History

• In 1948, Graham First Described the Middle Lobe Syndrome in 12 Patients with Atelectasis and Nontuberculous Pneumonitis of the Right Middle Lobe (Postgrad Med, 1948) [MEDLINE]
  • These Cases Had Presumed (But Not Bronchoscopically–Proven) Airway Compression by Peribronchial Enlarged Lymph Nodes
• In 1955, Effler and Ervin Published a Review on the Anatomic and Clinical Features of the Middle Lobe Syndrome (Am Rev Tuberc, 1955) [MEDLINE]
  • They Defined Middle Lobe Syndrome as a “Suppurative Process Which is Characterized by Recurrent Pneumonitis, Productive Cough, Recurrent Fever, and Frequent Hemoptyses”
  • They Stated “The Middle Lobe Syndrome Begins with a Phase of Obstructive Pneumonitis and Terminates with a Phase in Which There is Destruction of the Lung Parenchyma Distal to the Point of Obstruction”
• In 1966, Culiner Described the Middle Lobe Syndrome as “Obstructive Atelectasis of This Lobe, with the Obstruction Being Attributed to Compression by Peribronchial Nodes” (Dis Chest, 1966) [MEDLINE]

Definition

• Middle Lobe Syndrome is Most Consistently Defined in the Medical Literature as Recurrent or Chronic Right Middle Lobe Atelectasis (Collapse or Volume Loss) (see Atelectasis) (Postgrad Med, 1948) [MEDLINE] (Dis Chest, 1966) [MEDLINE] (Thorax, 1980) [MEDLINE] (Respiration, 2012) [MEDLINE]
  • A Similar Syndrome May Occur in the Lingula, Being Termed the “Lingula Syndrome” (Chest, 2004) [MEDLINE]

Epidemiology

• Middle Lobe Syndrome is Considered to Be a Rare Clinical Entity, But its Epidemiology Has Not Been Well-Described in the Medical Literature (Thorax, 1980) [MEDLINE] (Respiration, 2012) [MEDLINE]
  • Middle Lobe Syndrome Has Been Described in Childen and Adults of Both Sexes
  • Middle Lobe Syndrome Has Been Described in Both Primary and Tertiary Care Settings
  • Non-Obstructive Middle Lobe Syndrome Appears to Be More Common than Obstructive Middle Lobe Syndrome (Clin Respir J, 2009) [MEDLINE]
• Incidence
  • In a National Study from Iceland, the Incidence of Middle Lobe Syndrome Requiring Surgical Resection was Defined (JAMA, 1966) [MEDLINE]
    • Male: 1.43 milion males per year
    • Female: 2.94 milion females per year
• Sex-Predominance
  • Middle Lobe Syndrome is More Common in Females
    • The F:M Ratio is 1.5-3.0 in Most Studies (Respiration, 2012) [MEDLINE]
• Family History of Atopy
  • Family History of Atopy, Asthma, Chronic Obstructive Pulmonary Disease are Present in Up to 50% of Cases (Thorax, 1980) [MEDLINE] (Clin Respir J, 2009) [MEDLINE] (Respiration, 2012) [MEDLINE]
• Familial Clustering
  • Familial Clustering Has Been Reported

