Hepatocyte growth factor levels in Legionella pneumonia: A retrospective study
© Higa et al; licensee BioMed Central Ltd. 2011
Received: 7 July 2010
Accepted: 23 March 2011
Published: 23 March 2011
Hepatocyte growth factor (HGF) is known to be involved in the resolution of pulmonary inflammation and repair of acute lung injury. Legionella pneumonia is sometimes complicated by acute lung injury. Our study aimed to determine the role of serum HGF levels in Legionella pneumonia.
Sera from patients with Legionella pneumonia (42 cases), other bacterial pneumonia (33 cases), pulmonary tuberculosis (19 cases), and normal controls (29 cases) were collected. The serum HGF levels for each serum sample were determined by sandwich ELISA. Clinical and laboratory data were collected by reviewing the medical charts.
Serum HGF levels were higher in patients with Legionella pneumonia than in those with other bacterial pneumonia, pulmonary tuberculosis, and controls. The HGF levels were compared with white blood cell counts, C-reactive protein, Alanine amino- transferase, and lactate dehydrogenase (LDH). The HGF levels were correlated to serum LDH levels. Moreover, serum HGF levels were significantly higher in non-survivors than in survivors.
HGF levels increased in severer pneumonia caused by Legionella, suggesting that HGF might play a significant role in the Legionella pneumonia.
Hepatocyte growth factor (HGF) has been proved to be a multi-functional peptide growth factor, which plays important roles in lung development, lung inflammation, and repair . Possible sources of HGF within the lung include bronchial epithelial cells, alveolar macrophages , and neutrophils . The role of HGF in pulmonary infections has been studied in depth. Several studies have convincingly demonstrated that plasma/serum HGF levels become elevated in bacterial pneumonia [4, 5]. Serum HGF levels are considered to be associated with the response of pneumonia to antimicrobials . A study has previously shown that HGF is elevated in pulmonary fluid in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and that higher HGF levels are associated with increased mortality .
Legionella spp. is a common causative pathogen of pneumonia, which can be fatal if complicated with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) . The bacterial etiology of community-acquired pneumonia requiring ICU admission includes Legionella species as well as Streptococcus pneumoniae. However, the pathophysiology of fatal Legionella pneumonia remains unsolved. In this study, in order to clarify the role of HGF in Legionella pneumonia, the serum HGF concentrations in patients with Legionella pneumonia as well as other pulmonary infections were determined. We then evaluated the correlations between HGF levels and other clinical indicators and outcomes.
Our study included 42 consecutive cases of Legionella pneumonia diagnosed in our hospital. Further, 33 cases with other bacterial pneumonia, 19 cases with active pulmonary tuberculosis, and 29 age-adjusted control subjects were also included in this study. The pathogens isolated from the other bacterial pneumonia cases included Streptococcus pneumoniae (12 cases), Hemophilus influenzae (10 cases), Klebsiella pneumoniae (7 cases), Mycoplasma pneumoniae (4 cases), and others (3 cases). Control subjects were healthy without any infections, lung diseases, or liver diseases.
This study was approved by the University of the Ryukyus Institutional Review Board. The need for informed consent from each patient for inclusion in the study was waived because of the retrospective approach of this study, which caused no additional adverse events in any of the subjects. However, prior informed consent had been obtained from each patient before performing any procedure or obtaining any sample.
Blood samples were obtained for conventional clinical diagnosis from each patient. Bronchoalveolar fluids were obtained when required for the diagnosis of Legionella pneumonia. These samples were stored at -80°C until further use. Medical chart reviews were used to obtain information regarding the laboratory findings and clinical outcome of each patient.
Diagnosis of pneumonia and tuberculosis
The diagnosis of pneumonia was based on the clinical presentation (symptoms and physical examination), chest X-ray findings, and laboratory data. The diagnosis of Legionella pneumonia was confirmed by the detection of Legionella by culture, elevation of antibody titers in paired sera, and/or detection of its specific antigen in the urine. The other pneumonia cases were diagnosed based upon the bacteriological investigations (blood culture and culture of the expectorated sputa with satisfactory quality for examination), pulmonary tuberculosis was diagnosed following a positive smear test for acid-fast bacilli as well as positive culture.
