Authors:
B. Székács Department of Internal Medicine and Oncology, Geriatrics Section, Semmelweis University, Budapest, Hungary
Department of Geriatrics and Gerontopsychiatry, Szent Imre University Teaching Hospital, Budapest, Hungary

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S. Várbíró Department of Obstetrics and Gynecology, Faculty of Medicine, Semmelweis University, Budapest, Hungary

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L. Debreczeni Department of Central Laboratory, Szent Imre University Teaching Hospital, Budapest, Hungary

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Abstract

Purpose

We aimed to critically review the available information on the potential contribution of excessive kallikrein-kinin systems (KKSs) activation to severe respiratory inflammation in SARS-CoV-2 infection, and the likely consequence of ACE inhibition in seriously affected patients.

Methods

The literature related to the above topic was reviewed including papers that analysed the connections, actions, interactions, consequences and occasionally suggestions for rational interventions.

Results/Conclusion

Severe broncho-alveolar inflammation seems to be caused, at least in part, by upregulation of the KKS that increases plasma and/or local tissue concentrations of bradykinin (BK) in patients with COVID-19 infection. Besides KKS activation, suppression of ACE activity results in decreased bradykinin degradation, and these changes in concert can lead to excessive BK B1 and B2 receptor (BKB1R/BKB2R) activation. Aminopeptidase P (APP), and carboxypeptidase N also degrade bradykinin, but their protein expression and activity are unclear in COVID-19 infection. On the other hand, ACE2 expression is upregulated in patients with COVID-19 infection, so ACE2 activity is unlikely to be decreased despite blockade of part of ACE2 by the virus for entry into the cells. ACE2 cleaves lys-des-arginine9BK and arg-des-arginine9BK, the active metabolites of bradykinin, which stimulate the BKB1R receptor. Stimulation of BKB1R/BKB2R can exacerbate the pulmonary inflammatory response by causing vascular leakage and edema, vasodilation, smooth muscle spasm and stimulation of pain afferent nerves. Despite all uncertainties, it seems rational to treat comorbid COVID patients with serious respiratory distress syndrome with ARBs instead of high-dose ACE inhibitor (ACEi) that will further decrease bradykinin degradation and enhance BKB1R/BKB2R activation, but ACEi may not be contraindicated in patients with mild pulmonary symptoms.

Abstract

Purpose

We aimed to critically review the available information on the potential contribution of excessive kallikrein-kinin systems (KKSs) activation to severe respiratory inflammation in SARS-CoV-2 infection, and the likely consequence of ACE inhibition in seriously affected patients.

Methods

The literature related to the above topic was reviewed including papers that analysed the connections, actions, interactions, consequences and occasionally suggestions for rational interventions.

Results/Conclusion

Severe broncho-alveolar inflammation seems to be caused, at least in part, by upregulation of the KKS that increases plasma and/or local tissue concentrations of bradykinin (BK) in patients with COVID-19 infection. Besides KKS activation, suppression of ACE activity results in decreased bradykinin degradation, and these changes in concert can lead to excessive BK B1 and B2 receptor (BKB1R/BKB2R) activation. Aminopeptidase P (APP), and carboxypeptidase N also degrade bradykinin, but their protein expression and activity are unclear in COVID-19 infection. On the other hand, ACE2 expression is upregulated in patients with COVID-19 infection, so ACE2 activity is unlikely to be decreased despite blockade of part of ACE2 by the virus for entry into the cells. ACE2 cleaves lys-des-arginine9BK and arg-des-arginine9BK, the active metabolites of bradykinin, which stimulate the BKB1R receptor. Stimulation of BKB1R/BKB2R can exacerbate the pulmonary inflammatory response by causing vascular leakage and edema, vasodilation, smooth muscle spasm and stimulation of pain afferent nerves. Despite all uncertainties, it seems rational to treat comorbid COVID patients with serious respiratory distress syndrome with ARBs instead of high-dose ACE inhibitor (ACEi) that will further decrease bradykinin degradation and enhance BKB1R/BKB2R activation, but ACEi may not be contraindicated in patients with mild pulmonary symptoms.

