Introduction

MAC lung disease is caused by a group of bacteria called Mycobacterium avium complex (MAC). This is a nontuberculous mycobacterial (NTM) infection and not contagious. This condition is normally observed in middle-aged to elderly white people assigned female at birth (AFAB). Lady Windermere Syndrome (LWS) was first coined in 1992 by Reich and Johnson to describe Mycobacterium avium complex (MAC) pulmonary infection restricted to the right middle lobe or lingula without a considerable smoking history or chronic lung disease.^1,2

Epidemiology

Approximately 85% of NTM lung disease cases are due to Mycobacterium avium complex (MAC). The incidence and prevalence of MAC lung disease are increasing worldwide.^3,4

Pathophysiology

Mycobacterium avium complex (MAC) can be inhaled into the respiratory tract or ingested into the gastrointestinal tract. It then attaches to the mucosal epithelium and infects macrophages, spreading into the submucosal tissue and lymph nodes. Lymphatics carry the bacteria to the rest of the body. Normally, once the CD₄ count is less than 50 cells per microliter, it is considered a MAC infection. Reich and Johnson suggested that voluntary cough suppression in the affected individuals may cause poor draining of secretion from the middle lobe or the dependent section of the lingula, but this theory lacks evidence. It has also been hypothesised that this syndrome may be a connective tissue disorder because of its link with skeletal abnormalities in some studies.^2,5

Researchers previously postulated that low levels of oestrogens could play a part in developing LWS, as it often occurs in postmenopausal women. Notably, tall, thin people assigned females at birth (AFAB) are more affected, and studies have noticed that lowered subcutaneous fat (low body mass index (BMI)) is associated with increased adiponectin/leptin ratio, which affects Th-1 immune response, leading to increased susceptibility to Mycobacterium avium infection.²

Clinical presentation

The signs and symptoms of the Lady Windermere Syndrome (LWS) from previous reports include:^2,6

• Persistent cough
• Fatigue
• Weight loss
• Sputum production – may be minimal 
• Exertional dyspnea (shortness of breath on exertion)
• Possible bronchiectasis
• Lung opacities – can be scattered, linear, nodular, and “tree-in-bud” like

Diagnosis

Imaging

A chest computed tomography (CT) scan can show bronchiectasis and scattered linear and tree-in-bud nodularities, usually in the upper, middle and lower lobes of the right lung and lingula.^2,6,7

Microbiology

A microbiology workup includes culturing, smearing and staining of sputum or bronchoalveolar lavage(BAL) fluid produced by the patient. A QuantiFERON Gold test, which detects tuberculosis (TB) infection, can also be done, and it is usually negative. Since mycobacterium avium complex (MAC) organisms are gram-positive acid-fast bacilli (AFB), there can be positive results for AFB from stains and smears; however, if negative, cultures typically reveal mycobacterium avium complex.^2,5,6,7

Sputum samples can become contaminated, so more than one sample should be obtained, and the culture should yield positive results on at least two separate occasions.^2,5

Diagnostic criteria 

Due to the difficulty in diagnosing non-tuberculous mycobacterial (NTM) pulmonary disease, the British Thoracic Society (BTS) has integrated the diagnostic criteria of the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) into their guidelines. The criteria are described below:⁸

Clinical/Radiological

1a. Pulmonary symptoms

1b. Radiological, nodules, cavities and airways disease with bronchiectasis, bronchial wall thickening, mucus plugging and centrilobular nodules.

2. Appropriate exclusion of other diagnoses such as lung carcinoma and TB

Microbiological

1. Positive culture results from at least two separate expectorated sputum samples; if the results are non-diagnostic, consider repeat sputum acid-fast bacteria (AFB) smears and cultures.

2. Positive culture results from at least one bronchial wash or lavage.

3. Transbronchial or other lung biopsy with mycobacterial histopathological features (granulomatous inflammation or AFB) and positive culture for non-tuberculous mycobacteria (NTM) or biopsy showing mycobacterial histopathological features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are culture-positive for NTM.

Differential diagnosis

The symptoms of the Lady Windermere Syndrome (LWS) are non-specific, and the differential diagnosis is wide, so it can often times be underdiagnosed or misdiagnosed as a number of conditions, namely:⁶

• Asthma
• Chronic obstructive pulmonary disease (COPD)
• Gastroesophageal reflux disease
• Pneumonia
• Bronchiectasis
• Cystic fibrosis
• Interstitial lung disease
• Postnasal drip
• Lung cancer and heart failure

Management

It is not always necessary to treat NTM MAC lung disease, including Lady Windermere Syndrome (LWS), as symptoms and disease progression are variable. Notably, persons with serious symptoms, radiographic changes, and worsening conditions should be considered for management.⁶

Treatment aims to manage the underlying infection. A three-times-weekly (intermittent) antibiotic regimen is prescribed for around 12 months, including:

• Macrolide (azithromycin or clarithromycin)
• Ethambutol
• Rifampin

The last two drugs are added to prevent macrolide resistance. Also, an aminoglycoside may be used if there is widespread nodular bronchiectasis or fibrocavitary disease. Twelve (12) months of negative sputum cultures during therapy is the target. For patients who don’t improve with antibiotic therapy or symptomatic disease recurrence, surgery such as a thoracoscopic lobectomy/segmentectomy can be considered.^2,6

As management includes regimens with numerous drugs in an elderly population, possible drug interactions, other comorbidities, and serious effects must be considered and accounted for. Therefore, regular monitoring is crucial.⁶

Prognosis and challenges

Reports on the prognosis of the Lady Windermere Syndrome (LWS) are minimal. Symptoms usually resolve following antibiotic treatment; however, recurrence is often possible.^2,6

As the treatment regimen has a long duration, patients may struggle with adhering. Studies have shown that an intermittent regimen has higher compliance with fewer adjustments compared to a daily regimen. Additionally, as LWS mainly affects elderly persons, comorbidities and other medications may likely make treatment difficult.^2,6

Summary

Lady Windermere Syndrome (LWS) is a form of Mycobacterium avium complex (MAC) lung disease, a non-contagious infection primarily affecting middle-aged to elderly white women assigned female at birth. Named in 1992, the syndrome typically presents without a smoking history or chronic lung disease and is localised to the right middle lobe or lingula. MAC lung disease is increasingly common and constitutes about 85% of non-tuberculous mycobacterial lung infections. The bacteria can enter the body through inhalation or ingestion and spread via the lymphatic system. Although voluntary cough suppression was initially theorised to contribute to the disease, the more accepted understanding links LWS to postmenopausal status, low BMI, and a skewed adiponectin/leptin ratio that weakens the immune response.

Clinically, LWS presents with chronic cough, fatigue, weight loss, minimal sputum, and sometimes exertional dyspnea or bronchiectasis. Radiological signs include scattered lung opacities and characteristic nodular and “tree-in-bud” patterns. Diagnosis is complex and involves imaging, sputum or bronchoalveolar lavage cultures, and confirmation by multiple positive microbiological samples. Because symptoms overlap with various other pulmonary and systemic conditions, LWS is often under- or misdiagnosed.

Management depends on the severity of the disease. While some patients may not need treatment, those with significant symptoms or disease progression are typically prescribed a 12-month course of antibiotics, usually a combination of a macrolide, ethambutol, and rifampin, sometimes with an aminoglycoside. Surgical intervention is an option for persistent or severe cases. However, treatment can be challenging due to the long duration, potential side effects, and drug interactions, especially in older patients with other health issues. Although symptoms often resolve with therapy, recurrence is common, and ongoing monitoring is essential for optimal outcomes.