Sera were prepared conventionally and stocked at -80°C until further investigation. The stock period was up to years without freeze-thaw cycle. The HGF level for each serum sample was determined by a sandwich ELISA (R&D Systems, Minneapolis, MN) using recombinant human HGF as a standard. The lowest detection limit for HGF was 40 pg/mL. This kit detects both active form and pro-form of HGF. Inter- and intra-assay reproducibilities are reported as 7.0% and 5.6%, respectively.
Data are reported as mean ± standard deviation (SD). The logarithmic transformation of several data values (HGF, white blood cell counts (WBC), and lactate dehydrogenase (LDH)) allowed Gaussian approximation (demonstrated by the Kolmogorov -Smirnov and Shapiro-Wilk tests). Differences in the logarithmically transformed values for HGF levels between multiple groups were examined by using analysis of variance (ANOVA) and Bonferroni's multiple comparison test. Differences between two groups were examined using unpaired t-test with Welch's correction and Mann-Whitney test. The relationship between two parameters was determined by Pearson's correlation coefficient test. These tests were performed using statistical software programs (Prism 4, Graphpad Software Inc., California; and SPSS version 15.0J, SPSS Japan Inc., Tokyo). P < 0.05 was considered statistically significant.
Characteristics of cases for this study
Other bacterial pneumonia
58.9 + 12.0
58.3 + 18.2
56.7 + 16.4
54.2 + 19.1
37/ 5 a
21 / 15
10 / 9
18 / 11
34 / 8
34 / 2
known liver disease
n. s. b
66.4 + 58.7 c
32.9 + 34.5 c
21.2 + 16.2 c
< 0.01 c
807.3 + 748.9 d
218.4 + 88.6 d
239.1 + 302.4 d
< 0.001 d
Association of HGF and other clinical indicators
correlation coefficient ( r )
Our study confirmed that serum HGF levels were elevated in pulmonary infections as reported previously [5, 6, 9]. However, our findings offered a new perspective by comparing serum HGF levels in pulmonary infections due to different pathogens. Serum HGF levels in patients with Legionella pneumonia were higher than in those with pneumonia caused by other pathogens. In this study, the differences in the clinical characteristics of Legionella pneumonia and other bacterial pneumonia pertained to mortality and the male/female ratio. The mortality noted for patients with Legionella pneumonia in this study (19.0%) was similar to that in previous reports, i.e., 5-20% [10–12]. The mortality noted for patients with other bacterial pneumonia in this study (5.5%) was similar to the report of a huge cohort study, i.e., 5.2% . Therefore, the mortality for each group was considered typical. This study showed that HGF levels did not differ with gender. In present study, LDH and ALT activity was higher in Legionella pneumonia than other bacterial pneumonia and pulmonary tuberculosis. Higher LDH suggested severer organ damages and higher ALT suggested more frequent liver dysfunction. The factors influencing increased serum HGF levels in Legionella pneumonia might include severer form of the pneumonia and complication of liver dysfunction.
The results of previous studies evaluating the relationship between HGF levels and clinical outcomes seems to be controversial. One study demonstrated that serum HGF levels were lower in severe pneumonia than in non-severe pneumonia . In the study, however, the cause of death include myocardial infarction (4 cases among 10 non-survivors). On the other hand, HGF levels in pulmonary edema fluids from non-survivors were noted to be higher than those in survivors of acute lung injuries . Another study shows that serum HGF levels as a useful indicator of prognosis in inflammatory pulmonary diseases . Present study revealed that in patients with Legionella pneumonia, serum HGF levels were higher in non-survivors than in survivors. Non-survivors were complicated by acute lung injury. Different cause of death might cause the discrepancy between several studies.
In conclusion, our study showed that HGF levels increased in severer pneumonia caused by Legionella, and suggested that HGF might play a significant role in the Legionella pneumonia. Further studies that investigate the precise role of HGF in severe Legionella pneumonia are warranted.
This work was supported, in part, by the Program of Founding Research Center for Emerging and Reemerging Infectious Diseases from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan as well as the Takeda Foundation.