Introduction

The high mortality rate of elderly vulnerable hypertensive patients infected with acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is often associated with cytokine storm [1]. Several cytokines were measured or suggested to contribute to the development of serious pulmonary inflammation [2–4] but no direct information is available on the plasma or tissue concentrations of bradykinin and kallidin (lysine-bradykinin), and their active metabolites (bradykinin-related peptides). The kallikrein-kinin system (KKS) is upregulated in many inflammatory diseases [5], and in the bronchoalveolar lavage fluid of COVID-19 patients [6]. Therefore, it seems reasonable to assume that the concentration of bradykinin peptides is markedly elevated in COVID-19 patients. The consequent overactivation of bradykinin B1 and B2 receptors (BKB1R/BKB2R) prompted us to ask the question: is angiotensin converting enzyme (ACE) inhibitor treatment safe in patients with virus-induced severe pulmonary inflammation? (Fig. 1)

Fig. 1.
Fig. 1.

Relationship of RAS and kinin-kallikrein system and its changes in SARS-CoV-2 infection based on Veerdonk et al. [6]. Abbreviations: ANGI, ANGII: angiotensin I, angiotensin II; APA: aminopeptidase-A; AT1R: angiotensin II type 1 receptor; AT2R: angiotensin II type 2 receptor; ATIII: angiotensin III; B1R: bradykinin type 1 receptor; B2R: bradykinin type 2 receptor; Des Arg9BK: [des-Arg9]-bradykinin; Lys desArg9 BK: [Lys-des-Arg9]-bradykinin; NAD(P)H oxide: NAD(P)H oxidase. MAS: mitochondrial assembly receptor (PCR (G-protein–coupled receptor), through which Ang (angiotensin)-(1–7) signals

