Israel Medical Association Journal

The field of inborn errors of immunity (IEI), previously known as primary immune deficiencies, includes susceptibility to infections, autoimmunity, uncontrolled inflammation and malignancy is rapidly expanding. Novel scientific discoveries together with artificial intelligence and machine learning are transformed into advances in the diagnosis and treatment of affected patients. These changes require adjustments in the knowledge, skills and attitudes of health care providers, and particularly expert clinicians managing patients with IEI. In this perspective, we highlighted some of the educational needs that should be adapted to ensure that the next generation of physicians provide best care for those affected by IEI.

Inborn errors of immunity represent a heterogeneous group of disorders with variable clinical manifestations. Within this group of disorders, severe combined immunodeficiency (SCID) is the most profound disorder, where affected infants present clinically early in life, and have almost uniformly fatal outcome unless hematopoietic stem cell transplantation (HSCT) is performed. Gene therapy or enzyme replacement therapy are options in some specific SCID forms [1]. The estimated incidence of SCID in the United States is 1 in 58,000 live births, while in Israel the incidence is as high as 1 in 29,000 live births. This higher rate is due to a high rate of consanguineous marriages in certain communities [2].

Inborn errors of immunity (IEI), formerly referred to as primary immunodeficiencies, is a growing spectrum of over 550 genetically defined disorders of the immune system. As our understanding of the mechanisms of these disorders grows, immune dysregulation syndromes, autoimmunity, malignancy, bone marrow failure with immunodeficiency, and phenocopies are recognized as part of the clinical spectrum of IEI. Early recognition and accurate classification are critical as many IEI conditions have specific therapeutic implications, including targeted immune modulation, immunoglobulin replacement therapy, hematopoietic stem cell transplantation, and gene therapy. In this review, we present recent changes in classification, updated laboratory workup strategies, and therapeutic advances.

Inborn errors of immunity (IEI) are a heterogeneous group of monogenic disorders affecting immune function, associated with a broad clinical spectrum including recurrent infections and immune dysregulation consisting of poly-autoimmunity, multiple allergies, and malignancies. To date, more than 550 causative genes have been identified, with inheritance patterns that may be autosomal dominant, autosomal recessive, or X-linked. Pathogenic variants may result in loss-of-function, dominant-negative, or gain-of-function effects, leading to variable phenotypic presentations and, at times, incomplete penetrance. Despite advances in genomic technologies, a definitive molecular diagnosis is reached in only 30–35% of cases. Early and accurate genetic diagnosis is crucial for guiding targeted therapy and providing effective genetic counseling. This review presents an updated overview of IEI from the geneticist's perspective and offers a practical approach to the genetic evaluation and diagnosis of these conditions.

Background: Syndromic inborn errors of immunity (IEIs) are a heterogeneous group of disorders characterized by immune dysfunction associated with congenital anomalies and multisystem involvement. Tricho-hepato-enteric syndrome (THES) is an ultra-rare autosomal recessive syndromic IEI caused by biallelic pathogenic variants in TTC37 or SKIV2L. Delayed recognition is common because of its broad clinical spectrum.

Objectives: To describe the clinical, immunologic, genetic, and histopathologic characteristics of two children with THES and to highlight a structured diagnostic approach for syndromic immunodeficiencies.

Methods: We retrospectively reviewed the clinical presentation, laboratory investigations, immune phenotyping, endoscopic and histopathologic findings, and molecular analyses of two unrelated children diagnosed with THES at a tertiary pediatric immunology center. Molecular confirmation was obtained by whole-exome sequencing.

