Role of lactate dehydrogenase and other biomarkers in predicting prognosis of community-acquired pneumonia

Background An increase in serum lactate dehydrogenase (LDH) activity is commonly taken to support the presumptive diagnosis of some lung diseases and a variety of extrapulmonary disorders, but the role of LDH as an early prognostic factor in detecting outcome in patients with community acquired pneumonia (CAP) was not well studied before. Aim To assess the prognostic value of LDH and other laboratory markers [C-reactive protein (CRP), serum albumin, and neutrophil percentage] in patients with CAP. Patients and methods We compared levels of LDH and other laboratory markers (CRP, serum albumin, and neutrophil percentage) with each other and with CURB65 score, length of hospital stay, and worse outcomes (ICU admission, mechanical ventilation, and mortality) in 62 (33 males and 29 females) patients with CAP who were admitted to Pulmonology Department, Benha University Hospital, between March 2016 and March 2017 after ethical committee approval. Results Most of the patients with worse outcomes showed significant high levels of LDH, CRP, albumin, and neutrophil percentage early on admission. Conclusion LDH was a highly sensitive biomarker for early prediction of worse outcomes in patients with CAP.


Introduction
Community-acquired pneumonia (CAP) is a very common cause for hospital admission, with potentially life-threatening complications, which may occur particularly in the elderly and those with underlying health problems.These complications may include, empyema, lung abscess, acute respiratory distress syndrome, sepsis, and worsening of underlying health problems.Despite advances in diagnosis and treatment, CAP remains a common, potentially fatal disease associated with significant morbidity, mortality, and health care expenditure [1].Overall annual incidence is ∼1600/100 000 in the USA and 1100/100 000 in Europe, with ∼250 of 100 000 patients requiring hospitalization [2].Although mortality associated with CAP is below 5% among outpatients, it can be as high as 10% among inpatients and can exceed 30% among patients admitted to the ICU [3].
In patients with CAP requiring ICU admission, mortality may involve more than half of these patients compared with 4-18% mortality in ward admission and only less than 1% who do not need hospitalization [4].Identifying patients at high risk of mortality could substantially improve their treatment and management [5].The stratification of the severity and prognosis of CAP is a vital feature as it is one of the most common causes of mortality among other infectious diseases in the developed countries [6].To improve the outcomes in the management of CAP, there has recently been a significant attention to the use of evidence-based scoring systems and biological markers to predict treatment failure, justify hospital admission in either acute medical settings or ICU, and also to classify the disease severity, which will help in predicting the mortality rate [7].myocardial infarction, liver disease, lymphoma, HIV, pancreatitis, and hemolytic anemia were excluded.
A bundle of measures were performed within the first 3 h of admission, including serum LAH (done by semiautomated analyzer photometer 4010; RIELE, Robert Riele and CO, Berlin, Germany), CRP (done by latex agglutination; CRP-Latex cromatest, Biotrax Testing, Biotrax testing Laboratory INC, Cheektowaga, Newyork, USA), serum albumin, kidney and liver functions (done by Biosystems A15 auto-analyzer, Barcelona, Spain), and CBC with differential (done by automated hematology system; Sysmex XE-5000-Analyzer; Sysmex America Inc., SYSMEX, Ramsey, MN, USA).CURB65 score (which is a well validated severity score for predicting severity and mortality from pneumonia) was assessed for all studied patients according to the following criteria: confusion, blood urea nitrogen (BUN), respiratory rate, blood pressure, and age of at least 65 years old [7].Initiation of appropriate empirical broad-spectrum intravenous antibiotics was done.Treatment with intravenous crystalloids was given if indicated.
Patients with the following criteria were excluded from this study: tuberculosis, bronchiectasis, HIV infection, and solid organ or hematological malignancies.Patients admitted to hospital in the previous 14 days or with nursing home residents were also excluded.
The following criteria were considered as indicators for worse outcome in our studied group of patients: admission in the ICU, mechanical ventilation (MV), and death.All data were collected after ethical committee approval.

Statistical analysis [8]
The collected data tabulated and analyzed using SPSS version 16 software (SPSS for Windows, version 16.0.;SPSS Inc., Chicago, Illinois, USA).Data were presented using χ 2 -test to analyze them.Correlation coefficient was used to find relation between LDH and other variables.Quantitative data were presented as a mean ±SD.Students t-test and Mann-Whitney test were used to compare means of different groups of parametric and nonparametric data, assuming normality at P more than 0.05.P value less than 0.05 is significant, P value more than 0.05 is nonsignificant, and P value up to 0.001 is highly significant.

