A 39-year-old Ugandan male was admitted to the tuberculosis (TB) ward of Mulago National Referral Hospital as a referral from a public hospital, for further investigations and treatment following long-standing history of cough and B-symptoms lasting over a period of 1 year despite completion of TB treatment for smear-positive drug-sensitive pulmonary TB (PTB). The patient was first diagnosed with smear-positive PTB at the public hospital, where he was initiated on TB treatment as a new case, with 2 months of isoniazid (H), ethambutol (E), rifampicin (R), and pyrazinamide (Z) for the intensive phase and 4 months of rifampicin(R) and isoniazid (H) for the continuation phase (2HERZ/4RH), according to Uganda National TB Treatment Guidelines [7], which he took to completion. However, despite completion of the recommended 6-month TB treatment regimen, the cough persisted and the patient continued to get B-symptoms, with occasional difficulty in breathing. Following a positive sputum smear at completion of the 6-month TB regimen, the attending clinician at the public hospital made a clinical decision to extend the continuation phase of the TB treatment (RH) for another 2 months, which the patient took without any registered improvement. He was then referred to Mulago National Referral Hospital for further management.
At the initial visit to the TB clinic of Mulago Hospital, the patient reported a persistent productive cough with yellow sputum and B-symptoms despite taking first-line TB treatment for almost 8 months. He also reported general malaise, right chest pain, and shortness of breath, but no wheezing. Physical examination revealed a sick young male, wasted (body weight 44 kg with body mass index (BMI) of 15 kg/m2). His body temperature was 36.7 °C, and he had mild pallor of mucus membranes but without lymphadenopathy or pedal edema. He had tachycardia of 123 beats/minute with normal blood pressure of 110/70 mmHg. Respiratory examination revealed features suggestive of cavitation (amphoric breathing on auscultation) and a pneumothorax (hyperresonant percussion note with absent breath sounds) on the right hemithorax, which was further confirmed on chest X-ray (CXR) (Fig. 1a). Auscultation of the precordium revealed normal heart findings. An Xpert MTB/RIF test performed on a spot sample was positive for Mycobacterium tuberculosis (Mtb) with rifampicin resistance (Fig. 2), and smear microscopy on fluorescence microscopy on the same sample was also positive for acid-fast bacilli (AFB) grade 2+. Following these tests, a diagnosis of MDR-TB complicated by right pneumothorax was made, with a plan to initiate the patient on MDR-TB treatment following pretreatment assessment and investigations and to immediately relieve the pneumothorax by insertion of a chest tube (also known as underwater seal drainage). The chest tube was immediately inserted to relieve the pneumothorax in the right hemithorax, which significantly reduced, as shown on the check CXR following chest tube removal (Fig. 1b). An early-morning sample taken a day following admission revealed positive Mycobacterial Growth Indicator Tube (MGIT) and Lowenstein–Jensen (LJ) cultures for MTB with confluent growth, although the TB culture results were received several days after the initial confirmation of the diagnosis of MDR-TB on Xpert MTB/RIF test. According to the TB guidelines, presence of rifampicin resistance on a positive Xpert MTB/RIF test is indicative of MDR-TB. Line probe assay, HAIN GenoType MTBDRplus, and HAIN GenoType MTBDRsl further confirmed Mtb complex with resistance to rifampicin and isoniazid but susceptibility to second-line TB drugs, i.e, fluoroquinolones (FLQ) (ofloxacin and moxifloxacin) and injectables (kanamycin, amikacin/capreomycin, and viomycin).
All routine pre-MDR-TB treatment investigations were normal except for mild normocytic normochromic anemia (hemoglobin level 10.2 g/l) and sinus tachycardia with mild right axis deviation on electrocardiogram. Viral hepatitis B and C screening was performed as part of pre-MDR-TB treatment preparation and found to be negative. Renal function tests, liver function tests, serum electrolytes, urinalysis, audiometry, visual, and color tests were all normal. The CD4 cell count was 625 cells/µL, and HIV viral load was undetectable on RNA polymerase chain reaction (PCR).
