Nontubercular Mycobacterial Pulmonary Infection in Immunocompetent Men.

ABSTRACT

Background. Nontubercular mycobacteria (NTM) are increasingly recognized to cause lung disease in immunocompetent patients. We studied the occurrence of pulmonary infection due to NTM in immunocompetent men.

Methods. We retrospectively analyzed all sputum mycobacterial cultures at our institution over a 5-year period. Charts were reviewed to identify patients who met the American Thoracic Society's criteria for mycobacterial pulmonary infection.

Results. From the 7,380 sputum mycobacterial cultures obtained, 46 male patients had NTM identified. Forty-two patients were immunocompetent. Five of these patients were found to have NTM-2 with Mycobacterium kansasii, 2 with Mycobacterium avium-intracellulare, and 1 with Mycobacterium gordonae. All 5 patients responded to antimycobacterial therapy.

Conclusion. Twelve percent of our population of immunocompetent men from whom NTM were isolated from sputum were infected. This study should alert the clinician that NTM cause treatable pulmonary disease in immunocompetent men.

THE GENUS Mycobacterium contains more than 70 recognized or proposed species. These species can be divided into two groups based on their culture growth rate. [1] The slow-growing species require more than 7 days to form visible colonies on solid media, while the rapidly growing species require fewer than 7 days. The slow-growing species are often pathogenic for humans, while the rapidly growing species are usually considered nonpathogenic, though there are important exceptions. At least 28 species of nontubercular mycobacteria (NTM) have been reported to cause lower respiratory tract infections in humans.

The human immunodeficiency virus (HIV) epidemic and the secondary pulmonary infection with Mycobacterium avium complex that frequently accompanies this immunosuppressive disorder allowed the medical community to recognize this NTM as an important respiratory pathogen. Subsequently, M avium has been increasingly identified as a pathogen in the lower respiratory system of patients without an underlying immunosuppressive disorder or chronic pulmonary disease. [23]

During the same period, the incidence of lung disease due to other NTM has increased. [24] The reason for the observed general increase in pulmonary infections due to NTM is uncertain but is not solely due to the impact of the H1V epidemic. Although the predominant mycobacterial species may vary with geographic region, increased occurrence of pulmonary NTM infection has been reported in many of the developed nations worldwide.

Many patients with NTM pulmonary infections are initially suspected to have tuberculosis. However, the clinical course, response to conventional antimycobacterial drugs, and prognosis are important distinguishing features of NTM disease in the lower respiratory tract.

These differences between tubercular and non-tubercular infection emphasize the need for precise identification of the infecting mycobacterial organism. [5]

In addition, it appears that NTM pulmonary disease in previously healthy patients remains underappreciated, which can lead to delays in diagnosis and treatment. We undertook our study to identify and characterize pulmonary disease due to NTM in an elderly, nonimmunosuppressed male population.

MATERIALS AND METHODS

The Quillen Veterans Affairs Medical Center (VAMC) is a teaching facility that provides both inpatient and outpatient care to military veterans. All sputum mycobacterial stains and cultures obtained at this facility from January 1994 to December 1998 were reviewed. All mycobacterial specimens were cultured using the BACTEC liquid medium (Becton Dickinson, Sparks, Md). Isolates were identified and drug sensitivities were tested at the West Haven VAMC in Connecticut.

The electronic medical records of patients were examined to determine the clinical significance of a culture positive for mycobacteria. The diagnosis of pulmonary infection was based on the 1997 American Thoracic Society (ATS) criteria for diagnosis of disease caused by NTM. [6]

The charts were reviewed for the following information: age and sex of the patient, preexisting lung disease, a history of previously treated tuberculosis, general medical history, and chest radiograph findings at the time the sputum samples were obtained. Patients with a known immunosuppressive disorder were excluded from the study. Patient follow-up focused on the clinical, radiographic, and mycobacterial culture response to treatment. All patients diagnosed with NTM pulmonary disease had at least 12 months of follow-up after completion of treatment.

