|Year : 2020 | Volume
| Issue : 1 | Page : 83-90
Clinical-epidemiological profile and factors related to the mortality of patients with nontuberculous mycobacteria isolated at a reference hospital in Ceará, Northeastern Brazil
Matheus Alves De Lima Mota1, David Mendes De Melo2, Francisca Lillyan Christyan Nunes Beserra2, Gerardo Albino Nogueira Filho2, Lílian Macambira Pinto2, Raabe De Jesus Souza2, Sandrirla Da Silva Sousa2, Rosa Salani Mota3, Roberto Da Justa Pires Neto4, Terezinha Do Menino Jesus Silva Leit4
1 São José Hospital of Infectious Diseases; Health Sciences Center, School of Medicine, University of Fortaleza, Fortaleza, Ceará, Brazil
2 Department of Community Health, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
3 Department of Statistics and Applied Mathematics, Federal University of Ceará, Fortaleza, Ceará, Brazil
4 São José Hospital of Infectious Diseases; Department of Community Health, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
|Date of Submission||26-Jan-2020|
|Date of Decision||22-Feb-2020|
|Date of Acceptance||02-Feb-2020|
|Date of Web Publication||6-Mar-2020|
Matheus Alves De Lima Mota
Av. Washington Soares, 1321 – Edson Queiroz, CEP 60811-905, Fortaleza, Ceará
Source of Support: None, Conflict of Interest: None
Background: There is a significant shortage of official records that enable estimating the real prevalence of nontuberculous mycobacteria (NTM) infections in Brazil. The study aims to investigate the clinical, laboratory, and epidemiological aspects of patients with NTM isolation at an infectious diseases reference hospital, and to identify factors associated with mortality. Methods: This was an observational study in which clinical, epidemiological, and laboratory aspects were evaluated in patients with NTM isolated at care in Hospital São José, located in Northeastern Brazil, from 2005 to 2016. The records of the reference laboratory for NTM isolates were searched from the culture results of patients. Afterward, the medical records of the patients were reviewed. The analytical assessment was conducted by the Mann–Whitney and Fisher's exact test. The adopted level of significance was 5%. Results: A total of 69 patients were described, with a predominance of males (73.9%). The main clinical forms identified were: pulmonary (60.9%) and disseminated (27.5%). The most frequently NTM identified were Mycobacterium avium (24.6%) and Mycobacterium fortuitum (10.1%). Forty-eight (69.6%) patients had HIV infection. The mortality was 24.6%, and the risk factors for deaths identified were: origin from outside the metropolitan region; weight loss; HIV infection; anemia; hyperbilirubinemia; increased serum glutamic-oxaloacetic transaminase, alkaline phosphatase, lactate dehydrogenase; and impaired renal function. Among the patients with HIV, the main changes related to death were: lower counts of CD4+ and CD8+ T lymphocytes. Conclusion: Maintaining constant vigilance regarding the possibility of NTM infection is required, namely in patients co-infected with HIV/AIDS.
Keywords: Epidemiology, mortality, mycobacterioses, nontuberculous mycobacteria
|How to cite this article:|
De Lima Mota MA, De Melo DM, Christyan Nunes Beserra FL, Nogueira Filho GA, Pinto LM, Jesus Souza RD, Silva Sousa SD, Mota RS, Justa Pires Neto RD, Jesus Silva Leit TD. Clinical-epidemiological profile and factors related to the mortality of patients with nontuberculous mycobacteria isolated at a reference hospital in Ceará, Northeastern Brazil. Int J Mycobacteriol 2020;9:83-90
|How to cite this URL:|
De Lima Mota MA, De Melo DM, Christyan Nunes Beserra FL, Nogueira Filho GA, Pinto LM, Jesus Souza RD, Silva Sousa SD, Mota RS, Justa Pires Neto RD, Jesus Silva Leit TD. Clinical-epidemiological profile and factors related to the mortality of patients with nontuberculous mycobacteria isolated at a reference hospital in Ceará, Northeastern Brazil. Int J Mycobacteriol [serial online] 2020 [cited 2020 Apr 10];9:83-90. Available from: http://www.ijmyco.org/text.asp?2020/9/1/83/280134
| Introduction|| |
Nontuberculous mycobacteria (NTM) are ubiquitous in the environment, having been isolated from water, soil, animals, milk, and food.,, The species form biofilms, even in plumbing used for water distribution, and may inhabit body surfaces and human secretions, such as those of the respiratory or gastrointestinal tracts, without causing disease. As a result, the majority of them were considered contaminants or colonizers until the second half of the 20th century. With the development of microbiological methods, the importance of these bacteria as human pathogens became more clear.
