Clinical and Immune Features of Pneumocystis Pneumonia with Acute Respiratory Distress Syndrome in Immunocompromised Children
Abstract
Pneumocystis jirovecii pneumonia (PJP) is a common opportunistic infection in immunocompromised children, often causing acute fulminant pneumonia with respiratory failure. The prognosis of PJP in human immunodeficiency virus (HIV)-negative children with acute respiratory distress syndrome (ARDS) remains unclear.
This retrospective review (2015–2021) included 20 HIV-negative children with ARDS and PJP. Among them, 17 had hematological malignancies or solid tumors, and 3 had renal disease; 15 survived, 5 did not. Both groups had very low CD4+ T cell counts (<0.2×10⁹/L), severe ARDS (partial pressure of oxygen in arterial blood / fraction of inspired oxygen [PaO₂/FiO₂] ratio <150), and elevated lactate dehydrogenase (LDH) and (1,3)-β-D-glucan (BDG) levels. In non-survivors, anti-PJP therapy was initiated approximately 7 days later than in survivors.
Single-cell sequencing revealed CD4+/CD8+ T cell ratios of 0.16 (survivors) vs 2.13 (non-survivors), with a higher ratio of regulatory T cells (Tregs) to CD4⁺ T cells in non-survivors (33% vs. 10.6%). Non-survivors showed enrichment of neutrophil degranulation and activation pathways and expressed more proapoptotic and proinflammatory signals (e.g., FAS_FASLG, interferon-γ).
Early treatment initiation is critical. Prolonged CD8+ T cell deficiency, high Treg expression with proapoptotic genes, and excessive inflammation may predict poor prognosis.
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2. Matsumura Y, Shindo Y, Iinuma Y, Yamamoto M, Shirano M, Matsushima A, et al. Clinical characteristics of Pneumocystis pneumonia in non-HIV patients and prognostic factors including microbiological genotypes. BMC Infect Dis. 2011;11:76.
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4. Monnet X, Vidal-Petiot E, Osman D, Hamzaoui O, Durrbach A, Goujard C, et al. Critical care management and outcome of severe Pneumocystis pneumonia in patients with and without HIV infection. Crit Care. 2008;12(1):R28.
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8. Liu Y, Su L, Jiang SJ, Qu H. Risk factors for mortality from pneumocystis carinii pneumonia (PCP) in non-HIV patients: a meta-analysis. Oncotarget. 2017;8(35):59729-39.
9. Roblot F, Godet C, Le Moal G, Garo B, Faouzi Souala M, Dary M, et al. Analysis of underlying diseases and prognosis factors associated with Pneumocystis carinii pneumonia in immunocompromised HIV-negative patients. Eur J Clin Microbiol Infect Dis. 2002;21(7):523-31.
10. Gaborit BJ, Tessoulin B, Lavergne RA, Morio F, Sagan C, Canet E, et al. Outcome and prognostic factors of Pneumocystis jirovecii pneumonia in immunocompromised adults: a prospective observational study. Ann Intensive Care. 2019;9(1):131.
11. Fujii T, Nakamura T, Iwamoto A. Pneumocystis pneumonia in patients with HIV infection: clinical manifestations, laboratory findings, and radiological features. J Infect Chemother. 2007;13(1):1-7.
12. Cereser L, Dallorto A, Candoni A, Volpetti S, Righi E, Zuiani C, et al. Pneumocystis jirovecii pneumonia at chest High-resolution Computed Tomography (HRCT) in non-HIV immunocompromised patients: Spectrum of findings and mimickers. Eur J Radiol. 2019;116:116-27.
13. Liu Y, Zhou N, Zhou L, Wang J, Zhou Y, Zhang T, et al. IL-2 regulates tumor-reactive CD8(+) T cell exhaustion by activating the aryl hydrocarbon receptor. Nat Immunol. 2021;22(3):358-69.
14. Li S, Zhao Y, He X, Kim TH, Kuharsky DK, Rabinowich H, et al. Relief of extrinsic pathway inhibition by the Bid-dependent mitochondrial release of Smac in Fas-mediated hepatocyte apoptosis. J Biol Chem. 2002;277(30):26912-20.
15. Lavrik IN. Systems biology of death receptor networks: live and let die. Cell Death Dis. 2014;5(5):e1259.
16. Watts TH. TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol. 2005;23:23-68.
17. Wensveen FM, Unger PP, Kragten NA, Derks IA, ten Brinke A, Arens R, et al. CD70-driven costimulation induces survival or Fas-mediated apoptosis of T cells depending on antigenic load. J Immunol. 2012;188(9):4256-67.
