Views Until Saturation of Key Emergent Themes Was Achieved

Janssen et al. Orphanet J Rare Dis (2021) 16:289 https://doi.org/10.1186/s13023-021-01918-x

RESEARCH Open Access Which triggers could support timely identifcation of primary antibody defciency? A qualitative study using the patient perspective Lisanne M. A. Janssen1,2, Kim van den Akker3, Mohamed A. Boussihmad3 and Esther de Vries1,4*

Abstract Background: Patients with predominantly (primary) antibody defciencies (PADs) commonly develop recurrent respiratory infections which can lead to bronchiectasis, long-term morbidity and increased mortality. Recognizing symptoms and making a diagnosis is vital to enable timely treatment. Studies on disease presentation have mainly been conducted using medical fles rather than direct contact with PAD patients. Our study aims to analyze how patients appraised their symptoms and which factors were involved in a decision to seek medical care. Methods: 14 PAD-patients (11 women; median 44, range 16-68 years) were analyzed using semi-structured interviews until saturation of key emergent themes was achieved. Results: Being always ill featured in all participant stories. Often from childhood onwards periods of illness were felt to be too numerous, too bad, too long-lasting, or antibiotics were always needed to get better. Recurrent or persistent respiratory infections were the main triggers for patients to seek care. All participants developed an extreme fatigue, described as a feeling of physical and mental exhaustion and thus an extreme burden on daily life that was not solved by taking rest. Despite this, participants tended to normalize their symptoms and carry on with usual activities. Non-immunologists, as well as patients, misattributed the presenting signs and symptoms to common, self-limiting illnesses or other ‘innocent’ explanations. Participants in a way understood the long diagnostic delay. They know that the disease is rare and that doctors have to cover a broad medical area. But they were more critical about the way the doctors communicate with them. They feel that doctors often don’t listen very well to their patients. The participants’ symptoms as well as the interpretation of these symptoms by their social environment and doctors had a major emotional impact on the participants and a negative infuence on their future perspectives. Conclusions: To timely identify PAD, ‘pattern recognition’ should not only focus on the medical ‘red fags’, but also on less diferentiating symptoms, such as ‘being always ill’ and ‘worn out’ and the way patients cope with these problems. And, most important, making time to really listen to the patient remains the key. Keywords: Primary antibody defciency, Qualitative research, Timely diagnosis, Diagnostic journey, Patient perspectives, Trigger

Background *Correspondence: [email protected] Rare diseases are defned as occurring in less than 1:2000 1 Department of Tranzo, TSB, Tilburg University, PO Box 90153, 5000 people. However, since there are around 8000 rare dis- LE Tilburg, The Netherlands Full list of author information is available at the end of the article eases, some 30 million people in both Europe and in

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the USA sufer from a rare disease. Tis is an important were sought. Teir experiences and reasoning regarding problem for the patients as well as for the society they complaints and the diagnostic delay they sufered were live in because rare diseases are often diagnosed late, explored. New interviews were conducted until satu- especially when they share symptoms with common dis- ration of key emergent themes was achieved, meaning eases, leading to delayed and inadequate treatment. As a additional interviews were no longer adding new themes consequence, these patients sufer a decreased life quality to the data set. Methods and results are reported accord- as well as a decreased potential for societal participation ing to the COREQ checklist [16]. (school, work) [1, 2]. Predominantly (primary) antibody defciencies (PADs) Population are a typical example of such difcult-to-recognize rare Participants were recruited by an email sent by the diseases [3]. Hypogammaglobulinemias are by far the Dutch patient organization for primary immunodef- most common forms of PAD, comprising nearly half of ciency diseases to all their members (‘Stichting voor all primary immunodefciency (PID) diagnoses [4–6]. Afweerstoornissen’, SAS). Te email invited the members Afected persons commonly develop recurrent otitis to participate in an interview of about one hour at a place media, sinusitis, and pneumonia. Recurrent pneumonias of their choice and stated that it would be audiotaped. can lead to bronchiectasis, which serves as a negative All participants provided written and audio informed factor for long-term morbidity and mortality. Since the consent. Te interviews were primarily with study par- introduction of immunoglobulin replacement therapy, ticipants but the contribution of a relative, if present, was there have been dramatic improvements in survival [7, 8]. also welcomed. Recognizing symptoms and making a diagnosis is therefore vital to enable timely treatment. Data collection Although PADs are the most common primary immu- Te interviews were performed in October and Novem- nodefciencies (PIDs) in humans, they are still rare with ber 2016 at the patients’ homes. Te interviews were a prevalence of approximately 1:25,000 to 1:110,000, conducted by a master student in the last year of medi- depending on the type of PAD [3]. Tese patients often cal education (KvA). Questions were semi-structured, go unrecognized, because the general public as well as designed to address those items which the interviewer most healthcare professionals, who are not specialized in wished to raise, and also allowing participants the free- immunodefciency, do not consider PAD in patients with dom to express their own perspective and to ofer an recurrent “normal” infections. Because of the variability opportunity for serendipitous fndings. Te questions of presenting clinical manifestations, patients visit vari- (overview in Additional fle 1) were based on the litera- ous physicians of diferent specialties in search of a diag- ture related to clinical characteristics of primary anti- nosis, which increases the risk of missing the overarching body defciency [9, 17–19] and to psychosocial theories clinical pattern and thereby overlooking the underlying relating to symptom appraisal and care-seeking [20]. All hypogammaglobulinemia [9]. Timely diagnosis and treat- interviews were reviewed and discussed with an experi- ment will likely result in improved clinical and quality-of- enced medical immunologist with expertise in qualitative life outcomes for patients with PAD, higher participation methods (EdV). in society (school, work) and lower healthcare costs [10– 15]. Reducing diagnostic delay is therefore crucial. Data analysis Studies on disease presentation have mainly been con- All interviews were audiotaped and literally transcribed ducted using medical fles rather than direct contact (KvA and MAB), and analyzed using the framework with PAD patients. We aimed to explore the presenting method [21]. Data were anonymized by removing any pattern of PAD from the perspective of patients and to information that could identify the patient. Transcripts identify factors that afect a correct and timely diagno- were read and re-read to ensure familiarization, and inde- sis, by exploring the period leading to the PAD diagnosis pendently coded (MAB and LJ). Te coding was reviewed through narrative patient interviews. by a third coder (EdV), to ensure that the type and range of codes applied was appropriate and consistent. Te Materials and methods coding lists were used to develop a framework organ- Design and setting ized into categories. In total, we identifed 154 codes we Patient experiences regarding their journey to receiving a divided into 11 categories, which were organized in 3 diagnosis and adequate clinical care are best understood themes (Additional fle 2). Te coding was fnalized using via an in-depth qualitative approach. Trough individual the software package Atlas.ti Version 7.1.5 (Berlin, Ger- semi-structured interviews with patients who had a diag- many), and the coded data were exported (MAB). Tis nosis of PAD, new insights derived from their perspective export was read, re-read and then summarized for each Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 3 of 18

