Pneumocystis carinii

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Pneumocystis carinii

  1. 1. Pneumocystis carinii (jiroveci)
  2. 2. Pneumocystis carinii• 真核性の微生物で, 世界中, 様々な宿主に常在する真菌(原虫)• HIVや臓器移植患者, 免疫抑制療法中の患者における肺炎の原因として重要• 4つの形態で存在する;Trophozoites, Cysts, Precysts, SporozoiteTrophozoite; 2-4µmの単細胞様構造. 電子顕微鏡で検出可能.Cysts; 4-8µmの嚢胞. Giemsa, Papanicolaou, Grocott染色で検出可. Grocott染色, 免疫蛍光染色が診断に特異的. 部分的に肥厚しており, 内部にGrocott染色で黒く染まる顆粒を有する.Arch Pathol Lab Med. 2004;128:1023–1027Figure 1. Alveolar casts of Pneumocystiscarinii (Giemsa stain, original magnificationϫ400).Figure 2. Alveolar cast of Pneumocystis car-inii in smear prepared from a bronchoalveo-lar lavage specimen (Papanicolaou stain, orig-inal magnification ϫ400).Figure 3. Cysts of Pneumocystis carinii withcapsular dots. Note the position of dots variesin each cyst (Grocott methenamine silver ni-trate, original magnification ϫ1000).Figure 4. Cysts of Pneumocystis carinii inalveolar cast stained positive with 3F6 anti-body (immunoperoxidase, original magnifi-cation ϫ1000).Giemsa染色 Papanicolaou染色 Grocott染色 3F6抗体蛍光染色
  3. 3. PCPの臨床経過• PCPは小児期に感染したP cariniiの再活性化にて生じる.• P cariniiは動物-ヒト感染, 空気感染, 飛沫感染をする可能性.(大気中にDNAを検出する)• PCPは数週間の経過の乾性咳嗽, 発熱, 寝汗, 呼吸苦で発症することが多い.血痰での発症例も報告あり.身体所見では, fine crackles, 頻脈, 多呼吸, チアノーゼなど.• 画像所見ではびまん性のGGOや結節影を認めることが多い.• 肺のみにならず, リンパ行性, 血行性に播種し,特に甲状腺, 肝臓, リンパ節, 骨髄, 脾臓に播種しやすい(網様系)Arch Pathol Lab Med. 2004;128:1023–1027
  4. 4. • PCPの検査所見; 診断はBAL, 喀痰の細胞診• BAL, 誘発喀痰のGiemsa, Papanicolaou, Grocott染色が診断に有用.Gold standardは肺生検だが, 滅多に行われない.免疫化学検査やPCRも有用な検査だが, Cost-benefitが合わず,基本的にはBALが陰性でも疑わしい場合に考慮する.• 染色法と感度, 特異度• 313例の検体(BAL検体)を4つの染色法で評価;Calcofluor white(CW), Grocott-Gomori methenamine silver(GMS),  Diff-Quik(DQ), Merifluor Pneumocystis(MF)染色(免疫蛍光染色)• PCPは65/313.(Reference standard不明)• MF法が最も診断能が高い.Arch Pathol Lab Med. 2004;128:1023–1027JOURNAL OF CLINICAL MICROBIOLOGY 2004;42:3333–3335TABLE 1. Statistical parameters of four stains used for P. jiroveciaStainNo. ofpositiveslidesTotal no. ofslides examinedSEN (%) SPEC (%) PPV (%) NPV (%)CW 48 308 73.8 99.6 98.0 93.4MF 59 310 90.8 94.7 81.9 97.5DQ 31 307 48.4 99.6 96.9 88.0GMS 50 310 76.9 99.2 96.2 94.23334 NOTES
  5. 5. • 検体と鏡検による診断能のまとめand intensification of immu-utic regimens, PCP remainsonly, patients without a rec-developed PCP (152).st individuals are infected bydentification of organisms inrequency of infection variesphy. Given the absence of aoir, it was generally assumedn was involved in the patho-ls. However, following treat-uppression in animal modelsnce of infection in animalson; reinfection of those ani-ssible (8). Such aerosol trans-monstrated in animals and inn immunocompromised pa-th PCP (21, 42, 70, 152, 171).humans have demonstratedation of latent infection aree of disease (64, 97, 103).toxicities of the agents used for the treatment of PCP, it isadvantageous to have histopathologic confirmation of the di-agnosis. In general, noninvasive testing should be attempted inorder to make the initial diagnosis, but invasive techniquesshould be used when necessary and clinically feasible. Suspi-cion of PCP should lead to early consideration of an invasivediagnosis in the HIV-negative, immunocompromised host. Themost commonly used diagnostic techniques and their respec-tive yields are shown in Table 1. Sputum collected for routinebacterial and fungal cultures is rarely useful for the diagnosisof PCP (98). The technique of sputum induction with hyper-tonic saline has been very useful for all immunocompromisedTABLE 1. Diagnostic techniques for PCPTechnique (reference) Yield (%)Routine sputum (98, 173)..................................................................... PoorInduced sputum (40, 93)....................................................................... 30–55Induced sputum with immunofluorescent-antibodystaining (93, 96).................................................................................. 60–97Bronchoalveolar lavage (40, 160) ........................................................ 80–95Bronchoalveolar lavage and transbronchial biopsy (13, 40) ............ Ͼ95Open-lung biopsy (139)......................................................................... Ͼ95PNEUMOCYSTIS INFECTION IN HIV-NEGATIVE PATIENTS 771CLINICAL MICROBIOLOGY REVIEWS 2004;17:770–782