Results: Both patients presented during early infancy with intractable diarrhea, severe failure to thrive, characteristic dysmorphic features, brittle woolly hair, and inflammatory enteropathy requiring prolonged nutritional support. Immunologic evaluation demonstrated immune dysregulation, including inverted CD4/CD8 ratios, abnormalities of humoral immunity, and impaired vaccine-specific antibody responses. Histopathology revealed chronic active colitis with crypt distortion, inflammatory infiltrates, and crypt abscesses, consistent with very-early-onset inflammatory bowel disease-like enteropathy. Whole-exome sequencing identified homozygous pathogenic variants in SKIV2L in one patient and TTC37 in the other, establishing the diagnosis. Management included nutritional support, immunoglobulin replacement, antimicrobial prophylaxis, and immunomodulatory therapy.

Conclusions: Recognition of syndromic phenotype combined with comprehensive immune evaluation and early genomic testing facilitates prompt diagnosis, multidisciplinary management, genetic counseling, and consideration of emerging targeted therapies.

Background: Common variable immunodeficiency (CVID) is the most common clinically significant primary immunodeficiency disorder, typically presenting with hypogammaglobulinemia and recurrent infections. Mechanistically, CVID is caused by abnormal B-cell maturation or function. These abnormalities lead to an impaired ability to generate a normal quantity or diversity of antibodies and an impaired response to neo-antigens. In addition to the resulted immunodeficiency, CVID can also involve immune dysregulation affecting different organ systems, with the lungs being one of the more commonly involved organs. Granulomatous lymphocytic interstitial lung disease (GLILD) is a challenging and well known CVID-related complication. It is associated with high morbidity and increased risk of mortality.

Objectives: To describe the clinical and immunological features of five CVID patients with radiologic and/or pathologic features consistent with granulomatous lymphocytic interstitial lung disease.

Methods: We conducted a review of clinical, laboratory, imaging, and pathology data, as well as B-cell and T-cell immunophenotyping of patient PBMCs, focusing on unique characteristics of CVID GLILD patients.

Results: CVID GLILD patients showed several clinical characteristics, including multiorgan involvement with cytopenias and lymphoproliferation but without significant gastrointestinal involvement. B-cell phenotyping showed abnormal B-cell maturation and development with severely impaired class switching. In addition, unique T-cell phenotype with low to near-absent naive CD4⁺ T cells was observed.

Conclusions: Lung involvement in the form of GLILD is associated with significant co-morbidity and typical B-cell and T-cell immunophenotyping. Patients should be actively screened for the possibility of GLILD, especially when regularly performed lymphocyte immunophenotyping suggests similar patterns.

Background: Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) affects approximately 2.2 million people globally and is associated with accelerated liver disease progression, increased morbidity, and reduced quality of life (QoL). While direct-acting antivirals (DAAs) have revolutionized HCV treatment with high cure rates, evidence of their long-term impact on liver-related QoL and associated metabolic or immunologic shifts in HIV/HCV co-infected populations remains limited.

Objectives: To evaluate the effect of achieving sustained virologic response (SVR) with DAAs on long-term QoL in HIV/HCV co-infected patients and to examine associated changes in CD4 count, kidney function, and glucose levels.

Methods: This retrospective observational study was conducted at the Rambam Health Care Campus, between 2015 and 2019. We collected demographic, clinical, and laboratory data from all patients with HIV/HCV co-infection. QoL was evaluated for at least 6 months after the end of treatment. Metabolic variables were collected before and after treatment to test the effects of treatment.

Results: All 70 patients in the cohort achieved SVR. Successful treatment with DAAs resulted in a significant decrease in liver enzymes and globulin levels, and a substantial increase in CD4. A significant improvement in QoL after treatment was noticed in both sexes, regardless of liver fibrosis stage. FIB-4 calculations 6 months and 1 year after the end of therapy showed improved fibrosis levels after SVR.

Conclusions: The use of DAAs in HCV/HIV co-infected patients has improved the long-term QoL, metabolic factors, and fibrosis stage.

