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Schistosomiasis-associated pulmonary arterial hypertension: a systematic review

Daniela Knafl, Christian Gerges, Charles H. King, Marc Humbert, Amaya L. Bustinduy
European Respiratory Review 2020 29: 190089; DOI: 10.1183/16000617.0089-2019
Daniela Knafl
1Dept of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
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  • ORCID record for Daniela Knafl
Christian Gerges
2Dept of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
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  • For correspondence: christian.gerges@meduniwien.ac.at
Charles H. King
3Center for Global Health and Diseases, PAHO/WHO Collaborating Centre for Research and Training for Schistosomiasis Elimination, Case Western Reserve University School of Medicine, Cleveland, OH, USA
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Marc Humbert
4Faculté de Médecine, Université Paris-Sud and Université Paris-Saclay, Le Kremlin-Bicêtre, France
5INSERM UMR_S 999, Le Plessis-Robinson, France
6AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France
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Amaya L. Bustinduy
7Dept of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK
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  • FIGURE 1
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    FIGURE 1

    Flow diagram for search and selection of included studies [27].

  • FIGURE 2
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    FIGURE 2

    Main pathophysiologic pathways in schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH). Schematic diagram depicting the main pathophysiologic mechanisms involved in Sch-PAH, which have been described previously in idiopathic pulmonary arterial hypertension. ALK: activin receptor-like kinase; BMP: bone morphogenetic protein; BMP-R: bone morphogenetic protein receptor; cGMP: cyclic guanosine monophosphate; EC: endothelial cell; GMP: guanosine monophosphate; GTP: guanosine triphosphate; HIF: hypoxia-inducible factor; IL: interleukin; IL-13R: IL-13 receptor; IL-4R: IL-4 receptor; JAK: Janus kinase; NO: nitric oxide; NOS: nitric oxide synthase; PASMC: pulmonary arterial smooth muscle cell; sGC: soluble guanylate cyclase; STAT: signal transducer and activator of transcription; TGF-β: transforming growth factor β; TGF-βR: TGF-β receptor; TYK: tyrosine kinase; VEGF: vascular endothelial growth factor.

Tables

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  • TABLE 1

    Comparison of pathophysiological mechanisms in idiopathic pulmonary arterial hypertension (iPAH) and schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH)

    MoleculesExpressionPathways affectedVascular cells affectedTargeted therapies for iPAHSimilarities with Sch-PAHStudy designs in Sch-PAH studies[Ref]
    BMPR-II↓Cell apoptosis ↓
    Inflammation ↑
    EC, SMCFK506# indirectly by IL-2 inhibition+Animal study, Database study[30, 42, 43, 44–48]
    Caveolin-1↓Cell proliferation ↑EC−−Animal study[39, 43, 49]
    Endothelin-1↑Cell apoptosis ↓
    Cell proliferation ↑
    EC, SMC, AFERA (bosentan, macitentan, ambrisentan)NA−[43, 50]
    HIF-1α↑Cell proliferation ↑
    Cell apoptosis ↓
    EC, SMC, AF−+Animal study[28, 43, 51]
    IL-6↑Inflammation ↑ECTocilizumab#+/−Animal study[36, 43, 52–54]
    [K+] channels↓Cell apoptosis ↓
    Vasoconstriction ↑
    SMC−NA−[43, 87, 55]
    MIP-1α↑Inflammation ↑Macrophage−NA−[43, 56]
    MMP-2↑Cell proliferation ↑SMC−NA−[43, 57, 58]
    MT-MMP1↑Cell proliferation ↑SMC−NA−[43]
    Nitric oxide↓Cell proliferation ↑
    Clotting ↑
    Inflammation ↑
    EC, SMCPDE5i (sildenafil, tadalafil)
    Soluble guanylate cyclase stimulators (riociguat)
    +Animal study[39, 43, 50, 59]
    PDGF↑Cell proliferation ↑EC, SMC, AFPDGFR inhibitor (imatinib¶)+/−Case–control study[43, 60–62]
    E-selectin↑Cell proliferation ↑EC−+Case–control study[62]
    P-selectin↑Cell proliferation ↑EC−+Case–control study[62]
    Prostacyclin↓Cell proliferation ↑
    Clotting ↑
    EC, SMCProstacyclin analogues (e.g. epoprostenol, treprostinil)
    Prostacyclin receptor stimulator (selexipag)
    NA−[43, 63–65]
    CCL5/RANTES↑Inflammation ↑Macrophage−NA−−[43, 66]
    TGF-β↑Cell proliferation ↑SMC, AF+Case–control study, human necropsy study, animal study, in vitro study[31, 32, 35, 38, 40, 43, 67, 68]
    TGF-βR2↓Cell apoptosis ↓
    Inflammation ↑
    EC, SMC−+in vitro study[41, 43, 68, 69]
    TIMP-1↑Cell proliferation ↑SMC−NA−[43, 57, 70]
    VEGF↑Cell apoptosis ↓
    Cell proliferation ↑
    Clotting ↑
    Inflammation ↑
    EC, SMC+Animal study[28, 29, 43, 71]
    vWF↑Clotting ↑
    Inflammation ↑
    EC, SMC−NA−[43, 72]
    5-HT transporter/
    receptor
    ↑Cell proliferation ↑
    Vasoconstriction ↑
    SMCNA−[44, 73]