  6. 6. tomatic carriers of pneumocystis.30-35 Although methoprim–sulfamethoxazoleanddihydropteroate3Figure 2. Detection of Pneumocystis Forms with the Use of Different Stains.Panel A shows typical pneumocystis cyst forms in a bronchoalveolar-lavage specimen stained with Gomori methena-mine (¬100). Thick cyst walls and some intracystic bodies are evident. Wright–Giemsa staining can be used for rapididentification of trophic forms of the organisms within foamy exudates, as shown in Panel B (arrows), in bronchoalveo-lar-lavage fluid or induced sputum but usually requires a high organism burden and expertise in interpretation (¬100).Calcofluor white is a fungal cyst-wall stain that can be used for rapid confirmation of the presence of cyst forms, asshown in Panel C (¬400). Immunofluorescence staining, shown in Panel D, can sensitively and specifically identify bothpneumocystis trophic forms (arrowheads) and cysts (arrows) (¬400).A BC DA: Gomori methenamine B;Wright-Giemsa染色; 泡沫状の浸出液中にあるTrophic form(栄養態)を検出. 迅速診断が可能なのが利点C; Calcofluor white染色D; 免疫蛍光染色
  7. 7. • (1→3)-β-D-Glucan• 252名のHIV患者(内69%がPCPと診断)のβ-D-Glucanを評価したStudyでは,PCP群では408pg/mL[209-500] vs 37pg/mL[31-235]Cutoffを>80pg/mLとした場合, Sn 92%[87-96] Sp 65%[53-75]となる.ちなみにLDHは有意差無し.• β-D-Glucanは国内と海外で試薬が異なるため, 解釈には注意が必要.Participants received a median of 11 days (IQR, 9–13 d) of OItreatment before study entry.Table 2 shows b-glucan levels in participants with and with-out PCP. A statistically significant difference in b-glucan levelswas not observed between confirmed and probable cases of PCP(P 5 .81), nor was a suggestion of a trend observed. The medianb-glucan level in persons with PCP was 408 pg/mL (IQR, 209–500 pg/mL), with 92% of persons having a positive result (R80pg/mL). In persons without PCP, the median b-glucan level was37 pg/mL (IQR, 31–235 pg/mL), with 35% having a positiveresult. Both continuous and ordered categorical b-glucan levelswere different in persons with and without PCP (both P , .001).The results are displayed visually in Figure 1. In contrast, nostatistically significant difference was seen in the proportionof participants with elevated (.400 IU/mL) levels of lacticdehydrogenase in those with and without PCP (24% vs 19%;P 5 .41). Levels of b-glucan did not significantly differdepending on the number of days of OI treatment beforestudy entry. There was no statistically significant associationbetween b-glucan levels and use of adjunctive corticosteroids(Wilcoxon rank sum, P 5 .70) or the composite outcome ofnew OI or death (Wilcoxon rank sum, P 5 .60).Toxoplasmosis 13 (5%)CMV 9 (4%)Histoplasmosisa8 (3%)Oral/Esophageal candidiasis 112 (44%)NOTE. CMV, cytomegalovirus; IQR, interquartile range; OIs, opportunisticinfections; PCP, Pneumocystis jirovecii pneumonia.aCases of histoplasmosis were enrolled in 7 of 38 participating sites.Table 2. Results of b-Glucan Testing by Pneumocystis jirovecii Pneumonia (PCP) DiagnosisPCPb-glucan level (pg/mL) Yes (N 5 173) No (N 5 79) Total (N 5 252) PMean (SD) 349.8 (163.9) 142.0 (173.7) 284.6 (192.6) ,.001aMin, max 31, 500 31, 500 31, 500Median (Q1, Q3) 408 (209–500) 37 (31–235) 284.5 (70–500)Negative , 60 pg/mL 9 (5%) 48 (61%) 57 (23%) ,.001bIndeterminate 60–79 pg/mL 4 (2%) 3 (4%) 7 (3%)Positive R 80 pg/mL 160 (92%) 28 (35%) 188 (75%)and without Pneumocystis jirovecii pneumonia (PCP). The median valuefor those with PCP (horizontal line) was 408 pg/mL (interquartile range[IQR], 209–500 pg/mL) and for those without PCP was 37 pg/mL (IQR,31–235 pg/mL). Both continuous and categorical b-glucan levels weresignificantly different in persons with and without PCP (P , .001).Clinical Infectious Diseases 2011;53(2):197–202