of the 14 participants of the study. Each category was lungs. Tey also said: ‘how is that possible, you said then interpreted using an analytical memo to explore you only had pneumonia once, but from looking at emerging themes and concepts. the scan it seems as if it really cannot have been just once’. (Participant 10) Results Fatigue was present both before and after the diagno- In total, 14 participants were interviewed. Interviews sis in many participants and was described as a feeling lasted from 45 to 105 min. Eleven women and three of physical and mental exhaustion and thus an extreme men participated, median age 44 years, range 16–68; all burden on daily life. Most participants recalled that they participants were Dutch. Participant characteristics are slept very well, but still remained tired. Te decrease in summarized in Table 1. Tree interviewees were accom- energy level could result in the need for an afternoon nap. panied by a relative during the interview. Te results are presented under subheadings refecting the main steps in And really a lot of fatigue, I slept for three hours the diagnostic pathway, namely: presentation of PAD and during the day and ten hours at night. I really slept participants’ interpretation of symptoms, progression of thirteen to ffteen hours a day. Just to keep up. (Par- symptoms and realization that something is really wrong, ticipant 1) starting the patient journey, doctors’ interpretation of I spoke about it with my sister recently. I always symptoms, and triggers to diagnosis. Participants were thought, everybody works the whole day, fve days a also asked to refect on care provision and on the emo- week, but I actually can’t do that. It would tire me so tional toll of the diagnostic process. badly, it’s not possible. (Participant 6) Participants described they thought they exerted them- Presentation of primary antibody defciency selves too much, causing their symptoms themselves by and participants’ interpretation of symptoms working too hard, taking care of their whole family or Te presenting features of PAD described by partici- by being too active socially. Te degree of fatigue could pants were diverse, intermittent and sometimes non-spe- be signifcant before the participant really labelled it as a cifc, covering a broad range of behavioral and physical problem. Eleven participants reported their fatigue was changes (Table 1). Being always ill featured in all partici- so severe it took away all their free time, because after pant stories. It often occurred from childhood onwards a work/school day there was no energy left for social and was considered to be a problem by participants and/ activities. or their parents when periods of illness were felt to be too Ten I sleep the whole night, being just able to ful- numerous, too bad, too long-lasting, or when antibiotics fl the expectations set during the day. I don’t have were always needed to get better. any free time left, because when I come home, I go to Ten I got my penicillin course, then it was over sleep, and then another day begins. (Participant 10) within two days, but then the penicillin course was Participants had comorbidities, complications or mis- over again and two days later it started all over diagnoses, and tended to attribute their symptoms to again. (Participant 4) these conditions. For example, a participant with iron Many participants thought recurrent infections to be defciency anemia attributed her fatigue solely to this normal for children, or in some cases due to atopic dis- condition, and a participant with Graves’ disease attrib- ease. Seven adult participants just felt ill and did not have uted her fatigue solely to that. Whereas in both partici- a particular explanation for why they were more often ill pants these conditions could well be complications of than others but assumed that the symptoms would prob- their—unrecognized—PAD. Another participant with ably resolve with time. Participants tended to downplay a misdiagnosis of asthma thought her fatigue was the and/or normalize their symptoms. result of needing more potent inhalers. In total, four participants (1, 7, 9 and 12) attributed their symptoms to When it started with asthma, I had two to four asthma. respiratory tract infections a year. Tat’s not very strange, it is not what strikes you as abnormal if you At that time I got diagnosed with asthma, for which have asthma. (Participant 9) I had to use inhalers that just did not work. (Partici- I think everybody coughs sometimes with a little pant 7) mucus, but then I don’t feel very sick. Usually, it Participants carried on with their usual activities resolves with time. Eventually, when I was diagnosed despite signifcant limiting symptoms. with CVID, they did a Chest-CT. Ten they saw the beginning damage that fts the clinical picture and Just tired… I always went to work anyway, …what Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 4 of 18 too busy and takingtoo little rest too searching the internet an immune disorder searching and diverticulitis Patient’s attribution Patient’s Increased susceptibility due to pregnancy, being Increased susceptibility pregnancy, due to No considerations, but fear about the diagnosis but fear No considerations, Some kind of autoimmune disorder, sensitive lungs sensitive Some kind disorder, of autoimmune n/a XLA (after diagnosed was discovered in his brother) was discovered XLA (after diagnosed Some kind of immune disorder n/a n/a Initially Graves’ disease and asthma, later after disease and asthma, later Initially Graves’ Iron defciency anemia, some kind of viral infection n/a Combination of (severe) asthma and allergies of (severe) Combination Combination of iron defciency of iron Combination anemia, asthma fatigue, weight loss, anosmia, splenomegaly loss, weight fatigue, and bowel complaints and bowel alopecia areata, chronic fatigue chronic alopecia areata, recurrent rhinitis/ otitis/ pneumonia/ sinusitis, rhinitis/ otitis/ pneumonia/ sinusitis, recurrent diarrhea, chronic ITP, recurrent anosmia, fatigue, weight inguinal lymphadenopathy, meningitis, loss pneumonia, chronic cough, aphthous lesions, cough, aphthous lesions, pneumonia, chronic arthralgia, hyperreactivity, bronchial salpingitis, intolerance exercise fatigue, skin abscess, pneumonia, failure to thrive to skin pneumonia, failure abscess, varicella zoster/ Giardia lamblia, fatigue, warts, lamblia, fatigue, Giardia varicella zoster/ anosmia meningitis, tions, mumps, chickenpox (2x), asthma, Graves’ chickenpox (2x), asthma, Graves’ mumps, tions, disease supraclavicular lymph node, fatigue, oral aph - fatigue, lymph node, supraclavicular otitis/ recurrent ill, being always thous lesions, sinusitis growth retardation, chronic diarrhea chronic retardation, growth infections, fatigue, multiple allergies, asthma, multiple allergies, fatigue, infections, retropharyngeal abscess thy/ cystitis/thy/ sinusitis/ otitis/ respiratory tract diarrhea, chronic diverticu fatigue, - infections, litis Signs and symptoms Signs Recurrent sinusitis/ otitis/ rhinitis/ pneumonia, Chronic rhinitis, hypothyroidism, fatigue, stomach stomach fatigue, hypothyroidism, rhinitis, Chronic Chronic cough, recurrent otitis/ bronchitis, ITP, ITP, otitis/ bronchitis, cough, recurrent Chronic Being always ill, almost continuously fever, almost continuously fever, ill, Being always Recurrent meningitis/ pneumonia/ otitis/ sinusitis Recurrent meningitis/ Recurrent respiratory sinusitis/ infections/ Recurrent otitis/ rhinitis/ sinusitis, chronic