Tolerogenic properties of the Fc portion of IgG and its relevance to the treatment and management of hemophilia

Abstract Hemophilia, or inherited genetic deficiencies in coagulation factors, results in uncontrolled bleeding requiring replacement therapy with recombinant proteins given preventively or on demand. However, a major problem with these approaches is the potential for development of immune responses to the administered proteins due to the underlying genetic deficiency of the factor(s) throughout life. As such, there is great interest in developing strategies that avoid immunogenicity and induce immune tolerance. Recently, recombinant factor VIII (rFVIII) and rFIX fused to the crystallizable fragment (Fc) domain of immunoglobulin G (IgG) have been developed as therapeutic agents for hemophilia A and B, respectively. Although it is well known that the possession of an Fc domain confers IgG’s longer-lasting circulating half-life, it is not generally appreciated that the Fc domain also confers immunoregulatory properties that are associated with the induction of tolerance. Here, we review some of the latest advances in our understanding of the tolerogenic abilities of IgG Fc and the impact of Fc-fusion proteins of rFVIII on the treatment of hemophilia.

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The Role of Age at First Exposure and Therapy Regimen on the Development of Neutralizing FVIII Antibodies in Hemophilia A.

Blood ◽

10.1182/blood.v104.11.3082.3082 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3082-3082 ◽

Cited By ~ 2

Author(s):

Carmen Escuriola Ettingshausen ◽

Alexandra Zyschka ◽

Inmaculada Martinez Saguer ◽

Christine Heller ◽

Thomas Klingebiel ◽

...

Keyword(s):

Hemophilia A ◽

Inhibitor Development ◽

Therapy Regimen ◽

On Demand ◽

Intron 22 Inversion ◽

Group 2 ◽

A Prospective Study ◽

The Impact ◽

Group 1

Abstract In order to assess the impact of age at first exposure to F VIII and therapy regimen on neutralizing FVIII-antibodies in previously untreated patients (PUP) with hemophilia A a prospective study was performed. Over a 23-years study period a total of 74 severely affected hemophilia A -PUPs have been consecutively recruited, treated with F VIII and investigated for inhibitor development. The patients were divided into two groups according to their treatment regimen: Group 1 (n=23) started prophylaxis at the age of 1 year (before or immediately after the first relevant bleed). Group 2 (n=43) was treated on-demand or prophylaxis was started after more than 2 bleeds. The following parameters were equally distributed among both groups: caucasian ethnicity, intron-22-inversion, age at 1st ED >0.5 years. Out of 74 hemophilia A patients 23 developed inhibitors (31%). Inhibitor incidence was 0% (1 transient inhibitor out of 23 patients) in those patients who received early prophylaxis (group 1) and 42% (18/43 patients) in case of delayed prophylaxis or on-demand treatment (group 2) (p=0.002). No linear correlation was found between the age at first exposure and inhibitor formation. However, patients treated before the age of 0.5 years showed a significantly higher inhibitor incidence (62%) than those treated at an more advanced age. Our data confirm that very early age at first exposure is a risk factor for inhibitor development in severe hemophilia A patients. Early prophylaxis might be protective against inhibitor development. To confirm the data a larger patient cohort has to be investigated.

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An Insight into the Impact of Hemophilia a on Daily Life According to Disease Severity: A Preliminary Analysis of the CHESS II Study

Blood ◽

10.1182/blood-2020-136952 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-3

Author(s):

Declan Noone ◽

Francis Nissen ◽

Tao Xu ◽

Tom Burke ◽

Sohaib Asghar ◽

...