Obstructive Middle Lobe Syndrome

Intrinsic Obstruction

• Infection
  • Actinomycosis (see Actinomycosis)
  • Echinococcosis (see Echinococcosis) (BMJ Case Rep, 2016) [MEDLINE]
  • Mycobacterium Avium Complex (MAC) (see Mycobacterium Avium Complex)
    • However, as Noted Below, Most Cases of Middle Lobe Syndrome Associated with Nontuberculous Mycobacteria Have a Patent Right Middle Lobe Bronchus (Dis Chest, 1966) [MEDLINE]
    • Endobronchial Submucosal “Pearls” May Be Seen in HIV Patients (Biopsy of These is Usually Positive for Acid-Fast Bacilli)
  • Mycobacterium Tuberculosis (Tuberculosis) (see Tuberculosis)
  • Nocardiosis (see Nocardiosis)
• Neoplasm
  • Epidemiology
    • Neoplasms (Benign and Malignant) Account for Approximately 25% of Middle Lobe Syndrome Cases (Although Many Middle Lobe Syndrome Studies Have Excluded Patients with Identifiable Neoplasms) (Respiration, 2012) [MEDLINE]
  • Types of Neoplasms
    • Bronchial Adenoma (see Bronchial Adenoma)
    • Hamartoma (see Hamartoma)
    • Lung Cancer (see Lung Cancer)
    • Endobronchial Metastases (see Lung Metastases-Endobronchial)
• Mucoid Impaction (see Mucoid Impaction)
  • Allergic Bronchopulmonary Aspergillosis (ABPA) (see Allergic Bronchopulmonary Aspergillosis) (Eur Respir J, 1993) [MEDLINE]
  • Asthma (see Asthma): predominantly seen in pediatric cases with history of asthma or atopy
  • Bacillus Calmette-Guerin (BCG) (see Bacillus Calmette-Guerin)
  • Cystic Fibrosis (CF) (see Cystic Fibrosis)
  • Distal to Central Airway Obstruction (from Bronchial Atresia, Bronchial Carcinoid, Bronchogenic Cyst, etc)
  • Lung Cancer (see Lung Cancer)
  • Mycobacterium Avium Complex (MAC) (see Mycobacterium Avium Complex
  • Sjogren’s Syndrome (see Sjogren’s Syndrome)
• Other Endobronchial Mass/Nodule/Anatomic Distortion
  • Airway Foreign Body (see Airway Foreign Body): more commonly occurs in children
  • Amyloidosis (see Amyloidosis): due to endobronchial amyloidosis
  • Broncholithiasis (see Broncholithiasis): due to erosion of broncholith from adjacent lymph nodes into the right middle lobe bronchus
  • Sarcoidosis (see Sarcoidosis): due to endobronchial granuloma
  • Silicosis (see Silicosis): due to endobronchial silicosis
  • Tracheobronchopathia Osteochondroplastica (TPO) (see Tracheobronchopathia Osteochondroplastica) (Adv Respir Med, 2017) [MEDLINE]: due to endobronchial nodules

Extrinsic Obstruction

• Peribronchial Lymphadenopathy
  • Epidemiology
    • Peribronchial Lymphadenopathy is the Most Common Etiology of Extrinsic Compression of the Right Middle Lobe Bronchus (Chest, 1966) [MEDLINE]
  • Granulomatous Mediastinitis Disorders Which Cause Peribronchial Lymphadenopathy (see Granulomatous Mediastinitis and Fibrosing Mediastinitis)
    • Blastomycosis (see Blastomycosis)
    • Histoplasmosis (see Histoplasmosis): most common etiology in the US
    • Mycobacterium Avium Complex (MAC) (see Mycobacterium Avium Complex)
    • Mycobacterium Fortuitum (see Mycobacterium Fortuitum)
    • Mycobacterium Tuberculosis (Tuberculosis) (see Tuberculosis): common cause in the US
    • Sarcoidosis (see Sarcoidosis)
  • Fibrosing Mediastinitis Disorders Which Cause Peribronchial Lymphadenopathy (see Granulomatous Mediastinitis and Fibrosing Mediastinitis)
    • Blastomycosis (see Blastomycosis)
    • Familial Multifocal Fibrosclerosis
    • Histoplasmosis (see Histoplasmosis)
    • Hodgkin’s Disease (Nodular Sclerosing) (see Hodgkin’s Disease)
    • Methysergide (see Methysergide)
    • Paraffin: previously used for plombage to treat tuberculosis
    • Radiation Therapy (see Radiation Therapy)
    • Sarcoidosis (see Sarcoidosis)
    • Silicosis (see Silicosis)
    • Traumatic Mediastinal Hematoma
    • Tuberculosis (see Tuberculosis)
  • Other Disorders Which Cause Peribronchial Lymphadenopathy
    • Asbestos (see Asbestos)
    • Metastases to Peribronchial Lymph Nodes
• Other Extrinsic Etiology
  • Cardiovascular Anomaly
  • Esophageal Traction Diverticulum (see Esophageal Diverticulum) (Can Med Assoc J, 1981) [MEDLINE]
  • Situs Inversus (see Situs Inversus)