  8. 8. PCPと血清マーカー• 日本からのStudy.295名のBAL施行患者において, BAL細胞数,LDH, β-D-Glucan, KL-6, CRPを評価し, PCPとの関連を評価.• 57名がPCP(+), 238名はPCP(-).• BAL所見はPCP or Non-PCPで明らかな違いは無し.CHEST 2007; 131:1173–1180sequently received pentamidine due to failure oradverse effects of the trimethoprim/sulfamethox-azole treatment.The background characteristics and oxygenationindices of the patients analyzed are shown in Table 1.The patients with PCP were significantly youngerthan those without PCP (p Ͻ 0.0001). The commonunderlying diseases of the patients with PCP in-cluded hematologic malignancy, HIV infection, andcollagen vascular disease. The oxygenation index inthe patients with PCP was significantly lower than inthose without PCP (p ϭ 0.009).The underlying diseases of the 16 patients ex-cluded from analyses include hematologic malignan-cies (n ϭ 6), collagen vascular diseases (n ϭ 4), lungcancer (n ϭ 3), other malignancies (n ϭ 2), andCrohn disease (n ϭ 1). Most of these 16 patientsprobable diagnoses of those 16 patients includealveolar hemorrhage (n ϭ 3), radiation pneumonitis(n ϭ 2), drug-induced pneumonitis (n ϭ 2), pneu-monia due to Pseudomonas aeruginosa (n ϭ 2), cy-tomegalovirus pneumonia (n ϭ 2), and invasive pul-monary aspergillosis (n ϭ 1). The rest of the patientswere treated as having pneumonia due to an uniden-tified pathogen. Even if the 16 patients were in-cluded in the analysis, the results were not changed(data not shown).The recovery rate, cell counts, and differentials ofBAL fluid are summarized in Table 2. Neither therecovery rate nor total cell count of BAL fluid weredifferent between the PCP-positive and PCP-nega-tive patients. There were no differences in theproportions of macrophages, lymphocytes, neutro-phils, and eosinophils in BAL fluid between theTable 2—BAL Cell Counts and Differentials*ParametersPCP Positive(n ϭ 57)PCP Negative(n ϭ 222) p Value†BALFluid recovery, % 45.0 (32.3–54.5) 40.0 (30.0–50.0) 0.13Cell concentration, ϫ 105/mL 5.9 (3.0–11.9) 8.7 (4.4–15.0) 0.054Macrophages, % 36.5 (18.3–57.0) 39.8 (22.6–60.5) 0.52Lymphocytes, % 28.5 (13.5–53.0) 32.1 (13.2–56.9) 0.73Neutrophils, % 9.0 (3.0–35.1) 6.7 (1.8–26.7) 0.41Eosinophils, % 0.4 (0.0–1.8) 0.5 (0.0–2.1) 0.33CD4ϩ/CD8ϩratio 0.53 (0.33–1.45) 1.00 (0.54–1.80) 0.039Peripheral bloodWBC count, ϫ 103/␮L 6.7 (3.6–9.3) 6.6 (4.2–9.9) 0.64Neutrophils, % 88.0 (76.9–94.0) 79.0 (64.9–89.4) 0.003Lymphocytes, % 6.0 (3.8–11.3) 10.0 (4.0–18.9) 0.011
  9. 9. CHEST 2007; 131:1173–1180
  10. 10. • LDH, KL-6, β-D-glucanはPCPの方がより高値となるが,β-D-glucan以外は診断に有用とは言えない.• β-D-Glucan >31.1pg/mLでは,Sn 92.3%, Sp 86.1%でPCPを示唆.• LDL>268IU/Lでは,Sn 86%, Sp 45.3%でPCPを示唆する.• ちなみに, HIV PCPとnon-HIV PCPではβ-D-glucanの値は約1桁違う!CHEST 2007; 131:1173–1180Figure 2. ROC curves for LDH, ␤-D-glucan, and KL-6. Theareas under the curve values are 0.935 for ␤-D-glucan, 0.730 forKL-6, and 0.704 for LDH. There were significant differences inthe area under the curve value between for ␤-D-glucan and forthe other two markers (p Ͻ 0.01).www.chestjournal.org© 2007 American Collchestjournal.chestpDownloaded fromInter Med 48: 195-202, 2009 DOI: 10.2169/internalmedicine.48.1680aInter Med 2009;48:195-202CHEST 2007; 131:1173–1180
  11. 11. RA患者のPCP vs MTX肺 vs HIV患者のPCPの比較• 14例のRA患者のPCP(RA-PCP), 10例のMTX肺, 11例のHIV-PCP(Retrospective study, 日本国内)Inter Med 2008;47: 915-923Eleven cases of the AIDS-PCP cases wereTMP-SMX. Adjunctive corticosteroids were giv(oral prednisolone for 2 weeks). Three cases nesupplementation but none required mechanicaAll patients recovered.All MTX-P patients received steroid pulselowed by 30-60 mg/day oral prednisolone as anwith tapering. Although two cases required mec
  12. 12. Inter Med 2008;47: 915-923RA患者に生じるPCP,MTX肺は進行が日∼週の経過と速い.炎症, 症状, 低酸素もHIV患者より高度となる傾向LDHは3者同等.β-D-GlucanはPCP除外には有用かもしれない.RA-PCPとHIV-PCPでβ-D-Glucanの値は1桁違う* これは日本国内のStudyなのでβ-D-Glucanはそのまま解釈可