RESULTS

During the 5-year study period, 7,380 mycobacterial cultures of sputum were processed. Forty-six patients had NTM identified by sputum culture. Four of these patients were excluded from the data analysis due to immunocompromise (caused by HIV). Of the remaining 42 patients, 5 (12%) were determined to have a pulmonary infection with NTM. The 5 patients were infected with the following organisms: Mycobacterium kansasii, 2 patients; M avium, 2 patients; and Mycobacterium gordonae, 1 patient (Table 1). The staining of sputum was positive for acid-fast bacilli (AFB) in 2 of these patients, 1 patient with M avium and 1 patient with M gordonae. Of the 56 sputum cultures that grew NTM, 15 (27%) were from patients determined to be infected with the organisms. During the same period, 24 other patients not included in our study were found to have pulmonary infection with Mycobacterium tuberculosis.

The mean age of patients with NTM pulmonary infection was 65.2 years, and all five had chronic obstructive pulmonary disease (COPD) from tobacco use. One patient admitted to previous treatment for M tuberculosis. Two patients had gastroesophageal disease, and one was a current habitual alcoholic. Four patients had involvement of the upper lobes of the lung; two of them had cavitary disease. The remaining patient had infection of the middle lobe and lingula with M avium complex. Four patients were initially treated with antitubercular chemotherapy. The treatment regimen was changed in these four patients when the organisms were identified and sensitivities were available. In the remaining patient (with M avium of the middle lobe and lingula), treatment was started after the organism was identified by culture. All five responded to antimycobacterial therapy, with clinical and radiographic improvement and conversion of mycobacterial cultures to no growth.

Thirty-seven patients with sputum cultures positive for NTM did not meet the ATS criteria for respiratory infection from NTM (Table 2). Only 2 of these patients had smears positive for mycobacteria. The most common isolate was M gordonae (19 patients), followed by Mycobacterium terrae (7 patients) and Mycobacterium chelonae (5 patients). Interestingly, 3 patients met the ATS bacteriologic criteria for diagnosis of NTM but lacked clinical and radiographic findings to suggest infection and were presumed to be colonized with these organisms.

DISCUSSION

While the incidence of M tuberculosis infection has decreased in the United States, the incidence of NTM pulmonary infection has increased. [7] The reasons for this observed increase in NTM infection are not known but may be due to climatic and environmental change, increased prevalence of chronic lung disease, immune senescence in an older population, and/or newer laboratory diagnostic techniques that have improved the isolation and identification of NTM.

Most of the NTM organisms are ubiquitous in nature and have been isolated from water and soil. Infections are believed to occur from environmental exposures. Person-to-person transmission of NTM is not thought to occur. It is not known whether NTM can lie dormant in the lungs without causing disease like its tubercular counterpart M tuberculosis.

Nontubercular mycobacterial infection in the United States varies geographically in both the prevalence of disease and the mycobacterial species responsible for disease. Since NTM disease is not a reportable infection in the United States, no reliable estimates of incidence or prevalence of infection are available. [7] However, in an elderly, middle-class community setting, the incidence of NTM pulmonary disease may be as high as 91%. [8] In our population of nonimmunosuppressed military veterans, NTM were responsible for 17% of the pulmonary disease caused by mycobacterial organisms.

Mycobacterium avium complex and M kansasii are the first and second most common NTM pulmonary pathogens in the United States. [7] Mycobacterium gordonae, M terrae, M chelonae, Mycobacterium fortuitum, and Mycobacterium scrofulaceum, while capable of causing pulmonary disease in humans, most frequendy represent laboratory contamination. [9] Three of our patients from whom an NTM was isolated appeared to be colonized with the organism. All three had M gordonae identified by sputum culture. This organism is thought to be a rare colonizer of the human airways. Our data confirm these observations. The remaining positive culture results are thought to represent environmental contamination.

