Blog

Evaluation of periodontal status and cytokine/chemokine profile of GCF in patients with severe congenital neutropenia.

November 10, 2020 By Manish Butte

Evaluation of periodontal status and cytokine/chemokine profile of GCF in patients with severe congenital neutropenia.

Odontology. 2020 Nov 07;:

Authors: Acar B, Ayvaz DÇ, Tan Ç, Özbek B, Yaz İ, Yıldırım YD, Özşin-Özler C, Karaatmaca B, Gür-Çetinkaya P, Soyak E, Karabulut E, Tezcan İ, Berker E

Abstract
Severe congenital neutropenia (SCN) is a primary immunodeficiency characterized by defect in neutrophil count. Increased risk of infections in addition to periodontal problems, such as ulcerations of oral mucosa, gingival inflammation, and rapid loss of attachment are common in the course of the disease. The aim of the present study is to define the causal relationship between the severity of periodontal inflammation and severe congenital neutropenia through identification of cytokine profile in gingival crevicular fluid (GCF). A case-control study was performed in patients diagnosed with SCN and healthy controls. Demographic data, the molecular defect, laboratory work-up were gathered from the hospital registry. Periodontal indices were recorded and GCF samples were analyzed using multiplex analysis for the simultaneous measurements of the particular cytokines and chemokines. The present study included 14 patients and 22 control subjects. Both groups were comparable in terms of age and sex. Severity of gingival inflammation measured by the criteria of Löe was higher in the SCN cases (p < 0.05). Moreover, GCF levels of IFN-α, TNF-α, IL-10, IL-13, IL-15, IL-17, IL-2, IL-7, IL-33, IP-10, MIG, MIP-1β were significantly higher in the controls. Decreased cytokine secretion seems to correlate with the decrease in neutrophil counts. The severity of gingival inflammation in SCN patients may be due to the bacterial overgrowth and the change in the content of the oral flora due to the decreased neutrophil counts. Therefore, regular periodontal examinations, the motivation of oral hygiene as well as the compliance with therapy in SCN patients contribute to the periodontal health.

PMID: 33159599 [PubMed – as supplied by publisher]

Neonatal Erythroderma as an Early Sign of Primary Immunodeficiency.

November 6, 2020 By Manish Butte

Neonatal Erythroderma as an Early Sign of Primary Immunodeficiency.

J Pediatr. 2020 Nov 02;:

Authors: Betti L, Bendandi B, Dondi A, Neri I, Conti F, Lanari M

PMID: 33152372 [PubMed – as supplied by publisher]

Hematopoietic Stem Cell Transplantation Restores Naïve T-Cell Populations in Atm-Deficient Mice and in Preemptively Treated Patients With Ataxia-Telangiectasia.

November 6, 2020 By Manish Butte

Hematopoietic Stem Cell Transplantation Restores Naïve T-Cell Populations in Atm-Deficient Mice and in Preemptively Treated Patients With Ataxia-Telangiectasia.

Front Immunol. 2019;10:2785

Authors: Duecker R, Baer PC, Buecker A, Huenecke S, Pfeffermann LM, Modlich U, Bakhtiar S, Bader P, Zielen S, Schubert R

Abstract
Background: Ataxia-telangiectasia (A-T) is a multisystem disorder with progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and increased cancer susceptibility. Cellular immunodeficiency is based on naïve CD4+ and CD8+ T-cell lymphopenia. Hematopoietic stem cell transplantation (HSCT) offers a potential to cure immunodeficiency and cancer due to restoration of the lymphopoietic system. The aim of this investigation was to analyze the effect of HSCT on naïve CD4+ as well as CD8+ T-cell numbers in A-T. Methods: We analyzed total numbers of peripheral naïve (CD45RA+CD62L+) and memory (CD45RO+CD62L-) CD4+ and CD8+ T-cells of 32 A-T patients. Naïve (CD62LhighCD44low) and memory (CD62LlowCD44high) T-cells were also measured in Atm-deficient mice before and after HSCT with GFP-expressing bone marrow derived hematopoietic stem cells. In addition, we analyzed T-cells in the peripheral blood of two A-T patients after HLA-identic allogeneic HSCT. Results: Like in humans, naïve CD4+ as well as naïve CD8+ lymphocytes were decreased in Atm-deficient mice. HSCT significantly inhibited thymic lymphomas and increased survival time in these animals. Donor cell chimerism increased up to more than 50% 6 months after HSCT accompanied by a significant increase of naïve CD4 and CD8 T-cell subpopulations, but not of memory T-cells. This finding was also identified in the blood of the A-T patients after HSCT. Conclusion: HSCT seems to be a feasible strategy to overcome immunodeficiency and might be a conceivable strategy to avoid T-cell driven cancer in A-T at higher risk for malignancy. Naïve CD4 and CD8 T-cells counts are suitable markers for monitoring immune reconstitution post-HSCT. However, risks and benefits of HSCT in A-T have to be properly weighted.

