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SOHAG MEDICAL JOURNAL Vol. 23 No.1 Jan 2019

Acute Exacerbation of Chronic Obstructive Pulmonary Disease: Predictors of Outcome

Esraa A. Saad1, Kamal A. Ata2, Mona T. Hussein3, Abdellah H. Khalil4 1 Administrator ofChest Disease and Tuberculosis,Sohag University. 2 Professor of Chest Disease and Tuberculosis, Sohag University. 3 Assisstant Professor of Chest Disease and Tuberculosis, SohagUniversity. 4 Assisstant Professor of Chest Disease and Tuberculosis, Sohag University.

Abstract Background:Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is considered to be an important cause of morbidity, (ICU) admissionand mortality in COPD patients. Objectives:to identify the factors which could predict the outcome ofCOPDpatients. Patients and methods: A prospective study was conducted at Chest Department of Sohag University Hospital during the period from May 2016 to August 2017 and included 101 COPD patients with AECOPD. Patients were deemed to have AECOPD if this diagnosis appeared on their clinical histories. The studied variables included clinical parameters (symptoms & signs), and laboratory tests (complete count, , -ALT, AST and serum albumin- serum , gas test and sputum cultures), radiological data(plain chest x-ray, CT chest (if indicated) and echocardiographic data for every patient. The outcome in the studyincluded improvement or non-improvement (referral to ICU or death). Results:The study included 101 patients with AECOPD, the mean age of the patients was 60years, 66.34% of them were males and 33.66% females, according tothe outcome; 83 cases improved, 18 cases had poor outcome (i.e. need ICU admissionordied). Bacterial growth, in the sputum culture, was recorded in 65.35% of the cases. The most frequently recorded bacterial organism were: Streptococcus pneumonia, Haemophilus influenza and Pseudomonas aeruginosa (14.85%, 13.87% and 10.89% respectively). The factors, which had significant relation to poor outcome, were: male gender (P=0.04), frequent exacerbation (P=0.003), history of ≥2 hospital admission and previous ICU admission in the last year(P= 0.004 and 0.003 in order), history of prior LTOT(P=0.006),altered consciousness, tachycardia, tachypnea, fever, flapping tremor, pedal edema (P=0.009, 0.02, ˂0.0001, 0.03,˂0.0001and0.008 in order), associated comorbidities (bronchiectasis, corpulmonale and DM; P=0.047, 0.005 and 0.008respectively), lower mean values of pH, PaO2, SaO2 and higher mean values of PaCO2 on admission (P=0.007, 0.003, 0.001 and 0.01in order), leukocytosis, thrombocytopenia, elevated serum creatinine, elevated liver enzymes and (P= 0.008, 0.001, 0.02, 0.001and0.007 in order), presence of cardiomegaly or bronchiectaic changes as radiological findings (P= 0.001 and 0.047 in order), severe pulmonary artery hypertension as an echocardiographic finding (P=0.03), lower mean values of FEV1and FVC(P=0.01 and 0.02 in order), Staph. aureusand P. aeruginosa isolation in sputum cultures (P˂0.0001 and 0.002 in order). Conclusion:The significant factors in predicting poor outcome of AECOPD were: male gender, frequent exacerbations, prior hospital (≥2 hospital admission/year) and ICU admission in the last year, history of prior LTOT, associated comorbidities (bronchiectasis,corpulmonale and DM), consciousness alteration, tachycardia, tachypnea, fever, flapping tremor, lower limb edema, arterial blood gas parameters on

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al admission (higher mean values of PaCO2 and lower mean values of pH, PaO2 and SaO2), leukocytosis, thrombocytopenia, elevated serum creatinine, higher mean levels of ALT and AST, hypoalbuminemia, presence of cardiomegaly or bronchiectatic changes as radiological findings, severe pulmonary artery hypertension as an echocardiographic finding, lower mean values of FEV1 and FVC, P.aeruginosa and Staph.aureus isolation in sputum cultures. Key words:AECOPD, COPD, predictors, outcome.

Introduction The Global Initiative for Obstructive syndrome were excluded from the Disease (GOLD) defined an study. AECOPD as an acute worsening of Acute exacerbation of COPD was respiratory symptoms that result in diagnosed using the following additional (GOLD, 2018). symptoms (Anthonisen et al., It is important to identify the 1987):recent rapid worsening of prognostic factors of it as a respect to dyspnea, presence of sputum purulence the fact that AECOPD is an important and increase in sputum and common cause of emergency room volume.According to these symptoms, visits and is a major cause of morbidity exacerbations were classified into and death and the fact that following (Anthonisen et al., 1987): an acute exacerbation, many patients . Type 1 (severe AECOPD): experience a transient or permanent exacerbations include increased decrease in the quality of life (Connor dyspnea, sputum volume and et al., 1996 &Seemungal et al., 2000), sputum purulence. thus the economic and social burden of . Type 2 (moderate AECOPD): COPD exacerbation are extremely high exacerbations involve any two of (Lopez et al. 2006). those symptoms. The aim of the study: We aimedto . Type 3 (mild AECOPD): identify thefactors which could predict exacerbations includeonly one of the outcome of acute exacerbation in those symptoms plus one of the COPD patients. following (an upper Patients and methods:This infection in the past 5 days, fever prospective study was conducted in the without other causes, increased Chest Department of Sohag University wheezing or cough, or an increase Hospital. The study included 101 in heart rate or by patients with AECOPD who were 20% compared with the baseline admitted to the department from readings). outpatient chest clinic and emergency Patients who had positive sputum department during the period from culture, fever or purulent sputum, were May 2016 to August 2017. The study considered to have infectious was approved by the medical ethics AECOPD, while the others who had committee of Sohag Faculty of none of them were considered to have Medicine. Consent was taken from non-infectious AECOPD (Elkorashy et every patient to participate in the al., 2014). study.Patients who were <40 years old, All patients were subjected to full critical patients who needed ICU clinical evaluation (history and admission at the time of first examination), plain chest x- evaluation in emergency room, and the ray,electrocardiogram, computed patients who had pulmonary tomography (if indicated), abdominal tuberculosis or acute coronary ultrasonography, echocardiography,

