According to the study protocol, physicians from Austria, Germany and Switzerland were recruited. These physicians contacted their patients and asked for consent to participate in the study. The dsai invited patients from their network to give their consent to participate in this survey.

Primary data were collected via patient and physician interviews. Physicians were identified through publicly available contacts and approached by the study coordinator (FH); comprehensive coverage of all relevant physicians could not be guaranteed. Patients were recruited through participating physicians and the patient organization dsai. Participation was voluntary, and interviews were audio-recorded with explicit consent. Data collection occurred via telephone or online platforms (Microsoft Teams).

Semi-structured interview guides, developed for this study by RS and validated by FH, were tailored for patients (or legal guardians) and physicians to ensure comparability while capturing group-specific perspectives. Both guides addressed diagnostic pathways, therapeutic management, and challenges in APDS care. Patient interviews focused on the individual diagnostic odyssey, consultations prior to diagnosis, symptom onset, confirmation of APDS, disease burden, daily life changes, involvement in decision-making, and perceived care challenges. Physician interviews explored professional experiences, including age and disease stage at diagnosis, diagnostic procedures, specialties involved, factors contributing to delay, therapeutic strategies, care coordination, patient engagement, and systemic challenges.

Interviews were analyzed using qualitative content analysis (14), augmented by elements from Naeem et al. (15). All interviews were transcribed with verbatim. Coding combined inductive and deductive approaches: inductive codes emerged from the data, while deductive codes were based on established theoretical frameworks. Text segments were assigned to thematic categories, clustered into higher-order themes, and interpreted to integrate individual experiences into broader conceptual patterns. MAXQDA software supported data management and coding (16). Key quotations were selected for their relevance to study objectives and research questions. In addition, selected clinical and diagnostic information reported during the interviews were systematically extracted and summarized to provide a structured overview of individual diagnostic pathways.

The study was conducted in accordance with the Declaration of Helsinki and applicable legal regulations, including General Data Protection Regulation (GDPR). Ethical and legal approval was granted by the Ethics Committee of LMU Munich on November 27, 2024.

The study included four physicians from Austria (1), Germany (2) and Switzerland (1), all experienced in pediatric and adult immunology, rheumatology, hematology, and/or oncology. Each held board certification in clinical immunology, in pediatrics or in internal medicine, complemented by subspecialty training in immunology, rheumatology, and/or pediatric hematology/oncology. All had extensive experience in managing IEIs, including APDS, with patient loads ranging from one to seven APDS-individuals per physician. Some clinicians also supervised patients retrospectively diagnosed following the initial characterization of APDS in 2013. Collectively, the physician sample represented a highly qualified cohort with longitudinal, cross-age expertise in APDS diagnosis and management across diverse clinical settings.

Six patients participated in the survey, comprising three adult patients and three legal guardians of children diagnosed with APDS. Recruitment occurred through the dsai network and direct physician contact. Participants were drawn from Austria (one adult patient) and Germany (2 adult and 3 pediatric patients). Despite outreach efforts in Switzerland, no patients from this region were enrolled. For three of the six patients included, legal guardians answered the interview questions.

Qualitative content analysis assigned codes to three overarching themes and their associated concepts, as summarized in Table 1.

Both patient and physician surveys revealed that the diagnostic pathway for APDS was characterized by clinical heterogeneity, evolving diagnostic technologies and varying levels of awareness among healthcare providers. Table 2 provides a structured overview of the diagnostic pathways and treatment patterns reported by the six interviewed patients. Across cases, symptom onset occurred predominantly in childhood, while age at genetic confirmation varied widely, illustrating prolonged and heterogeneous diagnostic pathways. Participants reported that although molecular diagnostics had significantly advanced over the past decade, delays in diagnosis remained common. These delays were often multifactorial, involving nonspecific clinical presentation, limited disease recognition in primary care, and inconsistent access to specialized immunological evaluation.

Reported time to diagnosis ranged from 3.8 to 73 years, with a median of 11 years. Patients and physicians consistently described the diagnostic process as a prolonged and emotionally exhausting journey. One legal guardian summarized: “We were in and out of hospitals for years. Nobody thought to check the immune system. Only when our new pediatrician ran more comprehensive tests did things move forward.”

Several interviewees referred to the eventual diagnosis as a “lucky coincidence”, often triggered by a physician change or a referral to a university center: “We were lucky to end up at a university center. Without that referral, we might still be waiting.”

The following Figure 1 summarizes the diagnostic and treatment pathway of patients with APDS based on the results of the qualitative interviews.

The interviewed physicians mentioned that APDS diagnosis required molecular confirmation via genetic sequencing of PIK3CD and PIK3R1. Clinical features, including lymphoproliferation, autoimmune cytopenia, or hypogammaglobulinemia, raised suspicion but were insufficient for diagnosis. Biochemical assays, such as PI3K phosphorylation analysis, remained largely confined to research settings. Interpretation of novel variants required interdisciplinary evaluation. Operational issues, including outsourced genetic sequencing and limited data accessibility, could delay confirmation. Patients highlighted the burden of the uncertainty remaining until the definite diagnosis is confirmed: “It was a fight. Every test result brought new questions. Only when we got the genetic result did things finally make sense.” Physicians advocated for centralized diagnostic pathways and improved integration of next-generation sequencing into routine practice.

During the interviews it was described that patients with APDS typically presented in early childhood with recurrent respiratory infections, including otitis media, streptococcal pharyngitis, and febrile episodes, which often required hospitalization. These infections could persist year-round and were accompanied by lymphoproliferation, autoimmune cytopenia, colitis, growth retardation, and pulmonary complications such as bronchiectasis.

