Manish Butte

Cureus. 2021 May 19;13(5):e15124. doi: 10.7759/cureus.15124.

ABSTRACT

Primary diffuse large B-cell lymphoma of the tongue base (BOT) is an extremely rare entity with only a few cases described in the English literature to date. The incidence of BOT non-Hodgkin’s lymphoma (NHL) increases with age, most commonly after the sixth decade of life with no observed gender differences. Our patient presented with a six-month history of right neck swelling, one-month history of dysphagia, a change in voice, and ultimately acute airway distress, which led to a tracheostomy. We report an extremely rare case of a diffuse large B-cell lymphoma presenting with airway distress. The patient was treated using rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) chemotherapy, a five-day steroid course, and one intrathecal methotrexate. The patient recovered completely and is alive at the time of this writing. NHLs occur more commonly in patients like ours with a prior history of congenital immunodeficiency and celiac disease, exposure to radiation, acquired immune deficiency syndrome, rheumatoid arthritis, or Sjögren’s syndrome. Most reported cases of BOT NHLs may cause dysphagia, pharyngeal foreign body sensation, or progressive dyspnea. This case highlights that although NHL of the tongue is a very rare entity, it should not be overlooked and should always be in the differential diagnosis among various benign and malignant tumors and may cause rapid respiratory deterioration.

PMID:34159026 | PMC:PMC8213379 | DOI:10.7759/cureus.15124

Curr Opin Immunol. 2021 Jun 18;72:176-185. doi: 10.1016/j.coi.2021.05.010. Online ahead of print.

ABSTRACT

‘There is no gene for fate’ (citation from the movie ‘GATTACA’) – and there is no gene for CVID. Common Variable ImmunoDeficiency (CVID) is the most prevalent primary immunodeficiency in humans. CVID is characterized by an increased susceptibility to infections, hypogammaglobulinemia, reduced switched memory B cell numbers in peripheral blood and a defective response to vaccination, often complicated by autoimmune and autoinflammatory conditions. However, as soon as a genetic diagnosis has been made in a patient with CVID, the diagnosis must be changed to the respective genetic cause (www.esid.org). Therefore, there are genetic causes for primary antibody deficiencies, but not for CVID. Primary antibody deficiencies (PADs) are a heterogeneous group of disorders. Several attempts have been made to gain further insights into the pathogenesis of PAD, using unbiased approaches such as whole exome or genome sequencing. Today, in just about 35% of cases with PAD, monogenic mutations (including those in the gene TNFRSF13B) can be identified in a set of 68 genes [1^•]. These mutations occur either sporadically or are inherited and do explain an often complex phenotype. In our review, we not only discuss gene defects identified in PAD patients previously diagnosed with CVID and/or CVID-like disorders such as IKZF1, CTNNBL1, TNFSF13 and BACH2, but also genetic defects which were initially described in non-CVID patients but have later also been observed in patients with PAD such as PLCG2, PIK3CG, PMS2, RNF31, KMT2D, STAT3. We also included interesting genetic defects in which the pathophysiology suggests a close relation to other known defects of the adaptive immune response, such as DEF6, SAMD9 and SAMD9L, and hence a CVID-like phenotype may be observed in the future. However, alternative mechanisms most likely add to the development of an antibody-deficient phenotype, such as polygenic origins, epigenetic changes, and/or environmental factors.

PMID:34153571 | DOI:10.1016/j.coi.2021.05.010

Sci Rep. 2021 Jun 21;11(1):12940. doi: 10.1038/s41598-021-92381-y.

