Manish Butte

Host-Pathogen Interactions in Coccidioidomycosis: Prognostic Clues and Opportunities for Novel Therapies.

Clin Ther. 2019 Oct 21;:

Authors: Krogstad P, Johnson R, Garcia-Lloret MI, Heidari A, Butte MJ

Abstract
PURPOSE: Coccidioidomycosis (CM) is a systemic fungal disease caused by the dimorphic fungi Coccidioides immitis and Coccidioides posadasii. In its endemic areas of the United States, CM is growing as a public health challenge with a marked increase in incidence in the last 15 years. Although Coccidioides infection is asymptomatic in most cases, symptomatic pulmonary disease occurs in ~40% and disseminated coccidioidomycosis (DCM) occurs in ~1% of previously healthy children and adults. DCM is markedly more common in immunocompromised people, who often experience life-threatening disease despite use of antifungal medications. Although options for antifungal therapy have improved, lifelong therapy is needed for those who develop coccidioidal meningitis. The purpose of this article was to review the state of antifungal therapy and recent studies of host-pathogen interactions in CM in light of advances in immunomodulatory therapy.
METHODS: The study included a review of PubMed and abstracts of the Coccidioidomycosis Study Group (years 2000-2019).
FINDINGS: Current therapy for CM relies upon azole and polyene antifungal agents. Murine models and studies of DCM in patients with monogenic primary immunodeficiency states and acquired immunodeficiency have revealed the importance of both innate and adaptive immune responses in the control of infections with Coccidioides species. In particular, defects in sensing of fungi and induction of cellular immune responses have been frequently reported. More recently, polymorphisms in key signaling pathways and in the generation of Th17 and Th1 immune responses have been linked with DCM.
IMPLICATIONS: Antifungal therapy is sufficient to control disease in most cases of CM, but treatment failure occurs in cases of severe pulmonary disease and nonmeningeal disseminated disease. Lifelong therapy is recommended for meningitis in view of the very high risk of recurrence. Corticosteroid therapy is advised by some experts for severe pulmonary disease and for some neurologic complications of DCM. DCM is only rarely the result of a severe monogenic immunodeficiency. Case studies suggest that reorienting cellular immune responses or augmenting effector immune responses may help resolve DCM. Systematic investigation of immunotherapy for coccidioidomycosis is advisable and may help to address the recent marked increase in reports of the disease in endemic areas.

PMID: 31648806 [PubMed – as supplied by publisher]

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Postoperative Antibiotic Use Among Patients Undergoing Functional Facial Plastic and Reconstructive Surgery.

JAMA Facial Plast Surg. 2019 Oct 24;:

Authors: Olds C, Spataro E, Li K, Kandathil C, Most SP

Abstract
Importance: Best practices for antibiotic use after facial plastic and reconstructive procedures have been the subject of much debate, and there is a need for large-scale data to guide further development of evidence-based guidelines for antibiotic use in this setting.
Objective: To assess patterns of postoperative antibiotic prescriptions and infection rates after nasal and oculoplastic procedures.
Design, Setting, and Participants: A retrospective population-based cohort study was conducted using IBM MarketScan Commercial and Medicare Supplemental research databases of 294 039 patients who underwent facial plastic surgery procedures between January 1, 2007, and December 31, 2015. Patients were excluded if they were younger than 18 years, lacked continuous insurance coverage for 1 year before and after the procedure, or underwent additional procedures on the surgery date of interest. Statistical analysis was performed from January 1, 2007, to December 31, 2016.
Main Outcomes and Measures: Primary outcomes were antibiotic prescription patterns in the immediate postoperative period and rates of postoperative infectious complications. Explanatory variables included patient demographics, procedure type, and relevant comorbidities, which were used in multivariable logistic regression analysis.
Results: Of the 294 039 patients who met inclusion criteria (55.9% women and 44.1% men; mean [SD] age, 54.0 [18.6 years]), 45.2% filled prescriptions for postoperative antibiotics, including 55.3% of patients undergoing nasal procedures and 14.7% of patients undergoing oculoplastic procedures. Superficial surgical site infections occurred in 1.6% of patients, while deep surgical site infections occurred in 0.3% of patients. On multivariable logistic regression, patients receiving postoperative antibiotics were at significantly decreased risk of postoperative infections (nasal procedures: adjusted odds ratio [aOR], 0.144 [95% CI, 0.102-0.203]; oculoplastic procedures: aOR, 0.254 [95% CI, 0.104-0.622]) compared with those who did not receive postoperative antibiotics. Increased duration of postoperative antibiotics was not associated with reduced rates of infectious complications (nasal procedures: aOR, 1.000 [95% CI, 0.978-1.022]; oculoplastic procedures: aOR, 1.024 [95% CI, 0.959-01.092]). Despite being more likely to experience postoperative infections, patients with a history of tobacco use (aOR, 0.806 [95% CI, 0.747-0.870]), immunodeficiency (aOR, 0.774 [95% CI, 0.737-0.813]), or type 1 or 2 diabetes (aOR, 0.810 [95% CI, 0.772-0.850]) were less likely to be prescribed antibiotics than those without these conditions.
Conclusions and Relevance: Postoperative antibiotic prescriptions were associated with reduced rates of infections after facial plastic surgery. This study highlights the role of population-level data in the development of best practices for postoperative antibiotic use and identifies the need for additional examination of antibiotic use patterns and recommendations for populations at increased risk for postoperative wound infection.

