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Dermatol Reports. 2024 Apr 11;16(4):9864. doi: 10.4081/dr.2024.9864. eCollection 2024 Nov 21.

ABSTRACT

Ataxia telangiectasia (AT) is a rare autosomal recessive primary immunodeficiency disorder (PID) resulting from a mutation in the ATM gene involved in DNA repair. We describe the case of a young girl with cutaneous granulomas that developed after childhood vaccinations. Immunohistochemistry revealed granulomas induced by the rubella virus vaccine. This finding raises the question of the safety of live rubella vaccine strains in immunocompromised children.

PMID:39669881 | PMC:PMC11635345 | DOI:10.4081/dr.2024.9864

Immunol Res. 2024 Dec 12;73(1):8. doi: 10.1007/s12026-024-09571-9.

ABSTRACT

DOCK8 deficiency is the most common cause of autosomal recessive hyper-IgE syndrome (AR-HIES). The clinical spectrum is wide resulting in combined immunodeficiency, atopy, autoimmunity, and malignancies. To study the clinical and molecular profile of 20 patients with DOCK8 deficiency. Four hundred and eight patients with various inborn errors of immunity (IEIs) were diagnosed in the Pediatric Immunology Unit of our hospital during the study period of February 2017 to August 2023. Based on the clinical and immunological phenotype, DOCK8 deficiency was suspected in 31 patients. Genetic studies confirmed DOCK8 deficiency in 20 patients, and their profile was analyzed in detail. Twenty patients from 17 kindreds were diagnosed with DOCK8 deficiency. The female-to-male ratio was 1.2:1. The mean age at onset of symptoms and diagnosis was 9.8 and 69.8 months, respectively. Thirteen out of 17 families (76%) reported consanguinity. Eczema was the presenting manifestation in 19 patients (95%). Mucocutaneous manifestations included oromucosal hyperpigmentation (n = 8), scalp seborrhoea (n = 2), psoriasis (n = 2), and alopecia (n = 1). The spectrum of infections included pneumonia (n = 14), otitis media (n = 6), gastrointestinal infections (n = 6), cutaneous viral infections (n = 5), oral candidiasis (n = 4), and meningoencephalitis (n = 2). Three patients had developed bronchiectasis. Four patients had autoimmune manifestations including autoimmune hemolytic anemia (n = 2) and vasculitis (n = 2). The whole exome sequencing showed deletions (8 kindreds) as the most common mutation in the DOCK8 gene. Overall, 11 of these mutations were novel. Ten patients were on monthly intravenous immunoglobulin therapy and antibiotic prophylaxis at the time of writing this paper. Three patients underwent hematopoietic stem cell transplants elsewhere, two of whom succumbed to post-transplant complications and one is doing well. Nine patients died during the study period. We present one of the largest single-center experiences on DOCK8 deficiency from India. A significant delay in the diagnosis contributed to poor outcomes in our cohort.

PMID:39666233 | DOI:10.1007/s12026-024-09571-9

Arch Dermatol Res. 2024 Dec 12;317(1):110. doi: 10.1007/s00403-024-03652-3.

ABSTRACT

Hereditary angioedema with C1 inhibitor deficiency (HAE-C1-INH) is a rare disorder characterized by recurrent, potentially life-threatening swelling in various parts of the body, including the limbs, face, and airways Current treatments focus primarily on symptomatic relief and the management of acute attacks, without targeting the underlying genetic cause or the dysregulated bradykinin production. Donidalorsen, a novel antisense oligonucleotide, addresses a key driver of HAE-C1-INH by targeting prekallikrein (PKK) to reduce bradykinin levels. This meta-analysis evaluates the efficacy and safety of Donidalorsen versus placebo, focusing on two dosing regimens: 4-week and 8-week intervals. Data from two randomized controlled trials (110 patients) revealed that Donidalorsen significantly reduced the frequency of HAE-C1-INH attacks, with the 4-week regimen showing superior outcomes compared to the 8-week dosing. The 4-week group also experienced fewer moderate or severe attacks and a reduced need for on-demand therapy. Adverse events were comparable between the Donidalorsen and placebo groups. These findings suggest that more frequent dosing may optimize treatment outcomes in HAE-C1-INH.

