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 Pulmonology 28 (2022) 297 309

www.journalpulmonology.org

REVIEW

Pulmonary tuberculosis in intensive care setting, with a

focus on the use of severity scores, a multinational
collaborative systematic review
J. Galvina,b,1, S. Tiberia,b,1, O. Akkermand,e, H.A.M. Kerstjensd,e, H. Kunstb,c,
X. Kurhasanif, N. Ambrosinog, G.B. Migliorih,*

a
Department of Infection, The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
b
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University, London, United Kingdom
c
Department of Respiratory Medicine, Barts Health NHS Trust, London, UK
d
Department of Pulmonary Diseases and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen,
the Netherland
e
University of Groningen, University Medical Center Groningen, Tuberculosis center Beatrixoord, Haren, the Netherlands
f
UBT Higher Education Prishtina, Kosovo
g
Pneumology Unit, Istituti Clinici Scientifici Maugeri, IRCCS, Montescano, Italy
h
Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri, IRCCS, Via Roncaccio 16, Tradate
21049, Italy

Received 24 January 2022; accepted 25 January 2022

Available online 26 February 2022

KEYWORDS Abstract
Tuberculosis; Background and aim: Tuberculosis (TB) is associated with a high mortality in the intensive care
Intensive care; unit (ICU), especially in subjects with Acute Respiratory Distress Syndrome (ARDS) requiring
Mortality; mechanical ventilation. Despite its global burden on morbidity and mortality, TB is an uncommon
Acute respiratory dis- cause of ICU admission, however mortality is disproportionate to the advances in diagnosis and
tress syndrome; treatment made. Herein we report a systematic review of published studies.
Intravenous Methods: Our Literature search was conducted to identify studies on outcomes of individuals
antimicrobials with TB admitted to ICU. We report and review in-hospital mortality, predictors of poorer out-
comes, usefulness of severity scoring systems and potential benefits of intravenous antibiotics.
Searches from Pubmed, Embase, Cochrane and Medline were conducted from inception to March
2020. Only literature in English was included.
Results: Out of 529 potentially relevant articles, 17 were included. Mortality across all studies
ranged from 29-95% with an average of 52.9%. All severity scores underestimated average mor-
tality. The most common indication for ICU admission was acute respiratory failure (36.3%). Neg-
ative predictors of outcome included hospital acquired infections, need of mechanical
ventilation and vasopressors, delay in initiation of anti-TB treatment, more than one organ

* Corresponding author.
E-mail address: giovannibattista.migliori@icsmaugeri.it (G.B. Migliori).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.pulmoe.2022.01.016
2531-0437/© 2022 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 J. Galvin, S. Tiberi, O. Akkerman et al.

failure and a higher severity score. Low income, high incidence countries showed a 23.4% higher
mortality rate compared to high income, low TB incidence countries.
Conclusion: Mortality in individuals with TB admitted to ICU is high. Earlier detection and treat-
ment initiation is needed.
© 2022 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

