Francesca Tel

Discontinuation of Eculizumab Maintenance Treatment for Atypical Hemolytic Uremic Syndrome: A Report of 10 Cases

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy, and as many as 70% of patients with aHUS have mutations in the genes encoding complement regulatory proteins. Eculizumab, a humanized recombinant monoclonal antibody targeting C5, has been used successfully in patients with aHUS since 2009. The standard maintenance treatment requires life-long eculizumab therapy, but the possibility of discontinuation has not yet been tested systematically. We report the safety of discontinuing eculizumab treatment in 10 patients who stopped treatment with the aim of minimizing the risk of adverse reactions, reducing the risk of meningitis, and improving quality of life while also reducing the considerable treatment costs. Disease activity was monitored closely at home by means of urine dipstick testing for hemoglobin. During the cumulative observation period of 95 months, 3 of the 10 patients experienced relapse within 6 weeks of discontinuation, but then immediately resumed treatment and completely recovered. Our experience supports the possibility of discontinuing eculizumab therapy with strict home monitoring for early signs of relapse in patients with aHUS who achieve stable remission.

Complement functional tests for monitoring eculizumab treatment in patients with atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy characterized by hemolysis, platelet consumption, and renal injury. Eculizumab, a mAb that blocks complement activity, has been successfully used in aHUS.

Pandemic influenza A/H1N1 vaccine administered sequentially or simultaneously with seasonal influenza vaccine to HIV-infected children and adolescents.

In order to evaluate the immunogenicity, safety and tolerability of the 2009 A/H1N1 MF59-adjuvanted influenza vaccine administered sequentially or simultaneously with seasonal virosomal-adjuvanted influenza vaccine to HIV-infected children and adolescents, 36 HIV-infected children and adolescents, and 36 age- and gender-matched healthy controls were randomised 1:1 to receive the pandemic vaccine upon enrollment and the seasonal vaccine one month later, or to receive the pandemic and seasonal vaccines simultaneously upon enrollment. Seroconversion and seroprotection rates against the pandemic influenza A/H1N1 virus were 100% two months after vaccine administration in both groups, regardless of the sequence of administration. Geometric mean titres against pandemic and seasonal antigens were significantly higher when the seasonal and pandemic vaccines were administered simultaneously than when the seasonal vaccine was administered alone. Local and systemic reactions were mild and not increased by simultaneous administration. In conclusion, the 2009 pandemic influenza A/H1N1 MF59-adjuvanted vaccine is as immunogenic, safe and well tolerated in HIV-infected children and adolescents as in healthy controls. Its simultaneous administration with virosomal-adjuvanted seasonal antigens seems to increase immune response to both pandemic and seasonal viruses with the same safety profile as that of the pandemic vaccine alone. However, because this finding cannot be clearly explained by an immunological viewpoint, further studies are needed to clarify the reasons of its occurrence.

Early Volume Expansion and Outcomes of Hemolytic Uremic Syndrome

BACKGROUND: Hemolytic uremic syndrome associated with Shiga toxin–producing Escherichia coli (STEC-HUS) is a severe acute illness without specific treatment except supportive care; fluid management is concentrated on preventing fluid overload for patients, who are often oligoanuric. Hemoconcentration at onset is associated with more severe disease, but the benefits of volume expansion after hemolytic uremic syndrome (HUS) onset have not been explored. METHODS: All the children with STEC-HUS referred to our center between 2012 and 2014 received intravenous infusion targeted at inducing an early volume expansion (+10% of working weight) to restore circulating volume and reduce ischemic or hypoxic tissue damage. The short- and long-term outcomes of these patients were compared with those of 38 historical patients referred to our center during the years immediately before, when fluid intake was routinely restricted. RESULTS: Patients undergoing fluid infusion soon after diagnosis showed a mean increase in body weight of 12.5% (vs 0%), had significantly better short-term outcomes with a lower rate of central nervous system involvement (7.9% vs 23.7%, P = .06), had less need for renal replacement therapy (26.3% vs 57.9%, P = .01) or intensive care support (2.0 vs. 8.5 days, P = .02), and needed fewer days of hospitalization (9.0 vs 12.0 days, P = .03). Long-term outcomes were also significantly better in terms of renal and extrarenal sequelae (13.2% vs 39.5%, P = .01). CONCLUSIONS: Patients with STEC-HUS had great benefit from early volume expansion. It is speculated that early and generous fluid infusions can reduce thrombus formation and ischemic organ damage, thus having positive effects on both short- and long-term disease outcomes.

Factors conditioning effectiveness of a reminder/recall system to improve influenza vaccination in asthmatic children.

In order to verify whether a telephone recall system directly managed by pediatricians who usually follow up children for their asthma is more effective than an anonymous recall system, we randomly assigned 285 asthmatic children (177 males; mean age 10.3+/-3.4 years) to one of three groups: those whose mothers were to be called by a pediatrician not previously involved in caring for their asthmatic children and who received the vaccine in our immunisation clinic (group 1); those whose mothers were to be called by a pediatrician from our asthma clinic and who received the vaccine in the immunisation clinic (group 2); and those whose mothers were to be called by a pediatrician from our asthma clinic and who received the vaccine in the same clinic (group 3). Our findings highlight that the use of a reminder/recall system increases vaccination rates in asthmatic children, and show that the best results are obtained when the mothers are contacted and the vaccine administered by the pediatricians who usually follow up the child for asthma.

