e ICUNICAL INVESTIGATIONS

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1 e ICUNICAL INVESTIGATIONS Pulmonary Mycobacterial Infections due to Mycobacterium infracellulare-avium Complex" Clinical Features and Course in 100 Consecutive Cases David Y. Rosenzweig, M.D. One hundred consecutive cases of pulmonary infection due to Mycobacterium intrace"ulare-avium seen dur Ing a 3~-year period qualified for review on the basisof a compatible chest x-ray film, repeated Isolations from eultores of sputum, and follow-up of three to eight yean. ldfections with M intrace"ulare-avium represented 27 percent of all mycobacterial Infections seen during this period, including those due to M tuberculosis. The cases of disease due to M intracellulare-avium were predominantly in men with preexisting pulmonary disease, with a peak Incidence in the sixth decade, but nearly onethird of the eases were in younger penons free of coediting disease. The disease was chronic and indolent in most eases, and only a few showed a progressive coone. A stable course was frequently observed despite prolooged penisten8y positive cultures of sputum. A favorable prognosis was most often found in those with previously treated tuberculosis. Poor prognosis was often due to a serious associated disease, such as cancer, rather than to advancing mycobacterial infection itself. Age, &es, or race was unrelated to prognosis. Conversion to negative status on culture was attained In one-bah of the cases. Those with extensive radiographic Involvement or cavitation were more likely to have treatment fad bac:teriologlcady. No combination of chemotherapy appeared to be particularly effective, includidg the use of Ive or more drugs in eight CMeS demonstrating progressive disease. Surgery, too, was ultimately disappointing In that recurrence appeared in six of 18 carefudy selected cases. pulmonary infections with atypical mycobacteria have gained in prominence in recent years, at a time when infections due to Mycobacterium tuberculosis have declined in number. Each of these infections shares similar clinical and pathologic features, but several important differences relating to host factors, infectiousness, response to therapy, and prognosis exist. This report is a review of the experience with atypical infections due to M infracellulare-aoium complex at the principal tuberculosis facility in a medium-sized metropolitan area. The emphasis is placed on follow-up of cases seen within thepast decade and observed for a minimum of three years. The spectrum of disease appears wider and the prognosis in general better than other recent reports'" would suggest. From the Pulmonary Disease Section, Deparbnent of Medicine, Medical College of Wisconsin, Milwaukee County Medical Complex, Milwaukee. O.Associate Professor of Medicine. Manuscript received August 15, 1977; revision accepted July 25. Reprint requests: Dr. Rosenzweig, 8100 Wen Wl8conrin Aoenue, MilwiJukee CHEST, 75: 2, FEBRUARY, 1979 MATERIALS AND METHODS Consecutive cases were selected from the 3~year period for entry from October 1968 to April They fulfilled the following criteria: (1) lesions on chest x-ray Blm compatible with granulomatous infection; (2) persistent excretion of M intraceuulare-aoium on three or more weekly cultures of sputum, with moderate or numerous colonies; and (3) minimum follow-up of three years, unless death occurred earlier. The sources of these cases were admissions to the hospital and clinic who were referred for newly diagnosed mycobacterial infections or patients at the tuberculosis clinic who had controlled infection with M tubef"culosis and who later developed the problem of persistent excretion of atypical mycobacteria during the period of care at the clinic. Laboratory identification was by standard methods.s and identification of M intraceuulaf"e-avium complex was not further specified. Clinical evaluation was done by retrospective review of records and serial x-ray films. Judgments of radiographic extent and progress were done by the staff of the clinic and my own independent evaluation at a later date. Outcome was assessed by using radiographic and clinical criteria and also by using bacteriologic results, as follows: ( 1) the x-ray film was classified as improved (partial or complete resolution of injiltrates or cavities), stable ( no substantial change during the period of observation), or worse (either brief stepwise advance followed by stable PULMONARY MYCOBACTERIAL INFECnONS 115

2 Table I-NetfJCae. 01 MycobaeteriaJ ln/eeliora duri.. 3~ Year PeriodofSaudy Compared 10 Similar Period Fi"e Year. EarUer January October 1963 to 1968 to Organism July 1966 April 1972 M tuberculosis M intraceuulare-avium * M kansasii Other mycobacteria 4 4 Unspecified or mixed 16 0 *Includes 23 cases withheld from final group under study because of inadequate follow-up. periods of six months or more, or progressive infiltrates and cavities); (2) clinical condition was classified as asymptomatic, improved (improvement or clearing of respiratory symptoms), stable (no loss of weight, fever, or change in respiratory symptoms), or worse (stepwise or progressive systemic or respiratory symptoms); and (3) bacteriologic status was classified as negative status (continuously negative cultures after initial positive stage of variable duration), positive status (continuous