To the Editor,
In this journal, there have been three case reports on severe cases of patients with acute nephropathia epidemica (NE) caused by Puumala hantavirus (PUUV), who were treated with icatibant, a competitive bradykinin receptor type 2 antagonist [Citation1–3]. The two patients described by us survived [Citation1,Citation2], but the Swedish patient had a fatal outcome [Citation3]. Recently Malchair et al. [Citation4] showed in a randomised, open-label clinical trial that adding icatibant to standard care was safe and improved both COVID-19 pneumonia and mortality. Three 30-mg icatibant doses/day were given for three consecutive days in their study.
Hantaviruses cause two kinds of clinical syndromes, haemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) [Citation5]. HFRS-inducing hantaviruses include PUUV and Dobrava virus (DOBV) in Europe, and Hantaan and Seoul viruses in Asia. Sin Nombre, Andes and several other hantaviruses induce HCPS in South and North America [Citation5].
The typical findings in NE are high fever, thrombocytopenia, increased capillary leakage and acute kidney injury (AKI) [Citation5]. Pulmonary involvement is typical for HCPS, but renal involvement is less severe than in hantavirus infections causing HFRS. Pulmonary involvement occurs also in NE [Citation6]. The most common abnormality in chest radiography is pleural effusion but in rare cases severe alveolar oedema and strong pulmonary infiltrates are present. The severity of radiological findings associates with the level of hypoproteinemia, inflammation, and AKI [Citation6].
Our patients were treated in an intensive care unit [Citation1,Citation2]. Both were hypotensive due to severe capillary leakage. Mechanical ventilation was started because of respiratory failure and continuous renal replacement because of AKI. Patients received a single dose (30 mg) of subcutaneous icatibant. The dose was repeated after 6 h in the other patient [Citation2]. After that, the condition of the patients stabilised, followed by gradual improvement.
The pathophysiology of the first patient showed pronounced complement activation, extensive fibrinolysis and circulating histones [Citation7]. Interestingly, the first patient had undergone splenectomy due to congenital spherocytosis [Citation1] and the other had a lymphoproliferative disease involving the spleen [Citation2]. It is known that asplenic individuals are prone to life-threatening infections caused by encapsulated bacteria, additionally a case-report of severe post-splenectomy cytomegalovirus mononucleosis has been reported [Citation8].
The Swedish patient had very low levels of PUUV-neutralizing antibodies, which was suggested to have contributed to fatal outcome of the infection [Citation3]. We have recently reported that the levels of these antibodies do not correlate with the clinical severity of NE [Citation9]. It is possible that icatibant needs to be administered early in the course of the infection in order to be effective [Citation9].
Endothelial cells infected by hantaviruses have increased activation of kinin-kallikrein system (KKS) [Citation10]. This results in the liberation of bradykinin (BK), which is an inducer of vascular permeability, oedema formation and hypotension [Citation10]. COVID-19 infection activates many inflammatory pathways including KKS, complement and coagulation systems [Citation4]. The same features are quite typical for hantavirus infections [Citation5].
Icatibant is indicated for the treatment of acute episodes of hereditary angioedema. Difficulties in measuring BK in patient samples have probably limited the possibility to reveal the role of BK in different clinical settings. By using icatibant it is feasible to detect the role of BK and its blockade in various diseases.
There are similarities in the pathogenesis of infections caused by hantaviruses and COVID-19. The case-fatality rate in PUUV infection is less than 1% while it is about 10% in DOBV infection and up to 40% in patients with HCPS [Citation5]. To get more data about the possible effectiveness of icatibant in the treatment of hantavirus infections, we encourage to study it in severe cases with HFRS and especially in patients with HCPS.
Acknowledgements
The authors would like to acknowledge to contributions of their colleagues.
Disclosure statement
No potential conflict of interest was reported by the author(s).
References
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