Lung disease caused by Mycobacterium kansasii

Abstracts

BACKGROUND: Mycobacterium kansasii is a nontuberculous mycobacterium that can colonize the lungs and cause pulmonary infection. OBJECTIVE: To report authors' study of 6 patients with pulmonary disease caused by M. kansasii infection in a series of 6 patients diagnosed over 5 years. METHOD: Between June 1995 and June 2000, 1,349 patients diagnosed with tuberculosis were admitted to the Ipiranga Ari Nogueira da Silva Sanitarium. M. kansasii was identified in the sputum cultures of six (0.44%) of these patients. RESULTS: Patient ages ranged from 25 to 77 years, 5 of the 6 were male, and all presented symptomatic chronic lung disease. All patients tested negative for HIV. Chest radiographs confirmed a history of lung disease; all presented thin walled cavities and adjacent pleural thickening was seen in 2. All patients were initially treated with isoniazid-rifampin-pyrazinamide. In 2 patients, intolerance to pyrazinamide necessitated the substitution of pyrazinamide with ethambutol. Based on the culture results, pyrazinamide was also replaced by ethambutol in 2 other patients. All patients were treated for 9 months or longer, and only one patient suffered recurrence of the disease. After being considered cured of the M. kansasii infection, 1 patient died of respiratory insufficiency due to silicosis. CONCLUSIONS: Mycobacteriosis due to M. kansasii was found only rarely and may be attributable to the characteristics of our patients. Therapy with isoniazid, rifampin and pyrazinamide with eventual replacement of the latter by ethambutol was shown to be effective.

Mycobacterium kansaii; Lung diseases; Respiratory insufficiency

INTRODUÇÃO: O Mycobacterium kansasii é uma micobactéria não tuberculosa que pode causar colonização ou infecção pulmonar. OBJETIVO: Relatar experiência com doença pulmonar causada pelo M. kansasii em uma série de seis pacientes diagnosticados ao longo de cinco anos. MÉTODO: Entre junho de 1995 e junho de 2000 foram admitidos 1.349 pacientes no Dispensário do Ipiranga Ari Nogueira da Silva-Sanatorinhos, com o diagnóstico de tuberculose pulmonar, dos quais seis tiveram cultura positiva para M. kansasii. RESULTADOS: Cinco pacientes eram homens e a idade variou entre 25 e 77 anos. Todos apresentavam pneumopatia crônica e eram sintomáticos respiratórios com teste negativo para síndrome de imunodeficiência humana. As radiografias de tórax eram compatíveis com a presença de doença pulmonar prévia: cavidades de paredes finas foram notadas em todos e espessamento pleural subjacente às cavidades foi observado em dois pacientes. Todos foram tratados inicialmente com isoniazida, rifampicina, pirazinamida (INH-RMP-PZA) e etambutol (EMB) foi introduzido precocemente em dois pacientes por intolerância à pirazinamida, enquanto que em outros dois a introdução foi feita ao ser conhecido o resultado da cultura. Todos os pacientes foram tratados por mais de nove meses, tendo sido observada recidiva em um deles. Um paciente com silicose faleceu após dois anos por insuficiência respiratória, depois de ter sido considerado curado. CONCLUSÕES: A micobacteriose por M. kansasii foi encontrada com baixa freqüência, podendo estar relacionada às características dos pacientes encaminhados ao nosso serviço. O esquema INH-RMP-PZA, com substituição eventual da PZA por etambutol, mostrou sucesso terapêutico.

Mycobacterium kansasii; Pneumopatias; Insuficiência respiratória

ORIGINAL ARTICLE

Lung disease caused by Mycobacterium kansasii^*

Nelson Morrone^I; Maria do Carmo Cruvinel^II; Nelson Morrone Junior^III; José Antonio dos Santos Freire^II (TE SBPT); Lilia Maria Lima de Oliveira^IV; Carla Gonçalves^IV

^IClinical Director of the Dispensary. TE-SBPT (Specialist, as designated by the Brazilian Society of Pulmonology and Phthisiology)

^IIPhysician at the Dispensary. TE-SBPT (Specialist, as designated by the Brazilian Society of Pulmonology and Phthisiology)

^IIIPhysician at the Dispensary. TE-SBPT (Specialist, as designated by the Brazilian Society of Pulmonology and Phthisiology)

^IVFellow and Resident at the Ipiranga Hospital Medical Clinic

^{Correspondence}

ABSTRACT

BACKGROUND: Mycobacterium kansasii (M. kansasii) is a nontuberculous mycobacterium that can colonize the lungs and cause pulmonary infection.