Non-Obstructive Middle Lobe Syndrome (“Peripheral Middle Lobe Syndrome”)

• General Comments
  • Characterized by Absence of Demonstrable Right Middle Lobe Bronchus Obstruction by Bronchoscopy
  • Non-Obstructive Cases May Also Manifest Pathology in the Lingula on the Left Side (“Lingula Syndrome”) (Chest, 2004) [MEDLINE]
  • Commonly Manifests as Recurrent Pneumonia in Association with Asthma, Bronchitis, or Cystic Fibrosis (JAMA, 1966) [MEDLINE] (J Maine Med Assoc, 1972) [MEDLINE] (Arch Dis Child, 1992) [MEDLINE]
• Asthma (see Asthma)
  • Epidemiology
    • Predominantly Seen in Pediatric Cases with History of Asthma or Atopy
    • In a Series of Asthmatic Children with Middle Lobe Syndrome, Haemophilus Influenzae and Streptococcus Pneumoniae were the Predominant Organisms Recovered (see Haemophilus Influenzae and Streptococcus Pneumoniae) (Arch Dis Child, 1992) [MEDLINE]
• Bronchogenic Cyst (see Bronchogenic Cyst)
• Cystic Fibrosis (CF) (see Cystic Fibrosis)
• Idiopathic Middle Lobe Syndrome
  • Physiology
    • Unclear Pathogenesis
• Infection
  • Actinomycosis (see Actinomycosis)
  • Aspergillus (see Aspergillus)
  • Blastomycosis (see Blastomycosis)
  • Bordetella Pertussis (see Bordetella Pertussis)
  • Chlamydophila Psittaci (Psittacosis) (see Psittacosis)
  • Echinococcosis (see Echinococcosis)
  • Haemophilus Influenza (see Haemophilus Influenza)
  • Histoplasmosis (see Histoplasmosis)
  • Moraxella Catarrhalis (see Moraxella Catarrhalis)
  • Mycobacterium Avium Complex (MAC) (see Mycobacterium Avium Complex)
    • Most Cases of Middle Lobe Syndrome Associated with Nontuberculous Mycobacteria Have a Patent Right Middle Lobe Bronchus (Dis Chest, 1966) [MEDLINE]
    • In 1992, the “Lady Windermere Syndrome” was Described in a Series of Female Patients (n = 29) with MAC Infection Initially in Middle Lobe or Lingular Distributions (in the Absence of Airway Obstruction or Predisposing Pulmonary Disease) (Chest, 1992) [MEDLINE]
      • Lady Windermere was a Fastidious Female Character in the Victorian-Era (1892) Oscar Wilde Play, “Lady Windermere’s Fan”
      • The Authors Hypothesized that Voluntary Suppression of Cough May Have Led to the Development of Nonspecific Inflammation in the Poorly-Draining Middle Lobe or Lingula, Upon Which MAC Infection then Occurred
  • Mycobacterium Fortuitum (see Mycobacterium Fortuitum)
    • Most Cases of Middle Lobe Syndrome Associated with Nontuberculous Mycobacteria Have a Patent Right Middle Lobe Bronchus (Dis Chest, 1966) [MEDLINE]
  • Mycobacterium Tuberculosis (Tuberculosis) (see Tuberculosis)
  • Nocardiosis (see Nocardiosis)
  • Staphylococcus Aureus (see Staphylococcus Aureus)
  • Streptococcus Pneumoniae (Pneumococcus) (see Streptococcus Pneumoniae)
• Primary Ciliary Dyskinesia (see Primary Ciliary Dyskinesia)
• Pulmonary Infarction (see Pulmonary Infarction)
• Sjogren’s Syndrome (see Sjogren’s Syndrome)
  • Physiology
    • Lymphocytic Bronchiolitis in the Atelectatic Lobes (Med J Aust, 2006) [MEDLINE]

