Manish Butte

Bone Marrow Transplantation for Primary Immune Deficiency Disorders in India: Past, Present and Future.

Indian Pediatr. 2018 08 15;55(8):657-658

Authors: Yadav SP

PMID: 30218509 [PubMed – indexed for MEDLINE]

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Treatment of Granulomas in Patients With Ataxia Telangiectasia.

Front Immunol. 2018;9:2000

Authors: Woelke S, Valesky E, Bakhtiar S, Pommerening H, Pfeffermann LM, Schubert R, Zielen S

Abstract
Background: Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia, growth retardation, immunodeficiency, chronic pulmonary disease and chromosomal instability. Cutaneous granulomas are a known phenomenon in A-T but extra-dermal manifestation of granulomas at bone and synovia has not been reported so far. The clinical presentation, immunological findings, the long-term course and treatment options of eight patients with severe granulomas will be reported. Methods: From our cohort of 44 classical A-T patients, eight patients aged 2-11 years (18.2%) presented with granulomas. Immunological features of patients with and without granulomas were compared. Five patients suffered from cutaneous manifestation, in two patients we detected a bone and in one a joint involvement. Patients with significant extra-dermal involvement as well as one patient with massive skin manifestation were treated with TNF inhibitors. The patient with granulomas at his finger joint and elbow was treated with hematopoietic stem cell transplantation (HSCT). Results: Interestingly, seven of eight patients with granulomas were total IgA deficient, but there were no differences in IgG and IgM levels. All lymphocytes subsets were equally distributed except patients with granuloma had significantly lower naïve CD8 cells. In patients without treatment, four of eight showed a slow but significant enlargement of the granuloma. Treatment success with TNF inhibitors was variable. In one patient, treatment with TNF inhibitors led to a total remission for 3 years up to now. In two patients, treatment with TNF inhibitors led to a partial regression of granulomas. Treatment interruptions caused deterioration again. Conclusions: Granulomas in A-T progress slowly over years and can lead to significant morbidity.Treatment with TNF inhibitors was safe and in part successful in our patients. Interestingly HSCT leads to complete remission, and indicates that aberrant immune function is responsible for granulomas in A-T patients. What This Study Adds to the Field: Granulomas in A-T progress slowly over years and can lead to significant morbidity. Treatment with TNF inhibitors was safe and in part successful in our patients. AT A GLANCE COMMENTARY: Scientific knowledge on the subject: Little is known about the clinical presentation, course and treatment of granulomas in ataxia telangiectasia (A-T). In addition, this is the first report of extra-dermal manifestation of granulomas at bone and synovia in patients with A-T. What This Study Adds to the Field: Granulomas in A-T progress slowly over years and can lead to significant morbidity. Treatment with TNF inhibitors was safe and in part successful in our patients.

PMID: 30279689 [PubMed – in process]

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Phenotyping and long-term follow up of patients with hyper IgE syndrome.

Allergol Immunopathol (Madr). 2018 Sep 29;:

Authors: Alyasin S, Esmaeilzadeh H, Ebrahimi N, Nabavizadeh SH, Kashef S, Esmaeilzadeh E, Babaei M, Amin R

Abstract
INTRODUCTION AND OBJECTIVES: Long-term follow up of patients with hyper IgE syndrome (HIES), as a primary immunodeficiency disorder, has been poorly investigated. This study describes common clinical and immunological features of patients with HIES in the last 10 years in Shiraz University of Medical Sciences, Shiraz, Iran.
METHODS AND PATIENTS: In this cross-sectional study, the symptoms and medical records of 18 patients, who were diagnosed with HIES, were observed. Genetic and immunologic study was also performed.
RESULTS: Eighteen patients with the mean age of 13 years old were investigated. Ten patients were detected to have mutations in DOCK8 gene and autosomal recessive HIES (AR-HIES); and four patients were found with STAT3 mutation and autosomal dominant HIES (AD-HIES). So, 14 patients with known genetic results were considered for further data analysis. Food allergy, eczema, viral and skin infections were the major complications of AR-HIES patients. The major clinical complications of AD-HIES patients were pneumonia, skin infections and eczema. Food allergy and viral infection were significantly higher in DOCK8 deficient patients. The most common causes of hospitalization in both AR-HIES and AD-HIES patients were pneumonia, skin infections and sepsis. The most common cause of death was found to be sepsis.
CONCLUSIONS: AD-HIES and AR-HIES cannot be differentiated only based on the clinical presentations. Genetic features are also necessary for better diagnosis. This study, summarizing the clinical, immunological and genetic information of the patients with AD-HIES and AR-HIES, may open a way for better diagnosis and management of HIES.

PMID: 30279075 [PubMed – as supplied by publisher]

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Primary immunodeficiency.

