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Predictors of mortality among intensive care unit patients coinfected with tuberculosis and HIV

ABSTRACT

Objective:

To identify factors predictive of mortality in patients admitted to the ICU with tuberculosis (TB)/HIV coinfection in the Manaus, Amazon Region.

Methods:

This was a retrospective cohort study of TB/HIV coinfected patients over 18 years of age who were admitted to an ICU in the city of Manaus, Brazil, between January of 2011 and December of 2014. Sociodemographic, clinical, and laboratory variables were assessed. To identify factors predictive of mortality, we employed a Cox proportional hazards model.

Results:

During the study period, 120 patients with TB/HIV coinfection were admitted to the ICU. The mean age was 37.0 ± 11.7 years. Of the 120 patients evaluated, 94 (78.3%) died and 62 (66.0%) of those deaths having occurred within the first week after admission. Data on invasive mechanical ventilation (IMV) and ARDS were available for 86 and 67 patients, respectively Of those 86, 75 (87.2%) underwent IMV, and, of those 67, 48 (71.6%) presented with ARDS. The factors found to be independently associated with mortality were IMV (p = 0.002), hypoalbuminemia (p = 0.013), and CD4 count < 200 cells/mm3 (p = 0.002).

Conclusions:

A high early mortality rate was observed among TB/HIV coinfected ICU patients. The factors predictive of mortality in this population were IMV, hypoalbuminemia, and severe immunosuppression.

Keywords:
Mycobacterium tuberculosis; Critical care; Respiration, artificial; Acquired immunodeficiency syndrome

RESUMO

Objetivo:

Identificar fatores preditores de mortalidade em pacientes da UTI coinfectados por tuberculose (TB)/HIV em Manaus (AM).

Métodos:

Estudo retrospectivo de coorte com pacientes coinfectados por TB/HIV, com mais de 18 anos de idade e admitidos na UTI entre janeiro de 2011 e dezembro de 2014. Foram avaliadas variáveis sociodemográficas, clínicas e laboratoriais. Para identificar fatores preditores de mortalidade, foi empregado um modelo de riscos proporcionais de Cox.

Resultados:

Durante o período estudado, 120 pacientes com coinfecção por TB/HIV foram admitidos na UTI. A média de idade foi de 37,0 ± 11,7 anos. Dos 120 pacientes avaliados, 94 (78,3%) morreram; dos 94 óbitos, 62 (66,0%) ocorreram na primeira semana após a admissão. Havia dados sobre ventilação mecânica invasiva (VMI) e SARA referentes a 86 e 67 pacientes, respectivamente. Dos 86, 75 (87,2%) foram submetidos a VMI, e, dos 67, 48 (71,6%) apresentaram SARA. Os fatores que se relacionaram independentemente com a mortalidade foram VMI (p = 0,002), hipoalbuminemia (p = 0,013) e contagem de CD4 < 200 células/mm3 (p = 0,002).

Conclusões:

Elevada mortalidade precoce foi observada em pacientes com coinfecção por TB/HIV admitidos na UTI. Os fatores preditores de mortalidade nessa população foram VMI, hipoalbuminemia e imunodepressão grave.

Descritores:
Mycobacterium tuberculosis; Cuidados críticos; Respiração artificial; Síndrome de imunodeficiência adquirida

INTRODUCTION

Among communicable diseases, tuberculosis (TB) is the leading cause of death worldwide. In 2015, there were an estimated 10.4 million new TB cases and 1.8 million deaths worldwide, 400,000 of which occurred among HIV-infected individuals.11 World Health Organization. Global tuberculosis report 2016. Geneva: World Health Organization; 2016. The reported incidence of TB in Brazil was 32.4 cases per 100,000 population in 2016, with 2.2 TB-related deaths per 100,000 population in 2015. Of the 66,796 new TB cases in Brazil in 2015, 6.8% were cases of TB/HIV coinfection. In 2016, the incidence of TB in Brazil was highest in the state of Amazonas, with 67.2 cases per 100,000 population and a mortality rate of 3.2 per 100,000 population. In the city of Manaus, which is the capital of the state of Amazonas and where 50% of the state population is concentrated, there were 93.2 cases per 100,000 population and 3.5 deaths per 100,000 population in 2016.22 Brasil. Ministério da Saúde. Secretaria de Vigilância à Saúde. Indicadores prioritários para o monitoramento do Plano Nacional pelo Fim da Tuberculose como Problema de Saúde Pública no Brasil. Boletim Epidemiológico. 2017;48(8):1-11.

Previous studies have shown that people living with HIV are 30 times more likely to develop infection with TB and progress to active disease than are individuals who do not have HIV, which increases the risk of latent TB reactivation up to 20-fold.33 Pawlowski A, Jansson M, Sköld M, Rottenberg ME, Källenius G. Tuberculosis and HIV co-infection. PLOS Pathog. 2012;8(2):e1002464. https://doi.org/10.1371/journal.ppat.1002464
https://doi.org/10.1371/journal.ppat.100...
In TB/HIV coinfected individuals, the virus weakens the host immune response to Mycobacterium tuberculosis (Mtb), resulting in a more dramatic progression.44 Collins KR, Qui-ones-Mateu ME, Toossi Z, Arts EJ. Impact of tuberculosis on HIV-1 replication, diversity, and disease progression. AIDS Rev. 2002;4(3):165-76.