or sporadic positive cultures throughout course), or relapse (reemergence of positive cultures after more than six months of negative cultures). Deaths were separated into those primarily due to the infection itseh or those due to other causes. Cases were identified initially from records of the microbiology laboratory. Selections were ended after 100 consecutive cases due to M intraceuulate-aoium qualified for inclusion. Eighteen of these were treated surgically and will be discussed separately in terms of outcome. Twenty-three other cases were excluded because of inadequate follow-up, and five were excluded for lack of a visible radiographic lesion. RESULTS Table 1 shows the bacteriologic distribution of cases of all new mycobacterial disease during the interval in which the 100 cases appeared, as compared to a similar period five years earlier. The decline in cases due to M tuberculosis is matched by a considerable rise in the group with disease due to M intracellulare-avium. Other mycobacterial infections showed a small and steady incidence. The age, sex, and race of the 100 patients with infections due to M intracellulare-aoium are shown in Figure 1. It can be seen that men are predominantly affected, with peak incidence in the sixth decade. The racial distribution is similar to that in the Milwaukee metropolitan area, but blacks appear to be affected at an earlier age. On the basis of older criteria of the American Lung Association," radiologic extent of disease was minimal in 14 cases, moderately advanced in 62 cases, and far advanced in 24 cases. No extrapulmonary involvement, except in adjacent pleura, was recognized in any case. The mean follow-up period was 52 months (range, 36 to 96 months). Other diagnoses were present in these 100 cases of infection due to M intracellulare-aoium in the following numbers: obstructive pulmonary disease, 32 ( five with bullae only); previous tuberculosis (documented M tuberculosis), 28; alcoholism, 20; silicosis, 15; diabetes, ten; atherosclerosis or heart disease, nine; lung cancer, three; other cancer, two; gastrectomy, three; schizophrenia, two; and miscel- 20 (J) W (J) <t u L&.. o a:: w 10 m ~ ::) Z CJ White _ Black 6:::::1 AsianAmerican MEN WOMEN AGE (YEARS) FiGURE 1. Age (by decades), sex, and race of patients with infection due to M intraceuulareavium complex. 118 DAVID Y. ROSENZWEIG CHEST, 75: 2, FEBRUARY, 1979

3 r,,, Table 2-Outeome in 82 NOlUurpeaUy Treated ClUe. of DiM!tJM due 10 M intraeellulare-avium, Compariq Symplomatic and Radio.,.aplaic SItJIw Radiographic Status Worse, Worse, Step- Pro- Data Improved Stable wise gressive Symptoms Asymptomatic throughout Improved Stable Worse 1 5 (5) 3 (1) 7 (2) Outcome Died from mycobacterial disease Died from other causes 0 3 (3) 1 (1) 1 (1) *Numbers withinparenthesesindicatethose withineach group who had advancing co-morbid disease judgedto be separable from status of mycobacterial infection. laneous, five (one each). The common association with obstructive pulmonary disease, silicosis, tumor, or other deleterious local pulmonary host factors has previously been observed.v'" These underlying problems were frequently more important prog- nostically than the mycobacterial infection itself. In other words, the course which some cases pursued could be attributed more to the serious coexisting noninfectious problem than to the chronic infection. This can be illustrated in Table 2, which shows the comparative outcome of the nonsurgically treated cases in terms of symptomatic and radiographic status. In general, these outcomes corresponded closely, and most cases showed a stable or indolent course. Exceptions occurred in eight patients with stable x-ray films, five of whom had advancing symptoms attributable to chronic obstructive pulmonary disease (COPD) and three who died from cancer or cardiovascular disease. Similarly, radiographic improvement was noted in six other patients, all with COPD who had no symptomatic change. While certain underlying diseases conferred a.~ 10 U) <r u LL o 5 ~ I.LJ m ~ ::) Z TIME.YEARS FIGURE 2. Time of infection with M intraceuulare-ooium complex after original tuberculosis was treated and controlled. A Z 100% o iii a: l&j > l&jz ~8 ""u <1_ 50% ~(!) ig :)0 un: l&j t U c:r: CD I ",,~ ",,"".--- Improved 15cases -- Stable 49 cases.. Worse 18cases.",---.","",...~ ","" TIME.YEARS FIGURE 3. Cumulative bacteriologic results related to radiographic status in nonsurgically treated cases. poor prognosis in themselves, the combination of previous tuberculosis and later infection with M intraceuulare-aoium appeared rather benign. These secondary infections occurred from six months to several years after the original tuberculosis was controlled, with little change in incidence with time (Fig 2). Four of these patients showed no new radiographic flndings, while 24 had new but characteristically modest infiltrates or cavities. Only one of these 28 cases with secondary infections developed a progressive problem; the others maintained stab~e radiographic lesions with little or no symptomatic problems. Conversely, a number of infections due to M intraceuulare-aoium, some serious, occurred in otherwise healthy individuals. Twenty-one cases in men and ten in women under the age of 50 years were free of coexisting disease, and five of these 31 pursued a worsening