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Medicina Interna

versão impressa ISSN 0872-671X

Medicina Interna vol.30 no.3 Lisboa set. 2023  Epub 25-Out-2023

https://doi.org/10.24950/rspmi.1616 

Casos Clínicos/ Case Reports

Hemolytíc Uremíc Syndrome and SARS-CoV-2 lnfectíon: A Rare Assocíatíon

Síndrome Hemolítica Urémica e Infeção por SARS-CoV-2: Uma Associação Rara

Cristiana Honrado Martins1 
http://orcid.org/0000-0003-2177-2539

Guilherme Castro Gomes2 

José Damasceno Costa2 

Paulo Pereira2 

Ana Rita Matos2 

Vânia Gomes2 

1Serviço de Oncologia Médica, Hospital de Braga, Braga, Portugal

2Serviço de Medicina Interna, Hospital de Braga, Braga, Portugal


Abstract

Thrombotic microangiopathies (TMA) are rare diseases, with high morbimortality. Among them, atypical hemolytic ure-mic syndrome (HUS), associated with deregulation of alternative complement pathway (genetic/acquired), represents a diagnostic challenge. Characterized by thrombotic microangiopathy, acute renal failure is one of its main features. Etiological/precipitant detection (TMA triggers) is essential, even though about 30% of cases remain idiopathic. There is not a direct diagnostic test, which makes this an exclusion final diagnosis (after primary and secondary causes are ruled-out). Further testing for genetic variations is important for prognostic purposes. We describe the case of a 40 years old woman, whose final diagnostic was an atypical HUS associated with SARS-CoV-2 infection. This case stands out by its rarity.

We underline the importance of prompt initial diagnosis and timely target treatment beginning: Eculizumab, the only one available in Portugal at the moment. Plasmapheresis and/or renal replacement therapy must be considered case by case.

Palavras-chave: COVID-10/complicações; SARS-CoV-2; Síndrome Hemolítica Urémica Atípica/diagnóstico; Síndrome Hemolítica Urémica Atípica/tratamento.

Resumo

As microangiopatias trombóticas (MAT) são doenças raras, com elevada morbimortalidade. Destas, a síndrome hemolítica urémica (SHU) atípica, associado à desregulação da via alternativa do complemento (genética/adquirida), representa um desafio diagnóstico. Caracteriza-se por microangiopatia trombótica, sendo a lesão renal aguda uma das principais características. A detecção de fatores etiológicos/precipitantes (triggers de MAT) é fundamental, ainda que 30% dos casos permaneçam idiopáticos. Não existe um teste diagnóstico direto, acabando este por ser um diagnóstico final de exclusão (tanto causas primárias como secundárias). A testagem de variantes genéticas é importante em termos prognósticos.

Descreve-se o caso de uma doente de 40 anos, cuja marcha diagnóstica culminou num SHU atípico associado à infeção pelo SARS-CoV-2, que se destaca pela raridade. Ressalva-se a importância do diagnóstico inicial célere e início atempado de tratamento efetivo dirigido: Eculizumab, único atualmente disponível em Portugal. A instituição de plasmaferese e/ou terapêutica de substituição renal devem ser consideradas individualmente.

Palavras-chave: COVID-10/complicações; SARS-CoV-2; Síndrome Hemolítica Urémica Atípica/diagnóstico; Síndrome Hemolítica Urémica Atípica/tratamento.

Introduction

Thrombotic microangiopathies (TMA) are rare diseases, with high morbimortality.1 Among them, hemolytic uremic syndrome (HUS) related to deregulation of alternative complement pathway, also known as atypical HUS (aHUS), represents a diagnostic challenge.1,2

We describe a case of aHUS associated with SARS-CoV-2 infection.

Case Report

A 40-years-old woman, with a medical history of left chromophobe renal cell carcinoma, submitted to left nephrectomy two months before admission, was admitted to emergency department of a local hospital with complaints of vomiting, diarrhea, oliguria and facial edema, with a four days evolution. She had a positive test for SARS-CoV-2 in-fection, five days before admission, classified as respiratory moderate disease (pneumonia without hypoxemia) and indication to ambulatory treatment.

Analytical tests were performed: blood panel showed anemia (hemoglobin: 8.7 g/dL), thrombocytopenia (plate-let count: 16 000/mm3), total leukocyte count of 6000/mm3 and normal coagulation times; urea: 127 mg/dL, creatinine: 5.5 mg/dL, urinary sediment: 25 to 50 erythrocytes/field and proteinuria (urinary sediment proteins: 363 mg/dL); albumin: 2.9 g/dL; lactic dehydrogenase (LDH) > 1000 U/L, indoseable haptoglobin, negative Coombs’ test and peripheral blood smear showing schistocytes. This data revealed relevant acute renal failure (ARF) with proteinuria and microangiopathic hemolytic anemia (MHA).

Thoracic, abdominal and pelvic computed tomography (CT-TAP) and positron emission tomography (PET-SCAN) ruled out neoplastic recurrence.

