18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging features in patients with non-tuberculous mycobacterial infection

doi:10.21203/rs.3.rs-1734507/v1

Download PDF

Research Article

¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography imaging features in patients with non-tuberculous mycobacterial infection

https://doi.org/10.21203/rs.3.rs-1734507/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Objectives: Non-tuberculous mycobacterial (NTM) infection is a growing public health concern. Due to atypical clinical symptoms and poorly defined radiological findings, NTM is often misdiagnosed, resulting in treatment delay. The aim of the present study was to analyze the findings of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan imaging in patients with NTM infection in order to improve the diagnosis and treatment of NTM disease.

Methods: A total of 23 patients with confirmed NTM infection who underwent ¹⁸F-FDG PET/CT scan imaging were retrospectively analyzed. The data on clinical and ¹⁸F-FDG PET/CT imaging characteristics were reviewed. The ¹⁸F-FDG PET/CT images were analyzed both qualitatively and quantitatively using maximum standardized uptake value (SUV_max), SUV_Max(the most FDG-avid lesion in the whole body), SUR_Liver andSUR_Blood (SUV_Max ratio of lesion-to-liver and lesion-to-blood pool). The optimal cut-off of ⁸F-FDG was determined using receiver operating characteristic curve (ROC).

Results: Subgroup analysis showed significant differences in metabolic parameters of ¹⁸F-FDG-avid lesions, including SUR_Liver, SUR_Blood, and SUV_Max among the three groups with different immunological states (p = 0.007, 0.012, and 0.010, respectively). The cut-off point of 3.8 for SUR_Liver showed the best equilibrium between sensitivity and specificity (52.9% and 83.3%). In terms of the NTM lesion distribution, there were significant differences in SUR_Liver, SUR_Blood, and SUV_Maxbetween the localized and disseminated groups (p = 0.003, 0.009, and 0.005, respectively). The cut-off point of 3.3 for the SUV_Blood had high specificity (87.5%) and sensitivity (71.4%). Furthermore, in terms of NTM lesion severity, SUV_maxof lung lesions (SUV_I-lung), SUV_maxof marrow (SUV_Marrow), and platelet count significantly differed between severe and non-severe groups (p = 0.036, 0.006, and 0.007, respectively). When the cut-off values of SUV_Marrowand SUV_I-lung were set at 3.1 and 4.6, the sensitivity was 76.9% and 76.9%, respectively, while the specificity was 88.9% and, 55.9%, respectively.

Conclusion: In patients with NTM infection, ¹⁸F-FDG PET/CT is a unique and powerful tool in the diagnosis and evaluation of disease activity, immunological state, and extent of lesion involvement and it can help determine the appropriate treatment for NTM infection.

Non-tuberculous mycobacteria

PET/CT

18F-FDG

SUR

Immunological states

Distribution

Disseminated infection

Non-tuberculous mycobacteria (NTM) are mycobacterium (M.) species other than M. leprae and M. tuberculous. NTM are prevalent in the environment, such as soil, dust, plants, water sources, foods, and animals, and are more likely to infect healthy individuals, including immunocompromised or immunocompetent individuals ^[1]. The disease caused by NTM has increased in prevalence in recent years; for instance, in the United States, it rose from 40 to 85 per 100,000 people between 2010 and 2014 ^[2]. In China, this disease has also gradually increased over the last 20 years ^[3]. There are already more than 170 NTM species reported ^[4]. Although there are many different types of NTM, they can be classified into two types based on their growth rate: rapid-growing mycobacteria (RGM) and slow-growing mycobacteria (SGM). RGM, such as Mycobacterium abscessus, Mycobacterium massiliense, and Mycobacterium bolletii, form colonies within 3–7 days on Löwenstein-Jensen media, but SGM, such as Mycobacterium avium and Mycobacterium intracellulare, take seven or more days or even several weeks ^[2]. SGM are the most common cause of human NTM infection ^[5].

