Treatment and management of primary antibody deficiency: German interdisciplinary evidence‐based consensus guideline

This evidence‐based clinical guideline provides consensus‐recommendations for the treatment and care of patients with primary antibody deficiencies (PADs). The guideline group comprised 20 clinical and scientific expert associations of the German, Swiss, and Austrian healthcare system and representatives of patients. Recommendations were based on results of a systematic literature search, data extraction, and evaluation of methodology and study quality in combination with the clinical expertise of the respective representatives. Consensus‐based recommendations were determined via nominal group technique. PADs are the largest clinically relevant group of primary immunodeficiencies. Most patients with PADs present with increased susceptibility to infections, however immune dysregulation, autoimmunity, and cancer affect a significant number of patients and may precede infections. This guideline therefore covers interdisciplinary clinical and therapeutic aspects of infectious (e.g., antibiotic prophylaxis, management of bronchiectasis) and non‐infectious manifestations (e.g., management of granulomatous disease, immune cytopenia). PADs are grouped into disease entities with definitive, probable, possible, or unlikely benefit of IgG‐replacement therapy. Summary and consensus‐recommendations are provided for treatment indication, dosing, routes of administration, and adverse events of IgG‐replacement therapy. Special aspects of concomitant impaired T‐cell function are highlighted as well as clinical data on selected monogenetic inborn errors of immunity formerly classified into PADs (APDS, CTLA‐4‐, and LRBA‐deficiency).


Introduction
The International Union of Immunological Societies (IUIS) lists ten groups and 416 monogenetic primary immunodeficiencies (PID)/inborn errors of immunity (IEI) [1] (Table 1). Predominantly antibody deficiencies confer the largest group (group 3) [2]. In addition, antibody deficiency is of clinical relevance in many other PIDs. The present guideline focuses on diseases of IUIS group 3, however there are overlaps with other PIDs, in particular with combined immunodeficiency and monogenetic disorders previously categorized as CVID (e.g., activated PI3KCD syndrome (APDS), CTLA-4-deficiency, and LRBA-deficiency). This  (1)) I.
Immunodeficiencies affecting cellular and humoral immunity II.
Combined immunodeficiences (CID) with associated or syndromic features III.
Predominantly Antibody deficiencies IV.
Diseases of immune dysregulation V.
Defects in intrinsic and innate immunity VII.
Bone marrow failure X.
Phenocopies of PID guideline does not cover secondary antibody deficiencies. Patients with antibody deficiencies present with an increased susceptibility to infections, affecting predominantly the respiratory and gastrointestinal tract [3]. However, infections may neither be the first nor the leading clinical symptom [4,5]. Immune dysregulation, autoimmunity, and cancer affect a significant proportion of patients, including for instance immune cytopenia, lymphoproliferation, or granulomatous diseases [6]. Therefore, this guideline covers aspects of IgG-replacement as well as monitoring and treatment of "non-infectious" manifestations.

Methods
Literature search was conducted (date of search: 31.5.2018) in PUBMED (http://www.ncbi.nlm.nih.gov/pubmed/) using MeSH terms and keywords for the following terms: 1. Use of immunoglobulin replacement therapy in primary antibody deficiency 2. Immune cytopenia 3. Granulomatous disease including interstitial lung disease 4. APDS I / II, CTLA4 deficiency, LRBA deficiency 5. Bronchiectasis More details of the search strategy are shown in the Supporting Information (M1). Number of records and included citations are presented in Supporting Information Table M2.
This interdisciplinary guideline was developed by mandated members of 20 medical societies from Austria, Germany, and Switzerland including a representative of the German patient organisation for patients with primary immunodeficiencies. Recommendations were developed at S3-level of methodology according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). Evidence is rated according to Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence (see Supporting Information Table S1). Methodology was evaluated according to SIGN (Scottish Intercollegiate Guidelines Network). Recommendations were graded following a formal consensus procedure (see Supporting Information Table S2). This included nominal group processes and structured consensus conferences moderated by AWMF-representatives during which recommendations were formally voted on by the mandated members. Strength of consensus for each recommendation was graded as shown in Supporting Information Table S3. Recommendations without sufficient level of evidence were classified as "expert consensus." Additional studies and publications were identified when analyzing retrieved literature. Those studies did not impact on the recommendations of participants of the consensus conference. In an update, selected literature published after May 31, 2018 and not affecting recommendations of the consensus conference was included to the current manuscript. The present publication is a summary of the full-length version published in German (https://www.awmf.org/uploads/tx_szleitlinien/189-001l_S3_Therapie-primaerer-Antikoerpermangelerkrankungen-2019-05_01.pdf) and is the revised and extended second edition of the German evidence based and consensus guideline published in 2012 [7].