  13. 13. • 画像所見の比較• Type A; びまん性のGGOで小葉全体に広がる. → 正常肺とGGO境界が小葉間隔壁で明瞭.Type B; びまん性のGGOで小葉間隔壁で明瞭に分布が分かれない.TypeC; Consolidation + GGOといったその他のパターンInter Med 2008;47: 915-923Inter Med 47: 915-923, 2008 DOI: 10.2169/internalmedicine.47.0702Inter Med 47: 915-923, 2008 DOI: 10.2169/internalmedicine.47.0702Inter Med 47: 915-923, 2008 Dplasma β-D-glucan level of AIDS-PCP was significantlyhigher (965.4 pg/ml, mean) than that of RA-PCP (98.5 pgml, mean). The value was below the cut-off level in MTX-Pcases.The CD4 cell count was 780.0±497.1/μl in the MTX-Pgroup, 793.2±274.8/μl in the RA-PCP group, and 62.9±79.5μl in the AIDS-PCP group, respectively. Taking the preserved serum immunoglobulin G (IgG) level into accountRA-PCP patients, as with MTX-P patients, showed a slighto moderate degree of immunosuppression, which was markedly different from AIDS-PCP patients (Fig. 5). PCP is usually considered to be an opportunistic infection under imType A Type B Type CInter Med 47: 915-923, 2008 DOI: 10.2169/internalmedicine.47.0702such a situation, traditional staining is often not sufficientlysensitive. PCR for P. jirovecii is a much more sensitive tech-nique than traditional staining (5) and its usefulness in thediagnosis of PCP, especially with low organism burden, wasreported by many investigators (4, 6, 7). On the other handseveral studies found incontrovertible incidence of coloniza-tion of P. jirovecii among immunosuppressed patients, sug-gesting that a positive PCR result alone may lead to overdi-agnosis (8, 9). Meanwhile the measurement of β-D-glucan, ain non-HIV PCP (15).It is noteworthy that in our RA-PCP patientsnological status was not impaired as severelyPCP patients. These facts, i.e., relatively preservin RA-PCP patients, have been pointed out inports (22, 23). Why PCP can occur in patientsseverely immunosuppressed is a problem to be scially in relation to some particular immunomtions of anti-rheumatic drugs.
  14. 14. RA患者で生物的DMARD使用中に急性びまん性間質影を生じた26名を解析• Definite PCP; 気管分泌物の鏡検でPC陽性      もしくはPCR陽性 + β-D-glucanがCutoff以上Probable PCP; PCR陽性 もしくは β-D-glucan上昇 で定義したとき,• Definite PCPは13名, Probable 11名, MTX肺 2名であった.Intern Med 2011;50: 305-313Intern Med 50: 305-313, 2011 DOI: 10.2169/internalmedicine.50.4508Table 1. Demographic Features of Patients with AoDILD during the Treatment with Biological Agent3群でRA期間,MTX使用期間,Doseに有意差無し
  15. 15. • また, 検査値もβ-D-glucan以外は有意差無し.• 画像からも鑑別は困難であり, 疑えばBALによる鏡検, PCRが必要となる.The distribution of abnormal shadows on HRCT was simi-larly generalized in both groups (Fig. 1). In addition, thesharpness of the border and the homogeneity of abnormalshadows were also comparable. HRCT patterns showed dif-fuse GGO distributed unrelatedly to lobules (type BGGO (6, 18)) in 9 of 13 (69.2%) patients wand all 11 (100%) patients with probableThis finding showed a marked contrast toport on RA-PCP in which GGO distributedmultilobular distribution (type A GGO (6, 1Intern Med 2011;50: 305-313
  16. 16. Pneumocystis carinii DNA PCR• 喀痰, BAL検体のPCRはPCPの診断に有用である可能性.• 膠原病(SLE, DM/PM, MCDT, MPA)でPCPの可能性が濃厚な29名.(臨床症状, 画像所見)• 蒸留水10ml吸入し誘発した喀痰でカリニDNA PCRと細胞診を施行. → 54.5%でPCR陽性. 一方で細胞診で陽性だったのが4.5%.• なので誘発喀痰のPCRは有用! と結論づけているが,PCP診断のReference standardが一切不明. 確定診断していない!?ただの常在菌である可能性は?• このStudyの意図がよくわからないが,おそらくは誘発喀痰のPCRの感度が高い可能性を示唆しているRheumatology 2004;43:479-85こういう研究のケの字も知らない論文は日本製が多い
  17. 17. JOURNAL OF CLINICAL MICROBIOLOGY 1998;36:979–982for 10 min. After removal of the supernatant, an aliquot of the sediment was usedfor DFA staining. The quality of the IS specimens was not evaluated. BALspecimens were centrifuged at 1,875 ϫ g for 10 min, and a portion of thesediment was used for DFA staining. The remaining IS and BAL sediments werefrozen at Ϫ10 to Ϫ20°C until processed for PCR. BAL and IS specimens wereTABLE 1. Comparison of DFA and PCR for the detectionof P. carinii in respiratory specimensaPCRresultDFA stain result with specimen from:BALbIScϩ Ϫ ϩ Ϫϩ 17 2 17 10Ϫ 0 93 1d92aϩ, positive; Ϫ, negative.bFor BAL specimens, the sensitivity of PCR was 100% (17 of 17 specimensdetected); the specificity of PCR was 98% (93 of 95 specimens detected).cFor IS specimens, the sensitivity of PCR was 94% (17 of 18 specimensdetected); the specificity of PCR was 90% (92 of 102 specimens detected).dPatient was without evidence of clinical PCP (see text for details).980 CALIENDO ET AL.• HIVを含む免疫不全患者168名より232検体を採取し,Direct fluorescent-antibody(DFA)染色, PC DNA PCRを施行.• 誘発喀痰が120例, BAL検体が112例.• PCPの診断は, DFA染色にて菌体を確認することと規定.• BAL検体では,PCRの感度100%, 特異度98%.• 誘発喀痰では,PCRの感度94%, 特異度90%• * Reference standardがDFA染色陽性で定義されているが, DFA染色自体の感度, 特異度が90%前後(他のStudy)であり, それなりに期待できるのでは. 得に誘発喀痰でのPCRもそれなりの感度を示すのは検査が行いやすい.