Although NTMs are innocuous for most individuals, the number of people with NTM infection increases each year. The most common clinical presentations are disseminated, lung infection, skin and soft-tissue disease, and lymphadenitis.
Some studies conducted in Brazil evaluated the prevalence of NTM isolates in cultures of several clinical specimens, with or without associated disease. The assessments were carried out in several states, including Rio de Janeiro, São Paulo,,,,,, Rio Grande do Sul, Pará,,, and Rondônia. Fewer of studies have been performed in Northeastern Brazil. In Ceará, there have been no studies published in scientific journals on the subject.
Therefore, despite the mentioned studies done in Brazil, there is a significant shortage of official records that enable estimating the real prevalence of NTM infections. This scarcity may be due to the fact that these infections are not notifiable in Brazil, except in iatrogenic cases after surgical procedures performed in health services.
The objective of the present study was to investigate the clinical, laboratory, and epidemiological aspects of patients with disease caused by NTM at an infectious diseases reference hospital, and to identify factors associated with mortality.
| Subjects and Methods|| |
Study design and location
This was a cross-sectional, observational study, in which clinical, epidemiological, and laboratory aspects were evaluated in patients with NTM isolated from any site, at care in the infectious diseases reference Hospital São José (HSJ), located in the city of Fortaleza, State of Ceará, Northeast Brazil, from January 2005 to December 2016.
The records of the reference laboratory for NTM isolates in the state of Ceará (Central Laboratory of Public Health of Ceará – LACEN-CE) were searched from the culture results of patients cared at the HSJ, during the study period. Afterward, the medical records of the patients were reviewed, and a semi-structured form was filled out.
Inclusion criteria and analyzed variables
The inclusion criteria comprised patients of both sexes and any age with NTM isolation in at least one culture, from any biologic site cared at the HSJ. Patients whose records were unavailable were excluded. It is necessary to send out to LACEN-CE, NTM-positive culture results from at least two separate contaminated clinical specimen, as expectorated sputum, to redirect those samples for speciation at the national reference laboratory in Rio de Janeiro; otherwise, any given sterile site, as bronchoalveolar lavage, only one sample is sufficient for species identification.
The following variables were analyzed: sociodemographic (age, sex, place of origin, marital status, race, and educational level); clinical symptoms, hospital admission, clinical forms, previous pulmonary diseases (chronic obstructive pulmonary disease [COPD], sequelae of previous infections or neoplasias), other chronic diseases, immunosuppressive conditions (HIV/AIDS, neoplasias, diabetes mellitus, use of immunosuppressants), laboratory (hematological and biochemical tests, acid-fast bacilli [AFB] – surveys, cultures with identified NTM), radiological and tomographic alterations, and clinical outcomes. Among the people living with HIV/AIDS (PLWHA), the use of antiretroviral therapy (ART), viral load (VL), and CD4+ and CD8+ T lymphocyte counts were investigated.