IgG-replacement therapy in primary antibody deficiencies
Published evidence allows to group antibody deficiencies into diseases with "definitive benefit," "probable benefit," or "possible benefit" of IgG-replacement and into ones in which IgGreplacement is not beneficial. The definition along clinical effectiveness may not completely overlap with immunological definitions or the molecular genetic basis of antibody deficiencies (e.g., "hypogammaglobulinemia" or "NFkB1-deficiency" may be a condition with proven or only with probable benefit, depending on absence or presence of specific antibody responses to vaccinations). The indication for IgG-replacement in hypogammaglobulinemia should be based-at least-on increased susceptibility to infections and the assessment of specific vaccine responses. Before the start of IgG-replacement in hypogammaglobulinemia, specific antibody responses upon vaccination should be evaluated. Individual vaccine responses should be assessed together with experienced clinical immunologists. This should be performed before Ig replacement therapy as vaccine responses cannot be assessed with certainty after IgG-replacement. Alternatively, in non-vaccinated individuals antibody titers against pathogens documented in the patient (e.g., Haemophilus influencae) is also useful. In patients with agammaglobulinemia and/or severely ill patients the evaluation of vaccine responses is dispensable and must not delay initiation of IgG-replacement.

Consensus-based recommendation 1:
"Before initiating IgG-replacement therapy we recommend assessment of specific antibody-responses to vaccination. In clinical emergencies we do not recommend to delay start of therapy for diagnostic vaccination. In agammaglobulinemia assessment of vaccine responses is dispensable."

Expert consensus: strong consensus
Antibody deficiencies with proven effectiveness/definitive benefit of IgG-replacement

Hypogammaglobulinemia with impaired response to vaccinations
Hyper-IgM-Syndromes (Immunoglobulin class switch recombination deficiencies): Due to deficient class switch recombination, patients present with low levels of IgG and IgA, normal or elevated levels of IgM, normal numbers of B-cells and are characterized by severely impaired specific antibody responses upon vaccination. Effectiveness of IgG-replacement is proven [12,[14][15][16][17]. Due to the accompanying T-cell-deficiency, in particular in CD40Ldeficiency and in CD40-deficiency, there is still an increased risk for opportunistic infections [15,16]. Besides the initiation of IgGreplacement patients with HIGM should be evaluated for possible stem cell transplantation [18].
Common variable immunodeficiency disorders (CVID): The umbrella term, "CVID", comprises most of the clinically relevant antibody deficiencies. The current diagnostic criteria of the European Society for immunodeficiency (ESID) are listed in Supporting Information Table S4. There is proven effectiveness of IgGreplacement in CVID [11][12][13][14][19][20][21][22][23]. Patients may suffer from increased susceptibility to infections and from immune dysregulation (see section 5). Even in the absence of infectious susceptibility there is strong expert consensus that IgG-replacement should be considered in CVID patients on immunosuppressive therapy and/ or with immune cytopenia.

Consensus-based recommendation 3a:
"We recommend IgG-replacement therapy in hypogammaglobulinemia with absent or strongly impaired, specific IgGproduction and increased susceptibility to infections."

