Atypical HUS triggered by infection with SARS-CoV2

Introduction:

Atypical haemolytic and uremic syndrome (aHUS) as a form of thrombotic microangiopathy (TMA) is characterized by a genetic or acquired dysregulation of complement activation leading to endothelial cell lesions and thrombosis of the small vessels, haemolysis, thrombocytopenia, and acute kidney injuryS1.

Here, we report two cases of complement mediated aHUS triggered by infection with SARS-CoV-2.

 First case:

A 22-year-old female was travelling abroad in early January 2021 to visit her boyfriend. Returning to Germany a mandatory SARS-CoV2 antigen-test was performed. The antigen test and a subsequent PCR-test showed SARS-CoV-2 infection. Albeit no symptoms of a respiratory tract infection were present, she had to see her general practitioner (GP) due to diarrhoea with persistent vomiting and loss of taste. As the condition did not improve she presented to the emergency department of another hospital 4 days after she had returned from her trip. Physical examination revealed a normotensive, alert and oriented patient who was pale and in acute distress.

 Initial laboratory findings:

The laboratory findings at admission revealed a thrombocytopenia with 28,000/μl. Haemolytic anaemia was present with a haemoglobin level of 5.5g/dl, elevation of lactate dehydrogenase (LDH) to 2066 U/l and acute kidney injury (KDIGO 3) with a serum creatinine of 560 umol/l.

 Clinical course:During the first days of admission the patient received 5 packed red blood cell transfusions due to ongoing haemolysis. The detection of schistocytes on peripheral blood smear confirmed thrombotic microangiopathy and daily plasma exchange using fresh frozen plasma as substitution solution was initiated. After exclusion of ADAMTS13 deficiency the diagnosis of aHUS was made, plasma exchange treatment was stopped after the third session and treatment with the C5-inhibitor eculizumab was initiated. A renal biopsy confirming TMA was performed at day 9 after admission, which was complicated by a post-interventional bleeding which was treated by endovascular coiling (Figure 1). Platelet count normalized and haemolysis resolved during the first 10 days (Figure 2a). Hemodialysis treatment could be tapered and finally stopped. Notably, the ct value of this patient had already increased to over 35 before plasma exchange was initiated, marking the serologic recovery from SARS-CoV-2 before treatment for aHUS was initiated. During follow up, the likely pathogenic CFH (complement factor H) splice variant c.3493+5G>A (chr1:g.196715134G>A) was identified that affects a highly conserved residue and is predicted to be pathogenic by all eight bioinformatics prediction tools used. The change is not reported in any database (gnomAD minor allele frequency/MAF 0%) and has not been described in the literature so far. Internally, we have already detected this variant in our lab in one of our patients who demonstrated a similar phenotype and did not bear another variant of (likely) pathogenic character. Conclusively, it is most likely that the above CFH variant was causative in our patient.Figure thumbnail gr1

Figure 1Renal biopsy of first case. Representative micrograph of thrombotic microangiopathy revealing several glomerular thrombi (arrowheads), one of them extending from ectatic preglomerular arteriole into the glomerulum. Additionally, mesangiolysis with fibrillar appearance of mesangial tissue containing red blood cell fragments can be seen (arrow). Jones methenamine stain combined with H&E, bar represents 50 micrometers.

Figure thumbnail gr2

Figure 22a) Clinical course of first case. 2b) Clinical course of second case.1= platelets (*10ˆ3/μl), 2= creatinine (μmol/l), 3= lactic dehydrogenase (U/dl), 4= hemoglobin (g/dl),PE= plasma exchange, Ec= eculizumab, IHD= Intermittent hemodialysis

 Second case:

A 52-year-old female with a history of mild hypertension saw her GP due to flu-like symptoms, loss of taste and exhaustion. The GP initiated antibiotic treatment with amoxicillin. Ten days later the patient returned to the GP with additional abdominal pain and cramps. Blood sampling revealed acute kidney injury (KDIGO 2) with a serum creatinine of 3 mg/dl (264 μmol/l). The patient was readmitted to hospital. At presentation in the emergency unit point of care testing (Abbott) was positive for SARS-CoV-2. Physical examination showed a hypertensive (162/82 mmHg), alert and oriented patient in acute distress.

 Initial laboratory findings:

Laboratory findings at admission revealed a haemoglobin level of 9.4 g/dl, elevation of LDH to 885 U/l and acute kidney injury (KDIGO 1) with a serum creatinine of 2.9 mg/dl (255 μmol/l). Interestingly, platelets were normal with 318,000/μl, but were reported to have been “unusually high” in the past (>400,000/μl).