PMID:39666085 | DOI:10.1007/s00403-024-03652-3

J Pediatr Health Care. 2024 Dec 9:S0891-5245(24)00374-2. doi: 10.1016/j.pedhc.2024.11.006. Online ahead of print.

ABSTRACT

BACKGROUND: The transition to adult health care is challenging for adolescents and young adults (AYA) with Chronic Granulomatous Disease (CGD). This pilot study aimed to facilitate the learning of AYA with CGD about their health care and to aid in the development of life skills to enhance self-care.

METHODS: AYA and caregivers (for participants <18 years of age) completed an adapted Transition Readiness Assessment. Educational sessions were held both in person and via telehealth and included virtual meetings with subject matter experts or a designated program mentor. Twenty-five participants were invited, 13 entered the pilot and 8 completed the transition readiness assessment.

RESULTS: The pilot study was well-received by CGD participants and caregivers. In the future, a larger cohort may provide more data to comment on efficacy and outcome in the AYA population.

CONCLUSION: Expansion of an educational transition program for AYA with primary immunodeficiencies (PIDs) might be useful.

PMID:39665712 | DOI:10.1016/j.pedhc.2024.11.006

Malar J. 2024 Dec 11;23(1):369. doi: 10.1186/s12936-024-05207-3.

ABSTRACT

BACKGROUND: Post malaria neurologic syndrome (PMNS) is a rare complication of malaria, usually caused by Plasmodium falciparum. The clinical picture is highly variable and ranges from qualitative disturbances of consciousness and psychosis to damage to the peripheral nerves, usually occurring three to eight weeks after treated malaria.

CASE PRESENTATION: We report the case of a 54-year-old male who presented with recurrent clinical symptoms three and a half weeks after severe falciparum malaria. After ruling out recurrent malaria, autoimmune encephalitis was suspected. Corticosteroid therapy led to a rapid improvement of the clinical symptoms. The extended examinations (including cranial MRI and FDG-PET/CT) revealed no pathological findings. Routine serologic autoimmune diagnostics remained negative. However, anti-septin complex antibodies were detected in the serum in a cell-based and a tissue-based immunofluorescence assay. Twelve months after discontinuation of corticosteroid therapy, the patient was free of immunosuppressants and completely asymptomatic.

CONCLUSION: To our knowledge, this is the first case of septin complex autoimmunity with encephalitis associated with PMNS. All physicians treating malaria patients should therefore be aware of this rare condition and consider extended autoimmune diagnostics if routine panels remain unremarkable.

PMID:39663534 | DOI:10.1186/s12936-024-05207-3

J Asthma. 2024 Dec 11:1-14. doi: 10.1080/02770903.2024.2422410. Online ahead of print.

ABSTRACT

OBJECTIVE: Severe asthma (SA) is a serious disease with limited treatment options, which is closely linked to immune dysfunction. Therefore, immune-associated biomarkers may diagnose SA and offer therapeutic targets for SA.

METHODS: The gene expression profiles of SA patients and matched controls were from the National Center for Biotechnology Information database. Immune genes were downloaded from the ImmPort database. After screening for differentially expressed genes (DEGs) between SA patients and controls, and identifying gene modules highly associated with SA, immune-related DEGs were obtained. Then, protein-protein interaction analysis, Cytoscape software and receiver operating characteristic (ROC) curves were used to identify hub genes. Next, the relationship between hub genes and immune cells was explored, and single-sample gene set enrichment analysis (ssGSEA) was applied to conduct pathway enrichment analyses. Finally, the Least Absolute Shrinkage and Selection Operator (LASSO) combined with ROC analysis were used to confirm the diagnostic value of the hub genes.