Obstructive Middle Lobe Syndrome

Mechanisms

• Intrinsic Obstruction Due to Obstructing Endobronchial Lesion (Tumor, Mucous Plug, Mucoid Impaction, etc)
• Extrinsic Compression of the Middle Lobe Bronchus (by Peribronchial/Hilar Lymph Nodes Which Encircle the Right Middle Lobe Bronchus)

Therapy

• Surgery is the Typically the Preferred Therapy

Non-Obstructive Middle Lobe Syndrome (“Peripheral Middle Lobe Syndrome”)

Epidemiology

• Non-Obstructive Middle Lobe Syndrome (Characterized by an Absence of Airway Obstruction by Chest CT and/or Bronchoscopy) Accounts for the Majority of Middle Lobe Syndrome Cases (Respiration, 2012) [MEDLINE]
• Non-Obstructive Type May Also Occur in Other Lobes of the Lung, Most Commonly the Lingula

Possible Mechanisms (Respiration, 2012) [MEDLINE]

• Right Middle Lobe Bronchus Has a Narrow Diameter, Long Length, and an Acute Takeoff Angle, Creating Poor Conditions for Drainage (and Poor Clearance of Mucous)
  • Right Middle Lobe Bronchus Typically Has a “Fish-Mouth” Configuration (as Does the Lingular Bronchus)
  • Embryologic Factors
    • Early in Embryologic Development, the Smaller Left Endodermal Bud is Directed More Laterally than the Caudally-Located Right Endodermal Bud, Resulting in Asymmetry of the Mainstem Bronchi
    • Later in Embryologic Development, the Right Main Lung Bud Forms Three Lung Buds and the Left Lung Bud Forms Only Two Buds (Corresponding to the Later Pulmonary Lobes)
• Right Middle Has Relatively Poor Collateral Ventilation (as Compared to the Upper Lobes)
  • Right Middle Lobe is Anatomically Surrounded by Two Fissures (with Scant Parenchymal Bridges), Which Impedes Collateral Ventilation (Similar Anatomic Features Occur in the Lingula)
  • Poor Right Middle Lobe Collateral Ventilation (Especially in Patients with Complete Fissures) and Relative Anatomical Isolation Decrease the Probability of Reinflation Once Atelectasis Has Occurred (Radiology, 1983) [MEDLINE]
  • Right Middle Lobe Has a Greater Ratio of Pleural Surface to Nonpleural Surface, as Compared to the Upper Lobes
  • Collateral Ventilation in the Right Middle Lobe of Young Normal Subjects is Characterized by High Resistance and a Long-Time Constant, Relative to the Upper Lobes (Am Rev Respir Dis, 1978) [MEDLINE]
• Infection in the Right Middle Lobe
• Inflammation in the Right Middle Lobe

Therapy

• Medical Management is the Typically the Preferred Therapy

Association of Middle Lobe Syndrome with the Development of Bronchiectasis (see Bronchiectasis)

• Recurrent or Chronic Right Middle Lobe Syndrome May Result in Bronchiectasis
  • Due to Recurrent and/or Chronic Infection/Inflammation
• Bronchiectasis Occurs in 50% of Cases (Respiration, 2012) [MEDLINE]

Bronchoscopy (see Bronchoscopy)

• Required to Rule Out Endobronchial Pathology and Collect Specimens for Microbiologic Processing
  • Bronchoscopy is Abnormal in Approximately 40% of Cases
  • The Most Common Abnormalities Found are Right Middle Lobe Bronchial Stenosis or Endobronchial Tumor
• Endobronchial Ultrasound (EBUS) (seeEndobronchial Ultrasound)
  • Useful to Detect Lymphadenopathy and Calcification

Chest X-Ray (CXR)/Chest Computed Tomography (Chest CT) (see Chest X-Ray and Chest Computed Tomography)

• Findings
  • Normal: chest imaging may be normal in cases with intermittent or recurrent atelectasis
  • Right Middle Lobe Infiltrate
  • Right Middle Lobe Atelectasis
    • On the Lateral Chest X-Ray: Anterior Wedge-Shaped Density with Base Toward Pleura and Apex Pointing Toward the Hilum
  • Right Middle Lobe Bronchiectasis