Keyword(s):

Board Of Directors ◽

Disease Severity ◽

Research Funding ◽

Hemophilia A ◽

Daily Life ◽

Social Activity ◽

Publicly Traded ◽

Advisory Committees ◽

On Demand ◽

The Impact

Introduction: Hemophilia A (HA) is a congenital bleeding disorder caused by a deficiency in clotting factor VIII (FVIII). There are currently limited data on the impact of HA on daily life. Here we examine the impact of HA on the daily life of adult persons with HA (PwHA) without current FVIII inhibitors according to disease severity. Methods: The Cost of Haemophilia in Europe: a Socioeconomic Survey II (CHESS II) is a retrospective, burden-of-illness study in adults with mild, moderate, and severe HA or hemophilia B (defined by endogenous FVIII/IX [IU/dL] relative to normal; mild, 5-<40%; moderate, 1-5%; severe, <1%); this analysis includes only PwHA. Male participants (aged ≥18 years) diagnosed with HA (without FVIII inhibitors) at least 12 months prior to clinical consultation were enrolled from Denmark, France, Germany, Italy, the Netherlands, Romania, Spain, and the UK. Data on clinical outcomes and healthcare resource utilization were captured via electronic case report forms disseminated to hemophilia specialists. PwHA completed a paper-based questionnaire utilizing 5-point Likert scales to assess the disease burden on their daily life. Overall, 12 months' retrospective data were examined. Informed consent was obtained and the study was approved by the University of Chester ethical committee. Results: Of 258 PwHA completing questionnaires, 15.9% (n=41), 27.9% (n=72), and 56.2% (n=145) had mild, moderate, and severe HA, respectively. Of those with severe HA, 60.0% were currently receiving FVIII prophylaxis (standard of care for severe HA); in comparison, 4.9% and 6.9% of those with mild and moderate HA were receiving prophylaxis (Table 1). Treatment adaptation in anticipation of physical or social activity was reported by 19.5%, 23.6%, and 38.6% of those with mild, moderate, and severe HA, respectively. Over a third of participants with mild (36.6%) and moderate (44.4%) HA, and 64.8% of those with severe HA (58.6% with severe HA receiving on-demand treatment and 69.0% receiving prophylaxis) agreed or strongly agreed that HA had reduced their physical activity (Figure 1). Overall, 38.9% of those with moderate HA and 58.6% of those with severe HA (63.8% with severe HA receiving on-demand treatment and 55.2% receiving prophylaxis) agreed or strongly agreed that their HA had reduced their social activity; this was less pronounced in mild HA (9.8%). Additionally, 31.7%, 36.1%, and 64.1% of those with mild, moderate, and severe HA (62.1% with severe HA receiving on-demand treatment and 65.5% receiving prophylaxis) agreed or strongly agreed that their HA had caused them to miss opportunities. Correspondingly, frustration due to HA was felt by 19.5%, 34.7% and 57.9% (56.9% with severe HA receiving on-demand treatment and 58.6% receiving prophylaxis) of people, respectively. When asked whether they believed their daily life was compromised due to their hemophilia, 24.4%, 37.5%, and 63.4% of those with mild, moderate, and severe HA, respectively, agreed. Pain, as reported by the physician, was noted in 36.6% of people with mild HA (100% was reported as 'mild'); in people with moderate HA, pain was reported as 'mild', 'moderate', and 'severe' in 44.4%, 20.8%, and 1.4% of PwHA, respectively. In people with severe HA, pain was reported as 'mild', 'moderate', and 'severe' in 39.7%, 27.6%, and 8.6% for those receiving on-demand treatment, and 37.9%, 32.2%, and 8.0% for those receiving prophylaxis, respectively. Conclusions: In all disease severity groups, there was a notable group of PwHA that felt that they have had to reduce their physical and social activity, have had fewer opportunities and are frustrated due to their disease. While the impact on daily life is most pronounced in people with severe HA (including those receiving on-demand treatment and those receiving prophylaxis), it is also apparent in mild and moderate HA, indicating that there may be an unmet medical need in these groups. Disclosures Noone: Healthcare Decision Consultants: Membership on an entity's Board of Directors or advisory committees; Research Investigator PROBE: Research Funding; European Haemophilia Consortium: Membership on an entity's Board of Directors or advisory committees. Nissen:F. Hoffmann-La Roche Ltd: Current Employment; Actelion: Consultancy; Novartis: Research Funding; GSK: Research Funding. Xu:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Burke:University of Chester: Current Employment; HCD Economics: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Asghar:HCD Economics: Current Employment. Dhillon:F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. ; HCD Economics: Current Employment. Aizenas:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. O'Hara:HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy. Khair:Biomarin: Consultancy; HCD Economics: Consultancy; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medikhair: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Haemnet: Membership on an entity's Board of Directors or advisory committees.