Allergy Asthma Clin Immunol. 2018;14(Suppl 2):61

Authors: McCusker C, Upton J, Warrington R

Abstract
Primary immunodeficiency disorder (PID) refers to a large heterogeneous group of disorders that result from defects in immune system development and/or function. PIDs are broadly classified as disorders of adaptive immunity (i.e., T cell, B-cell or combined immunodeficiencies) or of innate immunity (e.g., phagocyte and complement disorders). Although the clinical manifestations of PIDs are highly variable, many disorders involve an increased susceptibility to infection. Early consultation with a clinical immunologist is essential, as timely diagnosis and treatment are imperative for preventing significant disease-associated morbidity. PIDs should be suspected in patients with: recurrent sinus or ear infections or pneumonias within a 1 year period; failure to thrive; poor response to prolonged use of antibiotics; persistent thrush or skin abscesses; or a family history of PID. Patients with multiple autoimmune diseases should also be evaluated. Diagnostic testing often involves lymphocyte proliferation assays, flow cytometry, measurement of serum immunoglobulin (Ig) levels, assessment of serum specific antibody titers in response to vaccine antigens, neutrophil function assays, stimulation assays for cytokine responses, and complement studies. The treatment of PIDs is complex and generally requires both supportive and definitive strategies. Ig replacement therapy is the mainstay of therapy for B-cell disorders, and is also an important supportive treatment for many patients with combined immunodeficiency disorders. The disorders affecting the activity of the T-cell arm of the adaptive system, such as severe combined immunodeficiency, require immune reconstitution as soon as possible. The treatment of innate immunodeficiency disorders varies depending on the type of defect, but may involve antifungal and antibiotic prophylaxis, cytokine replacement, vaccinations and bone marrow transplantation. This article provides an overview of the major categories of PIDs and strategies for the appropriate diagnosis and management of these rare disorders.

PMID: 30275850 [PubMed]

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Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism.

Adv Biol Regul. 2018 Sep 25;:

Authors: Choi YJ, Saba JD

Abstract
Sphingosine-1-phosphate lyase (SPL) is an intracellular enzyme that controls the final step in the sphingolipid degradative pathway, the only biochemical pathway for removal of sphingolipids. Specifically, SPL catalyzes the cleavage of sphingosine 1-phosphate (S1P) at the C2-3 carbon bond, resulting in its irreversible degradation to phosphoethanolamine (PE) and hexadecenal. The substrate of the reaction, S1P, is a bioactive sphingolipid metabolite that signals through a family of five G protein-coupled S1P receptors (S1PRs) to mediate biological activities including cell migration, cell survival/death/proliferation and cell extrusion, thereby contributing to development, physiological functions and – when improperly regulated – the pathophysiology of disease. In 2017, several groups including ours reported a novel childhood syndrome that featured a wide range of presentations including fetal hydrops, steroid-resistant nephrotic syndrome (SRNS), primary adrenal insufficiency (PAI), rapid or insidious neurological deterioration, immunodeficiency, acanthosis and endocrine abnormalities. In all cases, the disease was attributed to recessive mutations in the human SPL gene, SGPL1. We now refer to this condition as SPL Insufficiency Syndrome, or SPLIS. Some features of this new sphingolipidosis were predicted by the reported phenotypes of Sgpl1 homozygous null mice that serve as vertebrate SPLIS disease models. However, other SPLIS features reveal previously unrecognized roles for SPL in human physiology. In this review, we briefly summarize the biochemistry, functions and regulation of SPL, the main clinical and biochemical features of SPLIS and what is known about the pathophysiology of this condition from murine and cell models. Lastly, we consider potential therapeutic strategies for the treatment of SPLIS patients.

PMID: 30274713 [PubMed – as supplied by publisher]

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Unexpected Relevant Role of Gene Mosaicism in Primary Immunodeficiency Diseases.

J Allergy Clin Immunol. 2018 Sep 28;:

Authors: Mensa-Vilaró A, García-Morato MB, de la Calle-Martin O, Franco-Jarava C, Martínez-Saavedra MT, González-Granado LI, González-Roca E, Fuster JL, Alsina L, Mutchinick OM, Balderrama-Rodríguez A, Ramos E, Modesto C, Mesa-Del-Castillo P, Ortego-Centeno N, Clemente D, Souto A, Palmou N, Remesal A, Leslie KS, Gómez de la Fuente E, Bravo Gallego LY, Campistol JM, Dhouib NG, Bejaoui M, Dutra LA, Terreri MT, Mosquera C, González T, Cañellas J, García-Ruiz de Morales JM, Wouters CH, Bosque MT, Cham WT, Jiménez-Treviño S, de Inocencio J, Bloomfield M, Pérez de Diego R, Martínez-Pomar N, Rodríguez-Pena R, González-Santesteban C, Soler-Palacín P, Casals F, Yagüe J, Allende LM, Rodríguez-Gallego JC, Colobran R, Martínez-Martínez L, López-Granados E, Aróstegui JI