Hypogammaglobulinemia with normal response upon vaccination, yet increased susceptibility to infections
Unclassified antibody deficiency (uAD) or idiopathic hypogammaglobulinemia. This entity comprises conditions that do not fulfill defined criteria of agammaglobulinemia, CVID, or otherwise defined antibody deficiencies (e.g., selective IgA-deficiency; see Supporting Information Table S5 for ESID definition). Among this group, some patients may be classified as hypogammaglobulinemia with impaired antibody responses to vaccination (see above). There are no prospective studies on the effectiveness of IgGreplacement in these patients. The decision on IgG-replacement should be based on the level of IgG-deficiency and the severity of infections [24,25].
"Specific antibody deficiency" (SAD) is defined by impaired formation of specific antibodies (mostly against polysaccharides) despite normal total Ig levels and normal B cell counts [26,27]. In clinical practice, the response to non-conjugated pneumococcal vaccine is widely available as a surrogate to assess for SAD. Interpretation of antibody responses to polysaccharides and the indication for IgG-replacement should be discussed with an experienced center for primary immunodeficiencies [28,29]. The prophylactic use of antibiotics is recommended as first-line treatment in SAD [30]. IgG-replacement in SAD is recommended in patients: -with very frequent and/ or very severe infections; -with severely impaired response to vaccination with nonconjugated polysaccharide, pneumococcal vaccine (≤2 pneumococcal serogroups with concentration >1.3 μg/mL) -with severe side-effects due to antibiotic prophylaxis; or -without clinical improvement on antibiotic prophylaxis. SAD may be indicative for more severe primary immunodeficiencies and must initiate advanced immunological diagnostics.

Consensus-based recommendation 4 "We suggest IgG-replacement therapy in patients with increased susceptibility to infections with hypogammaglobulinemia and normal vaccine responses*."
Expert consensus: strong consensus (*see section 3 for vaccine response)

Transient hypogammaglobuliemia of infancy
Transient hypogammaglobuliemia of infancy (THI) is defined as prolonged IgG-levels below normal values, which resolve with age. Specific antibody responses upon vaccinations are normal. Data on IgG-replacement in THI are insufficient for evidencebased recommendations [43,44].

Selective IgA-deficiency
There is no indication for IgG-replacement in selective IgAdeficiency.

Selective IgM-deficiency
There are only retrospective studies with few patients using inconsistent definitions of IgM-deficiency. Some patients may present with increased susceptibility to infections [45][46][47]. Data on IgGreplacement are insufficient for evidence-based recommendations. "Selective IgM-deficiency" must initiate advanced immunological diagnostics as it may be indicative for severe primary immunodeficiencies.

IgG4-subclass-deficiency
Data on IgG-replacement in "IgG4-subclass-deficiency" are insufficient for evidence-based recommendations. Available data argue strongly against IgG-replacement.

Consensus-based recommendation 6:
"We do not recommend IgG-replacement therapy in selective IgA-deficiency, IgM-deficiency and IgG4-subclass-deficiency if vaccine responses are normal."

Antibody deficiencies in combined T/B cell deficiencies without defined genetic cause
In patients with hypogammaglobulinemia in combined T/B cell deficiencies with at least two of the following three criteria: (a) Reduction of CD4+T-cells: <300/μl in 2-6 years, <250/μl in 6-12 years, <200/μl in >12 years; (b) Reduced percentage of naïve CD4+T-cells: <25% in 2-6 years, <20% in 6-16 years, <10% in >16 years; (c) Reduced T-cell response upon T-cell-receptor stimulation or stimulation with mitogens an increased risk for (opportunistic) infections is likely [48]. Additional antibiotic prophylaxis with TMP/SMX is recommended [49] (see section 7). Genetic diagnostics are recommended. In severe impairment of T-cell immunity, assessment in a center with experience in allogenic stem cell transplantation is strongly recommended.