Because of immunosuppression, TB is frequently paucibacillary in HIV-infected individuals, meaning that diagnosis and treatment are often delayed.55 Klautau GB, Kuschnaroff TM. Clinical forms and outcome of tuberculosis in HIV-infected patients in a tertiary hospital in São Paulo - Brazil. Braz J Infect Dis. 2005;9(6):464-78. https://doi.org/10.1590/S1413-86702005000600004
https://doi.org/10.1590/S1413-8670200500...
Admission to the ICU is required in 1-3% of cases, invasive mechanical ventilation (IMV) being required in 1.5%.66 Silva DR, Menegotto DM, Schulz LF, Gazzana MB, Dalcin PT. Mortality among patients with tuberculosis requiring intensive care: a retrospective cohort study. BMC Infect Dis. 2010;10:54. https://doi.org/10.1186/1471-2334-10-54
https://doi.org/10.1186/1471-2334-10-54...
Patients coinfected with TB and HIV usually develop pulmonary lesions accompanied by intrapulmonary shunt and hypoxemic respiratory failure.77 Hagan G, Nathani N. Clinical review: tuberculosis on the intensive care unit. Crit Care. 2013;17(5):240. https://doi.org/10.1186/cc12760
https://doi.org/10.1186/cc12760...

Case-fatality rates are notoriously high in TB/HIV coinfected patients, ranging from 22.4% to 67%.66 Silva DR, Menegotto DM, Schulz LF, Gazzana MB, Dalcin PT. Mortality among patients with tuberculosis requiring intensive care: a retrospective cohort study. BMC Infect Dis. 2010;10:54. https://doi.org/10.1186/1471-2334-10-54
https://doi.org/10.1186/1471-2334-10-54...
,88 Erbes R, Oettel K, Raffenberg M, Mauch H, Schmidt-Ioanas M, Lode H. Characteristics and outcome of patients with active pulmonary tuberculosis requiring intensive care. Eur Respir J. 2006;27(6):1223-8. https://doi.org/10.1183/09031936.06.00088105
https://doi.org/10.1183/09031936.06.0008...

9 Levy H, Kallenbach JM, Feldman C, Thorburn JR, Abramowitz JA. Acute respiratory failure in active tuberculosis. Crit Care Med. 1987;15(3):221-5. https://doi.org/10.1097/00003246-198703000-00008
https://doi.org/10.1097/00003246-1987030...

10 Valade S, Raskine L, Aout M, Malissin I, Brun P, Deye N, et al. Tuberculosis in the intensive care unit: A retrospective descriptive cohort study with determination of a predictive fatality score. Can J Infect Dis Med Microbiol. 2012;23(4):173-8. https://doi.org/10.1155/2012/361292
https://doi.org/10.1155/2012/361292...

11 Calligaro GL, Theron G, Khalfey H, Peter J, Meldau R, Matinyenya B, et al. Burden of tuberculosis in intensive care units in Cape Town, South Africa, and assessment of the accuracy and effect on patient outcomes of the Xpert MTB/RIF test on tracheal aspirate samples for diagnosis of pulmonary tuberculosis: a prospective burden of disease study with a nested randomised controlled trial. Lancet Respir Med. 2015;3(8):621-30. https://doi.org/10.1016/S2213-2600(15)00198-8
https://doi.org/10.1016/S2213-2600(15)00...

12 Balkema CA, Irusen EM, Taljaard JJ, Koegelenberg CF. Tuberculosis in the intensive care unit: a prospective observational study. Int J Tuberc Lung Dis. 2014;18(7):824-30. https://doi.org/10.5588/ijtld.13.0044
https://doi.org/10.5588/ijtld.13.0044...

13 Madkour A, Fouda M, Mansour M. Outcome of active pulmonary tuberculosis patients requiring respiratory intensive care admission. Egypt J Bronchol. 2014;8(2):79-86. https://doi.org/10.4103/1687-8426.145692
https://doi.org/10.4103/1687-8426.145692...

14 Lee PL, Jerng JS, Chang YL, Chen CF, Hsueh PR, Yu CJ, et al. Patient mortality of active pulmonary tuberculosis requiring mechanical ventilation. Eur Respir J. 2003;22(1):141-7. https://doi.org/10.1183/09031936.03.00038703
https://doi.org/10.1183/09031936.03.0003...

15 Gachot B, Wolff M, Clair B, Régnier B. Severe tuberculosis in patients with human immunodeficiency virus infection. Intensive Care Med. 1990;16(8):491-3. https://doi.org/10.1007/BF01709398
https://doi.org/10.1007/BF01709398...

16 De Palo VA, Millstein BH, Mayo PH, Salzman SH, Rosen MJ. Outcome of intensive care in patients with HIV infection. Chest. 1995;107(2):506-10. https://doi.org/10.1378/chest.107.2.506
https://doi.org/10.1378/chest.107.2.506...

17 Lanoix JP, Gaudry S, Flicoteaux R, Ruimy R, Wolff M. Tuberculosis in the intensive care unit: a descriptive analysis in a low-burden country. Int J Tuberc Lung Dis. 2014;18(5):581-7. https://doi.org/10.5588/ijtld.13.0901
https://doi.org/10.5588/ijtld.13.0901...

18 Zahar JR, Azoulay E, Klement E, De Lassence A, Lucet JC, Regnier B, et al. Delayed treatment contributes to mortality in ICU patients with severe active pulmonary tuberculosis and acute respiratory failure. Intensive Care Med. 2001;27(3):513-20. https://doi.org/10.1007/s001340000849
https://doi.org/10.1007/s001340000849...