Pulmonary infection was defined according to criteria of the American Thoracic Society (ATS) as two clinical/radiological criteria (pulmonary symptoms, nodular/cavitary opacities on chest radiography, or chest tomography showing multifocal bronchiectasis with multiple small nodules; and exclusion of other diagnoses); and one microbiological criterion (positive culture of at least two sputum samples, or positive culture of at least one uncontaminated site, such as bronchoalveolar lavage; or pulmonary biopsy with histopathological findings of mycobacteria and a positive NTM culture, or biopsy with histopathological findings of mycobacteria and one or more sputum cultures or bronchoalveolar lavage positive for NTM). We also considered a pulmonary infection, the patient with only one positive sputum, but with clinical and imaging exams compatible with the diagnosis.
With respect to the remaining clinical forms, to define infection, the following factors were considered: isolation of NTM in the affected site and compatible symptoms.
Patients were considered cured when they presented clinical, laboratory, and/or radiological improvement after treatment. Patients were counted as death when they died during hospitalization. Loss of follow-up and transfer were identified according to the medical records.
Data were organized using version 365 of the Excel® program, and the statistical analysis was carried out with the SPSS® software, version 20 IBM SPSS Statistics for Windows, Version 22.0 (Armonk, NY, USA). The descriptive analysis was performed by measures of central tendency (proportions, mean, and median) and dispersion (standard deviation), and the analytical assessment was conducted by the Mann–Whitney test (for means comparison between independent variables) and Fisher's exact test (to evaluate the associations between categorical variables). The adopted level of significance was 5% (P < 0.05).
The study was approved by the Human Research Ethics Committee of the Federal University of Ceará, under Process Number: 85047718.0.0000.5054.
| Results|| |
A total of 105 patients with NTM isolation from clinical samples were identified; of these, 36 had unavailable medical charts, therefore, 69 records were reviewed. The main socio-demographic characteristics are summarized in [Table 1]. The studied patients had a mean age of 38.58 ± 14.03 years, ranging from 3 to 75.
|Table 1: Sociodemographic characteristics of the patients with nontuberculous mycobacteria isolation, São José Hospital, Ceará, 2005-20|
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The identified clinical forms were: pulmonary (42 patients; 60.9%), disseminated (19; 27.5%), lymphadenitis (five; 7.3%), skin and soft-tissue infection (two; 2.9%); and urinary (one; 1.4%). The identified NTMs and primary associated clinical conditions of patients with the pulmonary and the disseminated forms are summarized in [Table 2].
|Table 2: Species identified and associated clinical conditions of patients according to clinical form, São José Hospital, Ceará, 2005-2016|
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Among the 69 samples with NTM isolation, species identification was possible in 40.6%. Among the 42 patients presenting with the pulmonary form, 13 (31%) had two sputum samples or one bronchoalveolar lavage positive for NTM, and the others only one sample of nonsterile positive respiratory material.
In most cases (57.8%) classified as disseminated forms, the isolation of NTM was obtained from blood culture, although it was also possible from bone marrow aspirate, lymph nodes, sputum, and cerebrospinal fluid. Mycobacterium fortuitum was isolated in uroculture in one case of a patient with fever, urinary symptoms, and altered urinalysis, although three other urocultures and four AFB tests in urine samples were negative. The patient improved initially without specific treatment for NTM but was lost at outpatient follow-up, thus hampering urinary infection confirmation.
The two cases of soft-tissue infection were diagnosed from surgical site secretions with the isolation of M. fortuitum, one after inguinal herniorrhaphy, and the other after treatment of an abscess after lower limb injection of anabolic steroids. Among the five cases of lymphadenitis, the main chains involved were cervical and submandibular, and the NTM species identified were: Mycobacterium avium (four; 80%) and M. fortuitum (one; 20%).