Introduction ARDS and septic shock, as some studies have suggested they
consistently underestimate mortality in these groups.23,24
Tuberculosis (TB) was within the top ten causes of death and The low prevalence of TB in ICU is a further challenge. In
second cause of death from a single infectious agent world- published studies, small sample sizes limit the potential gen-
wide in 2020.1 4 The aim of treatment is to reduce the inci- eralisation of results.25 Further research and studies with
dence of resistance and achieve full bacterial clearance, larger patient groups are needed.
thereby limiting the risk of transmission.5,6 Success of drug This review aims to identify factors affecting poor out-
susceptible TB under trial conditions is up to 95% in non-crit- comes and mortality of individuals with pulmonary TB admit-
ical subjects; this success is underpinned by adequate con- ted to ICU. Further objectives include identifying factors
centrations of these drugs in the blood.7 leading to TB-related complications, the relevance of ICU
Although TB most commonly manifests sub-acutely or severity scores and the role of using first line intravenous
chronically, some individuals especially those with extensive anti-TB drugs in critically ill subjects. We hypothesise that
disease may progress rapidly, requiring admission to inten- identifying predictors of poor outcomes in TB patients
sive care unit (ICU). Up to 3% of all patients with TB require admitted to ICU can contribute to risk stratification and per-
ICU admission, a high proportion considering the availability sonalised treatment.
of curative treatment.8 The most common indication for ICU
admission is respiratory failure and acute respiratory dis-
tress syndrome (ARDS).9 11 The mortality for TB patients Methods
admitted to ICU is extremely high, more than any other
cause of respiratory failure including pneumonia.12 Reported Search strategy
mortality rates are variable across studies, and can range
from 24% to 81% in individuals requiring mechanical ventila- To avoid any influence of the effects of pandemic on recent
tion.13 The mortality for ARDS secondary due to TB has not publications,26 Pubmed, EMBASE, Cochrane and Medline
changed significantly over time, despite advances in new databases were searched from inception until March 2020.
treatment regimens and ventlilatory strategies in ICU. The Keywords included: (“Outcome*” or “mortality” or “impact”
heterogeneity of disease presentation and the difficulty in or “recovery” or “effect*”) and (“Mycobacterium tuberculo-
diagnosis remain a challenge. Co-morbidities including HIV, sis” or “tuberculosis” or “TB” or ‘MTB”) and (“intensive care
immunosuppressive disorders and diabetes increase the risk unit*” or “intensive treatment unit*” or “critical care” or
of complications in patients with TB.9 Poor prognostic indi- “CCU” or “ARDS” or “Acute respiratory distress syndrome”
cators include high Acute Physiology And Chronic Health or “mechanical ventilation” or “respiratory failure”) and
Evaluation II (APACHE II) or Simplified Acute Physiology Score (“scor*” or “severity” or “APACHE” or “APACHEII” or “GCS”
(SAPS) II scores, nosocomial infections, sepsis and delayed or “SOFA” or “SAPS” or “Charlson”), “Intravenous” or “anti-
start of anti TB treatment.14 The full extent of the associa- biotic*” or “Rifampin” or “Isoniazid” or “ethambutol” or
tion of TB with Covid-19 and the risk of admission to ICU and “Pyrazinamide”.
the need for mechanical ventilation is currently not
known.15 18 Study selection
Delays in diagnosis and treatment of pulmonary TB are
principal causes of death, especially in patients with acute Published studies were included if they reported on out-
respiratory failure.11,19,20 Early diagnosis and start of effec- comes of cohorts of patients with pulmonary TB admitted to
tive treatment is needed to prevent ICU admission and com- ICU Studies involving, individuals < 18 years and those
plications.9 It is imperative that the absorption of anti-TB involving <10 patients were excluded. Conference
treatment is maximised; a challenge in the critically ill indi- abstracts, posters, patient case studies and articles with no
vidual. Deranged physiological functioning and poor gastric reported outcomes were excluded.
absorption can lead to sub-therapeutic drug levels.21 Intra- In the first stage, we screened the titles and abstracts of
venous antibiotics may overcome these obstacles. Despite all citations for potentially relevant papers. In the second
the bioavailability of parenteral routes, the use of intrave- stage, we examined in detail the full texts of the retrieved
nous antimicrobials is seldom used in TB. If intravenous papers.
rifampicin, was more widely available, it may negate the
need for more toxic regimens. Data extraction
Severity scoring systems such as APACHE II have been
proven to predict mortality in individuals admitted to ICU.22 Information on study design, setting, population characteris-
This may not be the case for individuals with TB related tics including comorbidities, reason for ICU admission as well

298
 Pulmonology 28 (2022) 297 309

as ICU outcomes were obtained (see Table 1). Factors affect- in-hospital mortality with suspected infection outside the
ing outcomes were also recorded in a separate Table 2, and ICU and the Glasgow Coma Scale (GCS) were also used
including information on mechanical ventilation, length of across the studies. The average of the mean APACHE II
hospital and ICU stay, ICU related complications were score was 20.2 and median 19.1, across 8 and 6 studies,
obtained. Tuberculosis related outcomes such as time to ini- respectively. The average of the median SAPS II score
tiation of anti-TB treatment, drug susceptibility pattern, was 42.8 across 4 studies and median SOFA was 5.8 across
concomitant treatments, were recorded (Table 2). All ICU 6 studies. The mean and median values for severity
related severity scores were recorded. (Table 3). scores were consistently higher in fatalities than survi-
vors in all studies except for Pecego et al. with survivors
Quality assessment of included studies having a higher SAPS II score (Table 3).36 The average of
the mean APACHE II score was 22 and 16.4 for fatalities
The Newcastle-Ottawa assessment scale (NOS) for cohort and survivors, respectively across 5 studies. The average
studies was used to assess study quality and risk of bias.35 of the median of these scores were 23.3 and 16.5 for
The Newcastle-Ottawa assessment scale evaluates three fatalities and survivors, respectively, across 5 studies.
parameters; selection, comparability and outcome, award- Individuals requiring mechanical ventilation ranged from
ing a certain number of points. The maximum number a 37.5% to 100%. Across all studies 67.2% of cases required
study can receive is 9 points, indicating low risk of bias. Less mechanical ventilation and the duration in days was 14.5
than 5 points indicate a high risk of bias. The outcome used and 13.25 days for the median and mean values, respec-
for the checklist was mortality. tively. There was a large variation for example Erbes et al.
Fig. 1. PRISMA flow diagram of selected studies. provide a mean of 26 and a range of 1-106,14 similarly Lanoix
et al.30 provide a median of 8 with an interquartile range
(IQR) of 1-129.
Results Duration of hospital stay was reported in 9 studies. The
average of the median was 20.2 days across 6 studies and for
Characteristics of the studies the mean 51.2 days across 3 studies. The duration of ICU
stay was reported in 14 studies, the average of the median
Seventeen out of 529 studies fulfilled the inclusion criteria was 7.8 days across 9 studies and mean was 15.6 across 4
and were included in the review. The studies ranged from studies. Similarly, for the duration of stay for both hospital
1995 to 2018. The studies included were from high (South and ICU, there was a large spread of data throughout some
Africa, South Korea, India) and low/intermediate TB inci- studies, reflected by the large interquartile ranges in
dence countries (Canada, Germany, Taiwan, France, Turkey, Table 2.
Portugal). All studies were retrospective except Balkema Delay in initiation of anti TB treatment (ATT) within
et al.29 which was prospective. A total of 947 cases with hospital was only reported in 8 studies, the lowest being
active pulmonary TB who required ICU admission were 0 days and the largest mean value was 45 days in Penner
included across all studies, of which 652 were male. et al.27 The prevalence of drug resistance pattern was
reported in 11 studies and ranged between 0% to 28.6%,
Quality of studies 4.9% of cases having drug resistant strains when combin-
ing all studies. Steroids were given to 11.5% of cases
Quality of studies was generally high when assessed using and vasopressor support was given to 15.0% of cases.
NOS checklist. Selection bias across studies was greatest risk Other treatment management was given to a smaller
due to clinician selected cohort groups, with small sample number of individuals including extracorporeal mem-
sizes. All had follow up resulting in outcomes with all sub- brane oxygenation, tracheostomy and renal replacement
jects accounted for, and outcomes were clearly defined in therapy.
all studies. No study had an overall outcome <7 points indi- The most common reported complication was ARDS
cating low risk of bias (Table 4). affecting 19.5% of all cases, followed by ventilator asso-
To aid an inclusive qualitative analysis, the averages ciated pneumonia (10.8%), multiple organ failure (10.5%),
of medians and means were calculated, with each study sepsis (9.5%) and hospital acquired infections (8.2%).
weighted equally, regardless, of the number of cases. Other reported complications included shock, dissemi-
The mean or median age of cases ranged between nated intravascular coagulation, acute kidney infection,
31.6 76.9 years with 12/17 studies having a mean/ single organ failure and pneumothorax. In-hospital mor-
median age > 41 years. Common comorbidities included tality ranged from 29% to 95.1% giving a mortality rate of
HIV co-infection (27.1%), alcohol abuse (12.5%), diabetes 52.9% across all studies. In two studies a lower ratio of
(7.7%) and malnourishment (5.0%). 21% of cases were arterial oxygen tension to fractional inspired oxygen
smokers. Thirty-eight% of cases had a diagnosis of TB (PaO2/FiO2) indicated a poorer prognosis.38,33 Causes of
prior to ICU admission. The most common indication for death were reported in 6 studies with septic shock and
ICU admission was respiratory failure and ARDS (36.3%) organ failure (including respiratory failure) with, respec-
followed by pneumonia (9.3%), sepsis (4.3%) and massive tive values of 4.7% and 3.8% of total cases as the most
haemoptysis (3.8%). common causes. Other causes of death included hospital
Acute Physiology and Chronic Health Evaluation II was acquired infection, raised intracranial pressure, pulmo-
the most commonly used scoring system, reported in 13 nary embolism and hypoxaemia.
studies, however SAPS II, quick Sequential Organ Failure No studies using first line intravenous anti TB medications
Assessment (qSOFA) which identifies high-risk patients for in ICU were found.