PMID: 31849966 [PubMed – indexed for MEDLINE]

Modeling Cost-Effectiveness of On-Demand Treatment for Hereditary Angioedema Attacks.

November 6, 2020 By Manish Butte

Modeling Cost-Effectiveness of On-Demand Treatment for Hereditary Angioedema Attacks.

J Manag Care Spec Pharm. 2020 Feb;26(2):203-210

Authors: Bernstein JA, Tyson C, Relan A, Adams P, Magar R

Abstract
BACKGROUND: Hereditary angioedema (HAE) is a rare C1-inhibitor (C1-INH) deficiency disease. Low levels of functional C1-INH can lead to recurrent attacks of severe swelling occurring in areas such as the limbs, face, gastrointestinal tract, and throat. These attacks are both painful and disabling and, if not treated promptly and effectively, can result in hospitalization or death. Agents targeting the specific physiologic pathway of HAE attacks can offer improved outcomes with limited side effects compared with nonspecific therapies. However, these treatments display varying efficacy in HAE patients, including the need to redose or seek additional care if the treatment does not resolve symptoms effectively.
OBJECTIVE: To analyze the expected cost and utility per HAE attack when treated on-demand with HAE therapies indicated for the treatment of acute attacks.
METHODS: A decision-tree model was developed using TreeAge Pro software. Four on-demand HAE treatments were included: ecallantide, icatibant, plasma-derived (pd)C1-INH, and recombinant human (rh)C1-INH. The model uses probabilities for redosing, self-administration versus health care provider administration, and risk of hospitalization. Costs within the model consisted of the HAE treatments and associated health care system expenses. Nonattack baseline utility and attack utility were implemented for effectiveness calculations; time to attack resolution was considered as well. Effectiveness and overall costs per attack were calculated and used to estimate cost per quality-adjusted life-year (QALY). Variability and ranges in cost-effectiveness were determined using probabilistic sensitivity analyses. Finally, a budget impact model for a health plan with 1 million covered lives was also developed.
RESULTS: The base case model outputs show costs and calculated effectiveness per attack at $12,905 and 0.806 for rhC1-INH, $14,806 and 0.765 for icatibant, $14,668 and 0.769 for pdC1-INH, and $21,068 and 0.792 for ecallantide, respectively. Cost per QALY was calculated using 26.9 attacks per person-year, leading to results of $420,941 for rhC1-INH, $488,349 for icatibant, $483,892 for pdC1-INH, and $689,773 for ecallantide. Sensitivity analyses demonstrate that redose rates (from 3% for rhC1-INH to 44% for icatibant) are a primary driver of variability in cost-effectiveness. Annual health plan costs from the budget impact model are calculated as $6.94 million for rhC1-INH, $7.97 million for icatibant, $7.90 million for pdC1-INH, and $11.33 million for ecallantide.
CONCLUSIONS: Accounting for patient well-being and additional cost components of HAE attacks generates a better estimation of cost-effectiveness than drug cost alone. Results from this model indicate that rhC1-INH is the dominant treatment option with lower expected costs and higher calculated effectiveness than comparators. Further analyses reinforce the idea that low redose rates contribute to improved cost-effectiveness.
DISCLOSURES: Funding support was contributed by Pharming Healthcare. Relan and Adams are employed by Pharming Healthcare. Tyson and Magar are employed by AHRM, which received fees to perform the analysis and develop the manuscript. Bernstein reports grants, personal fees, and nonfinancial support from Shire, CSL Behring, and Pharming Healthcare; grants and personal fees from Biocryst; and nonfinancial support from HAEA, unrelated to this study.

PMID: 31841366 [PubMed – indexed for MEDLINE]

Hereditary and acquired angioedema.

November 6, 2020 By Manish Butte

Hereditary and acquired angioedema.