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al and arterial Pulmonary function tests data were blood gases analysis on admission (pH, obtained from the previous records of PaCO2, PaO2, SaO2% &HCO3)the the patients and when these were not samples were analyzed using available, PFTs were done while the automated blood gases analyzer patients were stable and free from all (ABL800 FLEX blood gas analyzer, the symptoms and the signs of acute radiometer, USA), blood chemistrywas exacerbation (at least after two weeks). done, including serum creatinine, liver The data were obtained for 91 patients, enzymes (ALT&AST), serum albumin as previous records and follow up data and serum electrolytes (Na+, K+, C a++) for the others were not available. PFTs (Roche/Hitachi cobas c 311systen, were performed with a spirometer of Germany). computer processing (Jaeger Master Sputum examination: Screen Diffusion, Viasys Healthcare, Bacterial sputum cultures was done for Gmbh, Hoechberg, Germany). Post- every patient. At hospital admission, spirometry the sputum was collected by measurements were recorded for the spontaneous or induced expectoration studied population to measure the (using nebulized hypertonic saline). values of forced expiratory volume in st Early morning sputum samples were 1 second (FEV1), forced collected in sterile containers before (FVC) and FEV1/FVC ratio. starting antibiotic treatment at the Postbronchodilator values were used hospital. The samples were transferred for the evaluation of COPD severity, to the bacteriology laboratory of Sohag according to GOLD guidelines (Stage University Hospital where they were I: mild COPD, FEV1> 80% of examined and the results were reported predicted FEV1 - Stage II: moderate by specialists.The sputa were cultured COPD, 50%≤ FEV1<80%-Stage III: only if the quality criteria were met in severe COPD, 30%≤ FEV1<50%-Stage a sputum Gram stain (<10 epithelial IV: very severe COPD, FEV1<30%) cells and >25polymorphonuclear (GOLD, 2018). leukocytes per low magnification field Outcome in the studied population x100). Samples were cultured on sheep was assessed as the following (Chow blood agar plates and mcConkey agar et al., 1992 &Mantero et al., 2017): (Dylan Inc., Edomonton, Alberta), then . Improvement was considered if incubated at 37◦C in a moist patients continued their treatment in atmosphere containing 5% CO2 (CO2 the ward until resolution or incubator, Grant Instruments Ltd) for reduction in the symptoms and signs 24hours (if no results further occurred without appearance of new incubation until 48hr was done). Only symptoms or signs associated with isolates with higher than 105 colony the exacerbation. forming units were reported as a . Non improvement was considered positive growth(Murray et al., when worsening of symptoms or 2003).VITEK 2 compact automated signs occurred and led toreferral to microbial system (bioMérieux, Inc. intensive care unit (ICU) or death. Hazelwood, USA) was used for Statistical analysis: Data was identification of the bacterial analyzed using STATA intercooled microorganisms using colorimetric version 14.2. Quantitative data was reagent cards that are incubated and represented as mean, standard interpreted automatically. deviation. Data was analyzed using Pulmonary function tests (PFT(: student t-test to compare means of two groups. When the data was not

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al normally distributed Mann-Whitney test or fisher exact test. Odds ratios test was used. Qualitative data was were obtained from logistic regression presented as number and percentage analysis. P value was considered and compared using either Chi square significant if it was less than 0.05 .

Results The study included 101 patient with AECOPD with mean age of 60 years, 66.34% of the cases were males and 33.66% of the cases were females. 47.52% of the cases were ex-smokers, 31.68% of the cases were current smokers and 20.79% of the cases were non-smokers(Table 1).

Summary Variable statistics Age (year) [ mean ± SD(range)] 60±8.52(44-85) Gender (n,%) Females 34 (33.66%) Males 67 (66.34%) Smoking status (n,%) Non-smoker 21 (20.79%) Current 32 (31.68%) Ex-smoker 48 (47.52%)

Table (1): Demographic characteristics of the studied population (n=101)

Etiology* Number %

Infectious Positive bacterial sputum culture 66 (65.35%) Negative bacterial sputum culture 29 (28.71%) Total 95 (94.06%)

Non infectious 6 (5.94%)

Table(2): Etiology of AECOPD of the studied population (n=101) *Patients who had positive sputum culture, fever or purulent sputum, were considered to have infectious AECOPD, while the others who had none of them were considered to have non- infectious AECOPD (Elkorashy et al., 2014). Table (2)shows that infectious causes of AECOPD weresuspected in94.06% of the patients. Positive bacterial sputum culture was found in65.35%of all cases.

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al Microbiology Number (%)

No growth 31(30.65%)

Positive sputum culture 66 (65.35%)

. Streptococcus pneumonia 15 (14.85%) . Haemophilus influenza 14 (13.87%) . Pseudomonas aeruginosa 11 (10.89%) . Staphylococcus aureus 9 (8.9%) . Klebsiella pneumonia 6 (5.94%) . Streptococcus pyogenes 5 (4.96%) . Streptococcus parasanguinis 4 (3.96%) . Enterococci 2 (1.98%)

Table (3): Microbiological findings (by sputum culture) in the studied population (n=101)

Table (3) shows that 65.35% of the patients had positive sputum cultures. The most frequent bacterial growth were: Strept.pneumonia, H. influenza, P. aeruginosa and Staph.aureus (14.85%, 13.87%, 10.89% and 8.9% respectively).

