The Role of Probiotics in Clostridioides difficile Disease Severity and Time to Disease Resolution

Abstract Background The role of nucleic acid amplification tests (NAAT) for diagnosing Clostridioides difficile (CD) infection remains controversial. Adding CD to multiplex molecular panels (GIPCR) that detects multiple GI pathogens of community origin, has the potential to introduce confusion leading to delayed diagnosis and unnecessary antibiotic use especially if pretest probability is not considered. Methods We conducted a retrospective study to determine the frequency at which clinicians characterize pretest probability and disease severity in adult patients with diarrhea who tested positive for CD by GIPCR (BioFire, Inc.) from July 1, 2017 to October 16, 2018. We excluded immunocompromised patients. Routine testing includes reflex to GDH and toxin A/B detection when GIPCR is positive for CD. Charts were reviewed and clinical suspicion (PTP) was assigned as high, medium, low, or not done. Disease severity was classified as mild, moderate and severe. Exposure to systemic antibiotic within 90 days prior to testing and stool frequency was also captured. Results In total, 447 patients were included in the analysis: 110 (24.6%) were positive for both GDH and Toxin (G+/T+), 158 (35.3%) were G+/T−, 179 (40%) were G−/T−, and 149 (33%) were not classified. Toxin positivity was highest in the setting of high PTP (67%) (figure). In contrast, toxin was negative in most cases when suspicion for CDI was low or not characterized (81%). For medium suspicion, only 36% were T+. Antibiotic exposure prior to testing was observed in 203 (45%) of the cases. More G+/T+ patients received antibiotics (63%) before testing and 66% of G−/T− did not receive antecedent antibiotics. Clinicians did not characterize frequency of diarrhea in 261 (58%) of the patients tested and 95% of cases did not undergo severity classification. When documented, 24% of tested patients had < 3 diarrheal episodes/day (Table 1). Most cases where multiple pathogens were detected were T− (84.5%) and G−/T− (44%) (Table 2). Conclusion Overall, characterization of diarrheal illness was poor and PTP was frequently omitted. A large proportion of GIPCR results positive for CD (40%) were negative for both GDH and Toxin. CD results in molecular testing with syndromic panels should be interpreted with caution. Disclosures All authors: No reported disclosures.

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Faculty Opinions recommendation of Forty-two novel COL7A1 mutations and the role of a frequent single nucleotide polymorphism in the MMP1 promoter in modulation of disease severity in a large European dystrophic epidermolysis bullosa cohort.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1168314.630476 ◽

2009 ◽

Author(s):

Dedee Murrell ◽

Heather Cohn

Keyword(s):

Single Nucleotide Polymorphism ◽

Disease Severity ◽

Epidermolysis Bullosa ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Dystrophic Epidermolysis Bullosa ◽

Mmp1 Promoter

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Spo0A Suppresses sin Locus Expression in Clostridioides difficile

mSphere ◽

10.1128/msphere.00963-20 ◽

2020 ◽

Vol 5 (6) ◽

Author(s):

Babita Adhikari Dhungel ◽

Revathi Govind

Keyword(s):

Diarrheal Disease ◽

Toxin Production ◽

The United States ◽

Upstream Region ◽

Pcr Analysis ◽

Bacterial Cells ◽

Master Regulator ◽

Content Type ◽

Clostridioides Difficile

ABSTRACT Clostridioides difficile is the leading cause of nosocomial infection and is the causative agent of antibiotic-associated diarrhea. The severity of the disease is directly associated with toxin production, and spores are responsible for the transmission and persistence of the organism. Previously, we characterized sin locus regulators SinR and SinR′ (we renamed it SinI), where SinR is the regulator of toxin production and sporulation. The SinI regulator acts as its antagonist. In Bacillus subtilis, Spo0A, the master regulator of sporulation, controls SinR by regulating the expression of its antagonist, sinI. However, the role of Spo0A in the expression of sinR and sinI in C. difficile had not yet been reported. In this study, we tested spo0A mutants in three different C. difficile strains, R20291, UK1, and JIR8094, to understand the role of Spo0A in sin locus expression. Western blot analysis revealed that spo0A mutants had increased SinR levels. Quantitative reverse transcription-PCR (qRT-PCR) analysis of its expression further supported these data. By carrying out genetic and biochemical assays, we show that Spo0A can bind to the upstream region of this locus to regulates its expression. This study provides vital information that Spo0A regulates the sin locus, which controls critical pathogenic traits such as sporulation, toxin production, and motility in C. difficile. IMPORTANCE Clostridioides difficile is the leading cause of antibiotic-associated diarrheal disease in the United States. During infection, C. difficile spores germinate, and the vegetative bacterial cells produce toxins that damage host tissue. In C. difficile, the sin locus is known to regulate both sporulation and toxin production. In this study, we show that Spo0A, the master regulator of sporulation, controls sin locus expression. Results from our study suggest that Spo0A directly regulates the expression of this locus by binding to its upstream DNA region. This observation adds new detail to the gene regulatory network that connects sporulation and toxin production in this pathogen.

