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(Chest. 2006;130:1234-1241.)
© 2006 American College of Chest Physicians

The Expanding Spectrum of Mycobacterium avium Complex-Associated Pulmonary Disease*

E. Andrew Waller, MD; Archana Roy, MD; Lisa Brumble, MD; Andras Khoor, MD; Margaret M. Johnson, MD, FCCP and Jeffrey L. Garland, MD, FCCP

* From the Divisions of Pulmonary Medicine (Drs. Waller, Johnson, and Garland) and Infectious Disease (Dr. Brumble), and the Departments of Hospital Medicine (Dr. Roy) and Pathology (Dr. Khoor), Mayo Clinic, Jacksonville, FL.

Correspondence to: E. Andrew Waller, MD, Mayo Clinic, Jacksonville, Department of Pulmonary Medicine, 4500 San Pablo Rd, Jacksonville, FL 32224; e-mail: waller.ernest{at}mayo.edu


   Abstract
TOP
 Abstract
Introduction
 Case Report
 Discussion
 References
 
Nontuberculous mycobacteria (NTM) are increasingly recognized as important pulmonary pathogens. Mycobacterium avium intracellulare complex (MAC) causes most lung infections due to NTM. Patients with preexisting lung disease or immunodeficiency are at greatest risk for developing MAC infection. The majority of MAC pulmonary cases, however, occur in immunocompetent elderly women in association with nodular infiltrates and bronchiectasis. More recently, pulmonary disease has also been described in immunocompetent patients after exposure to MAC-contaminated hot tubs. We describe a case of aggressive MAC lung disease in a young immunocompetent female patient without preexisting lung disease whose clinical and pathologic characteristics do not fit into any of these categories and may represent a unique manifestation of MAC lung disease.

Key Words: hot tub lung • Mycobacterium avium complex • nontuberculous mycobacterium


   Introduction
TOP
 Abstract
 Introduction
Case Report
 Discussion
 References
 
Pulmonary infection with nontuberculous mycobacteria (NTM), specifically Mycobacterium avium intracellulare complex (MAC), has become an increasingly recognized clinical problem over the past 20 years. The number of NTM isolates now surpass the number of Mycobacterium tuberculosis isolates cultured in most laboratories across the United States.12 Additionally, there is a greater appreciation of the pathogenic potential of NTM and their various clinical manifestations.1234 We describe a case of MAC lung disease the characteristics of which do not easily fit into any of the previously described clinical and/or pathologic presentations.


   Case Report
TOP
 Abstract
 Introduction
 Case Report
Discussion
 References
 
The Institutional Review Board of The Mayo Clinic does not require approval for the publication of single case reports; thus, institutional review board approval was not sought prior to this publication of this article. Care was taken by the authors to preserve the anonymity of the patient.

A 32-year-old woman presented with a 4-month history of progressively worsening nonproductive cough. She had no significant findings in her medical history and was a lifelong nonsmoker. She had no recent travel history outside of central Florida or known occupational exposures. Her history was notable, however, for frequent use of her neighbors’ outdoor hot tub.

Initial evaluation included a chest radiograph (CXR), the findings of which were suspicious for a cavitary lesion in the left base. She had not had a previous CXR for comparison. Due to worsening cough and dyspnea, she was hospitalized for further evaluation. A CT scan of the chest confirmed a cavitary lesion in the left lower lobe (LLL). There was no evidence of bronchiectasis. The initial results of laboratory tests, including a CBC count, serum chemistries, and HIV testing, were unremarkable. Sputum cultures and bronchial washings revealed MAC. She was initially treated with ethambutol, 1,200 mg/d, and azithromycin, 600 mg/d.

Over the course of a week, fevers up to temperatures of 102.4°F, night sweats, progressive dyspnea, and a worsening, now productive cough developed. A repeat chest CT scan revealed the development of bilateral lower lobe infiltrates and a persistent LLL cavity. The results of additional tests, including those for presence of Legionella antigen in the urine, skin sweat chloride levels, quantitative Ig A, G, G-subclasses, and E levels, and angiotensin-converting enzyme levels were all normal. Recurrent aspiration was excluded with a normal esophagogastroduodenoscopy and esophagogram. A two-dimensional echocardiogram suggested no evidence of endocarditis or valvular abnormalities. Therapy with ciprofloxacin, 400 mg bid, was added without noticeable benefit. After 23 days of hospitalization, she was transferred to our facility for further evaluation.