cough, chronic Recurrent otitis/ rhinitis/ sinusitis, Recurrent otitis/ rhinitis/ sinusitis/ pneumonia/ Recurrent otitis/ sinusitis/ pneumonia/ skin- infec Erythema nodosum, splenomegaly, enlarged enlarged Erythema nodosum, splenomegaly, Recurrent rhinitis/ otitis/ pharyngitis, fatigue, Recurrent sinusitis/ pharyngitis/ respiratory tract Iron defciency lymphadenopa - anemia, recurrent Delay (years) Delay 5 19 3 3 9 6 5 35 20 16 4 39 > 30 At time of At interview 38 35 35 51 59 57 36 58 46 24 16 44 68 5 4 At time of At diagnosis 33 32 29 46 13 51 40 42 23 40 68 Age (years) At startAt of symptoms 28 13 26 43 4 45 0 5 22 8 0 1 Not precisely knownNot precisely Symptom attribution and delay before diagnosis attribution before Symptom and delay 1 Table Patient 1, F, CVID 1, F, 2, F, sIgAdef 2, F, 3, F, CVID 3, F, 4, F, CVID 4, F, 5, M, agammaglobulinemia 6, F, CVID 6, F, 7, F, unPAD 7, F, 8, M, CVID 9, F, unPAD 9, F, 10, F, CVID 10, F, 11, M, sIgAdef 12, F, IgG subclass defciency 12, F, 13, F, Good syndrome 13, F, Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 5 of 18 chological factors (divorce) and menopause, later later and menopause, factors (divorce) chological the internet an immune disorder after searching Patient’s attribution Patient’s Initially in combination with psy - viral infections infections, sepsis, severe wound infection, infection, wound severe sepsis, infections, slightly chronic intolerance, exercise fatigue, body temperature elevated Signs and symptoms Signs Recurrent sinusitis and pneumonia, odontogenic Recurrent sinusitis and pneumonia, odontogenic Delay (years) Delay 10 At time of At interview 63 At time of At diagnosis 50 Age (years) At startAt of symptoms 40 (continued) 1 Table Patient selective PID primary IgA slgAdef n/a not applicable, thrombocytopenic M male, purpura, ITP idiopathic immunodefciency, IgG subclass defciency, IgGscdef F female, CVID variable immunodefciency common disorders, agammaglobulinemia unclassifed primary XLA X-linked defciency, antibody unPAD defciency, 14, F, CVID 14, F, Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 6 of 18

good is it to you to lie down on the couch all day. hospital, I recovered. So everyone was like, you’re (Participant 4) fne again, you can go home. So yeah, it was okay I have always done ftness at a fairly high level and I for a while, only after four episodes of six days, so did that three times a week. At one point it became four weeks of illness, they wanted to conduct further less and less due to fatigue. Tat I just couldn’t man- research. (Participant 1) age to exercise for an hour at eight o’clock in the Participants often recalled a pattern in the complaints. evening. Sometimes I had to force myself to do it, but In participants 1 and 12 the upper respiratory tract infec- then I just took an extra puf, so I could do it again. tion (otitis, pharyngitis and/or sinusitis) always pro- (Participant 1) gressed to a lower respiratory tract infection. Often, unusual and alarming signs for PID were not It progressed from an infection of the sinuses, to the recognized as unusual medical conditions by the consult- ears and then to the throat and airways. (Partici- ing doctors, for example: ITP, alopecia areata and recur- pant 1) rent infections in participant 3; recurrent chicken pox It often began with infections: lungs, sinus, yes very in participants 8 and 9; excessive oral aphthous lesions often my sinuses, and then it spread to my lungs and in participant 10; recurrent meningitis in participant throat at the same time. (Participant 12) 5; recurrent otitis in adult patients repeatedly needing tympanostomy tubes in participants 1, 2 and 8; exces- Four participants (1, 2, 3 and 8) repeatedly developed sive weight loss in participants 1 and 4; salpingitis after otitis—often after swimming—in adulthood and were swimming in participant 6, and impaired wound healing treated with tympanostomy tubes. in participant 9. Well, I mean, everybody might have an ear infection once a while, but every time I had it, it lasted a Progression of symptoms and realization that something month. Tat I really had so much pain for a month, is really wrong that you just wanted to hit your head against the Typically, the symptomatology evolved over weeks to wall, because you don’t know what to do about the months, with non-specifc early features such as recur- pain anymore. Ten the doctor told me: ‘yes, but rent “normal” infections, fever, chronic cough and antibiotics do not help against an ear infection, so I fatigue, mimicking those of common, self-limiting ill- do not really want to give that’. Ten it lasted just nesses. Some participants described a triggering event really long every time, but the GP did not think: ‘oh, (thyroid disease, pregnancy, weight loss or severe wound that is weird’. (Participant 3) infection after caesarean section) as starting point for a sudden increase in infections. Symptoms often pro- Participants 7 and 9 realized they difered from other gressed over time. Infections slowly became abnormally people when comparing the duration of recovery. recurrent, severe and/or persistent. I often had a cold. Another person had it for two It starts with only periods of coughing and then at days and if I had it was for two months. (Participant one point it’s actually all the time. (Participant 3) 7) I played handball and that is not a ‘sweet’ sport, to Four participants (4, 6, 8 and 12) sufered from chronic be fair, my wounds recovered badly… Tat was very rhinosinusitis and underwent sinus surgery. Tis resulted weird, the wound always got infected or it took four in only a short relief of complaints. In the sons of par- weeks to heal. With the other kids in my environ- ticipant 8, multiple sinus surgeries were performed in ment the wounds always recovered within a week or addition to weekly nasal irrigation and polypectomy. Te two. For me never, it always took longer. (Participant ENT specialist was alarmed by their voluminous medical 9) fle. Participant 6 recalled her infections to start rapidly and But the ENT-specialist told us: ‘you are right, at the become severe in a short time. whole ENT-department we have nobody with a fle as large as those of your sons’. We came there for only It could be that one moment I thought: ‘I’m going to three years. He said: ‘those fles are now already big- make it’, but then an hour later I would be so ill that ger than the fles of a ffty-year old’. (Participant 8) I didn’t make it. (Participant 6) Nine participants (1, 3–6, 8, 9, 12 and 14) recalled their Te burden of infections was perceived to be suscep- infections only resolved with antibiotic treatment. tible to change. Participants pointed out that they experienced positive as well as negative fuctuations in the As soon as I got my antibiotics intravenously in the Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 7 of 18