19 Amâncio FF, Lambertucci JR, Cota GF, Antunes CM. Predictors of the short- and long-term survival of HIV-infected patients admitted to a Brazilian intensive care unit. Int J STD AIDS. 2012;23(10):692-7. https://doi.org/10.1258/ijsa.2012.011389
https://doi.org/10.1258/ijsa.2012.011389...

20 Loh WJ, Yu Y, Loo CM, Low SY. Factors associated with mortality among patients with active pulmonary tuberculosis requiring intensive care. Singapore Med J. 2017;58(11):656-659. https://doi.org/10.11622/smedj.2016160
https://doi.org/10.11622/smedj.2016160...
-2121 Duro RP, Figueiredo Dias P, Ferreira AA, Xerinda SM, Lima Alves C, Sarmento AC, et al. Severe Tuberculosis Requiring Intensive Care: A Descriptive Analysis. Crit Care Res Pract. 2017;2017:9535463. https://doi.org/10.1155/2017/9535463
https://doi.org/10.1155/2017/9535463...
In patients coinfected with TB and HIV, death has been associated with the following: IMV; miliary (i.e., disseminated) TB; renal replacement therapy; use of vasoactive drugs; low Glasgow Coma Scale scores; high Simplified Acute Physiology Score II; high Acute Physiology And Chronic Health Evaluation II (APACHE II) scores; high Sequential Organ Failure Assessment scores; lymphopenia; concomitant nontuberculous mycobacterial infection; organ failure; sepsis; and hypoalbuminemia.88 Erbes R, Oettel K, Raffenberg M, Mauch H, Schmidt-Ioanas M, Lode H. Characteristics and outcome of patients with active pulmonary tuberculosis requiring intensive care. Eur Respir J. 2006;27(6):1223-8. https://doi.org/10.1183/09031936.06.00088105
https://doi.org/10.1183/09031936.06.0008...
,1111 Calligaro GL, Theron G, Khalfey H, Peter J, Meldau R, Matinyenya B, et al. Burden of tuberculosis in intensive care units in Cape Town, South Africa, and assessment of the accuracy and effect on patient outcomes of the Xpert MTB/RIF test on tracheal aspirate samples for diagnosis of pulmonary tuberculosis: a prospective burden of disease study with a nested randomised controlled trial. Lancet Respir Med. 2015;3(8):621-30. https://doi.org/10.1016/S2213-2600(15)00198-8
https://doi.org/10.1016/S2213-2600(15)00...

12 Balkema CA, Irusen EM, Taljaard JJ, Koegelenberg CF. Tuberculosis in the intensive care unit: a prospective observational study. Int J Tuberc Lung Dis. 2014;18(7):824-30. https://doi.org/10.5588/ijtld.13.0044
https://doi.org/10.5588/ijtld.13.0044...
-1313 Madkour A, Fouda M, Mansour M. Outcome of active pulmonary tuberculosis patients requiring respiratory intensive care admission. Egypt J Bronchol. 2014;8(2):79-86. https://doi.org/10.4103/1687-8426.145692
https://doi.org/10.4103/1687-8426.145692...
,1616 De Palo VA, Millstein BH, Mayo PH, Salzman SH, Rosen MJ. Outcome of intensive care in patients with HIV infection. Chest. 1995;107(2):506-10. https://doi.org/10.1378/chest.107.2.506
https://doi.org/10.1378/chest.107.2.506...
,1818 Zahar JR, Azoulay E, Klement E, De Lassence A, Lucet JC, Regnier B, et al. Delayed treatment contributes to mortality in ICU patients with severe active pulmonary tuberculosis and acute respiratory failure. Intensive Care Med. 2001;27(3):513-20. https://doi.org/10.1007/s001340000849
https://doi.org/10.1007/s001340000849...

19 Amâncio FF, Lambertucci JR, Cota GF, Antunes CM. Predictors of the short- and long-term survival of HIV-infected patients admitted to a Brazilian intensive care unit. Int J STD AIDS. 2012;23(10):692-7. https://doi.org/10.1258/ijsa.2012.011389
https://doi.org/10.1258/ijsa.2012.011389...

20 Loh WJ, Yu Y, Loo CM, Low SY. Factors associated with mortality among patients with active pulmonary tuberculosis requiring intensive care. Singapore Med J. 2017;58(11):656-659. https://doi.org/10.11622/smedj.2016160
https://doi.org/10.11622/smedj.2016160...
-2121 Duro RP, Figueiredo Dias P, Ferreira AA, Xerinda SM, Lima Alves C, Sarmento AC, et al. Severe Tuberculosis Requiring Intensive Care: A Descriptive Analysis. Crit Care Res Pract. 2017;2017:9535463. https://doi.org/10.1155/2017/9535463
https://doi.org/10.1155/2017/9535463...