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Patterns of Prior Treatment and Bleeds Among Patients with Severe Hemophilia a: Impact on Frequency of Dosing with Bay 81-8973 in the Leopold I Trial

Blood ◽

10.1182/blood.v126.23.1103.1103 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1103-1103 ◽

Cited By ~ 1

Author(s):

Nikki Church ◽

Rajeev Ayyagari ◽

Jennifer Pocoski ◽

Gautam Sajeev ◽

Sneha S Kelkar ◽

...

Keyword(s):

Factor Viii ◽

Research Funding ◽

Hemophilia A ◽

Prior Treatment ◽

Recombinant Factor Viii ◽

Average Dose ◽

Severe Hemophilia ◽

On Demand ◽

Dosing Frequency ◽

The Impact

Abstract Background: BAY 81-8973 is an investigational recombinant factor VIII (FVIII) product with recommended prophylactic dosing of 20-40 IU/kg at least 2x or 3x weekly for patients with severe hemophilia A. The frequency of dosing with FVIII is among several decisions made by treating physicians and potentially affects effectiveness and cost. The impact of prior bleeds or prior FVIII treatment on the choice of BAY 81-8973 dosing frequency has not been studied previously and may help clarify the association of dosing frequency with effectiveness. This study examines the association between prior treatment patterns and bleeds with dose frequency assignment in patients from the LEOPOLD I (LEO I) trial. Methods: Data from part B of the phase II/III randomized, open-label crossover LEO 1 trial were analyzed. The sample consisted of patients who received prophylactic treatment with BAY 81-8973 during the 12-month LEO I study period. At study start, patients were assigned to a dose and a frequency of either 2x/week or 3x/week at the investigator's discretion; once assigned, the dose and frequency were unchanged through the study period. This analysis compared physician-recorded pre-enrollment FVIII treatment frequencies and bleeds during the last 12 months prior to enrollment between the 2x/week and 3x/week groups. Wilcoxon rank sum tests were used to compare average dose per FVIII injection and number of bleeds, and chi-square tests were used for mode of treatment (on-demand or prophylaxis) and FVIII treatment frequencies. Results: Among 62 patients in the trial, mean age was 31.5 years and 89% were Caucasians. FVIII prophylaxis frequencies ranged from daily to 1x/week prior to enrollment. 11 patients in the 2x/week group had received pre-enrollment FVIII prophylaxis at a frequency of 2x/week (Table 1). 28 patients in the 3x/week group had received FVIII injections at a frequency of 3x/week prior to enrollment. Some of these patients in each group had also received pre-enrollment FVIII prophylaxis at other frequencies. Average FVIII doses per injection in IU/kg were higher in the 2x/week group for prior on-demand and prophylactic therapy, but these differences were not statistically significant. The majority of patients in the 2x/week group (56%) and the 3x/week group (59%) had received Bayer's sucrose-formulated recombinant factor VIII prior to enrollment. Regardless of prior mode of treatment, the average number of bleeds in the last 12 months before enrollment was higher in the 3x/week group (13.4 bleeds) than in the 2x/week group (7.1 bleeds). Conclusions: Investigator selection of 2x/week or 3x/week dosing frequency was correlated with the regimen patients were on prior to enrollment. Patients receiving FVIII 3x/week had, overall, more frequent bleeding episodes than patients in the 2x/week group in the year prior to enrollment, suggesting that a phenotypic approach can well be used for dosing with Bay 81-8973. Disclosures Church: Bayer Healthcare Pharmaceuticals: Employment. Ayyagari:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding. Pocoski:Bayer Healthcare Pharmaceuticals: Employment. Sajeev:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding. Kelkar:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding. Du:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding. Mass-Enriquez:Bayer Healthcare Pharmaceuticals: Employment. Xie:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding.