Citation: Physiology International 108, 1; 10.1556/2060.2021.00007

The kallikrein-kinin system

The KKS, an endogenous multiprotein cascade, has a basic physiological/pathophysiological role not only in the coagulation pathway (risk of thrombosis) but also in the inflammatory response via bradykinin and bradykinin-related peptides. There are 15 tissue kallikrein proteins, out of which kallikrein 1 is the main type expressed in the lung tissue of healthy persons. However, all 15 kallikreins are robustly expressed in COVID-19 patients. The bradykinin-related peptides cleaved from kininogens have a variety of actions including vasodilatory activity, increased vascular permeability and nitric oxide production, spasm of smooth muscle in airways, exaggerated release of several cytokines by leukocytes and of prostaglandins and leukotrienes by various cell types [7, 8]. The short bradykinin B2 receptor (B2) is constitutively expressed and stimulated mainly by bradykinin, and it is mainly involved in the early inflammatory reactions by causing vasodilation, smooth muscle contraction and by releasing arachidonate products and pro-inflammatory cytokines. Arachidonic acid release temporarily desensitises the B2 receptor, which is, however, rapidly re-sensitised by several factors, including angiotensin 1-9 and bradykinin [9, 10]. The actions of active bradykinin-metabolites, such as des-arginine9BK (DABK) and lys-des-arginine9BK (LYDABK) are mediated via BKB1R, which is induced by tissue injury and pro-inflammatory cytokines. BKB1R initiates an array of long-lasting intracellular and intercellular responses, including increased vascular permeability and release of a variety of biologically active pro-inflammatory agents [11, 12]. Therefore, in COVID-19 infection both BKB2R and BKB1R play a significant and complex role in severe pulmonary and multi-organ inflammation. Their signal transduction can even be enhanced by spontaneous BKB2R–BKB1R-complex formation [13]. The KKS has multiple interactions with other endogenous metabolic cascades, such as the renin-angiotensin system (RAS) and the complement system [14, 15]. SARS-Cov-2 activates the KKS axis in the bronchoalveolar tissue [16]. Although there are some uncertainties, the upregulated kallikrein is likely able to modulate the RAS by increasing prorenin expression [17]. On the other hand, both ACE and ACE2, the two major intrinsic regulators of RAS, have an inhibitory effect on KKS by their strong and specific kininase activity [11, 18]. Imai et al. stressed the significance of this relationship already in 2007 in acute respiratory distress syndrome (ARDS) [19]. Downregulation of ACE2 expression by HCoV-NL63 coronavirus was also proved (but some opposite results are also available) during that period [20, 21]. However, ACE2 mRNA expression was strongly induced in the bronchoalveolar lavage fluid of COVID-19 patients [16]. Based on the assumption that ACE2 activity is decreased by its occupation by the virus, and, consequently, decreased destruction of the inflammatory mediator des-arg9-bradykinin and consequent BKB1R activation can lead to worse disease outcome, it was suggested that blocking BKB2R and inhibiting plasma kallikrein activity can be beneficial [6]. Another problem is, whether or not the supposedly higher ACE2 expression induced by ACE inhibitor therapy promotes the dynamics of SARS-CoV-2 entering into respiratory tissues [22]. Thus, considering the relationship between severe respiratory inflammation and RAS inhibitor therapy, the majority of publications focused mainly on „bad” ACE2 as the receptor for SARS CoV-2 and „good” ACE2 promoting the conversion of the vasopressor and pro-inflammatory angiotensin II to vasodilator and anti-inflammatory angiotensin 1-7 [23]. The recommendation of papers and scientific societies was not to stop or change cardiovascular ACE inhibitor therapy after the start of infection in SARS-CoV-2 patients [24], although expression of ACE is increased and ACE2 is decreased in old, vulnerable patients that leads to higher AngII and lower Ang(1-7) concentrations and an unfavourable balance between AT1R and Mas receptor (MasR) activation [25]. One pillar of this initiative was that following SARS-CoV-2 infection, the vasoconstrictor and pro-inflammatory angiotensin II level was elevated [26], but it was assayed using a method criticised later [27]. However, these authors neglect the role of the closely related KKS.

The above-cited scientific knowledge on the KKS and the role of bradykinin as an important player that can directly affect the clinical outcome in severe respiratory and systemic inflammation and can contribute to the cytokine storm was mentioned in several papers [1, 6, 14, 28–30]. On the basis of earlier scientific findings, some researchers tried to prove the pathological importance of KKS in the inflammatory process by combined BKB1R and BKB2R blockade or kallikrein inhibition, assuming increased BK and DABK/LYDABK concentrations and higher BKB1R and BKB2R receptor activation in COVID-19 infection although no approved inhibitors are available [6, 15]. Some of these interventions improved pulmonary inflammation in experimental animals, supporting a role of KKS and BK in severe respiratory and systemic inflammation caused by SARS-CoV-2 infection [6, 15]. Replacing kininase activity of ACE2 (neprilysin) may offer partial therapeutic promises for severe COVID-19 patients in the future [6, 30]. Another potential way to inhibit BKB1R activity is blocking innate cytokines (IL-1) that upregulates BKB1R on endothelial cells at the site of inflammation [6].

RAS dysregulation

RAS dysregulation and dysregulated RAS-KKS interaction can have an important role in severe COVID-19 inflammation. Potential virus-induced kallikrein-prorenin upregulation was already mentioned above. The basic intrinsic regulator ACE2 enzyme/ACE2-receptor system appears to be Janus-faced in coronavirus infection [23]. The ACE2-receptor is the cellular entry point (spike protein) for coronaviruses that leads to severe inflammation in the lungs or in other organs [19, 23]. This could mean that increased expression of the ACE2 gene may accelerate SARS-Cov-2 replication. Moreover, it has been also described that bradykinin, angiotensin and coagulation system proteins are co-expressed with ACE2 in alveolar cells [31]. This relationship provoked much debate on the potential danger of ACE inhibitor treatment-induced ACE2 upregulation. However, this upregulation was supported by findings from animal experiments, but clinical studies or observations could not prove it [32].

