Induction failure in granulomatosis with polyangiitis: a nationwide case-control study of risk factors and outcomes.

OBJECTIVE: To identify characteristics of granulomatosis with polyangiitis (GPA) associated with induction failure, describe salvage therapies and their efficacy. METHODS: We conducted a nationwide retrospective case-control study of GPA with induction failure between 2006 and 2021. Each patient with induction failure was randomly paired to three controls matched for age, sex and induction treatment. RESULTS: We included 51 patients with GPA and induction failure (29 men and 22 women). At induction therapy, median age was 49 years. Twenty-seven patients received intravenous cyclophosphamide (ivCYC) and 24 rituximab (RTX) as induction therapy. Patients with ivCYC induction failure more frequently had PR3-ANCA (93% vs 70%, P = 0.02), relapsing disease (41% vs 7%, P < 0.001) and orbital mass (15% vs 0%, P < 0.01) compared with controls. Patients with disease progression despite RTX induction therapy more frequently had renal involvement (67% vs 25%, P = 0.02) with renal failure (serum creatinine >100 µmol/l in 42% vs 8%, P = 0.02) compared with controls. After salvage therapy, remission was achieved at 6 months in 35 (69%) patients. The most frequent salvage therapy was switching from ivCYC to RTX (or vice versa), showing an efficacy in 21/29 (72%). Remission was achieved in nine (50%) patients with inappropriate response to ivCYC, while in patients with progression after RTX induction, remission was achieved in four (100%) who received ivCYC (with or without immunomodulatory therapy), but only in three (50%) after adding immunomodulatory therapy alone. CONCLUSION: In patients with induction failure, characteristics of GPA, salvage therapies and their efficacy vary according to induction therapy and failure modality.

Complement Activation and Thrombotic Microangiopathy Associated With Monoclonal Gammopathy: A National French Case Series.

RATIONALE & OBJECTIVE: Hemolytic uremic syndrome (HUS), a thrombotic microangiopathy (TMA) with kidney involvement, is a rare condition in patients with monoclonal gammopathy. In the absence of known causes of TMA, the role of complement activation in endothelial injury in patients with monoclonal gammopathy remains unknown and was the focus of this investigation. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: We studied the 24 patients in the French national registry of HUS between 2000 and 2020 who had monoclonal gammopathy without other causes of secondary TMA. We provide the clinical histories and complement studies of these patients. FINDINGS: Monoclonal gammopathy-associated TMA with kidney involvement is estimated to be 10 times less frequent than adult atypical HUS (aHUS) in the French national registry. It is characterized by severe clinical features, with 17 of 24 patients requiring dialysis at disease onset, and with median renal survival of only 20 months. TMA-mediated extrarenal manifestations, particularly cutaneous and neurological involvement, were common and associated with poor overall prognosis. Complement studies identified low C3, normal C4, and high soluble C5b-9 levels in 33%, 100%, and 77% of tested patients, respectively, indicating a contribution of the alternative and terminal complement pathways in the pathophysiology of the disease. Genetic abnormalities in complement genes known to be associated with aHUS were found in only 3 of 17 (17%) who were tested. LIMITATIONS: Retrospective study without comparison group; limited number of patients, limited available blood samples. CONCLUSIONS: Within the spectrum of TMA, TMA associated with monoclonal gammopathy represents a distinct subset. Our findings suggest that HUS associated with monoclonal immunoglobulin is a complement-mediated disease akin to aHUS.

The effect of rituximab therapy on immunoglobulin levels in patients with multisystem autoimmune disease.

BACKGROUND: Rituximab is a B cell depleting anti-CD20 monoclonal antibody. CD20 is not expressed on mature plasma cells and accordingly rituximab does not have immediate effects on immunoglobulin levels. However, after rituximab some patients develop hypogammaglobulinaemia. METHODS: We performed a single centre retrospective review of 177 patients with multisystem autoimmune disease receiving rituximab between 2002 and 2010. The incidence, severity and complications of hypogammaglobulinaemia were investigated. RESULTS: Median rituximab dose was 6 g (1-20.2) and total follow-up was 8012 patient-months. At first rituximab, the proportion of patients with IgG <6 g/L was 13% and remained stable at 17% at 24 months and 14% at 60 months. Following rituximab, 61/177 patients (34%) had IgG <6 g/L for at least three consecutive months, of whom 7/177 (4%) had IgG <3 g/L. Low immunoglobulin levels were associated with higher glucocorticoid doses during follow up and there was a trend for median IgG levels to fall after ≥ 6 g rituximab. 45/115 (39%) with IgG ≥ 6 g/L versus 26/62 (42%) with IgG <6 g/L experienced severe infections (p=0.750). 6/177 patients (3%) received intravenous immunoglobulin replacement therapy, all with IgG <5 g/L and recurrent infection. CONCLUSIONS: In multi-system autoimmune disease, prior cyclophosphamide exposure and glucocorticoid therapy but not cumulative rituximab dose was associated with an increased incidence of hypogammaglobulinaemia. Severe infections were common but were not associated with immunoglobulin levels. Repeat dose rituximab therapy appears safe with judicious monitoring.

