Inborn errors of immunity (IEI), formerly known as primary immunodeficiencies (PID), are a group of hereditary conditions that affect the functioning of the immune system. The number of identified IEIs currently amounts to a reported 559, and with continued genetic research and given the rapid pace of discovery it is expected to increase continuously (1). IEI may clinically manifest as unusually frequent or severe infectious complications (immunodeficiency), as autoimmunity or autoinflammation (immune dysregulation), and may be associated with syndromic multi-organ diseases or developmental disorders (e.g., ataxia teleangiectatica (AT)). Due to improved diagnostic procedures and reporting, it becomes increasingly clear that the actual prevalence is far higher than originally assumed (2, 3). According to some reports, between one out of 1200 and 2000 people could be affected (2), which would similar to the prevalence of multiple sclerosis (MS) (4). Latest studies suggest that there is a large number of genetic variants that in addition to other organ systems also affect the immune system; the incomplete penetrance in some cases makes it even more difficult to estimate the number of people affected, but the rate could be as high as 1:500 (5). Unfortunately, awareness for IEI compared to MS is disproportionately low among health care providers (HCPs) (6), which is partly due to the fact that this highly heterogeneous group of diseases often manifests in unspecific ways. For most patients with IEI, the first contact point will be a practice-based pediatrician or a general practitioner, but a significant proportion of patients will eventually present to a practice-based specialist or a pneumology or hemato-oncology department, as many IEIs manifest by recurring respiratory complaints, suspected lymphoproliferative disorder or blood abnormalities (7).

The group of IEIs includes a large number of mostly hereditary diseases, though genetic mosaicisms or somatic mutations have also been described for a small number of conditions (8). Disease-causing variants can be located in genes whose function is predominantly related to the host immune defense, such as STAT3 in the Hyper-IgE syndrome (9), or in genes with very fundamental functions, e.g. ATM in the case of ataxia telangiectasia (10). From the evolution of the terms PID and IEI, it can be seen that these diseases were initially thought to only affect immune defense, whereas more recently it has been recognized that they can manifest both by immune deficiency and immune dysregulation (11, 12). Some IEIs are accompanied by pathological lymphoproliferation, which can increase the risk for hematologic malignancy, in particular of lymphomas (13), but also poses a challenge to differential diagnosis (14). The International Union of Immunological Societies (IUIS) currently recognizes 10 classes of IEI, including combined immunodeficiencies (with or without syndromic features), predominantly antibody deficiencies or diseases of immune dysregulation (1).

Due to the variety of clinical manifestations, IEI patients may primarily present at different specialists, e.g., to the pneumologist with recurrent respiratory tract infections, bronchiectasis or autoimmune granulomas of the lungs, or to the hemato-oncologist with cytopenia, lymphoproliferation or lymphomas (15–17).

As is the case with many rare diseases, diagnosing an IEI patient may be a challenging task. As a helpful guide, various lists of warning signs and guidelines have been developed for the detection of IEI, including the ELVIS/GARFIELD criteria (12, 18–20). In case of suspected IEI, patients first undergo basic immunologic testing, the assessment of lymphocyte subsets and antibody subclasses, which may trigger genetic testing. Depending on the basic immunologic testing, only a fixed set of genes is usually analyzed from the dataset (virtual panel analysis), whole exome and whole genome sequencing are on their way of becoming standard of care.

After the diagnosis has been established, treatment depends on the specific IEI and may include several strategies ( Table 1 ). This includes antibiotic prophylaxis and IgG substitution therapy (21–23) in immunodeficiency, whereas patients with disorders of immune regulation (autoimmunity, autoinflammation, lymphoproliferation) may benefit from treatment with immunosuppressants (24). In recent years, the elucidation of genetic causes has made it possible to offer targeted therapies for several IEIs. In some cases, approved drugs can be repurposed, but new drugs have been developed as well. Some examples include STAT inhibitors which can be used to treat different hyperinflammatory conditions or leniolisib, a PI3Kδ inhibitor currently approved in the US for patients with Activated PI3Kδ syndrome (APDS) (25–27). In some patients, hematopoietic cell transplantation (HCT) is indicated. Although it is associated with considerable risks, it can offer a real chance for cure to selected patients (28, 29). Newer strategies include gene therapy, e.g. for Chronic Granulomatous disease (CGD) (30) or Activated PI3Kδ syndrome (31), where patient stem cells are genetically altered to correct the disease causing variant (32, 33), but gene therapies are not widely available yet and their long term risks are insufficiently explored.