On presentation, she was febrile (temperature, 38.4°C) with a pulse of 111 beats/min, BP of 108/64, respiration of 24 breaths/min, and an oxyhemoglobin saturation of 96% on 2 L of oxygen via nasal cannula. The physical examination revealed a very toxic-appearing, tachypneic, thin white female. She became dyspneic after walking < 20 feet. The lung examination was notable for inspiratory crackles bilaterally, most pronounced in the bases, but present throughout all lung fields. There was some dullness to percussion in the bases. The remainder of the findings were normal without evidence of rashes, mucosal lesions, pectus excavatum, or lymphadenopathy.

An arterial blood gas test obtained on hospital admission revealed a pH of 7.460, PaCO2 of 34.6 mm Hg, and PaO2 of 72.3 mm Hg on 1 L of oxygen via nasal cannula. Her CXR revealed ill-defined, multifocal airspace consolidation in both the mid and lower lung zones (Fig 1 , top, A). On admission to our institution, therapy with ethambutol, azithromycin, and ciprofloxacin was discontinued. Further evaluation included a chest CT scan, which revealed dense areas of consolidation in the lingula and bilateral lower lobes. A 2.8 x 2.9 cm cavitary lesion was present in the LLL. There were scattered small centrilobular nodular opacities in the upper lobes that were consistent with bronchiolitis (Fig 1, bottom, B). A new sputum smear revealed 4+ acid-fast bacilli (AFB), and the culture grew 4+ MAC identified by DNA probe. A DNA probe was negative for M tuberculosis. A BAL from the LLL produced seven colonies of MAC; no other organisms were identified. Transbronchial biopsy specimens revealed a single vaguely formed granuloma. The results of blood cultures, cytoplasmic-antineutrophil cytoplasmic antibody, perinuclear-antineutrophil cytoplasmic antibody, {alpha}1-antitrypsin, urinalysis, tuberculin skin test, and fungal serologies were all negative or normal.


Figure 1
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  		Figure 1.. Top, A: hospital admission CXR revealing ill-defined, multifocal airspace consolidation in the mid to lower lung fields. Bottom, B: hospital admission CT scan of the chest revealing a 2.8 x 2.9 cm cavity in the LLL. Dense areas of consolidation are apparent in the lower lobes and lingula. Scattered small centrilobular nodular opacities in the upper lobes are consistent with infectious bronchiolitis.

 
In the absence of immunosuppression or underlying lung disease, the patient’s rapidly progressive deterioration was thought to be inconsistent with previously recognized manifestations of MAC lung disease. Therefore, an open lung biopsy specimen was obtained to exclude other etiologies and to confirm the diagnosis of MAC infection. Biopsy specimens obtained from the right middle and lower lobes revealed necrotizing granulomatous inflammation (Fig 2 , top, A) with well-formed, necrotizing granulomas. The appearance of the granulomas was clearly distinct from the vaguely formed granulomas that are characteristic of hypersensitivity pneumonitis or the nonnecrotizing granulomas typically seen in sarcoidosis. The pathologic appearance was most consistent with an infectious etiology. Acute inflammation suggestive of bacterial pneumonia was not seen. The Ziehl-Neelsen stain revealed rare AFB (Fig 2, bottom, B). The Gomori methenamine-silver stain was negative for fungal organisms. MAC was isolated from cultures of the lung tissue. Fungal culture and bacterial cultures for both aerobic and anaerobic bacteria from the lung tissue were negative. Cultures of the hot tub water failed to grow MAC.


Figure 2
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  		Figure 2.. Top, A: surgical lung biopsy specimen showing granulomatous inflammation with epithelioid histiocytes, multinucleated giant cells, and necrosis (hematoxylin-eosin, original x400). Bottom, B: Ziehl-Neelsen stain revealing rare AFB (consistent with MAC) in a necrotic area (original x600).