There are contradicting results whether ACE 2 expression was downregulated or upregulated after binding of the virus spike protein to the ACE2 receptor [33]. Previous experiments with other coronaviruses mostly found downregulation [20]. It should be noted that increased expression of ACE2 does not mean higher peptidase activity in COVID-19, because the ACE2 protein will likely be used for viral entry, i.e. invasion of host cells, and not for peptidase activity. A recent observation further complicates the issue, as binding of the spike protein to ACE2 increased peptidase activity, in vitro [34]. However, the clinical consequence and time-course of this finding is unclear, as the SARS-CoV-2-CAE2 complex is internalised shortly after binding.

After interaction with the viral spike protein, ACE2 is internalised along with the virus and the spike protein is proteolytically cleaved by type II transmembrane serine protease (TMPRSS2). The metalloproteinase domain 17 (ADAM17) and TMPRSS2 upregulation (activated partly by decreased ACE2 activity that increases Ang II concentration and AT1 receptor activation) leads to proteolytic cleavage of the ACE2 ectodomain, shedding it into the extracellular space. ADAM17 also cleaves TNFα, IL-6 and other proinflammatory molecules releasing them from the cell membrane [33]. The complexity of these events in COVID-19 can explain that the level of ACE2 in plasma measured by immunoassays can hardly inform us about the real (and changing) rate of expression and activity of membrane-bound ACE2 [20]. In the ‘post-infection’ phase ACE2 activity can probably provide some anti-inflammatory effects. Theoretically, the RAS inhibitor-induced ACE2 upregulation could be useful in this phase, if this effect exists at all. The anti-inflammatory activity of ACE2 and its relation to bradykinin activity has been first proven in a ‘virus-free’ experiment: the experimentally reduced ACE2 activity resulted in both increased activity of the BKB1R axis and the exacerbation of artificially induced inflammation in a cell culture [35]. One of the ACE2-induced potentially protective, anti-inflammatory mechanisms is that ACE2 can convert the vasoconstrictor and weak pro-inflammatory peptide Ang II to angiotensin 1-7, which in turn has some anti-inflammatory effect via MasR. Another protective, probably more important effect in COVID-19 is that ACE2 is also a kininase for DABK and LYDABK. Therefore, ACE2 can reduce the activation of the strong inflammatory mediator BKB1R and inhibit broncho-alveolar inflammation [19, 35]. The inter-individual and ethnic variability of infectivity and the clinical outcome of Covid-19 pneumonia can most likely be explained by the various levels of ACE2 activity before and/or after the entry of coronavirus via ACE2 into the bronchoalveolar cells. In this respect it is interesting that the individual expression rate and pattern of ACE2 gen (genetic variants of ACE2 with different affinities for spike protein) seem to depend on gender, age and perhaps ethnic factors (higher in women, lower in elderly and higher in East Asians) [5]. However, very recent publications highlighted contradictions and methodological problems in some studies, and drew attention to the need of reinvestigation using extended and up-to-date methodology [36]. If the similarly questionable validity of the suggested ACE2 upregulation by RAS inhibitor-treatment could be conclusively demonstrated, it would also support the anti-inflammatory usefulness of this intervention in the post-infection period [37]. The previously proposed ACE upregulation [38] has not been proven recently in essentially hypertensive patients with or without COVID-19 infection [16]. Similarly, no higher Ang II levels were found in their plasma, when really valid and sensitive assays were carried out [27]. ACE as a kininase also cleaves the bradykinin peptide. Inhibition of this ACE-related kininase activity results in the well-known side effects (cough, angioneurotic oedema) [6, 18, 29]. When a higher dose of ACEi is used, it results in a supra-normal level of bradykinin concentration in the bronchoalveolar tissue. This bradykinin excess-related irritative and inflammatory effect of ACE inhibitors can become more dangerous in COVID-19, as it adds on to the already markedly increased bradykinin level. Several pathological mechanisms in KKS-RAS inter-regulation can promote the development of the SARS-CoV-2 related inflammation, resulting in increased production and suppressed degradation of bradykinin and its active metabolites leading to highly activated BKB2R and DABK/LYDA BKB1R axles. The former possibility is based on the ‘Veerdonk model’, i.e. suppressed ACE2 expression and activity, similarly to the earlier coronavirus infections [6], and the latter is based on the model described by Garwin et al., i.e. lower ACE and enhanced ACE2 expression, but unknown ACE2 activity because of its fusion with coronavirus and cellular internalisation, and overexpression of BKB2R and BKB1R [16]. The most important arguments for a major role of RAS imbalance and KKS activation in unfavourable outcome in seriously infected patients are the following:

  1. a)The SARS-COV-2 virus can directly increase bradykinin production by kallikrein (and kallidin) upregulation [16].
  2. b)Binding of the virus spike protein to ACE2 uses up ACE2 and, consequently, decreases the cleaving of DABK and LYSDABK and increases BKB1R activation.
  3. c)In the case of lower ACE activity, Ang(1-9) (produced by ACE2 from angiotensin I in small amounts) is less converted to Ang(1-7) peptide, so it may facilitate BKB2R resensitisation [16]. Spontaneous BKB2R–BKB1R-complex formation may further increase BKB1R activation [11].
  4. d)A recent study from Garvin et al. highlighted the outstanding significance of not only the critically increased bradykinin axis (thousand-fold and hundred-fold upregulation of BKB1R and BKB2R mRNA, respectively), but also the surprisingly strong, 8-fold downregulation of ACE mRNA expression in bronchoalveolar lavage fluid (BALF) from COVID-19 patients [16]. The affinity of ACE is higher for the degradation of bradykinin than for Ang I-Ang II conversion [39]. Therefore, in this special pathological situation inhibition of ACE activity means rather less bradykinin cleaving, and, as a consequence, a critically dangerous activation of BKB2R and BKB1R [13, 16].

Conclusions

In severe COVID-19 pulmonary infection the excess of bradykinin and its active metabolites and the consequent BKB2R and BKB1R hyperactivation might play an important role in the development of critical bronchoalveolar inflammation and ARDS (bradykinin-cytokine storm).

The background of this pathological condition includes an increased production of bradykinin due to virus-induced kallikrein-kinin upregulation, dysregulated RAS-KKS relationship, consequently decreased kininase activity, insufficient degradation of BK, DABK and LYDABK, extremely high BKB2R and BKB1R (inducible) expression.

In this state, the inhibition of the already downregulated ACE activity may result in bradykinin-related critical worsening of the hyperinflammation in the lungs.

Switching from high dose ACEi to ARB or to other antihypertensive drugs in the most severe cases of RDS may help avoid ACEi-triggered harmful pharmacological enhancement of the severe bronchoalveolar BK-related hyperinflammation. In fact, a recent study aimed to inhibit kallikrein by aprotinin, a competitive inhibitor of several serine proteases, in combination with low molecular weight heparins, as it was suspected that the KKS-BK overactivation played a major role in the thrombotic and inflammatory responses in COVID infection [40]. However, in less severe cases ACEi is not contraindicated as shown recently [24, 41]. Therefore, our suggestion to avoid ACEi is restricted to the most severe SARS-Cov-19 infected, ARDS cases with life-threatening virus-activated cytokine storm.