Different categories of NTM may be more prevalent in specific natural geographic settings or niches, resulting in different clinical diseases in predisposed hosts and affecting various target organs or tissues ^[2]. NTM can cause a variety of clinical syndromes, ranging from lymphadenopathy to aseptic meningitis ^[6]. The most common clinical manifestation is lung infection secondary to NTM inhalation. Furthermore, extra-pulmonary NTM diseases, such as soft tissues, lymph nodes, or bone infections, can emerge as a result of NTM exposure ^[5]. However, there are no unique clinical manifestations of NTM diseases. Pulmonary NTM may be presented by coughing, expectoration, chest tightness, fever, or no symptoms ^{[7, 8]}, whereas extra-pulmonary NTM diseases may be presented by lymphadenitis, ulcer, granuloma, or abscess. NTM diseases are classified into four clinical types: (a) chronic pulmonary disease, (b) lymphadenopathy, (c) skin and soft tissues, and rarely bones and joints, and (d) disseminated diseases ^[6].Thus, the primary diagnostic methods are culture of clinical samples, NTM detection in body fluids, and/or histopathological examinations of tissue sections ^[9]. However, some of these methods are invasive, requiring the invasive acquisition of biopsies from the patients. In addition, the sensitivity and accuracy of these procedures are limited by sampling errors or contamination, as well as NTM heterogeneity in biopsy samples ^{[8, 9]}.

Computed tomography (CT) scanning enables a quantitative, repetitive, noninvasive examination of the entire course of NTM disease in patients, particularly for pulmonary NTM. However, the radiological features of NTM are not well defined. However, the most common radiological findings are bronchiectasis and solitary cavities or nodules. Therefore, based on the clinical and radiological features, NTM is frequently misdiagnosed as pneumonia, tuberculosis, and malignancy. Furthermore, according to the general NTM treatment guidelines, such as the Official ATS/ERS/JRS/ALAT Clinical Practice Guideline for Treatment of NTM in 2020 ^[10] and British Thoracic Society guidelines for the management of NTM pulmonary disease in 2017 ^[11], individuals may require a period of longitudinal assessment before treatment, including immunological state, the severity and risk of progressive NTM infection, and the extent of lesion involvement. Therefore, it is necessary to develop a valuable disease-specific activity and severity assessment tool ^[12].

¹⁸F-FDG PET/CT, a noninvasive and whole body imaging method, can reliably measure the pathological conditions characterized by infection and aseptic inflammation. In the fields of early identification of the source of infection or inflammation ahead of morphological changes, mapping the extent and severity of disease, and assessing therapy response, ¹⁸F-FDG PET/CT imaging outperforms traditional conventional anatomical imaging techniques such as CT and magnetic resonance imaging (MRI) ^[13]. The specific role of ¹⁸F-FDG PET/CT in mycobacterium tuberculosis infection has received little attention ^{[14, 15]}, and the available data on the ¹⁸F-FDG PET/CT findings of NTM is scarce. Therefore, we conducted a retrospective study to investigate ¹⁸F-FDG PET/CT imaging features in patients with NTM and to determine the clinical relevance of ¹⁸F-FDG PET/CT in the management of NTM.

Patients

In this study, 23 patients with NTM infection (19 men and 4 women, mean age 60 years) who underwent ¹⁸F-FDG PET/CT at our hospital between December 2016 and October 2021 were retrospectively reviewed. The flow diagram of the study design is presented in Fig. 1.NTM infection was diagnosed based on tissue culture (n = 9) and molecular diagnostic techniques such as metagenomic next-generation sequencing (mNGS) (n = 14). Data on clinical characteristics such as age, gender, risk factors, and syndromes, as well as laboratory results such as serum cytokines, immune cells, and mycobacterium species, were acquired from the medical records.

The included patients were divided into three groups based on their immunological state: a deficiency group with innate or acquired immune deficiency syndrome, such as those receiving chemotherapy; a slightly decreased group with a history of chemotherapy, cirrhosis, diabetes, long-term use of glucocorticoids, or splenectomy; and a normal group. They were also divided into localized and disseminated groups based on the distribution of the involved lesions. Furthermore, the patients were classified into severe and non-severe groups based on the British Thoracic Society guidelines for the management of NTM pulmonary disease in 2017 ^[3]. The severity was determined by the presence of acid-fast bacillus in respiratory tract sample smears, radiological evidence of lung cavitation or severe infection, and severe symptoms or signs of systemic illness.

All patients had ¹⁸F-FDG PET/CT scans at the time of initial NTM diagnosis. The protocol for this retrospective study was reviewed and approved by the Institutional Review Board of the First Affiliated Hospital of Zhejiang University. All participants provided a signed informed consent form for participation.