burden of infections due to weather conditions: four searching for the cause. Before the CVID diagnosis patients reported being sick throughout the year (1, 2, 4, was made in patient 8, he underwent recurrent sinus 8); three patients were almost never ill during the sum- surgeries resulting in only short relief of the (chronic) mer (5, 6, 9). sinusitis. Tese experiences kept him from seeking All except two participants were working age and ini- help after a while. Another theme that emerged was tially thought that their symptoms were a normal part of feeling delegitimized. Tis led them to feel distressed their busy lifestyle and job, but once recognized as abnor- by the way they were treated, by not being believed or mal by others (employers, colleagues) they sought help. listened to and not being able to cope with symptoms. Family members often witnessed participants struggling Participants reported the feeling that both healthcare with symptoms and encouraged them to seek help. Five professionals and others did not see them as having a participants (1, 2, 4, 5 and 7) often recalled that their legitimate illness and that the credibility of their symp- social environment thought they were sicker than they toms was frequently questioned. Patient 3 reported admitted themselves. that her symptoms were for a long time attributed to an unacknowledged mental health condition and which I just went to my job, I have often been sent home by made her feel that the symptoms were not due to an my boss. (Participant 1) underlying pathology. Tat’s also what my colleagues said, how often I was at the ofce with a sinusitis or otitis, that everybody I went to the doctor, who thought: ‘I think it’s not was like: ‘you shouldn’t do that, you’re ill’. Yes, I am that bad how often you are sick’. So then she said: ‘I very often ill, this isn’t even that bad. (Participant 1) think it is how you experience it, that it is in your head, but not real’. So then she initially referred me Most participants were quick to seek medical advice to a psychologist. (Participant 3) from their GP as soon as they realized something was really wrong. However, it took most participants a long Over time, having healthcare professionals ques- time to realize this; they continued to hope that the tioning their credibility made participants question symptoms would simply disappear. the legitimacy of their symptoms too. Participants described feeling guilty for wasting healthcare pro- Starting the patient journey fessionals’ time, or downgrading their symptoms by Te factors which triggered the seeking of care were normalization, waiting till another infectious episode various. One patient sought help because of the psycho- passed by. logical stress she sufered due to the many unexplained Once patients began to seek a diagnosis, delays also symptoms. Recurrent or persistent infectious episodes occurred within the healthcare system. Clinicians were like recurrent otitis, sinusitis, or pneumonia or endless not often familiar with PID and were challenged by the coughing, were the main triggers for patients to seek complexity and rarity of the disease. Tis impacted care. Often the fatigue and strain of coping in life while their ability to make a diferential diagnosis. Sometimes hindered by all the symptoms were the reason to go— healthcare professionals seemed to have difculties in again—to the GP. Combinations of problems could also abandoning an initial diagnosis. Participant 6 was treated be the fnal push. for bacterial pneumonia, but her general state of health Participants reported cumulative barriers that led to worsened with loss of condition, leading to the inability delays to seek help. Teir interpretation of the initial to climb the stairs. She suggested herself to screen for signs and symptoms of the disease infuenced whether possible PID because of recurrent Hemophilus Infuen- they sought help. Participants either got used to their zae pneumonia despite adequate antibiotic treatment, symptoms or hoped their symptoms would pass by. after which CVID was discovered. In addition to physician infexibility, this case reveals the importance of com- At a certain point you raise the bar and think by munication concerning symptoms from everyday life as yourself: ‘I am not using medicines or visit the doctor well as medical symptoms. Six participants (1, 6, 8, 9, 10 again’. You think: ‘I just keep taking pills’. Ten you and 14) recalled their social environment forming a bar- raise the bar again and wait and see for another day. rier in seeking help. Te social environment of these par- (Participant 1) ticipants downplayed the participants’ complaints. Tey Well, in the beginning you go to the doctor… But attributed the symptoms to stress/a busy life or told the when you are always ill, you just don’t go to the doc- participants it would resolve with time. tor anymore. (Participant 3) ‘It is probably because of the stress’, people say that Others no longer sought help because the health- a lot too. (Participant 10) care professional only treated symptoms instead of Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 8 of 18

Doctors’ interpretation of symptoms triggered the potential diagnosis). In two participants (2 Many participants recalled initially being ofered an and 11) PID was incidentally discovered while screening incorrect explanation for their symptoms (Table 2). Most for celiac disease (low serum IgA). doctors initially attributed the participant’s symptoms to Multidisciplinary consultations can support the diag- minor, viral illnesses, asthma, anatomical ENT-problems nostic process. In participant 10, who had splenomegaly, or to other ‘innocent’ explanations such as ascribing joint erythema nodosum and pancytopenia, one of the special- pains to sporting activities, episodic dyspnea to stress- ists recognized the symptom pattern and suggested to induced hyperventilation, feeling worn out to the combi- test for immunoglobulins. nation of working too hard and taking care of a newborn Eventually the internist told me: ‘I actually don’t child, erythema nodosum to mosquito bumps and exer- know what you have, I think it’s sarcoidosis, but your cise intolerance to menopause. In one participant XLA, blood doesn’t show that’… ‘I’m going to discuss you despite a positive family history, was only discovered one more time in a multidisciplinary consultation, if years after he already had several episodes of meningi- we don’t fnd it then, then we really don’t know’. In tis. In one participant, her symptoms were put down to that consultation I think one smartass said: ‘test for being pregnant. antibodies’. (Participant 10) Participants were referred to several diferent specialists (Table 2), often only after strongly insisting on it. In Alarm symptoms can trigger the diagnosis. For exam- two participants, their symptom attribution to psycho- ple, healthcare professionals were triggered to conduct logical factors, led to multiple visits to a psychiatrist. additional investigations when participant 1 and 4 suf- fered from excessive weight loss. Sometimes PID was I did not have severe infections, but I couldn’t do diagnosed while searching for another diagnosis. Partici- anything anymore. Well, what happens then: ‘psy- pant 1 sufered from weight loss, night sweats and sple- chic, menopause, divorce’. I started believing that nomegaly and was screened for leukemia or lymphoma. after a while. Ten I went to a psychiatrist. I went Instead, she was found to have CVID. Participant 3 suf- there for years. (Participant 14) fered from idiopathic thrombocytopenia and alopecia Two participants (2 and 8) appeared to have one or and was screened for some form of autoimmune disease. more decreased immunoglobulin isotypes years before Her IgG was found to be decreased instead of elevated; the fnal diagnosis, but this was not noticed by the doc- she was diagnosed with CVID. tor or the doctor did not know what this meant and Tey started searching for an autoimmune disease ignored the results. Tis refects the problem that most and they determined the total serum IgG level. Tey non-immunologists have minimal or no knowledge of expected that to be super high, because they thought PID. Even treatment failure—implying an unusual dis- of lupus or something like that. But it was very low ease course—did not alarm an ENT specialist to think of at that time. (Participant 3) potential PID. Abnormal symptom patterns can trigger the healthcare I had meningitis in 2011 and then I recovered and professional to conduct further investigations. In par- they thought it went better, but then I became sick ticipant 9 the ENT specialist noticed infammation on again. Ten I went to the ENT-doctor… Tey cleaned the inside of the nose, usually indicating allergic rhinitis. my sinuses. Tat was February 2012. Ten I became However, allergy tests were negative and antihistamines, sick again, they didn’t understand it anymore. Ten nasal corticosteroids and turbinate reduction did not I ended up in the hospital again in April. (Partici- alleviate her symptoms. Tis triggered the ENT specialist pant 4) to refer to an immunologist. When I entered, he inspected