A Survey of Diagnosis and Therapy of Inborn Errors of Immunity among Practice-based Physicians and Clinic-based Pneumologists and Hemato-Oncologists

Thomas Lehrnbecher¹Alexandra Russo^2*Gernot Rohde³

• ¹Department of Pediatrics, Division of Hematology, Oncology and Hemostaseology, Johann Wolfgang Goethe University, Frankfurt/Main, Germany, Frankfurt, Germany
• ²2Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University, Mainz, Germany, Mainz, Germany
• ³Department of Pneumology, Clinic for Pneumology, Intensive Care, and Sleep Medicine, University Clinic Marburg, Germany, Marburg, Germany

Incorrect supplementary material In the published article, there was an error in Supplementary Table 2, Questionnaire 2 Answers HaemO. The correct material statement appears below. Heme oncology Doctor (anonymised)123456 Paediatrician/adultPaediatricsAdult medicinePaediatricsPaediatricsPaediatricsPaediatrics NumberQuestion 1Size of the institution175 in total, Paediatric HaemOnc 14 + 9 day clinicIMC 14, ICU 12, 100 normal ward; 3200-3400Onco 8 beds, currently 25 patients; total 117 beds on 6 general paediatric wards and 19 ICUHäma 29 beds, 1-2 Onk, Immu each per week18 inpatient beds, 5 day clinic, 3500 outpatient contacts ~70 centre cases (OnkoZert centre)100 new diagnoses/year, 40 hsct, 19 beds, 7 transplants, many day clinics 2Importance of PID, number of casesSecondary topic, 5 requiring treatment/aSuspected 15/a, confirmed 1-2/a, treated 60/a mainly outpatientApprox. 10-15 suspected cases/year, 1-3 confirmed cases/year, some further treatment and co-treatment in RS CCI FreiburgImportant, separate area for this. Approx. 150-200 patients in total.Very important: discrimination between PID/SID Last 5 years: 20 suspected cases 10 confirmed 3 SCTSuspected cases for clarification approx. 150/year, proven (or in further care 15/year) 3HSCT?yesyesno, if then Freiburg (PID)/Tübingen (rest); 1 each CVID (LP), nfkb1, lp deficiencyYes>14 years->in domo, <14 years Co-op with Fra a myes, 40/a 4Years of experience: doctor, specialist, haemonkPhysician 40 a, Haemonk specialist 31 a11/5; 16/8a) 23 years b) 18 years c) 16 years16, 11, 5.527, 20, 1134, 29, 17 5How often too young lymphoma patients20/arare; occasionally consulted but can only happen when awareness is presentonly 1 caseall younger than expected, as paediatric ward1-2/year1/a, but 5-10 NHL/a, 30 leukaemia/a 6Lymphoma patients with PIDrare, more frequent PTLDyes, e.g. noticed due to infection complications; then with prophylaxis; but chemo must be done, sometimes family historyRather rare, the other way round is more common; in 24 a few patients in other clinics, autoimmune neutropenia, cvid/ hlh, nhl Yesyesyes but few, e.g. 2 with at; igg is not primarily measured, sometimes you can see that they do not recover after rituximab 7Young lymphoma patients -> PID thought?rather not, but alps AT is taken into accountYes, in case of pathological susceptibility to infection, autoimmune diseases, autoinflammation, granulomas in the medical historyAtypical course, viral co-infections (especially EBV), autoimmune phenomena (AIHA, thrombocytopenia...)Yes, always taken into considerationa lot, see questionnaireyes, in the case of a family or personal history, Igs or virus diagnostics, very poor tolerance 8Tests for PID patients, referralLymphocyte subtyping, Ig, complement, vaccination titre, then to CCISerum immunoglobulins, blood count with differentiation, lymphocyte phenotyping; further diagnostics in specialised laboratoriesImmunoglobulins, subclasses, immunophenotyping, vaccine antibodies, further diagnostics only in RS with CCI Freiburgother clinics do basic diagnostics beforehand, then he comes; he does everything.Immunophenotyping, vaccination titre, hair analysis (albinism) complement defects, exclusion of asplenia, autoimmune diagnostics WES as TrioWES with immunodeficiency panel, bone marrow failure syndromes. External: Functional analysesImmune status, immunoglobulins-then we already have relatively much; not primarily genetics, as we want to narrow it down first 9Change in therapy if PID known?sometimes, e.g. with TA increased sensitivity; PTLD requires lessAdditional connection to immunological outpatient