Skin Involvement in Atypical Hemolytic Uremic Syndrome

Skin involvement in atypical hemolytic uremic syndrome (aHUS) is very uncommon and therefore often unrecognized as a specific symptom of aHUS. We describe 3 cases of patients with aHUS who developed skin lesions that completely recovered when disease-specific treatment was established. These cases suggest that in individuals with aHUS, when skin lesions of unknown origin occur, the possibility that they are due to thrombotic microangiopathy should be considered.

Cryptic Activity of Atypical Hemolytic Uremic Syndrome and Eculizumab Treatment

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening disease often related to uncontrolled complement activation. The use of eculizumab has changed the management and the outcome of aHUS, becoming the frontline treatment of the acute disease and for the prevention of relapses. We report the case of a male patient with aHUS due to complement factor H gene mutation who was shifted from plasmatherapy to eculizumab for preventing disease relapses. The shift to eculizumab was associated with a significant decrease in proteinuria, revealing disease activity otherwise unsuspected, being the classic criteria of disease activity (platelet, haptoglobin, LDH, schistocytes), all in the normal range. The condition of proteinuria as the only sign of thrombotic microangiopathy activity is here designated as “cryptic activity of aHUS.”

Co-infection in children with bloody diarrhea caused by shiga toxin-producing escherichia coli: Data of the North Italian HUS network

ABSTRACTHemolytic-uremic syndrome (HUS) is an important cause of acute kidney injury in children often caused by Shiga toxin–producing Escherichia coli (STEC) enterocolitis. In a screening program for STEC infection in children with bloody diarrhea in northern Italy for early diagnosis of HUS, co-infection with Salmonella or Campylobacter was documented in as many as 35.6% of Shiga toxin–positive patients. It is speculated that infection by Salmonella or Campylobacter may increase the risk of STEC enterocolitis and therefore of HUS. The isolation of microorganisms (other then STEC) in HUS should not be necessarily regarded as the etiological agent for the thrombotic microangiopathy.

In reply to 'discontinuation of eculizumab maintenance treatment for atypical hemolytic uremic syndrome'.

To the Editor: Dr Ardissino and colleagues report successful discontinuation of eculizumab treatment in 7 of 10 patients with atypical hemolytic uremic syndrome (aHUS). This important report provides evidence that continued lifelong treatment may not be necessary in patients with aHUS, thus reducing side effects and costs. To ascertain generalizability and exclude selection bias, we should note the clinical characteristics of 12 patients who continued eculizumab treatment. Data presented in the first table of Ardissino et al suggest that discontinuing eculizumab treatment may be impossible in patients with a CFH mutation; in all 3 of these patients, treatment discontinuation was followed by recurrent disease that was evident within 6 weeks. We add data for eculizumab treatment discontinuation in patients with aHUS and a CFH mutation. To date, we have treated 4 such patients who were resistant to or dependent on treatment with plasmapheresis and received eculizumab in accordance with US Food and Drug Administration–proposed schedules. In our hospital, treatment is discontinued after 4 to 6 months if disease activity has disappeared and kidney function has improved and stabilized for at least 4 to 6 weeks. As shown in Table 1, eculizumab treatment was withdrawn in 3 of our patients, 2 of whom had no signs of disease activity as of their respective 11and 17month follow-ups. Recurrent disease developed in 1 patient 3 months after eculizumab therapy discontinuation. When comparing our patients with those of Ardissino et al, we noted a difference in the location of the CFH mutations, suggesting that patients with a mutation in exons 19 or 20 may be more prone to recurrence. Our data suggest that eculizumab therapy discontinuation is feasible in some patients with a CFH mutation. Future studies should evaluate the optimal treatment duration and risk of recurrence in relation to the patient’s underlying genetic lesion.

Comment to “Blood urea nitrogen to serum creatinine ratio is an accurate predictor of outcome in diarrhea-associated hemolytic uremic syndrome” by Keenswijk et al. Eur J Pediatr 2017; 176(3): 355–360

Dear Sir, We have read with great interest the paper by Keenswijk et al. [5] on the possible usefulness of blood urea nitrogen (BUN)-to-creatinine ratio (BCR) for predicting the outcome of Escherichia coli-related hemolytic uremic syndrome (eHUS) recently published on the European Journal of Pediatrics. An early predictor of outcome in this severe, life-threatening disease would be of paramount importance for guiding the clinician both in the early management of patients and for a correct parental and patient’s information. Unfortunately, the BCR did not prove to be useful when retrospectively applied to eHUS cases treated at our Center. Since 2000, we have managed a total of 184 eHUS (104 females), with a median age of 3.1 years (inter-quartile range (IQR) 1.5–6.3), a serum creatinine at presentation of 1.7 mg/ dL (IQR 0.9–3.23), and a BUN of 56.3 mg/dL (IQR 38.6– 86.9). Our series was categorized, as to disease outcome, using the same outcomes as described by Keenswijk et al. [5]: death, neurological involvement, need for intensive care support (either for hemodynamic instability or for ventilation), and chronic kidney disease or any long-term sequels. The