Mycobacterium Avium Complex (MAC) Lung Infection Mimics Lung Cancer Nodules But Improves After Antibiotic Therapy

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Robinson This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7328728/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract BACKGROUND Infection with non-tuberculous mycobacterium species commonly can present with lung nodules mimicking lung cancer on routine chest imaging leading to unnecessary invasive procedures. CASE SERIES The authors report three representative cases in which a probable Mycobacterium avium- complex (MAC) infection was discovered incidentally that mandated evaluation for a potential malignancy. After suspecting that the nodules were likely infectious and not malignant, the patients were empirically treated with azithromycin alone or in combination with other antibiotics. In each case, this treatment improved the appearance of these nodules on radiographic imaging in size, density, or both, documenting an infectious etiology thereby preventing more invasive studies and/or surgery. CONCLUSIONS These cases present typical examples of an increasingly prevalent infection commonly seen that can be mistaken for lung cancer by oncologists, particularly in endemic areas such as the Southeast U.S. Many non-malignant etiologies are capable of mimicking lung cancer including the most common, nontuberculous mycobacterium. An empiric 3-month course of azithromycin for highly suspected MAC lung infection that results in a significant reduction in the size of the nodule will verify that it is infectious and not malignant. Recognizing probable infectious lung nodules may prevent invasive, potentially morbid and expensive clinical evaluations including unnecessary surgery. Lung nodules Mycobacterium avium complex lung cancer macrolide antibiotics Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION An estimated 1.6 million people every year in the U.S are found to have a pulmonary nodule 1 . Although the rates of malignancy in lung nodules detected by imaging modalities is estimated to be at most 3–5% 2 , the detection of lung nodules is frequently followed by further testing to elucidate their diagnosis 1 . Considering that lung cancer is the leading cause of cancer death globally 3 , the discovery of a potential malignancy is a significant finding requiring prompt evaluation. Infectious agents are a well-documented cause of lung nodules that can mimic lung carcinoma 4 and lead to invasive and unnecessary testing and/or surgery. Non-tuberculous mycobacteria, such as Mycobacterium avium complex (MAC), is one such infectious agent that has previously been shown to mimic lung cancer in a variety of imaging modalities 5 . However, documentation of the clinical presentation and resolution of these cases remains lacking. The authors present several representative cases who were referred to our indeterminant lung nodule clinic with suspected lung cancer for surgery, which were discovered to be carcinoma-mimicking lung nodules caused by suspected or proven MAC infections. They substantially improved or resolved after an empiric course of azithromycin or azithromycin combination therapy. ILLUSTRATIVE CASES CASE 1 A 73-year-old Caucasian female former smoker with a history of mild emphysema presented to the indeterminant lung nodule clinic after having an abnormal chest x-ray demonstrated waxing and waning lung nodules five years previously. Outside of an isolated incident of hemoptysis one year prior, the patient reported no respiratory symptoms. Additionally, the patient’s social history included a 36 pack-year smoking history, although the patient quit smoking over fifteen years ago. Chest computed tomography (CT) and FDG-PET scan at presentation revealed a glucose avid 1.9 cm left upper lobe nodule, as well as tree-in-bud cluster of nodules in the contralateral medial right middle lobe (Fig. 1 A and 1B ) . The patient underwent a transbronchoscopic biopsy of the nodule which revealed granulomatous disease. Bronchoalveolar lavage cultures also revealed growth of MAC. However, there was still the concern that there was an underlying lung cancer, so the patient was referred to the thoracic surgery for a possible upper lobectomy. The thoracic surgeon fortunately recommended against the procedure and prescribed 250 mg per day azithromycin along with probiotics. After three months of the azithromycin, the patient returned for a follow up and a repeat chest CT showed a significant decrease in nodule size. At this point an infectious disease consultation was requested, and the patient was recommended to continue the prescribed monotherapy for a further nine months to complete a one-year course of azithromycin monotherapy. A repeat chest CT scan after completion of azithromycin course showed continued reduction in the size of the upper left lobe nodule with some persistent bronchiectasis and tree-in-bud nodules, in addition to decreased size of the multiple nodules in the medial segment right middle lobe at 1 year (Fig. 1 C). At this time the azithromycin therapy was discontinued, and the patient was followed with a yearly chest CT scan, with the expectation she might develop recurrent similar nodules over the succeeding years, but fortunately 6 years later this never occurred (Fig. 1 D). CASE 2 An 81-year-old Caucasian female with a history of tobacco use (39 pack-years) and moderate emphysema presented with a six-month history of mild respiratory symptoms and lung nodules. When the productive cough first began, she underwent a chest X-ray which revealed some nodular densities. She was treated with a 7-day course of levofloxacin which resolved most of the respiratory symptoms. A follow-up chest CT scan revealed the small nodules in the right middle lobe had decreased in size, but a new left lower lobe density was discovered. The patient was empirically prescribed a very short 5-day course of azithromycin and followed up after two months where it was discovered that the left lower lobe spiculated density had grown, approaching 1.3cm in diameter (Fig. 2 A). The patient was then referred to the thoracic surgery lung nodule clinic to rule out lung cancer. When the patient was seen upon referral, the patient’s cough had returned, and she was occasionally producing yellow to clear phlegm. Additionally, pulmonary function tests were significantly depressed with an FEV1 of 56% of predicted. The patient reported being on several inhaled medications for her emphysema. This patient’s case was discussed at the Thoracic Oncology Conference and considering the rapid growth of the nodule and the tree-in-bud pattern of the nodules, it was deemed likely that the underlying cause was infectious rather than cancer. She was prescribed an additional three-month course of azithromycin 250 mg daily plus a probiotic. Upon completion of the azithromycin the patient underwent a repeat chest CT scan which revealed that the left lower lobe nodule had decreased in size by about 80% (Fig. 2 B). The patient had previously declined to have bronchoscopy or a needle biopsy for diagnostic purposes. When infectious disease was consulted, the impression was a nodular pneumonia with tree-in-bud formations in the left lower and middle right lobes of the lung that was consistent with a MAC infection. The remaining nodules appeared stable in size and the patient was subsequently followed with a yearly chest CT scan with no subsequent change in the nodules. CASE 3 An 85-year-old Caucasian female with significant comorbidities was referred to radiation oncology for a spiculated PET scan positive nodule in the right upper lobe of the lung with no significant pulmonary symptoms. A core needle biopsy demonstrated a non-necrotizing granuloma with rare, atypical epithelial cells with negative stains and cultures. Because of concern that the nodule was actually a small cancer, the patient underwent a stereotactic radiation therapy regimen and subsequently returned every three months for CT scans. Upon follow up, the original nodule had dissolved into an area of hazy fibrosis, but a new, PET scan positive nodule was discovered in the right middle lobe (Fig. 3 A and 3 B). A core needle biopsy revealed necrotizing granulomatous inflammation that was negative for acid-fast bacilli, fungi, and other bacteria on staining. However, the culture from the needle biopsy grew MAC that was susceptible to many of the typical antibiotics, including ethambutol and clarithromycin. There was also a left pleural effusion noted. She was started on 250 mg/day azithromycin with a follow-up chest CT scan scheduled for 6 months later. After six months of azithromycin, the radiologist reported development of the nodule into a more mass-like consolidation and nodular conglomerate in the right middle lobe with improvement of the observed pleural effusion. At this time the patient was started on 800 mg/day ethambutol in addition to the azithromycin which was continued at the same dosage. After a further six months, a chest CT revealed the right middle lobe nodule decreased in size and density and was now visible as clusters of 0.5-1.0 cm nodules (Fig. 3 C). It was also noted that the pleural effusion had completely resolved. The patient agreed to continue the azithromycin and ethambutol therapy for a further six months and then return for reevaluation. Throughout the course of treatment, the patient denied any cough, fevers, trouble breathing, or other