DOES LOW MEAN CORPUSCULAR HEMOGLOBIN CONCENTRATION REALLY PREDICT MORTALITY IN ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE?

Objective: Several studies have shown low mean corpuscular hemoglobin concentration (MCHC) associations with mortality and poor clinical course in conditions associated with chronic inflammation, such as cardiac failure and COPD. Thus, this study aimed to determine the link between MCHC and readmission mortality in a large patient population with a minimum of 1 year of follow-up. Methods: We recorded clinical data at admission, laboratory data, the number of admissions to the emergency room due to acute exacerbation of chronic obstructive pulmonary disease (AECOPD) following the discharge of the last patient recruited, the number of admissions to the pulmonology unit, and the number of intensive care unit admissions between 2018 and 2019. The follow-up duration ranged between 12 and 36 months. Results: A total of 339 patients were included. Based on a ROC analysis, the cut-off value for MCHC was 32.35 g/dl. Comparison of clinical data according to this cut-off value showed an increase in the incidence of pneumonia during admission, hypercapnic respiratory failure, need for noninvasive mechanical ventilation (NIV), and the number of intensive care unit admissions within one year, as well as reduced survival in non-anemic subjects with MCHC ≤ 32.35 g/dL. In mu ltivariate cox-regression analysis, MCHC was not an independent predictor of mortality risk. Conclusion: We recommend careful monitoring and assessing comorbidities in acute exacerbation of COPD patients with low MCHC but without anemia. MCHC was not found to be an independent predictor of mortality, but there was a significant correlation between MCHC and survival in patients without anemia.


Introduction
COPD is the third leading global cause of death 1 , with a trend toward progressively increasing mortality. 2The most critical determinant of COPD mortality is the number of acute exacerbations during the disease. 3pproximately 10% to 30% of COPD patients have anemia 4 , associated with reduced exercise capacity, perceived dyspnea, and need for oxygen support. 5The purported causes of anemia in COPD include increased cytokine production due to chronic inflammation, iron deficiency, and anemia. 6,7As a result of chronic inflammation, the incidence of cardiovascular diseases is also increasing, causing an increase in mortality.Baykal and Bulcun reported in their study that chronic hypoxemia in patients with COPD led to pulmonary vascular remodeling and increased pulmonary artery pressure. 8In their study, Şahan and Bulut reported that as the clinical severity of COPD progresses, hypoxia increases, pulmonary hypertension appears, and some pathological changes occur in the right heart, which leads to atrial fibrillation. 9nly a few published studies offer insights into the relationship between COPD and iron deficiency.A crosssectional study involving a multivariate analysis of lung capacity and serum nutrition parameters identified a direct link between the forced expiratory volume at 1 sec (FEV1) and serum iron levels. 10MCHC is a hematological index of hemoglobin and total iron stores. 11,12Studies have suggested that MCHC is a reliable parameter of functional iron status. 13n a study of 197 outpatients with chronic cardiac failure, Simbaqueba et al. showed that MCHC was a reliable prognostic indicator, particularly in those without anemia.These authors found a higher risk of mortality and increased admissions due to cardiac failure during a 5-year follow-up in patients with low MCHC.Such observations confirm the association between relatively low MCHC, chronic cardiac failure, and functional iron deficiency. 14Again, Kento Sato et al. found higher 1month mortality in AECOPD patients with low MCHC. 15he objective of this study was to evaluate the prognostic value of MCHC during the clinical course of AECOPD patients.