18. O'Neill RE, Du W, Mohammadpour H, Alqassim E, Qiu J, Chen G, et al. T Cell-Derived CD70 Delivers an Immune Checkpoint Function in Inflammatory T Cell Responses. J Immunol. 2017;199(10):3700-10.
19. Barathan M, Gopal K, Mohamed R, Ellegård R, Saeidi A, Vadivelu J, et al. Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes. Apoptosis. 2015;20(4):466-80.
20. da Silva Antunes R, Mehta AK, Madge L, Tocker J, Croft M. TNFSF14 (LIGHT) Exhibits Inflammatory Activities in Lung Fibroblasts Complementary to IL-13 and TGF-β. Front Immunol. 2018;9:576.
21. Shui JW, Steinberg MW, Kronenberg M. Regulation of inflammation, autoimmunity, and infection immunity by HVEM-BTLA signaling. J Leukoc Biol. 2011;89(4):517-23.
22. Xu H, Cao D, Guo G, Ruan Z, Wu Y, Chen Y. The intrahepatic expression and distribution of BTLA and its ligand HVEM in patients with HBV-related acute-on-chronic liver failure. Diagn Pathol. 2012;7:142.
23. Shubin NJ, Chung CS, Heffernan DS, Irwin LR, Monaghan SF, Ayala A. BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction. J Leukoc Biol. 2012;92(3):593-603.
24. Boonsarngsuk V, Sirilak S, Kiatboonsri S. Acute respiratory failure due to Pneumocystis pneumonia: outcome and prognostic factors. Int J Infect Dis. 2009;13(1):59-66.
25. Dhawan M, Rabaan AA, Alwarthan S, Alhajri M, Halwani MA, Alshengeti A, et al. Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID. Vaccines. 2023.
26. Poddighe D. Mycoplasma pneumoniae-related extra-pulmonary diseases and antimicrobial therapy. Journal of Microbiology, Immunology and Infection. 2019.
27. Tang G, Tong S, Yuan X, Lin Q, Luo Y, Song H, et al. Using Routine Laboratory Markers and Immunological Indicators for Predicting Pneumocystis jiroveci Pneumonia in Immunocompromised Patients. Front Immunol. 2021;12:652383.
28. Jin F, Xie J, Wang HL. Lymphocyte subset analysis to evaluate the prognosis of HIV-negative patients with pneumocystis pneumonia. BMC Infect Dis. 2021;21(1):441.
29. de la Rua NM, Samuelson DR, Charles TP, Welsh DA, Shellito JE. CD4(+) T-Cell-Independent Secondary Immune Responses to Pneumocystis Pneumonia. Front Immunol. 2016;7:178.
30. Ruan S, Samuelson DR, Assouline B, Morre M, Shellito JE. Treatment with Interleukin-7 Restores Host Defense against Pneumocystis in CD4+ T-Lymphocyte-Depleted Mice. Infect Immun. 2016;84(1):108-19.
31. Galván-Peña S, Leon J, Chowdhary K, Michelson DA, Vijaykumar B, Yang L, et al. Profound Treg perturbations correlate with COVID-19 severity. Proc Natl Acad Sci U S A. 2021;118(37).
32. Zhu G, Liao Y, Liu S, Liu P, Yang K, Tan M, et al. Dysregulated Immune Responses in Sepsis: Insights From Treg-Related Gene Expression. Journal of Inflammation Research. 2025.
33. Ostermann L, Seeliger B, David S, Flasche C, Maus R, Reinboth MS, et al. S100A9 is indispensable for survival of pneumococcal pneumonia in mice. PLoS Pathogens. 2023.
34. Ortega-Mejia II, Romero-López N, Casasola-Vargas JC, Burgos-Vargas R, Domínguez-López ML, Romero-López JP. Treg cell plasticity as a driver of inflammation in spondyloarthritis and psoriasis. Frontiers in Immunology. 2025.
35. Jo H, Shin S, Agura T, Jeong S, Ahn H, Lee J, et al. The Role of α-Enolase on the Production of Interleukin (IL)-32 in Con A-Mediated Inflammation and Rheumatoid Arthritis (RA). Pharmaceuticals. 2024.
36. Schenten V, Plançon S, Jung N, Hann J, Bueb J-L, Bréchard S, et al. Secretion of the Phosphorylated Form of S100A9 from Neutrophils Is Essential for the Proinflammatory Functions of Extracellular S100A8/A9. Frontiers in Immunology. 2018.