Outcome Number (%)

Improvement 83 (82.18%)

Non improvementICU 14 (13.86%) admissionDeath 4 (3.96%) Total 18 (17.82%)

Table(4): Outcome of the studied population (n=101) ICU: intensive care unit Table (4) shows that 82.18% of the cases improved with management in the ward of Chest Department, 13.86% of the cases were referred to ICU, and 3.96% of the cases died.

Not Odds ratio P Variable Improved(n=83) improved(n=18) (95%CI) value

Age (year) (mean ± SD) 59.84±8.04 62.72±10.34 1.04 (0.98-1.10) 0.2

Gender(n,%). Females 32(38.55%) 2 (11.11%) 1 0.04 Males 51(61.45%) 16 (88.89%) 5.01 (1.08-23.29) Smoking status (n,%)

Smokers 64 (77.1%) 6 (88.89%) 2.38(0.50-11.26) 0.28 Nonsmokers 19 (22.9%) 2 (11..11%) 1

Table(5): Relation between patient's outcome and demographic characteristics Table (5) shows that poor outcome was significantly related to male gender (P= 0.04). Patients with poor outcome had higher mean age in comparison with patients who improved, but this relation was statistically not significant.

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al Improved Not improved Odds ratio(95% P Variable (n=83) (n=18) CI) value

Duration of the disease 11.88±8.46 13.83±6.93 1.03 (0.97-1.09) 0.36 (year) (mean±SD)

Prior LTOT (n,%) 12 (14.46%) 8(44.44%) 4.73 (1. 56-14.4) 0.006

Prior ICU admission ( last 5 (6.02%) 6 (33.33%) 7.8 (2.01-29.59) 0.003 year)(n,%)

Prior hospitalization (last year)(n,%) 39 (46.99%) 2 (11.11%) 1 . 0 23 (27.71%) 5 (27.78%) 4.24(0.76-23.65) 0.1 1 21(25.3%) 11(61.11%) 10.21 (2.07-50.5) 0.004 ≥2

Frequency of AECOPD( last year) (mean ± SD) 2.25±1.17 3.22±1 2.15 (1.29-3.6) 0.003

Exacerbation severity 60 (72.29%) 17 (94.44%) (n,%) Severe 6.52 (0.82-51.81) 0.08 23 (27.71%) 1 (5.56%) Moderate/ Mild 1

LTOT: long term therapy. ICU:intensive care unit.

Table (6): Relation between the patient's outcome and the characteristics of the disease and current exacerbation

Table(6) shows that there were significant relations between poor outcome andhistory of prior LTOT, priorICU admission,previous ≥2 hospital admissions in the last year and higher mean frequency of exacerbation in the last year (P=0.006, 0.003, 0.004 and 0.003 in order).

Not Improved Odds ratio Variable improved P value (n=83) (95%CI) (n=18) Increased sputum 76 (91.57%) 18 (100%) 3.83(0.00) 0.99 volume(n,%)

Increased dyspnea(n,%) 82(98.76%) 18 (100%) 3.55 (0.00) 1

Altered consciousness 10 (12.05%) 7 (38.89%) 4.65 (1.46-14.8) 0.009 (n,%)

Cyanosis (n,%) 48 (57.83%) 16 (88.9%) 3.47 (0.93-12.92) 0.06

Pulse rate (mean ± SD) 100.77±15.6 111.0±20.1 1.04 (1.01-1.07) 0.02

Respiratory rate (mean 26.2±3.99 31.11±3.99 1.36 (1.16-1.61) ˂0.0001 ± SD)

Fever (n%) 51 (61.45%) 17 (94.44%) 10.67(1.35-84.08) 0.03

Flapping tremor (n,%) 18 (31.67%) 14 (77.8%) 12.64 (3.7-43.14) ˂0.0001

Pedal edema (n,%) 33 (39.76%) 16 (88,9%) 5.04 (1.53-16.65) 0.008

Table (7):Relation between patient's outcome and their clinical data

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al Table (7) demonstrates that poor outcome was significantly related to presence of consciousness alteration, higher rates of pulse and , fever,flapping tremorsand pedal edema, in comparison with good outcome (P= 0.009, 0.02, ˂0.0001, 0.03,˂0.0001 and0.008respectively).

Variable Improved Not improved Odds ratio(95% P value (n=83) (n=18) CI)

Bronchiectasis (n,%) 8 (9.64%) 5 (27.78%) 3.60 (1.02-12.8) 0.047

Pneumonia (n,%) 13 (15.66%) 6 (33.33%) 2.69 (0.86-8.46) 0.09

Sleep disorders (n,%) 8 (9.64%) 3 (16.67%) 1.88 (0.45-7.89) 0.39

DCP (n,%) 36 (43.37%) 15 (83.33%) 6.53 (1.76-24.28) 0.005

IHD (n,%) 18 (21.69%) 7 (38.89%) 2.3 (0.78-9.78) 0.13

Hypertension (n,%) 35 (42.17%) 8 (44.44%) 1.1 (0.39-3.06) 0.86

DM (n,%) 20 (24.1%) 10 (55.56%) 3.94 (1.36-11.3) 0.008

Renal diseases (n,%) 4 (4.82%) 3 (16.67%) 3.95 (0.8-19.5) 0.09

Hepatic diseases (n,%) 7 (8.43%) 4 (22.22%) 3.1 (0.8-12) 0.1

Comorbidity (n,%) <2 19 (22.9%) 0 Omitted ≥2 64 (77.1%) 18 (100%) 4.54(0.00) 1

DCP: decompensated corpulmonaleIHD: ischemic heart disease DM: diabetes mellitus

Table (8)Relation between patient's outcome and comorbidities

Table (8)demonstrates that the patients with poor outcome had higher frequencies of associated comorbidities (i.e. bronchiectasis,DCP and DM) in comparison with the patients with good outcome (P= 0.047, 0.005 and 0.008 respectively).