Activated protein C improves macrovascular and microvascular reactivity in human severe sepsis and septic shock.

We tested the effects of activated protein C (APC) in macrovascular and microvascular beds within 60 min of treatment. Twelve patients treated with APC for severe sepsis were included. We assessed macrovascular reactivity by phenylephrine arterial dose response. Pharmacological modeling (EC50, Emax, and Hill coefficient) and individual dose-response curve were tested. Microvascular reactivity was tested with skin laser Doppler by using postocclusive reactive hyperemia with measurements of peak, time to peak (Tmax), time to half recovery (T1/2R), and myogenic and sympathetic tones. All measurements were done 30 min before, just before, and 30 and 60 min after APC infusion. Microvascular reactivity was also tested in eight healthy volunteers. In patients, arterial pressure did not increase significantly. However, 60 min after the beginning of APC infusion, reactivity to α-1 stimulation was improved: EC50 decreased from 15.3 (0.9-56) to 3.1 (1.0-6.2) (P = 0.04), and 5 of 12 patients improved their dose-response curve. As for microcirculatory parameters, as early as 30 min after the beginning of APC infusion, postocclusive reactive hyperemia peak increased from 102 (40-168) to 162 (35-196) (P = 0.04), Tmax was shorter: 30 s (14-52 s) versus 56 s (22-83 s) (P = 0.03), and the T1/2R also decreased, from 72.4 s (41.9-134.6 s) to 49.8 s (31.0-129.8 s) (P = 0.02). Myogenic tone increased (P = 0.03), whereas sympathetic tone decreased (P = 0.03), and myogenic tone was lower than controls before but not after APC treatment. In conclusion, APC improves vascular reactivity both at macrocirculatory and microcirculatory levels very quickly, suggesting that this is not due to protein synthesis or anticoagulant effect. The myogenic properties of vessels could partly drive this effect.

Adverse events during intrahospital transport of critically ill patients: incidence and risk factors.

BACKGROUND: Transport of critically ill patients for diagnostic or therapeutic procedures is at risk of complications. Adverse events during transport are common and may have significant consequences for the patient. The objective of the study was to collect prospectively adverse events that occurred during intrahospital transports of critically ill patients and to determine their risk factors. METHODS: This prospective, observational study of intrahospital transport of consecutively admitted patients with mechanical ventilation was conducted in a 38-bed intensive care unit in a university hospital from May 2009 to March 2010. RESULTS: Of 262 transports observed (184 patients), 120 (45.8%) were associated with adverse events. Risk factors were ventilation with positive end-expiratory pressure >6 cmH2O, sedation before transport, and fluid loading for intrahospital transports. Within these intrahospital transports with adverse events, 68 (26% of all intrahospital transports) were associated with an adverse event affecting the patient. Identified risk factors were: positive end-expiratory pressure >6 cmH2O, and treatment modification before transport. In 44 cases (16.8% of all intrahospital transports), adverse event was considered serious for the patient. In our study, adverse events did not statistically increase ventilator-associated pneumonia, time spent on mechanical ventilation, or length of stay in the intensive care unit. CONCLUSIONS: This study confirms that the intrahospital transports of critically ill patients leads to a significant number of adverse events. Although in our study adverse events have not had major consequences on the patient stay, efforts should be made to decrease their incidence.

Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: Rituximab is effective induction therapy in refractory or relapsing antineutrophil cytoplasmic antibody-associated vasculitis (AAV). However, further relapse is common, and maintenance strategies are required. The aim of this study was to reduce relapse rates using a fixed-interval rituximab re-treatment protocol. METHODS: Retrospective, standardized collection of data from sequential patients receiving rituximab for refractory or relapsing AAV at a single center was studied. Group A patients (n = 28) received rituximab induction therapy (4 infusions of 375 mg/m(2) or 2 infusions 1 gm) and further rituximab at the time of subsequent relapse. Group B patients (n = 45) received routine rituximab re-treatment for 2 years: 2 doses of 1 gm each for remission induction, then 1 gm every 6 months (total of 6 gm). Group C patients (n = 19) comprised patients in group A who subsequently relapsed and began routine re-treatment for 2 years. RESULTS: Response (complete/partial remission) occurred in 26 of the 28 patients (93%) in group A, 43 of the 45 patients (96%) in group B, and 18 of the 19 patients (95%) in group C. At 2 years, relapses had occurred in 19 of 26 patients (73%) in group A, 5 of 43 (12%) in group B (P < 0.001), and 2 of 18 (11%) in group C (P < 0.001). At the last followup (median of 44 months), relapses had occurred in 85% of those in group A (22 of 26), 26% of those in group B (11 of 43; P < 0.001), and 56% of those in group C (10 of 18; P = 0.001). Glucocorticoid dosages were decreased and immunosuppression therapy was withdrawn in the majority of patients. Routine rituximab re-treatment was well tolerated, and no new safety issues were identified. CONCLUSION: Two-year, fixed-interval rituximab re-treatment was associated with a reduction in relapse rates during the re-treatment period and a more prolonged period of remission during subsequent followup. In the absence of biomarkers that accurately predict relapse, routine rituximab re-treatment may be an effective strategy for remission maintenance in patients with refractory and relapsing AAV.

Recommendations for the use of rituximab in anti-neutrophil cytoplasm antibody-associated vasculitis.

OBJECTIVES: To perform a literature review and develop recommendations for the use of rituximab in ANCA-associated vasculitis. METHODS: A committee of experts (five rheumatologists, five nephrologists and one paediatrician) conducted a modified Delphi exercise to identify five topics for a systematic literature search. The evidence was then reviewed, categorized according to international criteria and assimilated to form five recommendations statements and a research agenda. RESULTS: Forty-three studies met the review criteria. These included two randomized controlled trials and a predominance of small, uncontrolled series. In refractory ANCA-associated vasculitis, remission rates of >80% are obtained with rituximab. In newly diagnosed disease, rituximab is at least as effective as conventional therapy. Fifteen recommendations were made. Their strength was restricted by the low quality of the evidence. Six areas for future research were identified. CONCLUSION: On the basis of the available evidence and expert consensus, recommendations have been made for the use of rituximab as a treatment of ANCA-associated vasculitis. Further questions, in particular regarding long-term outcomes, remain to be explored.

Fulminant hemophagocytic lymphohistiocytosis induced by pandemic A (H1N1) influenza: a case report.

INTRODUCTION: Hemophagocytic lymphohistiocytosis induced by viral diseases is a well recognized entity. Severe forms of H5N1 influenza are known to be associated with symptoms very similar to a reactive hemophagocytic syndrome. We report a case of fulminant lymphohistiocytosis associated with the pandemic A (H1N1) variant. CASE PRESENTATION: A 42-year-old Caucasian woman developed a syndrome of fatal hemophagocytic lymphohistiocytosis shortly after H1N1 influenza. Initial symptoms of the viral disease were unusual, with acute abdominal involvement. Our patient's course was complicated by diffuse skin rash and ileal ischemia. Our patient died of refractory shock and multi-organ failure. Skin, ileum and colon histology was consistent with an acute apoptosis combined with an increased cellular regeneration. CONCLUSIONS: Influenza may be complicated by severe forms of hemophagocytic lymphohistiocytosis. To ensure early recognition and treatment, physicians should be aware of the possible induction of the syndrome by the novel H1N1 variant. The rapid occurrence of a multi-organ involvement with evocative biological features of macrophage activation should alert clinicians.

New methods to clean ICU rooms.

Hospital-acquired infections (HAI) represent the most common adverse event in the intensive care unit (ICU). Their prevalence is high and they are associated with increased morbidity and mortality. The environment plays a central role in the transmission of hospital-acquired pathogens (HAP) and in the pathogenesis of HAI. Many bacteria, especially multidrug resistant ones, can survive for several months in the hospital environment in particular in areas close to the patients. It has been proven that pathogens are transmitted from the environment to the patients. Many studies have concluded that current cleaning methods are microbiologically ineffective. This failure concerns daily cleaning as well as terminal cleaning after patient discharge. It has been demonstrated that improvements in environmental cleaning are associated with a decrease in the rate of HAP and of HAI. New cleaning methods could enhance hospital cleaning efficiency. Three new technologies seem promising because they are microbiologically effective, easy and safe to use: (1) hydrogen peroxide vapor and (2) UV light decontamination are used for terminal cleaning. These techniques are effective even in difficultly accessible areas. (3) ultramicrofibers which can be associated with a copper-based biocide can be used for daily cleaning. Other methods such as ozone, steam or high-efficiency particulate air filtration are not efficient enough to be considered serious contenders for the improvement of the quality of the hospital environment. These new technologies have not been yet linked to a decrease in the prevalence and the incidence in HAP and HAI. It remains difficult to justify the extra-cost associated with these new methods until more studies can confirm their effectiveness in the management of HAI.