Advances in research on the extrapulmonary manifestations and its regulatory mechanism of <i>Legionella</i> infection_West China Medical Journal

Authors：

WANG Jiaxin , YU Mochi ,  CHEN Yu

Department of Respiratory and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110000, P. R. China;

Corresponding author：

CHEN Yu, Email: chenyusy@hotmail.com

Keywords：

Legionella; Extrapulmonary manifestations; Regulatory mechanism

DOI：

10.7507/1002-0179.202012169

Video：

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Legionella, one of the causative pathogens of atypical pneumonia, firstly outbroked during the period of American Legion’s convention in 1976, Philadelphia. Legionella infection can accompany multisystem involvement. In addition to pulmonary lesions, it also accompanies extrapulmonary manifestations, including gastrointestinal symptoms (primarily diarrhea and hepatic dysfunction), neurological symptoms (primarily headache, disorientation and confusion of consciousness), urinary symptoms (primarily hematuria, proteinuria and acute kidney injury), rhabdomyolysis, as well as electrolyte disorder mainly characterized by hyponatremia and hypophosphatemia. This article reviews the extrapulmonary manifestations and its regulatory mechanism of Legionella infection.

Citation： WANG Jiaxin, YU Mochi, CHEN Yu. Advances in research on the extrapulmonary manifestations and its regulatory mechanism of Legionella infection. West China Medical Journal, 2021, 36(1): 8-13. doi: 10.7507/1002-0179.202012169 Copy