my nose and said: ‘this Triggers to diagnosis is what an allergic nose looks like’. I said to him: ‘you can say that, but nobody can prove that I have aller- In none of the participants, the symptoms were attrib- gies’. Ten they cut it out and cleaned it, but I kept uted to potential PID by the GP, except for one partici- having a lot of complaints. Ten he started to look pant, in whom his children were already diagnosed with further. (participant 9) PID. Only two participants were referred directly to an immunologist, where referral immediately led to a cor- Te pediatric PID patients had a shorter diagnostic rect diagnosis. Two participants were diagnosed through delay than the adult PID patients in our study. Partici- a positive family history, although one of them had pant 7 sufered from recurrent otitis, rhinitis and sinusi- already sufered a meningitis eight times (which had not tis, as well as chronic cough, skin abscesses, pneumonia Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 9 of 18 - investigations after investigations which the CVID diagno sis was made immune disorder extensive examina - extensive CVIDtions leading to diagnosis lymphoma infections, weight weight infections, hospital frequent loss, - respira admission for tory night infections, splenomegaly sweats, Extensive laboratoryExtensive Immunologic or auto- See under ‘patient’ Immunologist Hospital admission, Immunologist Leukemia, non-HodgkinLeukemia, Recurrent upper airway Oncologist - immunologist/ immune disease rent otitis, burn-out otitis, rent alopecia ITP, symptoms, areata complaints, infltra - complaints, lesions enterocyte tive (Marsh 1) sidered, peppermint oil, peppermint oil, sidered, immunologist to referral after IgA-defciency was discovered increasing the dose increasing of inhalation corticos - prophylactic teroids, antibiotics dyspnea, especially at night Arranging own referral to to referral own Arranging rheumatologist Some kind of auto- Chronic cough, recur Chronic Stomach and bowel and bowel Stomach Irritable syndrome bowel Gluten-free diet was con - Gluten-free Patient Pulmonary function test, Gastro-enterologist Asthma Chronic cough, episodic Chronic Pulmonologist - google to fnd out the google to cause of complaints rent otitis, burn-out otitis, rent symptoms complaints, chronic chronic complaints, GP frequent fatigue, visits specifed tent symptoms, referral referral symptoms, tent gastro-enterologist to tympanoplasty infections tory) Advise to the patient to the patient to to Advise n/a Chronic cough, recur Chronic Stomach and bowel and bowel Stomach Gastritis not further Antacids, and after persis - Antacids, GP (2nd trajectory) Prednisone, antibiotics, antibiotics, Prednisone, GP (2nd trajectory) n/a Recurrent upper airway ENT specialist (2nd trajec - - being always ill, work ill, being always ing and taking of a care newborn child out symptoms spray infections tory) Referral back to GP back to Referral The combination of The Feeling worn out, burn- worn Feeling Chronic rhinitis Chronic Nasal septum deviation Septoplasty, steroid nasal steroid Septoplasty, Psychologist Polypectomy ENT specialist Nasal polyps Recurrent upper airway ENT specialist (1st trajec - - bronchodilators, referral referral bronchodilators, psychologist to in combination with factors psychological rent otitis, burn-out otitis, rent symptoms fatigue, hypothyroidism fatigue, further specifed infections Antibiotic treatment, Antibiotic treatment, Recurrent bronchitis Recurrent bronchitis Chronic cough, recur Chronic Chronic rhinitis, chronic chronic rhinitis, Chronic Chronic rhinitis not Chronic Referral to ENT specialist to Referral GP (1st trajectory) GP (1st trajectory) Referral to ENT specialist to Referral n/a Recurrent upper airway GP The journey towards a diagnosis of primary a diagnosis journeyThe towards antibody defciency Action Attribution Signs and symptoms Signs Signs and symptoms Signs Attribution Action Doctor Doctor Action Attribution Signs and symptoms Signs The diagnostic pathway diagnostic The Doctor 3 2 2 Table Patient 1 Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 10 of 18 respiratory infections, respiratory infections, inguinal meningitis, lymphadenopathy, loss weight tigations after which the CVID was diagnosis made Immunologist Persistent, recurrent recurrent Persistent, PID Extensive laboratoryExtensive - inves - respiratory infections, respiratory infections, meningitis referral to immunolo to referral after IgA-defciencygist was discovered Pulmonologist Persistent, recurrent recurrent Persistent, Bacterial pneumonia Chest X-ray, antibiotics, antibiotics, Chest X-ray, respiratory infections, respiratory infections, meningitis GP (2nd trajectory) Persistent, recurrent recurrent Persistent, n/a Referral to pulmonologist to Referral - - monia/ sinusitis drainage trajectory) niae pneumonia and Haemophilus persistent coloniza - infuenzae antibiotic tion despite treatment serum immunoglobu - with treatment lins, immuno intravenous globulins ENT specialist Recurrent rhinitis/ pneu - Obstruction of sinus Endoscopic sinus surgery Pulmonologist (2nd Pulmonologist Streptocococcus pneumo Streptocococcus After discoveryAfter of low Possible CVID Possible - monia/ sinusitis drainage, bacterialdrainage, pneumonia and prophylactic antibi - and prophylactic referral otic treatment, ENT specialist to otitis, chronic sinusitis, sinusitis, chronic otitis, family historypositive after investigations which the XLA diagno sis was made tory) infections / sinusitis infections pneumonia, bronchial fatigue, hyperreactivity, intolerance exercise peutic and prophylactic peutic and prophylactic antibiotic treatment asthma Pulmonologist Recurrent rhinitis/ pneu - Obstruction of sinus Chest X-ray, therapeutic Chest X-ray, Immunologist Recurrent meningitis, PID laboratoryExtensive Pulmonologist (1st trajec - Pulmonologist Recurrent respiratory Sputum cultures, thera - Sputum cultures, Bacterial pneumonia and monia/ sinusitis otitis, chronic sinusitis, sinusitis, chronic otitis, family historypositive infections / sinusitis infections pneumonia, bronchial fatigue, hyperreactivity, intolerance exercise GP (1st trajectory) Recurrent rhinitis/ pneu - n/a Referral to pulmonologist to Referral GP Recurrent meningitis, immunologist to Referral GP Recurrent respiratory Referral to pulmonologist to Referral n/a (continued) The diagnostic pathway diagnostic The Doctor Signs and symptoms Signs Attribution Action Signs and symptoms Signs Attribution Action Doctor Doctor Signs and symptoms Signs Action Attribution 2 Table Patient 4 5 6 Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 11 of 18 pneumonia despite PnPS PnPS pneumonia despite and Hib vaccination and antibiotic treatment tigations after which the was diagnosis unPAD made Immunologist Recurrent sinusitis and Possible PID Possible Extensive laboratoryExtensive - inves - - investigations after investigations which the CVID diagno sis was made pneumonia despite pneumonia despite and Hib vac - PnPS cination and antibiotic treatment sinus surgery and refer immunologist ral to sinusitis/ pneumonia, diag - two sons were nosed with CVID a by pediatrician, recurrent and varicella zoster - lamblia infec Giardia warts,tions, anosmia Extensive laboratoryExtensive ENT specialist Recurrent sinusitis and Possible PID Possible Functional endoscopic Functional Possible CVID Possible Recurrent otitis/ rhinitis/ Immunologist ing, chronic cough, chronic ing, respiratory recurrent infections inhalation corticos - repeatedly teroids, and oral prednisolone antibiotic treatment nosed with CVID a by pediatrician Referal to immunologist to Referal Pulmonologist Dyspnea, wheez - Asthma Increasing the dose of Possible CVID Possible His diag - two sons were GP (2nd trajectory) repeated therapeutic repeated antibiotic treatment bowel complaints bowel polyps sinusitis/ pneumonia Prophylactic and Prophylactic trajectory)GP (3rd Fatigue, stomach and stomach Fatigue, Graves’ disease Graves’ Antithyroid medication Antithyroid Nasal