Case Series

Infectious Causes of Right Middle Lobe Syndrome Aatif Rashid, MD, Sowmya Nanjappa, MBBS, MD, and John N. Greene, MD

Summary: Right middle lobe (RML) syndrome is defined as recurrent or chronic obstruction or infection of the middle lobe of the right . Nonobstructive causes of middle lobe syndrome include inflammatory processes and defects in the bronchial anatomy and collateral ventilation. We report on 2 case patients with RML syndrome, one due to infection with Mycobacterium avium complex followed by M asiaticum infection and the other due to allergic bronchopulmonary aspergillosis. A history of atopy, , or chronic obstruc- tive pulmonary disease has been reported in up to one-half of those with RML. The diagnosis can be made by plain radiography, computed tomography, and bronchoscopy. Medical treatment consists of bronchodilators, mucolytics, and antimicrobials. Patients whose disease is unresponsive to treatment and those with obstruc- tive RML syndrome can be offered surgical treatment.

Introduction monary disease due to MAC infection in immunocom- The term middle lobe syndrome (MLS) was first used petent individuals can be divided into a primary form, by Graham et al1 in 1948, and the disease is defined which occurs in healthy persons who do not smoke, as recurrent or chronic collapse or infection of the middle lobe of the right lung. MLS can present in per- sons of any age. The syndrome is divided into an ob- Table 1. — Obstructive and Nonobstructive Causes of structive type (demonstrable airway occlusion) and a Middle Lobe Syndrome nonobstructive type (patent right middle lobe [RML] Sign/Symptom Obstructive Non- ). Obstructive MLS can be caused either by Cause obstructive endobronchial lesions or extrinsic compression of the Cause RML bronchus. Malignancy is the most common cause Aspirated foreign body (especially in X of the obstructive type followed by an infectious etiolo- children) gy (Tables 1 and 2).2-14 Benign tumors (eg, hamartomas) Benign tumor (eg, hamartoma) X and malignant tumors (eg, primary lung cancer, me- Broncholiths endobronchially eroding X tastasis) alike can cause obstructive MLS and account from adjacent, calcified lymph nodes for up to 25% of cases.2 The most common cause of ex- Cardiovascular anomaly X trinsic compression of the RML bronchus is peribron- Endoluminal associated X chial lymphadenopathy due to infection, , with sarcoidosis and metastasis.3 Nonobstructive causes of MLS include Enlarged peribronchial lymph nodes X inflammatory processes and defects in the bronchial (infection, sarcoidosis, metastasis) 15,16 causing extrinsic compression of anatomy and collateral ventilation. right middle lobe bronchus We report on 2 cases of RML syndrome, one due Etiology not completely understood X to infection with Mycobacterium avium complex Inflammation of the middle lobe and X (MAC) followed by infection with M asiaticum and the lingual area other due to allergic bronchopulmonary aspergillo- Infectious etiology X sis (ABPA). MAC is the most common nontuberculous Mycobacteria (NTM) species to infect humans.6 Pul- Inspissated mucus associated with X or allergic bronchopul- monary aspergillosis From the Departments of Internal Hospital Medicine (SN) and Insufficient collateral ventilation X Infectious Diseases (JNG), H. Lee Moffitt Cancer Center & Research Institute (AF), and the University of South Florida Morsani Col- Malignant tumor (eg, primary lung X lege of Medicine (SN), Tampa, Florida. cancer, metastases) Address correspondence to John N. Greene, MD, Department of Primary ciliary dyskinesia X Infectious Diseases, Moffitt Cancer Center, 12902 Magnolia Drive, FOB-3 BMT PROG, Tampa, FL 33612. E-mail: [email protected] Situs inversus/other congenital X malformations Submitted March 1, 2016; accepted June 24, 2016. No significant relationships exist between the authors and the Traction diverticula of the X companies/organizations whose products or services may be Data from references 2 to 5, 7 to 10, and 13. referenced in this article.

