PLOS ONE

RESEARCH ARTICLE

Associations of hyponatremia and SIADH with

increased mortality, young age and infection
parameters in patients with tuberculosis
Christina Bal ID1*, Daniela Gompelmann1, Michael Krebs2, Lukasz Antoniewicz1,
Claudia Guttmann-Ducke1, Antje Lehmann1, Christopher Oliver Milacek1, Maximilian
Robert Gysan1, Peter Wolf2, Maaia-Margo Jentus ID1, Irene Steiner3, Marco Idzko1
1 Department of Pneumology, University Hospital Vienna AKH, Medical University of Vienna, Vienna,
a1111111111 Austria, 2 Department of Medicine III, Division of Endocrinology and Metabolism, University Hospital Vienna
a1111111111 AKH, Medical University of Vienna, Vienna, Austria, 3 Center for Medical Statistics, Informatics, and
a1111111111 Intelligent Systems (CeMSIIS), Section for Medical Statistics, Medical University of Vienna, Vienna, Austria
a1111111111
* christina.bal@meduniwien.ac.at
a1111111111

Abstract
OPEN ACCESS

Citation: Bal C, Gompelmann D, Krebs M, Background and objective

Antoniewicz L, Guttmann-Ducke C, Lehmann A, et Hyponatremia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH)
al. (2022) Associations of hyponatremia and
are associated with and can be caused by tuberculosis (TB) through meningitis by locally
SIADH with increased mortality, young age and
infection parameters in patients with tuberculosis. invading the hypothalamus, adrenal, or pituitary glands or possibly through ectopic ADH
PLoS ONE 17(10): e0275827. https://doi.org/ production. This study assessed the association of TB mortality with hyponatremia and
10.1371/journal.pone.0275827 SIADH in a large cohort of a university hospital in Austria.
Editor: Mao-Shui Wang, Shandong Public Health
Clinical Center: Shandong Provincial Chest Methods
Hospital, CHINA
This retrospective study enrolled patients with hyponatremia and patients diagnosed with
Received: October 14, 2021
TB from 01/2001-11/2019 to assess the prevalence of TB in hyponatremia and TB morbidity
Accepted: September 24, 2022 and mortality in patients with and without hyponatremia. Sex, age, microbiological results,
Published: October 13, 2022 laboratory tests and comorbidities were analysed and used to calculate survival rates.
Copyright: © 2022 Bal et al. This is an open access
article distributed under the terms of the Creative Results
Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in
Of 107.532 patients with hyponatremia (0.07%) and 186 patients with TB (43%), 80 patients
any medium, provided the original author and were diagnosed with both—hyponatremia and TB. Only three TB patients had SIADH, pre-
source are credited. cluding further SIADH analysis. In hyponatremia, young age and high CRP levels showed
Data Availability Statement: All relevant data are significant associations with TB diagnosis (p<0.0001). Survival rates of patients diagnosed
within the manuscript and its Supporting with TB with moderate to profound hyponatremia were significantly lower than those without
Information files (titled "Original Data").
hyponatremia (p = 0.002).
Funding: The authors received no specific funding
for this work.
Conclusion
Competing interests: I have read the journal’s
In this study of a large cohort from a tertiary care hospital in a non-endemic area of TB,
policy and the authors of this manuscript have the
following competing interests: Dr. Bal reports 0.07% of patients presenting with hyponatremia, but especially younger patients and
personal fees (lecture fee) from: AstraZeneca, patients with high CRP values, were diagnosed with TB. Crucially, patients with moderate to