The primary symptoms, described according to clinical form, are shown in [Table 3]. The cough was productive in 80.5% of the pulmonary and in 40% of the disseminated cases, and hemoptysis was observed in 22% of the pulmonary and in 6.7% of the disseminated cases.
|Table 3: Primary symptoms in the patients with nontuberculous mycobacteria isolation separated according to clinical form, São José Hospital, Ceará, 2005-2016|
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The predominant alterations present in 21 (67.7%) of the 31 chest radiographs described in the medical records of patients with the pulmonary form were: alveolar (29.0%), interstitial (16.1%) or mixed infiltrates (16.1%); and cavitation (12.9%). Among the patients with disseminated disease, the main alterations present in seven (87.5%) of the eight chest radiographs were: interstitial (50.0%) or alveolar (25.0%) infiltrates; pleural effusion (25.0%), and nodule (25.0%). In the nine performed computerized chest tomographies in patients with pulmonary form, the following main alterations were observed: cavitation (66.7%); fibrosis (66.7%); tree-in-bud pattern (55.6%); and nodules (44.4%).
A total of 25 (36.2%) patients were treated during an average period of 16.75 ± 15.51 months, ranging from 1 to 63, with a median of 12 months. The treatment regimens were quite variable. In the pulmonary form, 14 patients were treated, and a macrolide (Clarithromycin or Azithromycin) and ethambutol were the most frequently used in six patients (42.9%). Among the six treated patients with the disseminated disease, a macrolide (clarithromycin or azithromycin), rifampicin, isoniazid, and ethambutol was the main regimen used, in four patients (66.7%), and two of these also used pyrazinamide. Fifteen patients were treated with the basic therapeutic regimen for tuberculosis (TB), 11 of which were classified as pulmonary, two as disseminated, and two as lymphadenitis. Among these patients, 10 presented clinical improvement, two of which met ATS criteria for lung infection, with the identification of M. avium and M. fortuitum, respectively, which could be a partial response to TB treatment. No treatment schedule was found in the medical records of 29 patients.
Among the 69 patients, 48 (69.6%) were PLWHA; the mean CD4+ T lymphocyte count was 131.74 ± 157/mm3, and the mean VL (log) was 5.26 ± 5.63 copies/mm3. Thirty-two (71.1%) had received ART at least once in their lifetime. Their mean age was 37.6 ± 9.72 years, ranging from 20 to 62, and 40 (83.3%) of them were men. The clinical forms observed in this specific population were: pulmonary (54.2%); disseminated (35.4%); lymphadenitis (8.2%); and skin and soft tissue infection (2.1%). The findings concerning the species were: M. avium (33.3%), Mycobacterium colombiense (2.1%; one case, associated with M. avium); Mycobacterium abscessus (2.1%), M. fortuitum (2.1%) and Mycobacterium kansasii (2.1%); speciation was not possible in 29 samples.
Considering only the 61 patients with pulmonary and disseminated forms, AFB sputum screening was positive in at least one sample in 14 (23%) patients and negative in 34 (55.7%). Tests were also positive in three bronchoalveolar lavages, two lymph node aspirates, and one secretion collected from soft tissues.
Among the 42 patients classified with the pulmonary form, 11 (26.2%) met the ATS criteria for pulmonary infection. All of the 42 patients had symptoms compatible with the disease, meeting ATS clinical criteria. The main reasons for not meeting the other ATS criteria were: radiological (absence of image tests in the medical records) and microbiological (presence of only one positive sputum sample, due to insufficient sampling).
Considering the others clinical forms, all of the 27 patients had NTM infection.
Analysis of fatalities
Among the 17 (24.6%) patients who died, 12 had the disseminated form and five had the pulmonary form. The other outcomes were: 24 (34.8%) cured and 28 (40.6%) were lost at follow-up, transferred or undergoing treatment. The mean age of those who died (33.06 ± 10.40 years) was significantly different from that of those who survived (40.38 ± 14.66 years) (P = 0.03).