60 Cancer Control January 2017, Vol. 24, No. 1 and a secondary form, which occurs new changes in the left lower lobe, in persons with underlying lung dis- Table 2. — Infectious Causes of posterior , and distal Middle Lobe Syndrome ease (eg, chronic obstructive pulmo- nodularity when compared with the nary disease [COPD], latent tubercu- Actinobacteria results on CT obtained 4 years prior losis, bronchiectasis, cystic fibrosis). Aspergillus species (Fig 1). She was treated with azithro- In general, the primary form affects Blastomyces species mycin and trimethoprim/sulfa- elderly women who are otherwise Bordetella pertussis methoxazole and advised to undergo healthy nonsmokers, and it presents surgical removal of the RML. Chlamydophila psittaci with an interstitial/nodular pattern Six months later she underwent on chest radiography.6 M asiaticum is Echinococcal pulmonary hydatid disease RML resection due to progressive a slow-growing mycobacterium spe- Haemophilus symptoms and severe bronchiec- cies first recognized in Australia by Histoplasma species tasis predominantly in the RML. Blacklock et al17 in the early 1980s. Moraxella catarrhalis Findings on histopathology showed They surmised that M asiaticum Mycobacterium avium intracellulare necrotizing granulomatous bron- was a potential pulmonary pathogen Mycobacterium fortuitum chiolitis. Results from acid-fast ba- among individuals with an underly- cilli tissue staining were positive Mycobacterium ing chronic respiratory problem such with areas of chronic and as COPD.17 . She was then treated Persons with chronic lung dis- Streptococcus on azithromycin monotherapy for ease are at risk of Aspergillus coloni- Data from references 6, 8, and 11 to 14. approximately 5 years with inter- zation and infection.18 ABPA occurs mittent courses of trimethoprim/ as a result of hypersensitivity to colonizing Aspergillus sulfamethoxazole. species in the airways of persons with asthma, NTM Five years following resection of the RML, she infection, and cystic fibrosis.8 It affects 2% of those returned for evaluation with symptoms of hemopty- with asthma.19 MLS caused by ABPA has rarely been sis, persistent , and pleuritic . Find- documented.19 ings on CT demonstrated new areas of nodularity in the anterior medial lingular area with bronchial wall Case Reports thickening, tree-in-bud nodules in the right posterior Case 1 lung, and an increase in nodularity in the left medial A woman aged 55 years presented with a 10-year his- posterior lung (Fig 2). BAL cultures grew M asiaticum tory of chronic cough with no prior history of smoking. sensitive to amikacin, ciprofloxacin, azithromycin, Serial computed tomography (CT) of the chest was ob- ethambutol, , rifabutin, and trime- tained prior to her referral to our center. Bronchoalve- thoprim/sulfamethoxazole. olar lavage (BAL) was performed and the culture grew She was treated with azithromycin and trime- M avium intracellulare (MAI). She was treated with oral thoprim/sulfamethoxazole for 6 months. Her symptoms azithromycin, ethambutol, and rifampin for 1.5 years. resolved, and she has remained without any unwanted After several years of taking , she devel- change in weight or significant pulmonary complaints, oped . Repeat BAL was performed and the except for an occasional nonproductive cough, for culture grew methicillin-resistant Staphylococcus au- 3 years following the discontinuation of the antibiotics. reus, so she was treated with oral and trimethoprim/ sulfamethoxazole for 2 weeks. Following treatment the patient felt better but still had intermit- tent cough and periodic right lat- eral chest pain. Following 1 month off antibiotics, BAL was again performed and the culture grew both MAI and methicillin-resistant S aureus. CT of the chest was obtained and revealed persistent RML bron- chiectasis and distal nodularity, with new nodules and bronchiectasis in Fig 1. — Computed tomography showing the right middle lobe with large amounts of clustered the superior segment of the right bronchiectasis, distal nodularity. Nodules and bronchiectasis in the superior segment of the right lower lobe. CT results also showed and left lower lobes are also present.

January 2017, Vol. 24, No. 1 Cancer Control 61 Case 2 A white woman aged 48 years with a history of rheumatoid arthri- tis was receiving treatment with methotrexate, adalimumab, and sulfasalazine. She also had a history of asthma requiring therapy with a β-agonist inhaler and intermittent corticosteroids. Approximately 3 months prior to her presentation, she developed right upper quadrant abdominal pain. Imaging of her abdomen and Fig 2. — Computed tomography of the chest showing a large mass with a lobulated, scalloped border chest was obtained, the results of in the right middle lobe. which showed a large mass in her RML approximately 6 cm in diam- eter. Transthoracic needle biop- sy was performed that revealed chronic nongranulomatous inflam- mation with septate hyphae con- sistent with Aspergillus infection. No cultures were sent. Findings from acid-fast bacilli stains were negative. CT and positron emis- sion tomography were performed, and the results showed increasing uptake and a lesion thought to be postobstructive pneumonia (Fig 3). Repeat needle biopsy was per- formed and demonstrated septate Fig 3. — Findings on positron emission tomography showing increasing uptake and size of the lesion. hyphae, also consistent with Asper- gillus infection. After repeat needle biopsy, she experi- a more rapid resolution of the RML mass because of enced hemoptysis that lasted nearly 2 weeks. the 3-week course of voriconazole and short-term cor- She was referred to our institution to rule out can- ticosteroids she received, thereby suggesting an aller- cer and to consider surgical resection of the RML. At gic immune response to the aspergillosis with possible that time, she was having occasional cough and peri- , rather than an invasive infection. odic exacerbations of her asthma. We suspected that She remains asymptomatic except for occasional she had ABPA and chronic necrotizing Aspergillus in- bouts of asthma-like symptoms, which are controlled fection complicating her underlying asthma and caus- with inhaler therapy. ing RML syndrome. She was started on twice-daily oral voriconazole 200 mg. Discussion Although her treatment plan consisted of 3 months RML syndrome is a phenotype associated with infec- of therapy, she developed a diffuse rash after taking tive and noninfective etiologies (see Tables 1 and 2).2-14 voriconazole 200 mg for 3 weeks. Thus, voriconazole In general, the onset of symptoms of RML syndrome was discontinued; the rash disappeared approximately is insidious and can include chronic cough, purulent 1 week later. She was then started on oral posacon- production, unintentional weight loss, , azole, but after several days the drug was discontinued lethargy, hemoptysis, chest pain, and night sweats. because the patient experienced hematuria. Her cough Many patients with RML syndrome have chronic cough resolved while in our care, and she felt that her over- with purulent sputum production as their only symp- all condition had improved; thus, she decided to forgo toms. A history of recurrent or chronic pneumonia surgical intervention. may be present. Although RML syndrome occurs in all Follow-up CT was obtained 1.5 months later, the age groups, its precise incidence rate in children is un- results of which showed a residual area of bronchiec- known; however, it may occur twice as often in girls tasis and absence of a mass in the RML. The patient than boys.9 In adults, it is approximately 1.5 to 3 times discontinued immunosuppressive therapy for her more common in women.13 A history of atopy, asthma, rheumatoid arthritis. We surmise that the patient had or COPD has been reported in up to 50% of patients