OBJECTIVE: To report our study of 6 patients with pulmonary disease caused by M. kansasii infection.

Type of study: case reports.

METHOD: Between June 1995 and June 2000, 1349 patients diagnosed with tuberculosis were admitted to the Ipiranga Ari Nogueira da Silva Sanitarium. M. kansasii was identified in the sputum cultures of six (0.44%) of these patients.

RESULTS: Patient ages ranged from 25 to 77 years, 5 of the 6 were male, and all presented symptomatic chronic lung disease. All patients tested negative for HIV. Chest radiographs confirmed a history of lung disease; all presented thin walled cavities and subjacent pleural thickening was seen in 2. All patients were initially treated with isoniazid-rifampin-pyrazinamide. In 2 patients, intolerance to pyrazinamide necessitated substitution of pyrazinamide with ethambutol. Based on the culture results, pyrazinamide was also replaced by ethambutol in 2 other patients. All patients were treated for 9 months or longer, and only 1 patient suffered recurrence of the disease. After being considered cured of the M. kansasii infection, 1 patient died of respiratory insufficiency due to silicosis.

CONCLUSIONS: Mycobacteriosis due to M. kansasii was found only rarely and may be attributable to the characteristics of our patients. Therapy with isoniazid, rifampin and pyrazinamide – with eventual replacement of the pyrazinamide by ethambutol – was shown to be effective.

Key Words:Mycobacterium kansasii. Lung disease. Respiratory insufficiency.

Abbreviations used in this paper:

ATS - American Thoracic Society

EMB - Ethambutol

INH - isonicotinic acid hydrazide (isoniazid)

Mk - Mycobacterium kansasii

NTM - non-tuberculous mycobacteria

Mtb - Mycobacterium tuberculosis

PZA - Pyrazinamide

RMP - Rifampicin

SM - Streptomycin

Introduction

Within the Mycobacterium genus, Mycobacterium tuberculosis (MTN) complex is the species most commonly implicated in the etiology of human diseases and encompasses M. tuberculosis (Mtb), M. africanum and M. bovis. However, other mycobacteria may occasionally cause disease, mainly in the immunosuppressed, the elderly, and patients with chronic bronchopneumopathies. In addition, these mycobacteria may simply colonize some people. Therefore, definitive criteria must be established in order to differentiate colonization from infection.

Diseases caused by mycobacteria other than those belonging to the MTN complex often present clinical characteristics that may mask their true etiology during the initial examination. Accurate determination of etiology is important, principally because of differences in patient sensitivity to the various chemotherapeutic agents routinely used in the treatment of tuberculosis. It is important to note that human-to-human transmission of these diseases does not occur. Therefore, those who come into contact with these patients do not require the special attention given to those who have been exposed to tuberculosis.

These opportunistic mycobacteria were not initially given a designation but are presently known (collectively) as either atypical mycobacteria, mycobacteria other than tuberculosis, environmental mycobacteria or non-tuberculous mycobacteria (NTM).⁽¹⁾ The American Thoracic Society (ATS) suggests that only the last term (non-tuberculous mycobacteria) be used.⁽²⁾ The most common mycobacteria are M. kansasii (Mk), M. xenopi, M. szulgai, M. malmoense, M. leprae and the M. avium – M. intracellulare – M. scrofulaceum complex (MAIS complex). However, there are many species that are non-pathogenic, such as M. gordonae, M. terrae, M. flavecens, and M. smegmatis.

The objective of this study was to present 6 cases of Mk mycobacteriosis evaluated at our clinic, highlighting some controversial aspects.

Patients and Methods

Between June 1995 and June 2000, 1349 patients were diagnosed with pulmonary tuberculosis and admitted. Cultures were obtained from each patient and 6 tested positive for Mk. For all patients presenting expectoration and suspected of having pulmonary tuberculosis, sputum testing was performed through direct observation and culture. The cultures that tested positive for mycobacteria were sent to the Adolfo Lutz Institute to be typed. The Adolfo Lutz Institute is the laboratory of reference for the public health system in the state of São Paulo. The expertise of the technicians at this laboratory is well known, as is the international quality of their standards in the various health sectors across the spectrum, and both have been well documented. Therefore, all typing results were considered accurate.

