O slideshow foi denunciado.
Utilizamos seu perfil e dados de atividades no LinkedIn para personalizar e exibir anúncios mais relevantes. Altere suas preferências de anúncios quando desejar.

インフルエンザ

  • Seja o primeiro a comentar

インフルエンザ

  1. 1. インフルエンザ意外に知らないDeepな世界へ
  2. 2. これはインフル? (1月のERにて) • 症例1; 22歳男性 喫煙者. • 前日夜からの悪寒, 発熱. 咳嗽がひどく, 頭も痛い. – ill contactは職場でインフルエンザで休んでいる人がいるくらい – Vital; BT39.2 BP120/50 HR96 RR20 Sat100% 咽頭後壁に軽度発赤あり, 桃腫大(-) リンパ節腫大(-) 眼瞼結膜充血なし. 肺胞呼吸音. 皮疹(-) せんせ∼, 上気道炎でしょ。対症療法 外来詰まってますよぉ∼インフルかなぁ? インフル迅速Check!インフルだろ。タミフルいる?禁煙してから出直してきやがれ!
  3. 3. これはインフル? (1月のERにて)• 症例2; 32歳女性 妊娠1か月• 2日前からの発熱, 咽頭痛, 嘔吐 – 産婦人科外来で漢方薬をもらったものの, 嘔気強くてのめなかった – 夕方より頭痛も出現したためERを受診 – 咳嗽, 喀痰は無し. 下痢, 腹痛(-), 尿路症状(-) – ill contact; 咳をしていた従兄の子供 – Vital; BT39.7, BP122/74, HR113, RR18 Sat99%(RA) – 眼球結膜充血なし, 頭頸部リンパ節腫脹なし. 咽頭後壁は軽度発赤. 肺胞呼吸音.  上気道炎でしょ。対症療法 インフルかなぁ? インフル迅速Check! インフルだろ。タミフルいる? 産婦人科外来を予約し, 帰宅
  4. 4. インフルエンザ; 病歴, 所見 JAMA 2005;293:987-997• 全体 症状 Sn(%) Sp(%) LR(+) LR(-) 発熱 68-86 25-73 1.8[1.1-2.9] 0.40[0.25-0.66] 熱感 88 15 1.0[0.86-1.2] 0.70[0.27-2.5] 咳嗽 84-98 7-29 1.1[1.1-1.2] 0.42[0.31-0.57] 筋肉痛 60-94 6-38 0.93[0.83-1.0] 1.2[0.90-1.6] 怠感 73 26 0.98[0.75-1.3] 1.1[0.51-1.3] 頭痛 70-91 11-43 1.0[1.0-1.1] 0.75[0.63-0.89] 咽頭炎 75-84 16-33 1.0[0.98-1.0] 0.96[0.83-1.1] 鼻汁 33-50 59-69 1.2[1.0-1.5] 0.87[0.75-1.0] 鼻閉 68-91 19-41 1.1[1.1-1.2] 0.49[0.42-0.59] 悪寒 83 25 1.1[1.0-1.2] 0.68[0.46-0.99] ワクチン接種歴 2-12 82-83 0.63[0.37-1.1] 1.1[1.0-1.2] 発熱 + 咳嗽 64 67 1.9[1.8-2.1] 0.54[0.50-0.57] 発熱 + 咳嗽 + 急性発症 63 68 2.0[1.8-2.1] 0.54[0.51-0.58] 病歴で重要となるのは発熱, 呼吸器症状, 頭痛, 急性発症であること 筋肉痛や 怠感は実は診断にはあまり寄与しないが, インフルエンザだと確かに強い筋肉痛は多い(CID 2005;41:822-8)
  5. 5. インフルエンザ; 病歴, 所見 JAMA 2005;293:987-997• Age >= 60yr 症状 Sn(%) Sp(%) LR(+) LR(-) 発熱 34 91 3.8[2.8-5.0] 0.72[0.64-0.82] 熱感 47 78 2.1[1.2-3.7] 0.68[0.45-1.0] 咳嗽 53-66 56-77 2.0[1.1-3.5] 0.57[0.37-0.87] 筋肉痛 45-47 81-83 2.4[1.9-2.9] 0.68[0.58-0.79] 怠感 57 78 2.6[2.2-3.1] 0.55[0.44-0.67] 頭痛 44-68 57-79 1.9[1.6-2.3] 0.70[0.60-0.82] 咽頭炎 40-58 36-81 1.4[0.81-2.5] 0.77[0.66-0.89] 鼻汁 32 33 0.47[0.24-0.92] 2.1[1.4-3.1] 鼻閉 47 50 0.95[0.57-1.6] 1.0[0.67-1.7] 悪寒 46 82 2.6[2.0-3.2] 0.66[0.55-0.77] 発熱 + 咳嗽 30 94 5.0[3.5-6.9] 0.75[0.66-0.84] 発熱 + 咳嗽 + 急性発症 27 95 5.4[3.8-7.7] 0.77[0.68-0.85] 高齢者では様々な症状が出現する 重症感も強くなる 逆に, 元気そうであったり, 症状に乏しければインフルエンザらしくない
  6. 6. インフルでは高熱, 筋肉痛が強い• 流行シーズンのFlu like SymptomでERを受診した266名 – インフルエンザが20%, Picorna virusが10%, RSV 5% – インフルとPicorna virus感染の症状の差を比較 • BT > 38.0; 26% vs 0% 筋肉痛; 83% vs 46% と有意差を認める – インフルエンザ感染では, 他のViral infectionよりも 発熱, 筋肉痛が強い傾向がある. 恐らくは, サイトカインが多く分泌されるためとされる (CID 2005;41:822-8)
  7. 7. Influenza follicles Gen Med 2011;12:51-60 • インフルエンザ感染症の患者において, 後咽頭壁にイクラのような濾胞性病変を生じる.uenza follicles(IF)in seasonal A/H1N1 influenza(Panel A)and type B influen / • Definitive influenza follicles; evaluation(Panel C)and on day 3(Paneal findings in the same patient on initial小型で孤発性のリンパ濾胞(1-2mm). General Medicine vol. 12 no. 2, 2011follicles(IF)are flattened, have a broader base, and are cloudy.  半球状で, 境界明瞭, 起始部は広く, くびれは無い.(Y/F type II)and F show follicles in a febrile disease that is not influenza. The follicles are polym  緊満, 光沢を帯びた表面で, イクラ様と例えられる. aggregated small nodules. Even those that are round or rice grain-shaped andfollicles are usually not redder than the surrounding pharyngeal mucosa. 7
  8. 8. • Probable influenza follicles; Y/F type I様の形で左右対称性.  周囲の口咽頭粘膜よりも発赤が強く, 内容物は透過性が高い – 通常インフル感染後数日経ってから生じることが多い.Diagnosis of Seasonal and Novel Influenza from Pharyngeal FolliclesFigure 6. Yamada/Fukutomi(Y/F type)classification of ele- / /vated lesions(in the stomach)shown schematically with descrip-tions of physical appearance. Gen Med 2011;12:51-60 8
  9. 9. • Non-specific follicles; 典型例よりも大きく, 不整形.  様々な大きさのリンパ濾胞が咽頭後壁に認められる.  Y/F typeはII~Iが多い. – 白みを帯びた赤色のことが多く, 辺縁は収縮した様ないびつ. – インフルエンザ晩期で認められるが, 他の感染症でも認められることがあるため, 非特異的. Gen Med 2011;12:51-60 9
  10. 10. Influenza folliclesの診断能 Gen Med 2011;12:51-60• 新型インフルエンザへの適応 – 2009年 8月∼10月末までにFlu-like symptomで受診した87名で精査. – Influenza folliclesは23名で陽性. そのうち21名がPCRで新型インフルエンザ陽性. – Influenza follicles(-)であった64名は全例インフル陰性であった. – >> 感度100%, 特異度 97%.• 2003-2009年に診断された419名のインフルエンザ患者(迅速試験) – Influenza folliclesはインフルに対する感度 95.46%, 特異度 98.42% – インフルはA/H3N2, A/H1N1, Bが含まれている. 当然アデノウイルス等でもリンパ濾胞は生じるため, 季節や濾胞のタイプを考慮して臨床に適応すべきと言えるが, インフルエンザ流行期には非常に有用な所見と言える.