PLOS ONE | https://doi.org/10.1371/journal.pone.0275827 October 13, 2022 1 / 13

PLOS ONE Hyponatremia in tuberculosis: Increased mortality

IVEPA (Interessensverband Endoskopie Personal profound hyponatremia had a significantly higher mortality rate and thus required increased
Austria) outside the submitted work. Univ. Prof. Dr. medical care.
Gompelmann reports personal fees (lecture and
travel fees) from: Pulmonx, AstraZeneca,
BerlinChemie, Novartis, Böhringer Ingelheim,
Olympus, Uptake Medical, Grifols, outside the
submitted work. Univ. Prof. Dr. Krebs has nothing
to disclose. Dr. Antoniewicz, PhD reports personal Introduction
fees (lecture fee) from: Pfizer, Medizin Medien
Austria GmbH, Merck & Co Inc., Janssen-Cilag Hyponatremia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Pharma GmbH, outside the submitted work. Univ. are associated with [1–3] and can be caused [4] by the infectious disease tuberculosis (TB).
Prof. Dr. Idzko reports personal fees (lecture fee) SIADH causes about a third of all hyponatremia episodes [5]. It is a hypotonic euvolemic
from: AstraZeneca, Bayer, Berlin-Chemie, hyponatremia subform with urine osmolality exceeding >100 mOsmol/kg and sodium con-
Boehringer Ingelheim, Chiesi, CSL-Behring, GSK,
tent >30 mEq/L, absent of any other causative hormonal issues or Antidiuretic Hormone
Menarini, MSD, Novartis, Roche, Sanofi,
Thermofischer and advisory board fees from Alk- (ADH) suppression [1, 6]. Hyponatremia also arises from numerous other causes, including
Pharma, AstraZeneca, BerlinChemie, Boehringer renal failure, cerebral salt-wasting syndrome, diuretic therapy, and other medications [1].
Ingelheim, Chiesi, CSL-Behring, GSK, Novartis, Assessing volume and urine status adequately and excluding renal, hepatic, cardiac, and other
Sanofi, outside the submitted work. The other endocrinal causes for SIADH diagnosis to distinguish the correct hyponatremia cause is essen-
authors have nothing to disclose. For this study,
tial for treatment. In a systematic review, patients with TB showed generally adequate renal
we received no funding from the following
commercial sources, which provided lecture fees
and adrenal functionality, affirming SIADH as a frequent underlying mechanism of hypona-
to some of the authors outside of the submitted tremia in TB [7]. TB was reported to cause SIADH by displacing relevant functional cells
work (see above): AstraZeneca, Pulmonx, through invasion of the hypothalamus, the adrenal or pituitary gland in TB meningitis, or pos-
BerlinChemie, Novartis, Böhringer Ingelheim, sibly by route of pulmonary infections with ectopic ADH production [2, 8]. A critical
Olympus, Uptake Medical, Grifols, Bayer, Roche, unknown is the primary pathophysiological pathway through which TB causes SIADH: the
Sanofi and Pfizer. This does not alter our
first demonstration of ADH activity caused by TB in active inflammatory lung tissue vs regular
adherence to PLOS ONE policies on sharing data
and materials. tissue was already demonstrated in 1970 [9], yet current progress in the pathophysiology could
only reassess this hypothesis in a case report [10]. In fact, pituitary hormone analysis was only
Abbreviations: SIADH, syndrome of inappropriate
performed in a single study of TB meningitis [4], and no study to date differentiates ectopic vs
antidiuretic hormone secretion; TB, tuberculosis;
ADH, Antidiuretic Hormone; NTM, non- pituitary deranged ADH production in TB patients [8]. Mice models show that genes associ-
tuberculosis mycobacteria; CRP, C-Reactive ated with ADH production are upregulated from early infection and involve macrophages as a
Protein; CNS, central nervous system; COPD, principal target, possibly causing increased disease burden [11]. Further elucidation of TB-
chronic obstructive pulmonary disease; HIV, associated SIADH in pathophysiological studies would shed light on this clinically relevant
human immunodeficiency virus infection; ICU,
effect.
intensive care unit; GCS, Glasgow Coma Scale;
STROBE, Strengthening the Reporting of
Hyponatremia itself leads to various symptoms, from subclinical to severe, and is consis-
Observational studies in Epidemiology; SD, tently associated with worse outcomes and increased mortality [2, 12].
standard deviation; OR, odds ratio; CI, confidence However, few studies analysed the effects of hyponatremia in TB [13], especially regarding
limits; LL, lower limit; UL, upper limit; HR, Hazard episodes of SIADH. Furthermore, prior studies either had a high disparity in patient popula-
ratio; Q1, first quartile; Q3, third quartile; PCR, tion groups regarding severity, TB location, and patient characteristics or did not survey
Polymerase chain reaction.
patients with proven TB diagnosis [3, 14].
The primary objective of this paper was to assess the prevalence, and association of TB mor-
bidity and mortality with hyponatremia and SIADH in a large cohort of a university hospital,
to better provide information for more informed choices in monitoring and care of patients
with TB in non-endemic areas.