Route of administration
Different routes of administration are feasible for IgGreplacement.
IVIg: Intravenous IgG-replacement (IVIg) must be given under medical supervision in a hospital, an outpatient clinic or a private praxis familiar with the application of IVIG (legal obligation in Germany). Other countries also offer the possibility of IVIg treatment at home. SCIg: In subcutaneous IgG-replacement (SCIg) IgG is administered via catheter and pump (alternatively manually as "rapid push") into subcutaneous tissue (usually of abdomen, thighs, or arms). fSCIg: "Facilitated IgG-replacement" (fSCIg) combines the subcutaneous application of immunoglobulines with previously applied hyaluronidase [50][51][52] .
Subcutaneous IgG-replacement, SCIg and fSCIg, are licensed for home therapy. In patients on SCIg "Health-related quality of life" improved stronger than in patients on IVIg [53][54][55][56][57][58][59]. Prior to home-therapy informed consent for the application of IgG must be given to the prescriber. The intramuscular application of IgG (IMIg) is not recommended any more.

Dosing and management of therapy
General remarks: Success of IgG-replacement can be judged by trough levels that measures the concentration of IgG and the trough level needed for sustained clinical improvement ("biological trough level") [60,61]. "Trough level" is defined as the serum concentration of IgG before next IgG-replacement. There are minimal trough levels regarded as necessary for sufficient prophylaxis against infections. Due to the relatively stable levels of serum IgG in SCIg, which is applied more frequently than IVIG, the term steady state level is preferred. IVIg: The effectiveness of IVIg for the reduction of infections has been proven [11,13,62]. However, there is a broad individual range in trough levels required [23]. There is sufficient evidence that the severity of infections is reciprocally proportional to the IgG trough level and that a trough level > 4.5 g/L reduces the rate of bacterial infections [63]. A meta-analysis on the incidence of pneumonia in correlation with trough levels on IVIg showed a fivefold higher incidence at a trough level of 5 g/L (0.113 pneumonia/patient/year) compared to a trough level of 10 g/L (0.023 pneumonia/patient/year) [64]. Individual dosing and trough levels may also depend substantially on comorbidity (e.g., presence of bronchiectasis) and underlying cause for IgG-replacement. The general recommendation of IgG-trough level >4.5 g/L does therefore not exclude that some individuals may require IgG-trough levels > 10 g/L ("Expert opinion"). Most clinicians start IgG-replacement with 400-600 mg/kg body weight [65]. The usual interval for IVIg is 21-28 days. However, interval and dose must be adjusted individually [66]. We recommend starting IVIg with a 10% solution at a flow rate of 0.

Consensus-based recommendation 11:
"In obese patients we recommend dose calculation by using ideal/adjusted body weight."

Switch of application
Switching from one application to another is not uncommon [71]. When switching to SCIg, FDA recommends a conversion factor of 1:1.37 (IVIg:SCIg); however, most clinicians continue with the previous dose and adjust according to clinical and laboratory parameter [72][73][74].

Consensus-based recommendation 12a:
"We recommend to initiate IgG-replacement therapy in a dose of ≥ 400 mg/kg/month (sc or iv)."

g/kg/month of IgG for intravenous IgG-replacement therapy (IVIg). We recommend IgG-trough-levels ≥ 4.5 g/L. Maintenance therapy should by guided according to clinical response (biologic trough level)."
Level of evidence: 2; Level of recommendation: A Consensus-based recommendation 12c: "We suggest a dose of 0.4-0. 6

Monitoring and management of adverse events
We recommend monitoring of IgG levels every 3 months in the first year of treatment. In stable patients, we recommend monitoring IgG levels ≥2 times per year. Adverse events are rare [75].