Further TMA and ARF etiologic investigation revealed C3 complement consumption, without other positive findings: ADAMTS13 activity of 100%; negative Escherichia coli O157:H7 test; negative beta-hCG test; negative broad immu-nological study; normal methylmalonic acid (MMA) and methionine; negative infectious serologies; negative anti-factor H.

Therapy with plasmapheresis was performed until thrombotic thrombocytopenic purpura (TTP) exclusion, without further clinical and/or analytical improvement. The patient maintained oliguria, with difficult volume management (anasarca and recurrent right pleural effusion), leading to renal replacement therapy (RRT) with hemodialysis.

Genetic study revealed C3 heterozygous mutation and complement factor H (CFH) homozygous mutation. These results consolidated the main diagnosis of aHUS associated with complement deregulation, most probably triggered by SARS-CoV-2 infection.

Therefore, and while the patient was still in hospital internment, eculizumab treatment began,2 with major clinical and analytical improvements (mainly in hematological alterations). Given the induced iatrogenic immunosuppression state, recommended vaccines were administered.

At this point, the patient was discharged, keeping strict follow-up in Day Care Unit, with clinical observation and analytical studies, followed by eculizumab administration. Six months after discharge, the patient remains asymptomatic, with MHA complete resolution and stabilized creatinine in a new base line of 3.5 mg/dL, allowing RRT suspension. Since then, no other intercurrence was registered.

Discussion

Thrombotic microangiopathies are rare diseases, with multiple etiologies, characterized by MHA (negative Coom-bs test) and thrombocytopenia. It usually presents with high morbimortality, directly related to endothelial lesion provoked by microthrombotic phenomena and subsequent target organ damage.1,4 One of the recent TMA etiopathogenic classification subdivides primary TMA (including TTP and HUS, atypical and typical forms, the last one mainly in post-infectious and Escherichia coli productive Shiga toxin induced cases) and secondary TMA (induced by systemic disturbances, toxics, pregnancy, surgeries, among others).1

Hemolytic uremic syndrome is a systemic disease, characterized by thrombotic microangiopathy with endovascular affection, having the kidney as a particularly vulnerable organ. This way, ARF is one of its major features.3,4Nevertheless, extrarenal manifestations are present in about 20% of cases.2

Regarding atypical HUS, and unlike the socalled typical forms, there is a deregulation of alternative complement pathway, that can be either genetic or acquired.4 A variety of clinical conditions (infectious, neoplastic, and immunological) and toxicologic exposures can act as TMA triggers. In case of positive genetic mutation, a trigger is also usually needed to disease development.5 The presence of autoantibodies against complement activation inhibitors (among which complement anti-factor H autoantibody stands out) can produce similar phenotypes (acquired aHUS).1,2

In spite of all, about 30% of aHUS cases remain as idiopathic, with no trigger identification.3 There is not a specific test to direct aHUS diagnosis,1 which makes this a clinical and, essentially, an exclusion diagnosis.2 It is possible to detect complement alterations in about 50% to 60% of cases.6 In a first phase, diagnostic flow charts directed to TMA focus on TTP exclusion (ADAMTS13 activity quest: severely decreased in TTP) and Shiga toxin associated infectious HUS exclusion (E. coli O157:H7 quest). Simultaneously, secondary causes must be ruled out (pregnancy, surgical aggressions, immunological status evaluation, infectious serologies, methionine dosage). They can overlap aHUS, clinically and histopathologically.1-5Further testing for complement system genetic variations or other relevant autoantibodies (such as anti-factor H) is important in terms of prognostic.2

Atypical HUS target treatment is based on the blockage of complement inappropriate activation1,2and eculizumab (anti-C5 antibody) is the only effective treatment currently available in Portugal. The administration should begin as soon as possible,1 representing a significantly positive prognostic factor. Even so, etiological and/or precipitating factors exclusion is essential since the beginning of clinical symptomatology, in order to correct target treatment initiation or, at least, to begin supportive care strategies (such as RRT). Starting empirical plasmapheresis must be considered after an initial diagnosis of unknown etiology TMA, especially given TTP prevalence and the poor prognosis associated with delays in plasmapheresis initiation in those cases.1,2Plasmapheresis should be maintained until TTP exclusion and suspended after that, since it is not effective on aHUS. Plasmapheresis and eculizumab should not be done simultaneously, since monoclonal antibody can be removed by plasmapheresis, decreasing its efficacy.

Once aHUS become the most probable diagnosis, eculizumab should be started.1,2The recommended dosing schedule for eculizumab in aHUs is reported in trials: an initial phase (900 mg every week for the first 4 weeks), followed by a maintenance phase (1200 mg for the fifth week and then 1200 mg every fourteen days).2

Recently, European Medicines Agency (EMA) approved ravulizumab (another anti-C5 antibody) in aHUS treatment.7 However, this drug has not been approved for aHUS treatment in Portugal yet.

