164 AJTCCM VOL. 30 NO. 4 2024

ORIGINAL RESEARCH: ARTICLES

Background. Chitotriosidase is a chitinase enzyme that is expressed selectively through activated macrophages in humans. Increased

activity of chitotriosidase in both bronchoalveolar lavage samples and serum of patients with sarcoidosis has been reported. It has been

proposed that chitotriosidase could be used as a potential biomarker for diagnosis, monitoring and prognosis in sarcoidosis patients.

However, no studies in a South African (SA) cohort have evaluated this potential role.

Objectives. To analyse serum chitotriosidase activity in treated and untreated sarcoidosis patients, healthy controls and patients with

tuberculosis (TB). Sarcoidosis and TB are two diseases of diering aetiology that may be clinically dicult to distinguish between

in the SA setting, which is a high-burden area for TB. We hoped to determine whether chitotriosidase activity levels could help

dierentiate the one disease from the other.

Methods. Serum chitotriosidase activity was measured in an SA cohort of treated and untreated sarcoidosis patients and compared

with controls. In addition, activity in sarcoidosis patients was compared with that in TB patients. Overall, chitotriosidase activity was

assayed in the serum of 12 biopsy-proven sarcoidosis patients before treatment, 9 sarcoidosis patients aer at least a month’s treatment,

10 patients with conrmed pulmonary and/or disseminated TB before treatment, and 12 healthy controls. Plasma chitotriosidase

activity was assayed as previously described using 4-methylumbelliferyl-β-D-N,Nʹ,N″-triacetylchitotriose as a substrate.

Results. Signicantly higher serum chitotriosidase activity was observed in sarcoidosis patients, both untreated and treated, compared

with controls (p<0.05). Sarcoidosis patients had higher chitotriosidase levels than TB patients, but this dierence was not signicant.

While chitotriosidase activity was lower in patients with TB than in those with sarcoidosis, levels were elevated compared with

controls.

Conclusion. Chitotriosidase activity in patients with sarcoidosis was greater than in those with TB, and also greater compared with

controls. e increased chitotriosidase activity in sarcoidosis suggests that this enzyme may be involved in the disease pathogenesis.

Further investigation is required to validate these ndings.

Keywords. Chitotriosidase, sarcoidosis, tuberculosis, biomarker.

Afr J Thoracic Crit Care Med 2024;30(4):e1832. https://doi.org/10.7196/AJTCCM.2024.v30i4.1832

Study synopsis

What the study adds. Serum chitotriosidase activity in South African sarcoidosis and tuberculosis (TB) patients was evaluated. e study

adds to the research assessing the signicance of serum chitotriosidase in patients with sarcoidosis and TB.

Implications of the ndings. Chitotriosidase enzyme activity could potentially serve as a biomarker of possible diagnostic and/or prognostic

value in patients with sarcoidosis.

Chitotriosidase is a chitinase enzyme that is expressed selectively

through activated macrophages and epithelial cells in humans.[1] It

was initially documented as having markedly elevated activity in

patients with Gaucher’s disease. Increased activity of chitotriosidase

in both bronchoalveolar lavage (BAL) samples and serum of

sarcoidosis patients has been reported.[2-4] It has been proposed that

chitotriosidase could be used in patients with sarcoidosis as a potential

biomarker for monitoring as well as a prognostic marker,[1] and that it

may be a therapeutic target.[5]

The objective of the current study was to analyse serum

chitotriosidase activity in a South African (SA) cohort of untreated

sarcoidosis patients compared with a group of sarcoidosis patients

treated for at least 1 month with corticosteroids. In addition, activity

levels were compared between sarcoidosis patients and patients with

Serum chitotriosidase activity in South African patients with

sarcoidosis and tuberculosis

R Morar,1 MB ChB, FCP (SA), MMed (Int Med), PhD ; I Sinclair,2 BSc Hons; C Feldman,3 MB BCh, FCP (SA), PhD

1 Division of Pulmonology, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand and Charlotte Maxeke Johannesburg

Academic Hospital, Johannesburg, South Africa

2 Division of Human Genetics, National Health Laboratory Service, Johannesburg, South Africa

3 Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Corresponding author: R Morar (rajenmorar@webmail.co.za)

AJTCCM VOL. 30 NO. 4 2024 165

ORIGINAL RESEARCH: ARTICLES

tuberculosis (TB) to determine whether levels could dierentiate

between these two granulomatous disorders of diering aetiology

in a high-burden area for TB.