PMID: 31647506 [PubMed – as supplied by publisher]

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Transient derangements in Hepatitis B serology in patients post-intravenous immunoglobulin therapy-a case-based review.

Ir J Med Sci. 2019 Oct 23;:

Authors: King C, Sutton-Fitzpatrick U, Houlihan J

Abstract
Intravenous immunoglobulin (IVIg) is a commonly utilized therapy in multiple medical subspecialities, indicated for the management of various primary and secondary immunodeficiency states and autoimmune and inflammatory conditions. A lack of awareness exists among clinicians regarding the serological downstream effects of its use. An observed phenomenon post-IVIg is the passive transfer of antibodies from the product which can lead to transiently positive hepatitis B serology in recipients. When confounding viral serology is encountered, there is a risk to patients of treatment delays and mismanagement. Three patients encountered in the hematology department of a tertiary referral hospital developed spurious hepatitis B serology after administration of IVIg, whose cases are briefly outlined here. These cases highlight the need for routine pre-treatment viral screening and emphasize the importance of clinicians recognizing such potentially confounding results. This is of particular relevance to the sizeable subset of hematology patients who are planned for future immunomodulatory treatment (such as rituximab), where previous hepatitis B infection can often be a barrier to timely treatment.

PMID: 31643027 [PubMed – as supplied by publisher]

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Impact of IVIG vs. SCIG on IgG trough level and infection incidence in primary immunodeficiency diseases: A systematic review and meta-analysis of clinical studies.

World Allergy Organ J. 2019 Oct;12(10):100068

Authors: Shrestha P, Karmacharya P, Wang Z, Donato A, Joshi AY

Abstract
Background: Monthly intravenous immunoglobulin (IVIG) and weekly subcutaneous immunoglobulin (SCIG) have been regarded as therapeutically equivalent treatments for primary immunodeficiency diseases (PIDD). Immunoglobulin G (IgG) trough level is used as a monitoring measure for infection prevention.
Objective: A systematic review and meta-analysis were performed to elucidate the relationship between IgG dosing, trough IgG levels with overall infection incidence in patients with PIDD receiving IVIG and SCIG therapy.
Methods: Medline, EMBASE, Cochrane, Central, and Scopus were searched for studies published from Jan 2010-June 2018, fulfilling the inclusion criteria. DerSimonian and Laird random-effects method were used to pool the difference of IgG trough levels. Random-effect meta-regression was used to evaluate infection incidence per 100 mg/dl IgG trough increase though IVIG and SCIG.
Results: Out of 24 observational studies included, 11 compared IgG trough levels among SCIG and IVIG (mean difference: 73.4 mg/dl, 95% CI: 31.67-119.19 mg/dl, I2 = 45%, p = 0.05), favoring weekly SCIG. For every 100 mg/dl increase in the trough, a linear trend of decreased incidence rates of infection was identified in SCIG patients (p = 0.03), but no similar trend was identified in trough levels vs. infection rates for patients receiving IVIG (p = 0.67).
Conclusion: In our study, weekly SCIG attained a higher trough level in comparison to monthly IVIG. Higher SCIG troughs were associated with lower infection rates, while IVIG troughs demonstrated no relationship.

