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第19回 東京びまん性肺疾患研究会
(2018年10月,東京,砂防会館)

「予後不良なNSIP」

Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper(Lancet Respir Med 2018; 6: 138-53)
(1)CT pattern typical UIP


(2)CT pattern probable UIP

Probable UIP CT pattern
(A-E) CT images show basal predominant, subpleural predominant reticular abnormality, with peripheral traction bronchiectasis (circles in B) but no honeycombing. For this patient, UIP was proven with histology.


(3)CT pattern indeterminate for UIP

(A-E) CT images show reticular abnormality with traction bronchiectasis, without honeycombing. Although the abnormality is lower-lung predominant, the findings are not typical for UIP because of peribronchovascular extension (C), patchy ground glass abnormality, and mosaic attenuation (E). For this patient, UIP was proven at biopsy. UIP=usual interstitial pneumonia.


(A-D) Inspiratory CT images show diffuse, peripheral predominant reticular opacities admixed with patchy areas of decreased (mosaic) attenuation (arrows). For this patient, UIP was proven at biopsy. UIP=usual interstitial pneumonia.


(4)CT pattern most consistent with non-IPF diagnosis

(A-C) Inspiratory CT images show upper-lobe predominant peribronchovascular (bronchocentric) reticular opacities, architectural distortion, severe traction bronchiectasis, and areas of decreased attenuation (B and C; arrows). This CT pattern is consistent with the diagnosis of fibrotic hypersensitivity pneumonitis. IPF=idiopathic pulmonary fibrosis.


・Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline(Am J Respir Crit Care Med. 2018 Sep 1;198(5):e44-e68)

Table 4. High-Resolution Computed Tomography Scanning Patterns
UIP Probable UIP Indeterminate for UIP Alternative Diagnosis
  • Subpleural and basal predominant; distribution is often heterogeneous*
  • Honeycombing with or without peripheral traction bronchiectasis or bronchiolectasis†
  • Subpleural and basal predominant; distribution is often heterogeneous
  • Reticular pattern with peripheral traction bronchiectasis or bronchiolectasis
  • May have mild GGO
  • Subpleural and basal predominant
  • Subtle reticulation; may have mild GGO or distortion (“early UIP pattern”)
  • CT features and/or distribution of lung fibrosis that do not suggest any specific etiology (“truly indeterminate for UIP”)
  • Findings suggestive of another diagnosis, including:
    • CT features:
      • Cysts
      • Marked mosaic attenuation
      • Predominant GGO
      • Profuse micronodules
      • Centrilobular nodules
      • Nodules
      • Consolidation
    • Predominant distribution:
      • Peribronchovascular
      • Perilymphatic
      • Upper or mid-lung
    • Other:
      • Pleural plaques (consider asbestosis)
      • Dilated esophagus (consider CTD)
      • Distal clavicular erosions (consider RA)
      • Extensive lymph node enlargement (consider other etiologies)
      • Pleural effusions, pleural thickening (consider CTD/drugs)

(1)-1 indeterminate for UIP pattern

Indeterminate for usual interstitial pneumonia (UIP) pattern (early UIP pattern). (A and B) Transverse computed tomography (CT) section, (C) coronal reconstruction of both lungs, and (D) magnified view of the right lung in supine position showing ground-glass opacity and subtle reticulation in the subpleural areas (arrows) with a basal predominance. (E) Transverse CT section of the lower lung zones in prone position showing persistence of lung infiltration in nondependent areas, thus excluding gravitational abnormalities. UIP was proven at histology.


(1)-2 indeterminate for UIP pattern

Indeterminate for usual interstitial pneumonia pattern. (A-C) Transverse computed tomography sections showing extensive lung infiltration combining honeycombing, mild to marked ground-glass opacity, asymmetrical distribution between both lungs, and no subpleural predominance.


Indeterminate for UIP pattern
It is now recognized that atypical HRCT features frequently (i.e., about 30%) accompany a histopathologic pattern of UIP/IPF (81). Therefore, the category “indeterminate for UIP pattern” should be assigned when HRCT demonstrates features of fibrosis but does not meet UIP or probable UIP criteria and does not explicitly suggest an alternative diagnosis. This category includes a subset of patients with very limited subpleural ground-glass opacification or reticulation without obvious CT features of fibrosis, for whom there is a suspicion that early UIP or probable UIP is present. In such cases, it should be confirmed with prone inspiratory views that the subpleural opacities do not represent dependent atelectasis (Figure E2).