  18. 18. • 免疫不全患者で, PCPを疑った214名でBALを行い,BAL検体でPCRを施行.• Non-HIV患者は198名, 最終的にPCPと診断されたのは56名であった.(臨床的, 治療効果, 経過で矛盾しない, 他の診断が除外)• PCRはP cariniiの3つの遺伝子をTargetとして施行;mitochondrial large subunit rRNA(mtLSUrRNA) gene, major surface glycoprotein(MSG),  T1-T2 region of the large subunit ribosomal RNA gene(28S rRNA).• PCRは42/56(75%)で陽性; 感度75%, 特異度は95%一方で, 細胞診では8/56(14%)でのみ検出; 感度14%, 特異度100%Am J Med Sci 2011; 342(3):182–185.
  19. 19. • ReverseTranscriptase PCRキット(MycAssay Pneumocystis) → PCのミトコンドリアをTargetとしたPCRキット.• BAL検体110例で施行したStudyでは, 感度93%, 特異度91%でPCPを診断(RSは検査, 臨床で最終的にPCPと医師が判断.)• このStudyでもMerifluor Pneumocystisは感度93 特異度90-100と良好JOURNAL OF CLINICAL MICROBIOLOGY 2011;49:1872–1878
  20. 20. 診断検査まとめTable1Diagnostic performance of contemporary tests for diagnosing pneumocystis pneumoniaaMethod Specimen Sensitivity (%) Specificity (%) CommentsMicroscopy45Conventional stains BAL 49–79 99 Stains used in this study includedCW, GMS, and Diff-QuikIFA BAL 91 95 IFA stain used in this study wasMerifluor pneumocystisRT-PCR46–49BAL 94–100 96–100 Pneumocystis targets used in thesestudies included the cdc2, DHFR,DHPS, and HSP70 genesRT-PCR50BAL 100 86 Diagnostic performance declinedwith IS or OPW specimensb-glucan51Serum 92 86 Because of the study population,reported specificity may be higherthan that expected in a populationexposed to endemic fungiAbbreviations: BAL, Bronchoalveolar lavage; b-glucan, (1/3) b-D-Glucan; cdc2, Cell division cycle 2; CW, Calcofluor white;DHFR, Dihydrofolate reductase; DHPS, Dihydropteroate synthase; GMS, Grocott-Gomori methenamine-silver; HSP70, Heat-shock protein 70; IFA, Immunofluorescent antibody; IS, Induced sputum; OPW, Oropharyngeal wash; PCP, Pneumocystispneumonia; PCR, Polymerase chain reaction; RT-PCR, Reverse-transcriptase polymerase chain reaction.aSensitivity/specificity from author-selected recent publications studying performance of currently used diagnostictesting modalities for PCP.Pneumocystis PneumoniaClin Chest Med 30 (2009) 265–278
  21. 21. PCPの治療• 1st-line treatmentはST合剤のFull dose.• HIV感染患者では21日間の投与が推奨されるが,Non-HIV患者では14-17日間でOK.• 副作用でST合剤が使用できない症例では,2nd-lineとしてPentamidineもしくはClindamycine + PrimaquineまたはDapsone + trimethoprimが推奨される.• ステロイドの併用はHIV患者のPCPでは呼吸不全リスクを軽減する.Non-HIVでも呼吸不全, 人工呼吸器管理期間を改善させるとの報告はあるが,Retrospective cohortであり, Evidence levelは低い. (Chest 1998;113:1215-24)UpToDateではHIV患者のPCPのみで推奨している.• 死亡率は高く, non-HIV群で34-49%に及ぶ.Arch Pathol Lab Med. 2004;128:1023–1027
  22. 22. • 治療薬, Dose一覧• ステロイド• PSL 40mg bidを5日間 → 40mg/dを5日間 → 20mg/dを11日間投与.• 適応は, HIV患者のPCPで, Room airでのPaO2<70mmHgもしくはAlveolar-arterial O2 gradient≥35mmHgで推奨される.tomajoradvancesinourunderstandingofthebiol-ogy of pneumocystis in the past several years. Keymolecules have been identified in the mitotic cellcycle, cell-wall assembly, signal-transduction cas-cades, and metabolic pathways. The use of heter-ologous fungal systems to study the expression ofpneumocystis genes has helped this effort, butstandard biochemical and genetic analysis withintheorganismwillbenecessarytoconfirmthefunc-Table 2. Treatment of Pneumocystis Pneumonia.Drug Dose Route CommentsTrimethoprim–sulfameth-oxazole15–20 mg/kg75–100 mg/kgdaily in divid-ed dosesOral orintravenousFirst choicePrimaquine plusclindamycin30 mg daily600 mg threetimes dailyOralAlternatechoiceAtovaquone 750 mg twotimes dailyOral AlternatechoicePentamidine 4 mg/kg daily600 mg dailyIntravenousAerosolAlternatechoiceN Engl J Med 2004;350:2487-98.Clin Chest Med 30 (2009) 265–278
