Introduction
Pseudomonas aeruginosa (P. aeruginosa) is a usual causative organism of both hospital-acquired pneumonia and community-acquired pneumonia. Although, it is less commonly reported in otherwise healthy hosts, most patients have an identifiable risk factor for disease. These risk factors include those with structural lung abnormalities like bronchiectasis and those with a compromised immune system. With the emergence of multidrug resistant strains of P. aeruginosa, the severity of infection and mortality associated with pneumonia has increased drastically. The insight into the risk factors of Pseudomonas pneumomia helps to suspect and treat the condition at the earliest and thereby reduce the mortality as well as the duration of hospital stay.
Aim
To determine various risk factors associated with P. aeruginosa pneumonia.
Materials and Methods
An observational cross-divtional study was conducted from November 2018 to November 2020 at Jawaharlal Nehru Medical College, Aligarh, Uttar Pradesh, Inida, after obtaining Institutional Ethics Committee (IEC) approval. A total of 89 patients with diagnosis of Pseudomonas pneumonia, defined as the presence of signs and symptoms of pneumonia along with sputum or tracheal culture positive for P. aeruginosa were enrolled in the study. These patients were thoroughly assessed by clinical history, physical examination and relevant investigations to detect any risk factors like age, diabetes, smoking, Chronic Obstructive Pulmonary Disease (COPD), chronic steroid use and prior hospital admission. Data analysis was done using Statistical Package for Social Sciences (SPSS version 22.0). Categorical variables were compared with the Chi-square test.
Results
Out of 89 patients with Pseudomonas pneumonia, 77.5% were above 40 years of age, 37.08% were smokers, 25.84% had COPD, 22.47% had bronchiectasis, 31.46% were diabetic, 15.73% were on long term steroid use and 14.61% had history of prior hospital admission.
Conclusion
Age, smoking, structural lung diseases like COPD, bronchiectasis, long term steroid use and prior hospital admission are important risk factors for Pseudomonas pneumonia.
Introduction
Community Acquired Pneumonia (CAP) is an important cause of the morbidity and mortality all over the world [1]. It is estimated that around 5-6 billion people are diagnosed with CAP and more than 3.5 million people succumb to death yearly due to CAP [1,2]. P. aeruginosa is a gram negative, aerobic rod bacterium which belongs to the Gamma Proteobacteria bacterial class [3]. This microbe is commonly seen on the skin of humans and hence considered as skin flora. It is an opportunistic pathogen which respond to a breakdown of the skin and enter the body of immune-compromised individuals [4]. Soil, water, agriculture plants, animals, and humans are usual reservoirs of this microbe [5].
P. aeruginosa has two modes of virulence expression, resulting in atleast two forms of distinct pathogenetic behaviour:
Some strains remain confined to the lungs as a chronic, indolent coloniser {as occurs in many patients with Cystic Fibrosis (CF)}.
Other strains can invade tissues, causing pneumonia or bacteremia along with their potential complications of septic shock and death.
P. aeruginosa is one of the common causative organisms for both hospital-acquired pneumonia [6] and CAP. Although community acquired P. aeruginosa pneumonia is occasionally reported in otherwise healthy hosts [7], most patients have an identifiable risk factor for disease. The various risk factors that have been identified include structural lung diseases such as CF, bronchiectasis, compromised immune system (as in Human Immunodeficiency Virus (HIV) infected patients, those on immunosuppressive agents, neutropenic hosts), repeated exacerbation of COPD and recurrent use of glucocorticoids and antibiotics. Other known risk factors for Pseudomonas infection include cirrhosis, enteral tube feeding, intubation and prior hospital admission. Risk factors associated with hospital-acquired Pseudomonas infection include increasing age, duration of mechanical ventilation, previous use of antibiotics, admission to a high dependency unit or Intensive Care Unit (ICU), and admission in a ward with higher incidence of patients with P. aeruginosa infections [8]. Outbreaks of P. aeruginosa infection linked to contaminated healthcare equipment such as endoscopes have been occasionally reported [9].
