An Asymptomatic Haemorrhagic Pleural Effusion Mimicking Extra-Pulmonary Tuberculosis in a Young Woman with Thoracic Endometriosis Syndrome: A Case Report

Background: This case discusses the importance of thor- oughly investigating a haemorrhagic effusion in a setting where the tuberculosis is endemic. Case report: A young woman presented with an asymp- tomatic recurrent right sided pleural effusion. Pleural fluid full report showed neutrophilic and haemorrhagic effusion. Ade- nosine deaminase level in the pleural fluid was elevated and the Mantoux test was positive. Microbiological diagnosis was negative, and she was started on anti-tuberculous therapy on clinical grounds for extrapulmonary tuberculosis. Diagnostic Thoracoscopy revealed characteristic appearance suggestive of thoracic endometriosis which was confirmed by histology.

Thoracoscopy is valuable in rapid diagnosis of pleural based diseases such as thoracic endometriosis. It also provides option to drain tuberculous and other com- plicated effusions completely minimising the chance of later complications. This case discusses the importance of thor- oughly investigating a haemorrhagic effusion in a setting where the tuberculosis is endemic.

Haemorrhagic effusion, Catamenial haemothorax, Tubercu- losis, Thoracic endometriosis syndrome List of Abbreviations TB: Tuberculosis; TES: Thoracic Endometriosis Syndrome; BMI: Body Mass Index; CECT: Contract Enhanced Com- puted Tomography; ESR: Erythrocyte Sedimentation Rate; CRP: C-Reactive Protein; LDH: Lactase Dehydrogenase; ANA: Antinuclear Antibody; RF: Rheumatoid Factor; HIV: Human Immune Deficiency Virus; USS: Ultra-Sound Scan; RBC: Red Blood Cells; AFB: Acid- Fast Bacilli; ADA: Ade- nosine Deaminase; GeneXpert MTB/RIF: Mycobacterium Tuberculosis and Resistance to Rifampicin; BCG: Bacillus Calmette-Guérin; ATT: Anti-tuberculous Therapy; VATS: Vid- eo Assisted Thoracoscopic Surgery; SLE: Systemic Lupus Erythematosus; GnRH: Gonadotropin-Releasing Hormone