Improved Not improved Odds Variable P value (n=83) (n=18) ratio(95% CI)

pH(mean ± SD) 7.4±0.07 7.35±0.06 0.0001 (0-0.2) 0.007

PaCo (mean ± 2 47.73±16.83 59.89±17.45 1.04 (1.00-1.08) 0.01 SD)

PaO2(mean ± SD) 56.1±16.32 42.28±12.82 0.93 (0.88-0.98) 0.003

SaO (mean ± 2 82.52±11.73 70.64±12.78 0.93 (0.89-0.97) 0.001 SD)

HCO .(mean ± 3 26.36±5.44 28.56±6.11 1.07 (0.98-1.17) 0.14 SD)

..pH:potential of hydrogen.PaCO2: partial arterial tension of .PaO2: partial arterial tension of oxygen..SaO2: arterial .HCO3: .

Table (9): Relation between the patient's outcome and arterial blood gas parameters on admission

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al Table(9)shows that,on admission, the patients with poor outcome had lower mean values of pH, PaO2 and SaO2% in comparison with the patients with good outcome (P= 0.007, 0.003 and 0.001respectively). The patients with poor outcome had higher values of PaCO2 in comparison with patients with good outcome (P= 0.01).

Not improved Odds Variable Improved (n=83) P value (n=18) ratio(95% CI)

Leukocytosis (n,%) 32 (38.55%) 15 (83.33%) 1.13(1.03-1.24) 0.008

Polycythemia (n,%) 12 (14.46%) 3 (16.67%) 1.18 (0.3-4.7) 0.81

Thrombocytopenia (n,%) 7 (8.54%) 8 (44.44%) 8.57 (2.56-28.7) 0.001

Elevated serum creatinine 19 (22.89%) 9 (50%) 3.37 (1.17-9.68) 0.02 (n,%)

Elevated liver enzyme (n,%) 16 (19.28%) 11 (61.11%) 6.58 (2.2-19.63) 0.001

Serum albumin(mean ± SD) 3.62±0.58 3.19±0.57 0.19 (0.06-0.63) 0.007

Sodium(mean ± SD) 131.93±6.41 128.4±8.33 0.92 (0.84-1.01) 0.08

Potassium (mean ± SD) 3.25±0.65 3.2±0.65 0.88 (0.36-2.12) 0.78

Calcium (mean ± SD) 0.15 (0.0003- 1.01±0.08 0.99±0.10 0.55 84.5)

Table (10): Relation between the patient's outcome and the laboratory investigations

Table(10) shows that poor outcomewas significantly related to leukocytosis, thrombocytopenia, elevation of the serum level of creatinine, liver enzymes( ALT&AST) and lower meanserum level of albumin (P= 0.008, 0.001, 0.02, 0.001 and 0.007 respectively).

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al Improved Not improved Odds ratio (95% Variable P value (n=83) (n=18) CI)

Hyperinflation (n,%) 78 (93.98%) 17 (94.44%) 1.09 (0.12-9.94) 1

Cardiomegaly (n,%) 29 (34.94%) 15 (83.33%) 9.31 (2.49-34.82) 0.001

Bronchiectatic change 8 (9.64%) 5 (27.78%) 3.60 (1.02-12.8) 0.047 (n,%)

Pneumothorax (n,%) 4 (4.82%) 0 Omitted

Lung infiltrates (n,%) 13 (15.66%) 6 (33.33%) 2.69 (0.86-8.46) 0.10

Pleural effusion (n,%) 6 (7.23%) 2 (11.11%) 1.60 (0.30-8.68) 0.63

Hydro- 0 2 (11.11%) Omitted pneumothorax(n,%)

Lung abscess (n,%) 0 1 (5.56%) Omitted

Table (11): Relation between patient's outcome and radiological findings

Table (11) shows that the frequency of cardiomegaly and bronchiectatic changes as radiological findings in the patient with poor outcome was significantly higher than that in patients with good outcome (P= 0.001 and 0.047 respectively).

Improved (n=83) Not improved Odds PASP (n,%) P value (n=18) ratio(95%CI)

Normal (<25)mmHg 25(30.12%) 23 1 (5.56%) 3 1……………… 0.32 Mild (25:40)mmHg (27.71%) … (16.67%) … 3.26(0.32- 0.05 Moderate 23(27.71%)……12 8(44.44%)…… 33.61) 8.70(1.0- 0.03 (40:55)mmHgSevere (14.46%) … 6(33.33%) 74.99) (>55) mmHg 12.5(1.35- 115.79)

PASP: pulmonary artery systolic pressure. Table (12): Relation between pulmonary artery systolic pressure (according to echocardiography) and patient's outcome

Table(12) shows that poor outcome had a significant relation to severe (P= 0.03).

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al Variable Improved(n=82) Not Odds P value improved(n=9) ratio(95% CI)

FEV1 (L) (mean ± SD) 1.07±0.46 0.58±0.2 0.003(0.00-0.3) 0.01

FVC(L) (mean ± SD) 1.86±0.74 1.19±0.34 0.14(0.03-0.69) 0.02

FEV /FVC % (mean ± 0.59 (0.89- 1 57.24±9.37 51.82±17.94 0.15 SD) 1.02)

COPD staging (n,%) II/

III IV 1 55 (67.07%) 2 (22.22%) 7.13 (1.38- 27(32.93%) 7(77.78%) 0.02 36.66)

*Spirometric parameters were recorded foronly 91 patient so the total number of the studied population in this table is 91. st FEV1: forced expiratory volume in 1 secondFVC: forced vital capacity Table (13): Relation between patient's outcome and spirometricparameters

Table (13) shows that the patients with poor outcome had significantly lower mean values of FEV1 and FVC (P= 0.01 and 0.02 respectively) in comparison with the patient who improved. Poor outcome had a significant relationship with severe COPD stage (stage IV) (P=0.02).