Signs and symptoms of P. aeruginosa pneumonia are similar to that caused by other pyogenic bacteria or Legionella, and there are no features specific to P. aeruginosa which can reliably distinguish it from pneumonia caused by other organisms. Characteristic symptoms of acute P. aeruginosa pneumonia are cough productive of purulent sputum, fever, chills, dyspnoea, confusion and severe systemic toxicity. Ventilator-associated P. aeruginosa pneumonia patients may also present with increased tracheobronchial secretions and decreased ventilator performance, which can develop suddenly or gradually.
Radiographic findings associated with P. aeruginosa pneumonia are variable and there is no unique finding which is predictive or characteristic of the disease. It may present as diffuse bilateral infiltrates, with or without pleural effusion. Many patients may present with multifocal airspace consolidation. Other radiographic features include nodular infiltrates, tree-in-bud opacities, and necrosis [10]. Sometimes, areas of radiolucency suggestive of cavitary disease can be seen. However, classic lobar consolidation is uncommon. In case of P. aeruginosa pneumonia arising from haematogenous spread of the organism, the early radiographic findings may include pulmonary congestion and interstitial oedema. Later these patients often develop diffuse interstitial and alveolar infiltrates after 24 to 48 hours. Large haemorrhagic nodules with central necrosis or cavities are very rare in the course of the disease [11].
Histopathological changes seen in patients with P. aeruginosa pneumonia usually include microabscesses with focal haemorrhage and necrosis of the alveolar septae without evidence of bacterial invasion of vessel walls or vascular necrosis. In patients with pneumonia due to haematogenous spread, the pathologic changes usually include intraalveolar haemorrhage and necrosis around pulmonary vessels. In some patients, small (2-15 mm), yellow-brown, firm, necrotic nodules with areas of dark red haemorrhagic parenchyma may also be seen along with liquefactive necrosis or bacterial invasion of the alveolar cell walls [12].
Specifically, for the empiric management of CAP and hospital-acquired pneumonia, the guidelines from the Infectious Diseases Society of America and the American Thoracic Society are followed. The following antimicrobial combinations are recommended for patients with risk factors for both P. aeruginosa infection as well as drug resistance [13]:
An antipseudomonal beta-lactam PLUS an antipseudomonal quinolone
An antipseudomonal beta-lactam PLUS an aminoglycoside
An antipseudomonal quinolone PLUS an aminoglycoside
P. aeruginosa pneumonia can lead to high in-hospital mortality rates and prolonged duration of hospital stay [14, 15]. Now-a-days, circulating strains of P. aeruginosa with higher resistance patterns to antipseudomonal antibiotics have emerged, resulting in infections that are very challenging to treat [6].
The knowledge regarding specific risk factors associated with Pseudomonas pneumonia helps in the early diagnosis and prompt initiation of empirical treatment. This study was an attempt to throw more insight regarding various risk factors associated with P. aeruginosa infection. Also, this study was done to assess certain factors which are less studied as potential risk factors for Pseudomonas infection.
Materials and Methods
This was an observational, cross-sectional, hospital based study conducted in Jawaharlal Nehru Medical College, Aligarh, which is a tertiary care centre in the northern state, Uttar Pradesh, India. The participants were from the Department of Respiratory Medicine of the same hospital and the study data was collected from November 2018 to November 2020. The Institutional Ethics Committee approved the study (letter no: 260/FM/AMU).
Inclusion criteria: All patients with diagnosis of Pseudomonas pneumonia, defined as the presence of signs and symptoms of pneumonia with pulmonary infiltrates suggestive of pneumonia on thoracic imaging along with microbiological confirmation (sputum/tracheal culture positive) for P. aeruginosa were considered for the study. Among these patients those who gave informed consent and were above 18 years of age were included in the study.
Exclusion criteria: Patients suffering from other respiratory infections such as pulmonary tuberculosis, Coronavirus Disease (COVID)/viral pneumonia and other bacterial infections were excluded from the study.
