COVID-19重症肺障害の病態メカニズムを肺移植患者の肺から検討した

重症COVID-19における肺障害に対する最終手段として、アメリカでは肺移植が行われています（https://medicalxpress.com/news/2020-12-covid-lungs-badly-transplant.html?fbclid=IwAR3CULQ1661IS4ROkV1TTO2kRyed-7oUdx3Z-rGwYw5jGmRzYlKWfNerqSA）。Northwestern大学からの下記論文では、肺移植を受けた3名の患者および呼吸不全で亡くなった患者2名の肺組織を解析し、これらの患者肺ではsingle molecule fluorescent in situ hybridization (smFISH)でSARS-CoV-2ウイルスは検出されなかったこと、組織学的には重症な肺線維症に近い所見が認められたことを報告しています。また肺線維症の患者と重度のCOVID-19の患者の肺組織における線維芽細胞の遺伝子発現プロファイルが類似していることも明らかになりました。つまりいわゆるサイトカインストームを経て重症な呼吸不全をきたしたCOVID-19患者に対しては、ウイルスを取り除くような治療では十分ではないことがわかります。日本でも少しずつ肺移植が増えているとはいえ、年間2,700以上の肺移植が行われているアメリカとは比べるべくもありませんので、どうすればこのような状態にならないかという取り組みが必要です。最近Natureに報告された論文（Conlon, T.M et al. Nature 588, 151–156, 2020）では、LTβRを介したシグナルがWntの抑制を介して肺線維化を促進することが報告されていますが、このような観点からもCOVID-19治療戦略構築が必要かもしれません。

Bharat et al., Lung transplantation for patients with severe COVID-19 Science Translational Medicine  30 Nov 2020:eabe4282 DOI: 10.1126/scitranslmed.abe4282

Lung transplantation for patients with severe COVID-19

Lung transplantation can potentially be a life-saving treatment for patients with non-resolving COVID-19-associated respiratory failure. Concerns limiting lung transplantation include recurrence of SARS-CoV-2 infection in the allograft, technical challenges imposed by viral-mediated injury to the native lung, and the potential risk for allograft infection by pathogens causing ventilator-associated pneumonia in the native lung. Importantly, the native lung might recover, resulting in long-term outcomes preferable to those of transplant. Here, we report the results of lung transplantation in three patients with non-resolving COVID-19-associated respiratory failure. We performed single molecule fluorescent in situ hybridization (smFISH) to detect both positive and negative strands of SARS-CoV-2 RNA in explanted lung tissue from the three patients and in additional control lung tissue samples. We conducted extracellular matrix imaging and single cell RNA sequencing on explanted lung tissue from the three patients who underwent transplantation and on warm post-mortem lung biopsies from two patients who had died from COVID-19-associated pneumonia. Lungs from these five patients with prolonged COVID-19 disease were free of SARS-CoV-2 as detected by smFISH, but pathology showed extensive evidence of injury and fibrosis that resembled end-stage pulmonary fibrosis. Using machine learning, we compared single cell RNA sequencing data from the lungs of patients with late stage COVID-19 to that from the lungs of patients with pulmonary fibrosis and identified similarities in gene expression across cell lineages. Our findings suggest that some patients with severe COVID-19 develop fibrotic lung disease for which lung transplantation is their only option for survival.

Lung transplantation for patients with severe COVID-19