 
The patient was placed on therapy with ethambutol, 1,400 mg/d, rifampin, 600 mg/d, and clarithromycin, extended-release 1,000 mg/d, for a planned course of 12 to 18 months. Amikacin was added for the first 3 months at a dose of 15 mg/kg every other day and was adjusted according to serum levels. Oral prednisone therapy, starting at 40 mg/d and tapered over 4 weeks, was added to reduce the inflammation. By the time of hospital discharge, 5 days after beginning therapy, the patient showed dramatic clinical improvement and some radiographic improvement. At her 1-month follow-up visit, her symptoms had almost resolved. A chest CT scan performed at that time revealed dramatic improvement in the areas of consolidation and a decrease in the size of the LLL cavity (Fig 3 , left, A). High-resolution images obtained at the time revealed no evidence of chronic underlying bronchiectasis. Further follow-up images at 4 months demonstrated a continued decrease in the size of the LLL cavity and improvement in the small centrilobular nodular opacities consistent with resolving bronchiolitis (Fig 3, right, B).


Figure 3
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  		Figure 3.. Left, A: high-resolution CT scan of the chest performed at 1 month of follow-up revealing significant improvement in the bilateral lower lobe consolidation. Right, B: CT scan of the chest 4 months later revealing a decreasing size of the LLL cavity, resolving areas of consolidation, and improvement in bilateral centrilobular opacities.

 

   Discussion
TOP
 Abstract
 Introduction
 Case Report
 Discussion
References
 
Four distinct clinical and pathologic presentations of pulmonary MAC disease have been described in the literature. The symptoms that accompany these presentations include cough, sputum production, fatigue, malaise, dyspnea, fever, night sweats, hemoptysis, anorexia, and weight loss of varying severity.12 The American Thoracic Society has developed specific criteria for the diagnosis of NTM lung disease (Table 1 ). Epidemiology, preexisting medical conditions, radiographic appearance, pathologic findings, and disease course help to differentiate these distinct clinical entities (Table 2 ).


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  		Table 1.. American Thoracic Society Diagnostic Criteria of Nontuberculous Mycobacterial Lung Disease in HIV-Seropositive and HIV-Seronegative Hosts

 

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  		Table 2.. Comparison of Clinicopathologic Forms of MAC Lung Disease*

 
Fibrocavitary MAC
MAC pulmonary infection was first described in older patients (60 to 80 years of age), mostly men, with a smoking history and underlying structural lung disease, most commonly COPD.256 Over the last few decades, women have come to represent a greater proportion of these patients due to their increased use of tobacco and development of COPD. Other pulmonary conditions associated with MAC include pulmonary fibrosis, rheumatoid lung, healed tuberculosis, silicosis and other industrial pneumoconiosis diseases, previous chest surgery, and lung cancer.567 Nonpulmonary conditions including previous gastrectomy, chronic aspiration, esophageal disease, alcohol abuse, cardiovascular disease, and chronic liver disease have also been associated with fibrocavitary MAC.56 Children and young adults with cystic fibrosis represent a special subgroup of this presentation as they are much younger, lack a smoking history, and have no observed gender predominance. Airway colonization with NTM is common in these patients. NTM infection may also develop, as defined by ATS criteria, which typically demonstrates clinical and radiographic progression similar to that in patients with other chronic lung diseases.8

Symptoms of fibrocavitary MAC are most commonly insidious and often are attributed to the gradual worsening of preexisting lung disease. Radiographic findings can include the presence of bilateral thin walled cavitary or fibrocavitary disease with reticulonodular infiltrates or consolidation, and occasionally the presence of pleural thickening.6 There may also be cylindrical, cystic, or saccular bronchiectasis, and solitary or multiple pulmonary nodules.5 Lymphadenopathy and ground-glass opacification are usually not present. Pathologic examination of the nodules can reveal incompletely formed-to-extensively caseating granulomas, which can be indistinguishable from tuberculosis.9 The course is usually slowly progressive. Antimycobacterial therapy is often beneficial in those with severe disease or radiographic progression. However, recurrence is common, and the resection of isolated fibrocavitary disease is required in some cases. The treatment of underlying lung disease, specifically bronchial hygiene, is critical to the long-term management of this disease.56

MAC in Association With Immunodeficiency
The second group of MAC pulmonary diseases was characterized in the early 1980s in patients with AIDS. Subsequently, it has also been reported with immune deficiency due to steroids, organ transplants, leukemia, lymphoma, and severe combined immunodeficiency.157101112 Rare genetic defects in interleukin-12 and the interferon-{gamma} receptor have been linked to the development of severe life-threatening NTM infections, typically presenting in childhood with disseminated disease.1314