Results

The main demographic, clinical, radiological, therapeutic and evolutionary aspects are summarized in Tables 1, 2, and ³.

Patient ages ranged from 25 to 77 years and 5 of the 6 were male. Of the 6 patients, 4 were Caucasian, 1 was of African descent and 1 was of Asian descent. The 1 female was employed as domestic help, 2 patients worked in sandblasting (and reported work-related exposure to silica), 2 were retired salesclerks, 1 was a vendor in an open-air market.

In 4 cases, the initial diagnosis was pulmonary tuberculosis. An initial diagnosis of silicosis was made in 1 case, and mycobacteriosis was not confirmed until 18 months later. In 1 patient suffering from bronchiectasis, mycobacteriosis was confirmed after 8 months.

All 6 patients presented evidence of previous lung disease: 2 suffered from silicosis, 2 from chronic obstructive pulmonary disease (COPD), 1 from bronchiectasis and 1 from inactive tuberculosis that had been treated 30 years prior. Serology revealed that all patients were HIV-negative and that none presented any apparent communicable disease. All 6 also presented symptoms of respiratory illness, 3 reporting fever and presenting significant weight loss.

Chest radiographs, taken at the time of the mycobacteriosis diagnosis, revealed multiple thin-walled cavities in 5 of the 6 patients. These cavities ranged from 2 to 6 cm in diameter and were located in the superior lobes, except in 1 of the 5, the patient who suffered from bronchiectasis, in whom the cavities were located in the areas affected by the pre-existing disease. Expressive pleural thickening, subjacent to the cavities, was seen in 2 patients. Disseminated nodules in the cavitated lung were also seen in 2 patients. Radiological findings were consistent with pre-existing disease in all 6 patients: high-density diffuse micronodules (patients with silicosis), fibrosis and lobe retraction (bronchiectasis), hyperinflation and blisters (COPD) and fibrosis-related left superior lobe retraction (previously treated pulmonary tuberculosis). It is important to note that, in the 2 patients whose mycobacteriosis was not initially diagnosed, cavities were present only after the preliminary examination. Computer-assisted tomography (CT) scans of the chest did not detect cavities in either patient at that time.

Sputum bacilloscopy was positive in all 6 patients during the diagnosis phase. In 1 patient, both of the sputum samples collected were positive. In another patient, 3 samples were collected and only 1 was positive. Although Mk was not suspected in any bacilloscopy, all cultures, obviously, tested positive for Mk.

Tuberculosis skin test (PPD-2u) was only performed on 3 patients. Of those, 2 tested negative and the 1 patient who had previously been treated for TB tested positive (12 mm).

All patients were initially treated with isonicotinic acid hydrazide (INH), rifampicin (RMP), and pyrazinamide (PZA). Subsequently, sputum bacilloscopy was negative in 4 patients, including 1 patient presenting no expectoration. Of the other 2 patients, 1 tested negative 4 months later and the other 8 months later. In 2 of the 6, ethambutol (EMB) was substituted for PZA prior to analysis of the culture results. Gastric intolerance was seen in 1 of those patients and severe intolerance (repeated bouts of hypotension following ingestion of the medication) was observed in the other, who was referred to us after having been initially treated with INH-RMP-PZA in another clinic. The alternative regimen was streptomycin (SM), EMB and PZA, which was replaced with RMP-EMB-PZA prior to analysis of the culture results. Due to severe arterial hypotension observed in this patient after supervised administration, INH was not given. In 2 of the other 4 patients, EMB was substituted for PZA after analysis of the culture results. In the remaining 2 patients, the regimen was not changed.

Only 4 patients were treated for a full year and none had any recurrence during that period. Neither was there any recurrence in the 1 patient who was treated for only 9 months. Another patient was initially treated for only 2 months and experienced 2 recurrences, which were treated for 12 and 18 months, respectively. In that patient, the interval between the initial treatment and the first recurrence was 1 year, and there was a 9-month interval between the first and second recurrence. A patient who suffered from silicosis died of respiratory insufficiency 2 years after being considered cured. The other patients have not shown any evidence of recurrence to date (February 2003).

Discussion

The 6 cases related herein were diagnosed over a span of 5 years. During this period, 1349 cases of pulmonary tuberculosis were registered at our clinic. Among those, 973 (72.1%) tested positive for mycobacterium culture. All cultures were typed and Mk incidence was found to be 0.44%. However, since 27.9% of the samples tested negative, the real incidence is likely to be slightly higher. Therefore, in this region, mycobacteriosis caused by Mk might be more common than previously thought.