respiratory symptoms, nor any side effects from the antibiotics. She had no recurrence of symptoms or lung nodules long term. DISCUSSION The presence of lung nodules in the lingula segment of the left upper lobe and right middle lobe of the lung caused by MAC in elderly Caucasian females, as illustrated in several of these cases, fits the classical description of Lady Windermere Syndrome 6 . This is one of the well-known presentations of MAC characterized by older, slender post-menopausal women often never smokers who tend to suppress their cough due to social norms or a fastidious nature which allows secretions to accumulate in the airways creating a favorable environment for infection 6 , 7 . The older, thin leading lady in Oscar Wilde’s 19th century play Lady Windermere’s Fan was the syndrome’s namesake. Although this infection is uncommon, it appears to be increasing in prevalence in many parts of the world, particularly in warm, humid areas such as Florida where MAC is endemic 8 , 9 . (Fig. 6 Endemic MAC areas). Pulmonary MAC versus Lung Cancer Unfortunately, many patients with lung nodules of probable infectious etiology undergo aggressive follow-up care at similar rates as patients with malignant lung nodules, including procedures such as surgical lung resections, transbronchoscopic biopsy or and transthoracic lung biopsy 10 . These procedures carry significant risks, particularly in the usual elderly patients who may be frail and who are often quite reluctant to have an invasive procedure with its risks of pneumothorax, bleeding and need for a chest tube. CT-guided needle biopsies of lung lesions cause pneumothorax in 26% of procedures and carry a 0.12% mortality rate 11 . Navigational bronchoscopy is 79% accurate, similar to transthoracic needle biopsy, but also carries a pneumothorax and bleeding risk that many elderly patients are reluctant to undergo. 12 Nationally, 35% of the lung nodules removed at surgery were benign, with most of them found to be an infection. 13 Aside from the morbidity and potential mortality of an unnecessary lung resection for an infection, the most recent cost according to Medicare claims for lung resections (even a “surgical biopsy” as it is often called) averages $ 31,900, and most patients will have a significant out-of-pocket co-pay 14 . Avoiding these procedures is preferrable when the nodules have the clinical and radiographic characteristics of an infection rather than malignancy to avoid overtreatment and iatrogenic injury, in addition to the unnecessary medical costs. Studies have shown that only 17% of biopsied lung nodules were malignant, whereas 19% of biopsied lung nodules were definitely infectious in origin 15 . T. Lokhandwala and associates reported on a SEER database study that 43.7% of CT-guided lung biopsies are unnecessary and do not follow NCCN guidelines. 16 Aside from the potential morbidity to patients, the monetary cost of unnecessary procedures is considerable. It was documented that for Medicare patients ten years ago from 2011–2013, the median cost for an uncomplicated needle biopsy was $ 1,071; if there was a complication, the median cost rose to $ 14,824 16 . The median cost of a needle biopsy 4 years later in 2017 from the SEER database rose to $ 4157 16 . These costs further emphasize the need to recognize the presentation of infectious lung nodules to reduce the number of risky, costly, and unnecessary procedures. Obviously, differentiating infectious from malignant nodules is critically important. One key distinction is the evolution of lung nodules over time. Reviews of chest imaging have demonstrated that lung cancers tend to be “associated with a fairly steady or accelerated growth”, and that growth after 1-year follow up was a strong predictor of malignancy 17 . Lung nodules that shrink spontaneously are highly unlikely to be cancer. Additionally, there is evidence that supports the finding that spontaneously shrinking lung nodules are caused by NTM infections 18 . Nodule shrinkage in response to empiric antibiotics in selected patients is another way of differentiating malignancy from infections. FDG-PET scans will not discriminate between a benign infectious nodule and a malignant nodule since both will usually have some degree of glucose avidity since leucocytes which mediate the inflammatory response of infectious nodules primarily use glucose as their main energy source. 19 While lung cancer will not respond to antibiotics, bacterial infections, particularly NTM infections, will usually decrease in size in response to antibiotic therapy 20 . Who is a Candidate for Empiric Azithromycin Monotherapy as a Diagnostic Tool? Selective antibiotic treatment of a lung nodule(s) suspected to be infectious with antibiotics represents a safe, non-invasive approach to determine whether an infection is the cause of the abnormal chest CT scan findings. However, a thoracic surgeon or pulmonologist who is very experienced in evaluating lung nodules is the best provider to determine whether an indeterminant lung nodule is more likely an infection, perhaps MAC, and that an empiric antibiotic trial, usually at least 3 months in length , is indicated. If the nodule does not respond to empiric antibiotics, then an invasive procedure may be performed. If a lung cancer is ultimately documented, then the patient can still have potentially curative treatment, and it is highly unlikely that the peripheral cancer stage or chance for cure has been compromised by a 3-month delay of antibiotic treatment. For this reason, whenever possible, patients with indeterminant lung nodules may significantly benefit by referral to a dedicated lung nodule clinic where they can be evaluated by highly-experienced providers and selective empiric antibiotics may be given if there is a high index of suspicion that an infection is present, rather than a malignancy . Although there is significant overlap, there are some radiologic features that can help differentiate MAC infections from malignant nodules (Table 1 ). One of the classical features of MAC infections is its location preference for the right middle lobe and lingula of the left upper lobe, although the other lobes also are commonly involved 6 . MAC and other non-tuberculous mycobacterial infections also frequently present with the radiographic picture of a “tree-in-bud” nodularity that can be useful in identifying nodules of infectious origin 21 . However, spontaneous shrinking of nodules or a decrease in size in response to antibiotics such as azithromycin are further radiologic findings that are highly indicative of MAC infection. An empirical course of azithromycin is not intended as curative for presumed MAC infection but rather it is done as a diagnostic measure to see if there is significant decrease in the size of the nodule. Table 1 COMMON CHARACTERISTICS OF PATIENTS WITH MYCOBACTERIUM AVIUM COMPLEX (MAC) LUNG INFECTION CHARACTERISTIC FINDINGS Patient Factors Sex Postmenopausal female, frequently thin Age > 65 years old Cough Dry cough or with occasional clear to yellow mucus Activity Commonly works out in garden or yard Location Lives in endemic area, especially humid, warm climate Immune Function May or may not be immunosuppressed Smoking history Higher risk if current or former smoker Fever or Night Sweats Rare fevers but some with night sweats (may be difficult to differentiate from menopausal symptoms) Other symptoms Rare hemoptysis, weight loss, dyspnea or fatigue unless severe disease. Radiographic Features CT scan Speculated, peripheral infiltrative nodule(s). May have waxing and waning nodules over years. Most common location is right middle lobe and left upper lobe lingula. FDG-PET Scan Low-moderate level uptake of glucose (present in infection and in cancer); minimal or no uptake in lymph nodes Lymphadenopathy None or minimal Lesions in Other Areas of Lungs Nodular densities, especially if “tree-in-bud” pattern Evidence of Chronic Lung Disease Particularly susceptible to MAC, especially bronchiectasis or COPD Note: Few MAC lung infection patients will have all of these characteristics. The standard infectious disease recommendation for MAC treatment is triple drug therapy (macrolide, ethambutol and rifampin) for 12 months. 22 Macrolide monotherapy is discouraged because of the concern for rapid drug resistance and this has be reported in a few patients in several case studies, all of which involve patients with upper lobe cavitary disease, nodular disease with bronchiectasis, or cystic fibrosis where there is a high inoculum of organisms. 23 , 24 However another case series of 29 patients without human immunodeficiency virus but with fibrocavitary disease and bilateral disease who were treated for 6 months with azithromycin monotherapy resulted in 76% of patients with reduced positive sputums and no drug resistance during monotherapy. 25 A large multicenter study of 88 AIDS patients with disseminated MAC with symptoms and positive blood cultures treated with azithromycin monotherapy resulted in blood culture sterilization of 54% and drug resistance in only one patient (1.1%). 26 Macrolide resistance with monotherapy is a rare event and generally occurs only in high inoculum Mycobacterium infections found in large cavities and extensive bronchiectasis. But in lung nodules with granulomata, there is much less chance for resistance since there are less organisms. In fact, apparent refractory MAC infections are commonly caused by reinfection with new strains rather than the original strain which may explain the quite infrequent development of macrolide resistance. 