Patients with MAC disease who are immunodeficient often present with severe disseminated disease. Pulmonary disease is frequently aggressive and cavitary; it is rare in the absence of disseminated disease. Pathology often reveals necrotizing granulomatous inflammation and massive foamy histiocyte proliferation in which cells are filled with AFB.1015 There is considerable mortality even with treatment, but prophylaxis can be effective, particularly in AIDS patients.1

Reticulonodular MAC With Cylindrical Bronchiectasis
In 1989, Prince et al16 described a series with predominantly immunocompetent elderly female patients without preexisting lung disease who presented with a form of pulmonary MAC characterized by slowly progressive nodular opacities. Associated idiopathic cylindrical bronchiectasis has since been characterized as a key feature. It has been dubbed by some as the Lady Windermere syndrome (secondary to a hypothesis that fastidiousness among these women contributes to disease development).17 Patients are predominately female (up to 94%), though involvement in men has also been described. They are typically thin, nonsmokers with an average age of approximately 65 ± 10 years with cases reported in patients as young as 31 years of age.161718 The course is variable, but tends to be more chronic and indolent, and can evolve over months to years before a diagnosis is made.7 Radiographically, patients have multiple, small, well-circumscribed inflammatory pulmonary nodules with associated bronchiectasis, a tree-in-bud appearance, and ground-glass opacities. A study by Swensen et al19 found these CT scan finding to have a sensitivity of 80% and a specificity of 87%. There is also a predilection for the right middle lobe, lingula, and dependent areas of the lung.1720 Progression to cavitation and consolidation has been described.1618 Pathologically, granulomatous inflammation, with or without necrosis, is present. Antimycobacterial therapy, in conjunction with bronchial hygiene, often leads to clinical and radiographic improvement, but the disease is chronic with a course that is characterized by frequent relapses and reoccurrences.218

Hot Tub Lung
Lung disease secondary to aerosolized MAC from hot tubs has more recently been described as a new form of MAC lung disease. Our understanding of this disorder is based on its description in several case reports and a few case series.2122232425262728 Patients are typically young and immunocompetent with an average age of approximately 40 years (range 9–69). Women tend to be affected slightly more often than men. Patients often have had significant hot tub exposure for several months to years. Most cases occur with indoor hot tubs since they are believed to allow maximal concentration of the aerosolized water in a confined space.272829 Other sources of contamination, including household showers, have also been implicated in some cases.30 The typical signs and symptoms at presentation include cough, dyspnea, chest tightness, fatigue, and hypoxia that progresses over the course of several weeks to months prior to diagnosis.28 Diffuse interstitial or nodular infiltrates are noted on the CXRs of virtually all of the documented cases of hot tub lung (HTL).2729 A high-resolution CT scan of the chest typically demonstrates ground-glass opacities and scattered nodules. Mosaic attenuation is common and reflects air trapping consistent with bronchiolitis.2627 Some reports12427 have noted a lower lobe predominance, but the majority of documented cases reveal upper lobe-predominant disease.232629 Cavitary lung disease has not been described in this population.

Sputum cultures from patients with HTL are consistently positive for MAC. It is also helpful to grow MAC from the implicated hot tub water to confirm the diagnosis. In some case reports, MAC isolates obtained from patients and hot tub water were found to be identical strains when compared using restricted fragment length polymorphism analysis or multilocus enzyme electrophoresis.2125 However, it is not always possible to culture MAC from the suspected hot tub.28 Furthermore, a recent study by Angenent et al31 demonstrated that standard culture techniques are often inadequate and frequently fail to grow mycobacteria when attempting to culture from environmental sources known to contain MAC through culture-independent phylogenic analysis.

Pathologic examination most commonly reveals a characteristic histopathologic finding of discrete nonnecrotizing granulomas. Other reported histopathologic findings include organizing pneumonia, patchy interstitial pneumonitis, and occasional necrotizing granulomas. The granulomas and organizing pneumonia are centrilobular in distribution, and are bronchiolocentric with frequently observed cellular bronchiolitis.24 The histopathologic findings of HTL are in distinct contrast to those found in patients with hypersensitivity pneumonitis, who generally demonstrate loosely organized granulomas with prominent interstitial infiltrates.