  11. 11. 迅速検査は相手を選んで施行• キットによりSn 40-100%, Sp 52-100%と様々• 小児では感度70-90%, 成人では<40-60%と成人例では感度が低い.• 感度が低いため, 検査前確率が>14%である場合は Empirical treatmentと比較してコストパフォーマンスが悪い• 迅速検査は検査前確率が5-14%で, ワクチン未接種の場合に用いる (Ann Intern Med 2003;139:321-9; 検査前確率35%) (Am J Med 2002;113:300-7; 検査前確率60%) Kit Sn(%) Sp(%) LR(+) LR(-) Directigen Flu A Pediatr Infect Dis J FLU OIA QuickVue Influenza 72-95% 76-84% 4.7[3.6-6.2] 0.06[0.03-0.12] 2002;21:193-6 ZstatFlu A/B 鼻汁吸引 88[81-95] 94[69-100] >100[2.8-∞] 0.1[0.05-0.2] 小児科 鼻咽頭スワブ 83[64-97] 95[76-99] 47[3.5-92] 0.2[0.03-0.4] 2003;44:1979 口蓋咽頭スワブ 67[48-85] 93[80-100] >100[2.8-∞] 0.4[0.2-0.6] J Fam Pract ZstatFlu 65 83 3.82 0.42 2001;50:1051-6
  12. 12. 迅速検査のMeta-analysis Review Accuracy of Rapid Intern Med. 2012;156:500 –511. Ann Influenza Diagnostic Tests• 159 trialsのmeta. 26種類の迅速検査キットを調査 Table 2. Accuracy Estimates From Subgroup Analyses Characteristic Pooled Sensitivity P Value Pooled Specificity P Value (95% CI), % (95% CI), % Population Children (60 studies) 66.6 (61.6–71.7) Ͻ0.001 98.2 (97.5–99.0) 0.135 Adults (33 studies) 53.9 (47.9–59.8) Reference 98.6 (98.0–98.9) Reference Virus type Influenza A (72 studies) 64.6 (59.0–70.1) 0.62 99.1 (98.7–99.4) Ͻ0.001 Influenza B (27 studies) 52.2 (45.0–59.3) 0.050 99.8 (99.7–99.9) Ͻ0.001 Influenza A and B (47 studies) 62.3 (55.2–69.4) Reference 96.1 (94.4–97.8) Reference Study conducted during the H1N1 pandemic Yes (41 studies) 56.3 (48.7–63.9) 0.065 98.9 (98.3–99.5) 0.022 No (74 studies) 65.0 (59.7–70.4) Reference 97.5 (96.6–98.5) Reference Index test* BinaxNOW (17 studies)† 57.0 (45.9–67.5) 0.028‡ 98.6 (96.9–99.3) 0.057‡ Directigen Flu A (10 studies) 76.7 (63.8–86.0) 0.49‡ 97.2 (92.6–99.0) 0.62‡ Directigen Flu AϩB (30 studies) 57.2 (48.8–65.2) 0.011‡ 99.3 (98.8–99.6) Ͻ0.001‡ QuickVue Influenza (16 studies) 69.0 (58.1–78.2) 0.66‡ 95.8 (91.3–98.0) 0.82‡ QuickVue Influenza AϩB (21 studies) 48.8 (39.0–58.8) Ͻ0.001‡ 98.4 (96.8–99.2) 0.064‡ Reference standard RT-PCR (67 studies) 53.9 (48.2–59.6) Ͻ0.001 98.8 (98.3–99.3) 0.002 Culture (48 studies) 72.3 (66.8–77.9) Reference 96.7 (95.2–98.3) Reference Type of specimen Nasopharyngeal aspirate (15 studies) 66.6 (56.2–77.0) 0.42§ 97.8 (95.6–100) 0.34§ Nasopharyngeal swab (19 studies) 61.6 (52.0–71.3) 0.75§ 99.1 (98.4–99.9) 0.133§ Nasopharyngeal wash (3 studies) 50.7 (25.1–76.3) 0.32§ 98.1 (94.0–100) 0.82§ Nasal swab (10 studies) 65.9 (53.3–78.5) 0.61§ 99.2 (98.2–100) 0.28§ Throat swab (4 studies) 54.9 (32.7–77.1) 0.45§ 90.0 (74.7–100) 0.018§
  13. 13. Reference standard RT-PCR (67 studies) 53.9 (48.2–59.6) Ͻ0.001 98.8 (98.3–99.3) 0.002 Culture (48 studies) 72.3 (66.8–77.9) Ann Intern (95.2–98.3) Tests Med. 2012;156:500Reference Reference of Rapid Influenza Diagnostic Accuracy 96.7 –511. Review Type of specimen Nasopharyngeal aspirate (15 studies) 66.6 (56.2–77.0) 0.42§ 97.8 (95.6–100) 0.34§ Nasopharyngeal swab (19 studies) Table 2. Accuracy Estimates From Subgroup Analyses (52.0–71.3) 61.6 0.75§ 99.1 (98.4–99.9) 0.133§ Nasopharyngeal wash (3 studies) 50.7 (25.1–76.3) 0.32§ 98.1 (94.0–100) 0.82§ Nasal swab (10 studies) 65.9 (53.3–78.5) 0.61§ 99.2 (98.2–100) 0.28§ Characteristic (4 studies) Throat swab 54.9 (32.7–77.1) Pooled Sensitivity 0.45§ P Value 90.0 (74.7–100) Pooled Specificity P 0.018§ Value (95% CI), % (95% CI), % Testing at the point of care Population Yes (28 studies) 58.0 (48.8–67.2) 0.28 97.6 (96.1–99.1) 0.30 Children (60 studies) 66.6 (61.6–71.7) Ͻ0.001 98.2 (97.5–99.0) 0.135 No (91 studies) 63.6 (58.8–68.5) Reference 98.4 (97.7–99.0) Reference Adults (33 studies) 53.9 (47.9–59.8) Reference 98.6 (98.0–98.9) Reference Study quality Virus type Spectrum of disease Influenza A (72 studies) 64.6 (59.0–70.1) 0.62 99.1 (98.7–99.4) Ͻ0.001 During influenza season (105 studies) 60.6 (56.0–65.2) 0.032 98.2 (97.6–98.9) 0.62 Influenza B (27 studies) 52.2 (45.0–59.3) 0.050 99.8 (99.7–99.9) Ͻ0.001 Outside influenza season (14 studies) 74.2 (63.9–84.4) Reference 97.8 (95.8–99.8) Reference Influenza A and B (47 studies) 62.3 (55.2–69.4) Reference 96.1 (94.4–97.8) Reference Patient selection ILI defined (45 studies)࿣ 59.4 (52.2–66.6) 0.30 97.9 (96.9–99.0) 0.50 Study conducted during the H1N1 pandemic ILI not defined (74 studies) 64.1 (58.7–69.5) Reference 98.3 (97.7–99.0) Reference Yes (41 studies) 56.3 (48.7–63.9) 0.065 98.9 (98.3–99.5) 0.022 Blinding No (74 studies) 65.0 (59.7–70.4) Reference 97.5 (96.6–98.5) Reference Any blinding reported (54 studies) 61.7 (55.2–68.2) 0.78 97.8 (96.7–98.8) 0.20 No blinding reported (65 studies) 62.9 (57.0–68.7) Reference 98.5 (97.8–99.2) Reference Index test* Handling of indeterminate results BinaxNOW (17 studies)† 57.0 (45.9–67.5) 0.028‡ 98.6 (96.9–99.3) 0.057‡ Reported (19 studies) 66.9 (56.5–77.3) 0.37 98.0 (96.5–99.6) 0.82 Directigen Flu A (10 studies) 76.7 (63.8–86.0) 0.49‡ 97.2 (92.6–99.0) 0.62‡ Not reported (100 studies) 61.5 (56.7–66.2) Reference 98.2 (97.6–98.9) Reference Directigen Flu AϩB (30 studies) 57.2 (48.8–65.2) 0.011‡ 99.3 (98.8–99.6) Ͻ0.001‡ Industry sponsoring QuickVue Influenza (16 studies) 69.0 (58.1–78.2) 0.66‡ 95.8 (91.3–98.0) 0.82‡ Sponsored (23 studies) 73.3 (65.3–81.3) 0.007 97.4 (95.5–99.2) 0.24 QuickVue Influenza AϩB (21 studies) 48.8 (39.0–58.8) Ͻ0.001‡ 98.4 (96.8–99.2) 0.064‡ Not sponsored (96 studies) 59.4 (54.6–64.2) Reference 98.4 (97.8–99.0) Reference Reference standardILI ϭ influenza-like illness; RT-PCR ϭ reverse transcriptase, polymerase chain reaction. RT-PCR (67 studies) 53.9 (48.2–59.6) Ͻ0.001 98.8 (98.3–99.3) 0.002* See footnote in Table 1 for names of manufacturers of rapid influenza diagnostic tests. Culture (48Flu A and B and BinaxNOW Influenza A&B were pooled together because statistical tests showed that they† BinaxNOW studies) 72.3 (66.8–77.9) Reference 96.7 (95.2–98.3) (data not shown). performed similarly Reference‡ Reference category is the combination of the other tests.§Type of specimen is the combination of the other specimens. Reference category࿣ Article provided a clear definition of the clinical symptoms on 66.6basis of which patients were recruited for the study. Nasopharyngeal aspirate (15 studies) the (56.2–77.0) 0.42§ 97.8 (95.6–100) 0.34§ Nasopharyngeal swab (19 studies) 61.6 (52.0–71.3) 0.75§ 99.1 (98.4–99.9) 0.133§ Nasopharyngeal wash (3 studies) 50.7 (25.1–76.3) 0.32§ 98.1 (94.0–100) 0.82§ Rapid influenza diagnostic tests performed better Nasal swab (10 studies) 65.9 (53.3–78.5) had a noticeable effect on99.2 (98.2–100) 0.61§ 13 their accuracy. Also, the quality 0.28§when assessed against viral culture rather than (32.7–77.1) Throat swab (4 studies) 54.9RT-PCR criteria investigated (patient 0.45§ 90.0selection, blinding, and han- (74.7–100) 0.018§(pooled sensitivity, 72.3% [CI, 66.8% to 77.9%] for cul- dling of uninterpretable results) did not have a statistically
  14. 14. Ann Intern Med. 2012;156:500 –511.Review Accuracy of Rapid Influenza Diagnostic Tests Table 3. Studies That Provided Data on Effect of Duration of Symptoms on Test Accuracy Study, Year (Reference) Duration* Sensitivity (95% CI), % Specificity (95% CI), % Gordon et al, 2009 (69) Day 1 51.9 (40.3–63.3) 98.4 (95.3–99.7) Day 2 75.1 (68.3–81.1) 97.9 (96.0–99.1) Day 3 74.2 (62.0–84.2) 97.9 (94.1–99.6) Day 4 57.9 (33.5–79.7) 98.6 (94.2–100) Gordon et al, 2010 (68) Ͻ24 h 41.7 (22.1–63.4) 97.9 (88.9–99.9) Ն24 h 72.1 (59.9–82.3) 98.4 (94.3–99.8) Keitel et al, 2011 (83)† Յ12 h 35.0 (19.0–55.0) 100 (88.0–100) 12–24 h 66.0 (54.0–76.0) 97.0 (86.0–100) 24–48 h 92.0 (80.0–97.0) 96.0 (82.0–99.0) Ͼ48 h 59.0 (36.0–78.0) 100 (90.0–100) Nilsson et al, 2008 (100) 1–3 d 71.4 (58.7–82.1) 100 (95.1–100) 1–5 d 62.8 (51.7–73.0) 100 (96.7–100) Ͼ5 d 13.8 (3.9–31.7) 100 (90.0–100) Poehling et al, 2002 (108) Ͻ4 d 100 (63.1–100) 96.6 (90.4–99.3) Ն4 d 54.5 (23.4–83.3) 98.4 (94.4–99.8) Stein et al, 2005 (131) Ͻ48 h 58.3 (27.7–84.8) 96.2 (80.4–99.9) Ͼ48 h 25.0 (12.1–42.2) 98.6 (95.0–99.8) Stripeli et al, 2010 (132) Ͻ48 h 75.0 (42.8–94.5) 100 (92.1–100) Ն48 h 65.4 (44.3–84.8) 94.2 (88.4–97.6)* Duration of clinical symptoms at the time of testing by the rapid influenza diagnostic test.† Numbers taken directly from the study because there was not enough information to reconstruct the 2 ϫ 2 table.sensitivity (73.3% [CI, 65.3% to 81.3%]) than studies not 14 Rapid influenza diagnostic tests have a higher sensitiv-sponsored by industry (59.4% [CI, 54.6% to 64.2%]). ity for detecting influenza A than influenza B. Studies haveAlthough this difference was statistically significant, sensi- shown that infection with influenza A(H3N2) (the most
