Subclinical Cytomegalovirus Reactivation in Patients With Newly Diagnosed or Relapsed ANCA-associated Vasculitis and Adverse Clinical Outcomes
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- To determine the frequency of CMV reactivation during the acute phase (first 12 months) following diagnosis or relapse of AAV and commencement of induction of remission therapy
研究概览
简要总结
This is a prospective observational study to determine the frequency and magnitude of Cytomegalovirus (CMV) reactivation in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) in the acute phase of the disease (within 12 months of diagnosis or relapse and commencement of induction of remission therapy) and its association with clinical outcomes. The investigators will also explore whether CMV reactivation causes an increase in CCR2 expressing monocytes, and whether these monocytes cause persistent kidney damage in AAV.
The investigators hypothesise that reactivation of CMV during the initial 12 months following diagnosis or relapse of AAV occurs frequently but is generally asymptomatic. Based on the investigators' preliminary data the investigators further hypothesise that subclinical reactivation of CMV during this period will be associated with adverse clinical outcomes, including the severity of vasculitis, the response to treatment and the damage caused by vasculitis. Finally, they hypothesise that subclinical CMV reactivation leads to amplification of renal damage in AAV through a monocyte CCR2/CCL2 driven pathway.
The investigators' research has recently shown that asymptomatic reactivation of CMV is a frequent event in AAV patients, occurring in roughly 25% of AAV patients in remission. However, the frequency of asymptomatic reactivation of CMV during the acute phase of the disease is not known. The investigators have previously shown that CMV infection and surrogate markers of CMV reactivation in patients with AAV are associated with worse outcomes such as reduced kidney function, increased risk of infection and death, increased risk of blood clots and increased stiffness of the blood vessels, which is a risk factor for heart disease and stroke. The investigators also have preliminary findings suggesting that in patients with AAV and CMV reactivation, the more CCR2 expressing monocytes in the blood, the worse the kidney function. If CMV reactivation during the acute phase of the disease is common and linked with worse outcomes, this study may then lead on to future research involving treatment to prevent CMV reactivation aiming to improve patient outcomes.
The investigators will be looking to recruit patients under the care of the Queen Elizabeth Hospital with newly diagnosed or recently relapsed AAV in the last 2 weeks who are positive for previous CMV infection.The investigators will follow these patients up with 10 visits over 12 months; where possible these will coincide with participants' usual vasculitis clinic appointments. At each visit the participants will be required to give blood and urine samples and answer questions related to their vasculitis. Kidney biopsy tissue taken at diagnosis will be used to assess mechanisms of injury during CMV reactivation.
详细描述
INTRODUCTION/BACKGROUND:
This is an observational study to determine the frequency and magnitude of CMV reactivation in patients with AAV in the acute phase of the disease (within 12 months of diagnosis or relapse and commencement of induction of remission therapy).
AAVs are systemic autoimmune inflammatory conditions characterized by necrotising inflammation affecting small to medium blood vessels leading to end-organ damage. Without treatment AAV is life-threatening; treatment involves powerful immunosuppression to induce remission, followed by maintenance treatment to prevent disease relapse. Treatment induction for both new-onset AAV and major life-threatening relapses is usually in the form of corticosteroids in combination with either cyclophosphamide or rituximab. Whilst prognosis has significantly improved with current treatment options for AAV, there remains significant morbidity and mortality associated with these conditions, especially during the first 12 months following diagnosis and commencement of induction of remission therapy. Infection is the leading cause of death within the first 12 months, accounting for approximately 50% of mortality as well as considerable morbidity and hospitalisation.
Cytomegalovirus (CMV) is a widely prevalent herpesvirus that is not cleared after primary infection and establishes a state of persistent infection. CMV is present in over half the population by middle age and is thought to undergo a state of latency with intermittent periods of viral reactivation. This can be a significant clinical problem amongst patients that receive immunosuppression for bone marrow or solid organ transplants. Although, patients with AAV are heavily immunosuppressed, symptomatic CMV disease is uncommon in this patient group (2%). However, asymptomatic reactivation is not uncommon. In a proof-of-concept study, the investigators have shown that asymptomatic subclinical reactivation of CMV is a frequent event amongst patients with stable AAV in remission, occurring in approximately 1 in 4 CMV seropositive AAV patients in remission over a 12-month period. The investigators and others have shown that asymptomatic CMV infection is associated with key adverse clinical outcomes amongst patients with AAV, such as reduced kidney function, increased risk of infection and mortality, increased risk of venous thromboembolism, and increased arterial stiffness, a marker of cardiovascular mortality.