    Selected pathophysiological patterns for iPAH as presented at WSPH 2018 [42], sought for similarities in Sch-PAH. BMPR-II: bone morphogenetic protein receptor type 2; HIF-1α: hypoxia-inducible factor 1-α; IL: interleukin; MIP-1α: macrophage inflammatory protein 1-α; MMP-2: matrix metalloproteinase-2; MT-MMP1: membrane-type MMP-1; PDGF: platelet-derived growth factor; TGF-β: transforming growth factor β; TGF-βR2: transforming growth factor β receptor 2; TIMP-1: tissue inhibitor of metalloproteinases-1; VEGF: vascular endothelial growth factor; vWF: von Willebrand factor; 5-HT: serotonin; EC: endothelial cell; SMC: smooth muscle cell; AF: adventitial fibroblast; ERA: endothelin receptor antagonist; PDE5i: phosphodiesterase-5 inhibitor; NA: not applicable. −: different in iPAH and Sch-PAH; +: similar in iPAH and Sch-PAH. #: drugs currently under investigation, that are not yet approved for therapy of iPAH; ¶: negative trials in humans. Data from [43].

    • TABLE 2

      Comparison of haemodynamics of patients with schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) and (idiopathic pulmonary arterial hypertension) iPAH

      Haemodynamic variableSch-PAHiPAHp-value
      nmean±sdnmean±sd
      CO L·min−11814.4±1.31444.1±1.40.046
      CI L·min−1·m−21042.6±0.733882.3±0.8<0.001
      mRAP mmHg27711±5353210±60.007
      mPAP mmHg27754±17353255±150.290
      mPAWP mmHg19312±4314210±4<0.001
      PVR WU27710±6139613±7<0.001

      CO: cardiac output; CI: cardiac index; mRAP: mean right atrial pressure; mPAP: mean pulmonary artery pressure; mPAWP: mean pulmonary arterial wedge pressure; PVR: pulmonary vascular resistance. Bold in p-values idicates significance.

      • TABLE 3

        Comparison of survival of patients with schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) and idiopathic pulmonary arterial hypertension (iPAH)

        SurvivalSch-PAHiPAHp-value
        nmean±sdnmean±sd
        1-year19191.0±9.9365386.1±9.7<0.001
        2-year19184.3±20.8164475.7±11.7<0.001
        3-year19173.0±26.8365367.3±14.1<0.001
        5-year10279.0±14.1263052.5±19.9<0.001

        Bold in p-values indicates significance.

        Supplementary Materials

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          ERR-0089-2019_Supplementary material ERR-0089-2019_Supplementary_material

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        Schistosomiasis-associated pulmonary arterial hypertension: a systematic review
        Daniela Knafl, Christian Gerges, Charles H. King, Marc Humbert, Amaya L. Bustinduy
        European Respiratory Review Mar 2020, 29 (155) 190089; DOI: 10.1183/16000617.0089-2019

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        Schistosomiasis-associated pulmonary arterial hypertension: a systematic review
        Daniela Knafl, Christian Gerges, Charles H. King, Marc Humbert, Amaya L. Bustinduy
        European Respiratory Review Mar 2020, 29 (155) 190089; DOI: 10.1183/16000617.0089-2019
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