septum deviation/ Recurrent otitis/ rhinitis/ ENT specialist - repeated therapeutic repeated antibiotic treatment chronic cough chronic referral to pulmonolo to referral gist sinusitis/ pneumonia Prophylactic and Prophylactic GP (2nd trajectory) Dyspnea, wheezing, Asthma Inhalation corticosteroids, Bacterial pneumonia Recurrent otitis/ rhinitis/ Pulmonologist - and pulmonologist skin poor infections, chicken healing, wound (2x), mumps pox infancy sinusitis, chronic cough, chronic sinusitis, skin pneumo abscess, thrive to nia, failure after investigations diag - which the unPAD nosis was made sinusitis/ pneumonia GP (1st trajectory) Referral to ENT specialist to Referral Recurrent otitis/ sinusitis/ Recurrent infections in Recurrent infections None n/a Pediatrician Recurrent otitis / rhinitis / PID laboratoryExtensive Recurrent otitis/ rhinitis/ GP (1st trajectory) (continued) Doctor Action Signs and symptoms Signs Attribution Action Attribution The diagnostic pathway diagnostic The Doctor and symptoms Signs Attribution Action Signs and symptoms Signs Doctor 9 2 Table Patient 7 8 Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 12 of 18 - + sple colleague to test for for test colleague to the immunoglobulins, of CVIDdiagnosis was made despite prophylactic prophylactic despite antibiotics and multipe extreme ENT surgeries, - retarda growth fatigue, tion defciency confrmed nomegaly, enlarged enlarged nomegaly, lymph supraclavicular node After suggestion of a After Immunologist Persistent infections infections Persistent Possible selective IgA- Possible Selective IgA-defciency Internist (2nd trajectory) Erythema nodosum - splenomegaly, + splenomegaly, after histological exami - after histological nation of lymph node, discussion chest X-ray, in a multidisciplinary team despite prophylactic prophylactic despite antibiotics and multipe extreme ENT surgeries, - retarda growth fatigue, tion were negative; referral referral negative; were immunologist to sum - supraclavicu enlarged lar lymph node Exclusion of lymphoma Exclusion Pulmonologist Persistent infections infections Persistent Possible CF/PCD Possible Analyses for CF and PCD Analyses for Internist (1st trajectory) Erythema nodo Sarcoidosis - splenomegaly, + splenomegaly, tory) despite prophylactic prophylactic despite antibiotics and multipe extreme ENT surgeries, - retarda growth fatigue, tion infections in infancyinfections and factors psychological pulmonologist sum supraclavicular enlarged lymph node Referral to internist to Referral Pediatrician (2nd trajec - Pediatrician Persistent infections infections Persistent Combination of recurrent of recurrent Combination Referal to psychologist en psychologist to Referal GP (4th trajectory) Erythema nodo Possible malignancy Possible - - + splenomegaly pancytopenia; initially ‘wait and see’ otitis/ sinusitis, fatigue, fatigue, otitis/ sinusitis, retardation, growth diarrheachronic recurrent infections in infections recurrent infancy omy, tympanoplasty, tympanoplasty, omy, functional endoscopic sinus surgery sum tion Blood test showed mild showed Blood test ENT specialist Recurrent rhinitis/ Reactive mucosa, Tonsillectomy, adenot Tonsillectomy, GP (3rd trajectory)GP (3rd Erythema nodo Some kind- of viral infec - tory) otitis/ sinusitis, fatigue, fatigue, otitis/ sinusitis, retardation, growth diarrheachronic recurrent infections in infections recurrent infancy prophylactic antibiot prophylactic IgA was ics after low during discovered celiac for screening disease ‘Wait and see’ Pediatrician (1st trajec - Pediatrician Recurrent rhinitis/ Possible celiac disease, celiac disease, Possible Referral to dietician, to Referral GP (2nd trajectory) Erythema nodosum Mosquito bites otitis/ sinusitis, fatigue, fatigue, otitis/ sinusitis, retardation, growth diarrheachronic en pediatrician Iron supplementation GP Recurrent rhinitis/ Referral to ENT specialist to Referral GP (1st trajectory) Fatigue, aphthous lesions Fatigue, Iron defciency anemia (continued) Action Doctor Signs and symptoms Signs Attribution Action The diagnostic pathway diagnostic The Doctor Signs and symptoms Signs Attribution 11 2 Table Patient 10 Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 13 of 18 vomiting, recurrent recurrent vomiting, respiratory infections ectasis tally found on chest CTtally found scan, Good syndrome was diagnosed Pulmonologist Persistent abdominal pain, Persistent - possible bronchi CVID, Thymoma was coinciden - Thymoma - nal pain, vomiting, nal pain, vomiting, respiratory recurrent infections investigations after investigations which CVID was diag - pulmo to referal nosed, screening for nologist bronchiectasis for Internist (2nd trajectory) Persistent abdomi - Persistent n/a Extensive laboratoryExtensive trajectory) exacerbations despite high-dose inhalation corticosteroids multiple allergies discovered after immu - discovered screening nological nal pain diverticulitis and kidney stones Pulmonologist (2nd Pulmonologist Still frequent asthma Still frequent (Severe) asthma and (Severe) IgG-subclass defciency Internist (1st trajectory) Chronic diarrhea,Chronic abdomi - Possible diverticulitis Possible Abdominal CT confrmed - pharyngitis/ respiratory fatigue, tract infections, retropharyngeal abcess rial infections lectomy, multiple sinus lectomy, surgeries abdominal pain ENT specialist Recurrent sinusitis/ Reactive mucosa, bacte - tonsil Abscess drainage, GP (3rd trajectory)GP (3rd Chronic diarrhea,Chronic Possible diverticulitis Possible Referal to internist to Referal - - tory) sions due to asthma sions due to (> 40x) multiple allergies solone, increasing the increasing solone, dose of inhalation cor repeatedly ticosteroids, subcutane antibiotics, ous epinephrine always available infections (including infections pneumonia)/ proven sinusitis/ otitis monia corticosteroids, oral corticosteroids, prednisolone Pulmonologist (1st trajec - Pulmonologist Multiple hospital admi - (Severe) asthma and (Severe) - oral predni Frequently GP (2nd trajectory) Recurrent respiratory Asthma, bacterialAsthma, pneu - Antibiotics, inhalation Antibiotics, - - yngitis/ respiratoryyngitis/ tract fatigue infections, multiple allergies referal to pulmonolo to referal and ENT specialist gist recurrent lymphad - recurrent and cystitis, enopathy fatigue tion Pediatrician Recurrent sinusitis/ phar (Severe) asthma and (Severe) Inhalation corticosteroids, GP (1st trajectory) Iron defciency anemia, Some kind- of viral infec Follow-up (continued) The diagnostic pathway diagnostic The Doctor Signs and symptoms Signs Attribution Action Doctor Signs and symptoms Signs Attribution Action 2 Table Patient 12 13 Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 14 of 18 pneumonia, odon - infections, togenic exercise fatigue, sepsis, persistent intolerance, PyloriHelicobacter and - lamblia infec Giardia treatment, tions despite cystitis, chronic recurrent body slightly elevated temperature tigations after which CVID was diagnosed Immunologist Recurrent sinusitis and Possible PID Possible Extensive laboratoryExtensive - inves pneumonia, odon - infections, togenic exercise fatigue, sepsis, persistent intolerance, PyloriHelicobacter lamblia and Giardia despite infections recurrent treatment, slightly cystitis, chronic - body tem elevated perature immunologist Patient Recurrent sinusitis and Possible PID Possible Arranging own referral to to referral own Arranging - ance further specifed) Psychiatrist Fatigue, exercise intoler exercise Fatigue, Psychological factors Psychological Treatment for stress (not stress for Treatment - - ance logical factors logical GP (2nd trajectory) Fatigue, exercise intoler exercise Fatigue, Menopause and psycho Referral to psychiatrist to Referral after cesarean sectionafter cesarean during second cesarean during second cesarean section Gynaecologist Severe wound infection infection wound Severe Bacterial infection Prophylactic antibiotics Prophylactic - pneumonia, odonto sepsis genic infections, tions GP (1st trajectory) Recurrent sinusitis and - and bacterialViral infec Repeatedly antibiotics Repeatedly (continued) The diagnostic pathway diagnostic The Doctor Signs and symptoms Signs Attribution Action 2 Table Patient 14 n/a not M male, practitioner, thrombocytopenic GP general purpura, ITP idiopathic IgG-subclass defciency, IgGscdef ENT ear-nose-throat, CVID variable immunodefciency F female, common CF cystic disorders, fbrosis, agammaglobulinemia unclassifed primary XLA PCD primary X-linked applicable, defciency, antibody ciliary dyskinesia,unPAD selective PID primary IgA-defciency, slgAdef immunodefciency, Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 15 of 18