1.	Soni AJ, Peter A. Established association of Legionella with rhabdomyolysis and renal failure: A review of the literature. Respir Med Case Rep, 2019, 28: 100962.
2.	Sutarjono B, Alexis J, Sachidanandam JC. Legionella pneumonia complicated by rhabdomyolysis. BMJ Case Rep, 2019, 12(6): e229243.
3.	Engel MF, Van Manen L, Hoepelman A, et al. Diagnostic, therapeutic and economic Consequences of a positive urinary antigen test for Legionella spp. in patients admitted with community-acquired pneumonia: a 7-year retrospective evaluation. J Clin Pathol, 2013, 66(9): 797-802.
4.	Gacouin A, Le Tulzo Y, Lavoue S, et al. Severe pneumonia due to Legionella pneumophila: prognostic factors, impact of delayed appropriate antimicrobial therapy. Intensive care medicine, 2002, 28(6): 686-91.
5.	Cunha BA, Burillo A, Bouza E. Legionnaires’ disease. Lancet, 2016, 387(10016): 376-385.
6.	Van Riemsdijk, Van Overbeeke IC, Van den Berg B. Severe legionnaire’s disease requiring intensive care treatment. NethJ Med, 1996, 49(5): 196-201.
7.	Sopena N, Sabrià-Leal M, Pedro-Botet ML, et al. Comparative study of the clinical presentation of Legionella pneumonia and other community-acquired pneumonias. Chest, 1998, 113(5): 1195-1200.
8.	Dalal N, Athwal PSS, Tharu B, et al. Legionnaires disease presenting as diarrhea: a case report. Cureus, 2020, 12(9): e10593.
9.	Ba CH. Legionnaires' disease: clinical differentiation from typical and other atypical pneumonias. Infect Dis Clin North Am, 2010, 24(1): 73-105.
10.	Reisinger EC, Fritzsche C, Krause R, et al. Diarrhea caused by primarily non-gastrointestinal infections. Nat Clin Pract Gastroenterol Hepatol, 2005, 2(5): 216-222.
11.	Bishop RE. The lipid A palmitoyltransferase PagP: molecular mechanisms and role in bacterial pathogenesis. Mol Microbiol, 2005, 57(4): 900-912.
12.	Prichard W, Fick L. When diarrhea can become deadly: legionnaires’ disease complicated by bowel obstruction. Case Rep Gastroenterol, 2016, 10(3): 781-786.
13.	Morelli N, Battaglia E, Lattuada P. Brainstem involvement in Legionnaires' disease. Infection, 2006, 34(1): 49-52.
14.	Panagariya A, Sharma AK, Dev A, et al. Reversible neurological syndromes with atypical pneumonia. Ann Indian Acad Neurol, 2011, 14(2): 127-129.
15.	de Lau LM, Siepman DA, Remmers MJ, et al. Acute disseminating encephalomyelitis following legionnaires disease. Arch Neurol, 2010, 67(5): 623-626.
16.	Johnson JD, Raff MJ, Van Arsdall JA. Neurologic manifestations of Legionnaires’ disease. Medicine (Baltimore), 1984, 63(5): 303-10.
17.	Heath PD, Booth L, Leigh PN, et al. Legionella brain stem encephalopathy and peripheral neuropathy without preceding pneumonia. J Neurol Neurosurg Psychiatry, 1986, 49(2): 216-218.
18.	Muñoz JA, Díaz Ortuño A, Rodríguez González T, et al. Paralysis of the 3d cranial nerve in legionellosis. Rev Clin Esp, 1988, 182(1): 57.
19.	Lattimer GL, Rhodes L3. Legionnaires' disease. Clinical findings and one-year follow-up. JAMA, 1978, 240(11): 1169-1171.
20.	Morgan DJ, Gawler J. Severe peripheral neuropathy complicating legionnaires’ disease. Br Med J (Clin Res Ed), 1981, 283(636): 1577-1578.
21.	Lowry PW, Tompkins LS. Nosocomial legionellosis: a review of pulmonary and extrapulmonary syndromes. Am J Infect Control, 1993, 21(1): 21-27.