course. Other factors such as race, sex, and age were not found to be related to prognosis. Outcome was also assessed in terms of bacteriologic results. In the medically treated cases, lasting conversion to negative status was reached in 37 (45 percent) of 82 cases. There was considerable relationship between radiographic and bacteriologic results, as shown in Figure 3, which relates cumula~ve attainment of bacteriologic conversion to negative status over time to the radiographic status. This graph also shows that bacteriologic response ~as occasionally delayed well into the second or third year of treatment and that even in the large stable group, persistent excretion of organisms occurred. in half of the cases. The end point of lasting negative bacteriologic status was not always attained. Some cases had intermittent positive cultures for long periods, and these were considered as having positive status continuously. Also, nine cases held negative bacteriologic status for at least six months, only to suffer relapse at a later date, most often one year later, but sometimes as late as three years. Thus, CHEST, 75: 2, FEBRUARY, 1979 PULMONARY MYCOBACTERIAL INFECnONS 117

4 Table 3-Bae'erioloPe Outeome Related 10 Esteral of Di.-.e in Both Medically and SurPeall,. Trealetl CroulM *One relapse with infection due to M kamabii. Table 4--Bae'eriolope Reau'".,11 Set1eralCombirudioM of Chemo'herapy Regimen * Two drugs INH-EMB or INH-PAS Three drugs INH-PAS-SM INH-EMB-SM INH-EMB-RFN Subtotal Four drugs INH-PAS-SM-PZA Five or six drugs Retreatment with assorted five or six drugs Extent of Disease Moderate, Non- Moderate, FarAd- Data Minimal cavitary Cavitary vanced Medical therapy Negative status, lasting Negative status plus late relapse Positive status continuously Total cases Medical-surgical therapy Negative status, lasting 1 2 g. 0 Negative status plus late relapse 2 0 4* 0 Positive status continuously Total cases attaining bacteriologically negative status was advantageous, but failure to do so did not necessarily indicate a worsening course. Bacteriologic response was found to be related to the radiographic extent of disease, as well as the presence of a cavity (Table 3 ). The upper part of Table 3 shows the outcome of the medically treated cases. Failures were concentrated in those with extensive disease, while there was a small number with initial success but late relapse (after six months) in all groups. Treatment consisted of chemotherapy in all cases. Total Cases 2 (25) *INH, isoniazid; EMB, ethambutol; PAS, p-amin08alicylic a~id; ~M, streptomycin; RFN, rifampin; and PZA, pyrasinamide. 8 A Bacteriologic Conversion (percent) 19 8 (42) (39) (48) The standard regimen was three drugs, although regimens of four drugs or two drugs were also used. The last was usually given for minimal extent of infiltrates or in the very elderly. No selection of drugs was based on in vitro testing for sensitivity, as complete resistance to drugs was the rule in each case. Table 4 shows the relative success of various combinations. All were successful in one-thirdto onehalf of the patients receiving the regimen; and none, including those containing rifampin, showed special success. Regimens of five or six drugs for retreatment were offered in eight cases after 4 to 18 months of conventional chemotherapy. These patients all had worsening disease during the initial periodof treatmentand were not considered surgical candidates. While the regimens were reasonably well tolerated, their success was limited. Only two of these eight patients achieved bacteriologically negative status, and these two also showed clinical or radiographic improvement. Resectional surgery was done in 18 patients (16 men and two women). Their median age was 41 years (range, 24 to 56 years). All were carefully selected to have well-localized disease of minimal or moderate extent, and all but two had positive cultures after 6 to 12 months of chemotherapy. Lobectomy was done in each case, and chemotherapy was continued for an additional 6 to 12 months. While the procedures were well tolerated, with a major complication (bronchopleural fistula) in only one case, the long-term results were not uniformly good (Table 3, lower part). Seventeen of 18 patients had negative cultures following surgery, but consistently positive cultures were obtained 6 to 48 months later from five of these 17 cases, and one other developed" infection with M kansasii six years after surgery. In four of these six, radiographic involvement of the contralateral side appeared, and in the other two, ipsilateral new findings appeared. Three of the six developed recurrent respiratory symptoms as well. Because of the small numbers, no clear relation between extent of disease and relapse is seen. Thus, only 11 of 18 cases have achieved lasting stability, despite evidence from bilateral tomograms and at thoracotomy that the disease was confined to one lobe. DISCUSSION While the tuberculosis caseload has declined steadily in the past 10 to 15 years in ourclinic, cases of atypical mycobacterial infection, especially with M intraceuulare-avium, have grown from a trickle to numbers which currently rival those of tuberculosis. Their numbers alone minimize their importance, 118 DAVID Y. ROSENmlG CHEST, 75: 2, FEBRUARY, 1979