ABSTRACT

There are increasing evidences showing the contribution of somatic genetic variants to non-cancer diseases. However, their detection using massive parallel sequencing methods still has important limitations. In addition, the relative importance and dynamics of somatic variation in healthy tissues are not fully understood. We performed high-depth whole-exome sequencing in 16 samples from patients with a previously determined pathogenic somatic variant for a primary immunodeficiency and tested different variant callers detection ability. Subsequently, we explored the load of somatic variants in the whole blood of these individuals and validated it by amplicon-based deep sequencing. Variant callers allowing low frequency read thresholds were able to detect most of the variants, even at very low frequencies in the tissue. The genetic load of somatic coding variants detectable in whole blood is low, ranging from 1 to 2 variants in our dataset, except for one case with 17 variants compatible with clonal haematopoiesis under genetic drift. Because of the ability we demonstrated to detect this type of genetic variation, and its relevant role in disorders such as primary immunodeficiencies, we suggest considering this model of gene mosaicism in future genetic studies and considering revisiting previous massive parallel sequencing data in patients with negative results.

PMID:34155260 | DOI:10.1038/s41598-021-92381-y

Rev Iberoam Micol. 2021 Jun 18:S1130-1406(21)00031-0. doi: 10.1016/j.riam.2021.04.005. Online ahead of print.

ABSTRACT

In recent years, immunodeficiency condition has experienced a rise among children, who are at risk of invasive fungal infections (IFI) due to their health condition. Cancer, non-malignant hematological diseases, as primary immunodeficiencies, hematopoietic stem cell transplantation (HSCT), extreme prematurity, or critically ill condition in Pediatric Intensive Care Unit (PICU) are some immunosuppressive situations in children. The use of oncologic therapies, including immunotherapy and monoclonal antibodies, for the treatment of the aforementioned health conditions has led to an increase in morbidity and mortality rates of IFI in children. The underlying diseases and their management, comorbidities, the diagnostic tests used (both molecular and imaging), as well as the treatment used can be significantly different between adult patients and children admitted to PICU or with cancer. In pediatrics, the treatment of IFI is based primarily on pharmacokinetic studies performed in adults. In higher risk patients prophylaxis should be considered and, in the case of an IFI diagnosis, an antifungal treatment should be administered as early as possible, supported by the reversion of the immune dysfunction and surgery when appropriate.

PMID:34148786 | DOI:10.1016/j.riam.2021.04.005

Rev Alerg Mex. 2021 Jan-Mar;68(1):48-64. doi: 10.29262/ram.v68i1.894.

ABSTRACT

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency with an estimated prevalence of one in 10,000 to 50,000 inhabitants. This heterogeneous disease is characterized by decreased levels of serum immunoglobulins, a poor production of specific antibodies upon vaccination, and recurrent bacterial infections, particularly in the respiratory and gastrointestinal tract. A subgroup of patients is characterized by additional, and often predominant, manifestations of immune deregulation rather than pure immunodeficiency. Approximately, 30% of patients with CVID develop autoimmunity. Half of those complications can be attributed to autoimmune cytopenia, but also to other types of autoimmunity, such as organ-specific autoimmune diseases, often manifest as inflammatory disease, including inflammatory bowel disease, celiac disease, interstitial lung disease, some forms of arthritis, and vitiligo, among many others. New monogenic defects elucidate the immunopathological mechanism that causes the coincidence of immunodeficiency and autoimmunity. Autoimmune diseases have become the major clinical challenge in CVID, with new diagnostic tools, especially genetic ones, that improve the understanding of the different forms of immune deregulation.

PMID:34148328 | DOI:10.29262/ram.v68i1.894

J Allergy Clin Immunol. 2021 Jun 16:S0091-6749(21)00940-4. doi: 10.1016/j.jaci.2021.06.008. Online ahead of print.

ABSTRACT

BACKGROUND: Non-infectious complications are the greatest cause of morbidity and mortality in common variable immunodeficiency (CVID), but their pathogenesis remains poorly defined.

OBJECTIVE: Using high-throughput approaches we aimed to identify, correlate, and determine the significance of immunological features of CVID with non-infectious complications (CVIDc).

METHODS: We simultaneously applied proteomics, RNA sequencing, and mass cytometry to a large primary antibody deficiency (PAD) cohort.

