Exudative pleural effusions in patients over forty years of age--an analysis of seventy-six patients.PP Prabhudesai, AA Mahashur, N Mehta, R Ajay
Dept of Chest Medicine, KEM Hospital, Parel, Bombay, Maharashtra.
A prospective study of 76 consecutive patients over the age of 40 years, with exudative pleural effusion, was undertaken to determine the common causes of such a clinical condition. Malignant pleural effusions were the most common in this series, found in 49 patients (64.47%), all but one being metastatic from elsewhere. Forty were secondary to a carcinoma of the bronchus, 3 from carcinoma of the breast, 1 each from carcinoma of the ovary, oesophagus, and larynx; lymphoma accounted for the remaining 2. Infective causes accounted for 24 of the effusions (31.57%). Of the infections, tuberculosis was the most common, accounting for 17 of the 24. Other infective causes included bacterial empyemas in 4, ruptured amoebic liver abscess in 2, and actinomycosis in 1. Pancreatitis, pulmonary thromboembolism, and a post-cardiotomy syndrome were diagnosed in 1 patient each, while the diagnosis remained unknown in the remaining 5 patients. In 2 patients the diagnosis was made on autopsy.
Keywords: Adult, Age Factors, Aged, Aged, 80 and over, Exudates and Transudates, Female, Human, Infection, complications,epidemiology,Male, Middle Age, Neoplasms, complications,epidemiology,Pleural Effusion, chemistry,diagnosis,etiology,Population Surveillance, Prospective Studies,
One of the commonly encountered problems tin clinical practice of chest medicine is diagnosing tine aetiology of pleural effusion. The aetiology of transudative pleural effusions is usually obvious - the common causes being congestive heart failure, nephrotic syndrome, and hypoproteinemia. However, the aetiology of an exudative pleural effusion is often not clear. There is a tendency to label most exudative effusion as tubercular, empirically, and no concerted efforts are made to pursue the diagnosis. Often, the only diagnostic tests done are pleural fluid protein estimation, and pleural fluid cytology.
In young patients in this country, tuberculosis is the most common cause of exudative pleural effusions, and one may be justified in giving them empirical anti-tuberculous chemotherapy without actively pursuing a tissue diagnosis when X-ray chest shows no other abnormality. This approach may not be as justifiable in the older age groups where malignancy would arguably be an equally important differential diagnosis.
We therefore carried out a study to determine common causes of pleural effusions in patients above the age of forty years.
Seventy-six consecutive patients over the age of 40 years presented for the fivst time with exudative pleural effusions were included (either on out-patient basis or indoor admission basis) in this prospective study. Pleural fluid protein content of more than 3 gms %, or a pleural fluid to serum protein ratio of more than 0.5 were considered as indicative of an exudative pleural effusion. The attempt always was to reach the diagnosis in the quickest manner possible, and hence diagnostic procedures tended to vary from patient to patient.
At the initial presentation, the following was the approach: a detailed clinical history followed by a thorough physical examination and investigative procedure like chest roentgenograms, and thoracocentesis. The pleural fluid after noting the gross appearance was examined for protein content, total and differential white blood cell count and malignant cells. Gram staining and Ziehi-Nielson staining were also performed. For malignant cells about 100 mi of fluid in a heparinized container was examined after preparing a cell-block of the centrifugate. If the first sample did not test positive for malignant cells, repeat thoracocentesis was performed. A maximum of three thoracocenteses were performed in any one patient. The pleural fluid was also cultured for aerobic and anaerobic organisms wherever indicated. Other investigations depended on the clinical findings and the radiological picture. Sputum smears were examined for acid-fast bacilli and for malignant cells whenever the roentgenograms showed a parenchymal lesion. A closed pleural biopsy was performed using a Cope's pleural biopsy needle in those patients in whom, repeated pleural fluid cytology proved to be negative. Multiple biopsies were taken from the same site at one sitting. Pleural biopsies were repeated, as required, to a maximum of four. Any enlarged scalene nodes were biopsied. Fibreoptic bronchoscopy, MRI, bone scan, and USG of the abdomen were done wherever indicated. Thoracoscopy was done in one patient, and thoracotomy in two patients. In patients where a definite diagnosis was not reached, with the above mentioned investigations a therapeutic trial of anti -tuberculous treatment was given. In two patients, the diagnosis could only be made following autopsy.
Of the 76 patients included in this study, (60 males and 16 females; age range being 40 to 81 years; the mean age: 61,5 years) 31 (40.78%) were smokers. The diagnosis reached in these 76 patients is shown in [Table - 1].