The ATS established criteria to aid the clinician in the diagnosis of NTM pulmonary infection. [6] Unfortunately the identification of these organisms by the classical laboratory methods (cultivation and biochemical tests) is time consuming and may result in a significant delay that can adversely affect patient care and outcome. The new generation of rapid nucleic acid amplification techniques, such as polymerase chain reaction (PCR), has allowed for the early diagnosis of M tuberculosis, especially in patients with sputum smears that are positive for AFB. [10,11] Results of PCR are available within 24 to 48 hours after a specimen is received by the laboratory. If done by experienced personnel, both the sensitivity and specificity of this test are high. [12]

Conversely, if the DNA sequence that is unique to the M tuberculosis complex of organisms is not present in the sputum of a patient with sputum containing AEB, this result may be useful in excluding M tuberculosis in these patients. [13] Once M tuberculosis is excluded from the diagnosis in this subset of patients, NTM should be considered as a cause of the infection. Also, newly formulated probes for M avium and M kansasii are being investigated. [14,15] Similar assays for other NTM may follow. It is hoped that these new laboratory techniques will have a dramatic impact on our ability to rapidly and accurately diagnose NTM infection.

Nonimmunosuppressed patients most commonly affected by NTM are smokers with COPD. [5] All of our patients infected with NTM had tobacco-related COPD. Other reported risk factors are advanced age, alcoholism, bronchiectasis, previous tuberculosis, and chronic sinusitis. [16-18] Gastroesophageal disorders are also reported to be associated with pulmonary infection caused by rapidly growing mycobacteria. [19]

Elderly individuals without preexisting lung disease may have a predilection for M avium complex infection in the middle lobe and lingula, with a characteristic computed tomography pattern. [5,8] This subset of patients has no identifiable defect in immunity. Rather, the infections are thought occur due to a mechanical or functional disturbance of the airways and lungs, which promotes susceptibility to this infectious agent. [20]

When NTM are isolated from sputum specimens, the total number of specimens representing an actual pulmonary infection has been reported to be less than 1% when the ATS criteria are applied. [9] Most sputum isolates of NTM are not found to be pathogens, but are colonizers or contaminants. Our data, however, suggest that a higher number of sputum culture NTM isolates from elderly men may be pathogenic. Twenty-seven percent of the sputum specimens that were positive for NTM on culture were from patients who had a pulmonary infection with these organisms.

Other studies report that 10% to 50% of patients from whom NTM are isolated from respiratory specimens are infected with these agents. [5,21] Our data are in agreement with these reports. Twelve percent of our nonimmunosuppressed male patients from whom NTM were isolated from sputum samples were infected with these organisms.

Nontubercular mycobacterial lung infections in nonimmunosuppressed patients with COPD are frequently characterized radiographically by upper lobe lung infiltrates. The process is typically bilateral, with cavitation occurring in 16%. [22] Middle lobe and lingular infiltrates characterize the chest radiographic findings in elderly individuals without underlying lung disease or immunosuppressive disorder. These patterns are in contrast to the radiographic findings in immunosuppressed patients with NTM pulmonary infection; these have a variable appearance, but they most commonly reveal diffuse alveolar and/or interstitial infiltrates. [23] The radiographic findings in patients who have NTM infection associated with gastroesophageal disorders resemble those of aspiration pneumonitis. [22] Pulmonary nodules and pleural effusions are unusual features of NTM infection. [5]

Treatment of M kansasii is fairly standardized, and sputum culture conversion rates approach 100%. However, wild strains of other NTM have varying patterns of natural drug resistance. This heterogenous drug sensitivity of other NTM makes treatment far less predictable than therapy for M kansasii. In addition, a poor correlation between in vitro sensitivity results and clinical response has been observed. Therefore, the optimal therapeutic regimen and duration of treatment for other NTM have yet to be established.