299
 Table 1 Studies of patients with tuberculosis in the intensive care setting.
Study Country Study Duration Study Design Patients n Mean* age M:F Co-morbidities n (%) TB diagnosis Indication for
(incidence per of patients before ICU ICU admission
100.000) (years) admission n (%)
Penner et al 27 Canada 1984 1994 Retrospective 13 47 § 14.0 6:7 Alcohol abuse 6 (46.2) 7 (53.8) NR
(1995) (6) Malnourished 7 (53.8)

Erbes et al 14 Germany 1990 2001 Retrospective 58 44.7 § 17.7 36:12 Malnourished 30 (51.7) 46 (79.3) ARDS 47
(2006) (7) Liver damage 38 (65.5) (81.1%)
Alcohol abuse 35 (60.3)
Smoking 40 (69.0)
Sharma et al20 India 1980 2003 Retrospective 29 31.6 § 10.9 16:13 Liver damage 11 (39.3) 6(19) NR
(2006) (199) Alcohol abuse 3 (10.3)
Diabetes 2 (6.9)
Pregnancy/post partum 4 (13.8)
Ryu et al 7 Korea 1995 2005 Retrospective 32 69 20:12 Diabetes 4 (12.5) 6 (19) NR
(2006) (66) (25 88) Tuberculosis destroyed lung 4 (12.5)

J. Galvin, S. Tiberi, O. Akkerman et al.

Immunosuppressive therapy 5 (15.6)
Lin et al 28 Taiwan 2004 2005 Retrospective 59 76.9 § 9.8 46:13 COPD 12 (20.3) NR NR
(2009) (61) (F) CHF 11 (18.6)
70.8 § 18.9 DM 13 (22.0)
(S) Chronic steroid use 13 (22.0)
Malignancy 12 (20.3)
Valade et al 13 France 2000 2009 Retrospective 53 41 [32 52] 40:13 HIV 12 (23.6) 40 (75) NR
(2012) (9) Smoking 32 (60.4)
300

Alcohol use 22 (41.5)

IVDU 6 (11.3)
Balkema et al South Africa 2012 2013 Prospective 83 36.5 § 12.9 38:45 HIV 44 (53) 32 (38.6) ARDS 56 (67.5)
29
(2014) (520) DM 9 (10.8)
COPD 6 (7.2)

Lanoix et al 30 France 2000 2009 Retrospective 97 47.4 § 14.7 77:20 HIV 40 (41.2) NR Sepsis 7 (7.2)
(2014) (9) ARF 42 (43.3)
Neurological
disorder 25
(25.8)
Haemoptysis 7
(7.2)