Haemorrhagic pleural effusion is defined as pleural fluid hematocrit greater than 50% of the patient’s blood hematocrit. Spontaneous haemorrhagic effusions have a broad differential diagnosis which includes TB, malig - nancy, connective tissue disorders, pancreatic fistulas, leaking aortic aneurysms and other vascular malforma- tions, TES, ovarian hyperstimulation syndrome etc [1-4]. Co-existing aetiologies can lead to diagnostic and man- agement dilemma among physicians. TB remains one of the most frequent causes of pleural effusions globally, hence always is high up in the list of differential diag - noses [5]. Endometriosis is characterised by the presence of hormone sensitive endometrial tissue outside the uter- ine cavity. It is more commonly encountered in the de- pendent parts of the pelvis such as ovaries, fallopian tubes, uterine ligaments, pelvic peritoneum, cervix, la- CASe RepoRt Check for updates ISSN: 2378-3516 DOI: 10.23937/2378-3516/1410082 • Page 2 of 5 • Bataduwaarachchi et al. Int J Respir Pulm Med 2018, 5:082 The CECT scan of the thorax showed moderate to se- vere right sided pleural effusion extending into the right major fissure with associated basal collapse of the right lower lobe and mild volume loss with elevated right hemidiaphragm. Fibrotic parenchymal bands were seen in the right middle lobe with fibrous septa attached to the diaphragm. There were no intra-parenchymal le- sions present (Figure 2). Inflammatory markers were not elevated with the ESR of 07 mm and the CRP level below 3.0 mg/dL. Clot - ting profile and liver function tests were within normal ranges. Serum LDH level was 437 U/L (140 - 280 U/L). Autoimmune marker panel including ANA and RF was negative. HIV, hepatitis and syphilis serological screen - ings were also negative. The USS of abdomen was nor- mal and there was no clinical or radiographic evidence of pelvic endometriosis. bia, and the vagina [6]. TES is a distinct category with the presence of functional endometrial tissue in or around the lung. TES has four main clinical subtypes: catamenial pneumothorax, catamenial haemorrhagic effusion, hae- moptysis and pulmonary nodules. This case discusses the importance of thoroughly in- vestigating a haemorrhagic effusion in a setting where the prevalence of TB is high and the dilemma in diagno- sis and management in the presence of TES. Care Report A 43-year-old unmarried Sri Lankan woman working in Maldives was referred to the Respiratory Medicine unit of the National Hospital of Sri Lanka. She was di - agnosed with a right sided pleural effusion in the chest X-ray performed during her annual medical screening. she had been asymptomatic preceding this incident and thereafter. An abnormality was detected in her chest X-ray one year prior to this incident but she had not been further evaluated. Her previous chest X-ray was not available but according to her, it was also a right sided abnormality. She had never smoked, and her fam- ily history was not significant for any specific medical illness. There were no clinical clues to suspect an immu- nocompromised status. On examination, she was apparently healthy with a BMI of 22 Kg/m 2. Respiratory examination was compati- ble with a moderate right sided pleural effusion. Repeat chest X-ray confirmed the persistence of an encysted ef- fusion (Figure 1). Based on the clinical picture it was de- cided to continue with ATT on empirical basis which had already been started in Maldives. She was on isoniazid (10 mg/kg), rifampicin (15 mg/kg), pyrazinamide (35 mg/ kg) and ethambutol (20 mg/kg) and we converted it to multidrug combination tablets. Further diagnostic inves- tigations were planned to explore the definite diagnosis. Figure 1: Postero-anteror (a) and lateral (b) chest X-rays of the patient shows the pleural effusion. Lateral chest X-ray showed ‘rock of Gibraltar sign’(arrow) which is characteristic of subpulmonic effusions. Figure 2: Contrast CT of the thorax (single section is shown) shows a right sided pleural effusion. ISSN: 2378-3516 DOI: 10.23937/2378-3516/1410082 • Page 3 of 5 • Bataduwaarachchi et al. Int J Respir Pulm Med 2018, 5:082 and microbiological analysis. Cytology revealed reac - tive mesothelial cells. Histology confirmed endometrial tissue with abundant well-formed glandular structures confirming the diagnosis of TES (Figure 4). Microbio - logical testing was negative for TB in the Thoracoscopy samples. The patient was referred to a Gynaecologist for fur- ther treatment for TES and ATT was continued as a case of latent TB after discussing at the multidisciplinary meeting. Currently, she is on hormonal treatment with monthly intra-muscular medroxy progesterone acetate 150 mg injections and so far, six doses have been given. Her most recent chest X-ray shows no progression of the effusion. The ATT course is finished with two months of intensive phase (with 4 drugs) and four months of con - tinuation phase (with 2 drugs). She will be followed up The pleural fluid analysis was exudative in type with abundant RBCs and predominant neutrophils (Table 1). It also showed undefined