Manish Butte

Clinical Outcomes of COVID-19 Patients with Pre-existing, Compromised Immune Systems: A Review of Case Reports.

November 24, 2020 By Manish Butte

Icon for Ivyspring International Publisher

Clinical Outcomes of COVID-19 Patients with Pre-existing, Compromised Immune Systems: A Review of Case Reports.

Int J Med Sci. 2020;17(18):2974-2986

Authors: Corse T, Dayan L, Kersten S, Battaglia F, Terlecky SR, Han Z

Abstract
In the ongoing COVID-19 pandemic, all COVID-19 patients are naïve patients as it is the first-time humans have been exposed to the SARS-CoV-2 virus. As with exposure to many viruses, individuals with pre-existing, compromised immune systems may be at increased risk of developing severe symptoms and/or dying because of (SARS-CoV-2) infection. To learn more about such individuals, we conducted a search and review of published reports on the clinical characteristics and outcomes of COVID-19 patients with pre-existing, compromised immune systems. Here we present our review of patients who possess pre-existing primary antibody deficiency (PAD) and those who are organ transplant recipients on maintenance immunosuppressants. Our review indicates different clinical outcomes for the patients with pre-existing PAD, depending on the underlying causes. For organ transplant recipients, drug-induced immune suppression alone does not appear to enhance COVID-19 mortality risk – rather, advanced age, comorbidities, and the development of secondary complications appears required.

PMID: 33173418 [PubMed – indexed for MEDLINE]

Cutaneous fusariosis caused by Fusarium lichenicola in a child with hyper-immunoglobulin E syndrome.

November 24, 2020 By Manish Butte

Cutaneous fusariosis caused by Fusarium lichenicola in a child with hyper-immunoglobulin E syndrome.

J Dermatol. 2020 Feb;47(2):181-184

Authors: Shi M, Lu S, Li J, Cai W, Zhang J, Ma J, Li X, Xi L, Zhang J

Abstract
Fusariosis is the second most common mold infection after aspergillosis, and keratomycosis is the most encountered implantation infection. Here, we report a case of a 4-year-old Han Chinese girl presenting with an itchy mass on her right face of almost 2 years’ duration. Direct smear of the lesion sample was positive for fungal hyphae. Biopsy of the lesion showed many fungal hyphae in the epidermis and dermis. The pathogen was identified as Fusarium lichenicola by molecular sequencing and phylogenetic analysis based on the TEF-1α gene. Whole-exome sequencing analysis using her peripheral blood revealed a heterozygous mutation in the STAT3 gene, which is related to autosomal dominant hyper-immunoglobulin E syndrome (AD-HIES). The lesion improved following treatment with i.v. and intralesional amphotericin B, oral voriconazole and topical luliconazole cream. To our knowledge, this is the second reported case of a special localized cutaneous lesion caused by Fusarium species in a child with AD-HIES. Both cases suggest that STAT3 deficiency may increase susceptibility to fusariosis.

PMID: 31829468 [PubMed – indexed for MEDLINE]

Classic ataxia-telangiectasia: the phenotype of long-term survivors.

November 24, 2020 By Manish Butte

Classic ataxia-telangiectasia: the phenotype of long-term survivors.

J Neurol. 2020 Mar;267(3):830-837

Authors: van Os NJH, van Deuren M, Weemaes CMR, van Gaalen J, Hijdra H, Taylor AMR, van de Warrenburg BPC, Willemsen MAAP

Abstract
OBJECTIVE: Patients with classic ataxia-telangiectasia (A-T) generally die in the second or third decade of life. Clinical descriptions of A-T tend to focus on the symptoms at presentation. However, during the course of the disease, other symptoms and complications emerge. As long-term survivors with classic A-T develop a complex multisystem disorder with a largely unknown extent and severity, we aimed to comprehensively assess their full clinical picture.
METHODS: Data from Dutch patients with classic A-T above the age of 30 years were retrospectively collected. In addition, we searched the literature for descriptions of classic A-T patients who survived beyond the age of 30 years.
RESULTS: In the Dutch cohort, seven classic A-T patients survived beyond 30 years of age. Fourteen additional patients were retrieved by the literature search. Common problems in older patients with classic A-T were linked to ageing. Most patients had pulmonary, endocrine, cardiovascular, and gastro-intestinal problems. All patients had a tetraparesis with contractures. This led to immobilization and frequent hospital admissions. Most patients expressed the wish to no longer undergo intensive medical treatments, and waived follow-up programs.
CONCLUSIONS: Paucity of descriptions in the literature, and withdrawal from medical care complicate the acquisition of follow-up data on the natural history of long-term survivors. Irrespective of these limitations, we have obtained impression of the many problems that these patients face when surviving beyond 30 years of age. Awareness of these problems is needed to guide follow-up, counselling, and (palliative) care; decisions about life-prolonging treatments should be well considered.

PMID: 31776720 [PubMed – indexed for MEDLINE]

Fast fluorometric method for measuring circulating cell free DNA could aid the diagnosis of febrile children.

