elucidate the patients’ path to diagnosis and impact on certain aspects of quality of life surrounding the diagnosis of PNH.A 32-question survey related to the path to diagnosis was distributed to patients identified as having PNH from the Aplastic Anemia and MDS International Foundation and the National Organization for Rare Disorders databases.Patients reported a wide range of symptoms with multiple healthcare providers encountered prior to diagnosis.Although the average length of time to diagnosis was less than 2 years, the course remained emotionally taxing. Raising awareness of symptoms of PNH and approach to diagnosis is important in decreasing time to diagnosis and reducing distress associated with the process.

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Citation: Mitchell R, Salkeld E, Chisolm S, Clark M and Shammo JM. Path to Diagnosis of Paroxysmal Nocturnal Hemoglobinuria: The Results of an Exploratory Study Conducted by the Aplastic Anemia and MDS International Foundation and the National Organization for Rare Disorders Utilizing an Internet-Based Survey. SM Clin Med Oncol. 2017; 1(1): 1001. Page 2/4

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and the PNH Research and Support Foundation (PNHF), designed an internet-based study to explore the patient journey from the initial “disease-related medical episode” to document the path to PNH diagnosis.The experience of a diagnosis of an ultra-rare disease lies at the heart of this study, as better understanding of experiences encountered on the path to diagnosis identifies both professional and patient education opportunities to raise awareness and shorten time to diagnosis and treatment. Furthermore, early identification of PNH may prevent disease-associated morbidity and mortality.

Materials and MethodsStudy materials/surveys were approved by Western Institutional

Review Board (WIRB). Recruitment for both qualitative and quantitative sections of the study was conducted via social media channels and email lists. Consent was obtained via email for the interview portion and via internet link for the survey. Only individuals that participated in the interview received monetary compensation for their contribution.

Currently, there is no validated tool used as a quality of care measure specific for PNH. Therefore, we sought to construct one such tool for this survey that would serve as a qualitative measure of key issues pertaining to PNH patients as they undertook the path to diagnosis. Initially, we conducted 12 telephone interviews and then developed a survey encompassing the main themes and topics identified in the interviews to create an internet-based survey in order to assess a larger group of patients. AA&MDSIF and the National Organization for Rare Disorders (NORD) sent emails to patients and families from their respective databases, inviting patients with PNH to participate in the survey. Responses were collected over a one month period.

We collected basic patient demographic information as well as disease-specific information including date of first disease-related symptom, date of diagnosis, numbers of physicians encountered during the process, previous diagnoses and treatments received, information available on PNH as a diseaseand information regarding quality of life as defined by our study as issues including psychological stressors, social support and employment concerns resulting from a diagnosis of PNH. The survey also included areas of free text for participants to express their thoughts not otherwise captured that were relevant to the active pursuit, experience, and consequences of a PNH diagnosis.

ResultsOver 1 month, the survey was sent to 1066 patients with a total of

163 participants yielding a 15% response rate (Table 1).

The most prominent symptoms identified as the reason for seeking medical attention prior to diagnosis were fatigue, excessive weakness and hematuria, reported in 88%, 73% and 62% of surveys, respectively. Other common symptoms included dyspnea (66%), abdominal pain (52%), and back pain (53%). Interestingly, 12% of patients reported developing blood clots (Figure 1).

Fifty-four (54) percent of the participants identified their primary care physician as the first clinician consulted for symptoms, whereas, 15% sought care in the emergency department. Hematologists and obstetrician-gynecologists were also seen for initial evaluation, 11% and 7%, respectively. Only a third of patients were subsequently

referred to a hematologist. One hundred twenty-nine (129) patients consulted more than 1 provider prior to their diagnosis; 31% saw 2, 18.6% saw 3 and 12.4% saw 4. Nearly 38% indicated they saw 5 or more physicians prior to receiving a diagnosis of PNH. Interestingly, only 23% of patients were ever evaluated by an urologist. Furthermore, 11% of patients were sent to a mental health specialist and many were following multiple specialists’ evaluations (Table 2).