- Ware LB, Matthay MA: Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair. Am J Physiol Lung Cell Mol Physiol. 2002, 282 (5): L924-940.View ArticlePubMed
- Morimoto K, Amano H, Sonoda F, Baba M, Senba M, Yoshimine H, Yamamoto H, Ii T, Oishi K, Nagatake T: Alveolar macrophages that phagocytose apoptotic neutrophils produce hepatocyte growth factor during bacterial pneumonia in mice. Am J Respir Cell Mol Biol. 2001, 24 (5): 608-615.View ArticlePubMed
- Jaffre S, Dehoux M, Paugam C, Grenier A, Chollet-Martin S, Stern JB, Mantz J, Aubier M, Crestani B: Hepatocyte growth factor is produced by blood and alveolar neutrophils in acute respiratory failure. Am J Physiol Lung Cell Mol Physiol. 2002, 282 (2): L310-315.View ArticlePubMed
- Hojo SFJ, Yamadori I, Kishimoto T, Miyazaki H, Obayashi Y, Yamaji Y, Takahara J: Serial measurements of plasma hepatocyte growth factor in patients with pneumonia following cancer chemotherapy. J Infect Chemother. 1996, 2: 49-51. 10.1007/BF02355198.View Article
- Nayeri F, Millinger E, Nilsson I, Zetterstrom , Brudin L, Forsberg P: Exhaled breath condensate and serum levels of hepatocyte growth factor in pneumonia. Respir Med. 2002, 96 (2): 115-119. 10.1053/rmed.2001.1225.View ArticlePubMed
- Abednazari H, Xu J, Millinger E, Brudin L, Forsberg P, Nayeri F: Hepatocyte growth factor is a better indicator of therapeutic response than C-reactive protein within the first day of treatment in pneumonia. Chemotherapy. 2006, 52 (5): 260-263. 10.1159/000094868.View ArticlePubMed
- Verghese GM, McCormick-Shannon K, Mason RJ, Matthay MA: Hepatocyte growth factor and keratinocyte growth factor in the pulmonary edema fluid of patients with acute lung injury. Biologic and clinical significance. Am J Respir Crit Care Med. 1998, 158 (2): 386-394.View ArticlePubMed
- Demello D, Kierol-Andrews L, Scalise PJ: Severe sepsis and acute respiratory distress syndrome from community-acquired legionella pneumonia: case report. Am J Crit Care. 2007, 16 (3): 320-317.PubMed
- Nayeri F, Brudin L, Darelid J, Nilsson I, Fryden A, Soderstrom C, Forsberg P: Hepatocyte growth factor may act as an early therapeutic predictor in pneumonia. Scand J Infect Dis. 2002, 34 (7): 500-504. 10.1080/00365540110080890.View ArticlePubMed
- Dominguez A, Alvarez J, Sabria M, Carmona G, Torner N, Oviedo M, Cayla J, Minguell S, Barrabeig I, Sala M, et al: Factors influencing the case-fatality rate of Legionnaires' disease. Int J Tuberc Lung Dis. 2009, 13 (3): 407-412.PubMed
- von Baum H, Ewig S, Marre R, Suttorp N, Gonschior S, Welte T, Luck C: Community-acquired Legionella pneumonia: new insights from the German competence network for community acquired pneumonia. Clin Infect Dis. 2008, 46 (9): 1356-1364. 10.1086/586741.View ArticlePubMed
- Jespersen S, Sogaard OS, Schonheyder HC, Fine MJ, Ostergaard L: Clinical features and predictors of mortality in admitted patients with community- and hospital-acquired legionellosis: a Danish historical cohort study. BMC Infect Dis. 2010, 10: 124-10.1186/1471-2334-10-124.PubMed CentralView ArticlePubMed
- Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, Coley CM, Marrie TJ, Kapoor WN: A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997, 336 (4): 243-250. 10.1056/NEJM199701233360402.View ArticlePubMed
- Nayeri F, Nilsson I, Skude G, Brudin L, Soderstrom C: Hepatocyte growth factor (HGF) in patients with pneumonia: a comparison between survivors and non-survivors. Scand J Infect Dis. 1998, 30 (4): 405-409. 10.1080/00365549850160729.View ArticlePubMed
- Maeda J, Ueki N, Hada T, Higashino K: Elevated serum hepatocyte growth factor/scatter factor levels in inflammatory lung disease. Am J Respir Crit Care Med. 1995, 152 (5 Pt 1): 1587-1591.View ArticlePubMed
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/11/74/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.