Inborn errors of immunity (IEI), formerly known as primary immunodeficiencies (PID), comprise a diverse group of genetic disorders characterized by increased susceptibility to infections, autoimmunity, autoinflammatory conditions, allergies, and malignancies. These disorders exhibit a broad spectrum of clinical manifestations, including extra-hematopoietic manifestations, which may also present later in life. IEI diagnosis has significantly advanced, in line with the common use of next-generation sequencing-based genetic platforms, such as whole-exome and whole-genome sequencing. Treatment approaches have evolved beyond infection management to include curative therapies such as hematopoietic stem cell transplantation, gene therapy, and targeted pharmacologic treatments. In this review, we explore recent advancements in the understanding, diagnosis, and treatment of IEI, emphasizing the rapid progress in this expanding field.

Background: Adenovirus infections are prevalent in children. They usually cause a mild self-limited disease. However, this infection can be associated with considerable morbidity and mortality in specific populations, especially among immunocompromised children. Children with Down syndrome are susceptible to a higher frequency and increased severity of viral infections. Little is known about the severity and clinical course of adenovirus infections in children with Down syndrome.

Objectives: To characterize hospitalized children diagnosed with Down syndrome and presenting with adenovirus infection.

Methods: We performed a retrospective review of children admitted with adenovirus from January 2005 to August 2014 from a single tertiary pediatric medical center in Israel. Data were compared between patients with and without Down syndrome.

Results: Among the 486 hospitalized children with adenoviral infection, 11 (2.28%) were diagnosed with Down syndrome. We found that children with Down syndrome were more likely to experience a higher incidence of complications (18.2% vs. 2.4%, P = 0.008), a higher rate of admissions to the intensive care unit (36.4% vs. 2.4%, P < 0.001), and more prolonged hospitalizations (17 ± 15.9 days compared to 4.46 ± 3.16, P = 0.025).

Conclusions: Children with Down syndrome who were hospitalized with adenovirus infection represent a high-risk group and warrant close monitoring. If a vaccine for adenovirus becomes available, children with Down syndrome should be considered as candidates

Background: Common variable immunodeficiency (CVID) is the most common symptomatic primary immune deficiency of adulthood. Besides recurrent infections, autoimmune disorders–mainly cytopenias–affect 30% of patients with CVID.

Objectives: To describe the efficacy and safety of facilitated subcutaneous immunoglobulin (fSCIg), which is a combination of 10% [human] SCIg with recombinant human hyaluronidase for the treatment of CVID-linked cytopenias. 

Methods: We describe four women (mean age 54 years) with CVID associated with idiopathic thrombocytopenic purpura (ITP) (n=3) and autoimmune hemolytic anemia (AIHA) (n=1). Diagnosis of CVID was made according to the European Society of Immune Deficiencies / Pan-American Group for Immune Deficiency criteria. All were treated with fSCIg (bi-monthly, 20 g).

Results: After a median follow-up of 22 months, all patients achieved a stable remission from the cytopenias, characterized by increased platelet values in ITP (mean values 93000/mmc), and resolution of anemia. A reduction of the daily prednisone dose was documented in the patient with AIHA. No systemic adverse drug reactions were observed. 

Conclusions: Our preliminary data documented the efficacy and safety of fSCIg in the treatment of CVID associated with autoimmune cytopenias, with a good tolerability. We also noted the role of fSCIg as a steroid sparing agent. It is thus possible to suppose an immunomodulatory role for fSCIg, but linked to different mechanisms than IVIg, due to the peculiar pharmacokinetic and administration route of fSCIg. 

 

Background: Recurrent tuberculosis (TB) is one of the indices used to assess the effectiveness of the Israeli National TB Programs (NTP).

Objectives: To estimate the incidence of recurrent TB in Israel and to identify the associated risk factors.

Methods: We conducted a retrospective cohort study of all TB patients who were Israeli citizens and diagnosed between 1999 and 2011 with a treatment outcome recorded as “success." We compared those who had recurrent TB with those who did not. In addition, a nested case-control study included all those who had recurrent TB with a random sample from this cohort matched by age, gender, and year of TB diagnosis.