Only a few studies have assessed case-fatality rates in patients with severe TB,66 Silva DR, Menegotto DM, Schulz LF, Gazzana MB, Dalcin PT. Mortality among patients with tuberculosis requiring intensive care: a retrospective cohort study. BMC Infect Dis. 2010;10:54. https://doi.org/10.1186/1471-2334-10-54
https://doi.org/10.1186/1471-2334-10-54...
,1010 Valade S, Raskine L, Aout M, Malissin I, Brun P, Deye N, et al. Tuberculosis in the intensive care unit: A retrospective descriptive cohort study with determination of a predictive fatality score. Can J Infect Dis Med Microbiol. 2012;23(4):173-8. https://doi.org/10.1155/2012/361292
https://doi.org/10.1155/2012/361292...
,1212 Balkema CA, Irusen EM, Taljaard JJ, Koegelenberg CF. Tuberculosis in the intensive care unit: a prospective observational study. Int J Tuberc Lung Dis. 2014;18(7):824-30. https://doi.org/10.5588/ijtld.13.0044
https://doi.org/10.5588/ijtld.13.0044...
,1515 Gachot B, Wolff M, Clair B, Régnier B. Severe tuberculosis in patients with human immunodeficiency virus infection. Intensive Care Med. 1990;16(8):491-3. https://doi.org/10.1007/BF01709398
https://doi.org/10.1007/BF01709398...
,1717 Lanoix JP, Gaudry S, Flicoteaux R, Ruimy R, Wolff M. Tuberculosis in the intensive care unit: a descriptive analysis in a low-burden country. Int J Tuberc Lung Dis. 2014;18(5):581-7. https://doi.org/10.5588/ijtld.13.0901
https://doi.org/10.5588/ijtld.13.0901...

18 Zahar JR, Azoulay E, Klement E, De Lassence A, Lucet JC, Regnier B, et al. Delayed treatment contributes to mortality in ICU patients with severe active pulmonary tuberculosis and acute respiratory failure. Intensive Care Med. 2001;27(3):513-20. https://doi.org/10.1007/s001340000849
https://doi.org/10.1007/s001340000849...

19 Amâncio FF, Lambertucci JR, Cota GF, Antunes CM. Predictors of the short- and long-term survival of HIV-infected patients admitted to a Brazilian intensive care unit. Int J STD AIDS. 2012;23(10):692-7. https://doi.org/10.1258/ijsa.2012.011389
https://doi.org/10.1258/ijsa.2012.011389...

20 Loh WJ, Yu Y, Loo CM, Low SY. Factors associated with mortality among patients with active pulmonary tuberculosis requiring intensive care. Singapore Med J. 2017;58(11):656-659. https://doi.org/10.11622/smedj.2016160
https://doi.org/10.11622/smedj.2016160...
-2121 Duro RP, Figueiredo Dias P, Ferreira AA, Xerinda SM, Lima Alves C, Sarmento AC, et al. Severe Tuberculosis Requiring Intensive Care: A Descriptive Analysis. Crit Care Res Pract. 2017;2017:9535463. https://doi.org/10.1155/2017/9535463
https://doi.org/10.1155/2017/9535463...
and most had a small sample (of < 100 patients) and were retrospective in design. Prospective studies have focused on investigating ICU patients with TB (n = 83, 44 of whom were coinfected with HIV)1212 Balkema CA, Irusen EM, Taljaard JJ, Koegelenberg CF. Tuberculosis in the intensive care unit: a prospective observational study. Int J Tuberc Lung Dis. 2014;18(7):824-30. https://doi.org/10.5588/ijtld.13.0044
https://doi.org/10.5588/ijtld.13.0044...
or predicting survival among HIV-infected patients (n = 125, 58 of whom were coinfected with TB).1919 Amâncio FF, Lambertucci JR, Cota GF, Antunes CM. Predictors of the short- and long-term survival of HIV-infected patients admitted to a Brazilian intensive care unit. Int J STD AIDS. 2012;23(10):692-7. https://doi.org/10.1258/ijsa.2012.011389
https://doi.org/10.1258/ijsa.2012.011389...
There is a lack of studies investigating ICU patients with severe TB/HIV coinfection. In a retrospective study involving a small sample (of 12 patients), the reported mortality was 58.3%.1515 Gachot B, Wolff M, Clair B, Régnier B. Severe tuberculosis in patients with human immunodeficiency virus infection. Intensive Care Med. 1990;16(8):491-3. https://doi.org/10.1007/BF01709398
https://doi.org/10.1007/BF01709398...

Since 2004, strategies to minimize the impact of TB/HIV coinfection and improve the treatment of TB/HIV coinfected patients have been adopted, including improved integration between TB and HIV programs and early antiretroviral therapy (ART) to reduce the viral load in patients with a presumptive diagnosis of TB.2222 World Health Organization. A guide to monitoring and evaluation for collaborative TB/HIV activities--2015 revision. Geneva: World Health Organization; 2015. In the present study, we sought to describe the clinical features of a large cohort of severe TB/HIV coinfected patients admitted to the ICU of a referral hospital in the city of Manaus, Brazil, as well as to identify factors predictive of mortality in that population.

METHODS

This was a retrospective cohort study of TB/HIV coinfected patients admitted to the ICU of a referral hospital for infectious diseases in the city of Manaus, Brazil, between January of 2011 and December of 2014. The study was approved by the local research ethics committee in August of 2014 (Protocol no. CAAE 34073314.3.0000.0005).

HIV-infected patients who were 18 years of age or more and who were diagnosed with TB were included in the study. For a diagnosis of active TB, at least two of the following criteria had to be met1111 Calligaro GL, Theron G, Khalfey H, Peter J, Meldau R, Matinyenya B, et al. Burden of tuberculosis in intensive care units in Cape Town, South Africa, and assessment of the accuracy and effect on patient outcomes of the Xpert MTB/RIF test on tracheal aspirate samples for diagnosis of pulmonary tuberculosis: a prospective burden of disease study with a nested randomised controlled trial. Lancet Respir Med. 2015;3(8):621-30. https://doi.org/10.1016/S2213-2600(15)00198-8
https://doi.org/10.1016/S2213-2600(15)00...
: a) two AFB-positive sputum smears; b) one positive Mtb culture; c) chest X-ray findings suggestive of TB; and d) postmortem histopathological findings of TB granuloma, caseous necrosis, or AFB. ARDS was defined as low PaO2/FiO2, recent appearance of bilateral pulmonary infiltrates, and no clinical evidence of left atrial hypertension.2323 ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526-33.