  15. 15. • インフルエンザ迅速検査は 1回 2600円 • タミフル 2cp 5日分処方で約3000円 – シーズン(12末~2月)のインフル迅速検査の陽性率は20-40%. 臨床的に疑わしければタミフル処方でも良い. – 検査すべきは, 仕事の関係, 学童で診断書がいる場合例えば,検査前確率 a%とすると,(2600 x 100) + 3000 x a  =< 3000 x 100 3000a =< 400 x 100 a =< 40/3 = 13.3%検査前確率 <13.3%ならば,迅速検査を行う価値あり.←→ >14%ならば, 迅速せずに タミフル処方でも全然OKAnn Intern Med. 2003;139:321-329.
  16. 16. 症例のおさらい• 症例1; 外来も混んでいたし, かなりFluっぽかったため, “インフルエンザでしょー” と言ってタミフル処方、帰宅.• 症例2; (実際の研修医のAssessment) – インフルエンザ迅速検査を施行し, 陰性となったため対症療法にて 帰宅 – その2日後, 外来を受診 – WBC 4900, Hb13.3, PLT 19万 T-bil 2.9, AST 1163, ALT 1093, ALP 267, GGT 231, LDH 951 – 急性肝炎にて入院 教訓; 上気道症状のない“上気道炎”には気をつけろ! 背後に肝炎, 心膜炎, (HIV)が隠れているかも!
  17. 17. 症例; 72歳男性 (年末の症例)• 4日前に外来の定期受診. その際, 周りに咳をしている人が沢山いた• 来院前日から40度台の発熱, 悪寒あり. 元気がなくなってきたため家族が救急要請した – 咳嗽認めるが, 鼻汁は無し. 下痢, 腹痛なし. 尿路症状も無し – 頭痛, 筋肉痛も認めない – ワクチン未接種. – Vital; BT 39.9, BP 118/66, HR120, RR20, Sat 95% – 眼瞼結膜充血なし. 咽頭後壁は軽度発赤あり. 頭頸部リンパ節腫脹なし。右側胸部で軽度ラ音認める.  上気道炎でしょ。対症療法でバイバイ  救急車だし, 高齢者だし, 採血, 血培, ルートとって, あとレントゲンも  インフルだったらもうけもの!(帰れるから). インフルCheck!  インフルなんだから, タミフルだして返しちゃおう!
  18. 18. 検査結果• 血液検査  WBC 15000, Hb 11.5, PLT 20万, Neu 92.9%  AST 25, ALT 32, ALP 271, GGT 30, BUN 15.4, Cr 0.6, CRP 4.31• 尿中WBC (-), 細菌(-)• インフルエンザ迅速検査; 陽性• 胸部レントゲン; 右下肺野が若干汚い... 気がする.• (実際の研修医のAssessment) インフルエンザ陽性であり, 発熱のFocusで良いと考える 発熱して24hr以内であり, タミフルを処方し, 帰宅とする. あ∼, ハッキリした診断ができてよかったわ∼. お大事にネー. ん, なんか違和感が残るが・・・ まあインフルいいか・・・な? これは, インフルだけじゃないな. ○○が□□だし, 2日後に肺炎で入院 △△も××だから, ◎◎が合併している!
  19. 19. Leukocytosis(+)のインフルエンザでは合併症, 併発症を考える• インフルエンザでは通常WBC =<8000/mcLとなる• Left-shift; Neu >60%は Sn 41%, Sp 68%, LR(+) 1.29, LR(-) 0.87• Righ-shift; Ly >40%は Sn 8.7%, Sp 86%, LR(+) 0.64, LR(-) 1.06• Neutro上昇優位となるが, それで鑑別に影響するほどでもない• インフルエンザ陽性(+), WBC >8000-10000/mcLならば, なんらかの合併症(肺炎など)も考えて精査すべきである J Fam Pract 2001;50:1051-6 Test Sn(%) Sp(%) LR(+) LR(-) WBC=<4000 19 94 3.17 0.86 WBC=<6000 61 62 1.61 0.63 WBC=<8000 92 31 1.33 0.26 WBC=<10000 97.5 16.2 0.41 WBC=<12000 98.8 13.1 0.40 WBC>12000 0.10
  20. 20. 肺炎球菌性肺炎とインフルエンザ• 肺炎球菌もインフルエンザも冬季に多い感染症 – インフルエンザと肺炎球菌性肺炎には関連性がある.• アメリカの3地域のSurveyでは, (CID 2010;50:175-83) – Pneumococcal pneumonia全体における, Influenza-associated pneumococcal pneumoniaの占める割合 地域 Influenza シーズン 通年 北東地域 13.5%[12.3-14.7] 4.9%[4.5-5.3] 南部 11.4%[10.7-12.7] 5.4%[5.0-5.9] 西部 11.9%[11.1-13.6] 5.2%[4.8-6.0] A; 南部, B; 北東部, C; 西部   Invasive pneumococcal dis   Expected seasonal baseline(Non-flu period)   Expected seasonal baseline(Flu period)
  21. 21. H1N1は小児例における肺炎球菌菌血症リスクを上昇させる• イスラエルにおける, 2006-8年のインフル流行期と, 2009年(H1N1)流 行期のS aureus, S pneumoniae, S pyogenes菌血症を評価し, 比較. – 有意差がでたのは小児例における肺炎球菌菌血症のみ. H1N1流後期は他の流行期と比較して有意にBSIリスクが上昇している Clinical Infectious Diseases 2011;53(12):1199–207 Table 1. Incidence Rate Ratio and 95% Confidence Intervals for Steptococcus pneumoniae Bloodstrea IRR for S. pneumoniae BSI during pH1N1 compared with other periods pH1N109 summer pH1N109 fall-winter pH1N109 fall-winter post pH1N1 influenza Age group vs 2006–08 vs 2006–09 vs 06–09 influenza period vs 2009–10 (years) summers falls-winters active weeks fall-winter 0–4 14.8 (5, 43.7)*** 5.2 (3, 9) *** 6.5 (3.6, 11.8) *** 1.9 (1.4, 2.4) *** 5–14 Inf. (3.7, Inf.) *** 55.7 (7.54, 15.2) *** 32.5 (6.4, 165.9) *** 1.7 (1.2, 2.5) ** 15–39 1.5 (0.7–3.2) 1.2 (0.7–2) 1.1 (0.63–1.7) 1.4 (0.83–2.3) 40–64 1.2 (0.6–2.1) 1 (0.6–1.5) 0.9 (0.6–1.2) 2.6 (1.9–3.6)*** .65 0.95 (0.6, 1.6) 0.8 (0.6, 1.1) 0.6 (0.5, 0.9) ** 21 (1.1, 2.2) ** 1.6 Total 2 (1.5, 2.7) *** 1.5 (1.2, 1.9) *** 1.3 (1.1, 1.6) ** 1.8 (1.5, 2.1) *** Abbreviations: BSI, bloodstream infections; Inf., infinity; IRR, incidence rate ratio; pH1N1, pandemic H1N1 influenza.
  22. 22. • S aureus, S pyogenesも若干のリスク上昇は認められるが, 肺炎球菌ほどではなく, 実際の臨床上 実感できるほどでもないTable 2. Incidence Rate Ratio and 95% Confidence Intervals for Staphylococcus aureus and Streptococcus pyogenes Bloodstream Infections in Differing Age Groups and Seasons Age group pH1N109 2006–08 pH1N109 2006–09 pH1N109 06–09 influenza (years) summer summers IRR1 fall-winter falls-winters IRR2 fall-winter active weeks IRR3Comparison between the rates 0–4 3.8 0.7 5.9 (1.3, 27.2)* 2.1 0 Inf. (1.3, Inf.)* 2.1 0 Inf. (0.9, Inf.)* (in 100 000 person years) of S. aureus BSI 5–14 3.2 0.4 9.1 (2, 40.2)* 0.6 0 Inf. (0.6, Inf.) 0.6 0 Inf. (0.4, Inf.)