Globally, mycobacteriosis caused by Mk is infrequent. There are, for example, 40 to 70 cases per year in Great Britain.⁽³⁾ In the Los Angeles area (USA), the incidence was 2.4 cases/100,000 inhabitants, including HIV-positive patients.⁽⁴⁾ In South Africa, however, the incidence among HIV-positive and HIV-negative gold miners was, respectively, 0.32 and 0.10/100 people/year – approximately 20 times lower than that of tuberculosis.⁽⁵⁾

A search of the Latin American and Caribbean Literature on Health Sciences (LILACS) database produced no Brazilian article on this topic published within the last few years. Therefore, our sample is significant and its analysis is comparable to other, international, publications – especially on controversial aspects.

As far as geographical distribution is concerned, mycobacteriosis caused by Mk is considered to be basically urban and its incidence varies significantly throughout the world. In both immunocompetent and immunosuppressed patients, it is considered (in some locations) the most common mycobacteriosis and ranks second only to the MAIS complex in others.^(6-9) In the United States, the disease is predominant in the so-called "inverted T", that is, in the central and southern states, such as Illinois, California, Texas, and Florida,^(7,8) whereas, in Great Britain, it has been reported more frequently in London, in the Nottingham area, and in Ireland.^(3,10) In Los Angeles, the incidence in HIV-positive patients was more frequent in certain neighborhoods, although other, non-geographic aspects could not be entirely ruled out.⁽⁴⁾ In the 1980s, 62 strains of NTM were isolated in the analysis of 5182 mycobacterium cultures from 3130 patients in Buenos Aires, Argentina. Of those 62 strains, Mk was only isolated in 14 patients, only 4 (0.13%) of whom were considered sick.⁽¹¹⁾ Between 1985 and 1990, 289 NTM strains were isolated in 225 patients in São Paulo. In 29 patients, Mk was isolated 60 times, but only 12 of those patients were considered symptomatic by clinical and radiological standards.⁽¹²⁾ Near the city of São Paulo, in the area known as the ABCD (a neighboring industrial area which comprises the cities of Santo André, São Bernardo do Campo, São Caetano, and Diadema), 866 out of 6976 samples tested positive for Mycobacterium. Of those, 9 were NTM and were identified as Mk. All patients whose samples tested positive for Mk were symptomatic.⁽¹³⁾

Our patients resided in the Ipiranga district near the city of São Paulo (SP). This neighborhood is also near the ABCD, which might explain the prevalence of the bacillus in that area. Both Ipiranga and the ABCD are highly industrialized zones, and a correlation between diseases caused by M. kansasii and exposure to industrial particulate matter, even in the absence of silicosis, has been reported in 15% of cases.⁽¹⁰⁾

Since diseases caused by Mk are usually related to pre-existing lung disease, which are more common in men and the elderly, Mk-related diseases have been correlated with gender and age. The average age of a group of 173 patients who suffered from diseases caused by Mk in Great Britain was 56 ± 11 years, and 83% were men.⁽³⁾ However, the age range in our group of patients was considerable. Therefore, the higher incidence of these diseases in elderly patients might be explained by the presence of pre-existing lung disease. High incidence of the disease in men was also found in our study.

For many years, it has been recognized that there is a relationship between Mk and silicosis.^(14-16) In South Africa, there is a close relationship between silicosis and the degree of pneumoconiosis (in presumptive, precocious, and advanced silicosis, respectively, incidence of pneumoconiosis is 1.8 times, 2.2 times and 2.5 times that seen in non-exposed patients).⁽⁵⁾ Bronchiectasis is a symptom of the Lady Windermere syndrome (bronchiectasis in the middle lobe and in the lingula in the presence of NTM – especially those from the MAIS complex – in elderly women who, for reasons of politeness, cough without expectorating).⁽¹⁶⁾ Our patient who suffered from bronchiectasis might have also been afflicted with this syndrome. Patients who have blisters in the lungs, or who have been previously treated for pulmonary tuberculosis, also frequently test positive for Mk.^(1,2,17) At least 1 of these conditions was present in each of our patients. It is important to report that, in 2 of our patients, clinical and radiological findings allowed detection of Mk only after some months.