Methodology
A total of 89 patients with P. aeruginosa pneumonia were enrolled in the study and they were assessed with thorough history and clinical examination. A pretested interviewer administered questionnaire was used to obtain relevant information from the study population. Any significant risk factor for P. aeruginosa was assessed from the history like smoking, alcohol intake, diabetes mellitus, bronchiectasis, COPD, previous hospital admissions, recurrent glucocorticoid use, recent bronchoscopy/intercostal tube drainage, tracheostomy and congenital heart diseases. All these patients were thoroughly examined for any respiratory/cardiovascular/gastrointestinal/central nervous system abnormalities. Any systemic abnormalities noted other than respiratory abnormalities were referred to speciality departments for expert opinion.
All recruited participants were subjected to routine blood investigations, spirometry and chest X-ray. The following investigations were done for all participants like haemogram, renal fuction test, liver function test, blood glucose -fasting and postprandial, glycated Haemoglobin (HbA1c), Electrocardiogram (ECG), chest X-ray, Pulmonary Function Tests (PFT)- pre and post bronchodilator and HIV Enzyme Linked Immunosorbent Assay (ELISA). Additional investigation like High Resolution Computed Tomography (HRCT)/Contrast Enhanced Computed Tomography (CECT), were done when chest X-ray showed any abnormality.
Statistical Analysis
Data analysis was done using SPSS version 22.0. Descriptive statistics was done and the qualitative data were expressed in percentage. Categorical variables were compared with the Chi-square test. All tests were performed at 5% level of significance. All reported p-values were two tailed, p-value of <0.05 was considered significant, while p-value of <0.01 was considered highly significant.
Results
A total of 89 patients with Pseudomonas pneumonia were enrolled in the study, out of which 55 were males and 34 were females.
Age: Most of the patients were above 40 years. The data was statistically significant and showed that the incidence of Pseudomonas pneumonia increased with age. A 77.5% of the patients were above 40 years of age [Table/Fig-1].
| Age (years) | No. of cases | Percentage | p-value* |
|---|
| 18-40 | 20 | 22.5 | <0.05 |
| 41-60 | 37 | 41.6 |
| >60 | 32 | 35.9 |
| Total | 89 | 100 |
*Chi-square test; p-value <0.05 considered significant
Smoking: This study revealed that 33 (37.08%) patients out of the total 89 patients were significant cigarette/beedi smokers. Significant smoking was taken as smoking index more than 100 (smoking index=no of cigarettes per day×years of smoking) [Table/Fig-2].
Percentage of P. aeruginosa pneumonia patients with/without the risk factors.
| Risk factors | Number of cases (%) | p-value* |
|---|
| Yes | No |
|---|
| Smoking | 33 (37.08) | 56 (62.92) | <0.05 |
| COPD | 23 (25.84) | 66 (74.16) | <0.001 |
| Bronchiectasis | 20 (22.47) | 69 (77.53) | <0.001 |
| Chronic steriod use | 14 (15.73) | 75 (84.27) | <0.001 |
| Prior hospital stay | 13 (14.61) | 76 (85.39) | <0.001 |
| Diabetes mellitus | 28 (31.46) | 61 (68.54) | <0.001 |
*Chi-square test; p-value <0.05 considered significant
COPD: Among the patients with Pseudomonas pneumonia, 23 patients were diagnosed with or previously diagnosed with COPD. All subjects underwent PFT and Chest X-ray at the time of admission. COPD was considered in those subjects in whom Forced Expiratory Volume during one second (FEV1)/Forced Vital Capacity (FVC) <0.7 and relevant clinical history. Chest X-ray findings like hyperinflated lung fields, flattened diaphragm, tubular heart were considered as auxiliary findings to support the diagnosis of COPD [Table/Fig-2].
Bronchiectasis: Total 20 (22.47%) patients were detected to have bronchiectasis, of the total 89 study participants. Bronchiectasis was considered in those patients with relevant history and radiological features. Those patients with suspicious chest X-ray findings of bronchiectasis were confirmed with HRCT [Table/Fig-2].