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The Abstruse Side of Type I Interferon Immunotherapy for COVID-19 Cases with Comorbidities

Journal of Respiration ◽

10.3390/jor1010005 ◽

2021 ◽

Vol 1 (1) ◽

pp. 49-59

Author(s):

Selvakumar Subbian

Keyword(s):

Infectious Diseases ◽

Disease Severity ◽

Type I Interferon ◽

Host Factors ◽

Type I ◽

The Novel ◽

Inflammatory Drugs ◽

Precautionary Measures ◽

Inducible Genes

The Coronavirus Disease-2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has claimed 1.2 million people globally since December 2019. Although the host factors underpinning COVID-19 pathology are not fully understood, type I interferon (IFN-I) response is considered crucial for SARS-CoV-2 pathogenesis. Perturbations in IFN-I signaling and associated interferon-inducible genes (ISG) are among the primary disease severity indicators in COVID-19. Consequently, IFN-I therapy, either alone or in- combination with existing antiviral or anti-inflammatory drugs, is tested in many ongoing clinical trials to reduce COVID-19 mortality. Since signaling by the IFN-I family of molecules regulates host immune response to other infectious and non-infectious diseases, any imbalance in this family of cytokines would impact the clinical outcome of COVID-19, as well as other co-existing diseases. Therefore, it is imperative to evaluate the beneficial-versus-detrimental effects of IFN-I immunotherapy for COVID-19 patients with divergent disease severity and other co-existing conditions. This review article summarizes the role of IFN-I signaling in infectious and non-infectious diseases of humans. It highlights the precautionary measures to be considered before administering IFN-I to COVID-19 patients having other co-existing disorders. Finally, suggestions are proposed to improve IFN-I immunotherapy to COVID-19.

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THE ROLE OF MYELOPEROXIDASE AND NEUTROPHIL EXTRACELLULAR TRAPS IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa347.009 ◽

2021 ◽

Vol 27 (Supplement_1) ◽

pp. S4-S4

Author(s):

Belal Chami ◽

Gulfam Ahmad ◽

Angie Schroder ◽

Patrick San Gabriel ◽

Paul Witting

Keyword(s):

Disease Severity ◽

Hypochlorous Acid ◽

Tissue Injury ◽

Activity Index ◽

Critical Role ◽

Neutrophil Migration ◽

Sodium Sulphate ◽

Host Tissue ◽

Neutrophil Extracellular Trap

Abstract Neutrophils are short-lived immune cells that represent the major cell type recruited to the inflamed bowel releasing their azurophilic granules containing enzymes myeloperoxidase (MPO). Fecal and serum MPO levels has previously been shown to correlate to disease severity in IBD patients. MPO, in the presence of H2O2 and free Cl- undergoes a halogenation cycle, yielding the two-electron oxidant, hypochlorous acid (HOCl) - a potent bactericidal agent. However, chronic intestinal exposure to MPO/HOCl due to perpetual inflammation may cause secondary host-tissue injury and cell death. Neutrophil Extracellular Trap (NET)osis is a specialised form of neutrophil death where MPO is entrapped in a DNA scaffold and continues to elicit HOCl activity and may further contribute to host-tissue injury. We investigated the presence of NETs in surgically excised ileum samples from CD and healthy patients using advanced confocal microscopic techniques and found MPO, Neutrophil Elastase (NE) and Citrullinated Histone h3 (CitH3) - critical components of NET formation, individually positively correlate to the severity of histopathological intestinal injury. Furthermore, multiplex Opal™ IHC performed using LMS880 Airyscan-moduled microscopy with z-stacking revealed colocalization of NE, MPO, CitH3 and DAPI indicating the extensive presence of NETs in severely affected CD tissue. Using two pharmacological inhibitors of MPO in a dextran sodium sulphate (DSS) model of murine colitis, we demonstrated the pathological role of MPO in experimental colitis. MPO inhibitors, TEMPOL and AZD3241 delivered via daily i.p significantly rescued the course of colitis by abrogating clinical indices including body weight loss, disease activity index, inhibiting serum peroxidation, and preserving colon length, while significantly mitigating histoarchitectural damage associated with DSS-induced colitis. We also showed that MPO inhibition decreased neutrophil migration to the gut, suggesting MPO may play a role in perpetuating the inflammatory cell by further recruiting cells to the inflamed gut. Collectively, we have shown for the first time that MPO is not only an important clinical marker of disease severity but may also play a critical role in perpetuating host-tissue damage and inflammation.