22.	Socan M, Ravnik I, Bencina D, et al. Neurological symptoms in patients whose cerebrospinal fluid is culture-and/or polymerase chain reaction-positive for Mycoplasma pneumoniae. Clin Infect Dis, 2001, 32(2): E31-E35.
23.	路明, 沈宁, 朱红, 等. 表现为小脑功能不全的军团菌病一例并文献复习. 中华结核和呼吸杂志, 2020, 43(2): 126-131.
24.	Pendlebury WW, Perl DP, Winn WJ, et al. Neuropathologic evaluation of 40 confirmed cases of Legionella pneumonia. Neurology, 1983, 33(10): 1340-1344.
25.	Shelburne SA, Kielhofner MA, Tiwari PS. Cerebellar involvement in legionellosis. South Med J, 2004, 97(1): 61-64.
26.	Weir AI, Bone I, Kennedy DH. Neurological involvement in legionellosis. J Neurol Neurosurg Psychiatry, 1982, 45(7): 603-608.
27.	Wong KH, Moss CW, Hochstein DH, et al. “Endotoxicity” of the legionnaires’ disease bacterium. Ann Intern Med, 1979, 90(4): 624-627.
28.	Candler PM, Dale RC. Three cases of central nervous system complications associated with Mycoplasma pneumoniae. Pediatr Neurol, 2004, 31(2): 133-138.
29.	Contini C, Fainardi E, Cultrera R, et al. Advanced laboratory techniques for diagnosing Toxoplasma gondii encephalitis in AIDS patients: significance of intrathecal production and comparison with PCR and ECL-western blotting. J Neuroimmunol, 1998, 92(1/2): 29-37.
30.	Konno S, Kono H, Kitazono H, et al. Legionellosis presenting as singultus and external ophthalmoplegia. Neurol Sci, 2012, 33(6): 1435-1437.
31.	Malik GH. Rhabdomyolysis and myoglobin-induced acute renal failure. Saudi J Kidney Dis Transpl, 1998, 9(3): 273-284.
32.	Kennedy DH, Love WC, Pinkerton IW. Rhabdomyolysis and systemic infection. Br Med J (Clin Res Ed), 1983, 286(6376): 1517.
33.	Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis -- an overview for clinicians. Crit Care, 2005, 9(2): 158-169.
34.	Petejova N, Martinek A. Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review. Crit Care, 2014, 18(3): 224.
35.	Buzzard JW, Zuzek Z, Alencherry BP, et al. Evaluation and treatment of severe rhabdomyolysis in a patient with legionnaires' disease. Cureus, 2019, 11(9): e5773.
36.	Wiegele M, Krenn CG. Cytosorb™ in a patient with Legionella pneumonia-associated rhabdomyolysis: a case report. ASAIO J, 2015, 61(3): e14-e16.
37.	Mcconkey J, Obeius M, Valentini J, et al. Legionella pneumonia presenting with rhabdomyolysis and acute renal failure: a case report. J Emerg Med, 2006, 30(4): 389-392.
38.	Posner MR, Caudill M, Brass R, et al. Legionnaires’ disease associated with rhabdomyolysis and myoglobinuria. Arch Intern Med, 1980, 140(6): 848-850.
39.	Shimura C, Saraya T, Wada H, et al. Pathological evidence of rhabdomyolysis-induced acute tubulointerstitial nephritis accompanying Legionella pneumophila pneumonia. J Clin Pathol, 2008, 61(9): 1062-1063.
40.	Clement J, Maes P, Van Ranst M. Acute kidney injury in emerging, non-tropical infections. Acta Clin Belg, 2007, 62(6): 387-395.
41.	Chidiac C, Che D, Pires-Cronenberger S, et al. Factors associated with hospital mortality in community-acquired legionellosis in France. Eur Respir J, 2012, 39(4): 963-970.
42.	Brivet F, Pham Van T, Petitpretz P, et al. Rhabdomyolysis, acute renal failure and legionnaires’ disease. Chest, 1984, 86(6): 943-944.