Transfusion-related adverse events
Severe transfusion-related adverse events are very rare [75]. Most events are mild, reversible, and occur at fast infusion flow rates. In adverse events, during IVIg reduction of IVIg flow rate is recommended. Severe adverse events are treated according to recommendations for anaphylaxis. In patients with persistent adverse events or in patients with ongoing need for premedication on IVIg, switching to SCIg should be considered.

Hemolysis
Immunoglobuline products contain isohemagglutinins that may cause transfusion associated hemolysis. Hemolysis was almost exclusively reported in IVIg patients [76,77].

Anti-IgA antibodies
Serum IgG anti-IgA antibodies have been associated with the development of adverse reactions, to IVIg in patients with undetectable IgA levels [78][79][80][81]. Consequently, most manufactures consider the presence of anti-IgA antibodies as a contraindication to Ig replacement therapy. Due to the very low incidence of severe adverse events caused by anti-IgA antibodies, screening for these antibodies is not routinely performed. Monitoring of patients receiving their first IVIg infusion or IVIg infusions after a long treatment pause is mandatory. Patients with anaphylactic reaction upon IVIg should switch treatment to subcutaneous application (SCIg). The absence of IgA is no contraindication for Ig replacement therapy. Patients with known anti-IgA antibodies have a higher risk of anaphylaxis during IVIg treatment (in particular, with IgE-anti-IgA antibodies). SCIg application is considered safe in these patients.

Risk of pathogen transmission
Immunoglobulin products are produced from plasma of >10000 healthy donors. Due to the transmission of HCV in 1994, the processes for reducing pathogen contamination have improved significantly. Viral removal by depth filtration and nanofiltration as well as viral inactivation with low pH, pasteurization, caprylate, and detergent reduce the risk for viral transmission to almost zero. Nanofiltration can further remove non-lipid-coated viruses and prions [82].

Miscellaneous
Acute renal failure is usually mild and reversible [83]. Patients with renal disease and/or chronic heart failure might benefit from lower IVIg concentrations (5%). Thromboembolic events have been reported, however, a systematic review and meta-analysis of RCT found no evidence of an increased risk for thromboembolic among IVIg-treated patients [84]. Aseptic meningitis is rare [85] and usually observed in high dose IVIg treatment (1-2 g/kg BW) [86]. To avoid hyperviscosity patients with renal insufficiency require additional hydration. In patients with relevant proteinuria, SCIg seems more reasonable.
In IVIg products containing maltose, erroneously elevated blood sugar values can occur when using GDH-PQQ test strips [87]. Diagnostic assays using Beta-D-Glucan for fungal testing can be false positive [88]. Immunoglobulin treatment can transfer antibodies to blood groups, affecting serological test.

Immune cytopenia
Management of immune cytopenia follows recommendations for non-PID patients [92]. Present data support first-line treatment with steroids. If manageable as outpatients, oral application is preferred [93]. In severe courses, adjunctive treatment with high dose immunoglobulins may be considered. Rituximab is recommended as second-line therapy in PID patients [94,95]. There are only case reports for the use of thrombopoietin receptor agonists [94,96]. Risk of recurrence is high. In selected cases, splenectomy may be considered, but must be weighed carefully against the potentially increased risk of infections [97]. We recommend interdisciplinary follow-up for patients with antibody deficiency and immune cytopenia.

Expert consensus: strong consensus
Consensus-based recommendation 14b: "We suggest treatment of ITP and AIHA with steroids and adjunctive high dose of immunoglobulines in severe courses."

Pulmonary manifestations
The vast majority of patients with antibody deficiency suffers from chronic pulmonary manifestations [98][99][100][101]. Pulmonary manifestations affect survival in patients with CVID [102]. The two largest entities of pulmonary manifestations are bronchiectasis and granulomatous lymphocytic interstitial lung disease (GLILD).