RESULTS: Forty immune-related DEGs were obtained, and RNASE3, CAMP and LTF were determined as hub genes. The hub genes were closely associated with immune cells, and ssGSEA showed that lysosome was associated with high expressions of the hub genes, while primary immunodeficiency was related to low expressions of the hub genes. LASSO combined with ROC analysis confirmed the immune gene-based model (RNASE3, CAMP, LTF, and CD79A) could distinguish SA patients from healthy individuals with high sensitivity.

CONCLUSIONS: RNASE3, CAMP, LTF, and CD79A could act as diagnostic markers for SA, providing a theoretical basis for developing diagnostic targets for SA.

PMID:39661012 | DOI:10.1080/02770903.2024.2422410

Pediatr Allergy Immunol. 2024 Dec;35(12):e14268. doi: 10.1111/pai.14268.

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE) in children has specific features and requires multidisciplinary management.

METHODS: We performed a literature search and underwent in-depth discussions to provide practical tools for physicians.

RESULTS: HAE is a rare, life-threatening genetic disorder. Its epidemiology is poorly documented in children. Clinical manifestations usually appear during childhood or early adolescence. Classical signs, often preceded by prodromal symptoms, include transient, localized, non-pitting, non-pruritic swelling of deep dermal/subcutaneous or mucosal/submucosal tissues, leading to oedema of the extremities, face, lips, tongue, trunk and genitals, recurring gastrointestinal symptoms and laryngeal edema possibly causing asphyxiation and death. Diagnosis is often delayed due to low awareness in the medical community, and particularly challenging in case of isolated abdominal crises or atypical presentation and in neonates or infants. It relies on biological tests (measurement of serum/plasma levels of C1INH function, C1INH protein, and C4), genetic testing in selected cases, and imaging for differential diagnosis of acute abdominal crises. Main differential diagnosis for peripheral oedema is mast cell-mediated oedema that accounts for 95% of angioedema in clinical practice. Quality of life can be significantly impaired. Disease management includes treatment of attacks, short-term and long-term prophylaxis, psychological support, avoidance of triggers, patients’ and parents’ education and coordination of all stakeholders, ideally within a specialized healthcare network. New plasma kallikrein inhibitors, namely lanadelumab (subcutaneous route) and berotralstat (oral route) have facilitated long-term prophylaxis thanks to improved usability.

CONCLUSION: Diagnostic and treatment of HAE are particularly challenging in children and require specific management by multiple stakeholders.

PMID:39655944 | DOI:10.1111/pai.14268

Am J Otolaryngol. 2024 Dec 4;46(1):104541. doi: 10.1016/j.amjoto.2024.104541. Online ahead of print.

ABSTRACT

BACKGROUND: Primary immunodeficiency has been associated with chronic rhinosinusitis (CRS). However, limited evidence exists on how primary immunodeficiencies affect the severity of CRS.

OBJECTIVE: To assess how primary IgA and/or IgG immunodeficiency affects the severity of CRS.

METHODS: Adult patients at the Beth Israel Deaconess Medical Center in Boston with IgA and/or IgG deficiency (group A) or normal IgA and IgG (group B) were queried between January 1, 2016 and December 31, 2022. Other immunodeficiencies were excluded. The groups were analyzed for prevalence of CRS based on ICD-10 codes. The groups were matched based on demographics and comorbidities. Patients with CRS were analyzed for ≥3 acute rhinosinusitis (ARS) episodes, mean lifetime ARS episodes, and mean ARS episodes per year (all with or without antibiotic treatment). Additional analyses included need for functional endoscopic sinus surgery (FESS) and mean lifetime FESS procedures based on CPT codes. A logistic regression analysis was then performed over the same parameters.

RESULTS: A total of 346 patients had IgA and/or IgG deficiency (group A), and 11,438 patients had normal IgA and IgG (group B). CRS prevalence was higher in group A than group B (12 % vs. 5 %; p < 0.001). Group A had more patients with ≥3 ARS episodes, higher mean lifetime ARS episodes, and ARS episodes per year, though none of these findings were statistically significant. There was no difference in need for FESS or mean lifetime FESS procedures.