(2)alternative diagnosis

Computed tomography (CT) pattern suggestive of an alternative diagnosis for lung fibrosis. (A and B) Transverse CT sections obtained at deep inspiration showing disseminated lung infiltration, sparing some secondary pulmonary lobules in lung bases. (C) Transverse CT section obtained at expiration confirming lobular air trapping, all findings being highly suggestive of chronic hypersensitivity pneumonitis.


Alternative diagnosis
In some cases of fibrotic lung disease, there is clinical suspicion of IPF, but the HRCT pattern suggests an alternative diagnosis. Examples include bronchocentric fibrosis in the upper lobes or profuse mosaic attenuation that suggest hypersensitivity pneumonitis, posterior fibrotic retraction of the hila in sarcoidosis, or extensive ground-glass opacification with subpleural sparing in fibrotic nonspecific interstitial pneumonia (NSIP). Occasionally, the HRCT presentation may be that of a UIP, probable UIP, or indeterminate for UIP pattern, but ancillary findings suggest an alternative diagnosis. In such situations, an alternative diagnosis to IPF should be reconsidered.



Histopathology demonstrating usual interstitial pneumonia (UIP). (A) Low-magnification photomicrograph showing classical UIP/idiopathic pulmonary fibrosis (IPF) pattern characterized by dense fibrosis with a predilection for subpleural and paraseptal parenchyma with associated architectural distortion in the form of microscopic honeycomb change (arrow) juxtaposed with relatively unaffected lung parenchyma (*). Visceral pleura is seen in the upper portion of the figure. (B) Higher-magnification photomicrograph showing subpleural scarring and honeycomb change with associated fibroblast foci (arrow). (C) Low-magnification photomicrograph showing probable UIP/IPF pattern characterized by subpleural and paraseptal predominant patchwork fibrosis that is less well developed and lacks the degree of associated architectural distortion in the form of either destructive scarring or honeycomb change illustrated in A and B. (D) Higher-magnification photomicrograph showing patchy fibrosis and fibroblast foci (*) but without the extent of scarring and honeycomb change illustrated in A and B. (E) Indeterminate for UIP/IPF pattern in which there is mild nonspecific fibrosis that lacks a well-developed patchy and predominantly subpleural/paraseptal distribution, architectural distortion, and fibroblast foci characteristic of classical UIP/IPF. There is associated osseous metaplasia, a common but nonspecific finding in UIP. Although these findings are not diagnostic, they do not preclude a diagnosis of UIP/IPF in a patient with supportive clinical and radiological findings.

(1)<レクチャー:NSIP up to date>

  • pure NSIPはあるのか?⇒ほかのパターンの混合例が多い.
  • idiopathic NSIP(non IPAF)は予後不良?⇒ではすべてのIPAF-NSIPは予後が良いのか?⇒悪いものもある.
  • IPAFの診断基準にはANCAが入っていないのは今後の課題.
  • fibrotic NSIPはdisease behaviorが多様である時間経過が重要である).初期1年の治療反応性では予後はわからない.
  • 治療について:CostabelらのNintedanibはIPF急性増悪を抑制するとの報告(AJRCCM 2016)やYamakawaらのステロイド維持療法中の経過でパルスを2回,しかしその後維持療法のステロイドは増量しないようなやり方もヒントになる.
  • NSIPの大切な要素:①年齢,タバコ,②画像(Ssc型,DM型),③CTDのフレーバー,④肺機能の推移,⑤KL-6,SP-D,⑥悪性腫瘍の併発(PM/DM),⑦体重,⑧薬剤の副作用,⑨時間経過(disease behavior),⑩治療薬についての患者の価値観
  • GGOが多いとIPFにしないで,NSIPとする臨床医はやはり多い.
  • 画像はUIP possibleでも病理でUIPとなる,あるいは画像はnoでも病理でprobable UIPになるようなinconsistent with UIPは“すりガラス影の中に網状影”.Pathological UIPは3割くらいは画像でNSIPと診断されていることに注意(Radiology 2014; 272: 549)
  • 2018の診断基準にある“indeterminate for UIP”をどう考えていくか.
※<IPAF診断基準>
[前提]
1.HRCTまたはSLBで間質性肺炎が存在,2.他疾患の除外,3.膠原病の診断基準を満たさない,4.少なくとも2ドメインから1つを満たす

[ドメインA Clinical domain]

1.メカニックハンド,2.指尖部潰瘍,3.関節炎または朝の関節のこわばり(60分以上),4.手掌の血管拡張,5.レイノー症状,6.説明のつかない手指の浮腫,7.Gottron徴候