Rollas et al 8 Turkey 2009 2014 Retrospective 16 45 [24 74] 9:7 Immunosuppression 8 (50) NR Neurological 5
(2015) (16) Heart failure 2 (12.5) (31.3)
Sepsis 5 (31.3)
Haemoptysis 1
(6.3)
ARF 5 (31.3)

Filiz et al 31 Turkey 2010 2013 Retrospective 35 47 [16 83] 27:8 DM 8 (22.9) NR ARF 20 (57.1)
(2016) (16) Silicosis 2 (5.7) Sepsis 7 (20)
Massive hae-
moptysis 3
(8.6)
Extrapulmo-
nary TB 3 (8.6)
 Table 1 (Continued)
Study Country Study Duration Study Design Patients n Mean* age M:F Co-morbidities n (%) TB diagnosis Indication for
(incidence per of patients before ICU ICU admission
100.000) (years) admission n (%)
Kim et al 21 Korea 2011 2014 Retrospective 41 56.3 35:6 Hypertension 6 (14.6) 10 (24.4) NR
(2016) (66) [47 73] DM 5 (12.2)
Liver damage 4 (9.8)
Malignancies 3 (7.3)
Duro et al 32 Portugal 2007 2014 Retrospective 39 52 (37.5- 29:10 Immunodeficiency 18 (46.2) 39 (100) ARF 20 (51.3)
(2017) (24) 62.8) Smoking 13 (33.3) Septic shock 8
Alcohol abuse 8 (20.5) (20.5)
Drug addiction 9 (23.1) Post surgical 5
COPD 8 (20.5) (12.8)
Malnourished 10 (25.6) Post CPR 4
(10.3)
LOC 2 (5.1)
Kim et al 33 Korea 2005 2016 Retrospective 125 66 (57-74) 104:21 Smoking 59 (47.2) NR Pneumonia 73
(2018) (66) Diabetes 25 (20.0) (58)
Hypertension 31 (24.8) Acute exacer-

Pulmonology 28 (2022) 297 309

CHD/CVD 40 (32.0) bation 20 (16)
Chronic lung disease 53 (42.4) Haemoptysis 19
Liver disease 8 (6.4) (15)
Chronic kidney disease 5 (4.0)
Malignancy 13 (10.4)
Muthu et al 34 India 2001 2016 Retrospective 63 37.3 § 19 27:36 NR 55 (87.3) NR
301

(2018) (199)
Tatar et al 19 Turkey 2004 2010 Retrospective 40 55 (43-63) 33: 7 Smoking 22 (55) 7 (17.5) ARF 40 (100)
(2018) (16) COPD 12 (30)
Diabetes 7 (17.5)
Cardiovascular disease 3 (7.5)
Psychiatric disorder 3 (7.5)
 Table 2 Summary of studies showing patient variables and outcomes in ICU.
Study ICU Severity Invasive MV n Duration of Duration of Duration of Delay in ATT DRn (%) Additional ICU complications n In-hospital/ Predictors of Cause of
score (%) MV (d) hospital stay ICU stay (d) (d) treatment n (%) ICU Mortality fatality death n (%)
(d) (%) n (%)

Penner APACHE II, 13 (100) 15 § 10 50 § 35 19 § 12 45 § 33 0 (0) Steroids, 8 Sepsis, 6 (46.2) 9 (69.0) NR MOF 6
et al 27 26 § 4 (61.5%) MOF, 6 (46.2) (46.2)
(1995) Pneumothorax 2, RF 3 (23.1)
(15.4)
DIC, 1 (7.7)
ARDS, 8 (6.2)
Erbes et al APACHE II, 22 (37.9) 26 (1-106) 87.1 (3-340) 21.6 (3-229) 0 7 (12.1) Steroids, 40 ARDS 7 (12.1) 15 (25.9) ARF, MV, Chronic NR
14
13.1 § 5.6 (68.9) Pneumothorax 8 pancreatitis, Sep-
(2006) (13.8) sis, ARDS, Nosoco-
ARF 7 (12.1) mial pneumonia
Sepsis 15 (25.8)
MOF 2 (3/4)
HAI 39 (67.2)
Sharma APACHE II, 23 (79.3) 5 (3-26) 14 (3-90) 7 (3-90) NR NR Steroids, 6 UTI 5 (17.2) 12 (41.4) APACHE II>18, NR
et al 20 18.5 § 5.7 (20.7) DIC 5 (17.2) hyponatremia

J. Galvin, S. Tiberi, O. Akkerman et al.

(2006) MOF 4 (13.8) PaO2/FiO2 ratio
Pneumothorax 1 <108.2
(3.4)
Ryu et al 7 APACHE II, 16 32 (100) 9 (2-86) 20 (4-144) 11 (2-18) 2 (1-43) 2 (6.3) NR ARDS 9 (28.1) 19 (59) APACHE II >20, NR
(2006) [8-36] MOF 7 (21.9) TDL, Sepsis
HAI 9 (28.1)
Sepsis 16 (50)

Lin et al 28 APACHE II, 59 (100) NR NR NR NR 3 (5.1) NR VAP 29 (49.1) 40 (67.8) MOF, Nosocomial NR
302