The investigators have previously demonstrated that subclinical reactivation of CMV is associated with the expansion of a cytotoxic T-cell subset known as CD4+CD28null T-cells. Importantly, significant expansion of CD4+CD28null T-cells is exclusively seen in CMV seropositive patients. The investigators recently demonstrated that CD4+CD28null T-cells expansion is linked to a reduced functional capacity of the CD4 compartment and subsequent reduced response to the pneumonia vaccine, amongst patients with AAV in remission. Importantly, the investigators found that participants with evidence of subclinical CMV reactivation during the 6 months preceding the vaccination did not mount a response to the vaccine, but treatment with antiviral Valacyclovir suppressed CD4+CD28null T-cells expansion and suppression of CD4+CD28null T-cells was in itself associated with a better response to pneumococcal vaccination.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •New diagnosis of AAV as evidenced by relevant biopsy and / or clinical diagnosis in the context of a positive ANCA antibody OR major relapse of previously diagnosed AAV that requires re-induction of remission treatment with intravenous rituximab or cyclophosphamide together with high dose oral corticosteroids
- •Age >18 years
- •Willingness to participate in the study and attend clinic and study visits
- •Able to provide written informed consent
排除标准
- •Strong suspicion of alternative diagnosis other than AAV
- •Subjects who do not have capacity to consent to study participation as defined by the Mental Capacity Act 2005
- •Inability or unwillingness to attend study visits
结局指标
主要结局
To determine the frequency of CMV reactivation during the acute phase (first 12 months) following diagnosis or relapse of AAV and commencement of induction of remission therapy
时间窗: This will be assessed at month 12 (end of study)
As assessed by measurable viral load (titre \>20 viral copies/ml) on quantitative PCR assessment of any blood or urine sample during the 12 month study period
次要结局
- The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and patient well-being(This will be assessed at month 3 and month 12)
- The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and the incidence of non-CMV infections over the 12-month study period(This will be assessed at day 0, day 14, month 1, 2, 3, 4, 5, 6, 10 and 12)
- The correlation between subclinical CMV reactivation during the acute phase of AAV and the concentration of plasma markers of pro-coagulant activity(This will be assessed at baseline, month 3, 6, 10 and 12)
- The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and the concentration of urinary MCP-1 and CD163 across the study period(This will be assessed at day 0, day 14, month 1, 2, 3, 4, 5, 6, 10 and 12)
- The correlation between subclinical CMV reactivation during the acute phase of AAV and the concentration of plasma markers of inflammation(This will be assessed at baseline, month 3, 6, 10 and 12)
- The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and renal function at 12 months(This will be assessed at month 12.)
- The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and the Vasculitis Damage Index (VDI) at 12 months(This will be assessed at month 12)
- The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and the concentration of plasma CRP across the study period(This will be assessed at day 0, day 14, month 1, 2, 3, 4, 5, 6, 10 and 12)
- The correlation between subclinical CMV reactivation during the acute phase of AAV and the antibody response ratio following clinically recommended vaccinations at 8 weeks post-vaccination(Participants will be vaccinated with clinically indicated vaccinations as per standard of care at month 10. A plasma sample will be drawn immediately prior to vaccination and 2 months after vaccination (month 12))
- The correlation between subclinical CMV reactivation during the acute phase of AAV and the concentration of plasma markers of endothelial damage(This will be assessed at baseline, month 3, 6, 10 and 12)
- The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and urine albumin creatinine ratio (ACR) at 12 months(This will be assessed at month 12.)
- The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and the time to renal recovery(This will be assessed at day 0, day 14, month 1, 2, 3, 4, 5, 6, 10 and 12 to identify renal recovery)
- The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and frailty(This will be assessed at day 0, month 1 and month 12)
- The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and Birmingham Vasculitis Activity Score (BVAS)(This will be assessed at day 0, day 14, month 1, 2, 3, 4, 5, 6, 10 and 12.)
- The correlation between subclinical asymptomatic CMV reactivation during the acute phase of AAV and time to achieve disease remission(This will be assessed at day 0, day 14, month 1, 2, 3, 4, 5, 6, 10 and 12 to identify disease remission)
研究者
Dimitrios Chanouzas
Consultant Nephrologist
University Hospital Birmingham NHS Foundation Trust