Study Population
All patients admitted to our tertiary chest diseases branch hospital were evaluated between January 2018 and January 2019 with AECOPD.AECOPD was defined as acute exacerbation, acute worsening of respiratory symptoms requiring antibiotic and or steroid therapy.According to the treatment they received and their clinical status, the patients were categorized into the following groups; mild acute exacerbation (no treatment), moderate acute exacerbation (steroid and or antibiotic therapy), severe acute exacerbation (steroid and or antibiotic therapy combined with noninvasive mechanical ventilation (NIV) for respiratory failure or the need for oxygen therapy).We recorded age, gender, and presence of obstructive sleep apnea syndrome (OSAS), hypertension (HT), diabetes mellitus (DM), coronary artery disease (CAD), arrhythmia, dementia), thyroid dysfunction, cerebrovascular events, epilepsy, rheumatologic diseases, smoking history in all patients over 18 years of age hospitalized due to AECOPD.Also, we recorded the number of emergency room visits, hospital admissions, and intensive care unit admissions during a minimum one-year follow-up after discharge.Survival of the patients was calculated by the difference between AECOPD and hospitalization and date of death.We determined mortality during a minimum follow-up of 1 year for all patients after the last recruited patient.The study did not include patients with chronic heart failure, malignancy, interstitial lung disease, and inflammatory disease along with AECOPD.Among 491 patients who presented with AECOPD within a year, 70 had chronic heart failure, 74 patients had malignancy, four had interstitial lung disease, one had organized pneumonia, and one had acute cerebrovascular ischemia, and two patients had myotonic dystrophy.In total, 339 patients were included in the study.A hemoglobin level of < 13 g/dl and < 12 g/dl was considered diagnostic for anemia in male and female patients.This study was designed to obtain data retrospectively.

Statistical Analysis
We used SPSS 22.0 (Statistical Program for Social Sciences) software package for statistical analysis.Kolmogorov Smirnov test was used to determine variables with normal distribution.The homogeneity of the variance was tested with Levene's test.For quantitative data, descriptive statistics such as arithmetic mean and standard deviation were presented for data with normal distribution and median (min-max) for data without normal distribution.Also, we provided frequencies and percentages for qualitative data.We compared comparisons between two independent groups with Student's t-test for normal distribution and Mann-Whitney U test for data without normal distribution.We compared qualitative data between the groups with chi-square or Fisher's exact test.Univariate and multivariate Cox regression analyses were carried out to determine the effect of risk factors on mortality.Cut-off values for the relationship between mortality and MCHC were identified using ROC under the curve analysis.Survival curves according to median MCHC and exacerbation severity were prepared using the Kaplan-Meier methodology, and log-rank tests were used to compare the groups.We evaluated the association between continuous variables with Spearman's correlation analyses.All statistical analyses were performed at a 95% confidence interval and p-level of < 0.05.

Results
The mean age of 339 patients included in this study was 70.54, and 62.8% were male.The minimum follow-up period of the patient population was one year.Demographic data and comorbidities are shown in Table 1.The smoking histories of the patients were classified as active users, quitters, and non-smokers.According to this classification, 19.2% of the patients were active users, 52.4% quit, and 28.4% never smoked.The median hemoglobin value was 13.7 g/L (0.11-113.7).The median MCHC value was 31.8 g/dL (20.9-54.9).According to the ROC analysis to predict mortality (AUC=0.589,95% CI:0.527-0.652,p=0.006), we found the best cut-off point of the MCHC value to be 32.35, the sensitivity of MCHC at this point was 75.4%, the selectivity was 40.6%, positive and negative predictive values were respectively; 42% and 75% (Figure 1).There was a statistically significant difference in longterm mortality between the groups with MCHC higher and lower than 32.35 g/dL (p<0.001).Accordingly, we found the mortality rate higher for the group with MCHC≤ 32.35 g/dL (p<0.011).
MCHC less than 32.35 is associated with mortality in patients who had emergency admissions in the previous year.MCHC less than 32.35 is associated with mortality in patients who have had acute exacerbations in the previous year.For last year, there was no statistically significant relationship between the MCHC cut-off value and mortality in AECOPD patients admitted to the intensive care unit.For the group with MCHC≤32.35, the incidence of hypercapnic respiratory failure (PaCO2> 45 mmHg) (p<0.001), the rate of noninvasive mechanical ventilation use during hospitalization (p<0.001), the rate of admission to intensive care unit within one year (p=0.002) and pneumonia incidence (p=0.020) were found to be higher compared to the group with MCHC>32.35 (Table 2).There was a significant correlation between MCHC and survival in patients without anemia (p=0.005).Table 3 shows the results of univariate Cox proportional hazards regression analysis for all possible factors thought to have an impact on overall survival.Univariate analysis showed associations between mortality and advanced age (HR=1.030,95% CI: We fitted values associated with mortality in the univariate cox regression analysis into multivariate cox regression models.This analysis showed that advanced age, dementia, liver failure, increased emergency unit visits and ICU admissions due to COPD exacerbation within one year, and increased need for NIV during admission was associated with mortality.At the same time, MCHC was not an independent predictor of mortality (Table 4).