 Clinical course:During the following days the patient developed progressive haemolytic anaemia with detection of schistocytes on peripheral blood smear and platelets decreased to a minimum of 128,000/μl. Due to progressive renal injury a renal biopsy was performed four days after admission, which was complicated by a post-interventional bleeding with transfusion of four packed red blood cell concentrates. Hemodialysis treatment was started ten days after admission due to volume overload. Renal biopsy showed fibrin-rich glomerular and pre-glomerular thrombotic microangiopathy (Supplementary Figure S1). As ADAMTS13 deficiency had already been excluded (activity 36%), diagnosis of aHUS was made and treatment with the C5-inhibitor eculizumab was initiated. Platelets increased to a maximum of 531,000/μl and haemolysis resolved within 13 days (Figure 2b). Renal recovery was slow and the patient remained on dialysis treatment for almost two months. During follow up, diagnostic genetic testing revealed the heterozygous variant c.2792G>A p.(Cys931Tyr) (chr1:g.196709758G>A) in CFH. Almost all bioinformatic tools (20 out of 22 tools used) predict its pathogenicity. To our knowledge, this variant has not yet been reported in the literature (HGMD 2020.4) nor has it been annotated in any database (gnomAD/ MAF 0%). The change is located in the complement control protein 16 domain (CCP16) and affects one of four conserved cysteine residues of CCP16, which contribute to the tertiary structure of the protein via the formation of two disulfide bridges (Cys931-Cys973 and Cys959-Cys984, respectively). Pathogenic changes in these structurally important cysteines [e.g., p.(Cys959Tyr) and p.(Cys973Tyr)] have been described in patients with CFH deficiencyS2-S4. They result in severely impaired secretion of the resulting proteins (quantitative deficiency) and reduced ability to regulate complement in the liquid phase and at cell surfaces. Overall, the variant detected can be classified as likely pathogenic according respective ACMG guidelines. Both patients received vaccination against meningococci as recommended and complement inhibitor treatment is currently continued.Discussion:Endothelial cell activation and thrombotic as well as microangiopathic complications have been described in COVID-19 diseaseNoris M. Benigni A. Remuzzi G. The case of complement activation inCOVID-19 multiorgan impact.. These features, possibly mediated by complement activation, have led to the assumption of aHUS as a contributing factor in the pathomechanism in COVID-19 and have triggered clinical studies using C5-blockade in the treatment of COVID-19 diseasePeffault de Latour R. Bergeron A. Lengline E. et al.Complement C5inhibition in patients with COVID-19 - a promising target?.. Commonly recognized triggering factors of aHUS include infections, malignancies, transplantation, pregnancy, or systemic diseasesS1.

Here, we present two cases of female patients with first aHUS episodes after infection with SARS-CoV-2 and recovering from COVID-19 disease, who were successfully treated with eculizumab. In our patients, these episodes mark the first manifestations of aHUS. A pathogenic complement factor H mutation was found in both women presenting as young to middle-age adults.

Yu et al. have recently shown that the SARS-CoV-2 spike protein subunits may serve as potent activators of the alternative pathway of complement (APC) by possibly disturbing the binding capacity of Factor H to heparansulfate on cell surfaces and therefore significantly reducing the regulating capacities of factor H in inhibiting the activity of C3 convertaseu J. Yuan X. Chen H. Chaturvedi S. Braunstein E.M. Brodsky R.A. Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition.. In patients with inherent CFH mutations, this mechanism may become clinically relevant. In addition, a relapse case of triggering aHUS in a patient with a pathogenic MCP-mutation after a mild COVID-19 disease has been recently reported by Ville et al. Ville S. Le Bot S. Chapelet-Debout A. Blancho G. Fremeaux-Bacchi V. Deltombe C. Fakhouri F. Atypical HUS relapse triggered by COVID-19.. Therefore, also other genetic alterations in complement, with focus on membrane-bound factors, may cause an aHUS episode in patients after infection with SARS-CoV-2, even if the patient may have clinically recovered from the infection. Genetic abnormalities are thought to be present in 50% to 70% of patients with aHUS.Fremeaux-Bacchi V. Fakhouri F. Garnier A. et al.Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.In conclusion, our case reports underline that an infection with SARS-CoV-2 should be recognized as a potent trigger in patients with inherent complement defects, even when the symptoms of infection were mild or the patient has recovered from COVID-19 disease. Clinical and laboratory findings suspicious of haemolytic anaemia with/or thrombopenia should prompt further diagnostic workup regarding thrombotic microangiopathies (Table 1). Cases of unexplained thrombocytopenia as well as aHUS-like syndromes have been reported after vaccination against SARS-CoV-2CoViD vaccines and thrombotic events: EMA issued warning to patients and healthcare professionals.,

Tiede A, Sachs UJ, Czwalinna A, et al. Prothrombotic immune thrombocytopenia after COVID-19 vaccine [published online ahead of print, 2021 Apr 28]. Blood. 2021;blood.2021011958. doi:10.1182/blood.2021011958

. Vaccination against or infection with SARS-CoV-2 have been associated with new cases or relapses of certain nephropathies such as IgA-nephropathy or minimal change disease, hinting towards a link with immune dysregulations

Kervella D, Jacquemont L, Chapelet-Debout A, Deltombe C, Ville S. Minimal change disease relapse following SARS-CoV-2 mRNA vaccine [published online ahead of print, 2021 May 5]. Kidney Int. 2021;S0085-2538(21)00478-6. doi:10.1016/j.kint.2021.04.033

,Gross hematuria following vaccination for severe acute respiratory syndrome coronavirus 2 in 2 patients with IgA nephropathy.. Our cases suggest that patients with inherent complement defects may be at risk to relapse or present with a first episode of aHUS when infected with SARS-CoV-2. The endothelial damage and activation of the alternative complement system possibly mediated by the spike-protein or other virus components may therefore be independent of clearance of the virus and seroconversion.

Table 2Key teaching points

Disclosures:

The study was supported by the DEFEAT Pandemics platform of the Federal Ministry of Education and Research (BMBF) to TW. All other authors have nothing to disclose.

 Patient consent:

The authors declare that they have obtained consent from the patients discussed in this report.

留言 (0)

沒有登入
gif