¹⁸ F-FDG PET/CT imaging

The ¹⁸F-FDG was synthesized using a Siemens Eclipse cyclotron (Siemens Medical Solutions, Knoxville, TN 37932, USA) and an FDG4 chemical module. Patients were fasted for at least 4 hours before being injected with ¹⁸F-FDG at a dose of 4.44 to 5.55 MBq/kg. Images were acquired using a PET/CT (Biograph 16 and Version, Siemens Company, Germany). Two experienced nuclear medicine physicians independently reviewed PET/CT images in consensus. Semiquantitative analysis was performed using the maximum standardized uptake value (SUVmax). Furthermore, 8 parameters were also recorded: SUV_Max (the most FDG-avid lesion in the whole body), SUV_I−lung (SUV_max of lung lesions), SUV_E−lung (SUV_max of extra-lung lesions), SUV_Liver (SUV_max of liver), SUV_Spleen (SUV_max of spleen), SUV_Marrow (SUV_max of marrow), SUR_Liver (SUV_max ratio of lesion-to-liver), and SUR_Blood (SUV_max ratio of lesion-to-blood pool).

Statistical analysis

The quantitative data are presented as mean and standard deviation. All statistical analyses were performed using GraphPad Prism, version 8.0 (GraphPad Software, San Diego, CA, USA). The differences in distribution and severity were analyzed using the chi-square test. The differences in immunological state were analyzed using single-factor analysis. A p-value of less than 0.05 was considered statistically significant. ROC curves were used to determine the optimal cut-off values.

Patients’ clinical characteristics

In this study, 23 patients with NTM infection were included, and their demographics and clinical features are presented in Table 1. They were 19 men (82.6%) and four women (17.4%), with age ranging between 14 and 84 years (median: 60 years). The most common clinical manifestations were fever (12 cases, 52.2%), coughing and expectoration (8 cases, 39.1%), ostealgia (5 cases, 21.7%), fatigue (2 cases, 8.7%), chest tightness (1 case, 4.3%), and weight loss (1 case, 4.3%).

In terms of immunological status and risk factors, six patients (26.1%) had high risk factors due to immunological dysfunction, such as chemotherapy (3 cases, 13.0%), acquired immune deficiency syndrome (AIDS) (2 cases, 8.7%), and monocytopenia and mycobacterial infection syndrome (MonoMAc syndrome) (1 case, 4.3%). In addition, 8 patients (37.8%) had mild risk factors, such as a history of chemotherapy (4 cases, 17.4%), splenectomy (1 case, 4.3%), hepatitis B cirrhosis (1 case, 4.3%), tuberculosis (1 case, 4.3%) and use of small-dose glucocorticoids (1 case, 4.3%). Furthermore, six patients (26.1%) had mild chronic obstructive pulmonary disease as a result of long-term smoking, while three patients (13.0%) had no risk factors or underlying diseases.

NTM infection was diagnosed in the included cases using mNGS (14 cases, 60.9%) and specimen culture (9 cases, 39.1%). Specimens were collected from blood or alveolar lavage fluid, pus, surgical sites, and other sites. Regarding the NTM species, the following were identified: M. intracellulare in 12 cases (52.2%); M. avium (4 cases, 17.4%); M. abscessus (3 cases, 13.0%); M. paraintracellulare (1 case, 4.3%); and M. chimaera (1 case, 4.3%).

Laboratory characteristics

The laboratory characteristics of the 23 patients with NTM infection are presented in Table 2. The median white cell count was 7.6 × 10⁹/L [interquartile range (IQR): 2.3–22.8 × 10⁹/L], with nearly half of the patients having leukocytosis (10 cases, 43.5%). Of these patients, the neutrophil count was elevated in nine patients, and the lymphocytic count was elevated in one. The median platelet count was 226 × 10⁹/L [interquartile range (IQR): 85–492 × 10⁹/L], with more than one-third of the patients having polyplastocytosis (8 cases, 34.8%).However, red blood cell counts and hemoglobin levels were reduced in eight patients (34.8%) and 11 patients (47.8%), respectively, with eight patients having both decreased. Although the majority of patients had variable levels of elevation in C-reactive protein (CRP) (16 cases, 69.6%) and erythrocyte sedimentation rate (ESR) (15 cases, 65.2%), the procalcitonin (PCT) levels which is commonly used to determine bacterial infection were all within the normal range. The serum ferritin and CA125 levels were elevated in 13 (56.5%) and 9 (39.1%) patients, respectively. In addition, the median serum ferritin and CA125 levels were 326.6 (IQR: 43.2–2286.6 g/dL) and 34.6 (IQR: 2.1–290.8 U/L), respectively.

In terms of serum cytokine levels, the median interleukin 6 (IL-6) level was 13.9 pg/ml (IQR: 1.1–184.3 pg/ml), with 20 patients (87%) having significant elevations. In addition, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) levels were both elevated in two patients. Furthermore, serum IL-10 level was elevated in only one patient, whereas serum IL-2 and IL-4 levels were all within the normal range.