(2009) 21§6.5 ARF 6 (10.2) pneumonia,

GI bleed 14 (25) treatment delay
>30d

Valade et al GCS, 14 [12- 24 (45) 6 (3-17) NR 6 [3-16] 3 (0-21) 2 (3.8) Vasopressor HAI 11 (21) 20 (38) Miliary TB, MV and Organ fail-
13
15] 15 (28) VAP 11 (20.8) vasopressor ure 5 (9.4)
(2012) SAPS II, 31 requirement HAI/co-
[22-50] infection
14 (26.4)
PE 1 (1.9)
Balkema APACHE II, NR NR NR 11.9 (1-56) 1.6 (0-17) 3 (3.6) NR ARDS 26 (31.3) 49 (59) CD4 <200 NR
et al 29 20.7 § 8.3 Renal failure 31 Absent lobar con-
(2014) (37.3) solidation
VAP 19 (22.9) Higher APACHE
Septic shock 23 score, ARF
(27.7)
DIC 15 (18.1)
MODS 25 (30.1)
Haemoptysis 14
(16.9)
CAP 38 (45.8)
Lanoix et al SAPS II, 38 45 (46.4) 8 [1-129] NR 7 [3-15.5] NR 8 (8.25) Steroids 32 VAP 18 (40) 32 (33.3) Higher SAPS II/
30
[6-121] (33) SOFA score, 2+
(2014) SOFA, 4 [0- Vasopressor infections, MV,
17] 36 (37.1) ARDS, RRT
Vasopressor sup-
port, Low GCS
Lymphocytopenia
Hypoproteinaemia VAP 7 (7.2)
Rollas et al APACHE II, 10 (62.5) 7 (3-45) 41 (6-122) 10.5 (5-122) 1 (0-20) 1 (6.3) NR HAI 8 (50) 7 (43.8) Sepsis, MV Septic
8
21.5 (6-36) requirement, HAI, shock 5
(2015) SOFA, 6 (1- higher APACHE II (31.3)
 Table 2 (Continued)
Study ICU Severity Invasive MV n Duration of Duration of Duration of Delay in ATT DRn (%) Additional ICU complications n In-hospital/ Predictors of Cause of
score (%) MV (d) hospital stay ICU stay (d) (d) treatment n (%) ICU Mortality fatality death n (%)
(d) (%) n (%)

12) ARF 2
GCS, 11 (3- (28.6)
15)
Filiz et al 31 APACHE II, 18 24 (68.6) NR NR NR NR 10 (28.6) NR Shock 19 (54.3) 20 (57.1) Shock, MOF, MV, NR
(2016) (7-32) MOF 17 (48.6) DR
SOFA, 6 (1- ARF 13 (37.1)
14)
Kim et al 21 Charlson, 41(100) 6.3 [3-14] 13.2 [7-28] 7.8 [3-17] 1 4 (9.8) NR ARDS 19 (46.3) 39 (95.1) NR Hypoxemia
(2016) 0.76 § 1.28 VAP 15 (36.6) 9 (23.1)
APACHE II, Sepsis 30 (73.2) Septic
20 § 6.7 Shock 38 (92.7) shock 16
SOFA, 7 (4-9) AKI, 12 (29.3) (41.0)
MOF, 27 (65.9) MOF 14
(35.9)
Duro et al APACHE II, 29 (74.4) 17 [39] NR NR 0 [4] NR Steroids 5 ARDS 7 (17.9) 21 (53.8) Delayed ATT >3d NR
32
26 § 15.75 (12.8) ARF 8 (20.5) post ICU admis-
(2017) SAPS II, 55 Vasopressor MODS 11 (28.2) sion

Pulmonology 28 (2022) 297 309

[27.5] 21 (53.8) HAI 11 (28.2) MODS/Sepsis
ECMO 2 (5.1) HAI
Kim et al 33 APACHE II 19 125 (100) 8 [5-17] 20 [12-43] 11 [7-18] NR NR Vasopressor NR 46 (37) Age, vasopressor NR
(2018) [15-24] 58 (46) use, low PaO2/
SOFA, 8 [4- RRT 10 (8) FiO2 ratio, BNP
11]
Muthu et al APACHE II, 56 (88.9) 7.5 § 9.1 16.4 § 1.2 9.8 § 11.4 NR NR Tracheos- ARDS 18 (28.6) 28 (44.4) Baseline APACHE Severe
303

34
16.1 § 7.2 tomy 9 (14.3) VAP 10 (15.9) and SOFA score sepsis 16
(2018) SOFA, Steroids 18 Pneumothorax 4 higher, (25.4)
1.8 § 1.6 (28.6) (5.8) Raised ICP
7 (11.1)
Hypoxemia
5 (7.9)
Tatar et al APACHE II, 22 30 (75) 4 [2-18] 13 [5-27] 5 [2-18] NR 1 (2.5) NR ARDS 40 (100) 29 (72. 5) APACHE II >18 NR
19
[15-26] ARF 6 (15) Dyspnoea
(2018) Cardiac failure 8 Need for MV
(20) 1+ organ failure
Hepatic failure 4
(10)

n= number of patients (d)=days

Incidence is reported as estimated rate of tuberculosis per 100,000 from gov.org last updated 2019 (high incidence is > 40/100,000)
All averages are mean § SD unless stated otherwise; Median is signified in bold with (range) or [IQR]
APACHE II is worst score in 24 h of admission
Mortality is reported as ‘in-hospital mortality’ unless stated otherwise
F: fatalities
S: survivors
NR: data not reported
MV: mechanical ventilation
DR%: percentage of patients with drug resistant strains
ATT= anti-tuberculosis treatment
ARDS= acute respiratory distress syndrome
VAP=ventilator assisted pneumonia
 J. Galvin, S. Tiberi, O. Akkerman et al.