Despite widespread technical availability of genetic testing, institutional, financial, and awareness-related barriers continued to impede timely APDS diagnosis. Patients frequently first presented to generalists or organ-specific specialists, including ENT (Ear, Nose, Throat) physicians, rheumatologists, or gastroenterologists, who often did not initially consider an IEI. Limited familiarity with rare diseases contributes to missed diagnoses: “With over 8,000 known rare diseases, even highly trained clinicians are likely to overlook conditions they have never encountered,” noted one physician. Both clinicians and patients emphasized the need for heightened suspicion when clinical courses deviated from expectations or standard therapies failed. Patients frequently reported prolonged dismissal or misattribution of symptoms, describing the diagnostic pathway as emotionally exhausting and information scarce.

Physicians highlighted variability in diagnostic standardization, citing limited access to functional assays, unclear interpretation of genetic variants of unknow significance, and institutional heterogeneity. Although genetic sequencing access and awareness had improved, cost and procedural inconsistencies remained substantial barriers.

A confirmed diagnosis was considered as a turning point. It enabled targeted therapy and social reintegration. The psychological and functional impact of diagnosis varied by age and disease severity. Pediatric patients often adapted to restrictions early, while legal guardians experienced substantial emotional distress. Adolescents and adults perceived diagnosis as both a relief and a burden, which provided clarity but raised concerns about long-term complications. Physicians emphasized that definitive diagnosis stabilized patient self-perception and facilitated effective care. Patients and legal guardians echoed this and highlighted improvements in energy, infection control, and quality of life following initiation of immunoglobulin replacement therapy and other supportive measures. Nonetheless, structural complications such as bronchiectasis or inflammatory bowel disease could persist, necessitating ongoing multidisciplinary monitoring.

Challenges for the management of APDS were attributed to the clinical heterogeneity of the disease but also to multiple systemic and structural challenges such as multiple specialists and lack of awareness for APDS and time to diagnosis. Management of APDS required an individualized approach, considering disease severity, organ involvement, comorbidities, patient preferences, and access to targeted therapies. Shared decision-making was described as central, with children above eight actively involved in therapeutic discussions. Treatment strategies were structured around five pillars: (1) initiation of APDS-specific targeted therapy, ideally early; (2) symptomatic management of infections, inflammation, or malignancy; (3) immunoglobulin replacement for antibody deficiencies; (4) allogeneic hematopoietic cell transplantation for severe or refractory cases; and (5) close surveillance for complications requiring additional immunomodulation. Timely initiation of targeted therapy was considered critical to prevent irreversible end-organ damage. Access remained limited by administrative barriers, although participants anticipated shorter delays as experience with therapy grew. During the interviews, patients emphasized the potential of targeted APDS therapy. One parent recalled: “After he started the therapy, he was like a different child. He ran, he was full of energy, we realized for the first time that life could be better.” Physicians confirmed the necessity to initiate targeted therapy as soon as possible: “We used to wait and rely on substitution therapy. But now, knowing the publications and based on my experience, I would initiate the targeted APDS therapy as early as possible.” In the form of a case study one physician reported: “For one patient, there was no perspective before the targeted APDS therapy. He was hospitalized with multiorgan disease, opportunistic infections, colitis and cytopenia. After starting therapy, he returned to work, gained weight, and no longer needed prophylactic medication.”

Targeted therapies had improved expectations for APDS care, yet clinical decision-making remained complex. Physicians faced challenges in determining the need for additional APDS-specific therapy in clinically stable patients and navigating administrative hurdles to access new medications. Patients and families reported daily treatment burdens and emotional stress, while simultaneously expressing relief at the availability of effective therapies.

Disease monitoring combined immunological parameters, organ-specific diagnostics, and patient-reported outcomes. Immunoglobulin levels, lymphocyte subsets, infection frequency, and functional biomarkers were assessed regularly. Pulmonary function, gastrointestinal status, and growth parameters were monitored according to individual organ involvement. Multidisciplinary teams, led by immunologists and including pediatricians, rheumatologists, gastroenterologists, pulmonologists, infectious disease specialists, and hematologists-oncologists, coordinated care based on dominant symptoms. Interdisciplinary case conferences and centralized communication were considered essential to optimize outcomes.

Interviews consistently identified a need for validated tools to assess APDS disease activity. Physicians suggested combining objective laboratory measures with patient-reported outcomes to capture the multisystem, variable phenotype of APDS. While disease activity scoring was partially implemented in the ESID registry, its application remained inconsistent. Such tools were viewed as valuable for clinical monitoring, prognostication, and therapeutic decision-making, though methodological challenges existed due to subjective symptoms and organ-specific complications. Patients similarly expressed the desire for clarity regarding disease progression and treatment evaluation.

APDS management was complicated by clinical heterogeneity and systemic barriers. Physicians strongly supported routine genetic testing and standardized disease activity assessment but expressed mixed views on the feasibility of current diagnostic procedures. Consensus emerged regarding the urgent need for approved, evidence-based targeted therapies, reflecting limitations in access outside compassionate use programs.

At the end of the physician interviews, the four participants were asked whether they agreed or disagreed to a set of four hypotheses. The level of agreement was measured by a four-point Likert scale with the options to choose between “strongly disagree”, “somewhat disagree”, “somewhat agree” and “strongly agree”. The original, German, scale can be found as part of the interview guide as Supplementary Material. The following Figure 2 summarizes the results of this assessment. While most respondents strongly agreed on the necessity of routine genetic testing for IEIs and supported the development of a standardized system for assessing APDS disease activity, opinions were more divided regarding the standardization and feasibility of current diagnostic procedures. Importantly, there was broad consensus on the urgent need for new evidence-based and targeted therapeutic options. Physicians noted that responses were made under the assumption that currently available therapies were not broadly accessible outside compassionate-use programs and confirmed that the perceived need would be addressed once targeted agents received formal approval.