clinica) + b) Therapy only in a specialised centreIf necessary, prompt CMT if PGD, combination of cancer and PGD increases indication for CMTModification of therapy according to respective PID-> SCT indication, substitution IVIG etcConsultation with lymph/leuk study centre, increasingly better differentiation depending on genetics, e.g. for AT 10... if only diagnosed after therapy?very rare, but existing infection/colonisation must be taken into accountNo, not directly. Indirectly through increased infection complicationsIn Germany, more complicated course to be expected; less chance of success, more treatment breaks, infections; patient after gene therapy had unusual lymphoma (scid, a few have developed lymphoma, reason unknown)Depending on whether it has an influence on chemotherapy (DNA repair defects); large differences between casesNo dataonly for problems 11Insitution recommended for PID?noYesMany are sensitised, look e.g. for pneumocystis, approx. 1x/year extended disgnosticsyes yes 11aIf no: referrals?no Yes, e.g. after SCT I. If no: Is there a PID centre in your region to which you usually refer patients? FFM/FB with SCT indication 11a-IIf also no: which partner centre?CCI Freiburg CCI Freiburg 12What symptoms make you think of PID all, but he is not a paediatrician; particularly conspicuous e.g. V.A. sarcoidosis is not, polygland. Autoimmune phenomenaFor all 4 points and especially for a combination of several pointsSusceptibility to infection in general, also dysregulation, cytopenias/ autoimmune; in others also hepatosplenomegaly but need to catch up Rare pathogens, unusual localisation and pathogens (pneumocystis, aspergillosis), generally more bacteria/fungi 12aSusceptibility to infections/immune disordersyes conspicuous localisation, immune dysregulation/ autopinflammation, catopeniayes 12bAbnormal laboratory findingsyes, but is not readily ascertained yes 12cBenign lymphoproliferationYes, then e.g. ALPS long-lasting L-adenopathy, splenomegaly, evidence of granulomatous inflammationDifficult question, depends on the findings 12dDevelopmental disorderAre usually referred from neuropaediatricsdoes not really occur as he is not a paediatrician yes, albinism, vitiligo, dysmorphia, microceph, dental anomalies, congenital heart defects, organ malformations heart defects, organ malformations, hearing disorders, developmental retardation, vasculitis, enteropathyyes 13ELVIS/GARFIELD known?Yesyesyesyesyesyes 14Immune. Tests in your institution? allyes 14aIf yes, which in-house?Differential blood count (see above), phenotyping, no functional test (but with Freiburg, also for clinic); genetic tests at the Institute of Human Genetics or CCIDifferential blood count, soon with vaccine antibodies; immunophenotyping without lymphotests; genetics on UKK or CCIespecially 1, 2 and 3 also possible but more CCIeverythingallall except genetics (Cegat) 14bWhich ones did you request yourself?Newborn screenings, tests for HLH were carried outDifferential blood count incl. determination of immunoglobulin levels T- and B-cell FACS analysisalleverythingallnone, runs via immunodeficiency outpatient clinic (billing) 15If PID diagnosis, do you provide therapy?Differentself-initiate, if necessary interdisciplinary case conferenceCCI Freiburg; hypogamma most, receive s.c. ig, are hybridised in heilbronn, trnaplantations, she does not receive other therapiesit is a pid centreyes, in cooperation with pid centreyes yes 16aHow important (1-5)55, virtual, over 204555 16bWhich questions should be addressed?Rational diagnostics for suspected PIDnot only patient cases as too specific, rheumatological topicsWarning signs, differential diagnoses, symptom-orientated diagnostics; every format is welcome; basic understanding of the level at which defects can ariseDepending on the, annual meetings of professional societies in person, additional virtualvirtual, if malignant also test for iei without immunodeficiencyf2f, he mainly does infectious immunology 16cHow many have you attended?in the context of ASH, own contributions to NG screening for SCID >10he holds immunolog. training coursespure immu 2, with onco 10many The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.