Lady Windermere syndrome

Non-tuberculosis Mycobacterium spp (NTM) pulmonary disease is increasing in incidence and is a common cause of undiagnosed lung disease in older patients. NTM pulmonary disease occurring in patients without preexisting lung disease was only recently described by Prince in 1988. In 1992, Reich and Johnson presented a case series of six women describing a predilection of Mycobacterium spp pulmonary disease for the middle lobe, and its homolog, the lingula, in elderly women without preexisting pulmonary disease. Later high resolution computed tomography studies (HRCT) showed that the characteristic image findings in these cases were nodules and bronchiectasis most commonly occurring in the middle lobe and lingula. This subtype of disease is now usually referred to as nodular bronchiectasis, and some researchers have doubted whether there really is a predilection for the middle lobe. Although Reich and Johnson hypothesized that cough suppression in “polite” women was the mechanism of disease, there are no large studies which support this idea. Mutations in the cystic fibrosis transmembrane receptor, unique skeletal phenotypes, and impaired function of the modulators of granuloma formation are the most common characteristics found in patients with nodular bronchiectasis. These patients usually respond well to clarithromycin-based multidrug regimens, but surgery is sometimes required to resect the infected regions of the lung.


IntroductIon
Non-tuberculous Mycobacterium spp (NTM) are increasingly recognized as important pathogens in human diseases. 1This group includes mycobacterial pathogens other than Mycobacterium tuberculosis complex and Mycobacterium leprae.The incidence of NTM infections is increasing, and a recent study reported an 8.2% increase in prevalence per year between 1997 and 2007. 2 These mycobacterial species are a ubiquitous part of the normal flora in the soil and water. 1,35][6][7][8] The route of infection is through the inhalation of aerosols, 9 but recent studies have shown that person-to-person spread of disease is possible in patients with cystic fibrosis. 10Mycobacterium spp have a relatively impermeable cell wall and can form biofilms contributing to the difficulty in eradicating them with antibiotics or disinfectants. 11Non-tuberculous Mycobacterium infections can involve lymph nodes, bone and soft tissue, and most commonly the lungs. 1 M. avium and M. intracellular (Mycobacterium avium complex [MAC]) are important NTM pathogens which cause disease in patients with impaired host defenses and preexisting lung disease. 12,13However, MAC can also cause pulmonary disease in patients without these risk factors.
There are three common subtypes of MAC pulmonary disease in non-immunocompromised individuals: 1) fibrocavitary disease resembling tuberculosis commonly found in elderly, male smokers with preexisting pulmonary disease, 2) nodular bronchiectasis most commonly found in elderly, post-menopausal females, and 3) hypersensitivity-like disease known as "hot tub lung" that has both inflammatory and infectious components. 1,14,15This review focuses on nodular bronchiectasis since this pulmonary disease may account for up to 59% of MAC disease seen in pulmonary practices. 16

bronchIectAsIs
][19] Common symptoms include a chronic cough with sputum production, fatigue, and hemoptysis. 19,20atients with adult-onset bronchiectasis are often middle age to elderly women. 20,21Cystic fibrosis is a common cause of bronchiectasis which ususally presents in childhood, but adult-onset bronchiectasis can be associated with cystic fibrosis transmembrane conductance regulator (CFTR) mutations and cystic fibrosis. 22,23Non-cystic fibrosis bronchiectasis in adults often has no obvious cause or is a sequalae of infections but can occur in patients with immunodeficiency, chronic obstructive pulmonary disease, connective tissue disease, allergic bronchopulmonary aspergillosis (ABPA), and ciliary dyskinesia. 21,24ady Windermere syndrome (LWS), a unique subtype of M. avium pulmonary disease, is associated with bronchiectasis, but it is unknown whether bronchiectasis precedes M. avium infection or is a result of infection. 25Airway involvement in bronchiectasis is usually diffuse, but some diseases are associated with more focal distributions of bronchiectasis in the lung.Bronchiectasis in cystic fibrosis usually involves the upper lobes, ABPA the central airways, and LWS and tuberculosis the middle lobes. 18,22,26It has been proposed that the middle lobe predilection is due to obstruction of the long, right middle lobe bronchus by the lymphadenopathy associated with mycobacterial infections. 26