Discussion
MCHC is a hematologic laboratory parameter utilized for diagnosing and monitoring patients with iron deficiency anemia and measuring the oxygen-carrying capacity of red blood cells. 13,16ron deficiency associated with chronic inflammation is a known indicator of poor long-term prognosis, independent of anemia. 17Median Hg in our patient group was 13.7 g/dL, and MCHC was 31.8 g/dL.Overall, 101 patients were found to have anemia.However, we did not measure serum iron levels in our participants.According to our observations, MCHC had prognostic significance in patients without anemia.In a study by Huang et al., low MCHC in patients admitted to the intensive care unit following acute myocardial infarction was associated with an increased risk of inhospital mortality. 18In another study from 2013 by Simbaqueba et al. 14 involving patients with systolic heart failure, those with lower MCHC had an elevated risk of death and transplantation and an increased likelihood of hospitalization due to heart failure.
In the study of Kento Sato et al. for patients followed up with COPD acute exacerbation, a correlation was found between low MCHC value and 30-day mortality. 15 The ethics committee of Ankara Keçiören Training and Research Hospital approved this retrospective study.(Number of Approval: 2012-KAEK 15/2418; Date of Approval: November 9th, 2021).

Figure 1 .
Figure 1.ROC curve of MCHC levels to predicting mortality

Table 1 .
Demographic characteristics of cases according to MCHC levels regarding the cut-off point obtained from ROC analysis MCHC: Mean corpuscular hemoglobin concentration

Table 2 .
Clinical characteristics of cases according to MCHC levels regarding the cut-off point obtained from ROC analysis

Table 3 .
Univariate cox regression analysis to identify variables that predict survival in patients with chronic obstructive pulmonary disease with acute exacerbation Wald: test statistics, HR: hazard radio, Statistically significant p-values are in bold.

Table 4 .
Multivariate cox regression analysis applied to identify variables that predict survival in patients with chronic obstructive pulmonary disease with acute exacerbation Wald: test statistics, HR: hazard radio, Statistically significant p-values are in bold.
15en we compared the MCHC cut-off values with other studies, we inferred that the cut-off value was similar to our research's.Simbaqueba et al.reported that the patients whose MCHC was 32.7 g/dL and below had the worst prognosis.14Ina2016paper,Huangetal. reported that patients with an MCHC < 32.8 g/dl had an increased risk of in-hospital death.18In the study of Kento Sato et al., the MCHC cut-off value was 31.6 g/dL.15Inourstudy, the MCHC cut-off value was 32.35.In our multivariate regression models, factors associated with a significantly increased mortality risk at one year included advanced age, dementia, liver failure, a higher number of emergency room visits and ICU admissions due to COPD exacerbations during one year, and NIV use.These findings support that low MCHC may indicate poor outcomes in AECOPD patients.One of the most important limitations is that our study is a mono-centered, retrospective data analysis and lacks a common cut-off value that we can compare.Due to the study's retrospective nature, we could not obtain serum iron levels because it isn't done regularly.Future studies will investigate whether the MCHC value is an effective biomarker in determining the indication for intensive care hospitalization and the use of NIV in patients followed up with AECOPD.A second study should examine the association between the predictive power of MCHC and infection and determine their ability to distinguish non-bacterial AECOPD from bacteria.Patients with AECOPD often admit to emergency services.A Hemogram examination is among the first laboratory tests requested in the emergency admissions of these patients.It is cheap and easy to access.The study's most vital feature is its exclusion of the cases with malignancy and chronic heart failure known to affect the MCHC value and its comparatively larger sample size and longer follow-up vs. most previous studies.ConclusionOur results showed an increased risk of ICU admission, hypercapnic respiratory failure, need for ICU use, and pneumonia among patients with lower MCHC.Clinicians should pay adequate attention to low MCHC levels among AECOPD patients regardless of anemia.Compliance with Ethical Standards Health Sciences University Keçiören Education and Research Hospital, Clinical Studies Ethic Board Decision date: 09.11.2021,Decision number:2012-KAEK-15/2418.