Atypical HUS relapse triggered by COVID-19

To the editor:

Microvascular injury, including thrombotic microangiopathy, has been widely reported as a hallmark pathologic feature of organ injury in the setting of coronavirus disease 2019 (COVID-19).¹ Accumulating data suggest that complement activation is implicated in the pathogenesis of COVID-19, including endothelial cell damage.2, 3, 4, 5 Some of these features are characteristic of atypical hemolytic uremic syndrome (aHUS), a prototypic disease of complement-mediated endothelial cell injury. We report the first case of aHUS relapse triggered by COVID-19.

The patient, a 28-year-old white woman, was diagnosed with aHUS at the age of 3. Genetic analysis revealed the presence of a heterozygous pathogenic variant (R59Stop) in the membrane cofactor protein–encoding gene. Subsequently, she presented 3 aHUS relapses at the age of 5, 20, and 27 years. The second relapse required dialysis before hematologic and renal remission was obtained following 4 plasma exchanges and treatment with eculizumab for 12 months. The third relapse, triggered by an extrauterine pregnancy, was treated with 3 months of eculizumab. Kidney biopsy performed at that time revealed moderate interstitial (20%) and glomerular (20%) fibrosis. The patient had chronic kidney disease stage 3B (glomerular filtration rate = 42 ml/min per 1.73 m² estimated using the Modification of Diet in Renal Disease formula) and hypertension requiring a treatment combining a calcium channel blocker and an angiotensin-converting enzyme inhibitor.

In September 2020, she presented with fever, dysphagia, and headache. Clinical examination showed moderate fever, an erythematous throat, infracentimetric cervical adenopathies, and hypertension (150/105 mm Hg). She had no lung involvement with a normal chest X-ray. Laboratory tests showed mechanical hemolytic anemia (hemoglobin = 8.4 g/dl, lactate dehydrogenase level at 1.5× the upper limit of normal, and undetectable haptoglobin), mild thrombocytopenia (platelet count = 106 G/l), acute kidney injury (serum creatinine = 2.6 mg/dl vs. 1.7 mg/dl at baseline), and significant proteinuria (protein-to-creatinine ratio of 0.21 g/mmol vs. 0.05 at baseline). aHUS relapse was diagnosed, and the patient was admitted to our nephrology department. In the context of the re-emergence of the SARS-CoV-2 pandemic in our region, COVID-19 was suspected and confirmed by a positive polymerase chain reaction test in a nasopharyngeal swab. Additional workup showed a decreased C3 serum level (0.65 g/L; normal range, 0.9–1.8) and a normal C4 level. Inflammatory markers were normal or moderately increased (C-reactive protein < 0.4 mg/dl [<10], ferritin = 392 μg/l [13–150], D-dimer = 512 ng/mL [<500], and interleukin-6 = 1.8 pg/mL [< 7]). Serum creatinine peaked at 2.9 mg/dl, and the platelet count decreased to 88 G/l. Treatment with the C5 blocker eculizumab was immediately restarted combined with penicillin prophylaxis and anticoagulation due to the increased risk of thrombosis in the setting of COVID-19.⁶ Seven days after the start of eculizumab, the hematologic parameters (platelet count = 191 G/l) and renal function (serum creatinine = 2.2 mg/dl) improved, and the patient was discharged from the hospital. One month after diagnosis, the D-dimer level was normal (261 ng/ml), haptoglobin remained undetectable, and a mild decrease in the C3 plasma level persisted (0.65 g/l). Renal function improved, but serum creatinine (2.0 mg/dl) had not returned to baseline values.

It is well established that aHUS relapse may be precipitated by infections, including viral pathogens such as influenza or H1N1 virus.^{7 , 8} This case is an illustration that COVID-19 is to be added to the list of the potential triggers of aHUS relapse. In this setting, the deleterious effect of the coronavirus 19 may arise from (i) a direct toxic effect on endothelial cells, as suggested by autopsies studies,¹ and/or (ii) a complement activation with ultimately complement-mediated endothelial damage, most particularly in patients with a constitutional defect in complement regulation, as in the patient presented herein. Indeed, it has recently been shown that, in vitro, SARS-CoV-2 activates the complement alternative pathway via its spike surface protein.⁹ Similarly, markers of complement activation, including soluble C5b-9, are increased in a significant proportion of COVID-19 patients and correlate to the severity and prognosis of the disease prognosis.^{4 , 5} Furthermore, C3 deficiency protects against the development of SARS-CoV infection in mice.¹⁰ Finally, complement activation may also contribute to the hypercoagulable state in COVID-19 patients.³

Our patient had a clinically mild form of COVID-19 and no marked systemic inflammation. Nevertheless, virus-driven complement activation did occur and was most probably overamplified in the absence of a tight control of the complement alternative pathway, leading to the development of thrombotic microangiopathy. However, this is to date the only reported case of aHUS relapse triggered by COVID-19 despite the worldwide spread of COVID-19 epidemics. Nevertheless, our observation underlines the need for close monitoring of aHUS patients who discontinued eculizumab in the setting of COVID-19. It is also a further indication that complement blockade should not be discontinued in aHUS during infectious episodes, COVID-19 not being an exception.

Disclosure

FF has received consultancy and/or speaker honoraria from Roche, Alexion, Apellis, Achillion, Novartis, and Alnylam. VF-B has received fees from Alexion Pharmaceuticals, Roche, Apellis, Novartis, and Baxter for invited lectures and/or board membership and is the recipient of a research grant from Alexion Pharmaceuticals and Apellis. All the other authors declared no competing interests.