Methods
Patient recruitment
We acquired patient data retrospectively from the tertiary hospital of the medical university of
Vienna from 01/2001-11/2019 (Fig 1). All data was sourced from medical records and de-iden-
tified. Patients were included in the study if TB or hyponatremia was recorded, matching the
parameters below. This observational study was performed in accordance with the Declaration

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PLOS ONE Hyponatremia in tuberculosis: Increased mortality

Fig 1. Study cohort. Same-day serum osmolarity <275 mOsm/kg, urine osmolarity >100 mOsm/kg, and urine
sodium excretion >30 mmol/L identified SIADH (1087 of 7055 patients tested satisfied all criteria). Hyponatremia, as
noted in the flowchart, excluded hyperglycemia. TB, tuberculosis. SIADH, syndrome of inappropriate antidiuretic
hormone secretion.
https://doi.org/10.1371/journal.pone.0275827.g001

of Helsinki and approved by the Ethics Committee of the Medical University of Vienna. The
ethics committee waived the need for consent because of the study’s retrospective nature.

Parameters
Hyponatremia episodes began at the first measurement of sodium level of <136 mmol/L in
serum (S1 Table). SIADH applied to hyponatremia episodes if the definition of Schwartz and
Bartter [6], in agreement with current guidelines [1, 15], was fulfilled: same-day serum osmo-
larity <275 mOsm/kg, urine osmolarity >100 mOsm/kg and urine sodium excretion >30
mmol/L. A straightforward method to establish SIADH for this study was adopted from
Hoorn et al. 2017, as it provided a consistent urine sodium excretion cut-off (� 30 mmol/L)
which could exclude with acceptable sensitivity and specificity heart failure and liver cirrhosis
as well as nephrotic syndrome. Urine sodium excretion also indirectly identified euvolemia
[15], particularly as no manual patient record assessment for SIADH for such an extensive
database was possible. However, renal and cerebral salt wasting and rare or multi-faceted
causes of hyponatremia are not integrated well enough in this concise approach and necessi-
tate exclusion on a case-by-case basis in clinical praxis.
Two consecutive measurements of sodium levels in serum >135 mmol/L or a maximum of
30 days, to account for out-patient measurements [16], defined the end of an episode. The low-
est serum sodium value of an episode assigned hyponatremia severity as mild (135–130 mmol/
L), moderate (129–125 mmol/L) or profound (<125 mmol/L) [1].
The first positive Mycobacterium tuberculosis culture, Polymerase chain reaction (PCR)
result or Ziehl-Neelsen stain defined TB diagnosis (S2 Table). Subsequent positive TB tests or
TB episodes in the same patient were excluded from the analysis. Infections of the central ner-
vous system (CNS), miliar TB, or pulmonary TB marked different localisations. Out-patient,

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PLOS ONE Hyponatremia in tuberculosis: Increased mortality

in-patient or intensive care treatment modality distinguished TB severity. The analysis

excluded patients with only clinical suspicion of TB but included all verified TB cases.
Patients with TB were assigned to groups according to hyponatremia severity if at least one
hyponatremia episode occurred within one year of TB diagnosis and to groups without hypona-
tremia if no hyponatremia or an episode more than one year apart from TB diagnosis arose. This
method enabled a comprehensive detection of patients with both TB and hyponatremia [17].
The analysis included peak C-Reactive Protein (CRP, mg/dl) and leucocyte levels (G/L) as
continuous variables to mark inflammation status within each episode. A CRP level of >0.5
mg/dl and a leucocyte level >7.5 G/L were considered elevated. An assessment of overall sur-
vival covered the interval between TB diagnosis and death using the date last seen or death
recorded in the Austrian national death registry.

Statistical analysis
If not stated otherwise, we reported quantitative variables as mean ± standard deviation (SD)
and qualitative variables as absolute frequencies and percentages. Estimates with 95% Clopper-
Pearson confidence intervals delineate the prevalence of TB. To calculate the effect of age, sex
and infection parameters (CRP, leucocyte levels) on the development of TB in hyponatremia
patients, we performed univariate logistic regression models for correlated data (SAS Proc
genmod), whereby an independent correlation structure was assumed.
If the univariate model revealed a p-value less than 0.05, the variable entered a multivariable
logistic regression model for correlated data. The odds ratio (OR) with 95% confidence limits
(CI) and the p-value (H0: OR = 1) report the results of each model. We excluded from analysis
all episodes starting after TB diagnosis (n = 159 episodes of 56 patients) because of possible
treatment interference.
We performed a Kaplan-Meier curve including all 186 patients with TB to analyse the over-
all survival in patients in groups separated by hyponatremia at 1, 5, and 10 years (reported
with 95%CI; until query 10/2019). We analysed the effect of hyponatremia on overall survival
through a Cox regression adjusting for age and comorbidities (R-package survival, R-function
coxph). All evaluations were performed with R 3.6.1 and SAS 9.4. P values <0.05 defined sta-
tistical significance. Reports followed Strengthening the Reporting of Observational studies in
Epidemiology (STROBE) guidelines [18] (S1 Appendix).