Abstract
BACKGROUND: Post-zygotic de novo mutations lead to the phenomenon of gene mosaicism. The three main types are called somatic, gonadal and gonosomal mosaicism, which differ on the body distribution of post-zygotic mutations. Mosaicism has been occasionally reported in primary immunodeficiency diseases (PID) since early 90s, but its real involvement has not been systematically addressed.
OBJECTIVE: To investigate the incidence of gene mosaicism in PID.
METHODS: The amplicon-based deep sequencing method was employed in the three parts of the study that establish the allele frequency of germline variants (n:100), the incidence of parental gonosomal mosaicism in PID families with de novo mutations (n:92) and the incidence of mosaicism in PID families with moderate-to-high suspicious (n:36), respectively. Additional investigations evaluated body distribution of post-zygotic mutations, their stability over time and their characteristics.
RESULTS: The range of allele frequency 44.1-55.6% was established for germline variants. Those with minor allele frequency (MAF) <44.1% were assumed as post-zygotic. Mosaicism was detected in 30/128 (23.4%) PID families, with variable MAF (0.8-40.5%). Parental gonosomal mosaicism was detected in 6/92 (6.5%) families with de novo mutations, whereas a high incidence of mosaicism (63.9%) was detected among families with moderate-to-high suspicious. In most analyzed cases, mosaicism was found both uniformly distributed and stable over time.
CONCLUSION: This study represents the largest one performed to date to investigate mosaicism in PID, revealing that it affects ≈25% of enrolled families. Our results may have serious consequences regarding patients’ treatment and genetic counseling, and reinforce the use of NGS-based methods in the routine analyses of PID.

PMID: 30273710 [PubMed – as supplied by publisher]

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Brain and Spinal Epidural Abscess.

Continuum (Minneap Minn). 2018 Oct;24(5, Neuroinfectious Disease):1327-1348

Authors: Chow F

Abstract
PURPOSE OF REVIEW: Brain abscesses and spinal epidural abscesses are serious, potentially life-threatening infections of the central nervous system. This article outlines the clinical presentation, evaluation, and management of brain abscesses and spinal epidural abscesses, with a specific focus on bacterial infections.
RECENT FINDINGS: The overall incidence of brain abscesses has declined, in part because of fewer brain abscesses associated with otogenic infections. However, emerging patient populations at high risk for brain abscess include those with a history of penetrating head trauma, neurosurgery, or immunodeficiency. Improved mortality rates for brain abscess are attributable to modern diagnostic imaging, stereotactic-guided aspiration, and newer antimicrobials that readily penetrate into the central nervous system and abscesses. Brain MRI is more sensitive than CT for brain abscess, particularly in the early stages, but CT remains more widely available and can adequately identify potential abscesses and confirm response to treatment. With the advent of minimally invasive neurosurgical techniques, surgical excision is often employed only for posterior fossa, multiloculated, or superficial well-circumscribed abscesses. In select clinical scenarios, conservative medical management may be a safe alternative to a combined surgical and medical approach. Unlike brain abscess, the incidence of spinal epidural abscess is on the rise and has been attributed to higher prevalence of predisposing factors, including spinal procedures and instrumentation.
SUMMARY: Successful diagnosis and management of brain abscess and spinal epidural abscess requires a collaborative approach among neurologists, neurosurgeons, radiologists, and infectious disease physicians. The foundation of management of brain abscess includes surgical intervention for diagnostic purposes if a pathogen has not been identified or for decompression of larger abscesses or those with mass effect and significant surrounding edema; appropriate dosing and adequate duration of an antimicrobial regimen tailored to the presumptive source of infection and available culture data, and eradication of the primary source of infection. For spinal epidural abscesses, neurologic status at the time of presentation is directly related to outcomes, underscoring the importance of prompt recognition and intervention.

PMID: 30273242 [PubMed – in process]

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A Young Patient with Stroke and Primary Tuberculosis.