  23. 23. PCPのリスク, 予防• HIV患者ではCD4+T cell <200/µLならば予防が推奨.• CD4+T cell<300よりリスクが上昇.CD4+T cell<100は100-200群の2倍のリスクとなる.また,Total Ly poolの20%をきるとリスク上昇.Viral loadが1-log上昇毎にRR2.8,CD4+T cell<50/µL群ではViral load>50000/mlはRR3.2• 地域性でPCP患者が多い地域,PCP既往があるHIV患者でも予防投与の適応.>> HIV患者のPCPは治療後の1年再発率が60%と高い. また, アメリカ北部など地域性に頻度が高い場所がある.Arch Pathol Lab Med. 2004;128:1023–1027ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 1998;42:995–1004
  24. 24. • HIV患者では, 適切な予防でも20%でPCPを発症し得る• Primary prophylaxisでは16%/y, Secondary prophylaxisでは12.1%/yr.発症リスクのなかで最も関連が強いのがCD4+T cell数で,予防に失敗した76%がCD4+T cell<50µLであった.• HIV患者における予防投与の適応ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 1998;42:995–100410台, 成人例のHIVCD4+T cell数 <200µL2wk以上持続する原因不明の発熱口咽頭カンジダ症の既往Viral titerの急激な上昇CD4+T cell数の急激な低下<11moの小児HIV症例 CD4+T cell数<1500/µL1-5yの小児HIV症例 CD4+T cell数<1000/µL>5yの小児HIV症例 CD4+T cell数<500/µL全小児例 CD4+T cell数が24%以下
  25. 25. • 免疫抑制療法患者では具体的なルールは無いが,• 化学療法や放射線療法で免疫抑制となる患者や,PSL 20mg/dを4wk, 報告によっては3-6mo以上継続する患者,臓器移植後6mo以内,好中球減少症患者が高リスク群となり, 予防を考慮する.(決まったルールは無し.)Arch Pathol Lab Med. 2004;128:1023–1027ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 1998;42:995–1004臓器移植患者術後6m以上は予防を継続(米国)欧州では,ステロイドパルスや免疫抑制療法を継続する例,CMV感染合併例GVHDに対して骨髄移植施行例好中球減少持続例 で適応.
  26. 26. Non-HIV患者のPCP 116例の解析原疾患一覧Mayo Clin Proc 1996;71:5-13
  27. 27. • 血液疾患別のPCP発症率• 移植後患者のPCP発症率f immune T lymphocytesereas transfer of specificly protective (47). Thesehigh incidence of pneu-ϩcell counts. Mice withalso susceptible to PCPhage response by usinge the clearance of infec-and cytokines are not yetmacrophage colony-stim-bility to infection which isarance of organisms andnoff and J. A. Fishman,Pneumocystis and cyto-V is a systemic immuno-MV in the pathogenesis ofar. In vitro, CMV infec-n of organisms on feederONS FOR(3.8%), and rhabdomyosarcoma (4%). Neutropenia and radio-therapy were common cofactors in these patients. Over half ofthe patients did not receive corticosteroids in the month priorto onset of PCP; 20% did not receive corticosteroids within 3months before the infection. The risk of developing PCP inchildren with ALL has also been associated with the durationand intensity of chemotherapy, the presence of mediastinalmasses, and irradiation (73).In a recent retrospective study of 55 patients with hemato-logic disorders, the incidence of PCP in ALL was only 0.5%;TABLE 2. Reported attack rates for PCP by underlying conditionin patients not receiving prophylaxisUnderlying disorder (reference) Attack rate (%)Acute lymphoblastic leukemia (73, 78) ................................ 6.5–42.9Severe combined immunodeficiency syndrome (99)........... 27–42Rhabdomyosarcoma (76, 78) ................................................. 4–25Wegener’s granulomatosis (3, 46, 52, 67, 122) .................... 3.5–12Hodgkin’s disease (78)............................................................ 1.3Collagen vascular disease (52)............................................... Ͻ2Primary or metastatic central nervous system tumor(65, 154)................................................................................ 1.3–1.7N CLIN. MICROBIOL. REV.CLINICAL MICROBIOLOGY REVIEWS 2004;17:770–782olid tumors (152). SimilarPCP have been reportedents with primary or met-587 patients with primaryd PCP (1.7%), most ofand who developed symp-tapered (65). Other caseapy and lymphopenia asTABLE 3. Reported attack rates for PCP in transplant recipientsnot receiving prophylaxisOrgan transplanted (reference) Attack rate (%)Heart-lung/lung (32, 57) .......................................................... 6.5–43Heart (57, 83, 116, 125)........................................................... 2–41Renal (41, 104, 116, 153)......................................................... 0.6–14Liver (27, 61, 130) .................................................................... 3–11Allogeneic bone marrow (112, 153, 168)............................... 5–16PNEUMOCYSTIS INFECTION IN HIV-NEGATIVE PATIENTS 773