RESULTS: CVIDc is differentiated from uncomplicated CVID, other forms of PAD, and healthy controls by a distinct plasma proteomic profile. In addition to confirming previously reported elevations of 4-1BB, IL-6, IL-18, and IFN-γ, we found elevations of CSF-1, IL-12p40, IL-18R, OSM, TNF, and VEGFA to differentiate CVIDc. This cytokine dysregulation correlated with deficiency of lipopolysaccharide (LPS)-specific antibodies and increased soluble CD14, suggesting microbial translocation. Indicating potential significance of reduced LPS-specific antibodies and resultant microbial-induced inflammation, CVIDc had altered LPS-induced gene expression matching plasma proteomics and corresponding with increased CD14+CD16- monocytes, memory T cells, and tissue inflammation ameliorated by T cell-targeted therapy. Unsupervised machine learning accurately differentiated CVIDc subjects and supported cytokine dysregulation, antibody deficit, and T cell activation as defining and convergent features.

CONCLUSION: Our data expand understanding of CVIDc proteomics, establish its link with deficiency of IgA and LPS-specific antibodies, and implicate altered LPS-induced gene expression and elevated monocytes and T cells in this cytokine dysregulation. This work indicates CVIDc results when insufficient antibody neutralization of pathogen-associated molecular patterns, like LPS, occurs in those with a heightened response to these inflammatory mediators, suggesting a two-hit model of pathogenesis requiring further exploration.

PMID:34146579 | DOI:10.1016/j.jaci.2021.06.008

Laryngoscope. 2021 Jun 19. doi: 10.1002/lary.29694. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the outcome of immunoglobulin (IG) replacement therapy in adults with rhinosinusitis and primary humoral immunodeficiency disorders (PID).

STUDY DESIGN: Retrospective cohort study.

METHODS: Retrospective chart review of adult (18 years and older) patients who were diagnosed with PID and had the diagnosis of recurrent acute rhinosinusitis (RARS) and chronic rhinosinusitis (CRS) and who are on IG replacement therapy. Demographic data, associated conditions, and duration of treatment were reviewed. Number of yearly sinus infections, sinus CT Lund-Mackay (LM) score, and need for functional endoscopic sinus surgery (FESS) were reviewed before and after starting IG therapy.

RESULTS: Fifty-eight patients were included. Average age was 52 years (18-79 years). About 74% were female. Thirty patients (51.7%) had common variable immunodeficiency (CVID), 18 (31.1%) had hypogammaglobulinemia, and 10 (17.2%) had specific antibody deficiency (SAD). About 79% of patients had allergic rhinitis and 74% had asthma. Pretreatment LM score was 7.6 (±2.2, range of 0-24) compared to posttreatment score of 3.5 (±1.3, range of 0-16) (P = .01). Eleven patients (19%) had FESS pretreatment compared to only two patients (3.4%) requiring ESS after starting treatment on IG therapy (P = .004). Prior to starting IG therapy, five patients (8.6%) had more than 10 sinus infections per year, 33 patients (56.9%) had 5 to 10 infections, and 20 patients (34.5%) had 1 to 5 infections per year. After starting on IG, 34 patients (58.6%) had no infections reported anymore (P < .001), and 24 patients (41.4%) had only 1 to 5 infections reported per year CONCLUSION: IG therapy is a promising treatment option for recurrent rhinosinusitis in patients with PID.

LEVEL OF EVIDENCE: 4 Laryngoscope, 2021.

PMID:34146351 | DOI:10.1002/lary.29694

Multimed Man Cardiothorac Surg. 2021 Jun 4;2021. doi: 10.1510/mmcts.2021.033.

ABSTRACT

Complex chest and lung infections with bronchial fistula are life-threatening situations with a mortality rate of up to 20%. If medical treatment fails, these patients require aggressive procedures to heal. Transposition of the omentum is a valuable, nonstandard option in these complex cases with aggressive infection involving the pleural space, with or without a bronchial fistula, when medical treatment is unsuccessful. We present a 29-year-old female patient diagnosed with primary immunodeficiency and invasive fungal infection with involvement of the left upper lobe and mediastinal and vertebral bodies treated with a lobectomy and intrathoracic transposition of the omentum.