Some authorities have postulated that HTL is a hypersensitivity pneumonitis reaction; others have argued that it is an infectious process. Proponents of hypersensitivity pneumonitis reaction cite several salient points including the rapid onset of symptoms, temporal relationship to hot tub exposure, and rapid clinical improvement after removal of the exposure. Additionally, based on case reports,2229 patients have had resolution of clinical symptoms, radiographic abnormalities, and clearance of MAC regardless of the therapeutic regimen employed (eg, no therapy, corticosteroids, antimycobacterial drugs, or combination therapy including antimycobacterial drugs and corticosteroids). In addition, the response to treatment tends to be rapid with complete clinical and radiologic resolution having been described as occurring within 2 to 3 months of treatment.2127

Our patient’s clinical characteristics are not fully consistent with those of any of the four previously described categories of MAC pulmonary disease detailed above. The patient had no preexisting clinical or radiographic evidence of chronic lung disease. She was immunocompetent without a history of recurrent infections and had negative HIV test findings. Although we did not test for interleukin-12 or interferon-{gamma} receptor deficiencies, her age, the absence of dissemination, and the absence of a history of recurrent mycobacterial or other bacterial infections would strongly suggest against these entities. Our patient was female and a life-long nonsmoker, and had evidence of nodular infiltrates that are similar to those found in patients with Lady Windermere syndrome, but she was much younger than is typical for patients with this syndrome. More importantly, the severe, rapidly progressive nature of her disease, her toxic appearance at presentation, as well as the radiographic appearance of early cavitary disease, diffuse consolidation, and absence of bronchiectasis would be most atypical for patients with this form of MAC disease.

Our patient’s demographics and clinical history would be appropriate for HTL. The inability to grow MAC from water from her neighbor’s hot tub does not exclude this diagnosis; other water sources could have been origin of the infection. Her radiologic manifestation of cavitary disease, however, has not been described in patients with HTL. The diffuse necrotizing granulomatous inflammation found on her lung biopsy specimen is not characteristic of HTL and is more characteristic of an infectious process rather than a hypersensitivity reaction. The patient’s condition did not improve with simple removal from the source and continued to worsen during her hospital course prior to effective treatment. The initiation of treatment with appropriate antimycobacterial agents combined with a 1-month course of steroids led to rapid and dramatic improvement in both symptoms and gas exchange, as well as to improvement in radiographic findings. The initial improvement with steroids could suggest an underlying hypersensitivity component, and we suspect that hypersensitivity did play a role clinically despite its absence radiologically and pathologically. Clinical and radiologic improvement continued over the next 3 months during which the patient was treated with antimicrobial agents alone. Complete radiographic improvement did not occur within the typical period of 2 to 3 months as described with most cases of HTL.

There have been few controlled trials evaluating treatment for MAC lung disease. The most common therapy employed is a three-drug regimen of either clarithromycin or azithromycin, with ethambutol, and rifampin or rifabutin for 12 months after sputum conversion. This regimen results in sputum conversion in approximately 90% of those who tolerate the regimen.2323334 Drug intolerance, however, is a significant limitation to achieving sputum conversion. An aminoglycoside, such as streptomycin or amikacin, is frequently added to therapy for the first 2 to 3 months in patients with extensive or disseminated disease. Alternative medications used in patients with drug intolerance or clarithromycin-resistant strains include isoniazid or clofazimine and quinolones.2 We chose the basic three-drug regimen combined with 3 months of therapy with an aminoglycoside given the extensive and progressive nature of her illness. This resulted in sputum clearance in 6 months. Aksamit,29 in a review of 41 cases of HTL, suggested treatment with steroids in addition to antimycobacterial medications in those patients with severe disease. Our patient was placed on a short course of steroids, which resulted in rapid symptomatic improvement.

Our case represents a unique form of MAC pulmonary infection. Her disease presented initially in a subacute fashion, followed by rapid progression to hypoxemia and physical disability. Radiographically, the patient presented with cavitary lung disease that rapidly progressed to diffuse consolidation. This case may represent a more severe, fulminant form of HTL or it may represent a new form of MAC lung disease that can affect young immunocompetent patients. With these unique features, our case extends the clinical spectrum of MAC presentation. MAC lung disease must be considered in young, otherwise healthy individuals and can cause fulminant, aggressive cavitary lung disease in such patients.


   Footnotes
 
Abbreviations: AFB = acid-fast bacilli; CXR = chest radiograph; HTL = hot tub lung; LLL = left lower lobe; MAC = Mycobacterium avium intracellulare complex; NTM = nontuberculous mycobacteria

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication December 26, 2005. Accepted for publication March 23, 2006.


   References
TOP
 Abstract
 Introduction
 Case Report
 Discussion
 References
 

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