Bronchiectasis
In the presence of clinical symptoms or suggestive history, detection of bronchiectasis is usually performed by CT scan. Chest X-ray fails to identify bronchiectasis in up to 60% [103]. Management of bronchiectasis aims at reducing/preventing acute exacerbations and infections, improving mucocilliary clearance, and stabilizing pulmonary function. We recommend microbiological sputum surveillance every 3-6 months for early identification of colonization with potential harmful germs (Pseudomonas aeruginosa, MRSA), and for guidance of initial decision on empiric antibiotic treatment in acute infections, before current microbiological data are available. According to ERS (European Respiratory Society) guideline, duration of antibiotic treatment is 14 days [104]. Haemophilus influenzae, Pseudomonas aeruginosa, Moraxella catarrhalis, Staphylococcus aureus, or Enterobactericae ia frequently colonizing the airways in patients with bronchiectasis. Colonization with Pseudomonas aeruginosa was shown to affect long-term pulmonary function [105]. In agreement with ERS guidelines, we recommend early eradication of Pseudomonas aeruginosa. For additional treatment options, including inhaled therapy and exercise training, see section 8.
RCT assessing the role of antibiotic prophylaxis in non-CF bronchiectasis are only available for non-PID patients. Using macrolides, a significant reduction of exacerbation rate and symptoms was detected [106][107][108][109]. Development of non-susceptibility to macrolides, cardiac arrhythmia, and gastrointestinal adverse events need to be considered [107]. ERS guidelines recommend antibiotic prophylaxis with 250-500 mg Azithromycin three times per week in patients with >3 exacerbations/year. It is mandatory to test for colonization with non-tuberculous mycobacteria and to check QT time prior to macrolide prophylaxis. Two prospective cohort studies showed that CVID patients with bronchiectasis required higher IgG-dosing for reaching target IgG-levels [21,23]. Patients with or without bronchiectasis did not differ in rates of infection when treated at similar IgG trough levels [23]. In patients with bronchiectasis, IgG levels should be adapted individually.

Interstitial lung diseases
Granulomatous lymphocytic interstitial lung disease (GLILD) is found in 10-30% of CVID patients, either developing during disease course [110] or as first clinical presentation [5]. GLILD affects survival in patients with CVID [102]. For clinical diagnosis, radio-morphological findings as wells as lung function and histopathology must be taken into consideration [111]. We recommend annual pulmonary function testing including measuring DLCO (diffusion capacity) for surveillance of CVID patients. Routine chest imaging is not recommended. Its use should be reserved for deterioration of lung function or clinical symptoms. Lung MRI can avoid radiation [112]. GLILD should prompt a detailed (and genetic) immunological work-up [113]. There are no RCTs for the treatment of GLILD in CVID patients. Depending on the histopathology and/or BALF, it is reasonable to begin with steroids. Only limited data are available for second-line treatment of GLILD. Successful combination therapy targeting B-cells (using rituximab) and T-cells (using azathioprine or MMF) at the same time was reported by different groups [114][115][116][117] (see Supporting Information Table S6 for summary of treatment of GLILD in CVID). Treatment of GLILD should only be considered in cases with clinical symptoms, reduced pulmonary function, or radiomorphological progression, since many patients remain clinically stable [118]. There is some evidence that patients with CVID and GLILD might benefit from higher IgG trough levels [23,119]. We recommend interdisciplinary follow-up for patients with chronic pulmonary manifestations.

Expert consensus: strong consensus
Consensus-based recommendation 15c: "We suggest regular sputum analyses in patients with bronchiectasis."

Granulomatous lesions can affect all organs
In CVID patients, extra-pulmonary manifestations include lesions in spleen, liver, lymph nodes, skin, kidney, or CNS [118].
In histopathology most lesions present as "sarcoid-like," noncaseating epithelioid granuloma, while lymphocytic infiltrates can be detected as well. Granulomatous/lymphocytic organ manifestations should prompt a detailed immunological and genetic work-up. There are no RCT for treatments, case reports are summarized in Supporting Information Table S7. Treatment options should be evaluated in cooperation with an immunodeficiency center.