cells in significant amounts. The direct smears of pleural fluid were negative for AFB. ADA level in the pleural fluid was marginally elevated. However, the GeneXpert MTB/RIF test of the pleural fluid was negative. Sputum examination was negative for AFB. Her Mantoux reading was 14 mm which is significant in the context of previous BCG vaccination. She underwent fibro-optic bronchoscopy which did not reveal any en- dobronchial lesions followed by diagnostic thoracosco - py. Haemorrhagic fluid was noted in the right pleural cavity. There was abundant adhesion formation at the right costo-diaphragmatic angle suggestive of a chron - ic inflammatory process. Characteristic blueberry spots were noticed on the diaphragmatic pleura (Figure 3). We suspected TES at this point but were not confi - dent enough to exclude tuberculosis. Brush, wash and biopsy samples were sent for cytological, histological Figure 3: Thoracoscopic view of the diaphragmatic and parietal pleura. Islands of vascular areas interspersed with haemor- rhagic spots (a) on the parietal surface of the pleura along with multiple soft cyst-like nodules (b) on the diaphragmatic and visceral pleural surfaces. Figure 4: Histology of the pleural biopsy shows well-formed endometrial type glands lined by a columnar epithelium bear- ing regular nuclei, surrounded by endometrial type stroma. The glands and stroma show bland nuclear features. Findings are compatible with endometriosis of the pleura. Table 1: Pleural fluid analysis results from pleural aspiration. Parameter Result Appearance Blood stained pH 8.0 Glucose 99.3 mg/dL Protein 48.1 g/L LDH 954.4 U/L Cholesterol 129.4 mg/dL Pleural fluid haematocrit Blood haematocrit 25.5 40.1 ADA 56 U/L Leucocytes 568 per cu mm Polymorphs 50% Lymphocytes 20% Undefined cells 30% ISSN: 2378-3516 DOI: 10.23937/2378-3516/1410082 • Page 4 of 5 • Bataduwaarachchi et al. Int J Respir Pulm Med 2018, 5:082 co-exist with other pulmonary pathologies. Therefore, invasive investigations are justified early in the course of management. Diagnostic thoracoscopy and sampling is the best approach in an undiagnosed effusion with controversial findings. This case highlights the importance of Thora - coscopy for the rapid diagnosis of TES presenting as an effusion due to its characteristic macroscopic appear- ances such as red lesions, and endometriotic spots [16]. Early Thoracoscopy has an additional advantage of pro- viding the option for draining pleural fluid completely without leaving any radiological stigmata such as pleu - ral thickenings. It will also provide the option to perform surgical interventions such as curettage or pleurodesis for endometriosis following a timely histology report. However, this is debatable as it has not been properly assessed in controlled clinical trials but is an area which needs further investigations. Reasons for the silent nature of the TES in this case were not very clear which usually presents with month- ly cyclical symptoms in conjunction with menstruation [19]. Probably minor bleeding may have concealed with- in a fibrotic pocket under the subpulmonic area with - out irritating the pain sensitive parietal pleura. Release of chemical substances from the endometrial glands themselves to suppress pain is a theoretical possibility. Infrequent thoracic endometriosis without monthly re - crudescence could be a reason for silent presentations. Chronic cyclical inflammation leads to serious compli - cations if left unattended such as trapped lung due to pleural thickenings. Permanent stigmata on the chest X-ray can also cause problems in circumstances such as visa and job applications. Management of TES include medical and surgical treatment modalities. Suppression of the ectopic en- dometrium by inhibiting ovarian oestrogen secretion by hormonal treatment such as oral contraceptive pills, progestins, danazol or GnRH analogues has been widely used [9,20]. It is recommended to try hormonal therapy as the first choice in mild to moderate disease. However, if the response is poor surgical intervention is required. Pneumothorax and haemothorax recur in greater than 50% of the patients despite hormonal treatment, sug- gesting that regression of the pathological process is not complete and or that recurrent embolisation from pelvic foci [21]. Surgical ablation, pleurodesis or pleu - rectomy can be tried if the medical treatment is failed. Occasionally, patients can be refractory to all of the above treatment modalities. These patients respond to hysterectomy with bilateral salpingoophorectomy [22]. However, hormonal therapy should be continued to prevent recurrences following surgical treatment [23,24]. More evidence-based guidelines are required in future regarding the diagnosis and treatment of TES and multidisciplinary decision making will greatly help when managing complicated patients. by the Gynaecologist monthly and by the respiratory team six monthly. If there is any symptomatic or radio - logical progression plan is to evaluate further with a CECT scan of the thorax to decide on VATS and ablation or pleurodesis.