Mortality from NTM pulmonary infections other than those caused by M kansasii has been reported to be as high as 32%. [5] Although underlying disease may have played a part in the mortality in that report, the poor response to treatment is alarming. It has, therefore, been recommended that the patients with NTM (other than M kansasii) be treated with multiple antitubercular medications and that therapy be guided more by side effects, drug tolerance, and clinical response than in vitro sensitivities. Therapy should be continued until the patient has had sputum cultures negative for mycobacteria for 10 to 12 months. Although investigational, surgical resection of the affected lung may be appropriate in selected patients who have sufficient lung function. [24,25]

References

(1.) Shinnick TM, Good RC: Mycobacterial taxonomy. Eur J Clin Microbiol Infect Dis 1994; 13:884-901

(2.) Huang JH, Kao PN, Adi V, et al: Mycobacterium avium-intracellulare pulmonary infection in HIV-negative patients without preexisting lung disease. Chest 1999; 115:1033-1040

(3.) Prince DS, Peterson DD, Steiner RM, et al: Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med 1989; 321:863-868

(4.) Falkinham JO III: Epidemiology of infection by nontuberculous mycobacteria. Clin Microbial Rev 1996; 9:1 77-215

(5.) Contreras MA, Cheung OT, Sanders DE, et al: Pulmonary infection with nontuberculous mycobacteria. Am Rev Respir Dis 1986; 137:149-152

(6.) American Thoracic Society: Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am J Respir Crit Care Med 1997; 156:S1-S25

(7.) O'Brien RJ, Geiter LJ, Snider DE Jr: The epidemiology of (nontuberculous mycobacterial diseases in the United (States, results from a national study. Am Rev Respir Dis 1987; (135:1007-1014

(8.) Kennedy TP, weber DJ: Nontubercular mycobacteria: an underappreciated cause of geriatric lung disease. Am J Respir Crit Care Med 1994; 149:1654-1658

(9.) Ahkee S, Huang AK, Ramirez JA: Clinical significance of mycobacterium other than tuberculosis isolated from respiratory specimens at a university hospital. Ky Med Assoc J (1995; 93:53-55

(10.) Yuen KY, Chan KS, Chan CM, et al: Use of PCR in routine diagnosis of treated and untreated pulmonary tuberculosis. J Clin Pathol 1993; 46:318-322

(11.) Aslanzadeh J, de la Viuda M, Fille M, et al: Comparison of culture and acid-fast bacilli stain to PCR for detection of Mycobacterium tuberculosis in clinical samples. Mol Cell Probes 1998; 12:207-211

(12.) Richeldi L, Barnini S, Saltini C: Molecular diagnosis of tuberculosis. Eur Respir J 1995; 20:6895-700S

(13.) Schluger NW, Kinney D, Harkin TJ, et al: Clinical utility of the polymerase chain reaction in the diagnosis of infections due to Mycobacterium tuberculosis. Chest 1994; 105:1116-1121

(14.) Richter E, Niemann S, Rusch-Gerdes S, et al: Identification of Mycobacterium kansaii by using a DNA probe (AccuProbe) and molecular techniques. J Clin Microbial 1999; 37:964-970

(15.) Soini H, Eerola E, Villjanen MK: Genetic diversity among Mycobacterium avium complex AccuProbe-positive isolates. J Clin Microbiol 1996; 34:55-57

(16.) Kubo K, Yamazaki Y, Hachiya T, et al: Mycobacterium avium-intracellulare pulmonary infection in patients without predisposing lung disease. Lung 1998; 176:381-391

(17.) Wongwatana S, Sriyabhaya N: Nontuberculous mycobacterial infection of the lung in a chest hospital in Thailand. J Med Assoc Thai 1992; 75:1-10

(18.) Contreras MA, Cheung OT, Sanders DE, et al: Pulmonary infection with nontuberculous mycobacteria. Am Rev Respir Dis 1988; 137:149-152