It is crucial to underline the importance of a prompt initial diagnosis. This will allow a timely target treatment beginning (prognostic factor and therapeutic response predictor). It is recommended treatment maintenance until platelet count normalization, hemolysis complete resolution and renal function sustained improvement. As seen in the described case, renal response can be slow, requiring an eculizumab trial of, at least, six months.1,2We highlight the importance of meningococcal infections prophylaxis, with prophylactic antibiotherapy and vaccination as recommended.1,2Eculizumab discontinuation must be approached and discussed with a multidisciplinary team, being a key and mandatory factor in these patients' follow-up.2

The reported case stands out by the rarity of HUS associated with complement deregulation and SARS-CoV-2 showing up as the most probable decompensation factor (association considering temporal link between events and the absence of other plausible alternatives). Atypical HUS and SARS-CoV-2 virus (infection/vaccination) association is rare, with only a few described cases in literature.4,8-10

Previous Presentations

This paper was presented at “28º Congresso Nacional de Medicina In-terna”, format: poster with oral presentation.

REFERENCES

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2. Azevedo A, Faria B, Teixeira C, Carvalho F, Neto G, Santos J, et al. Portuguese consensus document statement in diagnostic and management of atypical hemolytic uraemic syndrome. Port J Nephrol Hypert. 2018;32:211-32. [ Links ]

3. Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C. Haemolytic uraemic syndrome. Lancet. 2017;390:681-96. doi: 10.1016/S0140-6736(17)30062-4. [ Links ]

4. Ferrer F, Roldão M, Figueiredo C, Lopes K. Atypical Hemolytic Uremic Syndrome after ChAdOx1 nCoV-19 Vaccination in a Patient with Homozygous CFHR3/CFHR1 Gene Deletion. Nephron. 2022;146:185-9. doi: 10.1159/000519461. [ Links ]

5. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676-87. doi: 10.1056/NEJMra0902814. [ Links ]

6. Phillips EH, Westwood JP, Brocklebank V, Wong EK, Tellez JO, Marchbank KJ, et al. The role of ADAMTS-13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies. J Thromb Haemost. 2016;14:175-85. doi: 10.1111/jth.13189. [ Links ]

7. European Medicines Agency. Ultomiris. [accessed March 2022] Available at: Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/ultomiris , last time [ Links ]

8. Trimarchi H, Gianserra R, Lampo M, Monkowski M, Lodolo J. Eculizumab, SARS-CoV-2 and atypical hemolytic uremic syndrome. Clin Kidney J. 2020;13:739-41. doi: 10.1093/ckj/sfaa166. [ Links ]

9. Gill J, Hebert CA, Colbert GB. COVID-19-associated atypical hemolytic uremic syndrome and use of eculizumab therapy. J Nephrol. 2022;35:317-21. doi: 10.1007/s40620-021-01125-8. [ Links ]

10. Boldig K, Batra R, Villegas A. COVID-19: A Rare Cause of Hemolytic Uremic Syndrome. Cureus. 2022;14:e27962. doi: 10.7759/cureus.27962. [ Links ]

Fontes de Financiamento: Não existiram fontes externas de financiamento para a realização deste artigo.

Confidencialidade dos Dados: Os autores declaram ter seguido os protocolos da sua instituição acerca da publicação dos dados de doentes.

Consentimento: Consentimento do doente para publicação obtido.

Proveniência e Revisão por Pares: Não comissionado; revisão externa por pares.

Financing Support: This work has not received any contribution, grant or scholarship.

Confidentiality of Data: The authors declare that they have followed the protocols of their work center on the publication of data from patients.

Patient Consent: Consent for publication was obtained.

Provenance and Peer Review: Not commissioned; externally peer reviewed.

© Autor (es) (ou seu (s) empregador (es)) e Revista SPMI 2023. Reutilização permitida de acordo com CC BY. Nenhuma reutilização comercial. © Author(s) (or their employer(s)) and SPMI Journal 2023. Re-use permitted under CC BY- commercial re-use.

Received: February 15, 2023; Accepted: May 22, 2023

Correspondence / Correspondência: Cristiana Honrado Martins - cristiana.honrado.martins@hb.min-saude.pt Serviço de Oncologia Médica, Hospital de Braga, Braga, Rua das Comunidades Lusíadas 133, Braga

Declaração de Contribuição CHM: Conceção do trabalho, rascunho do artigo e revisão crítica. JDC, PP: Recolha de dados e pesquisa bibliográfica. ARM: Conceção do trabalho, revisão crítica e aprovação da versão final. VG, GCG: Revisão crítica e aprovação da versão final. Todos os autores aprovaram a versão final a ser publicada Contributorship Statement CHM: concept of the work, draft of the paper, critical review. JDC, PP: data collection and bibliography research. ARM: concept of the work, critical review and approval of the final ver-sion. VG, GCG: critical review and approval of the final version. All authors approved the final draft

Conflitos de Interesse: Os autores declaram a inexistência de conflitos de interesse na realização do presente trabalho.

Conflicts of interest: The authors have no conflicts of interest to declare.

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