Results
The analysis included 107.532 patients with at least one hyponatremia episode (mean age
58 ± 18 years, 52% female) with a total of 272.579 hyponatremia episodes and 186 patients
with TB irrespective of hyponatremia. Eighty patients (0.07% [95%CI: 0.06%; 0.09%]) had
both TB and hyponatremia, with a mean of 2.64 hyponatremia episodes within the designated
timeframe (Figs 1 and 2).
Of 212 patients diagnosed with mycobacterial infections, 186 had tuberculosis (mean age
44 ± 19 years, 39% female) and 26 non-tuberculosis mycobacteria (NTM). Out of the 186
patients with TB, 80 patients (43.0%) developed hyponatremia within a year of TB diagnosis,
whereby laboratory tests revealed mild, moderate or profound hyponatremia in 62 (77.5%), 13
(16.3%) and 5 (6.3%) patients respectively. Ten patients (5.4%) presented hyponatremia more
than one year apart from the TB diagnosis, whereas 96 patients (51.6%) had no hyponatremia
episodes within the observation period.
Of 7055 patients tested for SIADH, 1087 satisfied all criteria. Only three patients (0.28%
[95%CI: 0.06%; 0.80%]) with verified SIADH were diagnosed with TB (Table 1). The small
patient number precluded further analysis.

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PLOS ONE Hyponatremia in tuberculosis: Increased mortality

Fig 2. Infection parameters and age in patients with hyponatremia. Patients with TB showed higher leucocyte count (A), higher CRP values (B) and younger
age (C) than patients without TB. Boxplots mark first IQR, median, and third IQR. The Whiskers extend to the minimum and maximum, and if outliers exist
(shown as open circles), to the smallest and largest value within the interval [first quartile –1.5x IQR; third quartile +1.5x IQR].
https://doi.org/10.1371/journal.pone.0275827.g002

Predictors for TB diagnosis in patients with hyponatremia

In univariate logistic regression models, young age and elevated infection parameter levels
showed associations with an increased risk of TB diagnosis. Every CRP level increase by 1 mg/
dl increased the odds [95%CI] of TB infection by 1.053 [1.038; 1.068] (p<0.0001), and leuco-
cyte count increase of 1 G/L by 1.006 [1.005; 1.0115] (p = 0.032). Sex was not significantly asso-
ciated with TB diagnosis (p = 0.8). In a multivariable logistic regression model, the influence
of age and CRP levels remained statistically significant (p<0.0001, Fig 3 and Table 2).

Survival analysis
Of 186 patients diagnosed with TB, 80 had �1 hyponatremia episode within a year of TB diag-
nosis, including 62 patients with mild hyponatremia and 18 with moderate to profound hypo-
natremia; 96 had no hyponatremia within the observation period. Additionally, ten patients
had episodes which did not overlap with the diagnosis.
In patients with moderate to profound hyponatremia, the proportion of patients that sur-
vived was 61.1% [42.3%; 88.3%] after 1 year and 49.4% [30.8%; 79.3%] after 5 years with no
observational follow-up data available for the time point of 10 years. In patients with mild
hyponatremia, the proportion of patients that survived was 88.7% [81.2%; 96.9%] after 1 year,
70.9% [58.2%; 86.2%] after 5 years, and 70.9% [58.2%; 86.2%] after 10 years. Of 106 patients
without related hyponatremia, the proportion of patients that survived was 90.6% [85.2%;
96.3%] after 1 year, 80.2% [71.1%; 90.5%] after 5 years and 70.2% [56.3%; 87.6%] after 10
years.
After adjusting for age and comorbidity, mortality was significantly higher in patients with
moderate or profound hyponatremia compared to patients without hyponatremia (HR [95%
CI]: 3.7 [1.6; 8.6], p = 0.002) (Table 3).
None of the three patients with TB and SIADH died within the observation period. The
death of five patients was directly attributed to TB; of these, all five had hyponatremia, and
none had SIADH.

