Advances and Challenges of the Decade: The Ever-Changing Clinical and Genetic Landscape of Immunodeficiency.

In the past 10 years, we have witnessed major advances in clinical immunology. Newborn screening for severe combined immunodeficiency has become universal in the United States and screening programs are being extended to severe combined immunodeficiency and other inborn errors of immunity globally. Early genetic testing is becoming the norm for many of our patients and allows for informed selection of targeted therapies including biologics repurposed from other specialties. During the COVID-19 pandemic, our understanding of essential immune responses expanded and the discovery of immune gene defects continued. Immunoglobulin products, the backbone of protection for antibody deficiency syndromes, came into use to minimize side effects. New polyclonal and monoclonal antibody products emerged with increasing options to manage respiratory viral agents such as SARS-CoV-2 and respiratory syncytial virus. Against these advances, we still face major challenges. Atypical is becoming typical as phenotypes of distinct genetic disease overlap whereas the clinical spectrum of the same genetic defect widens. Therefore, clinical judgment needs to be paired with repeated deep immune phenotyping and upfront genetic testing, as technologies rapidly evolve, and clinical disease often progresses with age. Managing patients with organ damage resulting from immune dysregulation poses a special major clinical challenge and management often lacks standardization, from autoimmune cytopenias, granulomatous interstitial lung disease, enteropathy, and liver disease to endocrine, rheumatologic, and neurologic complications. Clinical, translational, and basic science networks will continue to advance the field; however, cross-talk and education with practicing allergists/immunologists are essential to keep up with the ever-changing clinical and genetic landscape of inborn errors of immunity.

Secondary Immune Deficiency and Primary Immune Deficiency Crossovers: Hematological Malignancies and Autoimmune Diseases.

Primary immunodeficiencies (PIDs), a heterogenous group of inborn errors of immunity, are predetermined at birth but may evolve with age, leading to a variable clinical and laboratory presentation. In contrast, secondary immunodeficiencies (SIDs) are acquired declines of immune cell counts and or/function. The most common type of SID is a decreased antibody level occurring as a consequence of extrinsic influences, such as an underlying condition or a side effect of some medications used to treat hematological malignancies and autoimmune disorders. Paradoxically, immune deficiencies initially attributed to secondary causes may partly be due to an underlying PID. Therefore, in the era of immune-modulating biologicals, distinguishing between primary and secondary antibody deficiencies is of great importance. It can be difficult to unravel the relationship between PID, SID and hematological malignancy or autoimmunity in the clinical setting. This review explores SID and PID crossovers and discusses challenges to diagnosis and treatment strategies. The case of an immunodeficient patient with follicular lymphoma treated with rituximab illustrates how SID in the setting of hematological cancer can mask an underlying PID, and highlights the importance of screening such patients. The risk of hematological cancer is increased in PID: for example, lymphomas in PID may be driven by infections such as Epstein-Barr virus, and germline mutations associated with PID are enriched among patients with diffuse large B-cell lymphoma. Clues suggesting an increased risk of hematological malignancy in patients with common variable immune deficiency (CVID) are provided, as well as pointers for distinguishing PID versus SID in lymphoma patients. Two cases of patients with autoimmune disorders illustrate how an apparent rituximab-induced antibody deficiency can be connected to an underlying PID. We highlight that PID is increasingly recognized among patients with autoimmune cytopenias, and provide guidance on how to identify PID and distinguish it from SID in such patients. Overall, healthcare professionals encountering patients with malignancy and/or autoimmunity who have post-treatment complications of antibody deficiencies or other immune abnormalities need to be aware of the possibility of PID or SID and how to differentiate them.

Primary Immune Deficiency: Patients' Preferences for Replacement Immunoglobulin Therapy.

Purpose: Immunoglobulin (Ig) replacement therapy is an important life-saving treatment modality for patients with primary antibody immune deficiency disorders (PAD). IVIG and SCIg are suitable alternatives to treat patients with PAD but vary in key ways. Existing evidence on patient preferences for Ig treatments given the complexities associated with IVIG and SCIg treatment is limited and fails to account for variations in preferences across patients. For this reason, we sought to evaluate PAD patient preferences for features of IVIG and SCIg across different patient characteristics. Materials and Methods: 119 PAD patients completed a discrete-choice experiment (DCE) survey. The DCE asked respondents to make choices between carefully constructed treatment alternatives described in terms of generic treatment features. Choices from the DCE were analyzed to determine the relative influence of attribute changes on treatment preferences. We used subgroup analysis to evaluate systematic variations in preferences by patients' age, gender, time since diagnosis, and treatment experience. Results: Patients were primarily concerned about the duration of treatment side effects, but preferences were heterogeneous. This was particularly true around administration features. Time since diagnosis was associated with an increase in patients' concerns with the number of needles required per infusion. Also, patients appear to prefer the kind of therapy they are currently using which could be the result of properly aligned patient preferences or evidence of patient adaptive behavior. Conclusions: Heterogeneity in preferences for Ig replacement treatments suggests that a formal shared decision making process could have an important role in improving patient care.

Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees.

Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to acquired causes of decreased antibody production or increased antibody loss. Clarification regarding whether the hypogammaglobulinemia is secondary or primary is important because this has implications for evaluation and management. Prior receipt of immunosuppressive medications and/or presence of conditions associated with SHG development, including protein loss syndromes, are histories that raise suspicion for SHG. In patients with these histories, a thorough investigation of potential etiologies of SHG reviewed in this report is needed to devise an effective treatment plan focused on removal of iatrogenic causes (eg, discontinuation of an offending drug) or treatment of the underlying condition (eg, management of nephrotic syndrome). When iatrogenic causes cannot be removed or underlying conditions cannot be reversed, therapeutic options are not clearly delineated but include heightened monitoring for clinical infections, supportive antimicrobials, and in some cases, immunoglobulin replacement therapy. This report serves to summarize the existing literature regarding immunosuppressive medications and populations (autoimmune, neurologic, hematologic/oncologic, pulmonary, posttransplant, protein-losing) associated with SHG and highlights key areas for future investigation.

Precision Medicine in the Treatment of Primary Immune Deficiency Patients With Disorders of Immune Dysregulation.

There are now more than 450 described monogenic germline mutations for inborn errors of immunity that result in the loss of expression, loss of function (LOF), or gain in function (GOF) of the encoded protein. Molecular characterization of these inborn errors of immunity has not only allowed us to characterize on a genetic basis these immune deficiency disorders but has provided a better understanding of the immunobiology of these inborn errors of immunity. More recently, these advances have allowed us to apply targeted therapy or precision medicine in their treatment. Of particular interest related to this review are those inborn errors of immunity that result in gain-of-function (GOF) genetic abnormalities. Many of these inborn errors of immunity fall into a new category referred to as diseases of immune dysregulation in which many of the patients not only exhibit an increased susceptibility to infection but also have a clinical phenotype associated with autoimmune processes and lymphoproliferative disease.

Why Do Some People Develop Serious COVID-19 Disease After Infection, While Others Only Exhibit Mild Symptoms?

The year 2020 was a landmark year of a once-in-a-century pandemic of a novel coronavirus, SARS-CoV-2 virus, that led to a rapidly spreading coronavirus disease (COVID-19). The spectrum of disease with SARS-CoV-2 ranges from asymptomatic to mild upper respiratory illness, to moderate to severe disease with respiratory compromise to acute respiratory distress syndrome, multiorgan failure, and death. Early in the pandemic, risk factors were recognized that contributed to more severe disease, but it became evident that individuals and even young people could have severe COVID-19. As we started to understand the immunobiology of COVID-19, it became clearer that the immune responses to SARS-CoV-2 were variable, and in some cases, the excessive inflammatory response contributed to greater morbidity and mortality. In this review, we will explore some of the additional risk factors that appear to contribute to disease severity and enhance our understanding of why some individuals experience more severe COVID-19. Recent advances in genome-wide associations have identified potential candidate genes in certain populations that may modify the host immune responses leading to dysregulated host immunity. Genetic defects of the type I interferon pathway are also linked to a more clinically severe phenotype of COVID-19. Finally, dysregulation of the adaptive immune system may also play a role in the severity and complex clinical course of patients with COVID-19. A better understanding of the host immune responses to SARS-CoV-2 will hopefully lead to new treatment modalities to prevent the poor outcomes of COVID-19 in those individuals with pre-existing risk factors or genetic variants that contribute to the dysregulated host immune responses.

Diagnosis and management of Specific Antibody Deficiency.

Specific antibody deficiency is a primary immunodeficiency disease recognized by the International Union of Immunology Societies and defined by recurrent respiratory infections with normal immunoglobulins, but diminished antibody responses to polysaccharide antigens after vaccination with the 23 valent pneumococcal polysaccharide vaccine. Clinical immunologists struggle with diagnosis and treatment, because the definition of an adequate response to immunization remains controversial. Specific antibody deficiency is managed clinically with close follow-up and prompt treatment of infections, antibiotic prophylaxis, or immune globulin therapy. Treatment is individualized using clinical judgment and existing practice guidelines, which will likely evolve as more studies become available.

Nuts and Bolts of Subcutaneous Therapy.