* 15–39 1.6 0.7 2.2 (0.8, 6.3) 3.4 1.2 2.8 (1.3, 6)*** 3.4 1.4 2.4 (1.2, 4.9)** 40–64 15.5 9 1.7 (1.2, 2.4)*** 14.5 10.6 1.4 (1, 1.9) 14.5 11.2 1.3 (1, 1.8) .65 90.6 62.2 1.5 (1.2, 1.8)**** 88.5 63.3 1.4 (1.1, 1.7)** 88.5 62.9 1.4 (1.1, 1.7)*** Total 14.3 8.8 1.6 (1.4, 1.9)**** 13.8 9.4 1.5 (1.2, 1.7)**** 13.8 9.4 1.5 (1.2, 1.7) ****Comparison between the rates 0–4 5.8 0.7 8.8 (2, 39.2)** 3.2 1.2 2.5 (0.7, 8.9) 3.2 0.9 3.3 (0.7, 19.4) (in 100 000 person years) of S. pyogenes BSI 5–14 0 0 . 0.6 0 Inf. (0.7, Inf.) 0.6 0 Inf. (0.4, Inf.) 15–39 0.5 0.2 3.1 (0.4, 33) 1.7 0.5 3.5 (1.1, 11.8)* 1.7 0.4 4.4 (1.3, 17.3)** 40–64 0.8 0 Inf. (0.8, Inf.)* 3.4 0.7 4.6 (1.6, 15)*** 3.41 0.9 3.5 (1.3, 9.7)** .65 10.1 7.5 1.3 (0.7, 2.4) 6.7 3.8 1.7 (0.8, 3.8) 6. 2.9 2.2 (0.9, 6) Total 2.1 0.8 2.7 (1.6, 4.6) **** 2.5 0.9 2.8 (1.7, 4.6)**** 2.5 0.8 3.3 (1.9, 5.8) ****Abbreviations: Inf., infinity; IRR[1] and IRR[2], incidence rate ratios for S. aureus and S. pyogenes bloodstream infections (BSI) during summer (IRR[1]) and winter (IRR[2]) of pandemic H1N1 influenza (pH1N1) outbreakcompared with the previous 3 years respective seasons; IRR[3], incidence rate ratios for S. aureus and S. pyogenes BSI during winter of pH1N1 compared with 2006–09 influenza active weeks.*P , .05 Clinical Infectious Diseases 2011;53(12):1199–207**P , .01***P , .001****P , .0001 22
  23. 23. インフルでよく聞かれる質問 ∼何問解けるかな?∼Q. 発熱はどの位続くの?Q. 先月インフルの人と接触しましたけど、大丈夫でしょうか?Q. 感染性ってどのくらい続くのでしょうか?Q. ワクチン接種してますので, インフルではないと思います(研修医のプレゼンより)Q. 家族がインフルエンザなんですけど, 今からでもワクチン打った方がいいでしょうか?Q. 辛いので, タミフルください! 特効薬なんでしょ?Q. タミフル飲んだら感染性なくなりますか?Q. タミフルの副作用ってなにが多いのでしょうか?Q. ERではサージカルマスク or N95 ?
  24. 24. • インフルエンザは通常3日で解熱する (インフルエンザに伴う随伴症状の発現状況に関する調査研究) – >3日の発熱持続は, インフルエンザではない? もしくはインフル + 合併症の存在を示唆する!• インフルエンザ患者との接触歴 – 潜伏期間は1-4日. – 感染性は発熱前1日から,解熱後2-5日間は続くとされる 発症から5-8日は感染性アリ. 発症前の接触者も要注意!
  25. 25. • インフルエンザ患者との接触歴 – 潜伏期間は1-4日. – 感染性は発熱前1日から,解熱後2-5日間は続くとされる 発症から5-8日は感染性アリ. 発症前の接触者も要注意!• 鼻腔内のViral Titers (JAMA 2000;283:1016-24) – 発症<36hr以内の患者群で評価 – Oseltamivir使用では鼻咽頭ぬぐい液での陽性率は変わらない – Viral titerもPlaceboと同等であり, 5日以内で感染性を認める可能性 期間 Placebo Oseltamivir 75mg bid Oseltamivir 150mg bid 検出率 Titer 検出率 Titer 検出率 Titer Baseline 100% 3.5[0.5-6.5] 100% 3.5[0.5-6.0] 100% 3.3[0.5-6.0] Day 1 85% 2.3[0.0-5.5] 87% 1.8[0.0-6.0] 78% 1.3[0.0-5.3] Day 3 28% 0.0[0.0-5.0] 28% 0.0[0.0-4.0] 27% 0.0[0.0-3.5] Day 5 4% 0.0[0.0-2.3] 1% 0.0[0.0-0.5] 5% 0.0[0.0-0.5] Day 7 0 0.0 0 0.0 0 0.0 小児, 乳児では>=1wk, 免疫低下患者では数wk~mo存在するため, 無症状になっても周囲の人は要注意. (親など) (CID 2009;48:1003-32)
  26. 26. ワクチンしてればインフルではない?  そんなわけない!• ワクチン株が流行株に一致していれば70-90%の予防率 – 一致していない年は0-50%の予防率しかない (NEJM 2008;359:2579-85) – Rational Clinical Examinationではワクチン接種歴はLR 1• ワクチンは2-4wk経過してから効果が発現 – インフルエンザに暴露してからのワクチン接種は遅い – では暴露後の発症予防は・・・?
  27. 27. 妊婦へのInfluenza予防接種 NEJM 2008;359:Sep.
  28. 28. タミフル & リレンザ BMJ 2003;326:1235-42 †BMJ 2009;339:b5106• Oseltamivir; タミフル®, Zanamivir; リレンザ®• Neuraminidase阻害薬であり, インフルエンザに対する治療薬として有名• Outcome; 症状改善までの期間短縮(日) vs Placebo – 症状持続期間を半日~1日短縮する 小児 成人 老年 タミフル® 0.9[0.3-1.5] 0.9[0.3-1.4] 0.4[-0.7~1.4] リレンザ® 1.0[0.5-1.5] 0.8[0.3-1.3] 0.9[-0.05~1.5]• インフルエンザ予防効果; RR – 流行季節における予防 *1 – 家族内で発症者(+)の場合のPost-exposure prophylaxis *2 Flu発症予防 *1 家族内発症予防*2 – タミフル 1cp 7-10日間 タミフル® 0.26[0.08-0.84] 0.10[0.04-0.29] (保険適応外だけど・・・) † 0.39[0.18-0.85] リレンザ® 0.31[0.14-0.64] 0.19[0.09-0.38] † 0.41[0.25-0.65]
  29. 29. タミフルの効果, 副作用 JAMA 2000;283:1016-24• 2次性細菌感染予防効果もあるが, 副作用も強い• 627名の発熱+上気道症状(<36hr)患者 (内374名, 59.3%がインフルエンザ) 3群にRandomized; Oseltamivir 75mg bid, 150mg bid, Placebo• Outcome; (Oseltamivir 75mg, 150mg群では有意差無し) Outcome インフルエンザ患者(374) 母集団全体(627) – 2次感染合併頻度は減少するが, 副作用としては消化器症状 Placebo Oseltamivir 75mg Placebo Oseltamivir 75mg 症状改善までの時間(hr) 103.3[92.6-118.7] 71.5 [60.0-93.2] 97.0[86.3-113.6] 76.3[66.3-89.2] 咳嗽改善(hr) 55[36-73] 31[24-42] Placebo タミフル® 筋肉痛改善(hr) 28[24-36] 16[10-20] 副鼻腔炎 8.5% 4.1% 鼻閉改善(hr) 43[31-64] 33[25-43] 気管支炎 6.2% 3.3% 咽頭痛改善(hr) 21[8-29] 10[4-19] 肺炎 0.78% 0 怠感改善(hr) 41[26-50] 24[19-34] 2次合併症 15% 7% 頭痛改善(hr) 14[8-23] 8[6-15] 抗生剤使用 11% 4.9% 熱感改善(hr) 23[16-29] 10[8-14] 嘔気 7.4% 18% 嘔吐 3.4% 14%
  30. 30. 抗ウイルス薬を考慮すべき人々• 12-24moの乳幼児• 喘息, COPD, Cystic fibrosisを基礎疾患に持つ患者• 血行動態不安定な心疾患を持つ患者• 免疫不全患者• HIV感染患者• 鎌状血球症, 他のヘモグロビン症を有する患者• RAや川崎病などで長期のアスピリン内服が必要とされる患者• 慢性腎障害• 悪性腫瘍• DMなど慢性の内分泌疾患を有する患者• 神経筋疾患, 痙攣, 認知障害, 喀痰排泄能力が落ちている患者• >65yrの高齢者• 施設入所者, 長期入院患者 CID 2009;48:1003-32