Neoplasia
Patients with CVID express an elevated risk for neoplasia, in particular for lymphoma and gastric cancer [120][121][122]. In a recent large Italian cohort, gastric cancer was the leading cause of death in CVID patients [123]. Patients should be educated to report unusual or persistent lymphadenopathy. Annual screening for lymphadenopathy or hepatosplenomegaly by abdominal sonography is recommended. During clinical visits, history and examination should also cover specific symptoms (lymphadenopathy, weight loss, sweating at night, etc.). Annual CT scans for surveillance of asymptomatic patients are not recommended.

Gastrointestinal manifestations
Gastrointestinal manifestations, such as autoimmune gastritis, celiac disease, chronic diarrhea, malabsorption, nodular lymphatic hyperplasia, etc., may affect patients with primary antibody deficiencies [124]. We recommend assessing specifically gastrointestinal symptoms in all patients with antibody deficiency. Abdominal ultrasound is recommended in all patients with CVID at diagnosis and for annual follow-up examinations. In adult patients with CVID, esophago-gastroduodenoscopy (EGD) is recommended at diagnosis. There are no clinical trials that assessed the efficacy of early detection of gastric cancer in different screening settings. Some reports suggest follow-up examinations to be guided by histopathology [125]. In a recent large Italian cohort of 455 CVID patients, gastric cancer appeared on average 15 years earlier than in non-CVID patients. Based on their results, Pulverenti et al. recommend follow-up EGD every 24 months in patients with normal histology and every 12 months (in patients with atrophic gastritis or intestinal metaplasia) or even every 6 months (in patients with dysplasia). Due to the higher prevalence of gastric cancer in Italy, it is uncertain if those recommendations are applicable to other populations [123]. As non-invasive follow-up, we recommend annual Helicobacter pylori testing (by HP-Ag in stool or urea breath test) and measuring vitamin B12 in blood or methylmalonic acid in urine, since HP and autoimmune gastritis are known risk factors for gastric cancer. Autoantibody diagnostic (e.g., for Transglutaminase-Ab) may be misleading. Microbiological stool analysis should also cover parasites and Norovirus infections. Endoscopy may be required in patients with unclear enteropathies or, e.g., for diagnosing infection with Giardia lamblia. We recommend interdisciplinary follow-up for all chronic gastrointestinal manifestations.

Consensus-based recommendation 16a: "We suggest interdisciplinary follow up with a (pediatric) gastroenterologists in patients with liver and / or gastrointestinal manifestations."
Expert consensus: strong consensus Consensus-based recommendation 16b:

"We recommend ultrasound of the abdomen at diagnosis and yearly follow up in patients with CVID. We recommend esophago-gastroduodenoscopy and colonoscopy in symptomatic patients."
Expert consensus: strong consensus

APDS I and II
APDS (activated phosphoinositide 3-kinase delta syndrome) is caused by autosomal-dominant "gain of function" mutations in PI3KCD (APDS I) [126,127] or PI3KR1 (APDS II) [128]. Clinical symptoms include an increased infection rate, bronchiectasis, EBV viremia, lymphoproliferation, and autoimmunity. Approximately 50% of patients present with hypogammaglobulinemia or fulfill criteria for CVID. There are no RCTs on treatment in APDS. Current literature and data from ESID level 3 registry report improvement on rapamycin [129]. Targeted therapy using the selective PI3Kdelta-Inhibitor leniolisib was only tested in a small trial [130].