Regarding MDR-TB treatment, the patient was enrolled into an ongoing clinical trial on the TB ward of Mulago Hospital, in which he was initiated on a bedaquiline-based regimen which is superior when compared with standard of care as described in the Uganda National TB diagnosis and treatment guidelines [7] at the time. The MDR-TB treatment regimen that the patient was given included bedaquiline, high-dose isoniazid, prothionamide, clofazimine, ethambutol, levofloxacin, and pyrazinamide. In addition, the patient was given pyridoxine tablets to minimize isoniazid side effects, particularly isoniazid-induced neuropathy. Due to potential undesired efavirenz–bedaquiline drug interactions, the patient’s anti-retroviral therapy (ART) regimen was switched from tenofovir/lamivudine/efavirenz, which he had taken for 6 years, to a second-line ART regimen including tenofovir/lamivudine/lopinavir/ritonavir. The second-line ART regimen was believed to be better tolerable and was permissible for the TB trial. The patient also continued to take regular cotrimoxazole prophylaxis for opportunistic HIV infections. Serial CD4 cell counts and viral load tests performed as part of the patient’s HIV treatment monitoring indicated that he had sustained viral suppression, and his CD4 cell count ranged between 600 and 700 cells/µL. A month later, there was improvement in the pneumothorax with evidence of lung expansion on CXR (not shown).
Two months following MDR-TB treatment that was taken regularly under directly observed therapy (DOT), the patient still reported persistent cough with purulent sputum, and on and off low-grade fevers, although the excessive sweats and anorexia had subsided. The patient also reported persistent right chest pain, easy fatigability, and difficulty in breathing but no wheezing. On physical examination, the patient was dehydrated, and dyspneic with a respiratory rate of 27 breaths/minute and 91% oxygen saturation. He was febrile (T = 37.8 °C) and wasted (body weight 45 kg, BMI 15.5 kg/m2). Repeat CXR at this time (Fig. 1c) revealed a large cavity in the upper right lung field with features of a new hydro-pneumothorax on the same right hemithorax. There were no features to suggest tension pneumothorax on either physical examination or CXR. Aspiration of pleural fluid revealed empyema thoracis. The patient was thus diagnosed with recurrent pneumothorax and empyema thoracis in the right hemithorax.
As part of his management plan at the time, a cardiothoracic surgery team was immediately contacted for urgent assessment and management of the patient, and the surgeon promptly reinserted a chest tube. In addition, the patient was initiated on antibiotics, which included intravenous ceftriaxone and oral metronidazole for a period of 2 weeks, followed by a week of oral antibiotics with metronidazole and oral azithromycin. The patient reported slight improvement in symptoms, particularly difficulty in breathing and right chest pain, in the first few days after insertion of the chest tube. However, on daily monitoring of the chest tube drainage, persistent bubbling was noted after almost a week of insertion. A check CXR (Fig. 1d) was performed, which showed worsening pneumothorax and appearance of a new air–fluid level in the right hemithorax, despite presence of the chest tube. This was indicative of a possible communication between the bronchial tree and the pleural space. With the findings of persistent bubbling on chest tube drainage monitoring and increasing pneumothorax on check CXR, a chest computed tomography (CT) scan (Fig. 3) was performed, revealing a bronchopleural fistula in the right hemithorax. In addition, the chest CT scan showed a large pyo-pneumothorax with partial right middle and lower lung lobe collapse, a large thick-walled cavity in the residual right upper lobe, and mild mediastinal shift to the right side.
A diagnosis of an HIV-positive patient with MDR-TB complicated with a bronchopleural fistula and pyo-pneumothorax was made. The management for the pulmonary complications (bronchopleural fistula and pyo-pneumothorax) was taken over by the cardiothoracic surgeons, who maintained the chest tube drainage. The patient continued his MDR-TB treatment and ART as prescribed and was monitored for any complications that could arise from presence of a bronchopleural fistula, especially tension pneumothorax. The patient continued to be ill with respiratory symptoms, right chest pain, and occasional difficulty in breathing. Although a repeat CXR had indicated improvement in the pneumothorax after diagnosis of the bronchopleural fistula and management with a chest tube, a CXR (Fig. 1e) performed a month later showed recurring pneumothorax.
Concerning MDR-TB treatment, monthly monitoring of sputum with TB cultures indicated presence of culture conversion at approximately 4 months post MDR-TB treatment initiation. While on the ward, the patient continued to develop recurrent pneumothorax, possibly resulting from the bronchopleural fistula, despite the management he was receiving, until the family opted for his discharge from the ward against medical advice.
Notably, in the family and social history, it was discovered that the patient was in a HIV-discordant relationship (his wife being HIV negative) and had four children who lived with him in a small, one-roomed house. The patient reported taking moderate alcohol, mainly a local gin called waragi, until 2 months prior to the current readmission, when he stopped because he believed that the persistent cough was resulting from his social habits. The household contacts were traced and screened for TB as well. None of the contacts were found to have active TB. The patient received counseling about his social habits and possible ways to avoid transmission of MDR-TB to his contacts, especially his immediate family.