Chronic steroid use: Total 14 patients (15.73%) were on long term steroid for various medical conditions like arthritis, bronchial asthma etc. Chronic steroid use was considered as any use of steroid drugs for a period of more than two months. It included the use of inhaled corticosteroids used for the treatment of respiratory diseases [Table/Fig-2].
Prior hospital stay: Total 13 patients (15.61%) of the study population had prior hospital admission atleast for one day within 90 days of diagnosis. Prior hospital admissions for these subjects were done for both respiratory and non respiratory conditions [Table/Fig-2].
Diabetes mellitus: Total 28 patients (31.46%) were newly/previously diagnosed cases of type 2 diabetes mellitus. HbA1c value more than 7.5 was taken as the cut-off for the subjects. In those patients with HbA1c between 7-7.5, any blood glucose value more than 180 mg/dL were considered diabetic [Table/Fig-2].
Discussion
Pseudomonas aeruginosa is a gram negative bacterium which can cause life-threatening hospital acquired respiratory infections [2]. Now-a-days, CAP caused by Pseudomonas is also on the increasing trend. Although the true prevalence of P. aeruginosa CAP is unknown, a meta-analysis done by Chalmers JD et al., reported data from 22 studies showed a prevalence ranging from 0-23% in different CAP populations [16]. P. aeruginosa pneumonia often results in severe illness and poor clinical response to treatment [6]. This study aimed to determine various risk factors associated with Pseudomonas pneumonia and it was found that increasing age, smoking, diabetes mellitus, structural lung diseases like COPD, bronchiectasis, chronic use of steroids and previous hospital admission within in a period of 90 days were some of the risk factors associated with P. aeruginosa pneumonia.
Out of 89 patients with Pseudomonas pneumonia, 77.5% were above 40 years of age, 37.08% were smokers, 25.84% had COPD, 22.47% had bronchiectasis, 31.46% were diabetic,15.73% were on long term steroid use and 14.61% had history of prior hospital admission. Increasing age was found to be a predisposing factor for P. aeruginosa pneumonia in the study and it must be due to weakening of immunity as the age advances. Cigarette smoking impairs mucociliary clearance at the same time causing an increase in mucus production which might be the reason for it being a risk factor. COPD causes destruction of portions of airway, increased mucus production and chronic inflammation which increases the risk for P. aeruginosa pneumonia. Similarly structural damage caused by bronchiectasis leads to stasis of secretions, which might have increased the risk. Diabetes mellitus and long tern steroid use leads to immune suppression, probably the reason for their association with P. aeruginosa pneumonia in the study. Previous hospital admissions expose the individuals to nosocomial microbes and hence predispose to Pseudomonas pneumonia.
The antibiotic treatment for P. aeruginosa differs from the standard treatment protocol for pneumonia that targets the most common microorganism causing CAP (e.g., Streptococcus pneumoniae), and is extrapolated from Ventilator-Associated Pneumonia (VAP) and Health Care-Associated Pneumonia (HCAP) data. As per the recent guidelines for CAP in adult patients, P. aeruginosa empirical antibiotic treatment is recommended only in patients with specific clinical risk factors [16]. These risk factors for CAP due to P. aeruginosa in current clinical practice guidelines include smoking, COPD, bronchiectasis, long term use of oral steroids or any prior use of antibiotics within 90 days [17].
Sibila O et al., did a retrospective population based study in which 781 patients with P. aeruginosa pneumonia were identified in a cohort of 62,689 patients (1.1%) [18]. They summarised that risk factors recommended by current guidelines were only able to detect one third of the patients with CAP due to P. aeruginosa. They suggested that increasing age is a risk factor for Pseudomonas pneumonia, probably because of weakened immunity.
Chien J et al., also supported present study finding and suggested that cigarette smoke exposure not only increases the virulence of P. aeruginosa but can also impair the neutrophil mediated killing efficacy [19]. Their study also opined that exposure to cigarette smoke increases Pseudomonas biofilm formation which may be a reason for increased risk of Pseudomonas infection. Hatchette TF et al., suggested that pack years of more than 40 is a significant risk factor for Pseudomonas pneumonia [20].
