The impact of concomitant pulmonary infection on immune dysregulation in Pneumocystis jirovecii pneumonia

BMC Pulmonary Medicine

Shi-Chuan Chang²  Han-Chen Tsai¹  Fang-Chi Lin³  Chung-Wei Chou⁴ 

[1] Department of Nursing, Taipei Veterans General Hospital, Taipei, Taiwan;Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan;School of Medicine, National Yang-Ming University, Taipei, Taiwan;Department of Medical Affairs, Taipei Municipal Gan-Dau Hospital, Taipei, Taiwan

关键词: Pro-inflammatory cytokines;    Pneumocystis jirovecii pneumonia;    Non-acquired immunodeficiency syndrome;    Bronchoalveolar lavage fluid;    Anti-inflammatory cytokines;   

Others  :  1091284
DOI  :  10.1186/1471-2466-14-182

 received in 2014-08-16, accepted in 2014-11-10,  发布年份 2014

【 摘 要 】

Background

Concurrent infection may be found in Pneumocystis jirovecii pneumonia (PJP) of non-acquired immunodeficiency syndrome (AIDS) patients, however, its impact on immune dysregulation of PJP in non-AIDS patients remains unknown.

Methods

We measured pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, IL-17, monocyte chemoattractant protein-1 (MCP-1) and anti-inflammatory cytokines including IL-10 and transforming growth factor (TGF)-β1 and IL-1 receptor antagonist (IL-1RA) and inflammatory markers including high mobility group box 1, Krebs von den Lungen-6, receptor for advanced glycation end product, advanced glycation end product, surfactant protein D in bronchoalveolar lavage fluid (BALF) and blood in 47 pure PcP and 18 mixed PJP and other pulmonary infections (mixed PJP) in non-AIDS immunocompromised patients and explored their clinical relevance. The burden of Pneumocystis jirovecii in the lung was determined by counting number of clusters of Pneumocystis jirovecii per slide and the concentration of β-D-glucan in BALF. PJP severity was determined by arterial oxygen tension/fraction of inspired oxygen concentration ratio, the need of mechanical ventilation and death.

Results

Compared with pure PJP group, mixed PJP group had significantly higher BALF levels of IL-1β, TNF-α and IL-8 and significantly higher blood levels of IL-8. The BALF ratios of TNF-α/IL-10, IL-8/IL-10, IL-1β/IL-10, TNF-α/TGF-β1, IL-8/TGF-β1, IL-1β/TGF-β1 and IL-1β/IL-1RA were significantly higher in mixed than in pure PJP patients. There was no significant difference in clinical features and outcome between pure and mixed PJP groups, including inflammatory biomarkers and the fungal burden. In pure PJP patients, significantly higher BALF levels of IL-8 and the ratios of IL-8/IL-10, IL-1β/TGF-β1, MCP-1/TGF-β1, MCP-1/IL1RA and IL-8/TGF-β1 were found in the patients requiring mechanical ventilation and in non-survivors.

Conclusions

In summary, concurrent pulmonary infection might enhance immune dysregulation of PJP in non-AIDS immunocompromised patients, but did not affect the outcome as evidenced by morbidity and mortality. Because of limited number of cases studied, further studies with larger populations are needed to verify these issues.