Allergy Asthma Proc. 2019 11 01;40(6):441-445

Authors: Patel G, Pongracic JA

Abstract
Hereditary angioedema (HAE) is an autosomal dominant disorder defined by a deficiency of functional C1 esterase inhibitor (C1-INH). Acquired angioedema is due to either consumption (type 1) or inactivation (type 2) of CI-INH. Both HAE and acquired angioedema can be life-threatening. Of the three types of HAE, type 1 is most common, occurring in approximately 85% of patients and characterized by decreased production of C1-INH, which results in reduced functional activity to 5-40% of normal. Type 2 occurs in 15% of cases; C1-INH is detectable in normal or elevated quantities but is dysfunctional. Also, HAE with normal CI-INH (previously called type 3 HAE) is rare and characterized by normal complement studies. Specific genetic mutations have been linked to factor XII, angiopoietin-1, and plasminogen gene. Patients with unknown mutations are classified as unknown. The screening test for types 1 and 2 is complement component C4, which is low to absent at times of angioedema and during quiescent periods. A useful test to differentiate HAE from acquired angioedema is C1q protein, which is normal in HAE and low in acquired angioedema. The management of HAE has been transformed with the advent of disease-specific therapies. On-demand therapy options include plasma and recombinant C1-INH for intravenous infusion; ecallantide, an inhibitor of kallikrein; and icatibant, a bradykinin β₂ receptor antagonist, both administered subcutaneously. For long-term prophylaxis, intravenous or subcutaneous C1-INH enzyme replacement and lanadelumab, a monoclonal antibody against kallikrein that is administered subcutaneously, are effective agents.

PMID: 31690390 [PubMed – indexed for MEDLINE]

Primary Immunodeficiency Diseases and Gastrointestinal Distress: Coping Strategies and Dietary Experiences to Relieve Symptoms.

November 5, 2020 By Manish Butte

Primary Immunodeficiency Diseases and Gastrointestinal Distress: Coping Strategies and Dietary Experiences to Relieve Symptoms.

Qual Health Res. 2020 Nov 04;:1049732320967908

Authors: Brede KK, Wandel M, Wiig I, von der Lippe C

Abstract
In this article, we focus on adults with primary immunodeficiency disease (PID) and their experiences with gastrointestinal (GI) distress with the aim of exploring how they experience living with their condition and the actions they take to relieve GI distress. Twelve adults with PID and GI distress participated in semi-structured, in-depth interviews. The interviews were analyzed following the steps of thematic analysis (TA). The study revealed the complexity of the psychosocial aspects of living with PID and GI distress. Participants experienced GI distress to be highly challenging in daily life and felt they had to cope with the condition alone, without adequate help from the health care service. Participants used a wide and diverse range of coping strategies, and the search for normalcy was evident. Health care professionals should be more proactive in supporting individuals with PID in their struggle to find solutions to problems arising from GI distress.

PMID: 33146080 [PubMed – as supplied by publisher]

Outcome of Non-hematological Autoimmunity After Hematopoietic Cell Transplantation in Children with Primary Immunodeficiency.

November 4, 2020 By Manish Butte

Outcome of Non-hematological Autoimmunity After Hematopoietic Cell Transplantation in Children with Primary Immunodeficiency.

J Clin Immunol. 2020 Nov 03;:

Authors: Lum SH, Elfeky R, Achini FR, Margarit-Soler A, Cinicola B, Perez-Heras I, Nademi Z, Flood T, Cheetham T, Worth A, Qasim W, Amin R, Rao K, Chiesa R, Bredius RGM, Amrolia P, Abinun M, Hambleton S, Veys P, Gennery AR, Lankester A, Slatter M

Abstract
PURPOSE: Knowledge of post-hematopoietic cell transplantation (HCT) non-hematological autoimmune disease (AD) is far from satisfactory.
METHOD: This multicenter retrospective study focuses on incidence, risk factors, and outcomes of post-HCT AD in 596 children with primary immunodeficiency (PID) who were transplanted from 2009 to 2018.
RESULTS: The indications of HCT were severe combined immunodeficiency (SCID, n = 158, 27%) and non-SCID PID (n = 438, 73%). The median age at HCT was 2.3 years (range, 0.04 to 18.3 years). The 5-year overall survival for the entire cohort was 79% (95% cumulative incidence (CIN), 74-83%). The median follow-up of surviving patients was 4.3 years (0.08 to 14.7 years). The CIN of post-HCT AD was 3% (2-5%) at 1 year post-HCT, 7% (5-11%) at 5 years post-HCT, and 11% (7-17%) at 8 years post-HCT. The median onset of post-HCT AD was 2.2 years (0.12 to 9.6 years). Autoimmune thyroid disorder (n = 19, 62%) was the most common post-HCT AD, followed by neuromuscular disorders (n = 7, 22%) and rheumatological manifestations (n = 5, 16%). All patients but one required treatment for post-HCT AD. After multivariate analysis, age at transplant (p = 0.01) and T cell-depleted graft (p < 0.001) were significant predictors of post-HCT AD. None of the T cell-depleted graft recipients developed post-HCT AD. Patients with a lower CD3+ count at 6 months post-HCT had a significant higher incidence of post-HCT AD compared to disease controls. Graft-versus-host disease, viral infection, and donor chimerism had no association with post-HCT AD.
CONCLUSION: Post-HCT AD occurred in 11% at 8 years post-HCT and its occurrence was associated with older age at HCT and unmanipulated graft.