The study conducted by Lieberman D and Lieberman D, among unselected outpatients with acute exacerbations of COPD revealed that average rate of isolation of P. aeruginosa from the patients’ sputum was around 4%. This rate was even higher in COPD patients with severe airflow obstruction, in whom the rate of isolation of P. aeruginosa in sputum reached 8-13% of all episodes of acute exacerbations of COPD [21]. The study conducted by Garcia-Vidal C et al., showed that out of 188 COPD patients included, 31 (16.5%) had P. aeruginosa in sputum at initial admission [22]. The most important finding of their study was the strong correlation between Pseudomonas isolation at hospital admission and various markers of respiratory functional impairment used in COPD. The various markers of respiratory functional used were BODE index (BMI, Airflow Obstruction, Dyspnoea, Exercise Capacity), modified Medical Research Council (mMRC) grading of Dyspnoea, Home Oxygen therapy requirement etc. Their study concluded that acute exacerbation of COPD must be considered as high risk condition for Pseudomonas infection and antibiotics should be started accordingly [22].
Restrepo MI et al., confirmed present study findings suggesting bronchiectasis (OR 2.88, 95% CI 1.65-5.05) as one of the main risk factor for Pseudomonas infection. Their study also concluded that patients with bronchiectasis had increased chance of getting infection with multidrug resistant P. aeruginosa [23]. In an observational study, conducted by Pieters A et al., among patients with bronchiectasis, they identified patient characteristics which were associated with the presence of persistent P. aeruginosa colonisation [24]. They stated that P. aeruginosa is an important pathogen in bronchiectasis and functions as a marker for disease severity. As per their study, chronic colonisation with P. aeruginosa were seen in 25% of the patients with bronchiectasis.
As per the study conducted by Garcia-Vidal C et al., 31 patients were culture positive for Pseudomonas infection, out of which 4 patients (12.9%) were on chronic steroid use [22]. Sibila O et al., documented that 27.1% of Pseudomonas infection patients were on chronic steroid use [18]. Raman G et al., did a study which concluded that prior antibiotics use and previous hospital or ICU admissions were the most important risk factors for the development of resistant P. aeruginosa infections. They also stated that the risk of development of multidrug resistant P. aeruginosa compared with non-P. aeruginosa was significantly increased with prior use of cephalosporins (OR 3.96), carbapenems (OR 2.61), quinolones (OR 2.96), and prior hospital stay (OR 1.74) [25].
Sibila O et al., also stated that diabetes mellitus can be a risk factor for Pseudomans pneumonia [18]. Saibal MAA et al., suggested that a wide range of neutrophil and macrophage functions are impaired in diabetes mellitus [26]. These include chemotaxis, adherence, phagocytosis and the ability to kill the phagocytosed microorganism. The intracellular killing of microbes by free radicals, called respiratory burst are also reduced in diabetes. Gradual impairment of acquired immunity can also occur in diabetic patients. As a result of chronic hyperglycaemia, there will be alterations in the capillary endothelial function, Red Blood Cells (RBCs) rigidity and changes in the oxygen dissociation curve which may affect the hosts’ ability to combat infections.
Limitation(s)
This was an observational, one point study done only in those patients who were having P. aeruginosa pneumonia. Since it is not a case-control study; the odd’s ratio was not calculated. Many confounding factors might have affected the results. For example, in the study a patient who is a heavy smoker might also be having borderline diabetes mellitus. This could result in smoking being a confounding factor for diabetes or vice-versa. The confounding factors were not filtered.
Conclusion(s)
This study reveals important information regarding predisposing factors of Pseudomonas pneumonia. Seven risk factors were identified including increasing age, smoking, chronic obstructive lung disease, bronchiectasis, chronic steroid use, diabetes mellitus and prior hospital stay. The knowledge about these predisposing factors helps in suspecting P. aeruginosa infection at the earliest and prompt initiation of empirical antipseudomonal antibiotics.
*Chi-square test; p-value <0.05 considered significant*Chi-square test; p-value <0.05 considered significant
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