PMID: 31641401 [PubMed]

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A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation.

Nat Commun. 2019 Oct 21;10(1):4779

Authors: Tavernier SJ, Athanasopoulos V, Verloo P, Behrens G, Staal J, Bogaert DJ, Naesens L, De Bruyne M, Van Gassen S, Parthoens E, Ellyard J, Cappello J, Morris LX, Van Gorp H, Van Isterdael G, Saeys Y, Lamkanfi M, Schelstraete P, Dehoorne J, Bordon V, Van Coster R, Lambrecht BN, Menten B, Beyaert R, Vinuesa CG, Heissmeyer V, Dullaers M, Haerynck F

Abstract
Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.

PMID: 31636267 [PubMed – in process]

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Meningococcal Serogroup B Disease in Vaccinated Children.

J Pediatric Infect Dis Soc. 2019 Oct 21;:

Authors: Soler-Garcia A, Fernández de Sevilla M, Abad R, Esteva C, Alsina L, Vázquez J, Muñoz-Almagro C, Noguera-Julian A

Abstract
BACKGROUND: Neisseria meningitidis serogroup B (MenB) is the most frequent cause of invasive meningococcal disease (IMD) in Spain. The multicomponent vaccine against MenB (4CMenB) was approved in Spain in January 2014.
METHODS: We present 4 cases of children who developed MenB-associated IMD despite previous vaccination with 4CMenB. Extensive immunologic diagnostic work-up was performed in order to rule out any immunodeficiency. Also, molecular characterization of the MenB strain was conducted to determine whether bacterial antigens matched vaccine antigens.
RESULTS: Among the 4 patients (2 girls), 2 had previous risk factors for IMD (recurrent bacterial meningitis of unknown origin and treatment with eculizumab). All patients developed meningitis, but only 2 developed septic shock; they were all cured without sequelae. No other primary or secondary immunodeficiencies were detected. MenB sequence type 213 was identified in 3 cases. With the exception of neisserial heparin-binding antigen peptide 465 present in 1 isolate, the rest of the isolated strains harbored vaccine antigen variants that did not match antigen variants included in the vaccine.
CONCLUSIONS: We present 4 children who developed MenB-associated IMD despite previous vaccination with 4CMenB. In 2 cases, the antibodies induced by 4CMenB likely were not effective against the isolated strains. A high level of suspicion for IMD seems advisable regardless of the patient’s vaccination history.

PMID: 31634404 [PubMed – as supplied by publisher]

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Combined Immunodeficiency due to a loss of function mutation in DNA Polymerase Delta 1.

J Allergy Clin Immunol. 2019 Oct 16;:

Authors: Cui Y, Keles S, Charbonnier LM, Julé AM, Henderson L, Celik SC, Reisli I, Shen C, Xie WJ, Schmitz-Abe K, Wu H, Chatila TA

Abstract
BACKGROUND: Mutations affecting DNA polymerases have been implicated in genomic instability and cancer development, but the mechanisms by which they may impact the immune system remain largely unexplored.
OBJECTIVE: To establish the role of POLD1, encoding the DNA polymerase δ 1 catalytic subunit, as the cause of a primary immunodeficiency in an extended kindred.
METHODS: We performed whole-exome and targeted gene sequencing, lymphocyte characterization, molecular and functional analyses of the DNA polymerase delta (Polδ) complex, and T and B cell antigen receptor repertoire analysis.
RESULTS: We identified a missense mutation (c. 3178C>T; p.R1060C) in POLD1 in three related subjects who presented with recurrent, especially herpetic, infections and T cell lymphopenia with impaired T cell but not B cell proliferation. The mutation destabilizes the Polδ complex, leading to ineffective recruitment of replication factor C to initiate DNA replication. Molecular Dynamics simulation revealed that the R1060C mutation disrupts the intramolecular interaction between the POLD1 CysB motif and catalytic domain, and also between POLD1 and the DNA polymerase δ subunit POLD2. The patients exhibited decreased naïve CD4 and especially CD8 T cells in favor of effector memory subpopulations. This skewing was associated with oligoclonality and restricted T cell receptor beta chain V-J pairing in CD8+ but not CD4+ T cells, suggesting that POLD1R1060C differentially impacts peripheral CD8+T cell expansion and possibly thymic selection.
CONCLUSION: These results identify gene defects in POLD1 as a novel cause of T cell immunodeficiency.