Results
This study was carried out on 62 (33 males and 29 females) patients with CAP who were admitted to

Pulmonology
Department, Benha University Hospital, between March 2016 to March 2017.Their ages were 29-86 years (mean 53.4±12.57),and 33 patients were smokers.More than half of the studied group experienced hypertension (55.0%), 40.0% had DM, and 20.0% had asthma.Ten (16.1%) patients were admitted to ICU owing to severe condition; three of them were MV and two died.However, the other 52 (83.9%) patients were treated in the ordinary ward.The median hospital stay was 4 days, and interquartile range (IQR) ranged from 3 to 5 days (Table 1).
Serum LDH ranged from 266 to 1424 U/l, with mean ±SD of 598.1±286.79U/l.Serum CRP in patients had IQR from 22.75 to 202.25 mg/l, with a median value of 53.5 mg/l.Neutrophils% ranged from 49.4 to 84.5%, with a mean±SD value of 63.23±15.99%,whereas albumin ranged from 1.8 to 6.0 mg/dl, with a mean ±SD value of 3.64±0.67(Table 2).5).
Logistic regression showed that LDH was the most closely associated variable with poor outcomes (ICU admission, MV, and mortality) (Table 6).

Discussion
LDH has been studied in many pulmonary and nonpulmonary diseases, and high level of this marker was used as presumptive diagnosis of many pulmonary diseases, for example, tuberculosis,   Pneumocystis carinii pneumonia, and CAP [9], and also studied in interstitial lung diseases, acute respiratory distress, and obstructive lung diseases [10].
LDH is a cytoplasmic enzyme expressed in nearly all types of cells of the body.It is released into blood when the cells experience injury or death caused by dehydration, ischemia, bacterial toxins, drugs, and chemical poisonings.Because it is expressed in various organs/tissues by high concentration, the leakage of LDH from even a small scale of injured tissue can result in a significantly elevated serum level.It has been used as an indicator of cellular injury induced by various etiologies [11].
Reliable prediction of patients with CAP may substantially improve patient management, timely anti-infectious therapy, and nurse intervention [12].
In a study done by Lim et al. [7], mean age was 64 years, with male percentage constituted 51.5%.In another study done by Brogly et al. [11], males and females were equal.Bertsias et al. [13] found that smokers represented 41% of CAP cases.Smoking is an established risk factor for CAP, probably owing to its adverse effects on respiratory epithelium and the clearance of bacteria from the respiratory tract [14].Calle et al. [15] showed that mean age was 60.5 years, with 51.7 of them being males.Moreover, Yang et al. [16] found that median age was 61 years, with male percentage being 66.35%.Berstials et al. [13] found that 42% of patients with CAP had multimorbidity, with most frequent chronic conditions being heart diseases followed by COPD and type 2 DM.Comorbid conditions associated with an increased risk of CAP, including diabetes mellitus and impaired immune function, have previously been identified as risk factors for CAP [14].
In a study done by Ewig et al. [15], which included 92 patients with CAP, the mean age of patients was 51±19 years (range from 15-87 years); males constituted 67.4% of them, and 45% of the patients had at least one underlying chronic disease as a risk factor for acquiring CAP [15].Liu et al. [17] found that mean age of their studied patients with CAP was 64±19 years, males were 59.6%, and overall 37.6% of the patients were accompanied by one or more coexisting diseases (e.g.COPD and CHF).
Liu et al. [17] found in their study, median length of hospital stay was 10 days (IQR 7-15) and mortality was 8.2%.Ewig et al. [15] found that among 92 patients with CAP, 34.8% were admitted in ICU, 14.1% were MV, and mortality was 22%.Severity of disease and comorbidity may be responsible for this wide range of reported mortality.
This study showed that serum LDH had a significant positive correlation with CURB65 score and length of hospital stay.It also significantly increased among ICU admitted, died, and MV patients.This agrees with Ewig et al. [15], who reported that increased serum LDH values were associated with increased mortality in 92 patients with CAP.They showed that higher serum LDH level indicated more severe complications and worse prognosis [15].Moreover, previous studies done by Hoffman and Rogers [18], Schultze et al. [19], Quist and Hill [9], and Padilla et al. [20] have demonstrated that the elevated LDH in serum, bronchoalveolar lavage, and pleural fluid can help determine the extent of lung tissue damage and inflammation, such as pulmonary embolism, P. carinii pneumonia, tuberculosis, bacterial pneumonia, and influenza A.