All of the HIV-infected patients who were included in the present study had serologically confirmed HIV infection, in accordance with the criteria established by the Brazilian National Ministry of Health.2424 Brasil. Ministério da Saúde. Secretaria de Vigilância à Saúde. Manual técnico para o diagnósico da infecção pelo HIV. 2nd ed. Brasília: o Ministério; 2014. The microbiology laboratory in which the tests were performed is quality-controlled within the World Health Organization (WHO) scheme for external quality assurance.

Patients who habitually smoked cigarettes were classified as smokers regardless of the number of cigarettes smoked per day. Alcoholism was defined as consumption of ≥ 60 g of pure alcohol on at least one single occasion at least monthly, in accordance with the WHO criteria.2525 World Health Organization. Dept. of Mental Health and Substance Dependence. International guide for monitoring alcohol consumption and related harm. Geneva: World Health Organization; 2000. Drug use was defined as use of ecstasy, cocaine, heroin, cannabis, or any combination of the four in the last 12 months.

Sociodemographic and clinical data were collected from the electronic medical records of the participating patients. Laboratory data regarding Xpert MTB/RIF test results, smear microscopy results, Mtb culture results, and autopsy findings were collected from the laboratory database. All chest X-rays were assessed with IMPAX digital imaging software, version 1.0 build 1.0389 (Agfa HealthCare, Mortsel, Belgium) and reviewed by the same radiologist, who was unaware of the clinical outcomes.

Age, gender, smoking status, alcohol use, illicit drug use, fever, cough, weight loss, diarrhea, dyspnea, opportunistic infections, and comorbidities were analyzed. Time to anti-TB treatment initiation, therapeutic regimen, ART, time to ICU discharge, and ICU clinical outcome (discharge to the ward or death) were also analyzed.

Glasgow Coma Scale and APACHE II scores were used in order to assess the level of consciousness and prognosis in the ICU. Laboratory parameters included hemoglobin levels, leukocyte count, lymphocyte count, platelet count, albumin levels, and CD4 count.

Patients were treated in accordance with the WHO guidelines recommending at least 6 months of rifampin/isoniazid/pyrazinamide/ethambutol for all clinical forms of TB if the patient has never undergone treatment or has undergone up to 30 days of treatment. In people living with HIV/AIDS with active TB, ART should be started 2-8 weeks after initiation of anti-TB treatment.2626 Brasil. Ministério da Saúde. Manual de recomendações para o controle da tuberculose no Brasil. 1st ed. Brasília: o Ministério; 2011.,2727 Brasil. Ministério da Saúde. Protocolo Clínico e Diretrizes Terapêuticas para Manejo da Infecção pelo HIV em Adultos. Brasília: o Ministério; 2013.

Data on the study variables were imported into a spreadsheet and analyzed with the Stata statistical software package, version 9.0 (StataCorp LP, College Station, TX, USA) and the IBM SPSS Statistics software package, version 21.0 (IBM Corporation, Armonk, NY, USA). Data were expressed as mean ± standard deviation or median (interquartile range). Normality was assessed by the Kolmogorov-Smirnov test. Patient survival was analyzed by the Kaplan-Meier method and the log-rank test. Variables with values of p ≤ 0.20 in the univariate analysis were included in a Cox proportional hazards model adjusted for age and gender for survival analysis. The confidence interval was 95%, and values of p < 0.05 were considered significant.

RESULTS

Between January of 2011 and December of 2014, 858 patients were admitted to the ICU. Of those, 141 (16.4%) were diagnosed with TB, 131 (92.9%) being coinfected with HIV. A total of 120 patients were included in the study and underwent further analysis.

The mean age of the patients was 37.0 ± 11.7 years, and 70.0% were male. Alcohol consumption, smoking, and illicit drug use were identified in 48.9%, 36.7%, and 25.4%, respectively. As can be seen in Table 1, the most commonly reported signs and symptoms were weight loss (94.1%), dyspnea (86.4%), and cough (82.9%).

Table 1
Demographic, clinical, and laboratory characteristics of TB/HIV coinfected ICU patients who either survived or died in the 2011-2014 period.a

Pulmonary TB was found in 47.0%, and disseminated TB was found in 39.0%. The primary reason for ICU admission was acute respiratory failure (in 80.0%). Data on IMV and ARDS were available for 86 and 67 patients respectively. Of those 86, 75 (87.2%) underwent IMV, and, of those 67, 48 (71.6%) presented with ARDS. The median APACHE II score was 18 (interquartile range, 5-35). Comorbidities were found in 83 (69.2%) of the 120 patients evaluated: neurotoxoplasmosis, in 21.7%; pneumocystis pneumonia, in 15.8%; acute kidney injury, in 13.3%; pneumonia, in 10.8%; and histoplasmosis, in 7.5%.

A total of 80 patients underwent bacteriological screening for TB. Of those, 16 (13.3%) had positive smear results/positive culture results and 8 (6.6%) had negative smear results/positive culture results. Of the 99 patients who underwent chest X-rays or CT scans, 26 had findings suggestive of TB. Autopsy findings were consistent with TB in 5 of the 10 patients in whom an autopsy was performed.