Time from onset of symptoms to diagnosis of PNH varied widely (Figure 2). The majority of patients reported receiving a diagnosis within 2 years (38% in 1 year, 24% between 1 and 2 years), but the remaining 37% were diagnosed greater than 2 years from symptom onset with the majority of that subset receiving their diagnosis more than 5 years after symptom onset.

Active pursuit of diagnosis

Participants were offered the opportunity to describe their path to diagnosis. Three key areas emerged as important to patients during their diagnostic journeys: psychological distress during the diagnosis, interaction with the healthcare systems and lingering effects of the experience as well as the impact of the ultimate diagnosis of PNH.

Figure 1: Patient self-reported symptoms prior to diagnosis with PNH.

Table 1: Demographic characteristics of survey participants.

Total Respondents (n=163)

Age (years)

Mean 45

Median 45

Range 13-85

Sex

Not answered 5

Female 110 (70%)

Male 48 (30%)

Race/Ethnicity

Not answered 30 (18%)

White/Caucasian 112 (69%)

Asian 7 (4%)

Black 6 (4%)

Hispanic 4 (2%)

More than one race 4 (2%)

Citation: Mitchell R, Salkeld E, Chisolm S, Clark M and Shammo JM. Path to Diagnosis of Paroxysmal Nocturnal Hemoglobinuria: The Results of an Exploratory Study Conducted by the Aplastic Anemia and MDS International Foundation and the National Organization for Rare Disorders Utilizing an Internet-Based Survey. SM Clin Med Oncol. 2017; 1(1): 1001. Page 3/4

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Many patients shared the impact of emotional strife duringthe limbo period, some enduring periods of hopelessness and anxiety. Patients who encountered prolonged testing were significantly more frustrated with the uncertainty of a diagnosis whereas respondents whom had a more direct path to diagnosis expressed less emotional distress. The majority of study respondents were diagnosed within 2 years (Figure 2). Nonetheless, the responses used to describe the path produced an illustrative glance into the impact it had on people’s lives, even years later.

Some patients described their path as a series of disconnected events. Even in the case of one patient with an associated blood disorder (aplastic anemia) who was being actively monitored, the participant was unaware of the next step once her counts significantly dropped, seemingly for no reason. Some patients sought the advice of a regional expert in bone marrow failure. In a rare circumstance, a participant described an episode of severe and potentially life-threatening hemolytic anemia exacerbated by pregnancy. She had experienced symptoms prior to pregnancy which she felt were dismissed by healthcare providers.

The process of achieving to a diagnosis of PNH took an emotional toll on both patients and their families. Some patients felt that they were being dismissed by medical personnel resulting in feelings of isolation and anxiety. A few respondents even felt that the healthcare providers had given up on them. A long and misguided path to

diagnosis can have lasting effects on psychological well-being that may not be resolved after proper diagnosis.

Experience of PNH diagnosis

We aimed to capture the patient’s experience and impact of receiving a life-altering diagnosis. Responses varied widely and were mediated by factors such as time to diagnosis, severity of symptoms, and to some degree, a co-morbidity associated with aplastic anemia or Myelodysplastic Syndrome (MDS).

The most frequent reaction to the ultimate diagnosis of PNH was relief, experienced by those whom endured a prolonged course before the diagnosis was made.The second most common reaction was fear, as very few participants had even heard of PNH. A subset of participants recalled experiencing anger due to delays in diagnosis. Some patients struggled for years to find an answer for their symptoms and many felt misdiagnosed and dismissed. In patients whose diagnoses were incidental, the diagnosis came as a complete surprise and they struggled to comprehend what was relayed to them.

Information availability

The majority of patients sought PNH resources online. AA&MDSIF, PNH Foundation, NORD, Alexion/Eculizumab, Mayo Clinic and National Institutes of Health (NIH) websites were identified as sources of further information. Some participants reported the available information as insufficient with some sources even providing outdated information.

Consequence of PNH diagnosis

Many participants endorsed concerns regarding paying for both insurance premiums and deductibles. Others expressed concerns regarding the ability to hold employment while living with PNH. Only 52% of patients were able to maintain employment following the diagnosis with 74% of unemployed participants citing PNH as the reason for unemployment. Just as pre-diagnostic symptoms varied greatly among patients, the degree to which treatment controls various symptoms also varied.