  28. 28. • Non-HIV患者群で, PCP予防投与が推奨されるものnocompromisedS INFECTIONeptible patientsUnfortunately,tis in vitro fors has not beendels of P. cariniinical efficacy oftors merit con-ion of disease.y slow (7 to 10Second, of thead spectrum ofcystis, bacteria,some immuno-unless they are masked by immunosuppression. These reac-tions occur more commonly in HIV-positive patients. In gen-eral, the toxicity of TMP-SMX is overemphasized in compar-TABLE 4. Possible indications for the use ofanti-Pneumocystis prophylaxisSolid-organ transplant recipients and allogeneic HSCT or bone marrowtransplant recipients with institutional incidence of Ն5% or in high-risk patients:History of PCP or frequent opportunistic infectionsWith invasive CMV infection or at high risk for CMV diseaseDuring intensified immune suppression for acute allograft rejection orGVHDIndividuals receiving anti-T-cell therapiesAutologous bone marrow transplant recipients with leukemia orlymphoma, undergoing intensive conditioning or graft manipulation, orafter fludarabine or 2-CDAIndividuals with prolonged neutropenia (if marrow suppression istolerable)Individuals with corticosteroid doses of Ն20 mg of prednisone per dayfor Ն2–3 wkPNEUMOCYSTIS INFECTION IN HIV-NEGATIVE PATIENTS 775CLINICAL MICROBIOLOGY REVIEWS 2004;17:770–782
  29. 29.  Non-HIV患者のカリニ肺炎の解析(Mayo Clin Proc 1996;71:5-13)◦ 炎症性疾患患者 + カリニ肺炎では, 25%がプレドニン20mg/d投与期間も25%が8wkで発症している血液腫瘍(N=35)炎症性疾患(N=26)固型腫瘍(N=15)その他(N=11)臓器移植(N=29)ステロイド投与を受けている患者数ステロイド投与を受けている患者数ステロイド投与を受けている患者数ステロイド投与を受けている患者数ステロイド投与を受けている患者数ステロイド投与を受けている患者数カリニ肺炎発症1M以内 28 26 12 10 29診断時に使用 25 23 12 9 29ステロイドDose(プレドニン換算)ステロイドDose(プレドニン換算)ステロイドDose(プレドニン換算)ステロイドDose(プレドニン換算)ステロイドDose(プレドニン換算)ステロイドDose(プレドニン換算)平均値(mg/d) 56.5 40 33.3 30 2025th percentile 20 20 10 12 14.275th percentile 95 56.2 53 48.8 20ステロイド投与期間 wkステロイド投与期間 wkステロイド投与期間 wkステロイド投与期間 wkステロイド投与期間 wkステロイド投与期間 wk平均値 9 16 7.5 12 1425th percentile 5 8 5 5.5 10.275th percentile 17 59.8 9 15.2 24.2
  30. 30.  RA患者16788名のProspective Cohort (3.5年間)(Arthritis & Rheumatism 2006;54:628-34)◦ 使用薬剤と, 肺炎発症のRisk (Outcome; 肺炎による入院)Drug Ajusted HRPrednisone All 1.7[1.5-2.1]ステロイド不使用 1.0 (Ref)Prednisone =<5mg/day 1.4[1.1-1.6]Prednisone 5-10mg/day 2.1[1.7-2.7]Prednisone >10mg/day 2.3[1.6-3.2]MTX 1.0[0.8-1.2]Hydroxychloroquine 0.9[0.7-1.1]Sulfasalazine 0.7[0.4-1.0]Leflunomide 1.3[1.0-1.5]Infliximab 1.2[0.9-1.4]Etanercept 0.8[0.6-1.0]Adalimumab 1.1[0.6-1.8]
  31. 31. • PSLはMTXよりも感染Riskを上昇させる.• ≥65yrのRA患者で, DMARD使用中の15597名のCohort study.上記群において, Serious bacterial infectionは2.2/100pt-yr[2.0-2.4].• PSLはMTXと比較して, 感染リスク RR2.1[1.5-3.1]と上昇させる.• 感染症Risk; 他のDMARD vs MTX, Propensity score adjusted rate ratioARTHRITIS & RHEUMATISM Vol. 56, No. 6, June 2007, pp 1754–1764TNFα阻害薬 GlucocorticoidCytotoxicDMARDsNoncytotoxicDMARDs肺炎 0.72[0.32-1.87] 1.93[1.07-3.47] 0.69[0.26-1.84] 0.67[0.32-1.40]菌血症, 敗血症 1.28[0.62-2.66] 2.51[1.58-3.97] 1.71[0.85-3.42] 0.94[0.33-2.68]骨髄炎 1.07[0.24-4.77] 1.29[0.47-3.52] 0.99[0.19-5.25] 1.31[0.48-3.53]上記どれか 0.97[0.57-1.65] 2.11[1.47-3.03] 1.21[0.69-2.12] 0.84[0.54-1.29]細菌感染全体 1.01[0.60-1.70] 2.14[1.50-3.06] 1.29[0.74-2.23] 0.95[0.63-1.44]≤5mg/d 6-9mg/d 10-19mg/d ≥20mg/d肺炎 0.88[0.37-2.12] 2.01[0.87-4.66] 2.97[1.41-6.23] 6.69[2.83-15.8]菌血症, 敗血症 1.68[0.98-2.87] 1.61[0.84-3.09] 3.15[1.76-5.65] 6.83[3.68-12.7]骨髄炎 1.27[0.40-3.98] 0.84[0.23-3.10] 0.65[0.13-3.18] 0.27[0.03-3.07]上記どれか 1.37[0.85-2.21] 0.64[1.00-2.69] 2.86[1.80-4.56] 5.32[3.18-8.90]細菌感染全体 1.34[0.85-2.13] 1.53[0.95-2.48] 2.97[1.89-4.68] 5.48[3.29-9.11]