The median length of ICU stay was 5 days (interquartile range, 3-10.5 days). Information on TB treatment initiation was available for 107 patients. Of those, 90 (84.1%) had been receiving anti-TB treatment before ICU admission (for at least 1 month in 33.6%). Of the 120 patients evaluated, 94 (78.3%) died. Of those 94 deaths, 62 (66.0%) occurred within the first week after admission.

In the univariate analysis, mortality was found to be associated with illicit drug use, diarrhea, low CD4 count, hypoalbuminemia, and IMV (Table 1). As can be seen in Figure 1, the Kaplan-Meier method and the log-rank test showed that mortality was associated with low CD4 count (p = 0.008), hypoalbuminemia (p = 0.001), and IMV (p < 0.001).

Figure 1
Kaplan-Meier curves for survival among TB/HIV coinfected patients in the ICU. In A, albumin levels; in B, CD4 cell count; and in C, invasive mechanical ventilation.

All of the variables showing p ≤ 0.20 in the univariate analysis were included in a Cox proportional hazards model adjusted for age and gender. The factors found to be independently associated with mortality were IMV (hazard ratio [HR] = 0.10; 95% CI: 0.02-0.45; p = 0.002), hypoalbuminemia (HR = 0.47; 95% CI: 0.26-0.85; p = 0.013), and low CD4 count (< 200 cells/mm3; HR = 0.26; 95% CI: 0.08-0.87; p = 0.02; Table 1).

DISCUSSION

The objective of the present study was to describe the clinical features of a large cohort of severe TB/HIV coinfected individuals admitted to the ICU of a referral hospital in the Brazilian Amazon, as well as to identify factors predictive of mortality in that population. We found a mortality rate of 78.3% in the study population, most of the deaths having occurred within the first week after admission. The factors found to be independently associated with mortality were IMV, hypoalbuminemia, and low CD4 count.

The case-fatality rate observed in our cohort was higher than those reported by Balkema et al. (57%)1212 Balkema CA, Irusen EM, Taljaard JJ, Koegelenberg CF. Tuberculosis in the intensive care unit: a prospective observational study. Int J Tuberc Lung Dis. 2014;18(7):824-30. https://doi.org/10.5588/ijtld.13.0044
https://doi.org/10.5588/ijtld.13.0044...
and Silva et al. (65%)66 Silva DR, Menegotto DM, Schulz LF, Gazzana MB, Dalcin PT. Mortality among patients with tuberculosis requiring intensive care: a retrospective cohort study. BMC Infect Dis. 2010;10:54. https://doi.org/10.1186/1471-2334-10-54
https://doi.org/10.1186/1471-2334-10-54...
in South Africa and Brazil, respectively, as well as being higher than those reported by Zahar et al. (26.7%),1818 Zahar JR, Azoulay E, Klement E, De Lassence A, Lucet JC, Regnier B, et al. Delayed treatment contributes to mortality in ICU patients with severe active pulmonary tuberculosis and acute respiratory failure. Intensive Care Med. 2001;27(3):513-20. https://doi.org/10.1007/s001340000849
https://doi.org/10.1007/s001340000849...
Lanoix et al. (28%),1717 Lanoix JP, Gaudry S, Flicoteaux R, Ruimy R, Wolff M. Tuberculosis in the intensive care unit: a descriptive analysis in a low-burden country. Int J Tuberc Lung Dis. 2014;18(5):581-7. https://doi.org/10.5588/ijtld.13.0901
https://doi.org/10.5588/ijtld.13.0901...
and Valade et al. (42%)1010 Valade S, Raskine L, Aout M, Malissin I, Brun P, Deye N, et al. Tuberculosis in the intensive care unit: A retrospective descriptive cohort study with determination of a predictive fatality score. Can J Infect Dis Med Microbiol. 2012;23(4):173-8. https://doi.org/10.1155/2012/361292
https://doi.org/10.1155/2012/361292...
in France. However, none of these cohorts were designed for studying TB/HIV coinfected patients in the ICU; such patients were primarily evaluated in a subanalysis of larger studies. In addition, as previously mentioned, TB is usually paucibacillary in HIV-infected individuals, and diagnosis remains a challenge. Of the 120 patients in our sample, only 24 (20.0%) had a microbiological diagnosis of TB. Therefore, the case-fatality rate found in the present study can be attributed, at least in part, to histoplasmosis and other fungal diseases (which are generally underdiagnosed), as well as to noninfectious diseases that mimic TB. It is also of note that 89.0% of those patients had been receiving treatment. It is possible that some patients were diagnosed late, meaning that treatment was also delayed. Given the severity of the clinical conditions, it is possible that the doses of the anti-TB drugs used were lower than required, that adherence was suboptimal, or both. Therefore, the directly observed treatment strategy should be revised.