November 23, 2020 By Manish Butte

Fast fluorometric method for measuring circulating cell free DNA could aid the diagnosis of febrile children.

Acta Paediatr. 2020 Nov 22;:

Authors: Rabber L, Ernst TE, Miller Gelkop Y, Cohen Lahav M, Douvdevani A, Nahum A

Abstract
Circulating cell-free deoxyribonucleic acid (cfDNA) originates from cells undergoing necrosis and apoptosis or after active secretion and is constantly found in the blood stream. Elevated cfDNA has been reported in pathological conditions, including infections, malignancies and autoimmunity (1-3). We developed a simple fluorescent method to directly measure cfDNA concentrations in biological samples, without prior processing, in clinical laboratories (4).

PMID: 33222298 [PubMed – as supplied by publisher]

IL-2 contributes to cirrhosis-associated immune dysfunction by impairing follicular T helper cells in advanced cirrhosis.

November 20, 2020 By Manish Butte

IL-2 contributes to cirrhosis-associated immune dysfunction by impairing follicular T helper cells in advanced cirrhosis.

J Hepatol. 2020 Oct 23;:

Authors: Basho K, Zoldan K, Schultheiss M, Bettinger D, Globig AM, Bengsch B, Neumann-Haefelin C, Klocperk A, Warnatz K, Hofmann M, Thimme R, Boettler T

Abstract
BACKGROUND AND AIMS: Patients with decompensated liver cirrhosis suffer from recurrent infections and inadequate responses to prophylactic vaccinations. However, many patients present with hypergammaglobulinemia (HGG), indicating a sustained ability to generate antibody responses. As follicular T helper (Tfh) cells are central facilitators of humoral immunity by providing B cell help, we hypothesized that Tfh cell responses may be altered in advanced liver disease and aimed to identify underlying mechanisms.
METHODS: Tfh, regulatory T (Treg) cells and B cells, circulating cytokines and immunoglobulins were analyzed in cohorts of patients with compensated (n = 37) and decompensated cirrhosis (n = 82) and in non-cirrhotic controls (n = 45). Intrahepatic T cells were analyzed in 8 decompensated patients. The influence of IL-2 on Tfh cell function was evaluated in vitro, including Tfh cell cloning and T cell-B cell co-cultures with clones and primary tonsil-derived Tfh cells.
RESULTS: Tfh cell frequencies were reduced in patients with decompensated liver cirrhosis with phenotypic signatures indicative of increased IL-2 signaling. Soluble IL-2 receptor (sCD25) was elevated in these patients and CD4 T cells were more responsive to IL-2 signaling, as characterized by STAT5 phosphorylation. IL-2 exposure in vitro diminished the Tfh phenotype and resulted in impaired Tfh helper function in co-culture experiments with naïve B cells. Tfh cells were barely detectable in cirrhotic livers. IL-2 signatures on Tfh cells in decompensated patients correlated with immunoglobulin levels, which were found to be associated with improved survival.
CONCLUSIONS: Tfh cell impairment represents a previously underestimated feature of cirrhosis-associated immune dysfunction that is driven by IL-2. Presence of HGG in decompensated patients predicts an intact Tfh cell compartment and is associated with a favorable outcome.

PMID: 33211012 [PubMed – as supplied by publisher]

A Spontaneous RAG1 Nonsense Mutation Unveils Naturally Occurring N-Terminal Truncated RAG1 Isoforms.

November 20, 2020 By Manish Butte

A Spontaneous RAG1 Nonsense Mutation Unveils Naturally Occurring N-Terminal Truncated RAG1 Isoforms.

Immunohorizons. 2020 03 06;4(3):119-128

Authors: Burn TN, Lee KD, Dawany N, Robertson TF, Fisher MR, Bassing CH, Behrens EM

Abstract
The RAG1 and RAG2 proteins are essential for the assembly of Ag receptor genes in the process known as VDJ recombination, allowing for an immense diversity of lymphocyte Ag receptors. Congruent with their importance, RAG1 and RAG2 have been a focus of intense study for decades. To date, RAG1 has been studied as a single isoform; however, our identification of a spontaneous nonsense mutation in the 5′ region of the mouse Rag1 gene lead us to discover N-truncated RAG1 isoforms made from internal translation initiation. Mice homozygous for the RAG1 nonsense mutation only express N-truncated RAG1 isoforms and have defects in Ag receptor rearrangement similar to human Omenn syndrome patients with truncating 5′ RAG1 frameshift mutations. We show that the N-truncated RAG1 isoforms are derived from internal translation initiation start sites. Given the seemingly inactivating Rag1 mutation, it is striking that homozygous mutant mice do not have the expected SCID. We propose that evolution has garnered RAG1 and other important genes with the ability to form truncated proteins via internal translation to minimize the deleterious effects of 5′ nonsense mutations. This mechanism of internal translation initiation is particularly important to consider when interpreting nonsense or frameshift mutations in whole-genome sequencing, as such mutations may not lead to loss of protein.