Endometriosis can affect up to 15% of women in their reproductive years [7,8]. The mean age at presentation of TES is 35 years. Peak incidence for TES is reported between 30 and 34 years. Pneumothorax was the most common presentation (73%), followed by hemothorax (14%), hemoptysis (7%), and lung nodules in (6%) in a large case series of 110 patients. The right hemithorax was involved in more than 90% of all manifestations which is compatible with our patients’ presentation. Hemothorax was more often associated with the pres- ence of pleural and pelvic endometriosis compared with other manifestations (P < 0.003, P < 0.02) [9]. Although pelvic endometriosis was not present in our patient she need to be followed up for future occurrence. In a setting where pulmonary tuberculosis is endemic, TES causes diagnostic confusion in the absence of positive microbiological evidenced for TB. Therefore, timely clin- ical judgement and selecting the correct line of investi- gations are mandatory. Our patient had a neutrophil predominant effusion. Although, lymphocyte predominant pleural effusions are more common with pleural TB, neutrophil predom- inance does occur in tuberculous effusions [10]. Mar- ginally high ADA levels in the pleural fluid can cause diagnostic difficulties in the absence of microbiological confirmation for TB. ADA levels can be elevated in any chronic inflammatory process [11]. ADA levels > 50 IU/L support the diagnosis of TB in high prevalence areas, but do not exclude or differentiate tuberculosis from other diagnoses. Pleural fluid ADA has a high sensitivity (99%) but a lower diagnostic accuracy (75%) especial- ly in the presence of chronic inflammatory disorders of the pleura [12,13]. On the other hand, the presence of reactive mesothelial cells in the pleural fluid in our case is against the diagnosis of pleural tuberculosis [14]. Her Mantoux reading was 14 mm and it was just below the cutoff for a patient with previous BCG vaccination (cut off - 15 mm). Mantoux test is a sensitive but non-spe - cific test in the diagnosis of active tuberculosis [15]. Effusions in the subpulmonic space are less evident in clinical examination and in chest radiography. CECT tho- rax is a very useful investigation in this context. Thoracic imaging seems less useful as a definitive diagnostic tool in the diagnosis of TES as it does not have a characteris- tic radiological pattern [16]. In an endemic area where latent tuberculosis is common, it is mandatory to ex- clude active tuberculosis by other investigations in the presence of a significantly positive Mantoux reading. Empirical ATT is an acceptable practice in this context for patients in endemic areas [17, 18]. Tuberculosis can ISSN: 2378-3516 DOI: 10.23937/2378-3516/1410082 • Page 5 of 5 • Bataduwaarachchi et al. Int J Respir Pulm Med 2018, 5:082 5. 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TES should always be suspected in a woman of re - productive age group presenting with prolong or recur- rent haemorrhagic effusion especially on the right side. TB is an important diagnostic consideration in any pleu- ral effusion in endemic areas which can cause diagnostic and treatment dilemma in the absence of microbiolog - ical confirmation in the presence of other overlapping pulmonary pathologies. Early thoracoscopy is a useful diagnostic and treatment option in pleural TB as well as TES. Ethics Approval and Consent to Participate Written consent was obtained from the patient use clinical data and images for research purposes. Consent for Publication Written consent was obtained from the patient for publication. Competing Interests The authors declare that they have no competing in- terests.

The authors acknowledge the staff at the Depart- ment of Pathology, National Hospital of Sri Lanka for their help for histological analysis and the staff of the Radiology Department of the National Hospital of Sri Lanka for help in radiological studies. Authors Contributions VRB conceived the report and wrote the manuscript; CW coordinated patient management and presented the case in the multidisciplinary meeting; JJ helped in the management and follow up of the patient; AS per- formed bronchoscopy and Thoracoscopy in the patient; RC analysed the histological material and critically read the manuscript; KG took management decisions. All the authors have read and approved the final manuscript. Funding Not applicable.

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