Improved Not improved Odds ratio(95% Etiology P value (n=83) (n=18) CI)

Infectious (n,%) . . Positive sputum culture 51(61.5%) 15(83.3%) 3.14 (0.84-11.7) . Negative sputum 26(31.3%) 3(16.7%) 0.44 (0.12- 0.09 0.22 cultureNoninfectious 6(7.2%) 0 1.65)Omitted (n,%)

Table (14): Relation between the etiology of AECOPD and patient's outcome As regard the etiology of AECOPD, table (14) shows that bacterial infection was more frequent among the patients who had poor prognosis but statistically insignificant(P=0.09).

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al Not Improved Odds Bacterial growth improved P value (n=83) ratio(95% CI) (n=18)

Streptococcus 15 (18.07%) 0 Omitted pneumonia

Haemophilus influenza 12(14.46 %) 2(11.11 %) 0.53(0.08-3.7) 0.51

Pseudomonas 5(6.02%) 6(33.33 %) 0.07(0.01-0.39) 0.002 aeruginosa

Staphylococcus 0.03 (0.004- 2(2.41%) 7(38.89%) ˂0.0001 aureus 0.18)

Klebsiella pneumonia 6 (7.23 %) 0 Omitted

Streptococcus 5 (6.02%) 0 Omitted pyogenes

Streptococcus 4 (4.82%) 0 Omitted parasanguinis

Enterococci 2 (2.41%) 0 Omitted

Total (n=66) 51 (61.44%) 15(83.33%) 3.14 (0.84-11.7) 0.09

*Only 65.35% of the patients (66 patients) had bacterial growth in their sputum culture. Table(15):Relation between the bacterial growth and patient's outcome (n=101)*

Table (15) shows that there was a significant relation between poor outcome and isolation of Staphylococcus aureusand Pseudomonas aeruginosa from the sputum culture of the patients(P˂0.0001and 0.002 respectively).

Discussion Our study included 101 patients (67 Our study found that the most males and 34 females) diagnosed as commonly isolated bacteria in the AECOPD. 82.18% of the patients sputum culture of the studied COPD improved on treatment while 17.82% patients were: Strept. pneumoniae, H. of them had poor outcome (i.e. 13.86% influenzae, P. aeruginosa and Staphy. of the patients were referred to ICU aureus in (14.85%, 13.87%, 10.89% and 3.96% of the patients died). and 8.9% of the patients respectively). According to our results, bacterial The study of Hassan et al. recorded growth was recorded in 66 that the most commonly isolated cases(65.35%). In agreement with us, bacterial strains during AECOPD were other study, in Upper Egypt, found H. influenzae, Strept. pneumoniae, K. significant bacterial growth in 77% of pneumoniae, and methicillin-resistant patients during 81% of exacerbations Staphylococcus aureus (MRSA) (18%, (their study included 156 patients who 15%, , 14% and 11%) (Hassan et al., had 218 AECOPD during 18 months) 2016).Agmy et al., reported that the (Hassan et al., 2016).Sethi and Murphy most predominant organisms in reviewed that at least 70-80% of the AECOPD were H. influnzae followed AECOPD are infectious in origin. Of by Strept. Pneumonia and these infections, 40 to 50% are caused Maroxellacatarrhalis (30%, 25% and by bacteria (Sethi and Murphy, 2008). 18% respectively) (Agmy et al., 2013).

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al In this study, we found that the patients the gender and clinical outcome in with poor outcome hadhigher mean patients with AECOPD (Yousif et al., age in comparison with the patients 2016 &Elgazzar, 2018). who improved ; the mean age of the In our study, it was shown that poor patient with poor outcome was 62.72 outcome is significantly influenced by years in the other hand, the mean age the higher frequencies of COPD among the patients with good exacerbation in the previous 12 months prognosis was 59.84 years. Older (≥2 exacerbation /year) (P=0.003). patients were described to have worse Gaude et al. found that frequent clinical outcomes after acute exacerbation was a predictor of poor exacerbation in many previous studies outcome (death or treatment failure of (Connors et al., 1996; Groenewegen et AECOPD) (P=0.001) in their al., 2003, Roche et al., 2008 &Flattet et univariate logistic regression analysis al., 2017). The impact of age on (Gaude et al., 2015). Risk factors survival may be explained by a gradual associated with this type of patient and natural decline in lung function, could be due to the rapid decline in tendency to have multiple lung function and respiratory bacterial comorbidities, lower respiratory or viral colonization. (Donaldson et al., reserve and being more prone 2002). torespiratory muscle fatigue (Burrows According to the present study, prior et al., 1987&Groenewegen et al., hospital admissions (≥2 2003). However, our study shows that admission/year) and prior ICU there were no statistically significant admission, in the last year, also could relation between the outcome and the predict poor outcome (P=0.004 and age (P=0.2), this result supports the 0.003 respectively). As regard prior findings of Gunen et al. that showed no hospitalization, we are in line with significant relation between the age Gaude et al. who reported the prior and outcome in patients with AECOPD hospitalization as a predictor of poor (Gunen et al., 2005). outcome, i.e. death or readmission, (P= As regard the gender, our study found 0.04) (Gaude et al., 2015). Elgazzar that male gender is a significant study also mentioned that the prior predictor of poor outcome ofAECOPD ICU admission was a predictor of poor (P=0.04) in agreement with outcome (P=0.042). These results Singanayagam et al. (Singanayagam et could be explained as both history of al., 2013). In our community, female previous hospitalization or previous smoking is of less common than that of ICU admission due to AECOPD reflect male gender, so most COPD in females the severity of the underlying disease, is due to causes other than smoking. poor pulmonary reserve, poor This may explain the milder form of compliance to treatment and may be the disease in females, as it was found the resistance of infection (Elgazzar, that cigarette smokers have a higher 2018). prevalence of respiratory symptoms In our study, we also found that there and lung function abnormalities, a was a significant relation between greater annual rate of decline in FEV1 priorLTOT and poor outcome (P= and a greater COPD mortality rate than 0.006). These results coincided with nonsmokers (Rabe et al., 2007). the previous studies that showed a Moreover, morbidity due to COPD was significant relation between the LTOT thought to be greater in men than and outcome in patients with AECOPD women (Chapman, 2004). In contrast, (Connors et al., 1996; Yohannes et al., other studies found no relation between 2005 &Tsimogianni et al., 2009).