The sociodemographic, clinical, and radiological characteristics of the patients who died are shown in [Table 4]. Countryside origin, weight loss, and HIV co-infection were found to be significantly associated with death.
|Table 4: Sociodemographic, clinical, and radiological characteristics of the patients with nontuberculous mycobacteria isolation regarding death, São José Hospital, Ceará, 2005-201|
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The individuals who died had significantly lower levels of hemoglobin and lymphocyte counts; higher values of aspartate aminotransferase, bilirubin, alkaline phosphatase, urea, creatinine, and lactic dehydrogenase. Among PLWHA, the primary abnormality related to death were: lower counts of CD4+ and CD8+ T lymphocytes; reduced percentage of CD4+ T lymphocytes; and lower CD4+/CD8+ T lymphocyte ratio [Table 5].
|Table 5: Laboratory tests of the patients with nontuberculous mycobacteria isolation regarding death, São José Hospital, Ceará, 2005-2016|
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| Discussion|| |
The most prevalent identified NTM among patients with disseminated form and lymphadenitis in the present study was M. avium complex (MAC). It was also more frequent in the survey conducted in 2008 by researchers from a European NTM study group, which analyzed respiratory samples from 20,182 patients with NTM isolation from 62 laboratories distributed on six continents. The study did not mention the percentage of HIV co-infection, although 91 species of NTM were isolated, with predominance of MAC (47%) in most countries, followed by Mycobacterium gordonae (11%), Mycobacterium xenopi (8%), and M. fortuitum (7%). MAC was the most isolated NTM in North and South America, Australia, and South Africa. In China, MAC (63%), M. kansasii (25%), and M. abscessus/chelonae (16%) were the most frequent of 113 NTM cultures from 100 non-HIV co-infected patients.
A systematic review and meta-analysis were carried out on 37 studies published between 1940 and 2016 on NTM isolates in respiratory specimens of patients from African countries. A total of 3319 cases, with a mean age of 35 years, were included, of which 75% were male. Fifteen of them involved patients with HIV/AIDS. MAC was responsible for 28% of the isolated NTMs and was the most common in the samples in 19 studies. In our study, MAC was responsible for 24.6% of the isolated NTMs.
Some Brazilian studies also showed a predominance of MAC, varying between 26% and 71.8% of the evaluated samples.,,,,, However, differences between the surveys comprised the number of patients, predominant sex, presence or absence of HIV co-infection, and fulfillment of criteria for infection, possibly due to territorial dimension and regional differences. Some of the surveys were conducted using laboratory data alone, making it difficult to differentiate disease from colonization/contamination.,, In addition, the present study is remarkable for including cases of infection with all clinical forms.
The present results indicate a higher infection rate confirmed by ATS criteria when compared to other Brazilian studies, which found rates such as 24.6%, 12.4%, and 33.3%. Nonetheless, there are reports of higher rates, such as the study performed in São Paulo, which investigated 135 patients, with 94.8% of the cases meeting infection criteria.
In China, 1953 samples were analyzed; in which 113 were identified as NTM from 100 non-HIV co-infected patients. Eleven samples met ATS microbiological criteria, three presented no clinical or radiological criteria – indicating probable contamination or colonization – and 86 exhibited clinical or radiological criteria only. Nineteen cases had negative AFBs in sputum samples but had a positive culture for NTM. A relevant finding in this study was the amount of positive respiratory samples in cultures, although negative in AFB surveys, reinforcing the importance of continuing the investigation, with culture, in suspected cases. In the present study, 56.7% of the samples were negative in the AFB surveys, despite having a positive culture.
In Singapore, 485 patients (62% males), with a mean age of 70 years, who had isolation of NTM in at least one culture and who were admitted to a hospital between 2011 and 2012, were studied, totaling 560 isolates. The most common associated pulmonary diseases were bronchiectasis (28.7%) and COPD (14.2%). A total of 52 patients (10.7%) presented HIV co-infection. The majority (91%) of the positive cultures were from respiratory samples. The previous history of pulmonary TB was described in 167 (34.4%) patients. In the present study, the percentages of patients who had HIV co-infection and those with a history of the previous TB were higher, possibly because the data were from a reference hospital.