Results: Of 3515 TB patients diagnosed between 1999 and 2011, 37 (1.05%) had recurrent TB during the follow-up period, with an incidence rate of 1.55 cases per 1000 person-years (PY). Male gender [hazard ratio (HR) 3.2, 95% confidence interval (95%CI) 1.4–7.4], human immunodeficiency virus (HIV) infection (HR 3.9, 95%CI 1.5–10.4), positive sputum culture [odds ratios (OR) 2.7, 95%CI 1.1–6.9], and low adherence to anti-TB treatment (OR 3.2, 95%CI 1.0–10.3) were found to be risk factors for recurrent TB.

Conclusions: Male gender, HIV infection, positive sputum culture, and low adherence to anti-TB drugs during the initial TB episode were risk factors for developing recurrent TB.

Background: Pre-exposure prophylaxis (PrEP) for populations at high risk for human immunodeficiency virus (HIV) is still not available in Israel.

Objectives: To analyze post-exposure prophylaxis (PEP) treatment adherence rates among adult men in Tel Aviv, Israel, who have sex with men (MSM), and to obtain data on the demographics of PEP users, exposure types, timeline of exposure and PEP administration, incidence of side effects, number of treatments per individual, and satisfaction with selected elements of treatment provision.

Methods: The authors conducted an observational cohort study of adult MSM who requested PEP treatment in the Tel Aviv Sourasky Medical Center. Information from patients receiving treatment between January 2013 and June 2014 was obtained through telephone interviews by means of a 30-item questionnaire.

Results: Of 336 individuals requesting PEP treatment, 255 (75.9%) were adult MSM, and 100 (39.2%) satisfactorily completed the interview. The average age of the study cohort was 32.4 years (standard deviation of 7.5). Ninety-one (91%) reported completing a full 28-day course of treatment, 84% reported side effects, and 20% underwent multiple courses. Satisfaction was high for interactions with the HIV specialists. Patient experience with PEP treatment in the emergency room setting, and follow-up were inadequate deficient.

Conclusions: PEP adherence rates in Tel Aviv were significantly higher than previously reported. PEP should be administered in designated community settings. PrEP as a general treatment policy might suit the MSM population in Tel Aviv.

Background: Guidelines recommend hepatitis B virus (HBV) vaccination of all adults positive for human immunodeficiency virus (HIV). Immune responses to single-antigen HBV vaccine among HIV-positive patients are low when compared with HIV-negative adults. Sci-B-Vac™ is a recombinant third-generation HBV that may be advantageous in this population.

Objectives: To examine the immune responses to Sci-B-Vac among HIV-positive adults.

Methods: We conducted a prospective cohort study involving HIV-positive adults who had negative HBV serology (HBSAg, HBSAb, HBcoreAb). Sci-B-Vac at 10 µg/dose was administered intramuscularly upon recruitment and after 1 and 6 months. HBSAb levels were checked 1 month after each dose; a level > 10 mlU/ml was considered protective. Data regarding age, gender, CD4 level, and viral load were collected.

Results: The study group comprised 31 patients. Average CD4 count was 503 ± 281 cells/ml, and average viral load was 44 copies/ml. Median interquartile range (IQR) HBVAb titers after the first, second and third immunizations were 0 (0, 3.5), 30 (6, 126) and 253 (81, 408) mlU/ml. Significant titer elevations were found between the second and third immunizations (P = 0.0003). The rate of patients considered protected was 16% after the first, 65% after the second (P < 0.0001), and 84% after the third dose (P = 0.045). No adverse events were reported. More patients under the age of 40 years responded to the first immunization (28% vs. 0%, P = 0.038). CD4 level had no influence on immunization rates.

Conclusions: Sci-B-Vac might achieve better immunization rates among HIV-positive adults compared to the single-antigen vaccine and thus deserves further evaluation in a randomized, double-blind study in this population.