Smear- and Polymerase Chain Reaction (PCR)-Negative Tuberculosis: A Case Series Highlighting Diagnostic Limitations and the Role of Escalation

Tuberculosis (TB) remains a major global health concern, and its diagnosis can be particularly challenging when microbiological tests yield negative results. We present two diagnostically complex cases, one pulmonary and one pleural, in which tuberculosis was confirmed only after extended clinical evaluation and diagnostic escalation, resulting in delays of approximately eight weeks and two weeks, respectively. The first patient, a 31-year-old asymptomatic man with recent TB exposure, underwent bronchoalveolar lavage (BAL), with smear microscopy and polymerase chain reaction (PCR) both negative; cultures remained negative after eight weeks. He was later readmitted with hemoptysis, and repeat BAL ultimately yielded a positive culture for <i>Mycobacterium tuberculosis</i>, despite persistently negative PCR. The second patient, a 22-year-old woman presenting with pleuritic chest pain and a large unilateral pleural effusion, had markedly elevated inflammatory markers and exudative fluid on thoracentesis. Initial smear, PCR, and bronchoscopy were inconclusive. A definitive diagnosis of pleural TB was established only after thoracoscopic biopsy revealed necrotizing granulomatous inflammation. In both cases, early identification of bacterial co-infections contributed to diagnostic delay. These cases highlight the limitations of conventional diagnostics in both pulmonary and pleural TB, particularly in smear- and polymerase chain reaction (PCR)-negative presentations. They underscore the importance of clinical vigilance and timely escalation to tissue-based diagnostics, including repeat bronchoscopy and thoracoscopy, when initial evaluations are non-diagnostic. A structured, multimodal approach is essential to minimize diagnostic delays and ensure early initiation of appropriate therapy.