LAdy WIndermere syndrome
In 1987, Prince noted a new clinical syndrome characterized by M. avium pulmonary disease in elderly, non-immunocompromised women.M. avium pulmonary infection was previously associated with pre-existing pulmonary disease or HIV.These patients usually presented with cough and sputum production.Seventy-one percent of patients had nodules. 15In 1992, Reich and Johnson reported a case series on six elderly female patients with MAC pulmonary disease isolated in the middle lobe/lingula.These women had no hilar adenopathy or cavitary disease.Reich and Johnson hypothesized that voluntary cough suppression in elderly women led to retained secretions in the narrow, dependent right middle lobe bronchus.They coined the term LWS after the Victorian character with fastidious manners in the play Lady Windermere's Fan by Oscar Wilde (first performed in 1892).The paper stated that the defining features of LWS were "(1) initial involvement of the periphery of the lingula or of its counterpart, the middle lobe; (2) absence of clinically evident predisposing pulmonary disease; and (3) exclusivity of the features to female patients." 27udies in patients with nodular bronchiectasis have shown that most patients are females around age 60. 15,27,28 Most patients diagnosed in the United States are Caucasians or Asian. 16,29,30The majority of patients do not have a significant smoking history. 29,31hese individuals usually have nodular bronchiectasis with diffuse pulmonary involvement of 3-4 lobes; the right middle lobe and lingula are most commonly involved. 16,29,32Bronchiectasis in the middle lobe and lingula is highly suggestive of MAC disease. 32,33owever, isolated middle lobe and lingular disease is a rare manifestation of nodular bronchiectasis even on early high resolution computed tomography (HRCT) scans. 16In the Reich and Johnson study only 6/29 patients originally examined had middle lobe and lingular involvement.It is possible that these patients had more diffuse disease that was not seen on the older imaging modalities; most of their patients in this series did not have a CT scan.Baseline characteristics of patients with nodular bronchiectasis do not vary significantly from those with isolated middle lobe/ lingular disease as seen in Tables 1 and 2. We found no studies comparing treatment response in those with diffuse versus isolated disease.

PAthogenesIs
While most MAC infections occur in patients who are immunocompromised or have underlying pulmonary disease, 12,36 LWS/nodular bronchiectasis is a unique form of MAC infection that predominately occurs in elderly women without pre-existing pulmonary disease or overt immunodeficiency. 15,27Reich and Johnson, who named this syndrome, attributed the middle lobe/lingula predilection to cough suppression. 27][39] This idea is supported by a case series which showed that voluntary cough suppression could lead to cylindrical bronchiectasis. 40However, evidence for cough suppression prior to developing LWS is limited to case reports. 41,42Reich and Johnson had no data that their patients with middle lobe disease had a history  43 Additionally, a survey showed that 68% of patients with pulmonary NTM did not report reluctance to cough in public. 29ere are several well-established risk factors for this infection.These include host anatomic factors, host immune factors, genetic factors, and environmental factors. 44Important anatomic factors include skeletal abnormalities, low BMI, and mitral valve prolapse.Multiple studies have shown that skeletal abnormalities are more common in patients with MAC pulmonary disease.Iseman reported that 70% of these patients have scoliosis or pectus excavatum. 45Other studies have also reported an increased incidence of scoliosis and pectus excavatum, occurring in up to 51% of patients with pulmonary NTM. 29,46Mitral valve prolapse also occurs frequently in these patients.7][48] Decreased subcutaneous fat is associated with an increased adiponectin/leptin ratio; increased adiponectin/leptin ratios inhibit the Th-1 response, an important adaptive immune response to M. avium infection. 47,49,50Lady Windermere syndrome also occurs predominately in post-menopausal patients. 15,37Low estrogen levels in slender, post-menopausal women may increase susceptibility to MAC disease. 