The functional immune cell percentage in peripheral blood was within the reference range in the majority of patients, with only two patients having elevated total T lymphocytes, two patients having decreased assisted/induced T lymphocytes and inhibited/cytotoxic T lymphocyte, and one patient having decreased B lymphocytes.

¹⁸F-FDG PET/CT scan imaging characteristics

The ¹⁸F-FDG PET/CT scan imaging characteristics in patients with NTM infection are summarized in Table 3

Intra-pulmonary lesions

The ¹⁸F-FDG PET/CT scan imaging revealed that 21 patients (91.3%) had an intensive or moderate uptake of ¹⁸F-FDG in the pulmonary lesions, with a single lobe (5 cases) and double lobe involvement (16 cases). Of these patients, 18 (85.7%) had patchy infiltration on breath-holding lung CT. In addition, bronchiectasis (8 cases), cavitation (5 cases), pleural effusion (4 cases), nodular infiltration (3 cases), calcification (3 cases) and atelectasis (2 cases) were detected. Furthermore, high FDG-uptake (SUV_I-lung﹥2.5) lesions were found in 14 patients (Fig. 2A, blue arrows) and low FDG-uptake (SUV_I-lung ≤ 2.5) lesions were found in seven patients (Fig. 2B, white arrows).

Extra-pulmonary lesions

The ¹⁸F-FDG PET/CT scan imaging revealed abnormally high ¹⁸F-FDG FDG uptake in extra-pulmonary lesions in 17 patients (73.9%), with increased ¹⁸F-FDG accumulation in lymph nodes (14 cases), bone (6 cases), subcutaneous tissues (1 case), spleen (1 case), and adrenal glands (1 case).

Distribution of lesions

The ¹⁸F-FDG PET/CT scan imaging revealed that the lesion involved multiple systems in 16 patients, including the lung and lymph nodes (8 cases), lung and bone (3 cases) (Fig. 3), lung, lymph nodes, bone, and subcutaneous tissues (one case), lung, lymph nodes, and bone (one case), lung, lymph nodes, and spleen (one case), lung, lymph nodes, and adrenal gland (one case), and lymph nodes and bone (one case). Furthermore, NTM infection was found in multiple sites within a single-system in six patients (five patients with pulmonary involvement and one patient with lymph node involvement), whereas NTM infection was found in a single site within a single-system in one case (nodular infiltrate in the left upper lobe of the lung).

Metabolic parameters

The median SUV_Max in 23 patients with pulmonary involvement was 10.0 (range: 1.2–28.1).The median SUV_I-lung in 21 patients with pulmonary involvement was 5.5 (range: 1.2–13.9). The median SUV_E-lung in 23 patients was 5.4 (range: 1.8–28.1). The median SUV_Liver, SUV_Marrow and SUV_Spleen were 2.7 (range: 1.7–3.8), 3.1 (range: 1.7–6.7), and 2.1 (range: 1.7–6.0), respectively. The median SUR_Liver and SUR_Blood were 3.2 (IQR: 0.5–7.6) and 4.1 (IQR: 0.7–10.3), respectively.

¹⁸F-FDG PET/CT scan imaging characteristics in different immunological states, NTM lesion distribution and severity

The clinical and FDG PET/CT scan imaging characteristics of different immunological states, as well as NTM lesion distribution and severity, are presented in Table 4. In terms of the NTM lesion distribution, there were significant differences in the SUR_Liver, SUR_Blood and SUV_Maxof the ¹⁸F-FDG-avid lesions between the localized and disseminated groups (p = 0.009, 0.003, and 0.005, respectively) (Fig. 4A). In terms of the NTM lesion severity, SUV_I-Lung, SUV_Marrow, and platelet count significantly differed between the severe and non-severe groups (p = 0.036, 0.006, and 0.007, respectively) (Fig. 4C). Furthermore, one-way analysis of variance revealed significant differences in metabolic parameters of ¹⁸F-FDG-avid lesions, including SUR_Liver, SUR_Blood and SUV_Maxamong the three groups with different immunological states (p = 0.007, 0.012, and 0.010, respectively) (Fig. 4F).