Methods

e results of demographic, clinical, routine laboratory, radiographic

and lung function studies were documented in 12 consecutive

untreated patients with biopsy-proven sarcoidosis and in 9 patients

aer at least 1 month of corticosteroid treatment, as well as in 10

patients with newly diagnosed pulmonary and/or disseminated

TB and 12 healthy controls. The controls were healthy staff

members working in the hospital and laboratory. Sarcoidosis was

diagnosed according to the international criteria of the American

oracic Society/European Respiratory Society/World Association

of Sarcoidosis and other Granulomatous Disorders.[6] TB was

diagnosed based on microscopy, culture, molecular biology and

phenotypic evidence of Mycobacterium tuberculosis (MTB) in

sputum by GeneXpert, or on microscopic examination and culture

of biopsy specimens from extrapulmonary sites such as the bone

marrow and lymph nodes.

For measurement of chitotriosidase levels, blood samples

(5 mL) were obtained by venepuncture and collected into

ethylenediaminetetra-acetic acid-containing tubes. Plasma and

packed cells were separated by centrifugation at 1500 g for 10

minutes and stored at –80º until they were processed. Chitotriosidase

was assayed in the stored plasma samples essentially as described

by Hollak et al.,[7] using 4-methylumbelliferyl-β-D-N,Nʹ,N″-

triacetylchitotriose (Sigma-Aldrich, Germany) as an enzyme

substrate in McIlvain’s phosphate-citrate buer, pH 5.2, for 1 hour

at 37.0º in darkness. e reaction was terminated by adding 2.5

mL of 0.3M glycine/NaOH buer (pH 10.6). e reaction product,

uorescent 4-methylumbelliferone, was measured using a Perkin-

Elmer uorimeter (Perkin-Elmer, USA) at excitation wavelength 365

nm and 450 nm emission.

Statistical analysis

Chitotriosidase activity was expressed in nmol/h/mL. Data were

expressed as medians with interquartile ranges (IQRs). Comparisons

between groups were performed using the Mann-Whitney U-test and

the Kruskal-Wallis test, with signicance set at p<0.05. e Spearman

test was used to look for correlations between variables. Statistical

analysis and graphic representations of data were performed using

Prism 4.0 soware (GraphPad Soware, USA).

Ethical considerations

Written informed consent to participate in the study was obtained

from the patients and the control subjects, and ethical clearance from

the Human Research Ethics Committee (Medical) of the University

of the Witwatersrand (ref. no. M121016).

Results

e clinical, diagnostic, laboratory, radiographic and lung function

parameters in the cohort of patients with sarcoidosis are documented

in Tables 1 - 3, including data for the untreated group (Tables 1

and 2) and the group treated with corticosteroids (Table 3). The

characteristics of patients with active TB are shown in Table 4, and

those of the healthy controls in Table 5.

The 12 patients with sarcoidosis in the untreated group were

consecutive biopsy-proven patients (6 males, 9 black and 3 Indian

patients), with a median (IQR) age of 49 (41 - 53.5) years (minimum

and maximum 30 - 60 years) and a median serum angiotensin-

converting enzyme (sACE) level of 105 (68 - 153.5) U/L (minimum

and maximum 10 - 342 U/L) (Tables 1 and 2). ere were 9 patients

with sarcoidosis who had received treatment with corticosteroids for

least 1 month and up to 3 months (3 males, 6 black and 3 Indian

patients), with a median (IQR) age of 54 (49.5 - 65.5) years (minimum

and maximum 43 - 79 years) and a median sACE level of 67 (30.5 -

98.5) U/L (minimum and maximum 28 - 222 U/L) (Table 3). Of 10

patients with newly diagnosed TB, 4 were males, all were black, 6

were HIV positive, and 3 were on antiretroviral therapy; their median

Table 1. Demographic and clinical characteristics of

untreated patients with sarcoidosis

Characteristic n (%)*

Patients, N (1 smoker) 12

Ethnicity and sex (5 BM, 4 BF, 1 IM, 2 IF)