Discussion
TB prevalence was rare and reflected a non-endemic area in this large cohort from a tertiary
care hospital. Few patients presenting with hyponatremia were subsequently diagnosed with

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PLOS ONE Hyponatremia in tuberculosis: Increased mortality

Table 1. Characteristics of TB in patients grouped by hyponatremia. Patients with TB and hyponatremia had more frequent infectious, pulmonary, malignant and car-
diovascular comorbidities. When we analysed the cardiovascular comorbidities in-depth, neither arterial hypertonia nor coronary heart disease was associated with
increased hyponatremia. TB severity was not associated with hyponatremia. Group comparison is shown with absolute frequencies (n), percentages with 95% CI, and
unadjusted p-values (Chi-squared tests, if not stated otherwise). Note that the interpretation of the p-values is descriptive. TB, tuberculosis. CNS, central nervous system.
COPD, chronic obstructive pulmonary disease. HIV, human immunodeficiency virus infection. ICU, intensive care unit. GCS, Glasgow Coma Scale.
hyponatremia (n = 80) no hyponatremia (n = 106)
TB location n % of total 95% CI n % of total 95% CI p-value
at least pulmonary TB 50 63% [51; 73] 54 51% [41; 61] 0.2
isolated pulmonary TB 31 39% [28; 50] 37 35% [26; 45] 0.7
CNS–TB 3 4% [0.8; 11] 2 2% [0.2; 7] 0.71
TB in any other organ 34 43% [32; 54] 32 30% [22; 40] 0.1
Comorbidity
Cardiovascular comorb. 22 28% [18; 39] 17 16% [10; 24] 0.09
• arterial hypertonia 13 16% [9; 26] 10 9% [5; 17] 0.2
• coronary heart disease 6 8% [3; 16] 8 8% [3; 14] 1
Diabetes mellitus 8 10% [4; 19] 13 12% [7; 20] 0.8
Endocrine 24 30% [20; 41] 24 23% [15; 32] 0.3
Gastrointestinal 10 13% [6; 22] 7 7% [3; 13] 0.3
Immunosuppress. therapy 15 19% [11; 29] 10 9% [5; 17] 0.1
Infectious disease, any� 38 48% [36; 59] 23 22% [14; 31] <0.001
• HIV 13 17% [9; 26] 3 3% [0.6; 8] 0.003
• Hepatitis C 6 8% [3; 16] 2 2% [0.2; 6] 0.081
Neurological 18 23% [14; 33] 12 11% [6; 19] 0.06
Oncological 18 23% [14; 33] 9 8% [4; 16] 0.013
Pulmonary comordbidity 25 31% [21; 43] 18 17% [10; 26] 0.035
• COPD 8 10% [4; 19] 6 6% [2; 12] 0.4
Renal 15 19% [11; 29] 11 10% [5; 18] 0.2
TB severity
Mild (Outpatient) 11 14% 21 20% 0.32
Moderate (Inpatient) 67 84% 82 77%
• Moderate, with neurologic symptoms 15 19% 5 5%
Severe (ICU) 2 3% 3 3%
• Severe, with GCS 3 2 3% 0 0%
�
: including Hepatitis A, B, C, D; HIV, aspergillosis, genital herpes, abscess, pneumocystis, erysipelas, toxoplasmosis, and urinary tract infection.
1
Fisher’s exact test
2
Wilcoxon rank-sum test.

https://doi.org/10.1371/journal.pone.0275827.t001

TB, and the diagnosis was mainly associated with young age and elevated infection parameters.
In the current study, patients with TB and moderate to profound hyponatremia before or at
diagnosis showed a significantly increased mortality rate.
This study of a low-incidence area [19] showed few TB diagnoses in patients with hypona-
tremia (0.07%) or SIADH (0.28%) in contrast to other studies regarding SIADH, where rates
of TB-associated SIADH episodes ranged from 11% of initially idiopathic episodes [5] to 10%
of all SIADH episodes plus further 3% of all idiopathic episodes after a one-year follow-up
[17]. The highest previously reported prevalence reached up to 15 detections of TB in 46 inten-
sive care patients with SIADH [2]. One primary reason for the discrepancy in rate may be the
focus on idiopathic SIADH, which excluded other common causes. Hsu et al. further discussed
that the results were probably due to a high local TB prevalence and a targetted prevention
program with chest x-ray examinations [17, 20]. The small number of patients in the current

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PLOS ONE Hyponatremia in tuberculosis: Increased mortality

Fig 3. Mortality risk in patients with TB. The graph details the mortality rates of patients with TB with moderate to
profound hyponatremia (red), mild hyponatremia (blue), and non-hyponatremic patients (black).
https://doi.org/10.1371/journal.pone.0275827.g003

study ultimately precluded an in-depth assessment of TB-associated SIADH. Conclusively, TB

should be considered in unexplained causes of hyponatremia up to a year after the episode.
In the current study, younger age and higher CRP values conferred a higher likeliness of TB
diagnosis in patients with hyponatremia, whereas other studies corroborated this effect of
infection parameters [2, 21], indicating that signs of infection in this constellation potentially
warrant a thorough screening for tuberculosis [21]. Likewise, our study reaffirmed other stud-
ies explaining that sex was irrelevant regarding TB in patients with hyponatremia [8, 17].