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Application of Pharmacokinetics Programs in Optimization of Haemostatic Treatment in Severe Hemophilia a Patients: Changes in Consumption, Clinical Outcomes and Quality of Life

Blood ◽

10.1182/blood.v124.21.1502.1502 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1502-1502

Author(s):

María Eva Mingot-Castellano ◽

Dana Díaz-Canales ◽

Rocio Tamayo-Bermejo ◽

Ana Isabel Heiniger-Mazo

Keyword(s):

Quality Of Life ◽

Hemophilia A ◽

Annual Rate ◽

Routine Practice ◽

Daily Routine ◽

Severe Hemophilia ◽

Bleeding Events ◽

On Demand ◽

The Impact

Abstract BACKGROUND: Replacement therapy with factor VIII (FVIII) in patients with severe hemophilia A has a high cost. To optimize this consumption without an increase in bleeding events or a delay in the recovery of these bleeds is a question of great interest for any Health System. The tools we have to tailor this treatment are clinical evolution, the use of trough levels and lately pharmacokinetic (PK) programs. OBJECTIVES: To evaluate the impact of a FVIII dose adjustment program using pharmacokinetic (PK) in daily routine practice: To analyse FVIII consumption in different treatment schedules (prophylaxis and demand) before and after the adjustment dose using PK programs.In subjects under prophylaxis scheme of treatment, to assess if this setting changes the annual rate of bleedings.To assess changes in quality of life after applying PK adjustment. PATIENTS AND METHODS: Between January 2006 and December 2013, we performed pharmacokinetic studies in adult patients with severe hemophilia A (FVIII less than 1%) and no history of inhibitor that have changed from one FVIII product to a different one in our centre. The program is a Bayesian PK analysis. FVIII levels were determined by one-stage method. Samples were taken 30 minutes (recovery non used for PK), 6, 12, 24 and 48 hours after FVIII 50ui/kg infusion. After PK study, subjects on prophylaxis were evaluated every two months to adjust scheme of treatment to trough FVIII levels between 1 to 3% in absence of bleeding. After getting the established dose patients were reviewed every 6 months. Patients on demand were evaluated every 10 to 15 doses until they got 50 doses, and then every 12 months. Demographic and diagnostic data of patients were recorded for inclusion in the program. Information about FVIII consumption and bleeding events comes from patient diaries (PD) and records from Hospital Pharmacy Department. Quality of life (QoL) was analysed using the A 36 Hemophilia-QoL questionnaire (Spanish validated version). Our Centre Ethics Committee approved the project. Everything has been done according to the Declaration of Helsinki. Patients signed written informed consent. RESULTS: Of the 16 patients included in the program only 14 have been evaluable. The excluded ones did not complete DP or CV properly. Mean age of the analysed patients was 31.7+/-9.4 years old. Mean body mass index was 25+/-2.7m2. 85% of patients suffer from haemophilic arthropathy according to Petterson Score (knee 57%, elbows 57%, ankles 85%). Four patients have been moved from plasma derived FVIII (pdFVIII) to other pdFVIII and 10 from pdFVIII to recombinant FVIII (rFVIII). Regarding to treatment regimens, 6 patients were changed from on demand to tertiary prophylaxis, 4 maintained their secondary prophylaxis and 4 continued on demand after the change of factor. The prophylaxis frequencies of infusions were every 48 hours in 2 patients, twice a week in 3 and 3 times a week in 5 of them. The mean volume of distribution, half-life (T1/2) and FVIII clearance (Acl) were 56.2±19 ml/kg, 12.9±5.9 h and 3.4±1.4 ml/kg. We found a correlation between age (p 0.03) and levels of vWF:RCo (p 0.02) with Acl. No correlation was found with body surface or VWF:Ag. Patients treated with pdFVIII have lower Acl and T1/2, 2.05 vs 3.9ml/kg (p 0.015) and 18.5 vs 10.6 h (p0.01) respectively. After trough level evaluation no increase of dose was necessary and only 2 patients decreased PK dose. The implementation of PK study has saved 20.3% of FVIII units in subjects on prophylaxis, mean and SD of pre and post PK FVIII consumption was 3137.3+/-387.9 IU/kg/year vs 2501.2+/-308.4 IU/kg/year (p 0.005). There was no change in the annual rate of bleedings after PK adjustment (2.33+/-1.2 vs 2+/-2.6, p 0.321). We found no changes in consumption in subject on demand after PK. There was an improvement in all domains of QoL test (p<0.0001) in subjects who changed from on demand to prophylaxis. This seems not to be related with PK but to prophylaxis that induces a decrease in the annual rate of bleeding of 78.5% (p 0.002). Two patients developed transitory low inhibitor titer after FVIII change with no clinical implications. CONCLUSION: In our experience, the implementation of PK programs in the treatment of severe hemophilia A reduces FVIII consumption and optimizes schemes of prophylaxis. This saving does not modify bleeding rate or quality of life of patients. Disclosures No relevant conflicts of interest to declare.