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Editor-in-Chief

László ROSIVALL (Semmelweis University, Budapest, Hungary)

Managing Editor

Anna BERHIDI (Semmelweis University, Budapest, Hungary)

Co-Editors

  • Gábor SZÉNÁSI (Semmelweis University, Budapest, Hungary)
  • Ákos KOLLER (Semmelweis University, Budapest, Hungary)
  • Zsolt RADÁK (University of Physical Education, Budapest, Hungary)
  • László LÉNÁRD (University of Pécs, Hungary)
  • Zoltán UNGVÁRI (Semmelweis University, Budapest, Hungary)

Assistant Editors

  • Gabriella DÖRNYEI (Semmelweis University, Budapest, Hungary)
  • Zsuzsanna MIKLÓS (Semmelweis University, Budapest, Hungary)
  • György NÁDASY (Semmelweis University, Budapest, Hungary)

Hungarian Editorial Board

  • György BENEDEK (University of Szeged, Hungary)
  • Zoltán BENYÓ (Semmelweis University, Budapest, Hungary)
  • Mihály BOROS (University of Szeged, Hungary)
  • László CSERNOCH (University of Debrecen, Hungary)
  • Magdolna DANK (Semmelweis University, Budapest, Hungary)
  • László DÉTÁRI (Eötvös Loránd University, Budapest, Hungary)
  • Zoltán GIRICZ (Semmelweis University, Budapest, Hungary and Pharmahungary Group, Szeged, Hungary)
  • Zoltán HANTOS (Semmelweis University, Budapest and University of Szeged, Hungary)
  • Zoltán HEROLD (Semmelweis University, Budapest, Hungary) 
  • László HUNYADI (Semmelweis University, Budapest, Hungary)
  • Gábor JANCSÓ (University of Pécs, Hungary)
  • Zoltán KARÁDI (University of Pecs, Hungary)
  • Miklós PALKOVITS (Semmelweis University, Budapest, Hungary)
  • Gyula PAPP (University of Szeged, Hungary)
  • Gábor PAVLIK (University of Physical Education, Budapest, Hungary)
  • András SPÄT (Semmelweis University, Budapest, Hungary)
  • Gyula SZABÓ (University of Szeged, Hungary)
  • Zoltán SZELÉNYI (University of Pécs, Hungary)
  • Lajos SZOLLÁR (Semmelweis University, Budapest, Hungary)
  • Gyula TELEGDY (MTA-SZTE, Neuroscience Research Group and University of Szeged, Hungary)
  • József TOLDI (MTA-SZTE Neuroscience Research Group and University of Szeged, Hungary)
  • Árpád TÓSAKI (University of Debrecen, Hungary)

International Editorial Board

  • Dragan DJURIC (University of Belgrade, Serbia)
  • Christopher H.  FRY (University of Bristol, UK)
  • Stephen E. GREENWALD (Blizard Institute, Barts and Queen Mary University of London, UK)
  • Osmo Otto Päiviö HÄNNINEN (Finnish Institute for Health and Welfare, Kuopio, Finland)
  • Helmut G. HINGHOFER-SZALKAY (Medical University of Graz, Austria)
  • Tibor HORTOBÁGYI (University of Groningen, Netherlands)
  • George KUNOS (National Institutes of Health, Bethesda, USA)
  • Massoud MAHMOUDIAN (Iran University of Medical Sciences, Tehran, Iran)
  • Tadaaki MANO (Gifu University of Medical Science, Japan)
  • Luis Gabriel NAVAR (Tulane University School of Medicine, New Orleans, USA)
  • Hitoo NISHINO (Nagoya City University, Japan)
  • Ole H. PETERSEN (Cardiff University, UK)
  • Ulrich POHL (German Centre for Cardiovascular Research and Ludwig-Maximilians-University, Planegg, Germany)
  • Andrej A. ROMANOVSKY (University of Arizona, USA)
  • Anwar Ali SIDDIQUI (Aga Khan University, Karachi, Pakistan)
  • Csaba SZABÓ (University of Fribourg, Switzerland)
  • Eric VICAUT (Université de Paris, UMRS 942 INSERM, France)
  • Nico WESTERHOF (Vrije Universiteit Amsterdam, The Netherlands)