47Nutritional deficiencies may also contribute to the development of LWS since malnutrition is associated with increased risk of M. tuberculosis infection and with worse outcomes in NTM infections. 51,52veral genetic factors and subtle immune phenotypes are more common in patients with LWS than in the general population.Most notably, 36.5% of patients with pulmonary NTM had one CFTR mutations compared to 15.6% of individuals in the control population. 29Another study found that in patients presenting to a pulmonary clinic with bronchiectasis and MAC pulmonary disease 47.6% had a mutation in the CFTR gene. 23Cystic fibrosis is a known cause of diffuse bronchiectasis and impaired mucus clearance. 21,53While it is not clear whether the bronchiectasis associated with LWS precedes or is a result of MAC disease, 25 one possible explanation might involve mutations in CFTR which cause diffuse bronchiectasis and damaged airways susceptible to MAC pulmonary disease.Laboratory studies show that M. avium binding is mediated through fibronectin, a glycoprotein exposed on damaged epithelium. 54,55t seems possible that prior epithelial damage is required to establish MAC infections.Supporting this mechanism is the fact that LWS/ nodular bronchiectasis is much more common in Caucasian populations, 2,30 which have a higher rate of CFTR mutations than black or Hispanic populations. 56However, this does not explain the high incidence of LWS in Asian populations. 2Studies on conditions with impaired mucus clearance, such as chronic bronchitis, have shown that smoking can induce acquired mutations in CFTR. 57It is possible that either age-related acquired mutations or cumulative pulmonary damage from insidious lung disease caused by a less functional CFTR protein could explain the predilection for older individuals.However, most patients with LWS have never smoked, and this eliminates one possible explanation for chronic occult lung disease. 31nother factor not explained by the CFTR mutation theory is why LWS shows a middle lobe predilection since cystic fibrosis usually causes upper lobe bronchiectasis. 18,22However, CFTR mutations leading to diffuse bronchiectasis do help explain the multilobular lung involvement commonly seen in image studies of patients with nodular bronchiectasis. 29,35,58me studies on individuals with LWS have noted subtle immune defects that can increase susceptibility to LWS.The immune response to M. avium infection is mediated through a Th-1, cell-mediated pathway.Important cytokines in the cell-mediated response and in granuloma formation are IL-12, INF-γ, and TNF-α. 591][62] However, other studies have shown no difference in stimulated INF-γ production in NTM infections. 29,63Seventy-seven percent of individuals with interferon-γ receptor deficiencies had environmental mycobacterium disease, most commonly M. avium. 64However, another study in LWS patients did not find a significant association with interferon receptor deficiency. 16A recent study showed that elderly individuals' peripheral blood cells have decreased heme oxygenase-1 expression after M. avium stimulation. 65Heme oxygenase-1 is an important modulator in granuloma formation; decreased expression in elderly individuals may lead to poor granuloma formation and a higher disease burden. 66This could help explain the predilection on LWS for older individuals.Some authors have noted the phenotype of patients with LWS with a slender body habitus with skeletal abnormalities and mitral valve prolapse is similar to the phenotype seen in Marfan syndrome. 45,47hese authors proposed that perhaps patients with LWS have a defect in fibrillin postulated to increase the expression in TGF-β, a cytokine involved in the pathogenesis of M. avium. 29,47Supporting this hypothesis, TGF-β expression was increased in the blood of those with NTM pulmonary following stimulation with M. intracellulare. 67 summary, there are several phenotypic, genetic, and immune factors associated with LWS.Environmental exposure may also increase risk of M. avium disease since M. avium is a ubiquitous bacterium found in the soil and water. 3Increased soil exposure was associated with increased risk of M. avium infection while aerosol generating activities were not. 68,69NTM most commonly occurs in the southeast region of the United States. 2 The risk for LWS likely involves several factors which allow an environmental bacterium to cause disease in individuals without pre-existing lung disease or overt immunosuppression.