62 Cancer Control January 2017, Vol. 24, No. 1 with RML syndrome.2,20 When it is associated with cases.27 M asiaticum and MAC infections cause cavi- MAC infection, the disease typically occurs in wom- tary and nodular diseases. The clinical and radiograph- en with a slender build who have thorax or sternum ical characteristics of this clinical syndrome are initial deformities; for example, Pomerantz et al21 described involvement of the periphery of the lingula or its coun- most of their patients as slender women with skeletal terpart, the middle lobe, and the absence of clinically abnormalities (eg, pectus excavatum, mild scoliosis, evident predisposing pulmonary disorders, with these straight back syndrome, mitral valve prolapse). It has features being almost exclusive to older women.23 also been associated with the continuous use of anti- Pulmonary disease caused by Afumigatus infec- tussive drugs.22 In all cases, treatment is directed at the tion is classified into 3 groups: aspergilloma, ABPA, underlying etiology. and invasive aspergillosis. Diagnosis is based on serol- Reich and Johnson23 hypothesized that women ogy, examination of sputum/BAL fluid, and radiologi- were more likely to regard expectoration as socially cal imaging. The radiological features for Aspergillus unacceptable behavior, so they may habitually sup- infection–related lung disease include tree-in-bud nod- press voluntary cough, which leads to an inability to ules and cavities mimicking those of NTM infection. clear secretions (especially from the middle lobe and Clinical and serological criteria, including episodic lingula), resulting in a chronic nidus for inflammation bronchial obstruction (asthma), peripheral blood eo- that favors subsequent infection. sinophilia, and positive Aspergillus serology, are used Anatomically, the middle lobe and lingula have in to diagnose ABPA because the radiological features common long, narrow-diameter, dependent bronchi of ABPA (central bronchiectasis and pulmonary in- (in an upright position) at an acute angle, thus mak- filtrates) are difficult to differentiate in patients with ing it more difficult to clear secretions that predispose bronchiectasis and NTM infection.28 This is important them to infection. Furthermore, the middle lobe and because an association may exist between NTM infec- lingula contain minimal parenchymal bridges due to tion and Aspergillus infection–related lung disease. deep fissures that provide effective barriers to collat- These conditions may be associated with one another eral ventilation and isolate these lobes, thereby reduc- because patients with NTM infection receive multiple, ing the likelihood of reinflation once has broad-spectrum antibiotics that predispose them to occurred. Aspergillus infection.29 In addition, use of steroids or Nearly one-half of healthy adults aspirate small chronic immunosuppression due to chronic lung dis- amounts of oropharyngeal secretions while asleep.24 orders, such as RML syndrome, may predispose these A low burden of pathogenic in these secre- patients to both NTM infection and Aspergillus–related tions — together with forceful coughing, active ciliary lung disease.29 transport, and normal immune mechanisms — can re- sult in the clearance of infectious material without se- Imaging quelae. The risk of aspiration is higher in elderly per- Findings on chest roentgenography or CT in patients sons because of increased incidences of and with RML syndrome often show evidence of infection gastroesophageal reflux in this population.25 Adults of the RML or left lingular lobe of the lung. The volume with impaired cough or voluntary cough suppres- loss resulting from collapse of the RML is seen on chest sion are at risk for developing infection and aspiration radiographs as a triangular hyperdensity area between pneumonia, particularly in the RML.25 the minor fissure and the lower half of the major fis- In general, infectious agents associated with RML sure, with the apex at the hilum and the base periph- syndrome in children include Streptococcus pneumonia erally toward the pleura.30 Posterior radiography may and ; by contrast, the causes also reveal blurring of the right cardiac border called are more diverse in adults and include MAC and other the silhouette sign). Obtaining high-resolution CT may NTM, and M tuberculosis, as well as Histoplasma, be useful to delineate bronchial patency, any associ- Blastomyces, and Aspergillus species.6,12,13 Granulo- ated bronchiectasis, and other causes of extrinsic com- matous infections, such as tuberculosis, histoplasmo- pression of the RML airway. Flexible bronchoscopy al- sis, and blastomycosis, can cause enlargement of the lows the clinician to evaluate the patency of the RML peribronchial lymph nodes that may lead to RML syn- bronchus and collect specimens for the diagnosis of drome.13 Chronic infection with Pseudomonas aeru- infectious causes. Endobronchial ultrasonography can ginosa commonly occurs in cases of bronchiectasis help detect extrinsic compressions due to lymph-node and is associated with increased symptoms and a de- enlargement and calcifications. Ultrasonography can creased quality of life.26 also reveal occult lung atelectasis in neonates.12,31 Risk factors for MAC and M asiaticum infections are similar to those observed for other NTM species, Nonsurgical Treatment with COPD and bronchiectasis being the most com- Treatment is directed toward the underlying cause. monly observed preexisting conditions in pulmonary Bronchodilators, mucolytic agents, and antimicrobials

