scholarly journals Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenjing Zhang ◽  
Xuemei Chen ◽  
Guodong Gao ◽  
Shubin Xing ◽  
Lina Zhou ◽  
...  

Background: Germline mutations in signal transducer and activator of transcription 1 (STAT1), which lead to primary immunodeficiency, are classified as defects in intrinsic and innate immunity. To date, no comprehensive overview comparing GOF with LOF in early-onset immunodeficiency has been compiled.Objective: To collect and systematically review all studies reporting STAT1 GOF and LOF cases, and to describe the clinical, diagnostic, molecular, and therapeutic characteristics of all the conditions.Methods: A systematic review of the PubMed, EMBASE, Web of Science, Scopus, and Cochrane to identify articles published before May 23, 2020. Data pertaining to patients with a genetic diagnosis of STAT1 GOF or LOF germline mutations, along with detailed clinical data, were reviewed.Results: The search identified 108 publications describing 442 unique patients with STAT1 GOF mutations. The patients documented with chronic mucocutaneous candidiasis (CMC; 410/442), lower respiratory tract infections (210/442), and autoimmune thyroid disease (102/442). Th17 cytopenia was identified in 87.8% of those with GOF mutations. Twenty-five patients with GOF mutations received hematopoietic stem cell transplantation (HSCT), and 10 died several months later. Twelve of 20 patients who received JAK inhibitor therapy showed improved symptoms. Twenty-one publications described 39 unique patients with STAT1 LOF mutations. The most common manifestations were Mendelian susceptibility to mycobacterial diseases (MSMD) (29/39), followed by osteomyelitis (16/39), and lymphadenopathy (9/39). Missense, indel, and frameshift mutations were identified as LOF mutations. There were no obvious defects in lymphocyte subsets or immunoglobulin levels. Eighteen patients required antimycobacterial treatment. Three patients received HSCT, and one of the three died from fulminant EBV infection.Conclusions: STAT1 GOF syndrome is a clinical entity to consider when confronted with a patient with early-onset CMC, bacterial respiratory tract infections, or autoimmune thyroid disease as well as Th17 cytopenia and humoral immunodeficiency. HSCT is still not a reasonable therapeutic choice. Immunoglobulin replacement therapy and JAK inhibitors are an attractive alternative. STAT1 LOF deficiency is a more complicated underlying cause of early-onset MSMD, osteomyelitis, respiratory tract infections, and Herpesviridae infection. Anti-mycobacterial treatment is the main therapeutic choice. More trials are needed to assess the utility of HSCT.

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Milena Bergmann ◽  
Jörg Haasenritter ◽  
Dominik Beidatsch ◽  
Sonja Schwarm ◽  
Kaja Hörner ◽  
...  

Abstract Background Cough is a relevant reason for encounter in primary care. For evidence-based decision making, general practitioners need setting-specific knowledge about prevalences, pre-test probabilities, and prognosis. Accordingly, we performed a systematic review of symptom-evaluating studies evaluating cough as reason for encounter in primary care. Methods We conducted a search in MEDLINE and EMBASE. Eligibility criteria and methodological quality were assessed independently by two reviewers. We extracted data on prevalence, aetiologies and prognosis, and estimated the variation across studies. If justifiable in terms of heterogeneity, we performed a meta-analysis. Results We identified 21 eligible studies on prevalence, 12 on aetiology, and four on prognosis. Prevalence/incidence estimates were 3.8–4.2%/12.5% (Western primary care) and 10.3–13.8%/6.3–6.5% in Africa, Asia and South America. In Western countries the underlying diagnoses for acute cough or cough of all durations were respiratory tract infections (73–91.9%), influenza (6–15.2%), asthma (3.2–15%), laryngitis/tracheitis (3.6–9%), pneumonia (4.0–4.2%), COPD (0.5–3.3%), heart failure (0.3%), and suspected malignancy (0.2–1.8%). Median time for recovery was 9 to 11 days. Complete recovery was reported by 40.2- 67% of patients after two weeks, and by 79% after four weeks. About 21.1–35% of patients re-consulted; 0–1.3% of acute cough patients were hospitalized, none died. Evidence is missing concerning subacute and chronic cough. Conclusion Prevalences and incidences of cough are high and show regional variation. Acute cough, mainly caused by respiratory tract infections, is usually self-limiting (supporting a “wait-and-see” strategy). We have no setting-specific evidence to support current guideline recommendations concerning subacute or chronic cough in Western primary care. Our study presents epidemiological data under non non-pandemic conditions. It will be interesting to compare these data to future research results of the post-pandemic era.


2009 ◽  
Vol 34 (3) ◽  
pp. 197.e1-197.e10 ◽  
Author(s):  
Evridiki K. Vouloumanou ◽  
Gregory C. Makris ◽  
Drosos E. Karageorgopoulos ◽  
Matthew E. Falagas

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262057
Author(s):  
Claire A. Woodall ◽  
Luke J. McGeoch ◽  
Alastair D. Hay ◽  
Ashley Hammond

Respiratory tract infections (RTIs) are extremely common and can cause gastrointestinal tract symptoms and changes to the gut microbiota, yet these effects are poorly understood. We conducted a systematic review to evaluate the reported evidence of gut microbiome alterations in patients with a RTI compared to healthy controls (PROSPERO: CRD42019138853). We systematically searched Medline, Embase, Web of Science, Cochrane and the Clinical Trial Database for studies published between January 2015 and June 2021. Studies were eligible for inclusion if they were human cohorts describing the gut microbiome in patients with an RTI compared to healthy controls and the infection was caused by a viral or bacterial pathogen. Dual data screening and extraction with narrative synthesis was performed. We identified 1,593 articles and assessed 11 full texts for inclusion. Included studies (some nested) reported gut microbiome changes in the context of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (n = 5), influenza (H1N1 and H7N9) (n = 2), Tuberculosis (TB) (n = 4), Community-Acquired Pneumonia CAP (n = 2) and recurrent RTIs (rRTI) (n = 1) infections. We found studies of patients with an RTI compared to controls reported a decrease in gut microbiome diversity (Shannon) of 1.45 units (95% CI, 0.15–2.50 [p, <0.0001]) and a lower abundance of taxa (p, 0.0086). Meta-analysis of the Shannon value showed considerable heterogeneity between studies (I2, 94.42). Unbiased analysis displayed as a funnel plot revealed a depletion of Lachnospiraceae, Ruminococcaceae and Ruminococcus and enrichment of Enterococcus. There was an important absence in the lack of cohort studies reporting gut microbiome changes and high heterogeneity between studies may be explained by variations in microbiome methods and confounder effects. Further human cohort studies are needed to understand RTI-induced gut microbiome changes to better understand interplay between microbes and respiratory health.


2019 ◽  
Vol 38 (7) ◽  
pp. 1801-1809 ◽  
Author(s):  
Clement E. Tagoe ◽  
Tejas Sheth ◽  
Eugeniya Golub ◽  
Karen Sorensen

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