[ドメインB Serologic domain]
  1. ANA≧320 diffuse, speckled, homogeneousパターン もしくは
    1. Nuclear patternならわずかでも可
    2. Centromereならわずかでも可
  2. RF>30〜40
  3. 抗CCP抗体
  4. 抗ds-DNA
  5. SS-A
  6. SS-B
  7. 抗RNP抗体
  8. 抗Sm抗体
  9. 抗Scl-70抗体
  10. 抗ARS抗体(Jo1、PL-7、PL-12、EJ, OJ, KS, Zo, tRS)
  11. 抗Scl抗体
  12. 抗MDA-5抗体
[ドメインC Morphological domain]
  1. HRCTパターン
    1. NSIP
    2. OP
    3. NSIP with OP overlap
    4. LIP
  2. SLB(外科的肺生検)の病理学的パターン
    1. NSIP
    2. OP
    3. NSIP with OP overlap
    4. LIP
    5. 胚中心を伴うリンパ濾胞
    6. リンパ球・形質細胞のびまん性浸潤
  3. 間質性肺炎+αの所見
    1. 胸水、胸膜肥厚
    2. 心嚢液、心膜肥厚
    3. 肺機能・画像・病理いずれかにおける気道病変
    4. 血管病変

(2)<症例検討>

①・”subpleural sparing”は全体のGGOで,濃いところは内側,薄いところは外側のイメージ.外側のスペアされているところが(病理学的に)正常という訳ではない
・fNSIPの典型的な像は,下葉の“おうぎ形”の画像.この例は上葉は胸膜下に斑状・すりガラス影・微小結節.特に粒状影が多く,経過で無気肺硬化像になる.普通のfNSIPとは異なる.気道病変が強く,それが無気肺硬化像になっている.fNSIPとは思うが,CHPは鑑別になる.そしてUIPは否定できない.
IPFでも気道がやられるとairtrapが起こってくる
・NSIPを画像でwith CTD,with non CTDに分けることは不可能.
②・NSIPのどこを安定とするか?⇒自覚症状は1つ.しかし予後不良因子は自覚症状だけではないので(自覚症状に変化がなくても)肺機能(FVC)も考えなければ
③・上葉の胸膜下のフワッとした斑状の陰影(これはゆくゆく網状影になっていく)はSsc-IPの特徴
・Ssc-IPはなかなか陰影も消失せず,良くするというよりもいかに安定させるか,が大切.
・PM/DM型の抗ARS抗体症候群以外,IPで“良くなる”ということはないと思う.
④・なぜNSIPは“おうぎ形”の画像になるのか?⇒上葉にあるような淡い陰影は必ずしも気道周囲ではない.以前はこれが気道周囲に広がると思っていたが,病理と対比すると必ずしもそうではない.UIPが細葉辺縁とすると,NSIPはそれ以外のところから発症し,それらが連なると“おうぎ形”にみえる,と思っていたが・・・.正直よくわからない.
⑤・若年性IPではのう胞ができる人が少なくない.
⑥・下葉のconsolidationが強いパターン.これをNSIPとするのか?.OPではいけないのか?.Dr. Travisは画像で必ずconsolidationが多いかどうか聞いてくるので,consolidationが多ければNSIPとはしないだろう.Cellular NSIPはどこにいってしまったのか.最近は“fibrosing OP”という言葉をよく聞くが,これを分類に入れたい?,そんな意図を感じる.しかしこのようなパターンは最終的にfibrosing NSIPになる.
抗ARS抗体症候群のIPは,途中で時期によってOP的な画像になる.もともとNSIPなのだが,時期によってOPがのってくる.そう考えるのが妥当だと思う.
⑧・画像は上葉胸膜が不整で,斑状陰影.下葉優位GGOに重なった粒状陰影.上葉に無気肺硬化像があるのでCHPは鑑別に残したいが,fNSIPは確信度30%くらいで,indeterminate for UIPか.病理はUIPのところとNSIPのところ.10年で死亡.はじめはNSIP的であったが,経過から最終的にIPF(UIP)と考えた.はじめはNSIPとしか言えない.しかし予後不良であり,IPF(UIP)になった,と判断せざるをえない.
病理でどこまで炎症が強いのか,あるいは線維化が強いのか?⇒この情報がステロイドや免疫抑制剤を使うのか,抗線維化薬を使うのかの目安の1つになる.時期によって,クライオバイオプシーをやって確認するというのも1手かと考えている.
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