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Changing the Paradigm in Hemophilia Care: Extended Half-Life Products (rFVIIIFc and rFIXFc)

Blood ◽

10.1182/blood-2018-99-114905 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3514-3514 ◽

Cited By ~ 1

Author(s):

Louis M. Aledort ◽

Nisha Jain ◽

Nanxin Li ◽

Sangeeta Krishnan ◽

Benjamin Hagberg ◽

...

Keyword(s):

Half Life ◽

Hemophilia A ◽

The Other ◽

Treatment Regimens ◽

On Demand ◽

Fda Approval ◽

The Us ◽

Joint Health ◽

Viii And Ix ◽

The Impact

Abstract Background: Prophylactic treatment with factor products has demonstrated superior outcomes and care compared to on-demand treatment in hemophilia patients, including patients with pre-existing joint diseases. However, 40% to 50% of severe or moderate hemophilia A and B patients are still treated on-demand in the US. Recombinant factor VIII and IX Fc fusion proteins (rFVIIIFc and rFIXFc) were the first extended half-life (EHL) products approved in the US (in 2014) with the promise of optimizing prophylactic regimens by achieving low bleeding rates and improving joint health with fewer injections overall. Objective: This is the first real-world study to assess the impact of EHL rFVIIIFc and rFIXFc on overall prophylaxis rates, particularly to understand how patients have transitioned from on-demand treatment. Methods: A retrospective analysis was conducted on aggregate, de-identified United States Specialty Pharmacy Provider (SPP) records from Jan 2014 to June 2018 (data pull on June 14th, 2018). Adult hemophilia patients (age 18 and above) were included for an analysis of treatment regimens prior to and after switching to EHL rFVIIIFc and rFIXFc (on-demand or prophylaxis). The results were descriptively compared to those who switch to the other EHL PEGylated rFVIII and rFIX albumin Fusion Protein (rFIX-FP) and conventional factors. Results: A total of 304 hemophilia A patients who switched to rFVIIIFc and 133 hemophilia B patients who switched to rFIXFc were included in this study. For the hemophilia A and B patients, the median age was 31 and 32 years and median weight was 82 and 79 kg. The proportion of patients who switched from on-demand treatment with conventional factors to prophylaxis treatment with EHL rFVIIIFc and rFIXFc among all patients who switched to these products increased over time since the FDA approval (3 time points: 2014-2015, 2016-2017, and 2018: rFVIIIFc: 13%, 20%, and 21%; rFIXFc: 25%, 29%, and 57%). Such proportions were higher compared to those who switched from on-demand with conventional factors to prophylaxis with the other EHLs (2016-2017, 2018: PEGylated rFVIII: 16%, 18%; rFIX-FP: 18%, 13%, see comparison in the Figure) and with conventional factors (2014-2015, 2016-2017, and 2018: conventional rFVIII: 10%, 7%, and 9%; conventional rFIX: sample size was too small and not suitable for analysis). Discussion: rFVIIIFc and rFIXFc have transformed the paradigm of hemophilia care by shifting on demand patients to prophylaxis significantly faster than conventional factors and any other EHLs to date. This shift is significant as it is helping more hemophilia patients achieve optimal protection through low bleeding rates and improved joint health over the long-term. Figure. Figure. Disclosures Jain: Bioverativ: Employment. Li:Bioverativ: Employment. Krishnan:Bioverativ: Employment. Hagberg:Bioverativ: Employment. Su:Bioverativ: Employment.