37. Liu J, Zhang B, Zhang G, Shang D. Reprogramming of regulatory T cells in inflammatory tumor microenvironment: can it become immunotherapy turning point? Frontiers in Immunology. 2024.
38. Xing Y, Hogquist KA. T-cell tolerance: central and peripheral. Cold Spring Harb Perspect Biol. 2012;4(6).
39. Maessen L, Boers LS, Heylen J, van Someren Gréve F, Wauters J, Bos LDJ, et al. Viral reactivations and fungal infections in nonresolving acute respiratory distress syndrome. European Respiratory Review. 2025.
40. Zhang J, Sun X, Zhong L, Shen B. IL-32 exacerbates adenoid hypertrophy via activating NLRP3-mediated cell pyroptosis, which promotes inflammation. Molecular Medicine Reports. 2021.
41. Hiroshima Y, Hsu K, Tedla N, Wong SW, Chow S, Kawaguchi N, et al. S100A8/A9 and S100A9 reduce acute lung injury. Immunology and Cell Biology. 2017.
42. Zhuang H, Zhang Z, Chen B, Tang C, Chen X, Tan W, et al. Prognostic stratification based on HIF-1α signaling for evaluating hypoxia status and immune landscape in hepatocellular carcinoma. Journal of Big Data. 2023.
43. Klapsing P, Moerer O, Wende C, Herrmann P, Quintel M, Bleckmann A, et al. High-frequency oscillatory ventilation guided by transpulmonary pressure in acute respiratory syndrome: an experimental study in pigs. Critical Care. 2018.
44. Song L, Li K, Hong X, Xiao K, Mo G, Zheng M, et al. Transcriptomic evidence of lung repair in paediatric ARDS survival. Clinical and Translational Medicine. 2023.
45. Hua S, Gu X, Jin H, Zhang X, Liu Q, Yang J. Tumor-infiltrating T lymphocytes: A promising immunotherapeutic target for preventing immune escape in cholangiocarcinoma. Biomedicine & Pharmacotherapy. 2024.
46. Upadhyay R, Boiarsky JA, Pantsulaia G, Svensson-Arvelund J, Lin MJ, Wroblewska A, et al. A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-cell Immunotherapy. Cancer Discovery. 2021.
2. Matsumura Y, Shindo Y, Iinuma Y, Yamamoto M, Shirano M, Matsushima A, et al. Clinical characteristics of Pneumocystis pneumonia in non-HIV patients and prognostic factors including microbiological genotypes. BMC Infect Dis. 2011;11:76.
3. Tasaka S, Tokuda H. Pneumocystis jirovecii pneumonia in non-HIV-infected patients in the era of novel immunosuppressive therapies. J Infect Chemother. 2012;18(6):793-806.
4. Monnet X, Vidal-Petiot E, Osman D, Hamzaoui O, Durrbach A, Goujard C, et al. Critical care management and outcome of severe Pneumocystis pneumonia in patients with and without HIV infection. Crit Care. 2008;12(1):R28.
5. Ko Y, Jeong BH, Park HY, Koh WJ, Suh GY, Chung MP, et al. Outcomes of Pneumocystis pneumonia with respiratory failure in HIV-negative patients. J Crit Care. 2014;29(3):356-61.
6. Alvarez-Martínez MJ, Miró JM, Valls ME, Moreno A, Rivas PV, Solé M, et al. Sensitivity and specificity of nested and real-time PCR for the detection of Pneumocystis jiroveci in clinical specimens. Diagn Microbiol Infect Dis. 2006;56(2):153-60.
7. Fan LC, Lu HW, Cheng KB, Li HP, Xu JF. Evaluation of PCR in bronchoalveolar lavage fluid for diagnosis of Pneumocystis jirovecii pneumonia: a bivariate meta-analysis and systematic review. PLoS One. 2013;8(9):e73099.
8. Liu Y, Su L, Jiang SJ, Qu H. Risk factors for mortality from pneumocystis carinii pneumonia (PCP) in non-HIV patients: a meta-analysis. Oncotarget. 2017;8(35):59729-39.
9. Roblot F, Godet C, Le Moal G, Garo B, Faouzi Souala M, Dary M, et al. Analysis of underlying diseases and prognosis factors associated with Pneumocystis carinii pneumonia in immunocompromised HIV-negative patients. Eur J Clin Microbiol Infect Dis. 2002;21(7):523-31.
