18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in Patients with Non-Tuberculous Mycobacterial Infections

Following a recent article in this journal, 1 Yang J. Kong J. Li B. Ji Z. Liu A. Chen J. et al. Seventy years of evidence on the efficacy and safety of drugs for treating leprosy: a network meta-analysis. J Infect. 2023; S0163–4453 (Epub ahead of print)https://doi.org/10.1016/j.jinf.2023.02.019 Google Scholar we would like to point out the importance of applying new tools in the management of non-tuberculous mycobacteria (NTM). These are widespread microorganism that can lead to significant morbidity and mortality in selected hosts. 2 Cowman S. van Ingen J. Griffith D.E. Loebinger M.R. Non-tuberculous mycobacterial pulmonary disease. Eur Respir J. 2019; 541900250https://doi.org/10.1183/13993003.00250-2019 Google Scholar Pulmonary localization is the commonest site for NTM infection characterizing NTM lung disease (NTM-LD); it has been identified in patients with cystic fibrosis (CF), bronchiectasis and in those with HIV/AIDS. 2 Cowman S. van Ingen J. Griffith D.E. Loebinger M.R. Non-tuberculous mycobacterial pulmonary disease. Eur Respir J. 2019; 541900250https://doi.org/10.1183/13993003.00250-2019 Google Scholar Furthermore, with the increase in primary or secondary immune dysfunctions, the susceptible pool of individuals is continuously increasing. 2 Cowman S. van Ingen J. Griffith D.E. Loebinger M.R. Non-tuberculous mycobacterial pulmonary disease. Eur Respir J. 2019; 541900250https://doi.org/10.1183/13993003.00250-2019 Google Scholar Despite specific guidelines based on clinical, radiological and microbiological criteria symptoms are poorly specific and late diagnosis common. 3 Daley C.L. Iaccarino J.M. Lange C. Cambau E. Wallace Jr, R.J. Andrejak C. et al. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Clin Infect Dis. 2020; 71: e1-e6https://doi.org/10.1093/cid/ciaa241 Google Scholar Specific features, markers and tools are lacking in increasing the diagnosis yield, in predicting clinical outcomes and response to therapy. These issues are of outmost importance since anti-NTM treatment is long, poorly tolerated and incompletely effective. 2 Cowman S. van Ingen J. Griffith D.E. Loebinger M.R. Non-tuberculous mycobacterial pulmonary disease. Eur Respir J. 2019; 541900250https://doi.org/10.1183/13993003.00250-2019 Google Scholar , 4 Lipman M. Cleverley J. Fardon T. Musaddaq B. Peckham D. van der Laan R. et al. Current and future management of non-tuberculous mycobacterial pulmonary disease (NTM-PD) in the UK. BMJ Open Respir Res. 2020; 7e000591https://doi.org/10.1136/bmjresp-2020-000591 Google Scholar Additionally, the risk of relapse and/or reinfection is significant and this increases the challenge of deciding who should receive antibiotics for treating NTMs. 2 Cowman S. van Ingen J. Griffith D.E. Loebinger M.R. Non-tuberculous mycobacterial pulmonary disease. Eur Respir J. 2019; 541900250https://doi.org/10.1183/13993003.00250-2019 Google Scholar , 3 Daley C.L. Iaccarino J.M. Lange C. Cambau E. Wallace Jr, R.J. Andrejak C. et al. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Clin Infect Dis. 2020; 71: e1-e6https://doi.org/10.1093/cid/ciaa241 Google Scholar , 4 Lipman M. Cleverley J. Fardon T. Musaddaq B. Peckham D. van der Laan R. et al. Current and future management of non-tuberculous mycobacterial pulmonary disease (NTM-PD) in the UK. BMJ Open Respir Res. 2020; 7e000591https://doi.org/10.1136/bmjresp-2020-000591 Google Scholar 18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET), is a nuclear medicine technique assuring both good spatial definition and measuring of the functional activity of a radiological finding. It is increasingly available and routinely performed, both in the diagnostic and follow-up process of oncological, autoimmune and infectious diseases. 5 Kung B.T. Seraj S.M. Zadeh M.Z. Rojulpote C. Kothekar E. Ayubcha C. et al. An update on the role of 18F-FDG-PET/CT in major infectious and inflammatory diseases. Am J Nucl Med Mol Imaging. 