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Prophylaxis in Patients with Hemophilia a and Its Impact on Quality of Life Using the Specific Index Haem-a-Qol at a Hospital in Paraguay

Blood ◽

10.1182/blood.v128.22.4959.4959 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4959-4959

Author(s):

Cristobal A Frutos ◽

Barbara Konkle ◽

Jorge Batista ◽

Silvia Brizuela ◽

Elvira Enciso ◽

...

Keyword(s):

Quality Of Life ◽

Physical Health ◽

Prophylactic Treatment ◽

Hemophilia A ◽

Minor Trauma ◽

Severe Hemophilia ◽

On Demand ◽

Bleeding Episodes ◽

The Impact

Abstract Prophylactic replacement therapy with FVIII is considered the standard of care for patients with hemophilia although a protocol for administering the prophylaxis has yet to be defined by the World Federation of Hemophilia. Gaona in 2012 demonstrated a significant reduction in the number of hospitalizations due to bleeding episodes in patients with Hemophilia A treated with secondary prophylaxis at the Hematology Service of the Hospital Central del Instituto de Prevision Social (HCIPS) with a regimen of 25 IU/Kg per week in two infusions by reporting results from such regimen that had started at the HCIPS in 2010. This is a lower dose to those most frequently used in high resource countries like the Malmo or Utrecht protocols. The goal of this study was to assess the impact of our lower dose prophylaxis regimen on bleeding events, hospitalizations and quality of life as an alternative for low resource countries that cannot afford to provide their patients with higher dose treatments. The Dutch group Haemo-QoL designed the specific questionnaire for adult patients with hemophilia, the Haem-A-QoL with a Spanish version available for patients aged 17 and up. Results: The HCIPS currently has 36 patients receiving prophylactic treatment with FVIII. From these 18 patients consented to filling out the questionnaire. The mean age of the patients was 28. 3 of the patients were married, 2 were in a stable relationship and 13 were single. 62% of patients lived within 20 km of the Hospital and 38% lived further away going up to 200 km. 17 of the 18 patients had the highest level of education possible for their age. Only one patient, the oldest one, had stopped his education at primary school. All of them had severe disease with one or more affected joints. The average FVIII use per year was 68,000 IU ranging from 8,000 IU to 96,000 IU or 917 IU/kg/year. The strongest determinant for receiving less FVIII was missing appointments. Distance to the Hospital was not of significance. Bleeding episodes prior to prophylactic treatment was 2-3 minor traumatic bleeding episodes per week (after brushing their teeth, easy bruising from minor trauma), 2-3 joint bleeds per month at which point they would seek medical assistance and 1-2 major bleeding episodes per year requiring hospitalization. In the last year 5 patients were hospitalized once. One for pneumonia, one for phlebitis, one for dengue fever and two for hemathrosis. They reported a decrease in bleeding episodes at home from 2-3 joint bleeds per month to 1 every other month. Patients reported after traumatic events their bleeding was "normal" (i.e. when brushing their teeth if they started bleeding they would continue bleeding for days at a time whereas when in prophylaxis they would bleed right after the brushing and then it stopped which they took to be normal). Converting the results from the Haem-A-QoL questionnaire to a scoring system of 1-100 being 1 the best QoL and 100 the worst, the average QoL was 52. With scores of 60 for physical health, 50 for feelings, 52 for view of themselves, 48 for work/school, 53 for treatment, 56 for future, 47 for family planning and 45 for dating. Scores for sports and leisure though only amounting to 64, 33% of patients said that category did not apply to them since they did not practice any sports and the dealing category with a score of 37 was the lowest of all. When compared to results published by a Blood Center in Brazil with an on demand regimen patients with severe hemophilia in that study showed a physical health score of 55, 40 for feelings, 35 for self-perception, 60 for sports and leisure, 35 for work and school, 20 for coping, 45 for treatment, 45 for future and 25 for dating with an average overall score of 40. With an annual average usage of 63,683 IU on the severely affected patients. In summary, the proposed dosing of 25IU/kgs/week seems at first glance to reduce bleeding episodes among patients with severe hemophilia as well as hospitalizations. In general patients treated at the HCIPS have a regular to poor quality of life as measured by the Haem-A-QoL questionnaire which contrasts with results from the Brazilian study on quality of life from patients with on demand treatment and roughly same FVIII usage per year showing their patients with severe hemophilia had an overall quality of life from regular to good. Perhaps the psychological factor comes in to play? A follow up study after patients receive proper psychological evaluations may help clarify results. Disclosures No relevant conflicts of interest to declare.