Table 3 Severity scoring for survivors vs fatalities.

Study Severity Score All patients Survivors Fatalities
14
Erbes et al (2006) APACHE II 13 § 5.6 12.3 § 5.8 15.7 § 4.1
Lin et al 28 (2009) APACHE II 21 § 6.5 17.0 § 5.8 23.2 § 5.8
Valade et al 13 (2012) SAPS II 31 (22 50) 28 (20 34) 50 (36 69)
Balkema et al 29 (2014) APACHE II 20.7 § 8.3 18.1 § 7.4 22.6 § 8.5
Lanoix et al30 (2014) SAPS II 38 (6-121) 33.58 § 16.46 64.24 § 26.42
SOFA 4 (0 17) 3 (0 15) 11 (0 17)
Rollas et al 8 (2015) APACHE II 21.5 (6 36) 17 (6 29) 27 (18 36)
SOFA 6 (1 12) 4 (1 9) 9 (4 12)
Filiz et al 31 (2016) APACHE II 18 (7 32) 14 (7 21) 22 (16 32)
SOFA 6 (1 14) 2.5 (1 7) 9 (2 14)
Duro et al 32 (2017) APACHE II 26 (15.75) 20.5 (17) 30 (12.75)
SAPS II 55 (27.5) 42.5 (38.50) 58.0 (23.5)
Kim et al 33 (2018) APACHE II 19 (15 24) 18 (15 23) 21 (18 28)
SOFA 8 (4 11) 7 (4 10) 9 (7 11)
Muthu et al 34 (2018) APACHE II 16.1 § 7.2 14.2 1 § 5.8 18.5 1 § 8.2
SOFA 1.8 § 1.6 1 (1.4) 2.8 (3.3)
Tatar et al 19 (2019) APACHE II, 22 (15 26) 17 (15 22) 23 (20 26)

Discussion respiratory failure.36,37 Threshold for clinical suspicion

should be lower in these individuals, given their diminished
Acute respiratory failure, although a rare complication of symptom presentation.12,42
TB, carries a high fatality rate. There is little research focus
on the outcomes and factors affecting mortality in these
patient groups, thereby hindering the ability of clinicians to ICU complications
change clinical practice and improve prognosis.
Several ICU complications were reported. Critically unwell
Mortality and ARDS individuals are prone to drug interactions and adverse
effects due to complex pharmacology, polypharmacy, dis-
In this systematic review, average in-hospital mortality ease severity and organ failure.43 Hepatotoxicity is a partic-
across 17 studies was 52.9%. This value is especially high ular risk with isoniazid, rifampicin and pyrazinamide.
considering availability and efficacy of ATT worldwide and
the advancements in intensive care medicine. Attributable Citations results
factors include delay in diagnosis and ATT initiation, altered after initial search
drug absorption in critically ill patients, comorbidities and 529
TB related complications. The most common complication
and indication for ICU admission across the studies was found Excluded
to be ARDS/acute hypoxaemic respiratory failure. Tubercu- 454
losis related acute respiratory failure carries a mortality Unrelated: 319
Duplicates: 135
rate of up to 60%, pneumonia carries a 25% mortality.38 40
Multiple organ failure and sepsis were present in 10.5% Studies assessed for
and 9.5% of cases, respectively and were included as predic- review eligibility
tors of mortality in 9 studies. Three studies documented 75
individuals with disseminated intravascular coagulation.
This can be caused by miliary TB and is a negative predictor Excluded
for survival, with individuals more likely to develop ARDS 58
than those with isolated pulmonary TB; it carries a high mor- Duplicates 14
tality in the ICU setting, mostly attributed to septicaemia Poster/Abstracts: 13
and subsequent multiple organ failure.10 HIV/AIDS, alcohol Non ICU setting: 12
abuse, diabetes, smoking status and chronic pancreatitis Only TBM/extrapulmonary TB: 10
identified as independent risk factors for mortality.14 Not relevant: 3
Case studies: 2
Less than 10 subjects: 2
HIV and TB Non-English: 2

Tuberculosis is the main cause of death in people living with Studies included in
HIV.41 People living with HIV are 30 times more likely to systematic review
develop active TB, with more severe and atypical pulmonary 17
forms as the most common presentation.37 Two studies
reported an earlier age of hospitalisation and higher rate of Figure 1 Flow-chart of study selection.