5 since the large proportion remaining in a prolonged active state demand a greater share of the clinic's attention than the patients with infection due to M tuberculosis or M kansasii, who nearly always do very well. Although the isolation of these organisms has almost reached a point of banality in the Milwaukee metropolitan area, this has not necessarily been a general trend. The incidence has generally risen slowly in other cities but has remained at or below 10 percent of the incidence of tuberculosis; and in the Midwest in particular, infections with M kansasii have been more common than infections with M intracellulare-aoium. 11 The reasons for this epidemiologic trend are not known. The results of this review support our impression from clinical experience that these infections are indolent and run a benign course in the vast majority of cases. On the other hand, the spectrum is wide, and a few cases pursue a progressive inexorable course. Many have a subtle and stable disease, while others with casual isolates or normal x-ray films defy classification as true disease. These last may represent a saprophytic process or carrier state. The favorable response in those cases with previously treated tuberculosis was unexpected. One explanation could be that tuberculosis confers partial immunity to other mycobacterial infections. Another possibility is that these organisms usually require an impaired host response, and the region "at risk" after tuberculosis is focal and limited, as compared to a more general impairment (as in pneumoconiosis or COPD). Although previously treated tuberculosis was a favorable prognostic indicator in this series, unfavorable clinical indicators could not be identified, except for those diseases which themselves progressed independently of the mycobacterial infection; however, bacteriologic outcome was related to the extent of disease. Patients in this series did not undergo further testing, but we have subsequently examined six recent cases with progressive disease for immunologic deficiency. A battery of cutaneous tests, including purified protein derivative of tuberculin derived from Battey bacilli ( PPD-B), and other tests of both cellular and humoral immunity were performed. Normal findings or only minor deviations were seen in each case, and cutaneous reactivity was also present. Thus, the early identification of progressive infection continues as an elusive problem in our experience. Other recently reported series have indicated a serious prognosis and have advised a vigorous chemotherapeutic and surgical approach. These series differed from the present report in that either CHEST, 75: 2, FEBRUARY, 1979 they dealt with a selected referral population with more extensive and refractory problems,l.!,1 or the methods of analysis, including life table studies,8a failed to properly weigh the confounding roles of coexisting chronic disease which appears to set the stage for this infection. The present report tends to parallel the results of the Veterans Administration Armed Forces Cooperative Study," in which a small fraction of mortality (two of ten deaths) resulted from the infection itself, H one accepts that this report reflects the spectrum of disease seen in the community, then there are important therapeutic implications. H the course is variable but usually benign, if the disease is not contagious, and if the therapeutic effect is meager even with a combined medical-surgical approach, then it is logical to tailor therapy to the individual problem. Vigorous measures with multiple drugs and adjunctive resection should be reserved for those cases demonstrating an unfavorable course. In many cases, observation alone or simple nontoxic drug regimens are appropriate. Perhaps the most difficult problem is identification of the case with a poor prognosis. lleferences 1 Fischer DA, Schaeffer WB, Lester W: Infections with atypical mycobacteria: Five years' experience at the National Jewish Hospital. Am Rev Respir Dis 98:29-34, Lester W, Camwright L, Davidson P, et al: Results of antituberculosis chemotherapy in 130 cases of disease caused by atypical mycobacteria. In Transactions of the 30th Research Conference in Pulmonary Disease, VA Armed Forces, 1971, p 44 3 Yaeger H Jr, Raleigh JW: Pulmonary disease due to Mycobacterium IntraceUultJre. Am Rev Respir Dis 108: , Corpe RF, Liang JL, Sanchez ES: Early and late results with atypical group Hl tuberculosis. Am Rev Respir Dis III:915, Davidson PT: Treatment and longterm followup of patients with atypical mycobacterial infection. Bull Int Union Against Tuberc 51: , Vestal AL: Procedures for the isolation and identification of mycobacteria (DHEW-CDC publication ). Atlanta, Center for Disease Control, Diagnostic standards and classification of Tuberculosis. New York, American Lung Association, 1969, p 69 8 Rosenzweig DY: Silicosis complicated by atypical mycobacterial infection. In Transactions of the 26th VA Armed Forces Pulmonary Disease Research Conference, 1967,p47 9 Bates J: A study of pulmonary disease associated with mycobacteria other than Mycobacterium tuberculodb: Clinical characteristics. Am Rev Respir Dis 96: , Snider GL, Placik B: The relationship between pulmonary tuberculosis and bronchogenic carcinoma. Am Rev Respir Dis 99: , Wolinsky E: Nontuberculous mycobacterial infections of man. Med Clin N Am 58: , 1974 PULMONARY MYCOBACTERIAL INFECnONS 118