43.	Laivier C, Bleuze MO, Hantson P, et al. Extreme rhabdomyolysis, acute renal failure, and protracted ileus in a case of Legionella pneumonia. Case Rep Crit Care, 2019: 3472627.
44.	Sposato B, Mariotta S, Ricci A, et al. Legionnaire’s pneumonia with rhabdomyolysis and acute renal failure. A case report. Recenti Prog Med, 2003, 94(9): 391-394.
45.	Yogarajah M, Sivasambu B. Legionnaires disease presenting as acute kidney injury in the absence of pneumonia. BMJ Case Rep, 2015: bcr2014208367.
46.	Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet, 2019, 394(1212): 1949-1964.
47.	Shah A, Check F, Baskin S, et al. Legionnaires’ disease and acute renal failure: case report and review. Clin Infect Dis, 1992, 14(1): 204-207.
48.	Seegobin K, Maharaj S, Baldeo C, et al. Legionnaires’ disease complicated with rhabdomyolysis and acute kidney injury in an AIDS patient. Case Rep Infect Dis, 2017: 8051096.
49.	Yu VL. Legionnaires’ disease: importance of high index of suspicion in patients in the ICU with community-acquired pneumonia. Chest, 2014, 145(2): 202-205.
50.	Arancibia F, Cortes CP, Valdés M, et al. Importance of Legionella pneumophila in the etiology of severe community-acquired pneumonia in Santiago, Chile. Chest, 2014, 145(2): 290-296.
51.	Ba CH. Hypophosphatemia: diagnostic significance in Legionnaires’ disease. Am J Med, 2006, 119(7): e5-e6.
52.	Hill AR, Uribarri J, Mann J, et al. Altered water metabolism in tuberculosis: role of vasopressin. Am J Med, 1990, 88(4): 357-364.
53.	Dreyfuss D, Leviel F, Paillard M, et al. Resetting of the Vasopressin Osmostat during infectios Pneumonia. Am J Med, 1991, 90(3): 407-407.
54.	袁世洋, 谢军平. 军团菌肺炎致低钠血症机制的研究进展. 中华结核和呼吸杂志, 2017, 40(10): 772-774.
55.	Schuetz P, Haubitz S, Christ-Crain M, et al. Hyponatremia and anti-diuretic hormone in Legionnaires’ disease. BMC Infect Dis, 2013, 13: 585.
56.	Leach CL, Fuhrman BP, Morin F3, et al. Perfluorocarbon-associated gas exchange (partial liquid ventilation) in respiratory distress syndrome: a prospective, randomized, controlled study. Crit Care Med, 1993, 21(9): 1270-1278.
57.	Iovino M, Guastamacchia E, Giagulli VA, et al. Role of central and peripheral chemoreceptors in vasopressin secretion control. Endocr Metab Immune Disord Drug Targets, 2013, 13(3): 250-255.
58.	邬惟为, 冯永亮, 史晓红, 等. 脂多糖干预对军团菌肺炎作用的实验研究. 中华流行病学杂志, 2019, 40(6): 682-685.
59.	Eisenhut M. Changes in ion transport in inflammatory disease. J Inflamm (Lond), 2006, 3: 5.
60.	Ortiz PA, Garvin JL. Role of nitric oxide in the regulation of nephron transport. Am J Physiol Renal Physiol, 2002, 282(5): F777-F784.
61.	Dobrovolskaia MA, Vogel SN. Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect, 2002, 4(9): 903-14.
62.	Natarajan S, Kim J, Remick DG. Acute pulmonary lipopolysaccharide tolerance decreases TNF-alpha without reducing neutrophil recruitment. J Immunol, 2008, 181(12): 8402-8.
63.	Haines JJ, Calhoon H. Interstitial nephritis in a patient with Legionnaires’ disease. Postgrad Med, 1987, 81(3): 77-79.
64.	Watanabe S, Kono K, Fujii H, et al. Two cases of hypophosphatemia with increased renal phosphate excretion in Legionella pneumonia. Case Rep Nephrol Dial, 2016, 6(1): 40-45.