January 2017, Vol. 24, No. 1 Cancer Control 63 can be used in cases of nonobstructive MLS. MLS associated with asthma responds to inhaled corticoste- Surgical removal of the middle lobe is reserved for per- roids and bronchodilators. Antimicrobials are based on sistent, complex cases of MLS unresponsive to therapy culture or sensitivity reports from BAL fluid or sputum. and among those whose middle lobe bronchus is ob- Broad-spectrum antimicrobials that cover streptococci, structed. Recurrent hemoptysis in a patient with MLS H influenza, Moraxella catarrhalis, and Pseudomo- for whom interventional techniques have not nas species can also be used in certain circumstances. been successful is also an indication for surgery. Ma- Early use of aggressive therapy may more lignancy warrants removal of the middle lobe, togeth- successfully eradicate organisms such as Pseudomo- er with the surrounding hilar and mediastinal lymph nas species, and it may also have a beneficial role on nodes. Surgery may also be considered in patients with subsequent exacerbation rates, because chronic infec- MLS who have scarring, fibrosis, and abscess forma- tion with organisms such as P aeruginosa is associated tion. Surgical intervention can be considered in pa- with worse quality of life, increased exacerbation fre- tients with nonobstructive MLS if their symptoms per- quency, and rapidly declining lung function.26 sist and radiological evidence of chronic atelectasis is Consideration must also be given to atypical seen after prolonged medical therapy (~ 6 months).13 mycobacteria, fungi, and other unusual infections. Low-dose macrolide therapy may improve quality of Conclusions life — particularly if bronchiectasis is present — and Diagnosis of right middle lobe (RML) syndrome may some have advocated for the long-term rotation of be delayed or go unnoticed unless this unusual pattern antibiotics (3 weeks on, 1 week off, and then alternate is recognized and appropriate diagnostic studies are antibiotics).32 employed. Oftentimes, patients with RML syndrome The success rate of treating MAC-related lung will have a history of multiple treatments for recurrent disease with macrolide-containing antibiotic regi- pneumonia or asthma. The middle lobe and lingula are mens is between 60% and 80%; however, failed treat- predisposed to inflammation and infection because of ment responses occur in 20% to 40% of patients, and their anatomical structures and the absence of collater- some whose disease is successfully treated still expe- al ventilation. Most patients with nonobstructive mid- rience recurrence.33 Unlike M tuberculosis infection, dle lobe syndrome respond to bronchodilators, muco- MAC-related lung disease may be more likely to recur lytics, and broad-spectrum antibiotics. Patients whose in patients with factors predisposing them to the ac- disease is unresponsive to medical treatment and those quisition of new bacterial strains rather than the per- with obstructive RML syndrome may be candidates for sistence of the bacilli.33 The recurrence rate is also resection of the RML or lingula. significantly higher in patients with nodular bron- chiectatic forms of the disease than in those with a References fibrocavitary or unclassifiable type for radiological 1. Graham EA, Burford TH, Mayer JH. Middle lobe syndrome. Post 34 Grad Med. 1948;4(1):29-34. imaging. Furthermore, many patients with a nodu- 2. Bertelsen S, Struve-Christensen E, Aasted A, et al. 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