Female 6 (50.0)

Male 6 (50.0)

Biopsy conrmation 12 (100)

Age at disease onset (years), median (IQR);

min - max

49 (41 - 53.5);

30 - 60

Symptoms (multiple in some patients)

Cough 12 (100)

Weight loss 8 (66.7)

Chest pain 5 (41.7)

Night sweats 3 (25.0)

Nil 3 (25.0)

Dyspnoea 2 (16.7)

Skin rash 1 (8.3)

Eye symptoms 1 (8.3)

Arthralgia 1 (8.3)

Loss of appetite 1 (8.3)

Decreased eort tolerance 1 (8.3)

Blocked nose 1 (8.3)

Signs (multiple in some patients)

Nil 10 (83.3)

Crackles 4 (33.3)

Skin rash 4 (33.3)

Splenomegaly 1 (8.3)

Lymphadenopathy 1 (8.3)

Anterior uveitis 1 (8.3)

BM = black male; BF = black female; IM = Indian male; IF = Indian female;

IQR = interquartile range; min - max = minimum and maximum.

*Except where otherwise indicated.

166 AJTCCM VOL. 30 NO. 4 2024

ORIGINAL RESEARCH: ARTICLES

(IQR) age was 36.5 (25 - 45) years (minimum and maximum 18 - 57

years) (Table 4). e demographic data for the 12 healthy controls

(10 males), median (IQR) age 50 (45.5 - 51.5) years (minimum and

maximum 29 - 55 years), are shown in Table 5.

Table 6 and Fig. 1 show serum chitotriosidase activity in the three

patient groups and in the controls. Serum chitotriosidase activity

was significantly higher in the sarcoidosis patients than in the

controls, both in the untreated (p<0.0009) and the treated (p<0.003)

groups. Untreated sarcoidosis patients had significantly higher

chitotriosidase activity levels than TB patients (p<0.0192). Although

activity was lower in the treated sarcoidosis patients compared with

the untreated patients, this dierence was not signicant. While

activity in patients

with TB was lower than in sarcoidosis patients, it

was signicantly higher than in the controls (p<0.0007).

Discussion

In the present study, serum chitotriosidase activity was evaluated

for the first time in SA sarcoidosis patients as well as in patients

with TB. Chitotriosidase activity was found to be significantly

higher in patients with sarcoidosis, both before (p<0.0009) and after

treatment (p<0.003), compared with controls. Analysis of serum

chitotriosidase activity in our cohort of patients with sarcoidosis

verified the increase described in the literature, compared with

healthy controls. When comparing serum chitotriosidase levels

in TB patients with those in patients with sarcoidosis, two

granulomatous diseases of differing aetiology, higher activity

was found in the sarcoidosis patients, but this difference was not

significant.

Standard serum chitotriosidase activity ranges from 8 to 65

nmol/h/mL.[8,9] In the present study, activity levels were signicantly

higher in serum of sarcoidosis patients compared with healthy controls,

Fig. 1. Serum chitotriosidase activity levels in patients and controls. e

red lines represent median levels, with IQRs. (IQR = interquartile range.)