In Brazil, 25% of patients have a low CD4 count at diagnosis of HIV infection.2828 Brasil. Ministério da Saúde. Secr Vigilância Em Saúde. Departamento de DST, Aids e Hepatites Virais. Boletim Epidemiológico HIV/AIDS. Brasília: o Ministério; 2015. In the state of Amazonas, as many as 30% have a mean count of 282 cells/mm3 at diagnosis.2828 Brasil. Ministério da Saúde. Secr Vigilância Em Saúde. Departamento de DST, Aids e Hepatites Virais. Boletim Epidemiológico HIV/AIDS. Brasília: o Ministério; 2015. Most (79.0%) of the deaths among the patients included in the present study occurred in those with a CD4 count of < 200 cells/mm3 at ICU admission, a finding that is consistent with those of other studies.1212 Balkema CA, Irusen EM, Taljaard JJ, Koegelenberg CF. Tuberculosis in the intensive care unit: a prospective observational study. Int J Tuberc Lung Dis. 2014;18(7):824-30. https://doi.org/10.5588/ijtld.13.0044
https://doi.org/10.5588/ijtld.13.0044...
,2929 Koegelenberg CF, Balkema CA, Jooste Y, Taljaard JJ, Irusen EM. Validation of a severity-of-illness score in patients with tuberculosis requiring intensive care unit admission. South Afr Med J. 2015;105(5):389-92. https://doi.org/10.7196/SAMJ.9148
https://doi.org/10.7196/SAMJ.9148...
This is probably due to delayed HIV diagnosis and advanced AIDS. In highly immunosuppressed individuals requiring critical care, it is best to “hit hard and hit early” with active bactericidal agents in order to stop TB progression and save time in the ICU. Another issue that merits further investigation is whether there is a need to wait 2 weeks before initiating ART or whether ART should be initiated earlier. In HIV-infected patients, a low CD4 count is known to be associated with early ICU admission and increased case-fatality rates.3030 Croda J, Croda MG, Neves A, De Sousa dos Santos S. Benefit of antiretroviral therapy on survival of human immunodeficiency virus-infected patients admitted to an intensive care unit. Crit Care Med. 2009;37(5):1605-11. https://doi.org/10.1097/CCM.0b013e31819da8c7
https://doi.org/10.1097/CCM.0b013e31819d...
,3131 Khouli H, Afrasiabi A, Shibli M, Hajal R, Barrett CR, Homel P. Outcome of critically ill human immunodeficiency virus-infected patients in the era of highly active antiretroviral therapy. J Intensive Care Med. 2005;20(6):327-33. https://doi.org/10.1177/0885066605281087
https://doi.org/10.1177/0885066605281087...

Belperio & Rhew reported the prevalence and outcomes of anemia in HIV-infected individuals,3232 Belperio PS, Rhew DC. Prevalence and outcomes of anemia in individuals with human immunodeficiency virus: a systematic review of the literature. Am J Med. 2004;116 Suppl 7A:27S-43S. https://doi.org/10.1016/j.amjmed.2003.12.010
https://doi.org/10.1016/j.amjmed.2003.12...
in whom anemia is commonly caused by disseminated TB.3333 Kerkhoff AD, Meintjes G, Opie J, Vogt M, Jhilmeet N, Wood R, et al. Anaemia in patients with HIV-associated TB: relative contributions of anaemia of chronic disease and iron deficiency. Int J Tuberc Lung Dis. 2016;20(2):193-201. https://doi.org/10.5588/ijtld.15.0558
https://doi.org/10.5588/ijtld.15.0558...
Although low hemoglobin levels are common among HIV-infected patients and have previously been described as constituting an important predictor of mortality in such patients,3232 Belperio PS, Rhew DC. Prevalence and outcomes of anemia in individuals with human immunodeficiency virus: a systematic review of the literature. Am J Med. 2004;116 Suppl 7A:27S-43S. https://doi.org/10.1016/j.amjmed.2003.12.010
https://doi.org/10.1016/j.amjmed.2003.12...
we found no association between anemia and mortality in our cohort. However, anemia is a common sign of TB and HIV infection, being present not only in critically ill patients in the ICU but also in recently diagnosed patients in an outpatient setting. Therefore, it might have no impact on ICU prognosis.3333 Kerkhoff AD, Meintjes G, Opie J, Vogt M, Jhilmeet N, Wood R, et al. Anaemia in patients with HIV-associated TB: relative contributions of anaemia of chronic disease and iron deficiency. Int J Tuberc Lung Dis. 2016;20(2):193-201. https://doi.org/10.5588/ijtld.15.0558
https://doi.org/10.5588/ijtld.15.0558...

In the present study, acute respiratory failure was the main reason for ICU admission (in 80.0% of the patients) and a variable that was associated with high mortality rates among our patients. These results are similar to those of studies analyzing patients undergoing IMV.66 Silva DR, Menegotto DM, Schulz LF, Gazzana MB, Dalcin PT. Mortality among patients with tuberculosis requiring intensive care: a retrospective cohort study. BMC Infect Dis. 2010;10:54. https://doi.org/10.1186/1471-2334-10-54
https://doi.org/10.1186/1471-2334-10-54...
,1212 Balkema CA, Irusen EM, Taljaard JJ, Koegelenberg CF. Tuberculosis in the intensive care unit: a prospective observational study. Int J Tuberc Lung Dis. 2014;18(7):824-30. https://doi.org/10.5588/ijtld.13.0044
https://doi.org/10.5588/ijtld.13.0044...
,1313 Madkour A, Fouda M, Mansour M. Outcome of active pulmonary tuberculosis patients requiring respiratory intensive care admission. Egypt J Bronchol. 2014;8(2):79-86. https://doi.org/10.4103/1687-8426.145692
https://doi.org/10.4103/1687-8426.145692...

Potential factors responsible for low rates of bacteriological confirmation include the lack of quality assurance schemes3434 Khan MS, Dar O, Sismanidis C, Shah K, Godfrey-Faussett P. Improvement of tuberculosis case detection and reduction of discrepancies between men and women by simple sputum-submission instructions: a pragmatic randomised controlled trial. Lancet. 2007;369(9577):1955-60. https://doi.org/10.1016/S0140-6736(07)60916-7
https://doi.org/10.1016/S0140-6736(07)60...
and the empirical approach to TB treatment in the ICU. Suboptimal diagnostic quality can hinder differential diagnosis as well. In the present study, the rate of bacteriological confirmation among patients facing high case-fatality rates was found to be low (i.e., 27.5%). Despite evidence of increased mortality among patients without microbiological confirmation because of HIV-related immunosuppression,3535 Campos LC, Rocha MV, Willers DM, Silva DR. Characteristics of Patients with Smear-Negative Pulmonary Tuberculosis (TB) in a Region with High TB and HIV Prevalence. PLoS ONE. 2016;11(1):e0147933. https://doi.org/10.1371/journal.pone.0147933
https://doi.org/10.1371/journal.pone.014...
we found no significant differences in mortality rates between TB cases with and without microbiological confirmation.