PMID: 31629014 [PubMed – as supplied by publisher]

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Vaccine-Derived Poliovirus Infection among Patients with Primary Immunodeficiency and Effect of Patient Screening on Disease Outcomes, Iran.

Emerg Infect Dis. 2019 Nov;25(11):2005-2012

Authors: Shaghaghi M, Shahmahmoodi S, Nili A, Abolhassani H, Madani SP, Nejati A, Yousefi M, Kandelousi YM, Irannejad M, Shaghaghi S, Zahraei SM, Mahmoudi S, Gouya MM, Yazdani R, Azizi G, Parvaneh N, Aghamohammadi A

Abstract
Patients with immunodeficiency-associated vaccine-derived poliovirus (iVDPV) are potential poliovirus reservoirs in the posteradication era that might reintroduce polioviruses into the community. We update the iVDPV registry in Iran by reporting 9 new patients. In addition to national acute flaccid paralysis surveillance, cases were identified by screening nonparalyzed primary immunodeficiency (PID) patients. Overall, 23 iVDPV patients have been identified since 1995. Seven patients (30%) never had paralysis. Poliovirus screening accelerated the iVDPV detection rate in Iran after 2014.The iVDPV infection rate among nonparalyzed patients with adaptive PID was 3.1% (7/224), several folds higher than previous estimates. Severe combined immunodeficiency patients had the highest risk for asymptomatic infection (28.6%) compared with other PIDs. iVDPV2 emergence has decreased after the switch from trivalent to bivalent oral poliovirus vaccine in 2016. However, emergence of iVDPV1 and iVDPV3 continued. Poliovirus screening in PID patients is an essential step in the endgame of polio eradication.

PMID: 31625840 [PubMed – in process]

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Immune globulin subcutaneous, human – klhw 20% for primary humoral immunodeficiency: an open-label, Phase III study.

Immunotherapy. 2019 Oct 17;:

Authors: Sleasman JW, Lumry WR, Hussain I, Wedner HJ, Harris JB, Courtney KL, Mondou E, Lin J, Stein MR

Abstract
Aim: This prospective, Phase III study assessed the pharmacokinetics (PK), safety and tolerability of immune globulin subcutaneous, human – klhw 20% solution (IGSC-C 20%) in participants with primary humoral immunodeficiency (PI), compared with immune globulin injection (human), 10% caprylate/chromatography purified (IGIV-C 10%). Patients & methods: About 53 participants enrolled. Total 44 received IGIV-C 10% in the run-in phase and then entered the IV phase (with an additional nine who were already receiving IGIV-C 10% and entered the IV phase directly) for steady-state IV PK assessments. Total 49 entered the SC phase (weekly doses of IGSC-C 20% for ∼24 weeks). The PK profiles of IGIV-C 10% and IGSC-C 20% and their safety and tolerability parameters were compared. Results: At a dose adjustment factor of 1.37, IGSC-C 20% provided comparable (noninferior and bioequivalent) overall total immunoglobulin G exposure to IGIV-C 10% over an equal time interval. About 33 participants reported 79 adverse events during run-in + IV phases; 41 participants reported 141 adverse events during the SC phase, with most being local infusion site reactions. The majority of infusion site reactions were mild to moderate in severity. Conclusion: IGSC-C 20% was bioequivalent to IGIV-C 10% and was well tolerated, with a safety profile comparable with IGIV-C 10%, in this study. Trial registration: ClinicalTrials.gov identifier: NCT02604810.

PMID: 31621458 [PubMed – as supplied by publisher]

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Helping on call paediatricians to identify acute primary immunodeficiency diseases.

Acta Paediatr. 2019 Oct 16;:

Authors: Abrahamsen TG

PMID: 31621102 [PubMed – as supplied by publisher]

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