PMID:34143577 | DOI:10.1510/mmcts.2021.033

Ann Med Surg (Lond). 2021 Jun 1;66:102452. doi: 10.1016/j.amsu.2021.102452. eCollection 2021 Jun.

ABSTRACT

INTRODUCTION: Job’s syndrome or hyper-immunoglobulin E syndromes (HIES) is a rare, heterogeneous complex of primary immunodeficiency disorders. It is characterized by triad of extremely high serum immunoglobulin E (IgE) levels, recurrent cutaneous infections like chronic eczematous dermatitis, skin abscesses and recurrent sinopulmonary infections. These patients have characteristic facial appearance and many oral manifestations. Eosinophilia, retention of deciduous teeth and skeletal abnormalities are other important clinical features of this syndrome. Familial HIES is of two types depending on the type of gene involved; autosomal-dominant HIES (AD-HIES), which develops due to mutation in human signal transducer and activator of transcription 3 gene (STAT3) and autosomal recessive HIES caused by DOCK8 gene mutation, but most cases are sporadic.

CASE PRESENTATION: Hereby, we present a case of 5 years old female child who presented to our hospital with extensive eczematous lesions over flexural aspect of arms and over the gluteal region extending to the lower limb. The complete clinical presentation and lab investigations have confirmed AD-HIES syndrome. A novel missense mutation in exon 17 (c.1593A > T, p.K531 N) was identified in the STAT3 gene.

DISCUSSION: The therapeutic strategy is directed mainly toward the prevention and management of infections and symptoms. Children affected with HIES can develop life-threatening pulmonary infections. Pulmonary complications must be identified in the early stage of the disease to treat them effectively. Hence, early diagnosis and proper management are necessary.

CONCLUSION: To date, information about paediatric HIES is limited. This case presents the clinical features, investigational procedures and management strategy for that particular condition in paediatric population.

PMID:34141423 | PMC:PMC8187933 | DOI:10.1016/j.amsu.2021.102452

Int J Radiat Biol. 2021 Jun 17:1-28. doi: 10.1080/09553002.2021.1941378. Online ahead of print.

ABSTRACT

Purpose: The cytokinesis-block micronucleus (MN) assay is a widely used technique in basic radiobiology research, human biomonitoring studies and in vitro radiosensitivity testing. Fresh whole blood cultures are commonly used for these purposes, but immediate processing of fresh samples can be logistically challenging. Therefore, we aimed at establishing a protocol for the MN assay on cryopreserved whole blood, followed by a thorough evaluation of the reliability of this assay for use in radiosensitivity assessment in patients.Materials and methods: Whole blood samples of 20 healthy donors and 4 patients with a primary immunodeficiency disease (PID) were collected to compare the results obtained with the MN assay performed on fresh versus cryopreserved whole blood samples. MN yields were scored after irradiation with 220 kV X-rays (dose rate 3 Gy/min), with doses ranging from 0.5 – 2 Gy.Results: Application of the MN assay on cryopreserved blood samples was successful in all analyzed samples. The radiation induced MN and NDI scores in fresh and cryopreserved blood cultures were found to be similar. Acceptable inter-individual and intra-individual variabilities in MN yields were observed. Repeated analysis of cryopreserved blood cultures originating from the same blood sample, thawed at different time points, revealed that MN values remain stable for cryopreservation periods up to one year. Finally, radiosensitive patients were successfully identified using the MN assay on cryopreserved samples.Conclusions: To our knowledge, this study is the first report of the successful use of cryopreserved whole blood samples for application of the MN assay. The data presented here demonstrate that the MN assay performed on cryopreserved whole blood is reliable for radiosensitivity testing. Our results also support its wider use in epidemiological, biomonitoring and genotoxicity studies. The presented method of cryopreservation of blood samples might also benefit other assays.

PMID:34138661 | DOI:10.1080/09553002.2021.1941378