2019; 9: 255-273 Google Scholar Different tracers exist, allowing specific analysis and further characterization of radiological findings. Additionally, FDG-PET performed for differential diagnosis has shown promising results in the assessment of patients with pulmonary tuberculosis (TB) 6 Sánchez-Montalvá A. Barios M. Salvador F. Villar A. Tórtola T. Molina-Morant D. et al. Usefulness of FDG PET/CT in the management of tuberculosis. PLoS One. 2019; 14e0221516https://doi.org/10.1371/journal.pone.0221516 Google Scholar : a good sensitivity for diagnosis and a fair association with disease activity/severity and have been shown in patients TB. 5 Kung B.T. Seraj S.M. Zadeh M.Z. Rojulpote C. Kothekar E. Ayubcha C. et al. An update on the role of 18F-FDG-PET/CT in major infectious and inflammatory diseases. Am J Nucl Med Mol Imaging. 2019; 9: 255-273 Google Scholar , 6 Sánchez-Montalvá A. Barios M. Salvador F. Villar A. Tórtola T. Molina-Morant D. et al. Usefulness of FDG PET/CT in the management of tuberculosis. PLoS One. 2019; 14e0221516https://doi.org/10.1371/journal.pone.0221516 Google Scholar Despite several differences, TB and NTMs share common features. These data could interestingly lead to a tailored use of FDG-PET in the patients with NTM-LD. This work aims to describe the features of patients with NTM-LD who underwent FDG-PET for any clinical indication at our center. We performed a secondary analysis of a prospective observational cohort study including adult (≥18 years of age) patients with NTM-LD followed at the Amedeo di Savoia Hospital (Turin, Italy) who underwent FDG-PET/CT between 2015 and 2021. All patients were part of the prospective study from the Italian Register of pulmonary Non-tuberculous mycobactEria (IRENE), which comprises more than 900 NTM patients. 7 Aliberti S. Codecasa L.R. Gori A. Sotgiu G. Spotti M. Di Biagio A. et al. IRENE Network. The Italian registry of pulmonary non-tuberculous mycobacteria - IRENE: the study protocol. Multidiscip Respir Med. 2018; 13: 33https://doi.org/10.1186/s40248-018-0141-8 Google Scholar Informed consent was obtained from all participants included in the study. We evaluated demographic, clinic, radiological and therapeutic characteristics of our population. Patients underwent F-FDG PET/CT using a whole-body scanner according to standard operating procedures. Images were acquired with 3 General Electric PET/CT scans (Discovery ST-E, Discovery IQ, Discovery MI) using a dose of 18 F-fluorodeoxyglucose based on the patient’s weight. CT scans without contrast were also performed. Images were interpreted qualitatively and semi-quantitatively with the standardized uptake value (SUV) by an experienced radiologist in nuclear medicine. A total of 20 patients with NTM-LD were identified: features of the study population are reported in Table 1. All isolated NTM were sensitive to both macrolides and aminoglycosides, with M. abscessus showing inducible resistance to macrolides. Only one patient had a concomitant sputum culture for Pseudomonas aeruginosa. Twelve (60%) patients performed a base spirometry with FEV1 being above 80% predicted in eleven of them (11/12, 91.7%). The median (IQR) FEV1% prediction was 85% (IQR 81%−108%). Four patients performed 2 FDG-PET, two performed 3 FDG-PET and one patient 6 FDG-PET. The main reasons were differential diagnosis (particularly malignancies, in 15 patients, 75%). FDG-PET showed a median of 2 (2−3) positive pulmonary lesions with a diameter of 8 (5.8–10.3) mm. Median SUV max was 4.2 (IQR 3.6–5.3, with the minimum of 2.4 and the maximum of 8.6). We found no difference in SUV max according to demographic, radiological and clinical patients’ variables nor to different NTM species (MAC vs. Non-MAC). At univariate regression model, only asthma (p = 0.035) and HIV co-infection (p = 0.023) were independently associated with a significantly increased number of FDG-PET positive pulmonary lesions. We collected data on FDG-PET scans in patients with NTM-LD and observed that patients had a median 2–3 FDG-PET positive lesions with a SUV max between 2.4 and 8.6, which is in line to what is reported in previous case series/reports where median SUV max was 4.8 (with 1 to multiple positive lesions). 