10. Gaborit BJ, Tessoulin B, Lavergne RA, Morio F, Sagan C, Canet E, et al. Outcome and prognostic factors of Pneumocystis jirovecii pneumonia in immunocompromised adults: a prospective observational study. Ann Intensive Care. 2019;9(1):131.
11. Fujii T, Nakamura T, Iwamoto A. Pneumocystis pneumonia in patients with HIV infection: clinical manifestations, laboratory findings, and radiological features. J Infect Chemother. 2007;13(1):1-7.
12. Cereser L, Dallorto A, Candoni A, Volpetti S, Righi E, Zuiani C, et al. Pneumocystis jirovecii pneumonia at chest High-resolution Computed Tomography (HRCT) in non-HIV immunocompromised patients: Spectrum of findings and mimickers. Eur J Radiol. 2019;116:116-27.
13. Liu Y, Zhou N, Zhou L, Wang J, Zhou Y, Zhang T, et al. IL-2 regulates tumor-reactive CD8(+) T cell exhaustion by activating the aryl hydrocarbon receptor. Nat Immunol. 2021;22(3):358-69.
14. Li S, Zhao Y, He X, Kim TH, Kuharsky DK, Rabinowich H, et al. Relief of extrinsic pathway inhibition by the Bid-dependent mitochondrial release of Smac in Fas-mediated hepatocyte apoptosis. J Biol Chem. 2002;277(30):26912-20.
15. Lavrik IN. Systems biology of death receptor networks: live and let die. Cell Death Dis. 2014;5(5):e1259.
16. Watts TH. TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol. 2005;23:23-68.
17. Wensveen FM, Unger PP, Kragten NA, Derks IA, ten Brinke A, Arens R, et al. CD70-driven costimulation induces survival or Fas-mediated apoptosis of T cells depending on antigenic load. J Immunol. 2012;188(9):4256-67.
18. O'Neill RE, Du W, Mohammadpour H, Alqassim E, Qiu J, Chen G, et al. T Cell-Derived CD70 Delivers an Immune Checkpoint Function in Inflammatory T Cell Responses. J Immunol. 2017;199(10):3700-10.
19. Barathan M, Gopal K, Mohamed R, Ellegård R, Saeidi A, Vadivelu J, et al. Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes. Apoptosis. 2015;20(4):466-80.
20. da Silva Antunes R, Mehta AK, Madge L, Tocker J, Croft M. TNFSF14 (LIGHT) Exhibits Inflammatory Activities in Lung Fibroblasts Complementary to IL-13 and TGF-β. Front Immunol. 2018;9:576.
21. Shui JW, Steinberg MW, Kronenberg M. Regulation of inflammation, autoimmunity, and infection immunity by HVEM-BTLA signaling. J Leukoc Biol. 2011;89(4):517-23.
22. Xu H, Cao D, Guo G, Ruan Z, Wu Y, Chen Y. The intrahepatic expression and distribution of BTLA and its ligand HVEM in patients with HBV-related acute-on-chronic liver failure. Diagn Pathol. 2012;7:142.
23. Shubin NJ, Chung CS, Heffernan DS, Irwin LR, Monaghan SF, Ayala A. BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction. J Leukoc Biol. 2012;92(3):593-603.
24. Boonsarngsuk V, Sirilak S, Kiatboonsri S. Acute respiratory failure due to Pneumocystis pneumonia: outcome and prognostic factors. Int J Infect Dis. 2009;13(1):59-66.
25. Dhawan M, Rabaan AA, Alwarthan S, Alhajri M, Halwani MA, Alshengeti A, et al. Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID. Vaccines. 2023.
26. Poddighe D. Mycoplasma pneumoniae-related extra-pulmonary diseases and antimicrobial therapy. Journal of Microbiology, Immunology and Infection. 2019.
27. Tang G, Tong S, Yuan X, Lin Q, Luo Y, Song H, et al. Using Routine Laboratory Markers and Immunological Indicators for Predicting Pneumocystis jiroveci Pneumonia in Immunocompromised Patients. Front Immunol. 2021;12:652383.
28. Jin F, Xie J, Wang HL. Lymphocyte subset analysis to evaluate the prognosis of HIV-negative patients with pneumocystis pneumonia. BMC Infect Dis. 2021;21(1):441.
29. de la Rua NM, Samuelson DR, Charles TP, Welsh DA, Shellito JE. CD4(+) T-Cell-Independent Secondary Immune Responses to Pneumocystis Pneumonia. Front Immunol. 2016;7:178.