and failure to thrive since birth and was diagnosed with again’. (Participant 4) hypogammaglobulinemia at the age of 5 (during fol- Eight participants stated that their symptoms had a low-up a diagnosis of unclassifed primary antibody negative infuence on their future perspectives. Strug- defciency was made). Te sons of participant 8 were gling with their untreated symptoms they made diferent diagnosed with CVID by their pediatrician, triggered choices in their career paths or were hampered in getting by recurrent need for tympanoplasty and sinus surgery. promoted. While their father had severe and recurrent infections for several years, he was only diagnosed with CVID after this It always got in the way of everything. Because he was discovered in his two children. was really good at his job, he would be promoted, Participant 9 and 14 played a direct role in obtain- but then he was ill again. So another person got the ing their PID diagnosis by searching for a cause of their job. Tat was always very depressing. (Wife of par- symptoms on the internet and diagnosing a potential PID ticipant 8) by themselves. In others, symptoms prevented them from doing what Participants in a way understand the long diagnostic made them happy, because they felt themselves to be a delay. Tey know the disease is rare and a GP has to cover burden for their social environment. a broad medical area. Tey realize the diagnostic delay is due to not knowing, instead of not wanting to know. Concerts, yes I love that. I didn’t do that in a long time, because it is the worst annoyance of every It is of course so rare. Tere are so many things that orchestra member when somebody is coughing in the doctors should be aware of that I understand that it hall. (Participant 6) has not been directly diagnosed. (Patient 1) I haven’t, for example, been on vacation for years. I I don’t blame her, because you can’t know every- very often felt that I was a burden for other people. thing, but I thought: ‘Gosh, I felt really miserable When we went on vacation and I was sick again, then’. (Patient 2) that’s not what you want. (Participant 6) But participants are more critical about the way the Many participants reported that fatigue negatively doctors communicate with them. Tey feel that doctors infuenced multiple aspects of their social network. often don’t listen very well to their patients. Tey want Tey often could not participate in social activities due the doctor to acknowledge they don’t know what is the to fatigue or had to deal with the consequences of taking matter and to refer the participant to a specialist, and to part in social activities by sleeping all next day. Tis led to observe existing guidelines. social isolation and feelings of loneliness. Te stupid thing is that there is a pulmonology Every time they say: ‘we can’t come’. At seven o’clock guideline for recurrent airway infections. According they lie in bed and their friends go out. So then you to the protocol he had to make a referral. He didn’t won’t be asked anymore. (Mother of the sons of par- know that but then at least be honest enough to say ticipant 8, who also have CVID) that you don’t know. (Participant 9) You always have to disappoint people because you have to drop out last-minute. Tat’s why a lot of CVID patients get isolated, because at some point, Emotional toll of the diagnostic delay you don’t want to disappoint people anymore. (par- During the interviews it became increasingly clear that ticipant 8) the participants’ symptoms as well as the interpretation of these symptoms by their social environment and doc- Te daily limitations due to the PAD-related com- tors had a major emotional impact. Finally knowing they plaints were a heavy mental burden for many partici- have probably had PAD for years without being diag- pants. Eight patients mentioned that they had, to some nosed also negatively impacted their lives. Participants degree, lost the joy in life. recalled feeling a lack of understanding by their social Of course when being younger I really felt alone, environment, who often questioned or downgraded their sometimes even depressed. (Participant 12) complaints. Well I didn’t think it was hard to accept the fatigue and just go to bed. It was often more the incom- Discussion prehension of others, like: ‘Gosh, already? We just Tis study reveals presenting patterns that can help started’. (Participant 1) to identify those patients who are ‘always ill’ and ‘worn Ten they think: ‘there she comes again, she is sick out’ with PAD. Tis is important, because recurrent Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 16 of 18

respiratory infections and fatigue are much more preva- professionals to potential underlying disease. Participants lent without concomitant PAD [22]. Participants in this were referred to multiple physicians before a diagnosis study tended to normalize their symptoms and carry on was made, intensifying the time of worrying and wonder- with usual activities. Coping strategies of the extreme ing. Tese fndings highlight an important knowledge gap fatigue that PAD patients develop therefore difer from among general practitioners and non-immunologist hos- those with chronic fatigue syndrome, because patients pital doctors regarding the clinical presentation of PAD. with chronic fatigue syndrome often use escape/avoid- Education campaigns that address this issue could reduce ance strategies [23]. Also, PAD patients reported to the time between the onset of symptoms and treatment. sleep well, whereas chronic fatigue patients generally In addition, multidisciplinary consultations (MDC’s) report more difculty falling asleep and interrupted sleep with a number of specialists working together can sup- [24]. In addition to these non-medical aspects, partici- port the diagnostic process for patients presenting with pants recalled many medical aspects that could trigger non-specifc symptoms who have visited multiple physi- suspicion for potential PAD: infections being unusu- cians [29]. It would be interesting to explore health care ally frequent and/or severe, not clearly season-bound, professionals’ views about PAD and about recognizing requiring antibiotics to clear. Many participants under- rare disease. Tis would help to reveal what health care went repeated sinus surgery, tympanoplasty and/or pol- professionals need to be able to use this knowledge in ypectomy, at best only temporarily resulting in relieve their own practice. of symptoms. Tese aspects are in fact already known, A second major theme was an increasing reluctance to but their relevance is often missed in everyday practice. seek care, albeit in some participants more than others. Terefore, to timely identify PAD, ‘pattern recognition’ Reasons for this were diverse. Tey included getting so should not only focus on the medical ‘red fags’, but also used to symptoms that they were considered to be ‘nor- on less diferentiating symptoms, such as ‘being always mal’, the feeling of not being taken seriously, and oppos- ill’ and ‘worn out’ and the way patients cope with these ing ‘just being treated for symptoms anyway’ instead problems. And, most important, making time to really of being investigated for their cause. Te quality of the listen to the patient remains the key. doctor-patient relationship had a signifcant impact A wide range of factors afected the speed and accuracy on the process