Table 2. Epidemiologic factors associated with TB diagnosis in patients with hyponatremia. Young age and high CRP parameters conferred a higher TB diagnosis
risk in patients with hyponatremia in a multiple logistic regression model for correlated data. TB, tuberculosis. OR, odds ratio. CRP, C-reactive protein. n, number of
patients.
parameter univariate models n multiple model n
OR 95% CI p-value OR 95% CI p-value
sex 0.92 0.50, 1.71 0.8 272309 (107465) - - - 259641 (103972)
age 0.97 0.95, 0.98 <0.0001 272309 (107465) 0.97 0.95, 0.98 <0.0001
CRP 1.05 1.04, 1.07 <0.0001 264054 (105103) 1.05 1.04, 1.07 <0.0001
leucocytes 1.01 1.01, 1.01 0.032 264023 (105019) 1.00 0.97, 1.03 0.9
https://doi.org/10.1371/journal.pone.0275827.t002

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PLOS ONE Hyponatremia in tuberculosis: Increased mortality

Table 3. Increased mortality in patients with TB with moderate to profound hyponatremia. Patients with TB and moderate to profound hyponatremia episodes had a
significantly higher all-cause mortality rate. After correcting for hyponatremia-related comorbidities (Table 1), the effect remains significant. A Cox regression model was
calculated with hyponatremia groups and age as independent variables and reported as hazard ratio (HR) with a 95% confidence interval (95%LL, 95% UL) and p-value
(H0: HR = 1). TB, tuberculosis. LL, lower limit. UL, upper limit. Q1, first quartile. Q3, third quartile.
a. Characterisation of hyponatremia profundity in patients with TB
Hyponatremia severity n min Q1 median Q3 max
Non-hyponatremic (serum sodium �136 mmol/L) 106 136 - - - -
Mild hyponatremia 62 130 132 134 135 135
Moderate hyponatremia 13 125 127 128 129 129
Profound hyponatremia 5 116 119 121 121 124
b. Parameters associated with mortality in TB patients—univariate model
Parameter HR 95% LL 95% UL p-value logrank test
Mild hyponatremia (serum sodium 130–135 mmol/L) vs. non-hyponatremic 1.43 0.71 2.88 0.3 <0.0001
Moderate and profound hyponatremia (serum sodium <130 mmol/L) vs. non-hyponatremic 4.87 2.14 11.06 0.0002
Age (years) 1.06 1.04 1.08 <0.0001
c. Parameters associated with mortality in TB patients—multivariable model
Parameter HR 95% LL 95% UL p-value type 3 test
Mild hyponatremia (serum sodium 130–135 mmol/L) vs. non-hyponatremic 1.15 0.57 2.32 0.7 0.007
Moderate and profound hyponatremia (serum sodium <130 mmol/L) vs. non-hyponatremic 3.7 1.59 8.64 0.002
Age (years) 1.06 1.04 1.08 <0.0001
d. Parameters associated with mortality in TB patients—multivariable model including adjustment for comorbidities
Parameter HR 95% LL 95% UL p-value type 3 test
Mild hyponatremia (serum sodium 130–135 mmol/L) vs. non-hyponatremic 0.95 0.43 2.10 0.9 0.006
Moderate and profound hyponatremia (serum sodium <130 mmol/L) vs. non-hyponatremic 3.68 1.53 8.83 0.004
Age (years) 1.06 1.04 1.08 <0.0001
Any pulmonary comorbidity 1.25 0.63 2.51 0.5
Any infectious comorbidity 1.13 0.54 2.38 0.7
Any oncological comorbidity 1.55 0.73 3.30 0.3
https://doi.org/10.1371/journal.pone.0275827.t003