Pulmonary Manifestations

Chest Pain (see Chest Pain)

• Epidemiology
  • May Occur (Clin Respir J, 2009) [MEDLINE]

Cough (see Cough)

• Epidemiology
  • Occurs in 30-50% of Cases (Clin Respir J, 2009) [MEDLINE] (Respiration, 2012) [MEDLINE]
• Clinical
  • May Be Chronic or Recurrent
  • May Be Productive

Dyspnea (see Dyspnea)

• Epidemiology
  • May Occur (Clin Respir J, 2009) [MEDLINE]

Wheezing (see Wheezing)

• Epidemiology
  • May Occur
• Clinical
  • Wheezing May Be Localized in Cases with an Obstructive Etiology of the Middle Lobe Syndrome

Right Middle Lobe Atelectasis

• Diagnosis
  • May Be Incidentally Noted on Chest X-Ray (CXR) or Chest Computed Tomography (CT) (see Chest X-Ray and Chest Computed Tomography)
    • On the Posteroanterior Chest X-Ray, There is Obscuration of the Right Heart Border (Because the Medial Segment of the Right Middle Lobe is Adjacent to the Right Atrium)
    • On the Lateral Chest X-Ray, There is Triangle of Increased Density Between the Minor Fissure and the Lower Half of the Major Fissure
    • Chest CT Scan is Useful to Evaluate Bronchial Patency, Assess for Lymphadenopathy, Assess for Calcifications, and Detect Other Etiologies of Extrinsic Right Middle Lbe Airway Compression (Radiology, 1983) [MEDLINE]
  • Bronchoscopy (see Bronchoscopy)
    • Bronchoscopy is Critical to Evaluate for the Presence of Airway Abnormalities
    • Bronchoscopic Sampling (Bronchoalveolar Lavage) is Useful to Collect Diagnostic Specimens
      • Bacteria Studies: Gram stain, bacterial culture, etc
      • Fungal Studies: fungal stain, fungal culture, etc
      • Mycobacterial Studies: acid-fast bacterial (AFB) stain, mycobacterial culture, TB PCR, etc
      • Cytologic Studies: to rule out malignancy
  • Endobronchial Ultrasound (EBUS)
    • Useful to Assess for Lymphadenopathy and Calcifications
• Clinical
  • May Be Persistent or Intermittent
  • Decreased Breath Sounds Over the Right Middle Lobe

Pneumonia

• Physiology
  • Post-Obstructive Pneumonia (see Community-Acquired Pneumonia)
    • In One Histopathologic Study of Right Middle Lobe Syndrome Cases Cured Surgically (n = 60), 60% Had Chronic Suppurative Infection, 33% Had Neoplasm, and 7% Had Tuberculosis (Med Interne, 1982) [MEDLINE]
  • May Be Recurrent (Requiring Multiple Courses of Antibiotics, Bronchodilators, etc)
• Clinical
  • Cough (see Cough)
  • Fatigue (see Fatigue)
  • Fever/Chills (see Fever)
  • Hemoptysis (see Hemoptysis)
  • Weight Loss (see Weight Loss)
  • Vocal Fremitus (E->A Changes) Over the Right Middle Lobe: due to alveolar filling

Bronchiectasis (see Bronchiectasis)

• Epidemiology
  • Bronchiectasis Occurs in 50% of Cases (Respiration, 2012) [MEDLINE]
• Physiology
  • Due to Poor Secretion Clearance and Chronic/Recurrent Infection

General Measures

• Early Intervention (Especially in Children) May Helpt to Avoid Chronic Atelectasis or the Development of Bronchiectasis (Chest, 2005) [MEDLINE]
• Avoidance of Airway Irritants
• Avoidance of Tobacco Exposure (see Tobacco)

Treatment of Underlying Asthma (If Present) (see Asthma)

• Bronchodilators: see below
• Inhaled Corticosteroids (see Corticosteroids)
• Other Standard Measures