  31. 31. 投与量一覧 CID 2009;48:1003-32 Drug Patient Treatment Prophylaxis Oseltamivir 成人 75mg bid, 5d 75mg daily, 10d (タミフル®) 小児(>=12mo)  Wt =<15kg 30mg bid 30mg daily  15-23kg 45mg bid 45mg daily  24-40kg 60mg bid 60mg daily  >40kg 75mg bid 75mg daily Zanamivir 成人 10mg吸引 bid 10mg吸引 daily (リレンザ®) 小児 >=7yrで成人と同じ >=5yrで成人と同じ腎機能 DoseCCr >30mL/min 75mg bid>10-30mL/min 75mg/d or 30mg bid=<10mL/min 75mg 1回のみ投与透析患者 Low-flux HD; 透析後に30mg High Flux HD; 透析後に75mg CAPD; 週に1回 30mg Crit Care Med 2010;38:e43-51 CRRT High-flux; 30mg/d or 75mg q48hr
  32. 32. patients were graded as very low quality because of risk of bias or 3 fewer cases (2 to 5 cases) per 1000 patients imprecision. Table 4 shows the GRADE evidence Med. 2012;156:512-524. Ann Intern profile, and Supplement Table 4 (available at www.annals.org) 抗インフルエンザ薬; Meta-analysis 4 fewer cases (1 to 7 fewer cases) per 1000 patients 73 fewer cardiac events (128 fewer to 16 more shows the results of preplanned subgroup analyses. A small study in pregnant women (52) reported an ts events) per 1000 patients OR of 1.27 (CI, 0.07 to 22.16) for death with oseltamivir. 57 fewerOseltamivir, Zanamivir vs Placeboを比較した74 RCTsのMeta • cardiac events (19 to 80 fewer events) ts per 1000 patients Two other small studies (75, 76) were conducted in out- 00 101 fewer events (80 to 126 fewer events) per patient populations with mild uncomplicated influenza but – Oseltamivir vs No treatmentの比較deaths. The combined results of 5 Japa- 1000 patient-years did not report on nese studies in patients with confirmed influenza (31, 49, Outcome Evidence level (n/N; Control vs Oseltamivir) >48hrで内服 55, 74, 75) suggest that inhaled zanamivir may be associ-mptoms by approximately 23Low(59/242 vs 31/439) with a slightly shorter symptom duration than OR 0.33[0.12-0.86] 死亡リスク hours (CI, 17 ated OR 0.23[0.13-0.43] oralon the basis of a large SMD (Ϫ0.94 [CI, oseltamivir (7 hours [CI, 2 to 12 hours]; SMD, 0.26 [CI, Low(1238/100585 0.07 to 0.45]). However, data from another study (76), 0.52[0.33-0.81] 入院率 in outpatients (71), which66]). One study vs 431/50125) OR 0.75[0.66-0.89] ORncluded 肺炎合併 in the meta-analysis,Very showed a which could not be pooled, reported no statistically signif- 0.22[0.15-0.33] also Low(2111/100449 vs 647/50017) OR 0.83[0.59-1.16] OR in the duration of illness and a 40% reduc- icant difference in duration of symptoms. The 2 treatments 中耳炎 Low(546/40022 vs 285/38385) OR 0.75[0.64-0.87] 心血管イベント Low OR 0.58[0.31-1.10]m-effects meta-analysis of oral oseltamivir versus no antiviral therapy based on studies that provided adjusted effect 致命的な副作用 Low RR 0.76[0.70-0.81] Outcome Patients (Studies), n Pooled Odds Ratio (95% CI) Mortality 681 (3) 0.23 (0.13–0.43) Hospitalization 150 710 (4) 0.75 (0.66–0.89) Pneumonia 150 466 (3) 0.83 (0.59–1.16) Otitis media 78 407 (2) 0.75 (0.64–0.87) Cardiovascular events 100 830 (2) 0.58 (0.31–1.10) 0.0 0.5 1.0 1.5 Favors Oseltamivir Favors No Antiviral Therapy
  33. 33. Ann Intern Med. 2012;156:512-524.• Zanamivir vs No treatmentの比較 Outcome Evidence level (n/N; Control vs Zanamivir) 死亡リスク Very Low(5/74 vs 0/13) OR 0.47[0.02-8.97] 入院率 Very Low(69/2411 vs 22/2350) OR 0.66[0.37-1.18] Very Low(263/2337 vs 301/2337) OR 1.17[0.98-1.39] Review 肺炎合併 Influenza Treatment: Evidence From Observational Studies Antivirals for 中耳炎 Very Low(21/2337 vs 25/2337) OR 1.19[0.67-2.14]• Oseltamivir vs Zanamivir Oseltamivir Versus Inhaled Zanamivir Table 4. GRADE Evidence Profile for Oral Outcome Quality Assessment Summary of Findings Patients Overall Quality Study Event Rates, n/N (%) Relative Effect Anticipated Absolute Effects (Studies), n* of Evidence (95% CI) Zanamivir Oseltamivir Risk With Absolute Effect With Zanamivir Oseltamivir (95% CI) Mortality 489 (1) Very low†‡§࿣ 0/13 (0) 21/476 (4.4) OR, 1.27 5 deaths per 1000 1 more death (5 fewer (0.07–22.16)¶ patients** to 95 more deaths) per 1000 patients Hospitalization 489 (1) Very low†‡§࿣ 8/13 (61.5) 329/476 (69.1) OR, 1.4 (0.45–4.35) 615 hospitalizations 76 more hospital- per 1000 patients izations (197 fewer to 259 more hospitalizations) per 1000 patients ICU admissions, mechanical 489 (1) Very low†‡࿣ 3/13 (23.1) 71/476 (14.9) OR, 0.58 231 admissions per 83 fewer admissions ventilation, or respiratory (0.16–2.18) 1000 patients (185 fewer to 165 failure more