27 Therefore, a short diagnostic empiric trial of azithromycin monotherapy for 3 months for patients with non-cavitary minimally symptomatic disease to illicit a favorable radiographic response verifying a benign diagnosis is reasonable and safe and may prevent the need for a major invasive procedure including unnecessary surgical resection for an infection. Does Every Patient with MAC Need Treatment? Although the literature reports pulmonary MAC cure rates of 32–65% with 12-month macrolide-containing triple drug regimens, there are high rates of drug intolerance (43%) 28 and recurrent disease, usually from reinfection with different strains and not treatment failures. 21 , 27 , 29 Most of the drug intolerance leading to discontinuation of therapy is from the rifampin adverse effects. In fact there is good evidence that rifampin can be omitted so that a two drug regimen of azithromycin and ethambutol works equally well for MAC treatment (as seen in Case 3) without the frequent and serious rifampin toxicity. 30 The macrolide favored almost all of the time now is azithromycin with single-day dosage and rare side effects, unlike the poorly tolerated clarithromycin. Many regulatory agencies such as the U.S. Food and Drug Administration warn of the potential risk ventricular arrhythmias with macrolide antibiotics due to potential elongation of the corrected QT interval (QTc) on the electrocardiogram. This risk is quite overstated, and numerous studies strongly refute this risk in older patients > 65 years, even those with chronic kidney disease, congestive heart failure, coronary artery disease and concurrent use of a drug known to prolong the QT interval. 31 – 33 A 2015 study by M. Trac and associates in a very large population-based retrospective propensity-matched cohort study in Ontario found no higher risk of ventricular arrhythmias in 616,359 patients receiving macrolide versus 705,132 patients receiving non-macrolide antibiotics (amoxicillin, cefuroxime or levofloxacin). 31 However, in immunocompetent patients with good nutritional status, no AIDS, minimal or no symptoms and without fibro-cavitary or nodular bronchiectatic disease, the diagnosis of MAC does not require immediate initiation of treatment. As many as 40–60% of patients with MAC remain free of progression for years without treatment. Furthermore, 40–50% with untreated MAC achieve spontaneous culture negative conversion without antibiotic treatment. “Therefore, to avoid unnecessary treatments that might cause unwarranted medical expenses and adverse drug reactions, clinicians should consider the risk of disease progression and make timely decisions in the treatment initiation phase.” 29 Given the complexity of correctly identifying these infections, understanding the varying clinical presentations of non-tuberculous mycobacterial lung diseases is becoming increasingly important. The infections presented in this report were largely asymptomatic or presented only with a slight productive cough but were initially suspected of being malignancies. In two cases these infections were discovered incidentally during a screening procedure for a suspected lung carcinoma. In many such cases, suspicion of malignant nodules can lead to otherwise unnecessary aggressive procedures, such as the upper lobectomy that was almost performed in the patient in Case 1. Fortunately, the results of the bronchoalveolar lavage culture prevented an unnecessary and potentially harmful procedure. Similarly, Case 2 avoided adverse treatment, even though the infection could have been mistaken for lung cancer based on the initial imaging. Additionally, considering that the patient in Case 3 had already received radiation therapy for a suspected lung malignancy (although it was likely MAC), it is fortunate that she underwent a core biopsy before receiving unnecessary additional radiation. In each of these cases, the patient was successfully treated medically, but the ability of MAC infections to mimic lung cancer on imaging necessitates awareness of both the prevalence and clinical manifestations of this disease. CONCLUSIONS Many non-malignant etiologies are capable of mimicking lung cancer and can lead to invasive and expensive workups. Pulmonary nodules caused by nontuberculous mycobacterium are one of the most common mimics of lung cancer. Recognizing the classic patterning of peripheral nodules in a tree-in-bud pattern along with bronchiectasis, and mucous plugs on chest CT scans, combined with the rapid development in the size and number of nodules can suggest an infectious etiology such as MAC pneumonia. If there is a high suspicion of MAC by a highly- experienced pulmonary physician, then it is reasonable to proceed with an empiric course of azithromycin for 3 months without an initial biopsy followed by re-imaging. Due to its immune modulating properties to reduce inflammation and its consistent mycobactericidal activity, a trial of three months of empiric azithromycin can reduce the nodule size and confirm a non-cancer etiology. This therapy also has a low risk of promoting macrolide resistance should further non-tuberculous mycobacterial therapy be needed. In the end, this practice has reduced unnecessary surgery, invasive needle biopsy, and provided relief from the anxiety of having a cancer diagnosis. Follow up with regular chest CT scans for life can further alleviate fears of cancer and monitor possible progression of chronic pulmonary MAC infections that may warrant aggressive antibiotic treatment. Abbreviations CT scan: Computed tomography scan FEV1: Forced expiratory volume at 1 second. MAC: Mycobacterium avium complex FDG-PET scan: Fluorodeoxyglucose positron emission tomographic scan NCCN: National Comprehensive Cancer Network NTM: Non-tuberculous mycobacteria SEER: Surveillance, Epidemiology and End Results Program database Declarations Funding Sources: None Ethics Approval: This retrospective chart review of 3 de-identified cases was considered exempt from the need for IRB approval. Patient Consent: Written informed consent was obtained from the patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Availability of Data and Materials: Electronic medical record at Moffitt Cancer Center. Competing Interests: The authors declare no real or potential conflicts of interest. Authors Contributions: DJ: analyzed clinical data regarding lung nodules and wrote the initial manuscript draft. JG: provided the conceptualization and design, interpreted the clinical data, and revised the draft. LR: provided the patient data to analyze, interpreted the clinical data, made the decision to publish, and revised the draft to its final form. All authors read and approved the final manuscript. Acknowledgements: None Author’s Information: D.J. has a B.S. degree in microbiology and currently is a 3 rd year MD/PhD medical student at the University of South Florida College of Medicine, Tampa, FL. J.G. is Professor of Medicine, Infectious Diseases, Section Chief, Infectious Disease & Epidemiology, Moffitt Cancer Center, Tampa, FL. L.R. is Professor of Surgery in the Division of Thoracic Oncology, and is Director, Lung Cancer Early Detection (LEAD) Center and the Indeterminant Lung Nodule Clinic, Moffitt Cancer Center, Tampa, FL References Mazzone PJ, Lam L. Evaluating the Patient With a Pulmonary Nodule: A Review. Jama 2022;327:264-73. Osarogiagbon RU, Liao W, Faris NR, et al. Lung Cancer Diagnosed Through Screening, Lung Nodule, and Neither Program: A Prospective Observational Study of the Detecting Early Lung Cancer (DELUGE) in the Mississippi Delta Cohort. J Clin Oncol 2022;40:2094-105. de Groot PM, Wu CC, Carter BW, Munden RF. The epidemiology of lung cancer. Transl Lung Cancer Res 2018;7:220-33. Allison RD, Vincent AL, Greene J, Sandin RL, Field T. Infectious pulmonary nodules mimicking lung carcinoma. Infections in Medicine 2004;21:181-6. Hong SJ, Kim TJ, Lee JH, Park JS. Nontuberculous mycobacterial pulmonary disease mimicking lung cancer: Clinicoradiologic features and diagnostic implications. Medicine (Baltimore) 2016;95:e3978. Reich JM, Johnson RE. Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern. The Lady Windermere syndrome. Chest 1992;101:1605-9. Holt MR, Miles JJ, Inder WJ, Thomson RM. Exploring immunomodulation by endocrine changes in Lady Windermere syndrome. Clin Exp Immunol 2019;196:28-38. Prevots DR, Marras TK. Epidemiology of human pulmonary infection with nontuberculous mycobacteria: a review. Clin Chest Med 2015;36:13-34. Adjemian J, Olivier KN, Seitz AE, Holland SM, Prevots DR. Prevalence of nontuberculous mycobacterial lung disease in U.S. Medicare beneficiaries. Am J Respir Crit Care Med 2012;185:881-6. Figueroa CJ, Riedel E, Glickman MS. Clinical and radiographic differentiation of lung nodules caused by mycobacteria and lung cancer: a case–control study. BMC Infectious Diseases 2015;15:482. Mills M, Choi J, El-Haddad G, et al. Retrospective analysis of technical success rate and procedure-related complications of 867 percutaneous CT-guided needle biopsies of lung lesions. Clin Radiol 2017;72:1038-46. Lentz RJ, Frederick-Dyer K, Planz VB, et al. Navigational Bronchoscopy or Transthoracic Needle Biopsy for Lung Nodules. New England Journal of Medicine 2025;392:2100-12. Tanner NT, Aggarwal J, Gould MK, et al. Management of Pulmonary Nodules by Community Pulmonologists: A Multicenter Observational Study. Chest 2015;148:1405-14. Cowper PA, Feng L, Kosinski AS, et al. Initial and Longitudinal Cost of Surgical Resection for Lung Cancer. Ann Thorac Surg 2021;111:1827-33. Georgiadou SP, Sampsonas FL, Rice D, Granger JM, Swisher S, Kontoyiannis DP. Open-lung biopsy in patients with undiagnosed lung lesions referred at a tertiary cancer center is safe and reveals noncancerous, noninfectious entities as the most common diagnoses. Eur J Clin Microbiol Infect Dis 2013;32:101-5. Lokhandwala T, Bittoni MA, Dann RA, et al. Costs of Diagnostic Assessment for Lung Cancer: A Medicare Claims Analysis. Clin Lung Cancer 2017;18:e27-e34. Larici AR, Farchione A, Franchi P, et al. Lung nodules: size still matters. Eur Respir Rev 2017;26. Kinjo T, Uechi K, Kami W, Fujita J. Spontaneously shrinking lung mass due to Mycobacterium avium mimicking lung cancer. Clin Case Rep 2021;9:e05006. Kramer PA, Ravi S, Chacko B, Johnson MS, Darley-Usmar VM. A review of the mitochondrial and glycolytic metabolism in human platelets and leukocytes: Implications for their use as bioenergetic biomarkers. Redox Biology 2014;2:206-10. Thompson WH. Bronchioloalveolar carcinoma masquerading as pneumonia. Respir Care 2004;49:1349-53. Verma N, Chung JH, Mohammed TL. "Tree-in-bud sign". J Thorac Imaging 2012;27:W27. Haworth CS, Banks J, Capstick T, et al. British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). Thorax 2017;72:ii1-ii64. Griffith DE, Brown-Elliott BA, Langsjoen B, et al. Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2006;174:928-34. Loewenstein D, van Balveren L, Lemson A, Hanemaaijer N, Hoefsloot W, van Ingen J. Monotherapy: Key cause of macrolide-resistant Mycobacterium avium complex disease. Respir Med 2023;217:107366. Griffith DE, Brown BA, Girard WM, Murphy DT, Wallace RJ, Jr. Azithromycin Activity Against Mycobacterium avium Complex Lung Disease in Patients Who Were Not Infected with Human Immunodeficiency Virus. Clinical Infectious Diseases 1996;23:983-9. Koletar SL, Berry AJ, Cynamon MH, et al. Azithromycin as treatment for disseminated Mycobacterium avium complex in AIDS patients. Antimicrob Agents Chemother 1999;43:2869-72. Jhun BW, Kim SY, Moon SM, et al. Development of Macrolide Resistance and Reinfection in Refractory Mycobacterium avium Complex Lung Disease. Am J Respir Crit Care Med 2018;198:1322-30. Marmor M, Sharifi H, Jacobs S, Fazeli K, Ruoss S. Variables associated with antibiotic treatment tolerance in patients with Mycobacterium avium complex pulmonary disease. Respir Res 2024;25:123. Kwon YS, Koh WJ, Daley CL. Treatment of Mycobacterium avium Complex Pulmonary Disease. Tuberc Respir Dis (Seoul) 2019;82:15-26. Schildkraut JA, Raaijmakers J, Aarnoutse R, Hoefsloot W, Wertheim HFL, Ingen Jv. The role of rifampicin within the treatment of Mycobacterium avium pulmonary disease. Antimicrobial Agents and Chemotherapy 2023;67:e00874-23. Trac MH, McArthur E, Jandoc R, et al. Macrolide antibiotics and the risk of ventricular arrhythmia in older adults. Cmaj 2016;188:E120-e9. Khosropour CM, Capizzi JD, Schafer SD, Kent JB, Dombrowski JC, Golden MR. Lack of Association between Azithromycin and Death from Cardiovascular Causes. New England Journal of Medicine 2014;370:1961-2. Mortensen EM, Halm EA, Pugh MJ, et al. Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. Jama 2014;311:2199-208. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7328728","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":509616262,"identity":"05365dbf-c66f-464f-8c1b-9eb8697b495b","order_by":0,"name":"Derek Jacobs","email":"","orcid":"","institution":"University of South Florida Morsani College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Derek","middleName":"","lastName":"Jacobs","suffix":""},{"id":509616264,"identity":"55890033-fa7e-44f9-84b9-3caae15489ff","order_by":1,"name":"John Greene","email":"","orcid":"","institution":"Moffitt Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"","lastName":"Greene","suffix":""},{"id":509616268,"identity":"a49c88be-23ed-4058-b439-652ec2dd9064","order_by":2,"name":"Lary A. Robinson","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBUlEQVRIiWNgGAWjYBACPiidwAamKhgY2JsPNuDVwoaq5QwDA8+xxMaGA8RoAZOMbSAtCYz4tbCffSbBuMcmj0+6/eHjwnnb5HjYmNsff2CwyZd3wKGFJ91MguFZWjGbzBlj45nbbhvzsDGCHJZmuRGHVWwMaWwSDAcOJ7ZJ5LBJ8267nbhfvhGk5bCBYQMOLfzPYFrSn0nzzrmd2AOxBY8WCbgtCWbSvA1IWuRxeV/iGbNFwgGgXyRyjI15jkH8MuOMQZqBAQ4t/PxpjDc+HLDJk5+R/vAxT81tYIixP/hQUWFjII/DYUDAIpGAKQi0wuAATi3MH7CL47FlFIyCUTAKRhYAAMDrVdDgYLahAAAAAElFTkSuQmCC","orcid":"","institution":"Moffitt Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Lary","middleName":"A.","lastName":"Robinson","suffix":""}],"badges":[],"createdAt":"2025-08-08 15:38:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7328728/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7328728/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90894074,"identity":"7fb3ce98-774e-48e5-be7c-e52d75db8768","added_by":"auto","created_at":"2025-09-09 11:28:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":110824,"visible":true,"origin":"","legend":"\u003cp\u003eA. Chest CT September 18, 2017 and B. FDG-PET October, 2017 prior to treatment.\u003c/p\u003e\n\u003cp\u003eC. October 18, 2018 one year after treatment and D. November 21, 2024 6 years later.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7328728/v1/1255058f28b229fc68f645ee.png"},{"id":90892387,"identity":"7cecfe07-d87d-45fb-9540-7d9187cd25fc","added_by":"auto","created_at":"2025-09-09 11:20:11","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":342605,"visible":true,"origin":"","legend":"\u003cp\u003eA. Pre-treatment CT scan. B. CT scan after 3 months of azithromycin therapy.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7328728/v1/a87c4c24dc45c1675a0236be.png"},{"id":90891668,"identity":"a7aca882-0305-453e-89e0-2460bb7143ef","added_by":"auto","created_at":"2025-09-09 11:12:11","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":472084,"visible":true,"origin":"","legend":"\u003cp\u003eA. Initial FDG PET scan April 27, 2921. B. Pre-treatment CT scan September 9, 2021. C. Post 6 months treatment CT scan March 3, 2022.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7328728/v1/c80789059c93d6f935d57439.png"},{"id":90892389,"identity":"1f370f65-9b93-436f-9a32-9a66442e3488","added_by":"auto","created_at":"2025-09-09 11:20:11","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":371449,"visible":true,"origin":"","legend":"\u003cp\u003ePrevalence of Non-tuberculous Mycobacterial (NTM) Pulmonary Infections in Medicare Beneficiaries Over Age 65 years. (Reproduced by permission from the American Thoracic Society, Inc. Am J Respir Crit Care Med, https://www.atsjournals.org/doi/abs/10.1164/rccm.201111-2016OC)\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7328728/v1/ed2caa5228989c359795cb37.png"},{"id":92921137,"identity":"7959edbb-3772-4fbf-a1bf-70dc5ab2f64a","added_by":"auto","created_at":"2025-10-07 07:02:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1843126,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7328728/v1/a0e8f83b-b813-408f-85a1-64c55e36073a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Mycobacterium Avium Complex (MAC) Lung Infection Mimics Lung Cancer Nodules But Improves After Antibiotic Therapy","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAn estimated 1.6\u0026nbsp;million people every year in the U.S are found to have a pulmonary nodule\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Although the rates of malignancy in lung nodules detected by imaging modalities is estimated to be at most 3\u0026ndash;5%\u003csup\u003e2\u003c/sup\u003e, the detection of lung nodules is frequently followed by further testing to elucidate their diagnosis\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Considering that lung cancer is the leading cause of cancer death globally\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e, the discovery of a potential malignancy is a significant finding requiring prompt evaluation. Infectious agents are a well-documented cause of lung nodules that can mimic lung carcinoma\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e and lead to invasive and unnecessary testing and/or surgery.\u003c/p\u003e\u003cp\u003eNon-tuberculous mycobacteria, such as \u003cem\u003eMycobacterium avium\u003c/em\u003e complex (MAC), is one such infectious agent that has previously been shown to mimic lung cancer in a variety of imaging modalities\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, documentation of the clinical presentation and resolution of these cases remains lacking. The authors present several representative cases who were referred to our indeterminant lung nodule clinic with suspected lung cancer for surgery, which were discovered to be carcinoma-mimicking lung nodules caused by suspected or proven MAC infections. They substantially improved or resolved after an empiric course of azithromycin or azithromycin combination therapy.\u003c/p\u003e"},{"header":"ILLUSTRATIVE CASES","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eCASE 1\u003c/h2\u003e\n \u003cp\u003eA 73-year-old Caucasian female former smoker with a history of mild emphysema presented to the indeterminant lung nodule clinic after having an abnormal chest x-ray demonstrated waxing and waning lung nodules five years previously. Outside of an isolated incident of hemoptysis one year prior, the patient reported no respiratory symptoms. Additionally, the patient\u0026rsquo;s social history included a 36 pack-year smoking history, although the patient quit smoking over fifteen years ago. Chest computed tomography (CT) and FDG-PET scan at presentation revealed a glucose avid 1.9 cm left upper lobe nodule, as well as tree-in-bud cluster of nodules in the contralateral medial right middle lobe (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA \u003cstrong\u003eand 1B\u003c/strong\u003e\u003cem\u003e)\u003c/em\u003e.