dIAgnosIs
According to the 2007 ATS guidelines, the minimum diagnostic work-up for NTM lung disease in those with clinical symptoms includes: 1) a chest x-ray for those with cavitary disease or HRCT for those with nodular bronchiectasis (Figure ), 2) three sputum samples with acid-fast bacteria staining and cultures on solid and liquid media, and 3) exclusion of M. tuberculosis or other diseases with a similar presentation. 1Culture on both liquid and solid media increases the sensitivity of NTM detection by 15%. 70o be diagnostic, sputum culture should be positive on two separate occasions to rule out contamination; bronchial washings require one positive culture. 1 In LWS, HRCT scans usually show diffuse bronchiectasis with "tree and bud" opacities and small peripheral nodules involving the middle lobe; the chest X-ray is often normal. 1,33,71The middle lobe is most frequently involved. 1,29One study found that the presence of bronchiectasis with multiple small nodules on CT scan had a sensitivity and specificity of 80% and 87%, respectively, at predicting a positive MAC culture. 72solated middle lobe or lingular disease with nodules and bronchiectasis is highly suggestive of LWS even if MAC cultures are negative. 33is diagnosis can be difficult because of the lower bacterial burden in nodular bronchiectasis compared to cavitary disease; 1,32,70 one study demonstrated only 38% of patients with nodular bronchiectasis have positive sputum cultures. 73Another study found that 45% of patients need to undergo bronchoscopy due to a negative sputum cultures or an inability to provide adequate samples. 16Studies show that in patients with MAC pulmonary disease, cultures from bronchial lavages have a greater sensitivity than sputum cultures; positive cultures were present in 93.8% and 50% of bronchial washings compared to 64.3% and 23.1% of sputum samples, respectively. 74,75In suspected cases of LWS with three negative sputum samples, bronchoscopy with bronchial washings may be needed to confirm the diagnosis.Recently, polymerase chain reaction (PCR) and serodiagnostic tests have been utilized for rapid diagnosis.An enzyme immunoassay (EIA) test that detects serum anti-glycopeptidolipid (GPL) core IgA antibody has sensitivity and specificity ranging from 70.1%-81.3%and 88.3%-93.9%. 76,779][80] In addition, realtime PCR takes only two hours to confirm a diagnosis compared to eight days needed to detect M. avium in liquid culture and can provide early detection of antibiotic resistance of an M. avium isolate to clarithromycin at known alleles. 80,81Positron emission tomography using 18F-fluorodeoxyglucose is a promising tool for diagnosing disease severity and response to treatment that merits more investigation. 82,83eAtment Mycobacterium avium complex pulmonary disease is difficult to eradicate.Mycobacteria have relatively impermeable cell walls and can form biofilms which make eradication of these bacteria with antibiotics or disinfectants difficult. 11,84Nodular bronchiectasis may not require treatment.One study showed that only 48% of patients presenting with nodular bronchiectasis required treatment due to disease progression. 73The 2007 American Thoracic Society (ATS) NTM guidelines recommend treating MAC pulmonary disease with bronchiectasis with intermittent therapy three-times-weekly including clarithromycin 1,000 mg or azithromycin 500 mg as the backbone of the treatment regimen.These guidelines suggest adding ethambutol 25 mg/kg and rifampin 600 mg to the triweekly regimen to prevent macrolide resistance.This regimen should be continued for 12 months after negative sputum cultures. 1A meta-analysis of MAC treatment showed that regimens containing macrolides had better pooled success proportions. 85A recent study comparing daily to intermittent therapy (three times weekly) found that patients with intermittent dosing were less likely to modify their drug regimen.7][88] Studies with intermittent dosing also showed a non-significant trend toward better symptomatic relief, radiological improvement, and sputum conversion. 87A large trial of three-times weekly dosing showed that no patients in this study developed macrolide resistance on this regimen. 88ttle information is available to guide treatment options for patients failing intermittent therapy.The guidelines suggest adding streptomycin based on a study showing higher sputum clearance of MAC. 1,89There are no official guidelines on the use of fluoroquinolones in MAC pulmonary disease.Daily therapy and surgical intervention are promising treatment modalities for patients who fail intermittent therapy or who have cavitary disease.A recent study of patients who had failed 12 months of intermittent therapy showed that 30% of sputum specimens (6/20) converted when switched to daily therapy with azithromycin (250-500 mg), rifampin (600 mg) or rifabutin (150-300 mg), and ethambutol (15 mg/kg). 90reatment of patients with MAC pulmonary disease and macrolide resistance has low success rates with antibiotic therapy, and surgery is a possible treatment in these patients. 91,92Two surgical studies using lobectomy and segmentectomy for isolated disease or disease not responding to several months of antibiotics showed that 92%-100% of patients underwent sputum conversion after surgery. 28,34There was no operative mortality in these studies.Thus, surgery appears to be a relatively safe option for patients failing antibiotic therapy who have sufficient cardiopulmonary reserve.concLusIons Three types of NTM lung disease occur in nonimmunocompromised patients: 1) fibrocavitary disease most commonly found in elderly men with preexisting pulmonary disease, 2) nodular bronchiectasis most commonly found in elderly, post-menopausal women, and 3) hypersensitivity-like disease known as "hot tub lung."Nodular bronchiectasis was first described by Prince who noted nodular disease occurring predominately in elderly women without preexisting disease.Reich and Johnson noted a middle lobe/ lingular predilection in a case series of six patients.They named this disease caused by MAC occurring in the middle lobe/lingula of women LWS and suggested that cough suppression in well-mannered women was the likely mechanism for this infection.Although nodular bronchiectasis often shows a predilection for the middle lobe, diffuse nodules and bronchiectasis are usually present. 16,29Lady Windermere Syndrome with disease isolated to the middle lobe and lingula occurs rarely.This disease can occur in men although it is much more common in women. 28,93Most studies do not support cough suppression as an important factor

Figure. A 72
Figure.A 72-year-old man with NB-MAC with consolidations treated with anti-MAC therapy.(A) Axial CT shows multifocal cylindrical bronchiectasis and centrilobular nodules with volume loss in both lungs.(B) Plain radiograph obtained on the same day as Figure A shows multifocal consolidations and small nodular opacities in right lung and left lower lung zone.(C) Plain radiography 2 months later shows a decrease in the consolidations and nodules of both lungs.From Texas Tech University Health Sciences Center Library in Lubbock, TX -OPENi (beta) -search term-nodular bronchiectasis-accessed 3/10/2017.