admissions) per 1000 patients Duration of signs and 1932 (5) Very low due to 760 1172 – – Mean time was 0.26 symptoms risk of bias†࿣ SD higher (0.07 to 0.45 SD higher)†† Complications Not measured Critical adverse events 1045 (1) Very low due to 402 643 Rate ratio, 2.9 7 adverse events 14 more adverse risk of bias†࿣ (0.37–23.05) per 1000 patient- events (5 fewer to years 165 more events) per 1000 patient- years Viral shedding (persistent 46 (1) Very low due to 4/23 (17.4) 9/23 (39.1) OR, 3.05 174 cases of 217 more cases of virus) imprecision and (0.78–11.96) 33 persistent virus persistent virus (33 risk of bias§࿣ per 1000 patients fewer to 542 more cases) per 1000 patients
  34. 34. • RCTは全てLow quality evidence levelのみ. – Oseltamivirには症状持続期間, 重症度を緩和させる効果がある. Zanamivirにもあると考えられる. – OseltamivirとZanamivirには効果に差は無し. 34
  35. 35. サージカルマスク vs N95• インフルエンザシーズンのERにて – 看護師446を2群に割り付け, サージカルマスク, N95で比較 (JAMA 2009;302:1865-71) – Ouctome; PCR陽性, ペア血清で4倍以上の増加 – 9月~12月でインフルエンザは98名 サージカルマスク群で50名(23.6%) N95マスク群で48名(22.9%) ARD -0.73%[-8.8~7.3%]と有意差なし。 感染 Surgical Mask N95 ARD RSV 0.9% 0.5% -0.47[-2.07~1.13] Metapneumovirus 1.9% 1.4% -0.46[-1.98~2.89] Parainfluenza 0.5% 1.0% 0.48[-1.12~2.09] Rhinovirus-enterovirus 3.8% 4.8% 0.99[-2.87~4.85] Coronavirus 4.3% 5.7% 1.47[-2.68~6.78] URIでの受診 6.1% 6.2% -0.06[-4.53~4.65]
  36. 36. Clinical Infectious Diseases 2012;55(9):1198–204重症患者に対するNeuraminidase阻害薬• Californiaのサーベイランスにおいて, 2009年4月∼2010年8月までにH1N1インフルエンザで ICU入室した患者1950名. – その内1859名を解析. Neuraminidase阻害薬(NAI)は90%に投与. 平均年齢は37歳[1wk-93yr], 79%が1つ以上の合併症(+). – 死亡例は492例(26%) – NAI使用群と非使用群の違いは年齢(36y vs 44y), 妊娠, 免疫不全(9% vs 1%) (次スライド参照)• 両群の死亡率は, NAI使用群で25%, 非使用群で42%(p<0.0001) 36
  37. 37. Table 1. Critically Ill Case Patients With Influenza A(H1N1)pdm09 Who Were or Were Not Treated With Neuraminidase Inhibitors inCalifornia, April 2009–August 2010 All Hospitalized With Received Neuraminidase Antiviral Information Never Treated Inhibitor TreatmentaCharacteristic (n = 1859) (n = 183) (n = 1676) PDemographicFemale sex 893 (48) 78 (43) 815 (49) NSAge, years, median (range) 37 (0.02–93) 44 (0.02–92) 36 (0.02–93) .0109Race/ethnicityb NS Hispanic 764/1772 (43) 80/178 (45) 684/1594 (43) White, non-Hispanic 628/1772 (35) 62/178 (35) 566/1594 (36) Asian/Pacific Islander 169/1772 (10) 12/178 (7) 157/1594 (10) Black, non-Hispanic 146/1772 (8) 21/178 (12) 125/1594 (8) Other 53/1772 (3) 2/178 (1) 51/1594 (3) Native American 12/1772 (<1) 1/178 (1) 11/1594 (<1) Unknown 87 5 82ACIP comorbid conditionsb,cAny ACIP comorbidity 1473/1857 (79) 150/183 (82) 1323/1674 (79) NS Chronic cardiac diseased 358/1835 (20) 42/180 (23) 316/1655 (19) NS Chronic lung diseasee 786/1830 (43) 83/181 (46) 703/1649 (43) NS Asthma 454/1830 (25) 37/181 (20) 417/1649 (25) NS Metabolic diseasef 598/1840 (33) 72/182 (40) 526/1658 (32) .0322 Diabetes mellitus 413/1840 (22) 50/182 (27) 363/1658 (22) NS Renal disease 210/1840 (11) 28/182 (15) 182/1658 (11) NS Neurologic disorderg 389/1836 (21) 37/182 (20) 352/1654 (21) NS Immunosuppressive conditionsh 324/1845 (18) 38/182 (21) 286/1663 (17) NS Pregnant 72/887 (8) 1/78 (1) 71/809 (9) .0206 Obesityi 597/1422 (42) 62/137 (45) 535/1285 (42) NS BMI ≥40 223/597 (37) 27/62 (44) 196/535 (37) NSClinical complicationsPneumonia/ARDS 1411 (76) 137 (74) 1274 (76) NSSepsis 565 (30) 56 (31) 509 (30) NSAcute renal failure 107 (6) 8 (4) 99 (6) NSPulmonary embolus 4 (<1) 0 4 (<1) NSSecondary bacterial infectionj 188 (10) 17 (9) 171 (10) NSDeath 492 (26) 76 (42) 416 (25) <.0001Details of antiviral treatmentTime from symptom onset to antiviral … NA 4 (0–52) NA treatment, days, median (range)bDuration of antiviral treatment, days, … NA 5 (0–32) NA median (range)bTreated with oseltamivirb … NA 1671 (100) NAReceived double-dose oseltamivirb,k … NA 278/1671 (17) NATreated with oseltamivir plus other … NA 141 (8) NA antiviral(s)l,mTreated with antivirals other than … NA 5 (<1) NA oseltamivirnDetails of hospitalizationbMechanical ventilation 1052/1700 (62) 103/174 (59) 949/1526 (62) NSLength of hospital stay, days, median 9 (1–238) 6 (1–94) 10 (1–238) <.0001 (range)Time from symptom onset to hospital 3 (0–42) 2 (0–32) 3 (0–42) .016 admission, days, median (range)b
  38. 38. また, NAIの使用は早ければ早い程生存率も高い傾向がある. Clinical Infectious Diseases 2012;55(9):1198–204