\u003c/p\u003e\n \u003cp\u003eThe patient underwent a transbronchoscopic biopsy of the nodule which revealed granulomatous disease. Bronchoalveolar lavage cultures also revealed growth of MAC. However, there was still the concern that there was an underlying lung cancer, so the patient was referred to the thoracic surgery for a possible upper lobectomy. The thoracic surgeon fortunately recommended against the procedure and prescribed 250 mg per day azithromycin along with probiotics. After three months of the azithromycin, the patient returned for a follow up and a repeat chest CT showed a significant decrease in nodule size.\u003c/p\u003e\n \u003cp\u003eAt this point an infectious disease consultation was requested, and the patient was recommended to continue the prescribed monotherapy for a further nine months to complete a one-year course of azithromycin monotherapy. A repeat chest CT scan after completion of azithromycin course showed continued reduction in the size of the upper left lobe nodule with some persistent bronchiectasis and tree-in-bud nodules, in addition to decreased size of the multiple nodules in the medial segment right middle lobe at 1 year (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eC). At this time the azithromycin therapy was discontinued, and the patient was followed with a yearly chest CT scan, with the expectation she might develop recurrent similar nodules over the succeeding years, but fortunately 6 years later this never occurred (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eD).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eCASE 2\u003c/h3\u003e\n\u003cp\u003eAn 81-year-old Caucasian female with a history of tobacco use (39 pack-years) and moderate emphysema presented with a six-month history of mild respiratory symptoms and lung nodules. When the productive cough first began, she underwent a chest X-ray which revealed some nodular densities. She was treated with a 7-day course of levofloxacin which resolved most of the respiratory symptoms. A follow-up chest CT scan revealed the small nodules in the right middle lobe had decreased in size, but a new left lower lobe density was discovered. The patient was empirically prescribed a very short 5-day course of azithromycin and followed up after two months where it was discovered that the left lower lobe spiculated density had grown, approaching 1.3cm in diameter (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA).\u003c/p\u003e\u003cp\u003eThe patient was then referred to the thoracic surgery lung nodule clinic to rule out lung cancer. When the patient was seen upon referral, the patient\u0026rsquo;s cough had returned, and she was occasionally producing yellow to clear phlegm. Additionally, pulmonary function tests were significantly depressed with an FEV1 of 56% of predicted. The patient reported being on several inhaled medications for her emphysema. This patient\u0026rsquo;s case was discussed at the Thoracic Oncology Conference and considering the rapid growth of the nodule and the tree-in-bud pattern of the nodules, it was deemed likely that the underlying cause was infectious rather than cancer.\u003c/p\u003e\u003cp\u003eShe was prescribed an additional three-month course of azithromycin 250 mg daily plus a probiotic. Upon completion of the azithromycin the patient underwent a repeat chest CT scan which revealed that the left lower lobe nodule had decreased in size by about 80% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). The patient had previously declined to have bronchoscopy or a needle biopsy for diagnostic purposes. When infectious disease was consulted, the impression was a nodular pneumonia with tree-in-bud formations in the left lower and middle right lobes of the lung that was consistent with a MAC infection. The remaining nodules appeared stable in size and the patient was subsequently followed with a yearly chest CT scan with no subsequent change in the nodules.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eCASE 3\u003c/h3\u003e\n\u003cp\u003eAn 85-year-old Caucasian female with significant comorbidities was referred to radiation oncology for a spiculated PET scan positive nodule in the right upper lobe of the lung with no significant pulmonary symptoms. A core needle biopsy demonstrated a non-necrotizing granuloma with rare, atypical epithelial cells with negative stains and cultures. Because of concern that the nodule was actually a small cancer, the patient underwent a stereotactic radiation therapy regimen and subsequently returned every three months for CT scans. Upon follow up, the original nodule had dissolved into an area of hazy fibrosis, but a new, PET scan positive nodule was discovered in the right middle lobe (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eA and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). A core needle biopsy revealed necrotizing granulomatous inflammation that was negative for acid-fast bacilli, fungi, and other bacteria on staining. However, the culture from the needle biopsy grew MAC that was susceptible to many of the typical antibiotics, including ethambutol and clarithromycin. There was also a left pleural effusion noted. She was started on 250 mg/day azithromycin with a follow-up chest CT scan scheduled for 6 months later. After six months of azithromycin, the radiologist reported development of the nodule into a more mass-like consolidation and nodular conglomerate in the right middle lobe with improvement of the observed pleural effusion.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAt this time the patient was started on 800 mg/day ethambutol in addition to the azithromycin which was continued at the same dosage. After a further six months, a chest CT revealed the right middle lobe nodule decreased in size and density and was now visible as clusters of 0.5-1.0 cm nodules (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). It was also noted that the pleural effusion had completely resolved. The patient agreed to continue the azithromycin and ethambutol therapy for a further six months and then return for reevaluation. Throughout the course of treatment, the patient denied any cough, fevers, trouble breathing, or other respiratory symptoms, nor any side effects from the antibiotics. She had no recurrence of symptoms or lung nodules long term.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe presence of lung nodules in the lingula segment of the left upper lobe and right middle lobe of the lung caused by MAC in elderly Caucasian females, as illustrated in several of these cases, fits the classical description of Lady Windermere Syndrome\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. This is one of the well-known presentations of MAC characterized by older, slender post-menopausal women often never smokers who tend to suppress their cough due to social norms or a fastidious nature which allows secretions to accumulate in the airways creating a favorable environment for infection\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The older, thin leading lady in Oscar Wilde\u0026rsquo;s 19th century play \u003cem\u003eLady Windermere\u0026rsquo;s Fan\u003c/em\u003e was the syndrome\u0026rsquo;s namesake. Although this infection is uncommon, it appears to be increasing in prevalence in many parts of the world, particularly in warm, humid areas such as Florida where MAC is endemic\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. (Fig.\u0026nbsp;6 Endemic MAC areas).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003ePulmonary MAC versus Lung Cancer\u003c/h3\u003e\n\u003cp\u003eUnfortunately, many patients with lung nodules of probable infectious etiology undergo aggressive follow-up care at similar rates as patients with malignant lung nodules, including procedures such as surgical lung resections, transbronchoscopic biopsy or and transthoracic lung biopsy\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. These procedures carry significant risks, particularly in the usual elderly patients who may be frail and who are often quite reluctant to have an invasive procedure with its risks of pneumothorax, bleeding and need for a chest tube. CT-guided needle biopsies of lung lesions cause pneumothorax in 26% of procedures and carry a 0.12% mortality rate\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Navigational bronchoscopy is 79% accurate, similar to transthoracic needle biopsy, but also carries a pneumothorax and bleeding risk that many elderly patients are reluctant to undergo.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eNationally, 35% of the lung nodules removed at surgery were benign, with most of them found to be an infection.