In terms of patients with TB, almost half of the patients in the current study had prior hypo-
natremia and 2% SIADH, comparable to other studies showing high prevalences of hyponatre-
mia with up to 51%-60% presenting hyponatremia as the first symptom [2, 8]. In another
study, 45% of patients with TB were similarly diagnosed with hyponatremia and 4% with
SIADH [13]. A recent review summarised that hyponatremia was registered in more than half
of TB cases, with older age being a risk factor [7, 8, 22, 23], corroborating the results of our
study. We circumvented the age bias by performing an age-adjusted analysis as hyponatremia
is known to be generally more frequent in older patients [1]. Hyponatremia was reportedly
seen more often in patients who had lowered Glasgow Coma Scale scores and cerebral infarc-
tion [13, 24]. Neurologic comorbidities showed a trend towards more hyponatremia in the
current study; however, neither neurologic TB localisation nor neurologic complications in
our severity analysis yielded an association with hyponatremia, possibly because of a disparity
in patient numbers. The analysis of different TB severity levels and locations in the current
study, including CNS, miliar, and pulmonary TB, did not yield a significant difference in hypo-
natremia. However, the current study is highly underpowered for this analysis. Furthermore,
our study only registered three patients with TB and SIADH. TB involving the CNS reportedly
causes SIADH frequently, followed by pulmonary TB [2], with varied increased prevalences
[3] of SIADH in TB meningitis ranging from 9.6% [4] to 50% [25] in all patients with TB and
39% in children [26], where it was associated with increased intracerebral pressure [26].

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PLOS ONE Hyponatremia in tuberculosis: Increased mortality

Further studies to evaluate morbidity and mortality in such patients are warranted. Clini-
cally, a workup including blood cell count and CRP can direct the search for the cause of hypo-
natremia towards infections and lead to consideration of TB, whilst a higher disease burden
warrants increased diagnostic efforts [21, 27].
Crucially, in the current study, patients with TB and episodes of moderate to profound
hyponatremia prior to treatment had a significantly higher mortality rate than patients without
hyponatremia. Even though TB is reportedly associated with hyponatremia and hyponatremia
with increased mortality, different studies described their connection to the mortality rate dif-
ferently, only some corroborating our results [3, 12, 26–28]. In one study of miliary TB, hypo-
natremia was one of two independent risk factors for requiring mechanical ventilation, with
values above 124 mmol/L predicting a favourable outcome [12]. In children with TB, meningi-
tis increased mortality (52%) vs those without hyponatremia (13%). As the study did not pro-
vide cases with proven TB infection, the statement could be of limited validity [14]. However,
in other studies, only older age was a risk factor for mortality [13, 22], with possible reasons
for the discrepancy including low TB severity in some cohorts, another that hyponatremia was
mild or self-limited [8]. The current study included a large cohort of patients and was inclusive
of all TB localisations [29] and comorbidities [26, 30, 31], and could detect an association
between moderate to profound hyponatremia and increased mortality in patients with TB.
Evaluation of mortality and associated risk factors has become especially relevant in the
advent of multidrug-resistant TB [32] and diversified TB therapy regimens [33]. Regarding
patients with TB and SIADH in our study, only three patients with TB exhibited an episode of
SIADH, and none died. Other studies underscored associations between SIADH and mortal-
ity, firstly in TB meningitis in multiple regression analysis [26], further in children with a mor-
tality rate of 17% in SIADH vs 0% [27], lastly in an adult malnourished patient cohort with
drug abuse and human immunodeficiency virus (HIV) infection with a high mortality rate of
41% [26, 34]. Other studies detected SIADH in 66% of patients with lethal TB meningitis [3]
and showed that SIADH was a risk factor for poor outcomes [4]. Adrenal or pituitary insuffi-
ciency and brain lesions could cause the severe course of TB meningitis in patients with hypo-
natremia [12]. Studies highlighted hyponatremia as a marker for overall disease burden [12,
30], as cardiovascular [31, 35], pulmonary [36], and infectious [26, 34] comorbidities and the
location of TB [26] are pivotal epidemiologic factors determining disease burden. Conclu-
sively, in patients with verified TB diagnosis, patient history for hyponatremia and current
bloodwork should be surveyed to indicate a possible increased mortality risk, and these
patients warrant more controls and care.
Hsu et al. established the timeframe of one year to associate TB with episodes of hyponatre-
mia or SIADH. Half of all retrospectively identified initially idiopathic SIADH episodes were
associated with pulmonary TB [17], defining one year as diagnostically relevant for follow-up
and identification of SIADH cause [17].
The main strength of this analysis was the large cohort obtained at a tertiary care hospital
with over 100.000 patients and the long study timeframe for including patients diagnosed with
M. tuberculosis infection within the hospital. The main limitation of this paper was the bias
brought by clinical decisions in SIADH testing. The usual reasons for applying SIADH tests
were symptomatic or more severe hyponatremia or clinical routine such as in-patient treat-
ment. Overall, the hospital tested 7055 of 107.532 patients with hyponatremia. Clinical volemia
was assessed indirectly through urine sodium value [15]. However, most endpoints focused on
TB-positive patient records, which we thoroughly assessed manually. Hoorn et al. describe
SIADH diagnosis as challenging to achieve in clinical praxis, as other types of hyponatremia,
such as cerebral salt-wasting syndrome, are difficult to differentiate [13, 15, 37]. Whilst urine
sodium value was performed as a surrogate for volume status in this retrospective study,