Immune suppression caused by AIDS has been considered an important predisposing factor for lung disease caused by Mk. In South Africa, the incidence of Mk-induced lung disease is 3 times higher in HIV-positive patients than in HIV-negative patients, and the risk level is increased in those with silicosis.⁽⁵⁾ In HIV-positive patients in the USA, Mk is considered the second or third (varying by region) most common mycobacteriosis agent.^(4,6) A correlation between Mk-induced mycobacteriosis and AIDS has also been reported in Brazil. Radiographic images of the lower lobes of a patient who presented with acute respiratory symptoms revealed a nodular pattern in the left lobe and mixed infiltrate in the right. Although the diagnosis was not confirmed, the patient was treated with tuberculostatics and demonstrated significant initial clinical improvement. However, after 25 days, his condition worsened and new (non-cavitary) lesions appeared in radiographs of the upper lobes, whereas the original lesions remained unchanged. A transparietal aspirate culture was taken. Although the patient died before the results were known and necroscopic findings were not reported, Mk was detected in the culture.⁽¹⁸⁾ None of our patients tested positive for HIV, but it must be suspected when Mk is detected in patients with no predisposing conditions.

Clinically diagnosed symptoms (general and respiratory), as well as alterations detected through radiology, might be due as much to pre-existing disease as to Mk-induced disease. Therefore, it is crucial that any changes in the number or intensity of symptoms, as well as any new alterations evidenced in radiographs, be noted – especially those which do not respond promptly to treatments such as non-specific antibiotic regimens. Otherwise, a simple colonization may be characterized as a disease, the treatment of which could be harmful to the patient. The probability of simple colonization is controversial in the literature. Some studies have reported rates above 50%,^(11,12) whereas others report rates below 10%⁽⁸⁾, and still others have reported no incidence of simple colonization.⁽⁷⁾

In all of our patients, clinical pictures and radiographic findings were compatible with mycobacteriosis. Patients who were diagnosed some months after the initial examination and who presented remarkable changes in their clinical pictures and in their radiographs (appearance of cavities) are of particular interest. Productive cough, dyspnea, fever, and weight loss (pronounced in some patients) were frequent. Hemoptysis was detected in only 1 patient. Chest radiographs revealed cavitation in all patients.

In addition to pre-existing lung disease, chest radiography is capable of detecting alterations caused by the mycobacteriosis itself, such as thin-walled cavities with a small amount of parenchymal infiltrate and subjacent pleural thickening. Bronchogenic dissemination and pleural effusion are rare.^(3,6) In our patients, there was very little infiltrate around the cavities and no pleural effusion was observed. In 2 patients, pleural thickening was observed subjacent to the lesions. These parameters are undoubtedly very important indicators of mycobacteriosis.

Even including the clinical pictures of the AIDS patients, these symptoms (except for hemoptysis, which is more common in Mk-induced mycobacteriosis) are very similar to those seen in cases of tuberculosis.⁽¹⁰⁾ Acute respiratory insufficiency followed by early death has been reported in a patient who suffered from accelerated silicosis and concomitant Mk-induced mycobacteriosis.⁽¹⁵⁾ However, death from mycobacteriosis is very rare.⁽³⁾ In our study, only 1 patient died. The death occurred later, and the cause of death was also silicosis-related respiratory insufficiency.

In the bacteriological analysis and etiological diagnosis, direct examination of the rod morphology might indicate the presence of Mk, since they are larger than Mtb rods and are fusiform in shape.⁽¹⁷⁾

Through biochemical testing (such as for catalase production at high and low temperatures and for non-production of pyrazinamidase and niacin), Mk has been classified as photochromogenic.^(13,19) It is important not to exceed the recommended concentration of sodium hydroxide (NaOH) because of the high sensitivity Mk has to this agent. Taking cost into account, it is also recommended that culture broths be used if possible.⁽²⁾ Fast and accurate identification can be achieved through the use of other procedures not usually available to us, such as DNA and RNA probes, BACTEC^®and polymerase chain reaction (PCR).^(6,8,20,21) There are 5 Mk strains, of which types I and II are those most commonly isolated in patients, whereas the others are environmental. Therefore, serotyping might be useful in differentiating between colonization and disease.⁽²²⁾ Although Mk has been isolated in water from faucets and showers, it has not been identified in soil or freshwater.^(2,6,8,22) Contamination of humans most likely occurs through aerosol delivery (rather than by ingestion), since extra-pulmonary contamination (including that of the digestive system) is rare.