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Aside from the morbidity and potential mortality of an unnecessary lung resection for an infection, the most recent cost according to Medicare claims for lung resections (even a \u0026ldquo;surgical biopsy\u0026rdquo; as it is often called) averages \u003cspan\u003e$\u003c/span\u003e31,900, and most patients will have a significant out-of-pocket co-pay\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Avoiding these procedures is preferrable when the nodules have the clinical and radiographic characteristics of an infection rather than malignancy to avoid overtreatment and iatrogenic injury, in addition to the unnecessary medical costs.\u003c/p\u003e\u003cp\u003eStudies have shown that only 17% of biopsied lung nodules were malignant, whereas 19% of biopsied lung nodules were definitely infectious in origin\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. T. Lokhandwala and associates reported on a SEER database study that 43.7% of CT-guided lung biopsies are unnecessary and do not follow NCCN guidelines.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Aside from the potential morbidity to patients, the monetary cost of unnecessary procedures is considerable. It was documented that for Medicare patients ten years ago from 2011\u0026ndash;2013, the median cost for an \u003cem\u003euncomplicated\u003c/em\u003e needle biopsy was \u003cspan\u003e$\u003c/span\u003e1,071; if there was a complication, the median cost rose to \u003cspan\u003e$\u003c/span\u003e14,824\u003csup\u003e16\u003c/sup\u003e. The median cost of a needle biopsy 4 years later in 2017 from the SEER database rose to \u003cspan\u003e$\u003c/span\u003e4157\u003csup\u003e16\u003c/sup\u003e. These costs further emphasize the need to recognize the presentation of infectious lung nodules to reduce the number of risky, costly, and unnecessary procedures.\u003c/p\u003e\u003cp\u003eObviously, differentiating infectious from malignant nodules is critically important. One key distinction is the evolution of lung nodules over time. Reviews of chest imaging have demonstrated that lung cancers tend to be \u0026ldquo;associated with a fairly steady or accelerated growth\u0026rdquo;, and that growth after 1-year follow up was a strong predictor of malignancy\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Lung nodules that shrink spontaneously are highly unlikely to be cancer. Additionally, there is evidence that supports the finding that spontaneously shrinking lung nodules are caused by NTM infections\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Nodule shrinkage in response to empiric antibiotics in \u003cem\u003eselected\u003c/em\u003e patients is another way of differentiating malignancy from infections.\u003c/p\u003e\u003cp\u003eFDG-PET scans will not discriminate between a benign infectious nodule and a malignant nodule since both will usually have some degree of glucose avidity since leucocytes which mediate the inflammatory response of infectious nodules primarily use glucose as their main energy source.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e While lung cancer will not respond to antibiotics, bacterial infections, particularly NTM infections, will usually decrease in size in response to antibiotic therapy\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eWho is a Candidate for Empiric Azithromycin Monotherapy as a Diagnostic Tool?\u003c/h2\u003e\u003cp\u003eSelective antibiotic treatment of a lung nodule(s) suspected to be infectious with antibiotics represents a safe, non-invasive approach to determine whether an infection is the cause of the abnormal chest CT scan findings. However, a thoracic surgeon or pulmonologist who is very experienced in evaluating lung nodules is the best provider to determine whether an indeterminant lung nodule is more likely an infection, perhaps MAC, and that an empiric antibiotic trial, \u003cem\u003eusually at least 3 months in length\u003c/em\u003e, is indicated. If the nodule does not respond to empiric antibiotics, then an invasive procedure may be performed. If a lung cancer is ultimately documented, then the patient can still have potentially curative treatment, and it is highly unlikely that the peripheral cancer stage or chance for cure has been compromised by a 3-month delay of antibiotic treatment. For this reason, whenever possible, patients with indeterminant lung nodules may significantly benefit by referral to a dedicated lung nodule clinic where they can be evaluated by highly-experienced providers and selective empiric antibiotics may be given if there is a \u003cem\u003ehigh index of suspicion that an infection is present, rather than a malignancy\u003c/em\u003e.\u003c/p\u003e\u003cp\u003eAlthough there is significant overlap, there are some radiologic features that can help differentiate MAC infections from malignant nodules (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). One of the classical features of MAC infections is its location preference for the right middle lobe and lingula of the left upper lobe, although the other lobes also are commonly involved\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. MAC and other non-tuberculous mycobacterial infections also frequently present with the radiographic picture of a \u0026ldquo;tree-in-bud\u0026rdquo; nodularity that can be useful in identifying nodules of infectious origin\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. However, spontaneous shrinking of nodules or a decrease in size in response to antibiotics such as azithromycin are further radiologic findings that are highly indicative of MAC infection. An empirical course of azithromycin is not intended as curative for presumed MAC infection but rather it is done as a diagnostic measure to see if there is significant decrease in the size of the nodule.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCOMMON CHARACTERISTICS OF PATIENTS WITH MYCOBACTERIUM AVIUM COMPLEX (MAC) LUNG INFECTION\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCHARACTERISTIC\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFINDINGS\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ePatient Factors\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmenopausal female, frequently thin\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;65 years old\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCough\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDry cough or with occasional clear to yellow mucus\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eActivity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCommonly works out in garden or yard\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLocation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLives in endemic area, especially humid, warm climate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eImmune Function\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMay or may not be immunosuppressed\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSmoking history\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigher risk if current or former smoker\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFever or Night Sweats\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRare fevers but some with night sweats (may be difficult to differentiate from menopausal symptoms)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther symptoms\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRare hemoptysis, weight loss, dyspnea or fatigue unless severe disease.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRadiographic Features\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCT scan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSpeculated, peripheral infiltrative nodule(s). May have waxing and waning nodules over years. Most common location is right middle lobe and left upper lobe lingula.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFDG-PET Scan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow-moderate level uptake of glucose (present in infection and in cancer); minimal or no uptake in lymph nodes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLymphadenopathy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNone or minimal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLesions in Other Areas of Lungs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNodular densities, especially if \u0026ldquo;tree-in-bud\u0026rdquo; pattern\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEvidence of Chronic Lung Disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eParticularly susceptible to MAC, especially bronchiectasis or COPD\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eNote: Few MAC lung infection patients will have all of these characteristics.\u003c/p\u003e\u003cp\u003eThe standard infectious disease recommendation for MAC treatment is triple drug therapy (macrolide, ethambutol and rifampin) for 12 months.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Macrolide monotherapy is discouraged because of the concern for rapid drug resistance and this has be reported in a few patients in several case studies, all of which involve patients with upper lobe cavitary disease, nodular disease with bronchiectasis, or cystic fibrosis where there is a high inoculum of organisms.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e However another case series of 29 patients without human immunodeficiency virus but with fibrocavitary disease and bilateral disease who were treated for 6 months with azithromycin monotherapy resulted in 76% of patients with reduced positive sputums and \u003cem\u003eno\u003c/em\u003e drug resistance during monotherapy.