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Review 3: "Chronic Pulmonary Aspergillosis Incidence in Newly Detected Pulmonary Tuberculosis Cases during Follow-up"

Reviewers were mixed, with some finding the study well-written and important while others had concerns about generalizability, misclassification of CPA/TB, and interpretability of findings.

Published onApr 09, 2024
Review 3: "Chronic Pulmonary Aspergillosis Incidence in Newly Detected Pulmonary Tuberculosis Cases during Follow-up"
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key-enterThis Pub is a Review of
Chronic pulmonary aspergillosis incidence in newly detected pulmonary tuberculosis cases during follow-up
Chronic pulmonary aspergillosis incidence in newly detected pulmonary tuberculosis cases during follow-up

Abstract Background Chronic pulmonary aspergillosis (CPA) is known to complicate patients with post-tubercular lung disease. However, some evidence suggests that CPA might co-exist in patients with newly-diagnosed pulmonary tuberculosis (P.TB) at diagnosis and also develop during therapy. The objective of this study was to confirm the presence of CPA in newly diagnosed P.TB at baseline and at end-of-therapy.Materials & Methods This prospective longitudinal study included newly diagnosed P.TB patients, followed up at third month and end-of-therapy with symptom assessment, anti-Aspergillus IgG antibody and imaging of chest for diagnosing CPA.Results We recruited 255 patients at baseline out of which 158 (62%) completed their follow-up. Anti-Aspergillus IgG was positive in 11.1% at baseline and 27.8% at end-of-therapy. Overall, proven CPA was diagnosed in 7% at baseline and 14.5% at end-of-therapy. Around 6% patients had evidence of aspergilloma in CT chest at the end-of-therapy.Conclusions CPA can be present in newly diagnosed P.TB patients at diagnosis and also develop during anti-tubercular treatment. Patients with persistent symptoms or developing new symptoms during treatment for P.TB should be evaluated for CPA.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.


Review: Airborne Aspergillus spores pose a constant exposure risk to humans, leading to the development of Aspergillus-specific antibodies in most individuals by adulthood. This widespread exposure contributes to the global prevalence of over three million people affected by chronic and allergic forms of pulmonary aspergillosis. Antibody testing is one of the cornerstones for the diagnosis of these conditions [1].

The diagnosis of chronic pulmonary aspergillosis (CPA) necessitates a combination of characteristics: consistent appearance in thoracic imaging (preferably by CT), direct evidence of Aspergillus infection or an immunological response to Aspergillus spp., and exclusion of some alternative diagnoses. Mycobacterial infection typically serves as the main differential diagnosis for CPA, with pulmonary tuberculosis (TB) or non-tuberculous mycobacterial (NTM) infection potentially preceding, following, or occurring concurrently with CPA [1]. 

This study by Jha D. et al. poses diagnostic challenges, as only 160 out of 255 patients diagnosed with pulmonary TB were microbiologically confirmed. It remains unclear how many of the remaining 95 patients diagnosed based on clinical and imaging findings without bacteriological confirmation actually had CPA without tuberculosis. The authors also do not specify how many of the 18 patients classified as having CPA had bacteriological confirmation of tuberculosis. Additionally, the initial imaging assessment relied solely on chest radiography, which may inaccurately estimate certain lesions such as pulmonary emphysema and may struggle with differential diagnoses between cavities and cystic bronchiectasis.

Pulmonary samples for smear, mycobacterial nucleic acid amplification, and culture are crucial components of the differential workup for possible CPA. It's important to note that diagnosing a mycobacterial infection does not exclude CPA. Other potential differential diagnoses include necrotizing lung cancer, pulmonary infarction, vasculitis, and rheumatoid nodules [1]. Aspergillus-specific IgG antibody serves as a useful diagnostic biomarker supporting CPA diagnosis, especially in resource-limited countries [2]. However, pulmonary TB and CPA are both progressive and debilitating parenchymal lung diseases with overlapping risk factors, symptomatology, and radiological findings, often resulting in misdiagnosis of either disease. 
The authors present these aspects as limitations of their study, but at the same time these limitations represent an important obstacle to achieving the proposed aim of the study "to confirm the presence of CPA in newly diagnosed P.TB at baseline and at end-of -therapy". 

The aim of the current study is ambitious and could potentially be achieved by evaluating pulmonary TB cases where CPA co-infection can be histologically confirmed. Chronic cough is frequently encountered in CPA, but its diagnostic accuracy hasn't been systematically studied. Given that cough lasting more than 2 weeks is also used as a screening symptom for TB, it seems counterintuitive not to consider chronic cough as a possible indicator of TB. The misdiagnosis of isolated CPA or CPA-TB coinfection can be attributed, in part, to the low sensitivity and specificity of conventional testing methods.

This study faces numerous uncertainties, and while it's widely recognized that CPA can be mistaken for or coexist with TB, or even arise as a complication following anti-TB therapy, only a few prospective cohort studies have explored the progression, spontaneous resolution, and emergence of new CPA cases during and after TB therapy [2-6]. Some of these studies have focused solely on cases with bacteriologically proven pulmonary TB [3]. For instance, Kim et al. exclusively included patients with bacteriologically proven pulmonary TB and observed the development of CPA in 2.9% of patients during post-treatment follow-up.

Setianingrum et al. [6] in the Indonesian cohort employed comparable diagnostic criteria for CPA as those utilized by Jha D. et al. in the Indian cohort. However, an important distinction were noticed between the cohorts regarding the prevalence of cavitary syndrome evident on chest radiography. Specifically, 92% of patients in the Indonesian cohort exhibited cavitary syndrome [6], whereas only 29% of patients in the Indian cohort displayed similar radiographic findings. This difference raises concerns regarding whether the cases classified as CPA in the Indian cohort truly align with the diagnostic criteria for CPA.

Currently, there is a lack of comprehensive data regarding the co-occurrence of CPA and pulmonary TB, as well as the progression of CPA during and after pulmonary TB treatment. Further research is needed to elucidate the epidemiology, clinical characteristics, and optimal management approaches for individuals with concurrent or sequential diagnoses of pulmonary TB and CPA.

  1. Denning, D.W., et al., Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J, 2016. 47(1): p. 45-68.

  2. Salzer, H.J.F., et al., Seroprevalence of Aspergillus-Specific IgG Antibody among Mozambican Tuberculosis Patients. J Fungi (Basel), 2021. 7(8).

  3. Kim, C., et al., Serological Changes in Anti-Aspergillus IgG Antibody and Development of Chronic Pulmonary Aspergillosis in Patients Treated for Pulmonary Tuberculosis. J Fungi (Basel), 2022. 8(2).

  4. Oladele, R.O., et al., Prospective Evaluation of Positivity Rates of Aspergillus-Specific IgG and Quality of Life in HIV-Negative Tuberculosis Patients in Lagos, Nigeria. Front Cell Infect Microbiol, 2022. 12: p. 790134.

  5. Page, I.D., et al., Chronic pulmonary aspergillosis commonly complicates treated pulmonary tuberculosis with residual cavitation. Eur Respir J, 2019. 53(3).

  6. Setianingrum, F., et al., A prospective longitudinal study of chronic pulmonary aspergillosis in pulmonary tuberculosis in Indonesia (APICAL). Thorax, 2022. 77(8): p. 821-828.

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