  32. 32. PCPの予防薬• 予防方法• ST合剤; 1錠/dの内服でOK(TMP 80mg, SMZ 160mg) P carinii,Toxoplasma gondii, Listeria monocytogenes, Isospora belli, Nocardia asteroidesの予防効果を見込める. (ただし, Nocardiaは予防中でも発症する報告例がある)• Pentamidine(べナンバックス®); 300mgを注射用水3-5mlに溶解し, 3-4wkに1回ネブライザー吸入する予防方法がある. (粒子を1-3µm程度にできればよい) Secondary prophylaxisでは300mg吸入を2回/moがより効果的. その程度の吸入ならば生体内蓄積はまず起らない. 副作用としては期間刺激による症状程度. HIV患者(CD4+T cell<50/µL)でのPCP発症率は10-23%ある.ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 1998;42:995–1004
  33. 33. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 1998;42:995–1004Clin Infect Dis 1996;23:718-22ure rate for CIP vs. TMP-SMZ (P = .0005; RR, 8.27; CI,2.62-26.06) and a similar trend with regard to CIP vs. dapsone(P = .07; RR, 2.68; CI, 0.94-7.64) and dapsone vs. TMP-SMZ (P = .06; RR, 3.09; CI, 0.98-9.73).Because the percentage oftotal patient-years accrued as sec-ondary prophylaxis for PCP was significantly greater in theC/P group than in the other two groups, efficacy rates werefurther evaluated in all three treatment groups after stratificationby this variable. Rates of failure for subjects receiving primaryprophylaxis were 36.8, 2.8, and 9.5 events per 100 patient-years for CIP, TMP-SMZ, and dapsone regimens, respectively.Pairwise comparisons revealed significantly greater failurerates for primary prophylaxis with CIP than for TMP-SMZ(P = .0005; RR, 13.19; CI, 3.54-49.12) and, again, greaterfailure rates ofborderline significance for CIP than for dapsone(P = .04; RR, 3.85; CI, 1.12-13.31). Secondary-prophylaxisTable 2. Incidence ofprobable or definite PCP per 100 patient-yearsof prophylaxis among subjects receiving clindamycin/primaquine(C/P), trimethoprim-sulfamethoxazole (TMP-SMZ), or dapsone.Type of prophylaxis(total no. of patient-years)All (262.4)CD4 ",100 (196.5)Primary (209.5)Secondary (42.9)No. of events of PCP per 100 patient-years, per prophylaxis groupCIP TMP-SMZ Dapsone30.7* 3.4 11.034.lt 4.1 12.82.8 9.521.7 6.1 18.2• 予防方法(Con’d)• Dapsone ±TMP or Pyrimethamine; Pentamidine吸入よりも現在は好まれる. 半減期が50hrと長いため, 50-100mg/d∼100mg/wkで投与可能. 50-100mg/dの投与 + Pyrimethamine 25-50mg/wk投与が好ましい.  (>100mg/d群では副作用増加する) HIV患者におけるPCP予防に対する効果はST合剤に劣る  (ST合剤群ではPCP発症率3.7%@380d vs 15.2%)  しかしながら全体の死亡率は有意差なかった. DapsoneはST合剤と同様,Toxoplasmaへの予防効果も認められる. 副作用はST合剤並みに多いため, ST合剤からの変更には注意.• 他の予防Regimen; Pyrimethamine + atovaquone(未承認); Clindamycin-pyrimethamine; 206名のRetrospective studyでは 予防効果はST合剤に及ばず. Dapsoneとは有意差なし.
  34. 34. • 予防投与薬一覧medical progressel of trypanosome infection, and subsequently byAntonio Carinii, in infected rat lungs.4,5 Both in-vestigators believed they had identified new formsof trypanosomes. Several years later, however, theDelanoës recognized that Chagas and Carinii hadonly P. jirovecii has been found, and for that reason,specifying the name of the species will become im-portant only if additional species of pneumocystisare found to infect humans.The major obstacle to studying pneumocystisTable 1. Drugs for Prophylaxis against Pneumocystis Pneumonia.Drug Dose Route CommentsTrimethoprim–sulfamethoxazole1 double-strength tablet daily or1 single-strength tablet daily1 double-strength tablet 3 timesper weekOral First choiceAlternate choiceDapsone 50 mg twice daily or100 mg dailyOral Ensure patient does not have glucose-6-phosphate dehydrogenase deficiencyDapsone pluspyrimethamine plusleucovorin50 mg daily50 mg weekly25 mg weeklyOralDapsone pluspyrimethamine plusleucovorin200 mg weekly75 mg weekly25 mg weeklyOralPentamidine 300 mg monthly AerosolAtovaquone 1500 mg daily Oral Give with high-fat meals, for maximalabsorptionN Engl J Med 2004;350:2487-98.*Dapsone レクチゾール® 25mg錠あり.

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