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e A large multicenter study of 88 AIDS patients with disseminated MAC with symptoms and positive blood cultures treated with azithromycin monotherapy resulted in blood culture sterilization of 54% and drug resistance in only one patient (1.1%).\u003csup\u003e26\u003c/sup\u003e Macrolide resistance with monotherapy is a rare event and generally occurs only in high inoculum Mycobacterium infections found in large cavities and extensive bronchiectasis. But in lung nodules with granulomata, there is much less chance for resistance since there are less organisms. In fact, apparent refractory MAC infections are commonly caused by reinfection with new strains rather than the original strain which may explain the quite infrequent development of macrolide resistance.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Therefore, a short \u003cem\u003ediagnostic\u003c/em\u003e empiric trial of azithromycin monotherapy for 3 months for patients with non-cavitary minimally symptomatic disease to illicit a favorable radiographic response verifying a benign diagnosis is reasonable and safe and \u003cem\u003emay prevent the need for a major invasive procedure including unnecessary surgical resection for an infection.\u003c/em\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDoes Every Patient with MAC Need Treatment?\u003c/h3\u003e\n\u003cp\u003eAlthough the literature reports pulmonary MAC cure rates of 32\u0026ndash;65% with 12-month macrolide-containing triple drug regimens, there are high rates of drug intolerance (43%)\u003csup\u003e28\u003c/sup\u003e and recurrent disease, usually from reinfection with different strains and not treatment failures.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Most of the drug intolerance leading to discontinuation of therapy is from the rifampin adverse effects. In fact there is good evidence that rifampin can be omitted so that a two drug regimen of azithromycin and ethambutol works equally well for MAC treatment (as seen in Case 3) without the frequent and serious rifampin toxicity.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe macrolide favored almost all of the time now is azithromycin with single-day dosage and rare side effects, unlike the poorly tolerated clarithromycin. Many regulatory agencies such as the U.S. Food and Drug Administration warn of the potential risk ventricular arrhythmias with macrolide antibiotics due to potential elongation of the corrected QT interval (QTc) on the electrocardiogram. This risk is quite overstated, and numerous studies strongly refute this risk in older patients\u0026thinsp;\u0026gt;\u0026thinsp;65 years, even those with chronic kidney disease, congestive heart failure, coronary artery disease and concurrent use of a drug known to prolong the QT interval.\u003csup\u003e\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e A 2015 study by M. Trac and associates in a very large population-based retrospective propensity-matched cohort study in Ontario found no higher risk of ventricular arrhythmias in 616,359 patients receiving macrolide versus 705,132 patients receiving non-macrolide antibiotics (amoxicillin, cefuroxime or levofloxacin).\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eHowever, in immunocompetent patients with good nutritional status, no AIDS, minimal or no symptoms and without fibro-cavitary or nodular bronchiectatic disease, the diagnosis of MAC does not require immediate initiation of treatment. As many as 40\u0026ndash;60% of patients with MAC remain free of progression for years without treatment. Furthermore, 40\u0026ndash;50% with untreated MAC achieve spontaneous culture negative conversion without antibiotic treatment. \u0026ldquo;Therefore, to avoid unnecessary treatments that might cause unwarranted medical expenses and adverse drug reactions, clinicians should consider the risk of disease progression and make timely decisions in the treatment initiation phase.\u0026rdquo;\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eGiven the complexity of correctly identifying these infections, understanding the varying clinical presentations of non-tuberculous mycobacterial lung diseases is becoming increasingly important. The infections presented in this report were largely asymptomatic or presented only with a slight productive cough but were initially suspected of being malignancies. In two cases these infections were discovered incidentally during a screening procedure for a suspected lung carcinoma.\u003c/p\u003e\u003cp\u003eIn many such cases, suspicion of malignant nodules can lead to otherwise unnecessary aggressive procedures, such as the upper lobectomy that was almost performed in the patient in Case 1. Fortunately, the results of the bronchoalveolar lavage culture prevented an unnecessary and potentially harmful procedure. Similarly, Case 2 avoided adverse treatment, even though the infection could have been mistaken for lung cancer based on the initial imaging. Additionally, considering that the patient in Case 3 had already received radiation therapy for a suspected lung malignancy (although it was likely MAC), it is fortunate that she underwent a core biopsy before receiving unnecessary additional radiation. In each of these cases, the patient was successfully treated medically, but the ability of MAC infections to mimic lung cancer on imaging necessitates awareness of both the prevalence and clinical manifestations of this disease.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eMany non-malignant etiologies are capable of mimicking lung cancer and can lead to invasive and expensive workups. Pulmonary nodules caused by nontuberculous mycobacterium are one of the most common mimics of lung cancer. Recognizing the classic patterning of peripheral nodules in a tree-in-bud pattern along with bronchiectasis, and mucous plugs on chest CT scans, combined with the rapid development in the size and number of nodules can suggest an infectious etiology such as MAC pneumonia. If there is a high suspicion of MAC by a highly- experienced pulmonary physician, then it is reasonable to proceed with an empiric course of azithromycin for 3 months \u003cem\u003ewithout\u003c/em\u003e an initial biopsy followed by re-imaging. Due to its immune modulating properties to reduce inflammation and its consistent mycobactericidal activity, a trial of three months of empiric azithromycin can reduce the nodule size and confirm a non-cancer etiology. This therapy also has a low risk of promoting macrolide resistance should further non-tuberculous mycobacterial therapy be needed. In the end, this practice has reduced unnecessary surgery, invasive needle biopsy, and provided relief from the anxiety of having a cancer diagnosis. Follow up with regular chest CT scans for life can further alleviate fears of cancer and monitor possible progression of chronic pulmonary MAC infections that may warrant aggressive antibiotic treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eCT scan:\u0026nbsp;\u003c/strong\u003eComputed tomography scan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFEV1:\u003c/strong\u003e Forced expiratory volume at 1 second.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMAC:\u003c/strong\u003e \u003cem\u003eMycobacterium avium\u0026nbsp;\u003c/em\u003ecomplex\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFDG-PET scan:\u003c/strong\u003e Fluorodeoxyglucose positron emission tomographic scan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNCCN:\u0026nbsp;\u003c/strong\u003eNational Comprehensive Cancer Network\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNTM:\u003c/strong\u003e Non-tuberculous mycobacteria\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSEER:\u0026nbsp;\u003c/strong\u003eSurveillance, Epidemiology and End Results Program database\u0026nbsp;\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003eFunding Sources: None\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eEthics Approval:\u0026nbsp;\u003c/strong\u003eThis retrospective chart review of 3 de-identified cases was considered exempt from the need for IRB approval.\u003cbr\u003e\u003cstrong\u003ePatient Consent:\u0026nbsp;\u003c/strong\u003eWritten informed consent was obtained from the patients for publication of this case report and\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eaccompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials:\u003c/strong\u003e Electronic medical record at Moffitt Cancer Center.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e The authors declare no real or potential conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors Contributions:\u003c/strong\u003e DJ: analyzed clinical data regarding lung nodules and wrote the initial manuscript draft. JG: provided the conceptualization and design, interpreted the clinical data, and revised the draft. LR: provided the patient data to analyze, interpreted the clinical data, made the decision to publish, and revised the draft to its final form. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s Information:\u003c/strong\u003e \u003cstrong\u003eD.J.\u003c/strong\u003e has a B.S. degree in microbiology and currently is a 3\u003csup\u003erd\u003c/sup\u003e year MD/PhD medical student at the University of South Florida College of Medicine, Tampa, FL. \u003cstrong\u003eJ.G.\u003c/strong\u003e is Professor of Medicine, Infectious Diseases, Section Chief, Infectious Disease \u0026amp; Epidemiology, Moffitt Cancer Center, Tampa, FL. \u003cstrong\u003eL.R.