8 Del Giudice G. Bianco A. Cennamo A. Santoro G. Bifulco M. Marzo C. et al. Lung and nodal involvement in nontuberculous mycobacterial disease: PET/CT role. BioMed Res Int. 2015; : 1-8https://doi.org/10.1155/2015/353202 Google Scholar , 9 Demura Y. Tsuchida T. Uesaka D. Umeda Y. Morikawa M. Ameshima S. et al. Usefulness of 18F-fluorodeoxyglucose positron emissiontomography for diagnosing disease activity and monitoring therapeutic response in patients withpulmonary mycobacteriosis. Eur J Nucl Med Mol Imaging. 2009; 36: 632-639https://doi.org/10.1007/s00259-008-1009-5 Google Scholar Features of our study population did not differ from what has been reported in other cohorts, except for the high number of HIV patients in our series. We could not identify FDG-PET-specific differences between rapidly growing and slowly growing mycobacteria species nor between nodulary and cavitary disease. More frequently, FDG-PET exam was performed either for differential diagnosis or as follow-up of other conditions. Therefore, NTM-LD was in most cases diagnosed accidentally because of FDG-PET leading to subsequent analysis. Time of FDG-PET execution was not homogenous among our population. As expected, immune-suppressed patients showed more FDG-PET positive lesions. On the other hand, we could not identify an explanation for the finding of more pulmonary lesions in patients with asthma compared to others, although the use of inhalatory steroids should be assessed. As highlighted in a recent paper, radiomics may be useful for differentiating TB to NTM cavities and it may be applied to nuclear medicine imaging. 10 Yan Q. Wang W. Zhao W. Zuo L. Wang D. Chai X. et al. Differentiating nontuberculous mycobacterium pulmonary disease from pulmonary tuberculosis through the analysis of the cavity features in CT images using radiomics. BMC Pulm Med. 2022; 22: 4https://doi.org/10.1186/s12890-021-01766-2 Google Scholar In view of the complexity of NTM-LD, especially for the decision on whether starting antimycobacterial treatment or in case of relapse/reinfection, PET imaging may have a prominent role in the future, evaluating the presence of active lesions, and their relation to disease severity, microbiology and quality of life. Based on these observations, we suggest three possible scenarios for FDG-PET use in NTM: differential diagnosis, disease activity and treatment evaluation. Ideally, FDG-PET and SUVMax measurement should possibly be part of the baseline assessment for patients newly diagnosed with NTM-LD; that would allow a prospective comparison, also between NTM species. In conclusion, we described the largest case series of patient with NTM-LD undergoing FDG-PET. Prospective studies, possibly using alternative radiotracers, are warranted in order to investigate the role of nuclear medicine in the management of complex patients with NTM-LD. Table 1Clinical, demographic, microbiological and radiological features of the study population. Patients characteristicsN = 20 N or median Percentage or interquartile range Male sex 3 15% Age (years) 67.9 63.2–74.0 European ancestry 16 80% Body mass index (kg/m2) 19.7 15.2–22.8 Risk factors and clinical features:Active smokingPrevious smokingAlcohol abusePrevious tuberculosisHIV infectionMalignancyRheumatic disorders -Rheumatic arthritis -Psoriasis -Sjogren syndrome GERDDMDepressionAnxietyOsteoporosisCVd & AHT 3622833111816624 15%30%10%10%40%15%15%5%5%5%40%5%30%30%10%20% Pre-existing thoracic diseases:COPDAsthmaBronchiectasisChest wall deformity 1743106 85%20%15%50%30% SymptomsFeverProductive/Dry coughAstheniaDyspneaWeight lossHaemoptysis 5125182 25%60%25%5%40%10% Radiological patterns (CT)NodulesCavitationsBronchiectasis“Tree-in-Bud”ConsolidationPleural effusionRadiological patterns (PET)SUV MAXNumber of lesionsDiameter (mm) N13210751Median4.228 Percentage65%10%50%35%25%5%IQR; Min-MAX3.6–5.3; 2.4–8.62–3; 1–145.8–10.3; 5–11 Slow growing NTM isolates:M. aviumM. intracellulareOther species (M. celatum, M. lentiflavum, M. fortuitum, M. chimera, M. xenopi) N181035 Percentage90%50%15%25% Rapid growing NTM isolates:M. abscessus,M. fortuitum, 211 10%5%5% Open table in a new tab