In 5 patients a diagnosis of tuberculosis was made based on good response to anti-tuberculosis therapy, because diagnosis could not be made with repeated pleural aspirations or pleural biopsies. In two patients diagnosis was obtained following autopsy; one showed evidence of pulmonary tuberculosis and other of malignancy. Malignancy was found to be the most common cause of exudative pleural effusions in this series, being present in 49 (64.47%) of our patients. Out of 49 malignant pleural effusions, 40 patients had lung carcinoma, and 30 of them had adenocarcinoma while squamous cell carcinoma and undifferentiated carcinoma were seen in 5 each (12.5%). There was no evidence of obvious malignancy, like primary tumour, mediastinal nodes, cannon balls appearance or other metasteses in 44 (89.79%) patients, who were diagnosed to have malignant pleural effusion. Five patients had pleural effusion with obvious malignancy viz. 3 had breast cancer, 1 had carcinoma larynx and 1 had carcinoma of the oesophagus. Tuberculosis was diagnosed in 17 (22.36%). Empyema was seen in 4 patients, and ruptured amoebic liver abscess in 2 patients. Other causes included an empyema due to actinomycosis, pancreatitis, pulmonary embolism, and post-cardiac surgery in 1 patient each.
Almost all patients with malignancy and all the patients with tuberculosis were symptomatic. Most of our patients who were proved to have malignancy had chest pain (40 of 49 patients i.e. 81.6%), while it was noticed in only 7 of 17 patients with tuberculosis (41 %).
In our series, breathlessness was a common presenting complaint with malignant pleural effusions, being found in 31 patients (63.2%), while only 3 patients with tuberculosis (17.6%) had the same complaint. Cough was commoner in patients with tuberculosis being reported in 15 of the 17 patients, while only 25 patients with malignancy (51%) had the same complaint. Similarly fever was present in 15 patients of tuberculosis (88%), while in 8 patients only with malignancy, Haemoptysis was only present in 3 patients, all of whom subsequently turned out to have malignancy. Clubbing was seen more often in malignant effusions [8 patients (16.3%)], as compared to one with tuberculosis, but was most common in empyema (2 of 4).
Scalene nodes were palpable on the ipsilateral side in 3 patients, all of whom, turned out to have malignancy. Pleural rub was not specific for any condition, being found in 1 patient with malignancy, 3 with tuberculosis and 1 each with pulmonary embolism and ruptured amoebic liver abscess. In all 3 patients with carcinoma of the breast, the effusion was found to be malignant and ipsilateral. Encysted pleural effusions were only seen in benign conditions, 4 of whom had tuberculosis, and 1 of whom had a bacterial empyema. Twelve patients had parenchymal and mediastinal opacities seen after aspirations, in addition to the effusion - 6 patients with infiltration and cavitation had tuberculosis; of 3 patients with mediastinal nodes, 2 had lymphoma and 1 had tuberculosis; and 3 patients had nodular shadows in both lung fields, which were due to metastases.
Pleural fluid report is shown in [Table - 2].
In this series, sputum revealed malignant cells in only 4 of 17 patients examined, who subsequently proved to have malignant effusion. Sputum for acid fast bacilli was positive in 7 of 17 patients tested. One of these had a cavity and 5 had infiltration in lung and two of them had empyema. In no patient we could get sputum +ve for AFB in pure pleural effusion.
Pleural biopsy revealed malignancy in 22 of 41 patients (53.6%) with malignancy. Of these, in only 4 patients diagnosis was based on biopsy and not on pleural fluid examination. Pleural biopsy revealed tubercular granulomas in 5 patients out of 13 (38.4%) who subsequently proved to have tuberculosis.
Fiberoptic bronchoscopy was performed in 41 patients who subsequently proved to have malignancy. In 15 of these, this procedure yielded malignant cells, but in only 2 of these patients was this, the only procedure to do so - quite a low yield.
The diagnosis reached is shown in [Table - 3].
Lung carcinoma metastasizing to the pleura was the commonest cause of malignant pleural effusion, as found in our 40 patients (81.6%). Adenocarcinoma was the commonest cell type, being present in 30 patients (75%). This correlates with the fact tha adenocarcinomas are peripheral lung tumors and recent reports of increase in the incidence of adenocarcinomas in the lung. There are reports of adenocarcinomas more commonly associated with pleural effusion by other authors,.
Carcinoma of the breast ipsilateral to the pleural effusion formed the next most common cause of malignant pleural effusion. Primary pleural malignancy (malignant mesothelima) was found in only one instance - this patient underwent a thoracotomy and open pleural biopsy in order to reach the diagnosis.
Of the infective causes, tuberculosis was the most common being found in as many as seventeen patients (70.8%). In our study 7/17 (41.1%) had acid fast bacteria in their sputum. Bacterial empyemas were the next most common (16.6%), though the causative organism(s) was not grown in any of the samples. The diagnosis of bacterial empyema was made on the basis of finding of pus in the pleural space, with no AFB seen on smear, and with a response to antibiotics. Other causes of infective pleural effusion included actinomycosis in 1, and a ruptured amoebic liver abscess in 2 patients.