CONCLUSION: CRS prevalence is higher in patients with IgA and/or IgG deficiency, but IgA and/or IgG immunodeficiency does not predispose patients to ARS episodes or predict need for FESS.

PMID:39647184 | DOI:10.1016/j.amjoto.2024.104541

Autoimmun Rev. 2024 Dec 5:103715. doi: 10.1016/j.autrev.2024.103715. Online ahead of print.

ABSTRACT

Autoinflammatory diseases (AID) are conditions leading to a hyperactivation of innate immunity without any underlying infection, and may be poly- (e.g. Still’s disease) or monogenic. The number of monogenic AID is continuously expanding, with the discovery of novel pathologies and pathophysiological mechanisms, facilitated in part by easier access to pangenomic sequencing. Actinopathies with autoinflammatory manifestations represent a newly emerging subgroup of AID, associated with defects in the regulation of actin cytoskeleton dynamics. These diseases typically manifest in the neonatal period and variably combine a primary immunodeficiency of varying severity, cytopenia (particularly thrombocytopenia), autoinflammatory manifestations primarily affecting the skin and digestive system, as well as atopic and autoimmune features. Diagnosis should be considered primarily when encountering an early-onset autoinflammatory skin and digestive disorder, along with a primary immunodeficiency and either thrombocytopenia or a bleeding tendency. Some of these diseases exhibit specific features, such as a risk of macrophage activation syndrome (MAS) or a predisposition to atopy or lymphoproliferation. The complete pathophysiology of these diseases is not yet fully understood, and further studies are required to elucidate the underlying mechanisms, which could guide therapeutic choices. In most cases, the severity of the conditions necessitates allogeneic marrow transplantation as a treatment option. In this review, we discuss these novel diseases, providing a practical approach based on the main associated biological abnormalities and specific clinical characteristics, with a special focus on the newly described actinopathies DOCK11 and ARPC5 deficiency. Nonetheless, genetic testing remains essential for definitive diagnosis, and various differential diagnoses must be considered.

PMID:39644982 | DOI:10.1016/j.autrev.2024.103715

Hematology Am Soc Hematol Educ Program. 2024 Nov 25;2024(1):126-136. doi: 10.1182/hematology.2024000537.

ABSTRACT

Refractory autoimmune mutilineage cytopenias can present in childhood associated with chronic nonmalignant lymphoproliferation (splenomegaly, hepatomegaly, and/or lymphadenopathy). Cytopenias due to peripheral destruction and sequestration have been well recognized since the 1950s and are often lumped together as eponymous syndromes, such as Evans syndrome and Canale-Smith syndrome. Though their clinical and genetic diagnostic workup may appear daunting, it can provide the basis for early intervention, genetic counseling, and empirical and targeted therapies. Autoimmune lymphoproliferative syndrome (ALPS), activated phosphatidylinositol 3-kinase delta syndrome (APDS), and many other related genetic disorders are otherwise collectively known as inborn errors of immunity (IEI). They present in early childhood as refractory autoimmune cytopenias due to immune dysregulation leading to lymphadenopathy, splenomegaly, and increased susceptibility to lymphoma. More recently, controlled clinical trials have shown that some of these immune system disorders with hematological manifestations might be more readily amenable to specific targeted treatments, thus preventing end-organ damage and associated comorbidities. Over the last 20 years, both rapamycin and mycophenolate mofetil have been successfully used as steroid-sparing long-term measures in ALPS. Current therapeutic options for APDS/PASLI (phosphoinositide 3-kinase [PI3K]-associated senescent T lymphocytes, lymphadenopathy, and immunodeficiency) include the orally bioavailable PI3Kδ inhibitor, leniolisib, which was licensed by the US Food and Drug Administration (FDA) in 2023 for use in individuals older than 12 years as a targeted treatment. Paradigms learned from patients with rare genetic disorders like ALPS and APDS may help in exploring and streamlining molecular therapy strategies in the wider group of IEIs presenting with refractory cytopenias and lymphoproliferation.

PMID:39644063 | DOI:10.1182/hematology.2024000537