Receiver operating characteristic (ROC) curves were created to assess the consistency of ¹⁸F-FDG PET/CT metabolic parameters and clinical features (Fig. 4). In the localized and disseminated groups, the areas under the curve (AUCs) for SUV_Max, SUR_Liver, and SUR_Blood were 0.796 (p = 0.027), 0.853 (p = 0.008), and 0.826 (p = 0.015), respectively (Fig. 4B). When the cut-off values of SUV_Max, SUR_Liver, and SUR_Bloodwere set at 7.7, 2.9, and 3.3, respectively, the sensitivity of ¹⁸F-FDG PET/CT for lesion distribution was 68.8%, 75%, and 87.5%, respectively, while the specificity was 71.4%, 71.4%, and 71.4%, respectively. In the severe and non-severe groups, the AUCs for SUV_Marrow, SUV_I-lung, and platelet count were 0.897 (p = 0.001), 0.688 (p = 0.158), and 0.794 (p = 0.019), respectively (Fig. 4D). When the cut-off values of SUV_Marrow_,SUV_I-lung,andplatelet count were set at 3.1, 4.6, and 202.5 × 10⁹/L, the sensitivity of ¹⁸F-FDG PET/CT for severity detection was 76.9%, 76.9%, and 92.3%, respectively, while the specificity was 88.9%, 55.9%, and 55.6%, respectively. In the immunocompromised and immunocompetent groups, the AUCs for SUV_Max, SUR_Liver, and SUR_Bloodwere 0.759 (p = 0.05), 0.768 (p = 0.04), and 0.696 (p = 0.14), respectively (Fig. 4E). The cut-off values for SUV_Max, SUR_Liver, and SUR_Blood were set at 5.3, 3.8 and 3.0, respectively, and the sensitivity of ¹⁸F-FDG PET/CT for compromised immune function in patients with NTM infection was 88.2%, 52.9%, and 76.5%, respectively, while the specificity was 50.0%, 83.3% and 50.0%, respectively.

Correlations between metabolic parameters of ¹⁸F-FDG PET/CT scan imaging and clinical laboratory results

The Spearman’s correlation analysis (Fig. 5) revealed that PCT and IL-6 correlated positively with SUV_Marrowof the ¹⁸F-FDG PET/CT scan imaging (r = 0.507 and 0.530, respectively, both p < 0.05). Furthermore, PCT and ferritin correlated positively with SUV_Spleen(r = 0.577 and 0.558, respectively, both p < 0.05).

NTM is an opportunistic pathogen with obviously varying susceptibility across different populations. The pathogenicity of NTM is often mild and slowly progressive. Therefore, some patients do not require active treatment due to minor clinical symptoms. However, this organism markedly affects patients with chronic lung diseases, immunodeficiency, and nosocomial infections ^[1]. Given its difficulty in diagnosing, high antibiotic resistance, and high recurrence rate, clinicians need to precisely evaluate the state of NTM infection based on comprehensive clinical, laboratory, and imaging examination before choosing a standardized and individualized treatment option to improve the patients’ chance of cure and quality of life ^[7].

The symptoms of NTM infection were determined based on virulence and host immunological responses to the pathogen. NTM resided exclusively in macrophages and formed granulomas in humans, resulting in clinical features of progressive disease ^[1]. M. intracellulare is the most common pathogen (12/23, 52.2%), and it was found in all cases of lung disease in the present study. These findings were consistent with the previous study findings ^{[8, 9]}, but not with the results by I. Porvaznik ^[7], possibly due to presumed geographical or environmental factors.

In the present study, the presence of risk factors was assessed in all patients. The most prevalent predisposing factors were systemic immunological dysfunction caused by chemotherapy or local host defense alteration caused by an existing lung tumor, accounting for nearly one-third of the cases. Systemic immune deficiency syndrome included two patients having AIDS and one patient having MonoMAc syndrome (an autosomal dominant inherited disease by mutations in the GATA-2 gene ^[16]). In these patients, CD4 T lymphocytes significantly decreased and attenuated specific immune responses against NTM. Patients with splenectomy and hepatitis B cirrhosis had compromised immune systems that also needed to be identified and addressed.

In our study, NTM disease was presented with nonspecific symptoms including local symptoms such as cough, expectoration, and chest tightness and general symptoms such as fever, ostealgia, fatigue, and weight loss. The signs of systemic illness are usually advanced or extensive. The red blood cell count and hemoglobin levels were reduced in more than one-third of these patients, which could be attributed to a lengthy disease course and malnutrition. However, platelet counts were increased in approximately one-third of the patients. In addition, the platelet count in patients with severe NTM infection was higher than that in patients with non-severe NTM infection, which is contradictory to the majority of severe infections that cause thrombocytopenia ^[10]. Our findings could be explained by the fact that platelets greatly accumulate at the site of vascular endothelial infection to promote the development of inflammation and defense against blood spread in severe NTM infections.