PMID: 33141919 [PubMed – as supplied by publisher]

Deficiency of Wiskott-Aldrich syndrome protein has opposing effect on the pro-oncogenic pathway activation in nonmalignant versus malignant lymphocytes.

November 4, 2020 By Manish Butte

Deficiency of Wiskott-Aldrich syndrome protein has opposing effect on the pro-oncogenic pathway activation in nonmalignant versus malignant lymphocytes.

Oncogene. 2020 Nov 02;:

Authors: Han SS, Wen KK, Vyas YM

Abstract
Immunodeficiency is associated with cancer risk. Accordingly, hematolymphoid cancers develop in Wiskott-Aldrich syndrome (WAS), an X-linked primary immunodeficiency disorder (PID) resulting from the deficiency of WAS-protein (WASp) expressed predominantly in the hematolymphoid cell lineages. Despite the correlation between WASp deficiency and hematolymphoid cancers, the molecular mechanism underlying the oncogenic role of WASp is incompletely understood. Employing the WASp-sufficient and WASp-deficient cell-pair model of human T and B lymphocytes, we show that WASp deficiency differentially influences hyperactivation versus inhibition of both CDC42:ERK1/2 and NF-κB:AP-1 pro-oncogenic signaling pathways in nonmalignant versus malignant T and B lymphocytes. Furthermore, WASp deficiency induces a cell-type specific up/down-modulation of the DNA-binding activities of NF-κB, AP-1, and multiple other transcription factors with known roles in oncogenesis. We propose that WASp functions as a putative “tumor-suppressor” protein in normal T and B cells, and “oncoprotein” in a subset of established T and B cell malignancies that are not associated with the NPM-ALK fusion.

PMID: 33139832 [PubMed – as supplied by publisher]

Oral ulcerations in a patient with autosomal dominant hyper-IgE syndrome (AD-HIES).

November 4, 2020 By Manish Butte

Oral ulcerations in a patient with autosomal dominant hyper-IgE syndrome (AD-HIES).

BMJ Case Rep. 2020 Nov 02;13(11):

Authors: Borst J, Ma L

Abstract
A 23-year-old woman with autosomal dominant hyper-IgE syndrome complicated by recurrent pneumonia and sinusitis presented with 1 week of multiple painful oral ulcers unresponsive to empiric antiviral and antifungal treatment. Her ulcers progressively worsened and she required hospitalisation for intravenous hydration and pain control. PCR swab of an ulcer was positive for varicella-zoster virus. Her symptoms never fully resolved despite antiviral therapy, and within 2 weeks, she relapsed with new and worsening ulcers. Biopsy revealed chronic active inflammation with no evidence of viral inclusion bodies or fungal hyphae. She was diagnosed with recurrent aphthous stomatitis and referred to a local dentist for CO2 laser treatments with rapid resolution of her symptoms. This case highlights the broad differential for recurrent oral ulcers in people with a primary immunodeficiency. It also raises awareness of the benefits of laser therapy for aphthous stomatitis treatment and the importance of partnering with our colleagues in dentistry.

PMID: 33139362 [PubMed – in process]

[Secondary ITP in adults].

November 4, 2020 By Manish Butte

[Secondary ITP in adults].

Rev Med Interne. 2020 Oct 31;:

Authors: Michel M, Lega JC, Terriou L

Abstract
Secondary forms of immune thrombocytopenia (ITP) represent approximately 20% of all ITP cases in adulthood and this rate increases with age. Since some causes may influence both the prognosis and outcome but also the management of ITP, a minimal workup must be performed at ITP diagnosis to look for an associated or underlying cause. Among adults, B-cell lymphomas and mainly chronic lymphocytic leukemia, systemic auto-immune diseases such as systemic lupus or primary immunodeficiencies mainly represented by common variable immunodeficiency are the most frequent causes of secondary ITP. Whereas first-line therapy used for secondary ITP is usually similar to the one commonly used in primary ITP and relies mostly on corticosteroids±intravenous immunoglobulin according to the severity of bleeding, second and third-line treatments must take into account the type and degree of activity of the underlying disease.

PMID: 33139079 [PubMed – as supplied by publisher]