(19.) Hadjiliadis D, Adlakha A, Prakash UBS: Rapidly growing mycobacterial infection in association with esophageal disorders. Mayo Clin Proc 1999; 74:45-51

(20.) Reich JM, Johnson RE: Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern, the Lady Windemere syndrome. Chest 1992; 101:1605-1609

(21.) Wickman K: Clinical significance of nontuberculous mycobacteria, a bacteriological survey of Swedish strains isolated between 1973 and 1981. Scand J Infect Dis 1986; 18:337-345

(22.) Miller WT Jr: Spectrum of pulmonary nontuberculous mycobacterial infection. Radiology 1994; 191:343-350

(23.) Marinelli DL, Albelda SM, Williams TM, et al: Nontubertulous mycobacterial infection in AIDS: clinical, pathologic, and radiographic features. Radiology 1986; 160:77-82

(24.) Corpe RF: Surgical management of pulmonary disease due to Mycobacterium avium-intracellulare. Rev Infect Dis 1981; 3:1064-1067

(25.) Pomerantz M, Denton JR, Huitt GA, et al: Resection of the right middle lobe and lingula for mycobacterial infection. Ann Thorac Surg 1996; 62:990-993

TABLE 1.
Laboratory Findings and Treatment Response in Men With NTM Infection
                               No.     No. Sputum  No. AFB -Positive
Organism                     Patients  Specimens        Smears
Mycobacterium kansasii          71         5               0
                                64         3               0
Mycobacterium avium complex     67         3               3
                                68         3               0
Mycobacterium gordonae          56         3               3
                             No. Positive
Organism                       Cultures        Chest Radiograph
Mycobacterium kansasii            3        RUL infiltrate
                                  3        RUL cavity with infiltrate
Mycobacterium avium complex       3        RUL infiltrate
                                  3        RML and lingular infiltrate
Mycobacterium gordonae            3        LUL cavity with infiltrate
                             Therapy
Organism                     Response
Mycobacterium kansasii         Yes
                               Yes
Mycobacterium avium complex    Yes
                               Yes
Mycobacterium gordonae         Yes
NTM = Nontubercular mycobacterium;
AEB = acid-fast bacilli;
RUL = right upper lobe;
RML = right middle lobe;
LUL = left upper lobe.
TABLE 2.
Results of Mycobacterial Studies Representing
Environmental Contaminants or Airway Colonization
                             No. Positive  No. Positive  No. Positive
Organism                      Specimens       Smears      Cultures
Mycobacterium gardonae            3             0             1
                                  3             0             3
                                  3             1             1
                                  3             2             2
Mycobacterium terrae              3             0             1
Mycobacterium chelonae            3             0             1
                                  3             0             2
                                  3             0             3
Mycobacterium avium               3             0             1
 complex
Mycobacterium fortuitum           3             0             1
Mycobacteriutn scrofulaceum       3             0             1
Mycobacterium kansasii            3             0             1
                               No.
Organism                     patients
Mycobacterium gardonae         16
                                1
                                1
                                1
Mycobacterium terrae            7
Mycobacterium chelonae          3
                                1
                                1
Mycobacterium avium             2
 complex
Mycobacterium fortuitum         2
Mycobacteriutn scrofulaceum     2
Mycobacterium kansasii          1

KEY POINTS

* The incidence of infection due to Mycobacterium tuberculosis has decreased in the US, but the incidence of pulmonary infection due to nontubercular mycobacteria (NTM) has increased.

* Among 7,380 sputum mycobacterial stains and cultures obtained over a 5-year period, 46 male patients had NTM identified; 42 of the patients were immunocompetent.

* Of the 42 immunocompetent patients with NTM identified, five (12%) were found to have a pulmonary infection with NTM.

* Clinicians should be aware that immunocompetent men may have treatable pulmonary disease caused by NTM.