Evidence suggested that specific host responses to NTM were cellular immune-dependent, with cytokines like TNF-α and IL-6 required for granuloma formation and pathogen eradication in NTM infection lesions ^[1]. After mycobacterial infection, IL-6 can induce the production of T helper cells and promote the proliferation of granulocytes and macrophages ^[11–12], while TNF-α plays an important role in preventing the infection ^[13]. However, there have been few reports on the clinical significance and changes in serum cytokine levels and cellular immune function in NTM-infected patients. In the present study, 20 patients (87%) had significantly elevated IL-6 levels, but only two (8.7%) had elevated TNF-α levels. Serum TNF-α and IL-6 levels did not differ significantly among groups with different immunological states and NTM lesion distribution and severity. Therefore, we concluded that serum TNF-α and IL-6 were not effective markers of NTM infection severity, although playing a significant role in its development. In terms of cellular immunological function, the percentages of T lymphocyte subsets, B lymphocytes and natural killer cells in peripheral blood were within the reference range in the majority of patients and did not differ significantly among groups with different immunological states and NTM infection distribution and severity. In our future work, we aim to increase the sample size and conduct prospective experiments to further investigate the relationship between immunological function and NTM infection.

Recently, it has been found that some inflammatory markers in the peripheral circulation, such as PCT, CRP, ESR, white cell count, and neutrophil count, can appear abnormal in the early stages of a variety of infectious diseases and provide a basis for early treatment ^{[14, 15, and 17]}. However, these inflammatory markers, particularly PCT, have received little attention in NTM infections. The normal plasma PCT level is less than 0.10 ng/mL, and it rises to more than 0.50 ng/mL with systemic infection ^[18]. In the present study, CRP and ESR levels were elevated in more than half of the patients, while white cell count and neutrophilic granulocyte count were elevated in half of these patients. Surprisingly, PCT levels in all included patients were within the reference range. This discrepancy in the inflammatory marker levels was inconsistent with that observed in active tuberculosis infection and other general bacterial infections. Therefore, normal PCT levels along with other elevated inflammatory markers may suspect NTM infection. Furthermore, according to our statistical analysis, these inflammatory markers were also ineffective in assessing the NTM infection severity.

Unlike traditional imaging, ¹⁸F-FDG PET/CT detects functional or metabolic alterations in inflammatory cell activity prior to morphological abnormalities, regardless of post-inflammatory scar ^{[19, 20]}. Another advantage of ¹⁸F-FDG PET/CT is the ability to assess infection throughout the body ^{[21, 22]}. The most commonly markers used to assess FDG-uptake levels are SUV_max and SUR. In addition, Hautzel et al. found that using SUR_Liver of more than 1 significantly improved the specificity when compared to visual analysis ^[23]. The role of ¹⁸F-FDG PET/CT scan with semiquantitative parameters has been recognized in infectious or inflammatory diseases, but it remains vacant in NTM infection.

In our study, only metabolic parameters such as SUR_Liver, SUR_Blood, and SUV_Max were significantly different among the three groups with different immunological states and two groups with different lesion distribution. SUR_Liver, SUR_Blood, and SUV_Max in patients with a normal immunological state were apparently higher than those in patients with immunodeficiency or mildly decreased. Patients with normal immunity are more likely to develop inflammatory reactions that engulf bacteria and form granulomas. Furthermore, according to our ROC analysis, the cut-off point of 3.8 for SUR_Liver showed the best equilibrium between sensitivity and specificity. SUR_LIver ≤3.8 can help predict immunological dysfunction in patients with NTM infection. Clinicians should pay more attention to the treatment of the underlying diseases and search for hidden diseases that lead to immunological dysfunction in these patients. Meanwhile, SUR_Liver, SUR_Blood, and SUV_Max in disseminated NTM infection were significantly higher than those of patients with localized NTM infection. In particular, the cut-off point of 3.3 for SUR_Blood showed the best equilibrium between sensitivity and specificity. the SUR_Blood ≥3.3 could be used as a powerful basis for predicting NTM dissemination. These findings were crucial in directing treatment planning.