PLOS ONE | https://doi.org/10.1371/journal.pone.0275827 October 13, 2022 9 / 13

PLOS ONE Hyponatremia in tuberculosis: Increased mortality

similar to other studies [15], clear demarcation of hyponatremia cause and clinical evaluation
of volume status is essential in guiding treatment of TB-associated hyponatremia [13, 14]. Our
study included very few patients with both SIADH and TB; further studies exploring this spe-
cific subset of patients might be of interest. As our study included only three patients with
SIADH and TB, an important limitation is the inability of a more in-depth analysis of this sub-
group. In fact, one of the main shortcomings is a lack of pathophysiological explanation, as TB
has been reported to both cause SIADH by ectopic production as well as pituitary involvement,
and only few studies have analysed the cause of this relevant extrapulmonary effect of TB as
classic respiratory infection [4, 8, 11]. Thus, it is essential for further studies to directly eluci-
date the pathophysiology of TB-associated SIADH.
In-depth analyses of the current study regarding hyponatremia, morbidity and mortality vs
location and severity of TB were possibly underpowered.
Our study did not assess hyponatremia correction protocols, as we expected individual clin-
ical application of guideline-conform correction protocols and did not perform a longitudinal
analysis of hyponatremia.

Conclusion
In this study of a large cohort from a tertiary care hospital in a non-endemic area of TB, 0.07%
[0.06; 0.09%] of patients presenting with hyponatremia and 0.28% [0.06%; 0.80%] with SIADH,
but especially younger patients and patients with high CRP values, were diagnosed with TB.
Crucially, patients with moderate to profound hyponatremia had a significantly higher mortal-
ity rate than non-hyponatremic patients and thus required heightened medical care.

Supporting information
S1 Table. Database of patients with hyponatremia episodes. Sheet 1 includes data points of
patients with hyponatremia in the study. Sheet 2 includes the caption.
(XLSX)
S2 Table. Database of patients with tuberculosis. Sheet 1 includes parameters of all patients
with tuberculosis, including severity, location, comorbidities and date last seen / death, as well
as approximate age, diagnosis date and therapy. Sheet 2 includes the caption.
(XLSX)
S1 Appendix. STROBE checklist. The study reporting was performed according to the Strength-
ening the Reporting of Observational studies in Epidemiology (STROBE) checklist and guidelines.
(PDF)

Acknowledgments
We want to thank DI Ernst Eigenbauer from the IT Systems & Communications of the Medi-
cal University of Vienna for establishing an algorithm to extract data and assisting in data
acquisition.

Author Contributions
Conceptualization: Christina Bal, Daniela Gompelmann, Michael Krebs, Lukasz Antoniewicz,
Claudia Guttmann-Ducke, Antje Lehmann, Christopher Oliver Milacek, Maximilian Rob-
ert Gysan, Peter Wolf, Marco Idzko.
Data curation: Christina Bal, Maaia-Margo Jentus.

PLOS ONE | https://doi.org/10.1371/journal.pone.0275827 October 13, 2022 10 / 13

PLOS ONE Hyponatremia in tuberculosis: Increased mortality

Formal analysis: Irene Steiner.

Investigation: Christina Bal.
Methodology: Christina Bal, Irene Steiner, Marco Idzko.
Project administration: Christina Bal, Daniela Gompelmann, Marco Idzko.
Resources: Marco Idzko.
Supervision: Daniela Gompelmann, Lukasz Antoniewicz, Marco Idzko.
Validation: Christina Bal, Daniela Gompelmann, Michael Krebs, Lukasz Antoniewicz, Clau-
dia Guttmann-Ducke, Antje Lehmann, Christopher Oliver Milacek, Maximilian Robert
Gysan, Peter Wolf, Maaia-Margo Jentus, Irene Steiner, Marco Idzko.
Visualization: Maaia-Margo Jentus.
Writing – original draft: Christina Bal, Daniela Gompelmann.
Writing – review & editing: Christina Bal, Daniela Gompelmann, Michael Krebs, Lukasz
Antoniewicz, Claudia Guttmann-Ducke, Antje Lehmann, Christopher Oliver Milacek,
Maximilian Robert Gysan, Peter Wolf, Maaia-Margo Jentus, Irene Steiner, Marco Idzko.

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