Taken in context, the use of bacteriological analysis as a diagnostic tool is a fundamental protocol of this study and involves some controversial aspects. The first hurdle is to determine if the presence of Mk is due to simple colonization or to actual disease. As previously discussed, analysis of the clinical and radiological findings, as well as the patient response to treatment, allowed us to rule out simple colonization.

In order to arrive at a definitive diagnosis of Mk-related mycobacteriosis, it is important to consider the criteria put forth by the ATS.⁽²⁾ These criteria assume various possibilities and are divided into 3 groups (^{Appendix 1}). However, they are derived from the opinions of experts and not from evidence based on research. Among the guidelines that we consider inappropriate and problematic is the requirement that physicians perform multiple positive cultures and biopsies, neither of which is applicable in practice. Multiple cultures are not routinely performed,^(4,21) and although biopsies are useful for differentiating between colonization and disease, they do not aid in classifying the mycobacteria. On the other hand, in the first reported Brazilian case in which AIDS was associated with Mk-induced mycobacteriosis, the omission of the transparietal pulmonary puncture procedure, which would be the diagnostic equivalent of a transbronchial biopsy, invalidated the case.⁽¹⁸⁾ In South Africa, in a study involving gold miners, the ATS criteria proved to be inappropriate since 33 out of 56 patients whose samples tested positive for Mk (58.9%) were definitely ill, and the ATS criteria were not met.⁽²¹⁾

Between 1994 and 1998, 7380 mycobacterium cultures were studied in the state of Tennessee (USA). Of those, 46 cultures, 4 of which were from immunocompromised patients, tested positive for NTM. Only 5 (12%) of the 42 immunocompetent patients were considered sick, and 2 of those 5 tested positive for Mk. Another patient who tested positive for Mk was diagnosed as having a simple colonization. It is interesting to note that 3 patients who tested positive for NTM and who met the ATS criteria were diagnosed with simple colonizations.⁽⁹⁾ In the San Francisco Bay area (USA), 29 out of 250 patients (11.6%) who tested positive for Mk, including 8 patients in whom multiple cultures tested positive, were also diagnosed as having simple colonizations.⁽⁶⁾

Since multiple positive cultures were obtained in only 1 patient and no biopsies were performed, our cases also failed to meet the ATS criteria. If justified by the sputum bacilloscopy or the clinical and radiological findings, it is logical to begin treatment immediately. However, in practice, it is difficult to give patients sound orientation before the etiology of the disease has been determined. On the other hand, it is not necessary to examine people who come into contact with infected patients since human-to-human transmission has not been reported.

Since the presumptive diagnosis was pulmonary tuberculosis, all patients were initially treated with INH-RMP-PZA. A patient who was initially treated with INH-RMP-PZA in another hospital exhibited severe intolerance to INH-RMP-PZA and therefore we changed the regime for that patient. The standard INH-RMP-PZA regimen was prescribed for the other patients because an accurate diagnosis could not be made until the results of the cultures were known. Nevertheless, in the diagnostic process, it is possible that evidence of previous lung disease could be taken into consideration as an indicator. This was not done in our study.

Since there have been few controlled studies involving large patient cohorts, it is difficult to establish treatment standards. However, 2 aspects deserve special consideration: the role of INH and the duration of treatment.

In our study, the regimen efficacy was evidenced by the early reversion to negative in the culture results of most patients, as well as by the fact that no therapeutic failure was observed. Although 1 patient, after being cured of the mycobacteriosis, died due to silicosis-related respiratory insufficiency, no other deaths occurred over the course of our study. A patient who suffered recurrence of the disease was cured again with the same regimen, indicating that no resistance was acquired. These considerations do not necessary imply that INH has a beneficial effect. However, since Mk resistance to PZA is often considered absolute, the effect of INH must be considered adequate, considering that a disease with such high numbers of bacilli is not likely to be cured with monotherapy. Because resistance is usually detected in vitro,^(3,23) some authors doubt that INH can be effective and recommend use of the RMP-EMB regimen.⁽¹⁷⁾ Others have also suggested that sensitivity tests be performed with RMP alone.⁽²⁾ Others recommend routine inclusion of INH because the level of in vitro Mk resistance to INH is equal to that usually considered the minimal inhibitory concentration (MIC) for the establishment of in vitro Mtb resistance to INH.^(2,3,6-8,23) Some of those same authors suggest that Mk is sensitive to higher concentrations. To resolve this question, it should be determined whether concentrations of the drug in the lesions reach levels that would be considered bactericidal – or at least bacteriostatic.