1. Soni AJ, Peter A. Established association of Legionella with rhabdomyolysis and renal failure: A review of the literature. Respir Med Case Rep, 2019, 28: 100962.
2. Sutarjono B, Alexis J, Sachidanandam JC. Legionella pneumonia complicated by rhabdomyolysis. BMJ Case Rep, 2019, 12(6): e229243.
3. Engel MF, Van Manen L, Hoepelman A, et al. Diagnostic, therapeutic and economic Consequences of a positive urinary antigen test for Legionella spp. in patients admitted with community-acquired pneumonia: a 7-year retrospective evaluation. J Clin Pathol, 2013, 66(9): 797-802.
4. Gacouin A, Le Tulzo Y, Lavoue S, et al. Severe pneumonia due to Legionella pneumophila: prognostic factors, impact of delayed appropriate antimicrobial therapy. Intensive care medicine, 2002, 28(6): 686-91.
5. Cunha BA, Burillo A, Bouza E. Legionnaires’ disease. Lancet, 2016, 387(10016): 376-385.
6. Van Riemsdijk, Van Overbeeke IC, Van den Berg B. Severe legionnaire’s disease requiring intensive care treatment. NethJ Med, 1996, 49(5): 196-201.
7. Sopena N, Sabrià-Leal M, Pedro-Botet ML, et al. Comparative study of the clinical presentation of Legionella pneumonia and other community-acquired pneumonias. Chest, 1998, 113(5): 1195-1200.
8. Dalal N, Athwal PSS, Tharu B, et al. Legionnaires disease presenting as diarrhea: a case report. Cureus, 2020, 12(9): e10593.
9. Ba CH. Legionnaires' disease: clinical differentiation from typical and other atypical pneumonias. Infect Dis Clin North Am, 2010, 24(1): 73-105.
10. Reisinger EC, Fritzsche C, Krause R, et al. Diarrhea caused by primarily non-gastrointestinal infections. Nat Clin Pract Gastroenterol Hepatol, 2005, 2(5): 216-222.
11. Bishop RE. The lipid A palmitoyltransferase PagP: molecular mechanisms and role in bacterial pathogenesis. Mol Microbiol, 2005, 57(4): 900-912.
12. Prichard W, Fick L. When diarrhea can become deadly: legionnaires’ disease complicated by bowel obstruction. Case Rep Gastroenterol, 2016, 10(3): 781-786.
13. Morelli N, Battaglia E, Lattuada P. Brainstem involvement in Legionnaires' disease. Infection, 2006, 34(1): 49-52.
14. Panagariya A, Sharma AK, Dev A, et al. Reversible neurological syndromes with atypical pneumonia. Ann Indian Acad Neurol, 2011, 14(2): 127-129.
15. de Lau LM, Siepman DA, Remmers MJ, et al. Acute disseminating encephalomyelitis following legionnaires disease. Arch Neurol, 2010, 67(5): 623-626.
16. Johnson JD, Raff MJ, Van Arsdall JA. Neurologic manifestations of Legionnaires’ disease. Medicine (Baltimore), 1984, 63(5): 303-10.
17. Heath PD, Booth L, Leigh PN, et al. Legionella brain stem encephalopathy and peripheral neuropathy without preceding pneumonia. J Neurol Neurosurg Psychiatry, 1986, 49(2): 216-218.
18. Muñoz JA, Díaz Ortuño A, Rodríguez González T, et al. Paralysis of the 3d cranial nerve in legionellosis. Rev Clin Esp, 1988, 182(1): 57.
19. Lattimer GL, Rhodes L3. Legionnaires' disease. Clinical findings and one-year follow-up. JAMA, 1978, 240(11): 1169-1171.
20. Morgan DJ, Gawler J. Severe peripheral neuropathy complicating legionnaires’ disease. Br Med J (Clin Res Ed), 1981, 283(636): 1577-1578.
21. Lowry PW, Tompkins LS. Nosocomial legionellosis: a review of pulmonary and extrapulmonary syndromes. Am J Infect Control, 1993, 21(1): 21-27.
22. Socan M, Ravnik I, Bencina D, et al. Neurological symptoms in patients whose cerebrospinal fluid is culture-and/or polymerase chain reaction-positive for Mycoplasma pneumoniae. Clin Infect Dis, 2001, 32(2): E31-E35.
23. 路明, 沈宁, 朱红, 等. 表现为小脑功能不全的军团菌病一例并文献复习. 中华结核和呼吸杂志, 2020, 43(2): 126-131.
24. Pendlebury WW, Perl DP, Winn WJ, et al. Neuropathologic evaluation of 40 confirmed cases of Legionella pneumonia. Neurology, 1983, 33(10): 1340-1344.
25. Shelburne SA, Kielhofner MA, Tiwari PS. Cerebellar involvement in legionellosis. South Med J, 2004, 97(1): 61-64.
26. Weir AI, Bone I, Kennedy DH. Neurological involvement in legionellosis. J Neurol Neurosurg Psychiatry, 1982, 45(7): 603-608.
27. Wong KH, Moss CW, Hochstein DH, et al. “Endotoxicity” of the legionnaires’ disease bacterium. Ann Intern Med, 1979, 90(4): 624-627.
28. Candler PM, Dale RC. Three cases of central nervous system complications associated with Mycoplasma pneumoniae. Pediatr Neurol, 2004, 31(2): 133-138.
29. Contini C, Fainardi E, Cultrera R, et al. Advanced laboratory techniques for diagnosing Toxoplasma gondii encephalitis in AIDS patients: significance of intrathecal production and comparison with PCR and ECL-western blotting. J Neuroimmunol, 1998, 92(1/2): 29-37.
30. Konno S, Kono H, Kitazono H, et al. Legionellosis presenting as singultus and external ophthalmoplegia. Neurol Sci, 2012, 33(6): 1435-1437.
31. Malik GH. Rhabdomyolysis and myoglobin-induced acute renal failure. Saudi J Kidney Dis Transpl, 1998, 9(3): 273-284.
32. Kennedy DH, Love WC, Pinkerton IW. Rhabdomyolysis and systemic infection. Br Med J (Clin Res Ed), 1983, 286(6376): 1517.
33. Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis -- an overview for clinicians. Crit Care, 2005, 9(2): 158-169.
34. Petejova N, Martinek A. Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review. Crit Care, 2014, 18(3): 224.
35. Buzzard JW, Zuzek Z, Alencherry BP, et al. Evaluation and treatment of severe rhabdomyolysis in a patient with legionnaires' disease. Cureus, 2019, 11(9): e5773.
36. Wiegele M, Krenn CG. Cytosorb™ in a patient with Legionella pneumonia-associated rhabdomyolysis: a case report. ASAIO J, 2015, 61(3): e14-e16.
37. Mcconkey J, Obeius M, Valentini J, et al. Legionella pneumonia presenting with rhabdomyolysis and acute renal failure: a case report. J Emerg Med, 2006, 30(4): 389-392.
38. Posner MR, Caudill M, Brass R, et al. Legionnaires’ disease associated with rhabdomyolysis and myoglobinuria. Arch Intern Med, 1980, 140(6): 848-850.
39. Shimura C, Saraya T, Wada H, et al. Pathological evidence of rhabdomyolysis-induced acute tubulointerstitial nephritis accompanying Legionella pneumophila pneumonia. J Clin Pathol, 2008, 61(9): 1062-1063.
40. Clement J, Maes P, Van Ranst M. Acute kidney injury in emerging, non-tropical infections. Acta Clin Belg, 2007, 62(6): 387-395.
41. Chidiac C, Che D, Pires-Cronenberger S, et al. Factors associated with hospital mortality in community-acquired legionellosis in France. Eur Respir J, 2012, 39(4): 963-970.
42. Brivet F, Pham Van T, Petitpretz P, et al. Rhabdomyolysis, acute renal failure and legionnaires’ disease. Chest, 1984, 86(6): 943-944.
43. Laivier C, Bleuze MO, Hantson P, et al. Extreme rhabdomyolysis, acute renal failure, and protracted ileus in a case of Legionella pneumonia. Case Rep Crit Care, 2019: 3472627.
44. Sposato B, Mariotta S, Ricci A, et al. Legionnaire’s pneumonia with rhabdomyolysis and acute renal failure. A case report. Recenti Prog Med, 2003, 94(9): 391-394.
45. Yogarajah M, Sivasambu B. Legionnaires disease presenting as acute kidney injury in the absence of pneumonia. BMJ Case Rep, 2015: bcr2014208367.
46. Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet, 2019, 394(1212): 1949-1964.
47. Shah A, Check F, Baskin S, et al. Legionnaires’ disease and acute renal failure: case report and review. Clin Infect Dis, 1992, 14(1): 204-207.
48. Seegobin K, Maharaj S, Baldeo C, et al. Legionnaires’ disease complicated with rhabdomyolysis and acute kidney injury in an AIDS patient. Case Rep Infect Dis, 2017: 8051096.
49. Yu VL. Legionnaires’ disease: importance of high index of suspicion in patients in the ICU with community-acquired pneumonia. Chest, 2014, 145(2): 202-205.
50. Arancibia F, Cortes CP, Valdés M, et al. Importance of Legionella pneumophila in the etiology of severe community-acquired pneumonia in Santiago, Chile. Chest, 2014, 145(2): 290-296.
51. Ba CH. Hypophosphatemia: diagnostic significance in Legionnaires’ disease. Am J Med, 2006, 119(7): e5-e6.
52. Hill AR, Uribarri J, Mann J, et al. Altered water metabolism in tuberculosis: role of vasopressin. Am J Med, 1990, 88(4): 357-364.
53. Dreyfuss D, Leviel F, Paillard M, et al. Resetting of the Vasopressin Osmostat during infectios Pneumonia. Am J Med, 1991, 90(3): 407-407.
54. 袁世洋, 谢军平. 军团菌肺炎致低钠血症机制的研究进展. 中华结核和呼吸杂志, 2017, 40(10): 772-774.
55. Schuetz P, Haubitz S, Christ-Crain M, et al. Hyponatremia and anti-diuretic hormone in Legionnaires’ disease. BMC Infect Dis, 2013, 13: 585.
56. Leach CL, Fuhrman BP, Morin F3, et al. Perfluorocarbon-associated gas exchange (partial liquid ventilation) in respiratory distress syndrome: a prospective, randomized, controlled study. Crit Care Med, 1993, 21(9): 1270-1278.
57. Iovino M, Guastamacchia E, Giagulli VA, et al. Role of central and peripheral chemoreceptors in vasopressin secretion control. Endocr Metab Immune Disord Drug Targets, 2013, 13(3): 250-255.
58. 邬惟为, 冯永亮, 史晓红, 等. 脂多糖干预对军团菌肺炎作用的实验研究. 中华流行病学杂志, 2019, 40(6): 682-685.
59. Eisenhut M. Changes in ion transport in inflammatory disease. J Inflamm (Lond), 2006, 3: 5.
60. Ortiz PA, Garvin JL. Role of nitric oxide in the regulation of nephron transport. Am J Physiol Renal Physiol, 2002, 282(5): F777-F784.
61. Dobrovolskaia MA, Vogel SN. Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect, 2002, 4(9): 903-14.
62. Natarajan S, Kim J, Remick DG. Acute pulmonary lipopolysaccharide tolerance decreases TNF-alpha without reducing neutrophil recruitment. J Immunol, 2008, 181(12): 8402-8.
63. Haines JJ, Calhoon H. Interstitial nephritis in a patient with Legionnaires’ disease. Postgrad Med, 1987, 81(3): 77-79.
64. Watanabe S, Kono K, Fujii H, et al. Two cases of hypophosphatemia with increased renal phosphate excretion in Legionella pneumonia. Case Rep Nephrol Dial, 2016, 6(1): 40-45.

West China Medical Journal

Advances in research on the extrapulmonary manifestations and its regulatory mechanism of Legionella infection

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