The main symptoms associated with the pulmonary form include cough, fever, and weight loss in patients co-infected with HIV or not. The findings were consistent with this study. Regarding the disseminated disease, the main symptoms and signs are fever, diarrhea, weight loss, abdominal pain, sweating, hiccups, anemia, hepatomegaly, and splenomegaly. In our patients, fever and weight loss were among the most frequent findings.,
There are no consistent Brazilian data concerning death due to nontuberculous mycobacteriosis because the disease is not notifiable in the country. A study conducted in São Paulo showed a mortality rate in cases of NTM infection of 10.2%; however, death was attributed directly to NTM infection in only 6.1%. None of the evaluated patients presented HIV co-infection.
The younger patients, from the interior of the state, with weight loss and infected with HIV/AIDS, especially those with lower CD4+ and CD8+ T lymphocyte counts, presented higher mortality rates. It is well known that PLWHA with CD4+ T lymphocyte counts below 50/mm3 are more likely to develop the disseminated form and, therefore, evolve with an unfavorable outcome. Regarding origin, individuals from the countryside probably underwent greater difficulty in accessing the reference service in the capital, which could contribute to the delay in diagnosis and the negative outcome.
In Argentina, the mortality rate observed in patients with age and gender predominance similar to the present findings was 20%, but with a smaller number (27.8%) of patients co-infected with HIV. In Germany, a total of 22.4% of deaths were reported, while in the Netherlands, the rate was 46.8%. Other studies reported varying mortality rates: 12% in China, 16.9% in Singapore, and 9.7% in Iran.
In the United States, 9490 deaths were attributed to NTM infections between 1999 and 2014, corresponding to a rate of 2.3 deaths/1,000,000 people/year. HIV co-infection was present in 11% of the deaths, and the highest mortality rate was in white women of advanced age. Another study that identified risk factors for mortality corroborated these findings: age 55 years or older, female, and Caucasian. The present sample had a lower mean age at death than that reported in the American survey; the significant percentage of HIV co-infection, which was much higher than that of other national studies,,,,,,,, may justify such discrepancy.
The limitation of the present study was primarily due to the use of secondary data, in which some information was unavailable in the medical records, such as weight loss values, reinforcing the importance of complete and correctly filled medical documents. Other limitations included: (a) nonidentification of some NTMs due to the absence of two cultures of different sputum samples, which hampered fulfilling the ATS microbiological criteria and relating some species to death; (b) lack of image tests in some medical records, which hindered meeting ATS radiological criteria; and (c) the study was conducted in a reference hospital for HIV/AIDS treatment, which explains the percentage of co-infected patients and may have contributed to the found mortality rates.
In order to improve the approach to patients with NTM infection, we suggest: (a) optimization of the flowchart for the diagnosis of lung infection by NTM, with standardization of collection of at least two sputum samples, chest images exams and, in selected cases, bronchoscopy, in order to reduce the quantity of cases with only one result of positive sputum culture and patients without imaging; (b) implementation of public health policies aimed at combating NTM, with a guarantee of adequate diagnostic and treatment resources; and (c) facilitation of access to the reference services of individuals from the countryside.
| Conclusions|| |
Nontuberculous mycobacteriosis has become increasingly significant as a cause of disease in humans, especially in the pulmonary form. Therefore, understanding the criteria is necessary for the better conduction and investigation of these cases. Maintaining constant vigilance regarding the possibility of NTM infection is also required, namely in patients co-infected with HIV/AIDS, but also in people with suspected TB who did not respond adequately to standardized treatment.
Our thanks to the staff of the Medical Archive and Statistics Service, the Laboratory of Microbiology, and the Study Center of the São José Hospital for Infectious Diseases. We also thank the Laboratory of Mycobacteria of the Central Laboratory of Public Health of Ceará for their vital support during data collection.
Financial support and sponsorship
The present study was funded by the authors themselves.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]