 

Editorial Correspondence:
Physiology International
Semmelweis University
Faculty of Medicine, Institute of Translational Medicine
Nagyvárad tér 4, H-1089 Budapest, Hungary
Phone/Fax: +36-1-2100-100
E-mail: pi@semmelweis-univ.hu

Indexing and Abstracting Services:

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  • SCOPUS
  • WoS - Science Citation Index Expanded

 

2022  
Web of Science  
Total Cites
WoS
335
Journal Impact Factor 1.4
Rank by Impact Factor

Physiology (Q4)

Impact Factor
without
Journal Self Cites
1.4
5 Year
Impact Factor
1.6
Journal Citation Indicator 0.42
Rank by Journal Citation Indicator

Physiology (Q4)

Scimago  
Scimago
H-index
33
Scimago
Journal Rank
0.362
Scimago Quartile Score

Physiology (medical) (Q3)
Medicine (miscellaneous) (Q3)

Scopus  
Scopus
Cite Score
2.8
Scopus
CIte Score Rank
Physiology 68/102 (33rd PCTL)
Scopus
SNIP
0.508

2021  
Web of Science  
Total Cites
WoS
330
Journal Impact Factor 1,697
Rank by Impact Factor

Physiology 73/81

Impact Factor
without
Journal Self Cites
1,697
5 Year
Impact Factor
1,806
Journal Citation Indicator 0,47
Rank by Journal Citation Indicator

Physiology 69/86

Scimago  
Scimago
H-index
31
Scimago
Journal Rank
0,32
Scimago Quartile Score Medicine (miscellaneous) (Q3)
Physiology (medical) (Q3)
Scopus  
Scopus
Cite Score
2,7
Scopus
CIte Score Rank
Physiology (medical) 69/101 (Q3)
Scopus
SNIP
0,591

 

2020  
Total Cites 245
WoS
Journal
Impact Factor
2,090
Rank by Physiology 62/81 (Q4)
Impact Factor  
Impact Factor 1,866
without
Journal Self Cites
5 Year 1,703
Impact Factor
Journal  0,51
Citation Indicator  
Rank by Journal  Physiology 67/84 (Q4)
Citation Indicator   
Citable 42
Items
Total 42
Articles
Total 0
Reviews
Scimago 29
H-index
Scimago 0,417
Journal Rank
Scimago Physiology (medical) Q3
Quartile Score  
Scopus 270/1140=1,9
Scite Score  
Scopus Physiology (medical) 71/98 (Q3)
Scite Score Rank  
Scopus 0,528
SNIP  
Days from  172
submission  
to acceptance  
Days from  106
acceptance  
to publication  

2019  
Total Cites
WoS
137
Impact Factor 1,410
Impact Factor
without
Journal Self Cites
1,361
5 Year
Impact Factor
1,221
Immediacy
Index
0,294
Citable
Items
34
Total
Articles
33
Total
Reviews
1
Cited
Half-Life
2,1
Citing
Half-Life
9,3
Eigenfactor
Score
0,00028
Article Influence
Score
0,215
% Articles
in
Citable Items
97,06
Normalized
Eigenfactor
0,03445
Average
IF
Percentile
12,963
Scimago
H-index
27
Scimago
Journal Rank
0,267
Scopus
Scite Score
235/157=1,5
Scopus
Scite Score Rank
Physiology (medical) 73/99 (Q3)
Scopus
SNIP
0,38

 

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Physiology International
Language English
Size B5
Year of
Foundation
2006 (1950)
Volumes
per Year
1
Issues
per Year
4
Founder Magyar Tudományos Akadémia
Founder's
Address
H-1051 Budapest, Hungary, Széchenyi István tér 9.
Publisher Akadémiai Kiadó
Publisher's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Responsible
Publisher
Chief Executive Officer, Akadémiai Kiadó
ISSN 2498-602X (Print)
ISSN 2677-0164 (Online)

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