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Impact of influenza virus during pregnancy: from disease severity to vaccine efficacy

Future Virology ◽

10.2217/fvl-2020-0024 ◽

2020 ◽

Vol 15 (7) ◽

pp. 441-453

Author(s):

Ana Vazquez-Pagan ◽

Rebekah Honce ◽

Stacey Schultz-Cherry

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Immune Responses ◽

Pregnant Women ◽

Disease Severity ◽

Influenza A ◽

Antiviral Treatment ◽

Influenza Virus Infection ◽

Severe Influenza ◽

The Impact

Pregnant women are among the individuals at the highest risk for severe influenza virus infection. Infection of the mother during pregnancy increases the probability of adverse fetal outcomes such as small for gestational age, preterm birth and fetal death. Animal models of syngeneic and allogeneic mating can recapitulate the increased disease severity observed in pregnant women and are used to define the mechanism(s) of that increased severity. This review focuses on influenza A virus pathogenesis, the unique immunological landscape during pregnancy, the impact of maternal influenza virus infection on the fetus and the immune responses at the maternal–fetal interface. Finally, we summarize the importance of immunization and antiviral treatment in this population and highlight issues that warrant further investigation.

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Oxidative Stress Compromises Lymphocyte Function in Neonatal Dairy Calves

Antioxidants ◽

10.3390/antiox10020255 ◽

2021 ◽

Vol 10 (2) ◽

pp. 255

Author(s):

Wilmer Cuervo ◽

Lorraine M. Sordillo ◽

Angel Abuelo

Keyword(s):

Oxidative Stress ◽

Immune Responses ◽

Immune Cell ◽

Lymphocyte Activation ◽

Dairy Calves ◽

Lymphocyte Function ◽

Newborn Calves ◽

Ifn Γ ◽

The Impact

Dairy calves are unable to mount an effective immune response during their first weeks of life, which contributes to increased disease susceptibility during this period. Oxidative stress (OS) diminishes the immune cell capabilities of humans and adult cows, and dairy calves also experience OS during their first month of life. However, the impact that OS may have on neonatal calf immunity remains unexplored. Thus, we aimed to evaluate the impact of OS on newborn calf lymphocyte functions. For this, we conducted two experiments. First, we assessed the association of OS status throughout the first month of age and the circulating concentrations of the cytokines interferon-gamma (IFN-γ) and interleukin (IL) 4, as well as the expression of cytokine-encoding genes IFNG, IL2, IL4, and IL10 in peripheral mononuclear blood cells (PBMCs) of 12 calves. Subsequently, we isolated PBMCs from another 6 neonatal calves to investigate in vitro the effect of OS on immune responses in terms of activation of lymphocytes, cytokine expression, and antibody production following stimulation with phorbol 12-myristate 13-acetate or bovine herpesvirus-1. The results were compared statistically through mixed models. Calves exposed to high OS status in their first month of age showed higher concentrations of IL-4 and expression of IL4 and IL10 and lower concentrations of IFN-γ and expression of IFNG and IL2 than calves exposed to lower OS. In vitro, OS reduced lymphocyte activation, production of antibodies, and protein and gene expression of key cytokines. Collectively, our results demonstrate that OS can compromise some immune responses of newborn calves. Hence, further studies are needed to explore the mechanisms of how OS affects the different lymphocyte subsets and the potential of ameliorating OS in newborn calves as a strategy to augment the functional capacity of calf immune cells, as well as enhance calves’ resistance to infections.

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