Immunoglobulin replacement therapy is standard of care in treatment of many primary immunodeficiency diseases. The goal of replacement therapy is to reduce infections in individuals with primary immune deficiency and improve their quality of life. Immunoglobulin replacement therapy is most often lifelong, therefore ease of administration is vital for adherence to treatment. Self-infusion via subcutaneous intravenous immunoglobulin (SCIG) allows patient input to design an individualized and optimal treatment plan. Because SCIG regimens are flexible and allow for increased autonomy, patients receiving SCIG report improved quality of life. This article summarizes the dosing, administration, and adverse event management of SCIG infusions.

Geographical Distribution, Incidence, Malignancies, and Outcome of 136 Eastern Slavic Patients With Nijmegen Breakage Syndrome and NBN Founder Variant c.657_661del5.

Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to lymphoid malignancies. The majority of NBS patients are identified with a homozygous five base pair deletion in the Nibrin (NBN) gene (c.657_661del5, p.K219fsX19) with a founder effect observed in Caucasian European populations, especially of Slavic origin. We present here an analysis of a cohort of 136 NBS patients of Eastern Slav origin across Belarus, Ukraine, Russia, and Latvia with a focus on understanding the geographic distribution, incidence of malignancy, and treatment outcomes of this cohort. Our analysis shows that Belarus had the highest prevalence of NBS (2.3 per 1,000,000), followed by Ukraine (1.3 per 1,000,000), and Russia (0.7 per 1,000,000). Of note, the highest concentration of NBS cases was observed in the western regions of Belarus and Ukraine, where NBS prevalence exceeds 20 cases per 1,000,000 people, suggesting the presence of an "Eastern Slavic NBS hot spot." The median age at diagnosis of this cohort ranged from 4 to 5 years, and delay in diagnosis was more pervasive in smaller cities and rural regions. A total of 62 (45%) patients developed malignancies, more commonly in males than females (55.2 vs. 34.2%; p=0.017). In 27 patients, NBS was diagnosed following the onset of malignancies (mean age: 8 years). Malignancies were mostly of lymphoid origin and predominantly non-Hodgkin lymphoma (NHL) (n=42, 68%); 38% of patients had diffuse large B-cell lymphoma. The 20-year overall survival rate of patients with malignancy was 24%. However, females with cancer experienced poorer event-free survival rates than males (16.6% vs. 46.8%, p=0.036). Of 136 NBS patients, 13 underwent hematopoietic stem cell transplantation (HSCT) with an overall survival of 3.5 years following treatment (range: 1 to 14 years). Indications for HSCT included malignancy (n=7) and immunodeficiency (n=6). Overall, 9% of patients in this cohort reached adulthood. Adult survivors reported diminished quality of life with significant physical and cognitive impairments. Our study highlights the need to improve timely diagnosis and clinical management of NBS among Eastern Slavs. Genetic counseling and screening should be offered to individuals with a family history of NBS, especially in hot spot regions.

Correction to: Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials.

The article Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials, written by Mark Ballow, Richard L. Wasserman, Stephen Jolles, Helen Chapel, Mel Berger, Siraj A. Misbah, was originally published Online First without open access.

Corrigendum: Specific Antibody Deficiency: Controversies in Diagnosis and Management.

[This corrects the article on p. 586 in vol. 8, PMID: 28588580.].

Precision medicine in the treatment of primary immunodeficiency diseases.

PURPOSE OF THE REVIEW: Since the 1990s with the advances in molecular biology, a number of genetic defects have been described. The International Union of Immunological Sciences has recently updated the classification of genetic defects associated with primary immune deficiencies that now number 354. With the ever-expanding list of new monogenic disorders and a better understanding of the immunobiology and function of these defective genes, new therapies have emerged particularly aimed at the autoimmune and inflammatory conditions that plague these patients. RECENT FINDINGS: Immune deficiencies associated with gain-of-function (GOF) mutations are a potential category for targeted therapies to control the GOF activities of the mutated gene. In addition to the increased susceptibility to infections these patients have autoimmune and inflammatory diseases that are difficult to control with conventional therapies. The dysregulated immune functions of the activated phospholipase-3-kinase δ syndrome, cytotoxic T lymphocyte-associated antigen-4 haploinsufficiency, lipopolysaccharide-responsive beige-like anchor deficiency, the GOF mutations of signal transducer and activator of transcription 1 and 3 immune deficiencies will be reviewed. The targeted therapies for each of these immune deficiencies using small molecule kinase inhibitors and fusion protein biologic modifiers will be described. SUMMARY: In this review, we explore the recent advances in precision medicine treatment of several primary immunodeficiency syndromes in which immune dysregulation is a key feature. Understanding the immunobiology associated with these GOF mutations has led to the use of biologic therapies to better control the associated autoimmune and inflammatory manifestations.