30. Ruan S, Samuelson DR, Assouline B, Morre M, Shellito JE. Treatment with Interleukin-7 Restores Host Defense against Pneumocystis in CD4+ T-Lymphocyte-Depleted Mice. Infect Immun. 2016;84(1):108-19.
31. Galván-Peña S, Leon J, Chowdhary K, Michelson DA, Vijaykumar B, Yang L, et al. Profound Treg perturbations correlate with COVID-19 severity. Proc Natl Acad Sci U S A. 2021;118(37).
32. Zhu G, Liao Y, Liu S, Liu P, Yang K, Tan M, et al. Dysregulated Immune Responses in Sepsis: Insights From Treg-Related Gene Expression. Journal of Inflammation Research. 2025.
33. Ostermann L, Seeliger B, David S, Flasche C, Maus R, Reinboth MS, et al. S100A9 is indispensable for survival of pneumococcal pneumonia in mice. PLoS Pathogens. 2023.
34. Ortega-Mejia II, Romero-López N, Casasola-Vargas JC, Burgos-Vargas R, Domínguez-López ML, Romero-López JP. Treg cell plasticity as a driver of inflammation in spondyloarthritis and psoriasis. Frontiers in Immunology. 2025.
35. Jo H, Shin S, Agura T, Jeong S, Ahn H, Lee J, et al. The Role of α-Enolase on the Production of Interleukin (IL)-32 in Con A-Mediated Inflammation and Rheumatoid Arthritis (RA). Pharmaceuticals. 2024.
36. Schenten V, Plançon S, Jung N, Hann J, Bueb J-L, Bréchard S, et al. Secretion of the Phosphorylated Form of S100A9 from Neutrophils Is Essential for the Proinflammatory Functions of Extracellular S100A8/A9. Frontiers in Immunology. 2018.
37. Liu J, Zhang B, Zhang G, Shang D. Reprogramming of regulatory T cells in inflammatory tumor microenvironment: can it become immunotherapy turning point? Frontiers in Immunology. 2024.
38. Xing Y, Hogquist KA. T-cell tolerance: central and peripheral. Cold Spring Harb Perspect Biol. 2012;4(6).
39. Maessen L, Boers LS, Heylen J, van Someren Gréve F, Wauters J, Bos LDJ, et al. Viral reactivations and fungal infections in nonresolving acute respiratory distress syndrome. European Respiratory Review. 2025.
40. Zhang J, Sun X, Zhong L, Shen B. IL-32 exacerbates adenoid hypertrophy via activating NLRP3-mediated cell pyroptosis, which promotes inflammation. Molecular Medicine Reports. 2021.
41. Hiroshima Y, Hsu K, Tedla N, Wong SW, Chow S, Kawaguchi N, et al. S100A8/A9 and S100A9 reduce acute lung injury. Immunology and Cell Biology. 2017.
42. Zhuang H, Zhang Z, Chen B, Tang C, Chen X, Tan W, et al. Prognostic stratification based on HIF-1α signaling for evaluating hypoxia status and immune landscape in hepatocellular carcinoma. Journal of Big Data. 2023.
43. Klapsing P, Moerer O, Wende C, Herrmann P, Quintel M, Bleckmann A, et al. High-frequency oscillatory ventilation guided by transpulmonary pressure in acute respiratory syndrome: an experimental study in pigs. Critical Care. 2018.
44. Song L, Li K, Hong X, Xiao K, Mo G, Zheng M, et al. Transcriptomic evidence of lung repair in paediatric ARDS survival. Clinical and Translational Medicine. 2023.
45. Hua S, Gu X, Jin H, Zhang X, Liu Q, Yang J. Tumor-infiltrating T lymphocytes: A promising immunotherapeutic target for preventing immune escape in cholangiocarcinoma. Biomedicine & Pharmacotherapy. 2024.
46. Upadhyay R, Boiarsky JA, Pantsulaia G, Svensson-Arvelund J, Lin MJ, Wroblewska A, et al. A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-cell Immunotherapy. Cancer Discovery. 2021.
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| Acute Immunocompromised host Pneumonia Pneumocystis Respiratory distress syndrome Regulatory T-lymphocytes T-lymphocytes | ||
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How to Cite
1.
Feng D, Chen C, Huang H, Huang X. Clinical and Immune Features of Pneumocystis Pneumonia with Acute Respiratory Distress Syndrome in Immunocompromised Children. Iran J Allergy Asthma Immunol. 2026;:1-15.