The severity of non-tuberculous mycobacterial pulmonary disease (NTM-PD) was determined by symptoms, radiological changes, and mycobacterial culture results of acid-fast bacilli smears, although these measurements were subjective and took long time to assess ^[4]. In our severity analysis, SUV_Lung and SUV_Marrow were higher in patients with severe NTM infection than in those with non-severe NTM infection. High FDG uptake of NTM-PD indicates inflammatory activity, significant mycobacterial pathogenicity, or an elicited systemic response (such as patient 1 in Fig. 2), while normal or low FDG uptake indicates inflammation regression or scar formation (such as patient 2 in Fig. 2). The use of a cut-off value of 3.1 for SUV_Marrow and 4.6 for SUV_Lung simultaneously helped to better delineate NTM-PD severity, guide NTM-PD treatment, and monitor treatment responses.

There are some limitations to this study. First, it was conducted at a single center, with a limited sample size (n = 23). Second, because this was a retrospective study, the use of ¹⁸F-FDG PET/CT in the assessment of patients introduced a potential bias toward a disseminated NTM infection cohort. Third, in our study, ¹⁸F-FDG PET/CT was only used for the pre-treatment assessment of NTM infection, with no post-treatment reassessment. Last, metabolic measurements reflected the FDG uptake by inflammatory cells rather than the NTM itself. NTM-specific radiolabeled compounds and imaging approaches were urgently needed to be developed. Therefore, a multicenter, prospective analysis will be designed in a future study to attain a better representation of NTM-infected patients.

To the best of our knowledge, the present study is the first to analyze the findings of ¹⁸F-FDG PET/CT scan imaging in patients with NTM infection. ¹⁸F-FDG PET/CT is a unique and powerful tool in the diagnosis and evaluation of disease activity, immunological state, and extent of lesion involvements, and it can help determine the appropriate treatment for NTM infection.

Acknowledgements

We are thankful to the parents of patient for the support given in providing the data.

Authors’ contributions

DC and XS: Study conception and design; drafting of manuscript; critical revision; review, analysis and interpretation of scientific literature; YC was involved in the management of the specimen samples of the patient; drafting of manuscript; KZ, TL, KL, ZW, SY and GW: Drafting of manuscript; review, analysis and interpretation of scientific literature. All authors have contributed to the manuscript and approved its final version.

Funding

This work was supported by grants from the National Natural Science Foundation of China (NSFC) (82071965) and Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China (LHDMZ22H300010).

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of The first Affiliated Hospital, college of Medicine, Zhejiang University.

Consent for publication

Written informed consent was obtained from the patient’s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.