J Neurosci Rural Pract. 2018 Oct-Dec;9(4):613-615

Authors: Arulprakash N, Narayanan L, Narayanan S

Abstract
A 21-year-old woman presented with left hemiparesis, fever, dyspnea, tachycardia, and pericardial rub on examination. She was provisionally diagnosed with infective endocarditis and received the final diagnosis of the primary pulmonary tuberculosis (PTB) and extra PTB (EPTB) with pericardial effusion and thoracic lymphadenitis. Left hemiparesis due to a pontine infarct was attributed to TB with neurovasculitis. The diagnosis was supported by findings on imaging studies such as echocardiography, computed tomography of the thorax, and magnetic resonance imaging of the brain. She improved with anti-TB treatment. It is interesting to note that she was not immunodeficient, with the usual suspects such as acquired immunodeficiency syndrome, diabetes mellitus, and renal failure ruled out. We conclude that PTB and EPTB must be considered in any febrile illness, even in patients who are not immunodeficient, considering its atypical presentation and prevalence in India.

PMID: 30271059 [PubMed]

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Enterovirus infections in pediatric hematologic/oncologic patients.

Pediatr Blood Cancer. 2018 Sep 30;:e27448

Authors: Strenger V, Kessler HH, Stelzl E, Aberle SW, Keldorfer M, Zach K, Karastaneva A, Sperl D, Lackner H, Benesch M, Urban C, Dornbusch HJ

Abstract
BACKGROUND: Enteroviruses (EV) are a large group of Picornaviruses associated with respiratory, gastrointestinal, and neurologic symptoms in the immunocompetent host. Little is known about the epidemiologic and clinical impact in pediatric hematologic/oncologic patients.
PROCEDURE: From 2001 through 2017, different clinical specimens were collected from pediatric hematologic/oncologic patients and were tested for enteroviral RNA.
RESULTS: Of 13 004 specimens collected from 761 patients, 38 (0.3%) obtained from 14 patients (1.8%) tested positive for EV RNA. Viral shedding was observed without viremia and vice versa. None of 80 cerebrospinal fluid specimens obtained from 60 patients with neurologic symptoms were positive for EV RNA. None of 14 patients positive for EV RNA showed EV-specific symptoms. In 11/14 patients, EV RNA was found to be negative in the follow-up specimen. The remaining patient with a severe primary immune deficiency showed repeated positive EV RNA results for >5 years.
CONCLUSIONS: In this pediatric hematologic/oncologic cohort, EV infection occurred rarely and without related symptoms. Specimens concurrently obtained from one patient are commonly not in accordance with each other. In the vast majority of patients, EV RNA appears to turn negative in the follow-up specimen. EV infections seem to have a low impact in this patient cohort.

PMID: 30270558 [PubMed – as supplied by publisher]

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Follow-up and outcome of symptomatic partial or absolute IgA deficiency in children.

Eur J Pediatr. 2018 Sep 29;:

Authors: Moschese V, Chini L, Graziani S, Sgrulletti M, Gallo V, Di Matteo G, Ferrari S, Di Cesare S, Cirillo E, Pession A, Pignata C, Specchia F

Abstract
Selective IgA deficiency is defined as absolute or partial when serum IgA level is < 7 mg/dl or 2 SD below normal for age, respectively. Few data are available on partial selective IgA deficiency, as probably most children with low serum IgA are seldom referred to a specialist clinic in common pediatric practice. The aim of our study was to better define the profile of both symptomatic forms and their clinical outcome in a pediatric immunology setting. Thus, clinical and immunological data from 103 symptomatic patients with selective IgA deficiency (53 absolute and 50 partial), 4-18 years of age, were collected at diagnosis and 80 patients (44 absolute and 36 partial) were monitored for a mean period of 5 years. Also, the prevalence of TNFRSF13B mutations has been assessed in 56 patients. The most common clinical features were infections (86/103; 83%), allergy (39/103; 38%), and autoimmunity (13/103; 13%). No significative differences were observed between absolute and partial selective IgA deficiency patients. However, a significative difference in the rate of IgA normalization between partial and absolute selective IgA deficiency patients (33 vs 9%, p = 0.01) was detected. Furthermore, a lower incidence of infections was associated to a normalization reversal compared to a final absolute or partial defect status (12 vs 53 and 64% respectively, p < 0.01).
CONCLUSIONS: Regardless of a diagnosis of absolute or partial defect, monitoring of symptomatic patients with selective IgA deficiency is recommended overtime for prompt identification and treatment of associated diseases. Further, diagnostic workup protocols should be revisited in children with IgA deficiency. What is Known: ● Selective IgA Deficiency is the most common primary immunodeficiency and is usually asymptomatic. ● Symptomatic pediatric patients with selective IgA deficiency mostly suffer with respiratory and gastrointestinal infections. What is New: ● Symptomatic children with partial IgA defect may have similar clinical, immunological, and genetic features than symptomatic children with absolute IgA deficiency. ● Symptomatic children with partial IgA deficiency deserve accurate monitoring for associated diseases as per children with absolute IgA deficiency.

PMID: 30269248 [PubMed – as supplied by publisher]

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