Few studies have examined treatment adequacy and patient adherence.55 Klautau GB, Kuschnaroff TM. Clinical forms and outcome of tuberculosis in HIV-infected patients in a tertiary hospital in São Paulo - Brazil. Braz J Infect Dis. 2005;9(6):464-78. https://doi.org/10.1590/S1413-86702005000600004
https://doi.org/10.1590/S1413-8670200500...
It is of note that although 75.0% of our patients were started on TB treatment before ICU admission, the mean time from admission to treatment in most studies is 1.6-5 days.99 Levy H, Kallenbach JM, Feldman C, Thorburn JR, Abramowitz JA. Acute respiratory failure in active tuberculosis. Crit Care Med. 1987;15(3):221-5. https://doi.org/10.1097/00003246-198703000-00008
https://doi.org/10.1097/00003246-1987030...
,1010 Valade S, Raskine L, Aout M, Malissin I, Brun P, Deye N, et al. Tuberculosis in the intensive care unit: A retrospective descriptive cohort study with determination of a predictive fatality score. Can J Infect Dis Med Microbiol. 2012;23(4):173-8. https://doi.org/10.1155/2012/361292
https://doi.org/10.1155/2012/361292...
,1212 Balkema CA, Irusen EM, Taljaard JJ, Koegelenberg CF. Tuberculosis in the intensive care unit: a prospective observational study. Int J Tuberc Lung Dis. 2014;18(7):824-30. https://doi.org/10.5588/ijtld.13.0044
https://doi.org/10.5588/ijtld.13.0044...
The high prevalence of TB/HIV coinfection in Brazil pushes health professionals to the edge. There are currently few ART regimens that can be prescribed in combination with anti-TB drugs; new regimens based on different drugs might make it easier to combine the two in the future.

ICU patients with severe TB pose a major challenge in TB diagnosis (microbiological confirmation of TB) and treatment (poor absorption of anti-TB drugs; organ dysfunction; and apparent deterioration of TB during appropriate treatment, i.e., paradoxical reactions).77 Hagan G, Nathani N. Clinical review: tuberculosis on the intensive care unit. Crit Care. 2013;17(5):240. https://doi.org/10.1186/cc12760
https://doi.org/10.1186/cc12760...
The potential role of malabsorption of anti-TB drugs in severe cases and the potential utility of therapeutic drug monitoring have been poorly studied and deserve more attention.3636 Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, et al. Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016;63(7):853-67. https://doi.org/10.1093/cid/ciw566
https://doi.org/10.1093/cid/ciw566...
,3737 Sotgiu G, Nahid P, Loddenkemper R, Abubakar I, Miravitlles M, Migliori GB. The ERS-endorsed official ATS/CDC/IDSA clinical practice guidelines on treatment of drug-susceptible tuberculosis. Eur Respir J. 2016;48(4):963-971. https://doi.org/10.1183/13993003.01356-2016
https://doi.org/10.1183/13993003.01356-2...
To our knowledge, this is the first study to evaluate TB/HIV coinfected ICU patients in the Amazon region, being the largest of its kind. Information on how to improve TB/HIV coinfection management in the ICU is still anecdotal, and important issues (such as uncertainty regarding severity classification, mortality scores, vulnerable populations, and effective treatment) have yet to be resolved.

Our study has several limitations. First, all data were obtained retrospectively by reviewing patient medical records and were probably not as complete or accurate as are data that are collected prospectively. Second, although our cohort is the largest available sample of TB/HIV coinfected patients in the ICU, its power was too low to allow subanalyses to be undertaken. Despite these limitations, our results provide important implications for similar demographic areas and clinical settings. In addition, our study poses questions on how to approach TB/HIV coinfected patients and how to predict their prognosis while providing timely interventions.

The high mortality rate found in the present study underlines how difficult it is to manage TB in the ICU. Pre-ICU interventions (including early diagnosis and effective treatment) can have a major impact on TB/HIV mortality in the ICU, as well as improving the quality of TB control.

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    » https://doi.org/10.1371/journal.pone.0147933
  • 36
    Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, et al. Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016;63(7):853-67. https://doi.org/10.1093/cid/ciw566
    » https://doi.org/10.1093/cid/ciw566
  • 37
    Sotgiu G, Nahid P, Loddenkemper R, Abubakar I, Miravitlles M, Migliori GB. The ERS-endorsed official ATS/CDC/IDSA clinical practice guidelines on treatment of drug-susceptible tuberculosis. Eur Respir J. 2016;48(4):963-971. https://doi.org/10.1183/13993003.01356-2016
    » https://doi.org/10.1183/13993003.01356-2016
  • 1
    Study carried out at the Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus (AM) Brasil.
  • Financial support:

    This study received financial support from the Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM, Foundation for the Support of Research in the State of Amazonas).

Publication Dates

  • Publication in this collection
    Mar-Apr 2018

History

  • Received
    02 Sept 2017
  • Accepted
    14 Jan 2018
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