For those who did face challenges with employment, the effects were similar to other chronic diseases. Some patients with PNH controlled their symptoms well enough to maintain adequate work life, but at times were unsuccessful at maintaining a balanced lifestyle. Daily energy and fatigue appeared to be a great challenge to many afflicted with PNH, and although they managed to remain employed, it was at the expense of other valuable aspects of life. Importantly, more than half of respondents noted a negative impact on work life as well as physical activity.

DiscussionThis mixed method study of the path to diagnosis for PNH

patients was designed to explore pre-diagnosis disease related symptoms, characteristics of patient interface with the health care system during the process of diagnosis, and quality of life issues throughout the process. Our results were consistent with much of the medical literature relative to fatigue, weakness and hematuria as the most common symptoms associated with PNH. Through our novel approach to collecting retrospective data on patient-physician interaction, we identified that primary care and emergency

Table 2: Order of physicians consulted prior to diagnosis.

MD n 1st 2nd 3rd 4th 5th Never

Cardiologist 114 4 3 4 3 5 95 (83%)

ER MD 124 24 27 3 3 5 52 (42%)

Hematologist 150 19 50 42 17 12 10 (6%)

Nephrologist 102 2 7 7 7 3 76 (74%)

Neurologist 99 0 4 4 2 5 84 (85%

OB/GYN (n=110) 82 11 10 5 1 1 53 (66%)

PCP 148 90 18 4 4 5 19 (12.8%)

Mental health 94 2 1 1 2 4 84 (89%)

Pulmonologist 99 2 1 0 3 2 91 (92%)

Urologist 107 5 8 6 2 3 83 (77%)

Other* 65 7 10 8 4 5 30

*Other medical specialists identified: Gastroenterologist (12), Endocrinologists (2), BMT specialist (1), Dermatologist (3), Infectious disease specialist (2), Ophthalmologist (1) Rheumatologist (3), Liver doctor (3), Oncologist (5), Proctologist (1).

Citation: Mitchell R, Salkeld E, Chisolm S, Clark M and Shammo JM. Path to Diagnosis of Paroxysmal Nocturnal Hemoglobinuria: The Results of an Exploratory Study Conducted by the Aplastic Anemia and MDS International Foundation and the National Organization for Rare Disorders Utilizing an Internet-Based Survey. SM Clin Med Oncol. 2017; 1(1): 1001. Page 4/4

Gr upSM Copyright Shammo JM

room physicians were among the first providers patients sought for assessment of symptoms. Interestingly, hematologists were consulted following the initial evaluation in only a third of participants. Even more striking was that 11% of patients were referred for mental health evaluation. The average length of time to a valid PNH diagnosis was under 2 years; however, there was still significant psychological distress associated with the process. Once the diagnosis of PNH was made, the majority of participants felt they received sufficient support and information from their healthcare providers. We also found that the diagnosis of PNH negatively impacted work life, social life and physical activity with no reported difference in personal/family life.

ConclusionsThis study clearly illustrates the emotional toll of delayed

diagnosis of PNH. Although most patients receive a confirmatory diagnosis from a hematologist, better education of primary care and emergency department physicians is essential for an accurate and timely diagnosis of PNH and referral to hematology when appropriate. While patient education from reliable resources such as AA&MDSIF, PNH Foundation, NORD and NIH can provide great benefit to patient’s post-diagnosis, professional education is just as essential for early diagnosis of PNH and speeding patients to appropriate care. It is important to note that this study was not designed to capture adverse outcomes related to delayed diagnosis except for impact on certain aspects of patient-reported quality of life nor has the survey utilized been prospectively validated in a larger, more encompassing study.

AcknowledgementsSpecial thanks to Kylene Ogborn for her assistance in designing

and formatting the survey.

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TitleAbstractIntroductionMaterials and MethodsResultsActive pursuit of diagnosisExperience of PNH diagnosisInformation availabilityConsequence of PNH diagnosis

DiscussionConclusionsAcknowledgementsReferencesTable 1Table 2Figure 1Figure 2