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Is Bisphosphonate-Related Osteonecrosis of the Jaw an Infection? A Histological and Microbiological Ten-Year Summary

International Journal of Dentistry ◽

10.1155/2014/452737 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 24

Author(s):

A. M. Hinson ◽

C. W. Smith ◽

E. R. Siegel ◽

B. C. Stack

Keyword(s):

Systematic Review ◽

Disease Severity ◽

Large Scale ◽

Clinical Signs ◽

Signs And Symptoms ◽

Osteonecrosis Of The Jaw ◽

Multifactorial Disease ◽

Clinical Signs And Symptoms ◽

Surgical Treatments

The role of infection in the etiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is poorly understood. Large-scale epidemiological descriptions of the histology and microbiology of BRONJ are not found in the literature. Herein, we present a systematic review of BRONJ histology and microbiology (including demographics, immunocompromised associations, clinical signs and symptoms, disease severity, antibiotic and surgical treatments, and recovery status) validating that infection should still be considered a prime component in the multifactorial disease.

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Role of KL-6 in evaluating the disease severity of rheumatoid lung disease: comparison with HRCT

Respiratory Medicine ◽

10.1016/j.rmed.2004.04.003 ◽

2004 ◽

Vol 98 (11) ◽

pp. 1131-1137 ◽

Cited By ~ 35

Author(s):

Fumiko Kinoshita ◽

Hidefumi Hamano ◽

Hiromi Harada ◽

Toshibumi Kinoshita ◽

Tadashi Igishi ◽

...

Keyword(s):

Lung Disease ◽

Disease Severity ◽

Rheumatoid Lung

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Molecular Characterization of Pathogenicity Locus (PaLoc) and tcdC Genetic Diversity Among tcdA+B+ Clostridioides Difficile Clinical Isolates in Tehran, Iran

10.21203/rs.3.rs-56651/v1 ◽

2020 ◽

Author(s):

Mansoor Kodori ◽

Zohreh Ghalavand ◽

Abbas Yadegar ◽

Gita Eslami ◽

Masoumeh Azimirad ◽

...

Keyword(s):

Genetic Diversity ◽

Molecular Characterization ◽

Disease Severity ◽

Genetic Variants ◽

Rflp Analysis ◽

Clostridioides Difficile ◽

Pcr Rflp ◽

The Common ◽

Healthcare Associated

Abstract Background: Clostridioides difficile is the main cause of healthcare-associated diarrhea worldwide. It is proposed that certain C. difficile toxinotypes with distinct pathogenicity locus (PaLoc) variants are associated with disease severity and outcomes. Additionally, few studies have described the common C. difficile toxinotypes, and also little is known about the tcdC variants in Iranian isolates. We characterized the toxinotypes and the tcdC genotypes from a collection of Iranian clinical C. difficile tcdA+B+ isolates with known ribotypes (RTs).Methods: Fifty C. difficile isolates with known RTs and carrying the tcdA and tcdB toxin genes were analyzed. Toxinotyping was carried out based on a PCR-RFLP analysis of a 19.6 kb region encompassing the PaLoc. Genetic diversity of the tcdC gene was determined by the sequencing of the gene.Results: Of the 50 C. difficile isolates investigated, five distinct toxinotypes were recognized. Toxinotypes 0 (33/50, 66%) and V (11/50, 22%) were the most frequently found. C. difficile isolates of the toxinotype 0 mostly belonged to RT 001 (12/33, 36.4%), whereas toxinotype V consisted of RT 126 (9/11, 81.8%). The tcdC sequencing showed six variants (35/50, 70%); tcdC-sc3 (24%), tcdC-A (22%), tcdC-sc9 (18%), tcdC-B (2%), tcdC-sc14 (2%), and tcdC-sc15 (2%). The remaining isolates were wild-types (15/50, 30%) in the tcdC gene.Conclusions: The present study demonstrates that the majority of clinical tcdA+B+ isolates of C. difficile frequently harbor tcdC genetic variants. We also found that the RT 001/ toxinotype 0 and the RT 126/ toxinotype V are the most common types among Iranian isolates. Further studies are needed to investigate the putative association of various tcdC genotypes with CDI severity and its recurrence.

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