The efficacy of treatment in our study was similar to that observed in a study conducted by the British Research Committee.⁽³⁾ After a 3-month period of treatment with and without INH, only 11 patient cultures tested positive, whereas 55 tested negative. In addition, coughing was alleviated in 30 patients, corresponding to simultaneous negative culture results in those patients. In 4 of our patients, EMB was substituted for PZA because of PZA intolerance in 2 patients and because of the final etiological diagnosis in the other 2. However, we are not convinced that this substitution was relevant to the eventual therapeutic success.

Although PZA resistance is widely recognized, only 6 out of 9 samples from our region showed sensitivity to the drug.⁽¹³⁾ The inclusion of this drug in the initial treatment might have been beneficial to these patients, although there is no consistent affirmative evidence of that in the literature.

Other drugs have been studied, mainly in vitro, with good results. Those which have been studied include many quinolones (ofloxacin, sparfloxacin, ciprofloxacin) and macrolides. Various aminoglycosides have also been proven effective against some strains, although resistance to streptomycin (SM) is common. Ethionamide, cycloserine and rifabutin are also viable alternatives.^(17,20,21) In our study of 30 Mk strains, all were resistant to INH. A previous study showed that 16.7% of the same 30 strains were resistant to RMP, 30% to SM, 10% to ethionamide, and 45.7% to kanamycin.⁽²⁴⁾

There is consensus that most cases of mycobacteriosis are curable. Of 173 patients who began treatment in Great Britain,⁽³⁾ 9 died from other causes during treatment, and 1 patient who refused treatment also died. In 154 patients, the treatment was completed, and success was confirmed by negative cultures. During a 5-year follow up, 30 patients died of other diseases unrelated to mycobacteriosis. Over the same period, mycobacteriosis recurred in 15 patients, 8 of whom presented aggravating factors such as non-compliance with treatment, carcinomatosis, use of corticoids, malnutrition or bronchiectasis. In 3 patients, radiology revealed alterations in previously unaffected areas of the lungs. Those alterations were attributed to exogenous reinfection. Therefore, there were only 4 patients who suffered recurrence for no apparent reason. In a group of 53 mycobacteriosis patients in South Africa, 18 were HIV-positive and 35 were HIV-negative. Among the former, 15 were considered cured and 2 died, whereas in the latter group, 4 were transferred, 31 were considered cured and 1 died of unspecified causes.⁽⁵⁾ In that study, there were no deaths related to mycobacteriosis. In our study, only 1 patient experienced recurrence and, since the alterations were in the same areas as in the initial occurrence of the disease, exogenous reinfection was ruled out.

There is no agreement regarding the appropriate length of treatment, and recommended duration ranges from 6 to 18 months. There is no evidence of a correlation between results and duration of treatment, although some authors recommend long-term treatment. In our cohort of patients, 4 were treated for 1 to 2 years, and there was no recurrence. Another patient suffered 2 recurrences and was successfully treated for 12 and 18 months, respectively. Therefore, it is probable that treatment for 24⁽⁶⁾, 18, 15⁽⁷⁾ or even 12 months after cultures test negative is excessive.

We can conclude that Mk-related mycobacteriosis is found only rarely in the Ipiranga district and other environs of the city of São Paulo (SP), including the ABCD area (the disease seems to occur more frequently in this area). The disease is most commonly found in patients who suffer from chronic pre-existing lung diseases. We believe that, since they are not routinely met, the ATS diagnostic criteria should be modified. In addition, since etiology can only be confirmed some weeks after the initial diagnosis, we feel that treatment with INH-RMP-PZA should begin immediately – in accordance with official guidelines set forth by the Brazilian government. A 1-year regimen seems adequate, although the need for substituting EMB for PZA is debatable. Treatment failure is very rare and risk of death from mycobacteriosis is negligible.

References

Submitted: 13/3/03. Accepted, after revision: 30/7/03

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Appendix 1

*

Study carried out at the Ipiranga Ari Nogueira da Silva Dispensary – Sanatorinhos – Community Action for Health

Publication Dates

• Publication in this collection
  12 May 2004
• Date of issue
  Dec 2003

History

• Received
  13 Mar 2003
• Accepted
  30 July 2003