304
 Pulmonology 28 (2022) 297 309

Table 4 Bias according to the Newcastle-Ottawa assessment scale.35

Study Selection Score Comparibility Score Outcome Score Total Score
27
Penner et al (1995) 2 2 3 7
Erbes et al 14 (2006) 2 2 3 8
Sharma et al 20 (2006) 3 2 3 7
Ryu et al 7 (2006) 2 2 3 7
Lin et al 28 (2009) 2 2 3 7
Valade et al 13 (2012) 2 2 3 7
Balkema et al 29 (2014) 2 2 3 7
Lanoix et al 30 (2014) 2 2 3 7
Rollas et al 8 (2015) 2 2 3 7
Filiz et al 31 (2016) 2 2 3 7
Kim et al 21 (2016) 2 2 3 7
Pecego et al 36 (2016) 2 2 3 7
Duro et al 32 (2017) 2 2 3 7
Kim et al 33 (2018) 2 2 3 7
Muthu et al 34 (2018) 2 2 3 7
Tatar et al 19 (2019) 2 2 3 7
Ferreira et al 37 (2018) 2 2 3 7

Patients with underlying hepatic sequelae including prior conditions, Tseng et al reported oral fluoroquinolone usage
hepatitis, alcoholic liver disease are more vulnerable. Acute as independently associated with better survival in those
kidney injury and glomerular hyperfiltration can affect anti- with TB mimicking severe pneumonia in ICU.46
TB drug elimination with pyrazinamide and ethambutol Survival of individuals with TB can be significantly
renally excreted.44 Decompensated or end stage renal fail- improved if therapy is started within 14 days of hospitalisa-
ure in ICU negatively influences patient outcome especially tion.46 Erbes et al found a significant increase in mortality in
in those requiring dialysis, 45 individuals across these studies individuals not receiving optimal treatment including isonia-
had renal failure.14 Patients in multiple organ failure are less zid and rifampicin.14 In addition, Duro et al found that start-
tolerant to the toxic side effects of anti-TB drugs, creating ing ATT within 3 days of ICU admission improved survival.32
clinical dilemmas as therapy interruption can increase risk Two studies with the longest delay in treatment initiation
of drug resistance and death. were from lower incidence countries.13,27 Delays are com-
Hospital acquired infections (HAIs) were found to be a neg- mon in areas with fewer TB cases, probably as a result of
ative predictor of survival and were present in 8.2% of cases. lack of experience.47 Almost half of the studies did not
Tuberculosis suppresses monocyte activity, causing immuno- report on treatment delay. The variation in delay ranged
suppression and increasing infection risk.34 Lin et al reported from 0-45 days globally, and may contribute to poorer prog-
nosocomial pneumonia incidence was four times higher in nosis. This review found only 38.3% of individuals diagnosed
non-surviving individuals with pulmonary TB.28 Ventilator prior to admission.
associated pneumonia was found in numerous individuals who
had been ventilated,14 and was independently associated Drug resistance
with hospital mortality.14 Other infections include urinary
tract and central venous catheter associated bloodstream Rifampicin resistance is increasing and a major threat, with
infections which are associated with length hospital stay. Hos- half a million people currently estimated to be infected with
pital acquired infections can prolong length of stay, contribut- rifampicin resistant strains carrying a higher mortality.2,24
ing to an already elevated mortality rate.45 The number of individuals with drug resistant TB was 46
(4.9%). Drug resistance may have been under reported in
Diagnostic delay these studies and this might explain why resistance was not
found to be a predictor of mortality.
Smear microscopy and culture have turnaround times of few
days and several weeks, respectively. GeneXpert NAAT TB- Intravenous anti-TB treatment
PCR test and urinary LAM (Fujifilm) may allow for results
within hours.9 Despite the growing availability of fast and Tuberculosis treatment in ICU is complicated by organ dys-
reliable point of care tests, thinking of TB remains a chal- function, drug toxicity and sub-therapeutic levels. First line
lenge. Misinterpretation of clinical and radiological presen- drugs such as rifampicin and isoniazid are generally well
tation, and lack of resources contribute to unreliable absorbed when administered orally at the correct dose. In
diagnosis and delays in treatment initiation. It can be chal- critically unwell individuals, absorption and pharmacoki-
lenging to radiologically distinguish TB from severe bacterial netic drug properties are altered. The pharmacokinetic pro-
pneumonia as a cause of ARDS, many individuals are treated file of anti-TB drugs has shown that there is a dose
incorrectly before TB is considered in the differential. dependent relationship between concentration and clinical
Empirical fluroquinolone could be beneficial covering both outcomes.48 Critical illness alters gut motility, impairs