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al LTOT reflects more severe stages of response which may reflect the the disease that could be associated severity of the infection(Elgazzar, with corpulmonale, (which is a well- 2018). known adverse prognostic factor) thus Our study also demonstrates that pedal the relation between LTOT and poor edema is a predictor sign for poor outcome could be explained (Connors outcome (P=0.008), thus coincided et al., 1996 &Yohannes et al., 2005). withRoche et al. and Singanayagam et As regard the clinical parameters: al. (Roche et al., 2008 &Singanayagam altered consciousness and flapping et al., 2013). It could be explained as tremor were predictors of outcome in lower limb edema in COPD patient our study (P=0.009 & ˂0.0001 reflects the presence of right sided respectively).Theyare considered as heart failure and more severe illness. neurological manifestation of the With respect to the pattern of hypercapnic encephalopathy which is comorbidities, in the present study, caused by higher values of PaCO2 and bronchiectasis andbronchiectatic respiratory . Roche et al also changes in radiological found that these factors were predictors assessmentwerefound to be significant of ICU admission or mortality (Roche predictors for poor outcome in et al., 2008). AECOPD (P=0.047). Previous With regard to vital signs, the present research foundthat the patients with study also showed that the patients COPD and coexisting bronchiectasis with poor outcome had higher mean have greater bronchial inflammation rates of pulse and respiration, on and greater chronic colonization of admission, in comparison with patients bronchial mucosa by a potentially with good outcome (P= 0.02 and pathogenic microorganism, this can ˂0.0001 in order). Tabak and lead to more frequent exacerbations collaegues considered tachycardia as a with longer duration (Sethi and predictor of hospital mortality in Murphy, 2001 & Patel et al., 2002). In patients with AECOPD (Tabak et al., agreement with us, Du et al. found that 2009). Tachycardia may capture comorbid bronchiectasis in COPD interactions between volume status, patients increased the risk of mortality , and general distress.The (Du et al., 2016). In contrast to our risk of death or readmissions is results, Crisafulli et al.found that increased in patients presenting severe bronchiectasis had no effects on the tachypnea already noted across clinical impact on hospital admission, different studies, perhaps because the clinical presentation, the rate and respiratory rate is at an intersection the risk of short and long term ofmanypathophysiological processes, mortality. Moreover, they found that in such as muscle dysfunction,respiratory the patients with AECOPD, the failure and prevalence of ICU admission in the (Cretikos et al., 2008 &Flattet et al., patients with bronchiectasis was less 2017). than the prevalence of ICU admission Our results also demonstrates that in the patients without bronchiectasis fever had as a significant relation with (Crisafulli et al., 2018(. the poor outcome (P= 0.03). In Corpulmonale and cardiomegaly agreement with us,fever was reported weresignificant predictors for poor as a predictor of poor outcome, in outcome in our results (P=0.005 and ventilated COPD patients, in Elgazzar 0.001 respectively). Previous studies study which explained it byacting as a considered corpulmonale to be a sign of systemic inflammatory predictor of poor outcome in AECOPD

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(Connors et al., 1996 and explained that because low PaO2 is a Singanayagam et al., direct evidence for limited pulmonary 2013).Cardiomegaly could be reflect reserve and increased presence of corpulmonale. It can be ventilation/ mismatch, thus, explained as they reflect the severity of could reflects the severity of the the disease and could aggravate the underlying disease. These patients acute illness. became less tolerant to alterations in In our study, diabetes mellitus their clinical condition, thus, showing a appeared to be a significant factor in poorer prognosis (Gunen et al., poor outcome prediction (P= 0.008). In 2005).Higher mean values of PaCO2at Baker et al., the higher blood hospital admission also was significantly predicted adverse clinical significantly associated with the poor outcomes (death or prolonged hospital outcome(P= 0.01).As regard stay) in AECOPD (Baker et al., 2006). thesurvival in AECOPD,previous In acute illness, cytokines, hormones studies prescribed a worse prognosisin and up regulate expression the case of high value of and membrane localization of glucose PaCO2(Groenewegen et al., 2003 transporters in many cell types. &Flattet et al., 2017). PaCO2 is a Cellular glucose overload results in reflection of alveolar ventilation and is increased glucose , in turn a reflection of the severity of the increasing superoxide and exacerbation. peroxynitrite production which may As shown in the present study, poor impair mitochondrial activity (Van den outcome is related to leukocytosis(P= Berghe, 2004).Hyperglycaemia could 0.008). In agreement with this, also cause adverse outcomes from leukocytosis was found as a factor with AECOPD by predisposing to infection a significant relation to poor outcome through systemic or local effects on in hospitalized patients with AECOPD host immunity or bacterial admitted to ICU, i.e. death(Ashmawi et growth(Philips et al., 2003 & Wood et al., 2017). Leukocytosis is an indicator al., 2004). of inflammation which reflects With respect to the arterial blood gas presence of infection in those patients on admission: lower mean values of so its relation with poor outcome in arterial blood pHat admission was a AECOPD could be explained. On the significantly associated with the poor other hand, Elgazzar study foundthat outcome, according to our leukocytosis were not related to study(P=0.007).In contrast, outcome in AECOPD (Elgazzar et al., Tsimogianniet al found that arterial 2018). blood pH was not related to mortality, Also, in the present study poor and the author attributed this to the fact outcome was related to that the patients with significant thrombocytopenia (P=0.001).In were transferred to agreement with that, thrombocytopenia the intensive care unit and was found to be a significant predictor subsequently excluded from their study of poor outcome (i.e. hospital (Tsimogianni et al., 2009(. In addition, mortality, need for ICU admission or lower values of PaO2 and SaO2% were , P=0.001, 0.008 found to be poor outcome predictors and 0.001 respectively) in patients with according to our AECOPD (Rahimi-Rad et al., 2015). study(P=0.003&0.001).Gunen et al. Thrombocytopenia may reflect some also found that lower values of PaO2 pathophysiologic disturbances, are predictors of poor outcome andthey including disseminated intravascular

