A 78-year-old man with underlying hypertension presented to the emergency department with dry cough, loss of weight and intermittent fever for two months with recent progressive shortness of breath for the past two weeks. He was normotensive and apyrexial, and not tachycardic. He had a normal oxygen saturation of 98% under room air but was mildly tachypnoeic (respiratory rate of 21 breaths per minute). Clinically, he appeared cachexic. Chest radiograph showed bilateral nodular and airspace opacities with left mid zone consolidation (Fig. 4A). NPOP sample sent for COVID-19 polymerase chain reaction testing was positive, and he was admitted for isolation and treated with oral favipiravir. ATT was immediately commenced in view of suggestive chest radiograph and constitutional symptoms. Subsequently, sputum smear examination was positive for acid fast bacilli. Chest radiograph on day 14 of admission showed partial resolution of the left mid zone consolidation with residual nodular opacities (Fig. 4B). He was discharged well to continue his TB treatment as an outpatient. He did not require oxygen supplementation throughout his admission.
Individuals with active PTB are at higher risk of contracting COVID-19 due to alterations in lung immunity driven by attenuated interferon-gamma host response to SARS-CoV-2 virus. Meanwhile, reactivation of latent TB in the setting of COVID-19 infection is plausible, given that the two diseases augment each other with a transient decrease in cellular immunity. Meta-analysis showed that the summary proportion of active PTB among COVID-19 patients is higher than WHO estimates for annual incidence of tuberculosis in high tuberculosis burden countries such as China, India, Nigeria, Philippines, and South Africa. This is not surprising, given that both COVID-19 and PTB spread through airborne transmission of close contacts. Furthermore, stay-at-home recommendations and national lockdown policies may have exacerbated crowded living conditions among underprivileged communities.
A large meta-analysis of 43 studies by Aggarwal et al. showed that patients with active PTB and COVID-19 carried a two-fold higher relative risk of death, which was comparable to relative risk of mortality in COVID-19 patients with diabetes, hypertension, and cardiovascular diseases. In resource-limited settings, poverty and malnutrition might play an important role in increasing morbidity and mortality. The proportion of PTB in our cohort of COVID-19 patients is 0.6%, or 3 out of 498 cases, presenting over a span of five months. This proportion is not generalizable as this was a single-centre study conducted in a limited time frame and did not include the entirety of COVID-19 patients admitted to non-tertiary quarantine centres or other tertiary hospitals in the state.
This case series represents varying scenarios in which TB might present in the setting of COVID-19. One of the uncommon forms of pulmonary tuberculosis is endobronchial TB, as described in the case of patient 1. While PTB commonly presents with cough (88%), loss of weight (58.1%), loss of appetite (57.3%), fever (56.4%), night sweats (30%), and haemoptysis (30%), endobronchial TB tends to present with dry cough, chest discomfort, and less commonly, wheezing or stridor in the presence of bronchial stenosis. Further obscuring the diagnosis of TB are the shared x-ray abnormalities of endobronchial TB and COVID-19. Endobronchial TB may present as patchy parenchymal infiltrates, consolidations, segmental and lobar collapse, bronchiectasis, and consolidation while COVID-19 present as ground glass opacities, coarse linear opacities, and consolidations.
CT may prove essential in differentiating endobronchial TB and COVID-19. Endobronchial TB tends to present with centrilobular nodules, tree-in bud appearance, consolidations, thickening of the bronchial wall and interlobular septa, while COVID-19 tends to show ground glass opacities (GGO), intralobular septal thickening, consolidations, and parenchymal bands. Interestingly, in one case series, nearly half the HRCT in coinfection cases had no TB characteristic changes. In the absence of CT, lung ultrasonography may prove useful - one small study demonstrated that COVID-19 subpleural lesions differed significantly from similar ones observed in bacterial pneumonia, pulmonary abscess, tuberculosis, atelectasis, and cardiogenic pulmonary edema. However, whether tuberculosis changes can be differentiated from COVID-19 on LUS has yet to be demonstrated.
Resolution of GGO tends to occur after day fourteen of diagnosis of COVID-19, whereas consolidation and intralobular septal thickening tend to persist. By 2 months post-COVID diagnosis, a third of COVID-19 patients showed complete resolution, while nearly half had residual parenchymal bands. Similarly in our patient, the repeated CT on day 40 showed resolution of her initial consolidation and septal thickening. There are no known studies on the short-term effect of TB treatment on CT abnormalities in endobronchial TB. One study demonstrated complete resolution of changes in 60% (33 out of 55) of patients after treatment course completion. Nodules (inter and intra-lobular) are not a common CT feature of COVID-19 infection, hence should raise suspicion of an alternate diagnosis, such as TB. The differences between the two CTs in patient 1 may demonstrate not only the resolution of COVID disease, but also an unmasking of underlying endobronchial TB.
Patient 2 illustrates a case of severe COVID-19 complicated by hospital acquired pneumonia with posthumous diagnosis of smear-negative, culture-positive PTB. The absence of acid-fast bacilli on respiratory samples may have reflected poor sampling quality or low tuberculous load in the lungs. The use of high dose steroids has been associated with TB reactivation; our patient was given dexamethasone for the treatment of COVID-19 infection which may have contributed to a worsened outcome. Given her constitutional symptoms and initial chest radiograph showing unilateral pleural effusion, follow-on rapid diagnostic methods like Xpert MTB/RIF may have contributed to a more favourable outcome in this case by ensuring early commencement of ATT. Xpert MTB/RIF has been quoted to have a detection rate of 95%. Another method is interferon-gamma release assay (IGRA) (QIAGEN, https://www.qiagen.com), which has been reported to pick up TB in Xpert MTB/RIF negative cases. While several countries have proposed bidirectional screening of COVID-19 and PTB, implementation is difficult in resource-limited settings. In resource-limited settings, we propose sputum smear for acid-fast bacilli as preliminary screening in COVID-19 patients with high risk for PTB.
Finally, patient 3 illustrates a clinical scenario that allows for a high index of suspicion for TB, and thus, early commencement of ATT. A history of chronic loss of weight and fever is not a feature of acute COVID-19 infection and warrants further investigation for TB. The resolution of changes on chest radiograph after two weeks may reflect either resolution of COVID-19 infection or response to ATT, nevertheless, a repeat chest radiograph and sputum examination after treatment course is warranted.