CTLA4 deficiency
Haploinsufficiency caused by autosomal-dominant "loss of function" mutations in CTLA4 [131]. Overall 84% of patients present with hypogammaglobulinemia. Clinical symptoms are lymphoproliferation (73%), autoimmune cytopenia (62%), and lymphocytic infiltration of various organs (lung, gastrointestinal tract, CNS, skin, etc.). There are no RCTs on treatment. Current data report clinical improvement on CTLA4-IgG-fusionprotein (Abatacept) or rapamycin [132]. LRBA deficiency LRBA (LPS-responsive beige-like anchor protein) deficiency: caused by autosomal-recessive mutation in LRBA [133]. There are no RCTs on treatment. Analysis of different treatments in an international multicenter cohort reported an overall survival after HSCT in 70% (mean follow-up 20 months). Immunosuppressive treatment with Abatacept or rapamycin was associated with significantly lower disease scores than was treatment with steroids [134].

Antimicrobial treatment
At the time of consensus meeting, no RCTs on the use of antimicrobial prophylaxis in primary antibody deficiency were available. A recent publication by Milito et al. is included to the present version of these guidelines due to its clinical importance. In a 3-year, double-blind, placebo-controlled, randomized clinical trial, it was shown that oral azithromycin (250 mg administered once daily 3 times a week for 2 years) reduced respiratory exacerbations in patients with primary antibody deficiency. The rate of additional antibiotic treatment per patient-year was 2.3 (95% CI, 2.1-3.4) in the intervention group and 3.6 (95% CI, 2.9-4.3) in the placebo group (p: 0.004). There was no difference in safety or in nonsusceptibility rates to macrolides [135].
In patients with agammaglobulinemia or CVID with persistently increased susceptibility to bacterial infections despite adjustment of IgG trough level, antibiotic prophylaxis with TMP/SMX may be considered [49]. Persistently increased infection rates should prompt reevaluation of the immune status and identification of putative foci (bronchiectasis, chronic sinusitis, etc.).
Patients with antibody deficiency and additional impairment of T-cellular immunity (i.e. CID, HIGM due to mutation in CD40L) have an increased risk for opportunistic infections and require antimicrobial prophylaxis [15]. TMP/SMX is recommended trice a week for patients with CD4 cell counts <200/μl or <15% of lymphocytes. An increased mortality and risk for opportunistic infections was shown for CVID patients with low naive CD4 cells (<20/μL) [48].
In acute infections, direct microbiological testing is recommended, since serological tests are difficult to interpret under immunoglobulin replacement treatment and classic early IgMreponse to specific pathogens is not likely to occur in most patients with primary antibody deficiency.

Consensus-based recommendation 17b:
"In patients with symptomatic bronchiectasis, additional antibiotic prophylaxis may be considered."

Physiotherapy and airway treatment
According to current ERS (European Respiratory Society) guidelines [104], respiratory physiotherapy is recommended for patients with bronchiectasis. Regular pulmonary rehabilitation should be offered in patients with respiratory distress [136][137][138].
BTS (British Thoracic Society) guidelines for non-CF bronchiectasis recommend special breathing techniques, (oscillating) PEP therapy (positive expiratory pressure), positional drainage and forced exhalation techniques as well as autogenic drainage [139]. It is recommended to use bronchodilators and inhaled mucolytic drugs before physiotherapy, and before inhaling antibiotics . Longacting bronchodilators should not be offered routinely for all patients with bronchiectasis.
Despite the undisputed high occurrence and clinical relevance of chronic or recurrent sinusitis, there are no controlled studies on the treatment of chronic sinusitis, which could lead to evidence-based recommendations. Symptomatic management (saline irrigation, analgesic treatment, etc.) is recommended. Patients require an allergic work up and ENT consultation.

Consensus-based recommendation 18a:
"We suggest to initiate respiratory physiotherapy early in the course in symptomatic patients with bronchiectasis."

Expert consensus: strong consensus
Consensus-based recommendation 18b: "We recommend physical exercise and pulmonary exercise training for all patients with clinically symptomatic bronchiectasis."

Further measures
Possible burdens of treatment or side effects of a lifelong therapy should be addressed proactively by the attending physician [140,141]. Contacting (local) patient organizations is encouraged. We suggest participation in structured, patient-centered educational workshops.