    Seja o primeiro a comentar

    Entre para ver os comentários

  • takoyakick

    Mar. 13, 2016
  • patimiuzahiko1987

    Apr. 6, 2016
  • ssuserf457eb

    May. 8, 2016
  • sayakaisobe

    Oct. 30, 2016
  • MasahikoSumii

    Nov. 28, 2016
  • ssuser782082

    Jan. 3, 2017
  • ssuser7ba16b

    Feb. 26, 2017
  • ShoichiroMizukami1

    Mar. 3, 2017
  • yujirookada73

    Apr. 2, 2017
  • kawaitakeshi

    Apr. 27, 2017
  • ssuser88e2ca

    Nov. 11, 2017
  • TsubasaNakai1

    Nov. 11, 2017
  • ssuserabecf3

    Nov. 22, 2017
  • MasanoriHiguchi

    Dec. 10, 2017
  • 441lovinson

    Jan. 8, 2018
  • KenitiroTanaka

    Jan. 17, 2019
  • MomoIshii

    Jan. 21, 2020
  • YukiSodani

    Jun. 11, 2020
  • ssuser340304

    Sep. 30, 2020
  • TAIKISHISHIDO

    Feb. 8, 2021

Vistos

Vistos totais

8.420

No Slideshare

0

De incorporações

0

Número de incorporações

2.177

Ações

Baixados

0

Compartilhados

0

Comentários

0

Curtir

32

×