of obtaining a correct diagnosis. A GP’s of diagnosing PAD. First and foremost, both patients and prior view of a patient as being ‘thin-skinned’ or ‘a wor- non-immunologist healthcare professionals tended to rier’ could infuence how seriously they investigated their persist in misattributing the presenting signs and symp- complaints. Tese two themes highlight the full range of toms to common, self-limiting illnesses or other ‘inno- factors potentially infuencing a timely diagnosis, rather cent’ explanations. Both patients and non-immunologist than the presenting medical features of the underlying healthcare professionals initially attributed “being always disease alone. ill” and “feeling worn out” to ‘doing too much’ or ‘sleep- All this led to a signifcant mental burden for the par- ing too little’, or to medical conditions such as nasal pol- ticipants. Te period prior to the diagnosis was particu- yps, nasal septum deviation, asthma or chronic rhinitis. larly challenging, with people feeling dismissed by health Te prevalence of most presenting symptoms of PAD care professionals, in spite of their distress. Te lack of a in the general population is high. A population preva- defnitive diagnosis not only left them open to self-doubt, lence of 11% is for instance reported for sinusitis, and but also to the negative judgements of others including in a symptom prevalence study 28% of patients expe- family, friends and employers. Tis concept is not unique rienced coughing in the previous 7 days, and 11% had to PAD as other conditions which are challenging to experienced fatigue [25, 26]. Tis can explain why ‘nor- diagnose, such as systemic lupus erythematosus (SLE), malizing’ prevalent symptoms such as fatigue or recur- elicit similar ‘journeys’. In patients with SLE, the percep- rent infections is so widespread. Te normalization of tion of being dismissed and of the lacking of empathy symptoms and symptom misattribution to less serious from a health care professional has been described as or pre-existing conditions have been reported to account leading to feelings of emotional neglect [30]. Participants for appraisal delays in various cancers, particularly when in this study reported relief when they found a name the early symptoms were commonly occurring non-spe- for their symptoms after they had spent years fghting cifc symptoms (e.g., fatigue) [27, 28]. Remarkably, also searching for that. Although the PAD diagnosis helped the appraisal of less common and more alarming signs, them by legitimizing their symptoms, validating their such as immune thrombocytopenic purpura (ITP), exces- sufering and improving their emotional status by being sive oral aphthous lesions, recurrent meningitis, and believed and listened to, they still had to cope with the recurrent otitis repeatedly needing tympanostomy tubes burden of their disease and its treatment for the rest of in an adult, did not alert both patients and health care their lives. While it has already been shown that PAD can Janssen et al. Orphanet J Rare Dis (2021) 16:289 Page 17 of 18

result in a considerable disease burden [14, 31], our qual- Abbreviations COREQ: consolidated criteria for reporting qualitative research; COPD: chronic itative study adds the perspective of the patients them- obstructive pulmonary disease; CVID: common variable immunodefciency selves. Participants found the impact of being ‘always ill’ disorders; GP: general practitioner; ITP: idiopathic thrombocytopenic purpura; and ‘worn out’ on their daily functioning to be a key fac- PAD: predominantly (primary) antibody defciency; PID: primary immunodefciency; SAS: stichting voor afweerstoornissen (Dutch patient organization for tor determining their emotional well-being. Tey expe- immunodefciency). rienced serious limitations in their social functioning, causing social isolation and feelings of loneliness. Tis Supplementary Information is in line with results from a previous study on COPD- The online version contains supplementary material available at https://doi. related fatigue, which stated that fatigue infuences org/10.1186/s13023-021-01918-x. physical, cognitive, and psychological functioning [32]. Another study related fatigue to perceived health and Additional fle 1. Interview questions. concluded higher fatigue correlated to a lower perceived Additional fle 2. Codes, categories, and themes used in the qualitative health [33]. Other pathologies, such as diferent types of analysis. cancer, showed fatigue being a driver in the impact of quality of life in patients [34–36]. Tese results highlight Acknowledgements the need for more attention to the potential patient bur- The main contributors of this article are the patients with PAD and their family members who have given us their time and generosity. We would like to den in the diagnostic delay of PADs. thank the SAS (Stichting voor Afweerstoornissen’) organization for their support and help in contacting and recruiting the participants. Limitations Authors’ contributions Because of the relatively small sample, whilst the size of EdV and KvA participated in the original design of the study. Identifcation and the sample is in keeping with the in-depth nature of qual- recruitment of participants for interviews and interviewing of participants was conducted by KvA, supervised by EdV. Data cleansing and qualitative analysis itative research, this explorative study should perhaps be were performed by LJ and MAB. MAB wrote a frst draft of the manuscript validated by future studies. Te sample included patients under supervision of LJ and EdV. LJ and EdV wrote the fnal version of the who had been diagnosed some years previously. Tis may manuscript. All authors read and approved the fnal manuscript. have contributed to recall bias. Nevertheless, the study Funding produced a rich amount of material and the fndings pro- Not applicable. vide insight into areas of potential future research. Availability of data and materials The dataset used and/or analyzed during the current study are available from Conclusions the corresponding author upon reasonable request. Tis study revealed non-medical patterns that can help to recognize patients with potential PAD. With in-depth Declarations interviewing, it became clear that—although fatigue can Ethics approval and consent to participate be one of their major complaints—these patients are All study participants provided informed consent. diferent from patients with chronic fatigue syndrome: Consent for publication patients with PAD tend to normalize their symptoms and Not applicable. carry on with usual activities. Te difculty experienced by clinicians, as well as patients, in recognizing unusual Competing interests The authors declare that there are no potential conficts of interest with and alarming signs and attributing symptoms correctly, respect to the research, authorship, and/or publication of this article. illustrates that non-immunologists have little knowledge of PAD. Tis is not surprising, since PAD is a rare disease. Author details 1 Department of Tranzo, TSB, Tilburg University, PO Box 90153, 5000 LE Tilburg, Although this underlines the importance of education The Netherlands. 2 Department of Pediatrics, Amalia Children’s Hospital, programs, which should not only focus on the medical Nijmegen, The Netherlands. 3 Radboud University, Nijmegen, The Netherlands. ‘red fags’ of PID, but also on coping strategies of more 4 Jeroen Bosch Academy Research, Jeroen Bosch Hospital, ’s‑Hertogenbosch, common, less diferentiating symptoms, such as ‘being The Netherlands. always ill’ and ‘worn out’, this cannot be the fnal solution. Received: 28 January 2021 Accepted: 13 June 2021 It is impossible for non-experts to know about all > 8000 rare diseases. Hopefully, modern developments in auto- mated pattern recognition can be developed to ofer ‘red fags’ in the electronic patient fle that alert a physician References to potential underlying problems. Te results obtained in 1. 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