Liu et al. [17] found that the expanded CURB-65 score, which extends independent risk factors to eight variables (including serum LDH, albumin and platelets) in assessing CAP severity, significantly improves identifying high-risk patients than CURB-65 and other assessment tool, through decreasing the relative weight of age and blood pressure and eliminating the use of imaging and comorbid illnesses in the calculation.They concluded that expanded CURB-65 is a relatively simpler and more effective marker in assessing the severity of hospitalized patients with CAP.
This study showed that albumin had a significant negative correlation with CURB65 and length of hospital stay, and it was significantly decreased among ICU admitted, died patients, and patients subjected to MV. Hypoalbuminemia, which can be caused by malnutrition, liver cirrhosis, or infection process, contributes to an increased mortality in hospitalized patients [21].There is a close correlation between low serum albumin concentration and mortality in patients with CAP [22].A study done by Liu et al. [17] showed that serum albumin less than 3.5 g/l was significantly associated with 30-day mortality in patients with CAP. Lee et al. [22] concluded that low serum albumin was significantly different between survivors and nonsurvivors and was associated with 28-day mortality in hospitalized patient with CAP.
This study showed that CRP had a significant positive correlation with CURB65 score and length of hospital stay, and it was increased significantly among died patients and patients subjected to MV.Similarly, Lee et al. [22] found that elevated CRP was significantly different between survivors and nonsurvivors, and that increased CRP was associated with 28-day mortality.Li et al. [23] concluded that CRP of at least four times the mean or median for the patient center was an independent predictive risk factor that correlated with adverse outcomes in elderly patients.Hohenthal et al. [24] found that high CRP levels more than 100 mg/l on day 4 after the admission were significantly associated with complications (P<0.01).There was a trend for an association between the level of CRP on admission and the time to reach clinical stability (P<0.01).They concluded that CRP may be valuable for revealing the development of complications in CAP.It may also be useful to assess the disease severity.
This study found that serum neutrophils increased significantly among patients admitted to ICU, and it showed significant increase among died patients and patients subjected to MV.In agreement with this study, Jose et al. found that increased neutrophil cell percentage was associated with substantial increase in the risk of mortality.They found that unlike most of the predictive markers used in clinical practice, basic blood count could provide parameters with the potential of high predictive capacity for mortality in patients with CAP, which are easy to handle and cost effective [25].Li et al. [23] found that higher neutrophil percentage was an independent predictive risk factor that correlated with adverse outcomes.
Ewig et al. [15] showed that serum levels of LDH (with cutoff value≥260 μ/l, with P=0.0154), heart rate (with cutoff value≥90 beats/min and P=0.03), and systolic blood pressure (with cutoff value≤80 and P=0.142) were the variables most closely associated with fatal outcome in multivariate analysis.They found a discriminant role of these three variables to achieve high predictive value [15].Lim et al. [7] found that serum albumin less than 30 g/dl (P=0.001) and age of at least 65 years (P=0.003)were both independably associated with 30-day mortality.Liu and colleagues found that elevated serum LDH level (>230 μ/l), thrombocytopenia (platelet count<10 5 /ml), and hypoalbuminemia (albumin level<3.5 g/dl) were independent risk factors for death on multivariate analysis [16].
Limitations of this study included relatively small size of the studied group, and blood samples were collected as soon as patients were admitted, so there were variations in the time of collecting them.

Conclusion
LDH, albumin, CRP, and neutrophils% are important serum markers in determining CAP prognosis.They should be performed on admission to predict the course and probable complications in patients with CAP.

Table 3
Correlation between neutrophils, lactate dehydrogenase, C-reactive protein, and serum albumin with each other and with CURB 56 and hospital stay CRP, C-reactive protein; LDH, lactate dehydrogenase.*Significant.**Highlysignificant.

Table 2
Mean values of laboratory markers in the studied patients LDH and CAP prognosis Hendy et al. 541 [Downloaded free from http://www.ejbronchology.eg.

Table 6
Logestic regression to predict worse outcome