Miscellaneous causes included pancreatitis in one, wherein the pleural fluid and the serum amyise levels were high (2000 IU in the pleural fluid), and USG of the abdomen showed a pseudocyst of the pancreas. Another patient had a presumptive diagnosis of pulmonary thromboembolism made on the basis of clinical features of sudden onset dyspnoea and pleuritic chest pain in an elderly male confined to bed following operation for a fracture of the neck of the femur, and findings of a pleural rub with a few crackles and reduced breath sounds at the right base, and mild right sided pleural effusion which was found to be haemorrhagic on thoracocentesis. A third patient had a left sided pleural effusion without pericardial effusion, one week after coronary artery by-pass grafting. The X-ray chest taken immediately after surgery was normal. The pleural fluid cytology showed a predominance of lymphocytes and an absence of acid fast bacilli and malignant cells. However, prolonged duration and large size of effusion created diagnostic problem in him. It resolved on its own over the next one and half months,
Chernow and Sahn have reported that dyspnoea and cough were the main complaints in their series, while chest pain was more common in our patients.
In our series, the size of the effusion was not suggestive of any particular condition, though moderate and large effusions were found to be malignant more often than benign. Similarly, bilateral effusions were as likely to be tubercular as malignant. This ipsilaterality of the effusion was also reported by Chernow and Sahn .
The colour of the fluid was important for diagnosis, blood tinged effusions being always malignant in our series, except in 1 patient with pulmonary thromboembolism. This contrasts with the findings of Leuallen and Carr  who had found blood stained effusions in patients with tuberculosis and congestive heart failure almost as often as in patients with malignancy. Straw coloured fluid was found to be less conclusive, as lymphocyte predominance in straw coloured effusions was seen in as many as 20 patients (40.8%) who subsequently proved to have malignancy. This has also been reported by other authors like Leullen and Carr and Fishmans. None of those who had tuberculosis had polymorphonuclear predominance of blood stained effusions. Sputum examination for acid fast bacilli malignant cells were found to be the least invasive and the most helpful in providing the diagnosis, It has been reported by Berger and Mejia that 12 of 40 (30%) patients with tuberculous pleural effusion had tubercle bacilli in their sputum or gastric lavage. Ten of these patients had visible pulmonary lesions on chest X-ray. Tubercle bacilli cultured from sputum or gastric content in 0 to 32% cases. Thirty percent fluid cultures in tuberculous effusion were positive. Of the 17 patients with tuberculosis whose pleural fluid was examined for acid fast bacilli, none tested positive on smear in our series. In cases of malignancy, however, pleural fluid examination for malignant cells was very rewarding, being positive in 32 of 49 patients (65.3%). The yield of positive reports was maximum in 1st aspiration (68.75%) but 25% patients had second aspiration positive for malignant cells, which is very important to note. Two patients (6.25%) had to undergo 3 aspirations. We suggest whenever there is high suspicion for malignancy atleast 3 times aspirations should be sent for malignant cells. It has been shown that the yield of pleural fluid cytology for malignant cells increased significantly when repeated aspirations were done.
Rao et al  reported that pleural biopsies in tuberculous effusions could be diagnostic in 90% cases. However, they do not state clearly whether the histopathological picture of infiltration with round cells and histocytes is compatible with a diagnosis of tuberculosis. Fishman  has mentioned diagnostic value of pleural biopsy in 80% cases. In our series 38.4% case showed positive biopsy. This may be probably due to the lesser number of repeat pleural biopsies done in this series. Of 5 patients who underwent biopsy, in 3 it was positive on 1st attempt and in 2 on 2nd attempt. In our study, pleural biopsy was diagnostic in 90.9% in first two biopsies in malignancy (12/22 patients after 1st attempt, 8 on 2nd and 2 on 3rd attempt revealed malignancy). We could do pleural biopsies only in 5 of 13 patients who were diagnosed as tuberculosis.
Pleural effusion in elderly patients should be investigated till a definitive diagnosis is reached. Secondaries in the pleura are a most common cause even in our country where there is high incidence of pulmonary tuberculosis. Persistent dull chest pain, moderate to severe dyspnoea, absence of fever helps to suspect malignancy. Absence of smoking does riot rule out malignancy in pleura. Blood tinged effusion gives high suspicion but straw-coloured effusion does not rule out malignancy. Heparinized pleural fluid should be sent for malignant cells in a large quantity (around 100mi). If negative, repeat aspiration sample should be sent for malignant cells. Bronchoscopy alone gives diagnosis less often. But it should be attempted in an undiagnosed pleural effusion. If fibreoptic bronchoscopy and all other investigations were negative then thoracoscopy or thoracotomy would be the ideal investigations to achieve the diagnosis. Empirically AKT should be advised to the patients of pleural effusion with age more than forty only after reasonable investigations are carried out to achieve the diagnosis. This has been the experience of other authors too.
[Table - 1], [Table - 2], [Table - 3]