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al , , macrophage According to the echocardiography, activation, vitamin deficiencies, drug- severe pulmonary hypertension was a induced toxicity orother unidentified significant predictor of poor outcome factors (Moreau et al., 2007). in our results (P= 0.03) in agreement The present study showed that higher with Hurdmanet al.(Hurdman et al., serum level of creatinine were 2013), it could be explained of that associated with the risk of poor they reflect the severity of the disease outcome(P=0.02).Fluttet et al., 2017 and could aggravate the acute illness. also found that impaired renal function Concerning lung function, our study is associated with poor outcome (i.e. showed that lower mean values of mortality or readmission). A raised FEV1and FVC had significant relation creatinine level in any acute medical to poor outcome (P=0.01 and 0.02 condition may also represent an respectively) and the patient with very underlying poor hydration state prior to severe COPD (stage IV according to admission . GOLD,2018) had the worse outcome As regard elevated liver enzymes, we than the patients with less severity of also observed that AECOPD patients the COPD (P=0.02). Such results have with elevated serum levels of liver been reported in similar studies and are enzymes (ALT and AST) had higher probably explained by the degree of risk of poor outcome(P=0.001). It ventilatory impairment and the higher could be explained by hypoxic risk of colonization by aggressive hepatitis, due to arterial hypoxia and bacteria causing exacerbation may be due to hepatic venous (Miravitlles et al., 2000 &Flattet et al., congestion in patients of severe 2017). decompensated corpulmonale(Henrion Staph.aureusandP.aeruginosaisolation et al., 1999). (in sputum culture) were predictors of In our study, we also observed that poor outcome in our study hypoalbuminemiacould predict poor (P˂0.0001and 0.002 respectively). outcome(P=0.007).The importance of With respect to Staph.Aureus,Hassan hypoalbuminemia as a predictor of et al. reported that it could be due to poor outcome of AECOPD was that all Staph.aureus strains in their consistent with results from other COPD patients were MRSA (Hassan et studies of AECOPD (Connors et al., 2016). This coincided with Borg et al.,1996; Ai-Ping et al., 2005 al. who found that the prevalence of &Asiimwe et al., 2011). In contrast, MRSA in invasive isolates from blood Flattet et al. found no association cultures from nine hospitals in Egypt between values of albumin and the was 52% (Borg et al., 2007).This high clinical outcomes(Flattet et al., 2017). prevalence of MRSA in these studies Low levels of this maybe due should be an alarm for the increasing to combined effect of poor nutritional prevalence of MRSA among state in addition to the effect of the hospitalized patients in our inflammation during AECOPD and it locality.Previous studies agreed with is also a good indicator for long-term the point that P.aeruginosa isolation in health status in chronically ill patients. patients with AECOPD is a risk for The suggested mechanisms for their mortality (Renom et al., roles in increased long-term mortality 2010&Almagro et al., 2012). This are respiratory muscle weakness, microorganism is more frequent in impaired and impaired advanced stages of the disease, and immune response (Connors et al., studies performed in outpatients with 1996& Don and Kaysen, 2004). acute exacerbation showed an inverse

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al relationship between P.aeruginosa and Staph.aureusor P.aeruginosaisolation in pulmonary function. Thus, sputum culture of AECOPD patients. P.aeruginosa is a marker of severity in COPD, which explains the poor References prognosis associated with it(Garcia- 1. Agmy G, Mohamed S, Gad Y, Vidal et al., Farghally E, Mohammedin H and 2009)However,Groenewegen et al. and Rashed H (2013) Bacterial profile, Ko et al. reported that the presence of antibiotic sensitivity and resistance of lower respiratory tract infections in bacterial isolates did not influence the Upper Egypt. Mediterr J Hematol clinical outcomes, including the length Infect Dis.; 5: e2013056. of hospitalization and need for 2. Ai-Ping C, Lee K and Lim T (2005) In- intensive care unit admission, and they hospital and 5-year mortality of did not discover the type of bacteria as patients treated in the ICU for acute a prognostic factor (Groenewegen et exacerbation of COPD: a retrospective al., 2003 &Ko et al. 2005). study. Chest; 128: 518–524. Conclusions 3. Almagro P., Cabrera F. J., Diez J Boixeda R, Alonso Ortiz MB, Murio . Bacterial isolation,in the C and Soriano JB (2012) Comorbidities sputum culture, was found in 65.35% and short-termprognosis in patients of the patient with acute exacerbation hospitalized for acute exacerbation of of COPD . COPD: the EPOC en servicios de . The most common bacterial medicinainterna (ESMI) study. Chest; strains, in sputum culture of patients 142(5):1126–1133.) with AECOPD were: 4. Anthonisen N, Manfreda J, Warren Strept.pneumonia, H. influenza, CP,Hershfield ES, Harding GK and P.aeruginosa, Staph.aureus . Nelson NA (1987) Antibiotic therapy . The significant factors in in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med.; predicting poor outcome (ICU referral 106:196–204. or death) in AECOPD were: male 5. Ashmawi S,Riad N &Saeed M. (2017) gender, prior LTOT, prior hospital Assessment of serum Retinol-Binding admission (≥2 admission/year) or prior Protein-4 Levels in patients with acute ICU admission in the last year, exacerbation of chronic obstructive frequent exacerbations,associated disease at intensive care unit. Egyptian comorbidities Journal of Chest Diseases & (bronchiectasis,corpulmonale and Tuberculosis; 66: 739-743 DM), consciousness alteration, 6. Asiimwe A, Brims F, Andrews N, tachycardia, tachypnea, fever, flapping Prytherch, D, Higgins, B, Kilburn, tremor, pedal edema, arterial blood gas S &Chauhan, A (2011) Routine laboratory tests can predict in-hospital parameters (higher mean values of mortality in acute exacerbations of PaCO2 and lower mean values of pH, COPD. Lung; 189(3): 225–232. PaO2&SaO2), leukocytosis, 7. Baker E, Janaway C, Philips B, thrombocytopenia, elevated serum Brennan A, Baines D Wood DM creatinine,elevated liver and Jones PW (2006) Hyperglycaemia enzymes(ALT& AST), is associated with poor outcomes in hypoalbuminemia, presence of patients admitted to hospital with acute cardiomegaly or bronchiectatic exacerbations of chronic obstructive changes as radiological findings, pulmonary disease. Thorax; 61(4): severe pulmonary artery hypertension 284–289. according to echocardiography, lower 8. Borg M, De Kraker M, Scicluna E, Van de Sande-Bruinsma N, Tiemersma mean values of FEV and FVC, and 1 E, Monen J and Grundmann H (2007)