305
 J. Galvin, S. Tiberi, O. Akkerman et al.

mucosal barrier integrity, distorts commensal flora, delays resources.55 Individuals with a higher mortality risk may ben-
gastric emptying leading to reduced absorption.10,25,49 efit from earlier, targeted and potentially more aggressive
Hypoalbuminemia was found to be a predictor of mortality treatment, given the small intervention window and a higher
in this review with 47 individuals suffering from malnutrition risk of death; this may outweigh risk of iatrogenic harm.56
pre-admission.37 Hypoalbuminemia may lead to oedema, Many studies have shown APACHE II and SAPS consistently
increasing the volume of distribution of drugs, as well as underestimate mortality among individuals with pulmonary
impair drug absorption all leading to lower drug concentra- TB, especially those with ARDS and the mechanically
tions in serum.44,50 Parenteral administration or higher doses ventilated.55,31 This highlights a shortfall in accurate risk
of drugs may be required to reach therapeutic effect. stratification in these individuals, with a need for better tai-
Although no studies regarding intravenous antibiotics lored, ARDS specific scoring systems. APACHE does not
were found, a study by Hill suggested a role for their use.25 include mechanical ventilation as an adverse outcome pre-
They compared patient groups over 2 weeks, administering dictor a factor in its inaccuracy.22 In the literature it has
standard oral versus a 33% higher dose of intravenous rifam- been reported than an APACHE score >18 is associated with
picin, finding a three times higher ‘geometric mean area a higher mortality giving a predicted mortality of >29%.44
under the time concentration curve’ up to 6 h, in the intra- The average of mean APACHE II produced about 36% pre-
venous group. Mortality was substantially lower in individu- dicted mortality and using median a value about 32%. The
als given intravenous rifampicin with no reported increase in median SAPS II and SOFA scores gave an estimated about 25%
toxicity. They also found an increased survival compared to and <10%, respectively. Most of these results drastically
the standard oral dose, including more rapid resolution of underestimate the calculated mortality of 52.9%. The data
coma and reduced mortality at 2 months and 8 months.25 set in Table 3 showed that the fatalities vs survivors had a
Koegelenberg et al investigated the pharmacokinetics of higher score throughout (except for Pecago et al. 36).
enteral anti-TB drugs in intensive care individuals, finding Villar et al. designed an outcome score calculating 24hr
that a fixed dose of rifampicin administered via nasogastric post ARDS diagnosis, age, PaO2/FiO2 and plateau
tube resulted in sub-therapeutic plasma concentrations in pressure.56,57 Similarly Kim et al. developed a mortality pre-
the majority of individuals.48 diction model for individuals with TB-destroyed lung on
Although intravenous rifampicin is available, it is not widely mechanical ventilation.33 This model included age, vaso-
accessible in low income countries.51 Other first line drugs are pressor use, PaO2/FiO2 ratio and Brain Natriuretic Peptide
not always accessible or available,48 with no intravenous ATT (all predictors of ICU mortality in these individuals) finding
formulation included current WHO Model List of Essential Med- this score more accurate at mortality prediction than
icines (2019).52 This leads to use of second line drugs such as APACHE II and SOFA.33 Lung injury severity 24 h after ARDS
fluroquinolones and aminoglycosides in the ICU setting.53 onset is a key determinant of outcome, reflecting the neces-
sity for a reliable mortality prediction.56 Two studies found a
Mechanical ventilation and steroids low PaO2/FiO2 ratio to be a predictor of fatality.38,33
Although promising results have been obtained, further
Several studies identified mechanical ventilation as a risk studies with perhaps additional variables are needed for
factor for mortality.8,30 The four highest mortality rates external validation.58
reported were from Kim et al. 2016 (95.1%),21 Ferreira et al.
(78.3%),37 Tatar et al. (72.5%),19 and Penner et al. (69.0%),27 High vs low burden areas
having the highest proportion of mechanically ventilated
individuals (75-100%). Studies with the lowest proportion of Nine out of the 17 studies were from high burden areas. Per-
mechanically ventilated individuals had the lowest reported centage of individuals diagnosed before admission was
mortality, such as Erbes et al.14 with 37% ventilated and higher in low prevalence, resource rich areas, ranging from
25.9% mortality.13,14,30 Those with more severe, dissemi- 53.8% to 75% over 4 studies (one not reported).13,14,30,27 In
nated forms of disease were more likely to require mechani- comparison to 24.4% to 38.6% (two not reported) over 4
cal ventilation and develop ARDS, reflecting a referral bias, studies,21,29,33,28 showing that more individuals are living
most unwell more likely to die.12 Duration of mechanical with undiagnosed tuberculosis in poorer areas. This differ-
ventilation has been associated with worse prognosis, possi- ence may be due to better diagnostic tools available in
bly due to more HAIs, and pneumothorax.14 wealthier regions. The mortality in the low prevalence areas
Adjuvant corticosteroid use is indicated for meningeal and was 41.5% compared to the high prevalence at 64.9% with
pericardial disease, and pulmonary TB related ARDS.12,32 the highest mortality being the Kim et al 2016 study at
Some studies have shown that systemic glucocorticoids are 95.1%.21 The association between TB and low-income areas
associated with improved prognosis, however this was non- is known, with poverty being a cause and consequence of
specific for the critically unwell population.54 The benefit of infection. Many risk factors for disease reactivation and pre-
steroid use in TB individuals in ICU specifically remains dictors of mortality in ICU are associated with a lower socio-
unclear. We found that steroid use did not alter prognosis. economic background, including HIV infection, malnutrition,
Vasopressor support was found to be a predictor of fatality. alcohol use disorder and smoking.
More individuals were mechanically ventilated in high
Severity scoring systems in ICU prevalence areas with higher mortality. Mechanical ventila-
tion remains a predictor of mortality even in low burden
Scoring systems for critically ill individuals are commonly areas. In these areas renal failure, sepsis, ARDS and APACHE
used for estimating general ICU mortality, guiding clinical II scoring are non-specific risk factors to TB.30 There was no
decision making and influencing distribution of hospital difference in the APACHE II score, in contrast to the differing

306
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