【 授权许可】

   
2014 Chou et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Thomas CF Jr, Limper AH: Pneumocystis pneumonia. N Engl J Med 2004, 350:2487-2498.
• [2]Sepkowitz KA: Opportunistic infections in patients with and patients without acquired immunodeficiency syndrome. Clin Infect Dis 2002, 34:1098-1177.
• [3]Tasaka S, Tokuda H, Sakai F, Fujii T, Tateda K, Johkoh T, Ohmagari N, Ohta H, Araoka H, Kikuchi Y, Yasui M, Inuzuka K, Goto H: Comparisons of clinical radiological features of pneumocystis pneumonia between malignancy cases and acquired immunodeficiency syndrome cases: A multicenter study. Intern Med 2010, 49:273-281.
• [4]Limper AH, Offord KP, Smith TF, Martin WJ 2nd: Pneumocystis carinii pneumonia. Differences in lung parasite number and inflammation in patients with and without AIDS. Am Rev Respir Dis 1989, 140:1204-1209.
• [5]Sepkowitz KA: Pneumocystis carinii pneumonia in patients without AIDS. Clin Infect Dis 1993, 17(Suppl 2):416-422.
• [6]Benfield TL, Vestbo J, Junge J, Nielsen TL, Jensen AB, Lundgren JD: Prognostic value of interleukin-8 in AIDS-associated Pneumocystis carinii pneumonia. Am J Respir Crit Care Med 1995, 151:1058-1062.
• [7]The National Institutes of Health-University of California Expert Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia: Consensus statement on the use of corticosteroids as adjunctive therapy for pneumocystis pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 1990, 323:1500-1504.
• [8]Wright TW, Gigliotti F, Finkelstein JN, McBride JT, An CL, Harmsen AG: Immune-mediated inflammation directly impairs pulmonary function, contributing to the pathogenesis of Pneumocystis carinii pneumonia. J Clin Invest 1999, 104:1307-1317.
• [9]Tasaka S, Kobayashi S, Kamata H, Kimizuka Y, Fujiwara H, Funatsu Y, Mizoguchi K, Ishii M, Takeuchi T, Hasegawa N: Cytokine profiles of bronchoalveolar lavage fluid in patients with pneumocystis pneumonia. Microbiol Immunol 2010, 54:425-433.
• [10]Chou CW, Lin FC, Tsai HC, Chang SC: The importance of pro-inflammatory and anti-inflammatory cytokines in Pneumocystis jirovecii pneumonia. Med Mycol 2013, 51:704-712.
• [11]Baughman RP, Strohofer S, Colangelo G, Frame PT: Semiquantitative technique for estimating Pneumocystis carinii burden in the lung. J Clin Microbiol 1990, 28:1425-1427.
• [12]Bozzette SA, Arcia J, Bartok AE, McGlynn LM, McCutchan JA, Richman DD, Spector SA: Impact of Pneumocystis carinii and cytomegalovirus on the course and outcome of atypical pneumonia in advanced human immunodeficiency virus disease. J Infect Dis 1992, 165:93-98.
• [13]Hayner CE, Baughman RP, Linnemann CC Jr, Dohn MN: The relationship between cytomegalovirus retrieved by bronchoalveolar lavage and mortality in patients with HIV. Chest 1995, 107:735-740.
• [14]Jacobson MA, Mills J, Rush J, Peiperl L, Seru V, Mohanty PK, Hopewell PC, Hadley WK, Broaddus VC, Leoung G, Feigal DW: Morbidity and mortality of patients with AIDS and first-episode pneumocystis carinii pneumonia unaffected by concomitant pulmonary cytomegalovirus infection. Am Rev Respir Dis 1991, 144:6-9.
• [15]Miles PR, Baughman RP, Linnemann CC Jr: Cytomegalovirus in the bronchoalveolar lavage fluid of patients with AIDS. Chest 1990, 97:1072-1076.
• [16]Benfield TL, Helweg-Larsen J, Bang D, Junge J, Lundgren JD: Prognostic markers of short-term mortality in AIDS-associated pneumocystis carinii pneumonia. Chest 2001, 119:844-851.
• [17]Jensen AM, Lundgren JD, Benfield T, Nielsen TL, Vestbo J: Does cytomegalovirus predict a poor prognosis in pneumocystis carinii pneumonia treated with corticosteroids? A note for caution. Chest 1995, 108:411-414.
• [18]Kim T, Moon SM, Sung H, Kim MN, Kim SH, Choi SH, Jeong JY, Woo JH, Kim YS, Lee SO: Outcomes of non-HIV-infected patients with pneumocystis pneumonia and concomitant pulmonary cytomegalovirus infection. Scand J Infect Dis 2012, 44:670-677.
• [19]Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, Davis J, Hsu A, Asher AI, O'Shea J, Holland SM, Paul WE, Douek DC: Impaired T(h)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 2008, 452:773-776.
• [20]Ma CS, Chew GY, Simpson N, Priyadarshi A, Wong M, Grimbacher B, Fulcher DA, Tangye SG, Cook MC: Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med 2008, 205:1551-1557.
• [21]Huang W, Na L, Fidel PL, Schwarzenberger P: Requirement of interleukin-17A for systemic anti–Candida albicans host defense in mice. J Infect Dis 2004, 190:624-631.
• [22]Zelante T, De Luca A, Bonifazi P, Montagnoli C, Bozza S, Moretti S, Belladonna ML, Vacca C, Conte C, Mosci P, Bistoni F, Puccetti P, Kastelein RA, Kopf M, Romani L: IL-23 and the Th17 pathway promote inflammation and impair antifungal immune resistance. Eur J Immunol 2007, 37:2695-2706.
• [23]Rudner XL, Happel KI, Young EA, Shellito JE: Interleukin-23 (IL-23)–IL-17 cytokine axis in murine Pneumocystis carinii infection. Infect Immun 2007, 75:3055-3061.
• [24]Hu T, Takamoto M, Hida S, Tagawa Y, Sugane K: IFN-gamma deficiency worsen Pneumocystis pneumonia with Th17 development in nude mice. Immunol Lett 2009, 127:55-59.
• [25]Iriart X, Witkowski B, Courtais C, Abbes S, Tkaczuk J, Courtade M, Cassaing S, Fillaux J, Blancher A, Magnaval JF, Pipy B, Berry A: Cellular and cytokine changes in the alveolar environment among immunocompromised patients during Pneumocystis Jirovecii infection. Med Mycol 2010, 48:1075-1087.
• [26]Gigliotti F, Wright TW: Immunopathogenesis of Pneumocystis carinii pneumonia. Expert Rev Mol Med 2005, 7:1-16.
• [27]Sun HY, Singh N: Opportunistic infection-associated immune reconstruction syndrome in transplant recipients. Clin Infect Dis 2011, 53:168-176.