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SM Clinical and Medical Oncology
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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.
OPEN ACCESS
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:
[email protected]
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.
https://creativecommons.org/licenses/by/4.0/https://creativecommons.org/licenses/by/4.0/
-
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
Gr upSM Copyright Shammo JM
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%)
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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 3/4
Gr upSM Copyright Shammo JM
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