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SOHAG MEDICAL JOURNAL Acute Exacerbation of Chronic Obstructive Vol. 23 No.1 Jan 2019 Esraa A. Saad.et al ARMed Project Members and (2002) Relationship between Collaborators: Prevalence of exacerbation frequency and lung methicillin-resistant Staphylococcus function decline in chronic obstructive aureus (MRSA) in invasive isolates pulmonary disease. Thorax; 57: 847– from southern and eastern 852. Mediterranean countries. J 17. Du et al., 2016: Du Q., Jin J., Liu X. AntimicrobChemother ; 60:1310–1315. and Sun Y. (2016) Bronchiectasis as a 9. Burrows B, Bloom J, Traver G comorbidity of chronic obstructive and Cline M (1987) The course and pulmonary disease: a systematic review prognosis of different forms of chronic and meta-analysis. PLoS airways obstruction in a sample from One;11(3):e0150532. the general population. N Engl J Med.; 18. Elgazzar A. (2018) Clinical phenotype 317(21): 1309–1314. as a predictor of outcome in 10. Chapman K. (2004) Chronic mechanically ventilated chronic obstructive pulmonary disease: are obstructive pulmonary disease patients. women more susceptible than Egypt J Bronchol.; 12: 180-186. men?.Clin Chest Med.; 25 (2): 331– 19. Elkorashy R and Elsherif R.H (2014) 341. Gram negative organisms as a cause of 11. Chow AW, Hall CB, Klein acute exacerbation of COPD. Egyptian JO, Kammer RB, Meyer RD and J of Chest Disease and Tuberculosis; Remington JS (1992) Evaluation of pp: 345-349. new anti-infective drugs for the 20. Flattet Y, Garin N, Serratrice J, Perrier treatment of respiratory tract infections. A, Stirnemann J and Carballo S (2017) Clin Infect Dis.;15:S62–S88. Determining prognosis in acute 12. Connors A., Dawson N., Thomas C., exacerbation of COPD. International Harrell F., Desbiens N., Fulkerson Journal of COPD; 12 : 467-475. WJ, et al. (1996) Outcomes following 21. Garcia-Vidal C, Almagro P, Romaní V, acute exacerbation of severe chronic Rodríguez-Carballeira M, Cuchi E, obstructive lung disease. The Canales L, et al. (2009) Pseudomonas SUPPORT investigators (Study to aeruginosa in patients hospitalised for Understand Prognoses and Preferences COPD exacerbation: a prospective for Outcomes and Risks of study.EurRespir J.;34(5):1072-8. Treatments). Am J RespirCrit Care 22. Gaude G., Rajes h B., Chaudhury Med.;154:959–967. A., and Hattiholi J. (2015) Outcomes 13. Cretikos M, Bellomo R, Hillman associated with acute exacerbations of K, Chen J, Finfer S and Flabouris A chronic obstructive pulmonary disorder (2008) Respiratory rate: the neglected requiring hospitalization. Lung India; vital sign. Med J Aust.; 188(11): 657– 32(5): 465–472. 659. 23. Global Initiative for Chronic 14. Crisafulli E., Guerrero M., Ielpo Obstructive Lung Disease(GOLD): A., Ceccato A., Huerta A., Gabarrús Global strategy for diagnosis, A., Soler N., Chetta A. and Torres A. management, and prevention of COPD (2018) Impact of bronchiectasis on (2018). outcomes of hospitalized patients with 24. Groenewegen K., Schols A. and acute exacerbation of chronic Wouters E. (2003) Mortality and obstructive pulmonary disease: A mortality-related factors after propensity matched analysis. Scientific hospitalization for acute exacerbation Reports;volume 8, of COPD. Chest; 124(2): 459–467. Article number: 9236. 25. Groenewegen, K.H. and Wouters, 15. Don BR. and Kaysen G. 2004 Serum E.F. Bacterial infections in patients albumin: relationship to inflammation requiring admission for an acute and nutrition.Semin Dial.;17(6):432- exacerbation of COPD; a 1-year 437. prospective study. Respir 16. Donaldson G., Seemungal T., Med. 2003; 97: 770–777. Bhowmik A. and Wedzicha J.

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