The aim of the study was to get an overview of the IEI diagnostic landscape outside specialized IEI centers, in particular in practices and clinics that do not deal with IEI patients on a daily basis. The targeted physicians include office-based physicians, and in the second instance physicians from pneumology and hemato-oncology clinics. Key points we investigated were: Significance of the topic IEI day-to-day, awareness for signs and symptoms of IEI, number of suspected, diagnosed and referred or treated IEI patients, handling and management of IEI patients (tests performed in-house, patient referral, collaboration with IEI clinics/centers), request for training events and materials. Further, we compared the situation in clinics and doctor’s offices according to these criteria to identify potential issues in the diagnosis of IEI patients and to identify possibilities for improvement in recognition and consecutive diagnosis if IEIs.

Due to the wide range of symptoms and severity of IEI, we asked which symptoms were considered to be particularly indicative of IEI, including susceptibility to infection, abnormal laboratory findings, organ manifestations (e.g. bronchiectasis or lymphadenopathy) and developmental disorders or syndromic characteristics.

Most participants (10/14) stated that all parameters listed in the questionnaires could, in principle, be indicators of IEI, but that they are weighted differently ( Figure 5 ). For example, bronchiectasis and lymphadenopathy can be indicators of IEI, but only lead to a suspected diagnosis in combination with other factors. In contrast, recurrent severe infections were considered the strongest single indicator. The same is true for developmental disorders such as delayed growth, hearing loss and facial dysmorphia, which also were considered conditional indicators of IEI. In case of susceptibility to infections, frequency of infections alone was reported to be insufficient to formulate a suspected diagnosis; instead, attention should be paid to unusual pathogens, e.g. fungal infections of the lungs. Other participants cited autoimmune phenomena (7/14 participants, specifically 2/8 pneumologists, 5/6 hemato-oncologists), e.g. autoimmune cytopenia, enteropathy and sarcoidosis.

These statements correspond well with the warning signs formulated by the professional societies (12, 19, 20) and indicate that the interviewees are largely well informed about IEI.

Treatment options for PID patients can be divided into symptomatic (e.g., immunoglobulin replacement therapy = IRT, antibiotic administration), targeted and curative treatment (e.g., hematopoietic cell transplantation). The latter two treatment options are highly complex and require expertise for immunodeficient patients. We therefore asked our interview partners which treatment options they offer IEI patients and when a specialist center is consulted.

Not surprisingly, all participants responded that organ-specific manifestations of IEI such as bronchiectasis and lymphoma are treated in their pneumology or hemato-oncology clinics. Furthermore, several participants from pneumology and hemato-oncology stated that they order and perform IRT themselves. In larger hemato-oncology clinics, there is often extensive expertise in HCT. However, several interviewees stated that they do not transplant IEI patients themselves or only in close coordination with an IEI center. This reflects the special characteristics of IEI patients compared to cancer patients in the transplant setting. For example, the decision whether or not to transplant requires specific knowledge on IEIs. There are also differences in the conditioning and care of IEI patients in the different phases after transplantation compared to cancer patients (29, 43). Targeted therapies have been used in hemato-oncology for some time, and with the advent of new drugs for the treatment of CF and autoinflammatory lung diseases, they are also becoming increasingly common in pneumology. However, participants from both pneumology and hemato-oncology predominantly stated that they do not carry out targeted therapies in IEI patients themselves but refer patients to a specialist center for this purpose ( Figure 6 ). Participants who reported offering targeted therapies to IEI patients themselves were mostly those employed at a clinic specializing in IEI.

A minority of practice-based physicians stated that further information on the topic of IEI was desired, and the responses demonstrated again that IEI is considered more important among pediatricians than adult physicians overall (adults: 59/992 = 5.9%; pediatricians: 47/523 = 9.0%). Differences were also seen between comparable sub-specializations ( Figure 7 ).

Strikingly, the interest in educational material on IEI in each group of specialization or pediatric sub-specialization strongly correlated with the experience of having treated patients with IEI ( Supplementary Figure S1 ).

In contrast to practice-based physicians, clinic-based pneumologists and hemato-oncologists had a high level of awareness and a significant knowledge of the topic. However, the comparison is limited by the facts that the surveys contained different questions and may also have a selection bias. All of the respondents of the clinic-based physicians considered further education on IEI to be very important (5/5 = very high priority) or important (4/5 = high priority). Several participants stated that they preferred training courses individually tailored to their need compared to more general events. For example, trainings highlighting the pneumological aspects of IEI were preferred to general introductions to IEI. Opinions differed on whether virtual events or on-site training should be preferred. Those in favor of virtual events pointed to practical considerations. Training sessions at the relevant specialist conferences were seen as a chance to reconcile the desire for personal exchange with the problem of potentially long journeys to in-person trainings.