\u0026nbsp;\u003c/strong\u003eis Professor of Surgery in the Division of Thoracic Oncology, and is Director, Lung Cancer Early Detection (LEAD) Center and the Indeterminant Lung Nodule Clinic, Moffitt Cancer Center, Tampa, FL\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMazzone PJ, Lam L. Evaluating the Patient With a Pulmonary Nodule: A Review. Jama 2022;327:264-73.\u003c/li\u003e\n\u003cli\u003eOsarogiagbon RU, Liao W, Faris NR, et al. Lung Cancer Diagnosed Through Screening, Lung Nodule, and Neither Program: A Prospective Observational Study of the Detecting Early Lung Cancer (DELUGE) in the Mississippi Delta Cohort. J Clin Oncol 2022;40:2094-105.\u003c/li\u003e\n\u003cli\u003ede Groot PM, Wu CC, Carter BW, Munden RF. The epidemiology of lung cancer. Transl Lung Cancer Res 2018;7:220-33.\u003c/li\u003e\n\u003cli\u003eAllison RD, Vincent AL, Greene J, Sandin RL, Field T. Infectious pulmonary nodules mimicking lung carcinoma. Infections in Medicine 2004;21:181-6.\u003c/li\u003e\n\u003cli\u003eHong SJ, Kim TJ, Lee JH, Park JS. Nontuberculous mycobacterial pulmonary disease mimicking lung cancer: Clinicoradiologic features and diagnostic implications. Medicine (Baltimore) 2016;95:e3978.\u003c/li\u003e\n\u003cli\u003eReich JM, Johnson RE. Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern. The Lady Windermere syndrome. Chest 1992;101:1605-9.\u003c/li\u003e\n\u003cli\u003eHolt MR, Miles JJ, Inder WJ, Thomson RM. Exploring immunomodulation by endocrine changes in Lady Windermere syndrome. Clin Exp Immunol 2019;196:28-38.\u003c/li\u003e\n\u003cli\u003ePrevots DR, Marras TK. Epidemiology of human pulmonary infection with nontuberculous mycobacteria: a review. Clin Chest Med 2015;36:13-34.\u003c/li\u003e\n\u003cli\u003eAdjemian J, Olivier KN, Seitz AE, Holland SM, Prevots DR. Prevalence of nontuberculous mycobacterial lung disease in U.S. Medicare beneficiaries. Am J Respir Crit Care Med 2012;185:881-6.\u003c/li\u003e\n\u003cli\u003eFigueroa CJ, Riedel E, Glickman MS. Clinical and radiographic differentiation of lung nodules caused by mycobacteria and lung cancer: a case\u0026ndash;control study. BMC Infectious Diseases 2015;15:482.\u003c/li\u003e\n\u003cli\u003eMills M, Choi J, El-Haddad G, et al. Retrospective analysis of technical success rate and procedure-related complications of 867 percutaneous CT-guided needle biopsies of lung lesions. Clin Radiol 2017;72:1038-46.\u003c/li\u003e\n\u003cli\u003eLentz RJ, Frederick-Dyer K, Planz VB, et al. Navigational Bronchoscopy or Transthoracic Needle Biopsy for Lung Nodules. New England Journal of Medicine 2025;392:2100-12.\u003c/li\u003e\n\u003cli\u003eTanner NT, Aggarwal J, Gould MK, et al. Management of Pulmonary Nodules by Community Pulmonologists: A Multicenter Observational Study. Chest 2015;148:1405-14.\u003c/li\u003e\n\u003cli\u003eCowper PA, Feng L, Kosinski AS, et al. Initial and Longitudinal Cost of Surgical Resection for Lung Cancer. Ann Thorac Surg 2021;111:1827-33.\u003c/li\u003e\n\u003cli\u003eGeorgiadou SP, Sampsonas FL, Rice D, Granger JM, Swisher S, Kontoyiannis DP. Open-lung biopsy in patients with undiagnosed lung lesions referred at a tertiary cancer center is safe and reveals noncancerous, noninfectious entities as the most common diagnoses. Eur J Clin Microbiol Infect Dis 2013;32:101-5.\u003c/li\u003e\n\u003cli\u003eLokhandwala T, Bittoni MA, Dann RA, et al. Costs of Diagnostic Assessment for Lung Cancer: A Medicare Claims Analysis. Clin Lung Cancer 2017;18:e27-e34.\u003c/li\u003e\n\u003cli\u003eLarici AR, Farchione A, Franchi P, et al. Lung nodules: size still matters. Eur Respir Rev 2017;26.\u003c/li\u003e\n\u003cli\u003eKinjo T, Uechi K, Kami W, Fujita J. Spontaneously shrinking lung mass due to Mycobacterium avium mimicking lung cancer. Clin Case Rep 2021;9:e05006.\u003c/li\u003e\n\u003cli\u003eKramer PA, Ravi S, Chacko B, Johnson MS, Darley-Usmar VM. A review of the mitochondrial and glycolytic metabolism in human platelets and leukocytes: Implications for their use as bioenergetic biomarkers. Redox Biology 2014;2:206-10.\u003c/li\u003e\n\u003cli\u003eThompson WH. Bronchioloalveolar carcinoma masquerading as pneumonia. Respir Care 2004;49:1349-53.\u003c/li\u003e\n\u003cli\u003eVerma N, Chung JH, Mohammed TL. \u0026quot;Tree-in-bud sign\u0026quot;. J Thorac Imaging 2012;27:W27.\u003c/li\u003e\n\u003cli\u003eHaworth CS, Banks J, Capstick T, et al. British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). Thorax 2017;72:ii1-ii64.\u003c/li\u003e\n\u003cli\u003eGriffith DE, Brown-Elliott BA, Langsjoen B, et al. Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2006;174:928-34.\u003c/li\u003e\n\u003cli\u003eLoewenstein D, van Balveren L, Lemson A, Hanemaaijer N, Hoefsloot W, van Ingen J. Monotherapy: Key cause of macrolide-resistant Mycobacterium avium complex disease. Respir Med 2023;217:107366.\u003c/li\u003e\n\u003cli\u003eGriffith DE, Brown BA, Girard WM, Murphy DT, Wallace RJ, Jr. Azithromycin Activity Against Mycobacterium avium Complex Lung Disease in Patients Who Were Not Infected with Human Immunodeficiency Virus. Clinical Infectious Diseases 1996;23:983-9.\u003c/li\u003e\n\u003cli\u003eKoletar SL, Berry AJ, Cynamon MH, et al. Azithromycin as treatment for disseminated Mycobacterium avium complex in AIDS patients. Antimicrob Agents Chemother 1999;43:2869-72.\u003c/li\u003e\n\u003cli\u003eJhun BW, Kim SY, Moon SM, et al. Development of Macrolide Resistance and Reinfection in Refractory Mycobacterium avium Complex Lung Disease. Am J Respir Crit Care Med 2018;198:1322-30.\u003c/li\u003e\n\u003cli\u003eMarmor M, Sharifi H, Jacobs S, Fazeli K, Ruoss S. Variables associated with antibiotic treatment tolerance in patients with Mycobacterium avium complex pulmonary disease. Respir Res 2024;25:123.\u003c/li\u003e\n\u003cli\u003eKwon YS, Koh WJ, Daley CL. Treatment of Mycobacterium avium Complex Pulmonary Disease. Tuberc Respir Dis (Seoul) 2019;82:15-26.\u003c/li\u003e\n\u003cli\u003eSchildkraut JA, Raaijmakers J, Aarnoutse R, Hoefsloot W, Wertheim HFL, Ingen Jv. The role of rifampicin within the treatment of \u0026lt;i\u0026gt;Mycobacterium avium\u0026lt;/i\u0026gt; pulmonary disease. Antimicrobial Agents and Chemotherapy 2023;67:e00874-23.\u003c/li\u003e\n\u003cli\u003eTrac MH, McArthur E, Jandoc R, et al. Macrolide antibiotics and the risk of ventricular arrhythmia in older adults. Cmaj 2016;188:E120-e9.\u003c/li\u003e\n\u003cli\u003eKhosropour CM, Capizzi JD, Schafer SD, Kent JB, Dombrowski JC, Golden MR. Lack of Association between Azithromycin and Death from Cardiovascular Causes. New England Journal of Medicine 2014;370:1961-2.\u003c/li\u003e\n\u003cli\u003eMortensen EM, Halm EA, Pugh MJ, et al. Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. Jama 2014;311:2199-208.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Lung nodules, Mycobacterium avium complex, lung cancer, macrolide antibiotics","lastPublishedDoi":"10.21203/rs.3.rs-7328728/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7328728/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBACKGROUND\u003c/b\u003e\u003c/p\u003e\u003cp\u003eInfection with non-tuberculous mycobacterium species commonly can present with lung nodules mimicking lung cancer on routine chest imaging leading to unnecessary invasive procedures.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCASE SERIES\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe authors report three representative cases in which a probable \u003cem\u003eMycobacterium avium-\u003c/em\u003e complex (MAC) infection was discovered incidentally that mandated evaluation for a potential malignancy. After suspecting that the nodules were likely infectious and not malignant, the patients were empirically treated with azithromycin alone or in combination with other antibiotics. In each case, this treatment improved the appearance of these nodules on radiographic imaging in size, density, or both, documenting an infectious etiology thereby preventing more invasive studies and/or surgery.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCONCLUSIONS\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThese cases present typical examples of an increasingly prevalent infection commonly seen that can be mistaken for lung cancer by oncologists, particularly in endemic areas such as the Southeast U.S. Many non-malignant etiologies are capable of mimicking lung cancer including the most common, nontuberculous mycobacterium. An empiric 3-month course of azithromycin for highly suspected MAC lung infection that results in a significant reduction in the size of the nodule will verify that it is infectious and not malignant. Recognizing probable infectious lung nodules may prevent invasive, potentially morbid and expensive clinical evaluations including unnecessary surgery.\u003c/p\u003e","manuscriptTitle":"Mycobacterium Avium Complex (MAC) Lung Infection Mimics Lung Cancer Nodules But Improves After Antibiotic Therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-09 11:12:06","doi":"10.21203/rs.3.rs-7328728/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8e938962-8c76-4d2c-a767-a1130a0932bf","owner":[],"postedDate":"September 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-07T06:54:20+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-09 11:12:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7328728","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7328728","identity":"rs-7328728","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}