PMID: 32144186 [PubMed – indexed for MEDLINE]

Mutation Analysis of Three Infantile Cases of X-linked Severe Combined Immunodeficiency.

November 20, 2020 By Manish Butte

Mutation Analysis of Three Infantile Cases of X-linked Severe Combined Immunodeficiency.

Clin Lab. 2020 Jan 01;66(1):

Authors: Yu C, Wang Y, Min L

Abstract
BACKGROUND: Mutations in the IL2RG gene are known to cause X linked severe combined immunodeficiency (XSCID). More than 250 unique variants of the IL2RG gene have been reported to be identified in SCID patients so far, while many of them are of unknown significance which complicate the interpretation of mutation analysis results; furthermore, there are still many novel variants seen in clinical practice.
METHODS: In this study we reviewed the testing results in three unrelated SCID families. All three probands had very severe immunodeficiency phenotypes and died in infancy. Next generation sequencing methods based on either SCID gene panel or exome sequencing were applied in causal variant screening for three probands. Sanger sequencing was used for verification of the variants of interest and carrier status study for the family members. STR analysis using the GoldeneyeTM DNA ID system (PeopleSpot Inc., China) was applied to verify the kinship of the family members when a de novo mutation was identified.
RESULTS: Causal mutations were identified in all three SCID male probands, among which one was novel (c.557dupT), one was reported to be identified in a common variable immunodeficiency patient in literature (Leu87Pro), and one was a “hot-spot-mutation” (Arg226Cys). The patient with the missense mutation Leu87Pro in this study had much more severe infection phenotypes compared with the reported case in literature.
CONCLUSIONS: Combining our findings and the published evidence together, Leu87Pro can be classified as a pathogenic variant following the ACMG guidelines. Correct and undoubted classification of the variants is of great importance for clinical gene testing.

PMID: 32013372 [PubMed – indexed for MEDLINE]

Reply.

November 20, 2020 By Manish Butte

Reply.

J Allergy Clin Immunol. 2020 03;145(3):1029-1030

Authors: Bustamante Ogando JC

PMID: 31955818 [PubMed – indexed for MEDLINE]

The panorama in diagnoses of severe combined immunodeficiency begins to change in Brazil.

November 20, 2020 By Manish Butte

The panorama in diagnoses of severe combined immunodeficiency begins to change in Brazil.

J Allergy Clin Immunol. 2020 03;145(3):1029

Authors: Mazzucchelli J, Aranda CS, Gouveia-Pereira M, Barreiros LA, Costa Carvalho BT, Condino-Neto A, de Moraes-Pinto MI

PMID: 31955817 [PubMed – indexed for MEDLINE]

Early diagnosis of ataxia telangiectasia in the neonatal phase: a parents’ perspective.

November 20, 2020 By Manish Butte

Early diagnosis of ataxia telangiectasia in the neonatal phase: a parents’ perspective.

Eur J Pediatr. 2020 Feb;179(2):251-256

Authors: Schoenaker MHD, Blom M, de Vries MC, Weemaes CMR, van der Burg M, Willemsen MAAP

Abstract
Ataxia telangiectasia (A-T) is a severe neurodegenerative disorder with variable immunodeficiency. Together with the Dutch A-T community, we investigated the opinion of A-T parents on an early A-T diagnosis in the asymptomatic phase of the disease. During an annual national meeting for A-T patients and families, the topic of an early A-T diagnosis was discussed in relation to the recent introduction of neonatal screening for severe combined immunodeficiency (SCID) in the Netherlands. Based on the discussion, individual arguments were identified and processed into a questionnaire, which was sent out to 64 A-T parents (32 families). Arguments included were insecurity to diagnosis, possible medical advantages, appropriate genetic counseling and family planning, loss of “golden” year(s), and early cancer screening for parents. The response rate was 55% (n = 35 parents). Twenty-six (74%) parents felt that the advantages of an early diagnosis outweighed the disadvantages, five parents thought that the disadvantages would outweigh the advantages (14%), and four parents did not indicate a preference.Conclusion: The majority of parents of a child with A-T would have preferred an early diagnosis during the asymptomatic phase of the disease, because the uncertainty during the diagnostic process had had a major impact on their lives. In addition, the knowledge of being carriers of an ATM gene mutation influenced decisions about family planning. Parents who opposed against an early diagnosis emphasized the joy of having a seemingly healthy child until diagnosis.What is Known:• Ataxia telangiectasia (A-T) is a devastating DNA repair disorder with a huge impact on quality of life of patients and their parents.• Patients with A-T may incidentally be identified at birth as the consequence of neonatal screening for severe combined immunodeficiency (SCID).What is New:• The majority of Dutch parents of A-T patients (74%) would have preferred an early diagnosis of their child in the asymptomatic phase of the disease.• Major arguments for an early A-T diagnosis were (1) the experienced insecurity in diagnostic trajectories and its impact on families and (2) the knowledge of being ATM mutation carriers when deciding about family planning. An argument against an early diagnosis is losing the joy of having a seemingly healthy child until diagnosis.

PMID: 31709473 [PubMed – indexed for MEDLINE]