Taiwo B, Glassroth J. Nontuberculous mycobacterial lung diseases. Infect Dis Clin North Am. 2010 Sep;24(3):769-89.
Somoskovi A, Salfinger M. Nontuberculous mycobacteria in respiratory infections: advances in diagnosis and identification. Clin Lab Med. 2014 Jun;34(2):271-95.
Daley CL, Iaccarino JM, Lange C, Cambau E, Wallace RJ Jr, Andrejak C, Böttger EC, Brozek J, Griffith DE, Guglielmetti L, Huitt GA, Knight SL, Leitman P, Marras TK, Olivier KN, Santin M, Stout JE, Tortoli E, van Ingen J, Wagner D, Winthrop KL. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Eur Respir J. 2020 Jul 7;56(1):2000535.
Haworth CS, Banks J, Capstick T, Fisher AJ, Gorsuch T, Laurenson IF, Leitch A, Loebinger MR, Milburn HJ, Nightingale M, Ormerod P, Shingadia D, Smith D, Whitehead N, Wilson R, Floto RA. British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). Thorax. 2017 Nov;72(Suppl 2):ii1-ii64.
Vaidyanathan S, Patel CN, Scarsbrook AF, Chowdhury FU. FDG PET/CT in infection and inflammation--current and emerging clinical applications. Clin Radiol. 2015 Jul;70(7):787-800
Henkle E, Aksamit T, Barker A, Daley CL, Griffith D, Leitman P, Leitman A, Malanga E, Marras TK, Olivier KN, Prevots DR, Prieto D, Quittner AL, Skach W, Walsh JW, Winthrop KL; NTMRC Patient Advisory Panel. Patient-Centered Research Priorities for Pulmonary Nontuberculous Mycobacteria (NTM) Infection. An NTM Research Consortium Workshop Report. Ann Am Thorac Soc. 2016 Sep;13(9):S379-84.
Porvaznik I, Solovič I, Mokrý J. Non-Tuberculous Mycobacteria: Classification, Diagnostics, and Therapy. Adv Exp Med Biol. 2017;944:19-25
O'Brien DP, Currie BJ, Krause VL. Nontuberculous mycobacterial disease in northern Australia: a case series and review of the literature. Clin Infect Dis. 2000 Oct;31(4):958-67.
Polverosi R, Guarise A, Balestro E, Carloni A, Dalpiaz G, Feragalli B. High-resolution CT of nontuberculous mycobacteria pulmonary infection in immunocompetent, non-HIV-positive patients. Radiol Med. 2010 Mar;115(2):191-204.
Stasi R, Willis F, Shannon MS, Gordon-Smith EC. Infectious causes of chronic immune thrombocytopenia. Hematol Oncol Clin North Am. 2009 Dec;23(6):1275-97
Jang S, Uematsu S, Akira S, Salgame P. IL-6 and IL-10 induction from dendritic cells in response to Mycobacterium tuberculosis is predominantly dependent on TLR2-mediated recognition. J Immunol. 2004 Sep 1;173(5):3392-7.
Nagabhushanam V, Solache A, Ting LM, Escaron CJ, Zhang JY, Ernst JD. Innate inhibition of adaptive immunity: Mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-gamma. J Immunol. 2003 Nov 1;171(9):4750-7.
Noss EH, Pai RK, Sellati TJ, Radolf JD, Belisle J, Golenbock DT, Boom WH, Harding CV. Toll-like receptor 2-dependent inhibition of macrophage class II MHC expression and antigen processing by 19-kDa lipoprotein of Mycobacterium tuberculosis. J Immunol. 2001 Jul 15;167(2):910-8.
Zhao J, Zhang S, Zhang L, Dong X, Li J, Wang Y, Yao Y. Serum procalcitonin levels as a diagnostic marker for septic arthritis: A meta-analysis. Am J Emerg Med. 2017 Aug;35(8):1166-1171.
Black S, Kushner I, Samols D. C-reactive Protein. J Biol Chem. 2004 Nov 19;279(47):48487-90.
Hsu AP, Johnson KD, Falcone EL, Sanalkumar R, Sanchez L, Hickstein DD, Cuellar-Rodriguez J, Lemieux JE, Zerbe CS, Bresnick EH, Holland SM. GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood. 2013 May 9;121(19):3830-7, S1-7.
Tang H, Huang T, Jing J, Shen H, Cui W. Effect of procalcitonin-guided treatment in patients with infections: a systematic review and meta-analysis. Infection. 2009 Dec;37(6):497-507.
Tchou-Wong KM, Harkin TJ, Chi C, Bodkin M, Rom WN. GM-CSF gene expression is normal but protein release is absent in a patient with pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 1997 Dec;156(6):1999-2002.
Hot A, Maunoury C, Poiree S, Lanternier F, Viard JP, Loulergue P, Coignard H, Bougnoux ME, Suarez F, Rubio MT, Mahlaoui N, Dupont B, Lecuit M, Faraggi M, Lortholary O. Diagnostic contribution of positron emission tomography with [18F]fluorodeoxyglucose for invasive fungal infections. Clin Microbiol Infect. 2011 Mar;17(3):409-17.
Bleeker-Rovers CP, Warris A, Drenth JP, Corstens FH, Oyen WJ, Kullberg BJ. Diagnosis of Candida lung abscesses by 18F-fluorodeoxyglucose positron emission tomography. Clin Microbiol Infect. 2005 Jun;11(6):493-5.
Chen D, Dong M, Zhao K, Sun F, Wang H, Liu Z. Unusual synchronous liver and brain abscesses infected by rare Aerococcus viridiansin a patient with pulmonary arteriovenous malformations on FDG PET/CT: A case report and literature review. Medicine, 2017, 96(49):e9048.
Chen D, Chang C, Chen M, Zhang Y, Zhao X, Zhang T, Wang Z, Yan J, Zhu H, Zheng L, Zhao K. Unusual disseminated Talaromyces marneffei infection mimicking lymphoma in a non-immunosuppressed patient in East China: a case report and review of the literature. BMC Infect Dis. 2020 Oct 28;20(1):800.
Besson FL, Parienti JJ, Bienvenu B, Prior JO, Costo S, Bouvard G, Agostini D. Diagnostic performance of ¹⁸F-fluorodeoxyglucose positron emission tomography in giant cell arteritis: a systematic review and meta-analysis. Eur J Nucl Med Mol Imaging. 2011 Sep;38(9):1764-72.

Tables 1 to 4 are available in the Supplementary Files section

Download PDF

Version 1

posted

You are reading this latest preprint version

¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography imaging features in patients with non-tuberculous mycobacterial infection

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Patients

Statistical analysis

Results

Discussion

Conclusion

Declarations

References

Tables

Supplementary Files

Status:

Version 1