Bronchodilators

• Short-Acting β2-Adrenergic Receptor Agonists (SABA’s) (see Β2-Adrenergic Receptor Agonists)
  • Albuterol (Ventolin, Salbutamol, etc) (see Albuterol)
• Long-Acting/Ultra Long-Acting β2-Adrenergic Receptor Agonists (LABA’s) (see Β2-Adrenergic Receptor Agonists)
  • Formoterol (Foradil, Oxeze, Oxis, Atock, Atimos, Perforomist) (see Formoterol)
  • Olodaterol (Striverdi Respimat) (see Olodaterol)
  • Salmeterol (Serevent) (see Salmeterol)
  • Vilanterol (see Vilanterol)
• Short-Acting Muscarinic Receptor Antagonists (SAMA’s) (see Muscarinic Antagonists)
  • Ipratropium Bromide (Atrovent) (see Ipratropium Bromide)
• Long-Acting Muscarinic Receptor Antagonists (LAMA’s) (see Muscarinic Antagonists)
  • Tiotropium (Spiriva) (see Tiotropium)

Mechanical Secretion Clearance Modalities

• Not Well-Studied in the Treatment of Middle Lobe Syndrome (Chest, 2005) [MEDLINE]
• Modalities
  • Chest Physical Therapy (CPT) (see Chest Physical Therapy)
  • Flutter Valve (see Flutter Valve)
  • High-Frequency Oscillation Respiratory Therapy (Vest) (see High-Frequency Oscillation Respiratory Therapy)
  • Postural Drainage
    • May Be Useful (Chest, 2005) [MEDLINE]

Mucolytics

• N-Acetylcysteine (Mucomyst) (see N-Acetylcysteine)

Antibiotics

• Empiric Antibiotic Coverage Against the Following Should Be Considered
  • Haemophilus Influenzae (see Haemophilus Influenzae)
  • Moraxella Catarrhalis (see Moraxella Catarrhalis)
  • Streptococcus Pneumoniae (see Streptococcus Pneumoniae)
• Directed Antibiotic Coverage Against Specific Organisms Recovered from Bronchoscopy
  • Mycobacteria
  • Pseudomonas Aeruginosa (see Pseudomonas Aeruginosa): may be present in some difficult cases
• Low-Dose Roxithromycin (Macrolide) Therapy
  • May Be Useful (Especially if Bronchiectasis is Present) (Respiration, 2001) [MEDLINE]
• Use of Nebulized Antibiotics Has Not Been Well Studied in Middle Lobe Syndrome

Bronchoscopy (see Bronchoscopy)

• Bronchoscopy May Be Useful to Enhance Secretion Clearance
• Intrabronchial Air Insufflation: to treat lobar collapse
• Balloon Dilation/Argon Plasma Coagulation/Electrocautery/Cryosurgery/Laser Therapy/Stent Placement: may be used in some cases

Surgical Resection (see Pulmonary Lobectomy)

• Right Middle Lobectomy May Be Required in Some Cases
  • Cases with Obstructive Right Middle Lobe Syndrome are More Amenable to Surgical Intervention
• Indications for Right Middle Lobectomy
  • Resistant/Complex Cases (Which are Unresponsive to Medical Therapy) and Who Have Proven Right Middle Lobe Bronchial Obstruction (Clin Respir J, 2009) [MEDLINE]
  • Resistant/Complex Cases with Chronic Atelectasis (>6 Months) Despite Medical Therapy: especially if patient has associated debilitating symptoms (such as persistent cough, fever, failure to thrive, etc)
  • Recurrent Hemoptysis, Not Amenable to Interventional Radiology Angioembolization (see Hemoptysis)
  • Presence of Malignancy (or Concern for Underlying Malignancy) in Right Middle Lobe
• Surgical Approach
  • Video-Assisted Thoracoscopic Approach is Feasible for the Surgical Management of Middle Lobe Syndrome in Selected Patients with No Severe Calcified Lymph Nodes Surrounding the Hilus Pulmonis (World J Surg, 2017) [MEDLINE]