DĞĚŝĂŶƐĞƌƵŵĐŚŝƚŽƚƌŝŽƐŝĚĂƐĞĂĐƚŝǀŝƚǇŝŶƉĂƚŝĞŶƚƐĂŶĚĐŽŶƚƌŽůƐ

Untreated sarcoidosis patients

Treated sarcoidosis patients

TB patients

Controls

500

1,000

1,500

5000

5200

5400

5600

5800

6000

p < 0.0009

p < 0.0192

p < 0.003

p < 0.0007

WĂƚŝĞŶƚ'ƌŽƵƉƐ

dсdƵďĞƌĐƵůŽƐŝƐ

ŶŵŽůŚƌŵ>

Figure Error! No text of specified style in document..1. Median serum chitotriosidase

activity levels in patients and controls (red line represents median levels with

interquartile range)

6 000

5 800

5 600

5 400

5 200

5 000

1 500

1 000

Chitotriosidase activity (nmol/h/mL), median (IQR)

Controls

Group

500

Untreated

sarcoidosis

patients

Treated

sarcoidosis

patients

Tuberculosis

patients

Table 2. Details of biopsy sites and laboratory, radiographic

and lung function characteristics of untreated patients with

sarcoidosis

Var iable n (%)*

Patients, N12

Biopsy sites (sometimes multiple)

Transbronchial lung 10 (83.3)

Skin 4 (33.3)

Lymph node 3 (25.0)

Supraclavicular 2 (16.7)

Mediastinal 1 (8.3)

Bone marrow trephine 1 (8.3)

Nose mass 1 (8.3)

Open lung 1 (8.3)

sACE (U/L), median (IQR); min - max 105 (68 - 153.5);

10 - 342

Chest radiograph

Stage I 2 (16.7)

Stage II 6 (50.0)

Stage III 2 (16.7)

Stage IV 2 (16.7)

Lung function tests

FVC <80% 6 (50.0)

FEV1 <80% 4 (33.3)

FEV1/FVC <70% 3 (25.0)

Low DLCO 7 (58.3)

sACE = serum angiotensin-converting enzyme; IQR = interquartile range; min - max =

minimum and maximum; FVC = forced vital capacity; FEV1 = forced expiratory volume in 1

second; DLCO = diusion capacity for carbon monoxide.

*Except where otherwise indicated.

AJTCCM VOL. 30 NO. 4 2024 167

ORIGINAL RESEARCH: ARTICLES

as was shown by Bargagli et al.[10] Signicantly raised levels have been

reported in patients with sarcoidosis compared with patients with TB,

asbestosis, idiopathic pulmonary brosis and systemic sclerosis.[10,11]

Bennet et al.[12] showed that chitotriosidase activity correlated with

severity of disease, as indicated by the presence of pulmonary brosis,

multiorgan involvement, and the need for high-dose corticosteroid

therapy. Grosso et al.[9] found that serum chitotriosidase activity

may be a useful marker for monitoring sarcoidosis disease activity

and prognosis. Harlander et al.[13] reported that chitotriosidase activity

correlates with certain sarcoidosis phenotypes such as Löfgren’s

syndrome, and that serial measurements correlate with clinical

symptoms, chest radiographic stage and lung function. While increased

chitotriosidase is not specic for sarcoidosis, it has shown promise to be

a very sensitive biomarker of active sarcoidosis and has more sensitivity

and specicity than other commonly used sarcoidosis biomarkers such

as angiotensin-converting enzyme (ACE) and lysozyme.[14,15]

Approximately 6% of individuals are homozygous for a mutant

allele that renders chitotriosidase unstable and enzymatically inactive,

resulting in low levels of chitotriosidase in the blood.[16] It is important

to bear this in mind, as it may aect chitotriosidase levels in various

diseases.[17,18] In addition, an age-dependent increase in serum

chitotriosidase activity occurs and may aect analysis,[19] especially

with small sample sizes and in the younger HIV cohort with TB in the

present study.

Sarcoidosis and TB are both granulomatous disorders, characterised

by enhanced alveolar macrophage activation, which in both has an

integral role to play in granuloma formation.[20,21] e observation of

substantially higher chitotriosidase activity in patients with sarcoidosis

than in patients with TB and controls, as well as evidence of an increase

of >10 times compared with controls, indicates that this enzyme

may be important in sarcoidosis, and could have a role to play in its

pathogenesis.[22] is test alone is not diagnostic and will be unable

to completely differentiate sarcoidosis from TB; however, normal

chitotriosidase activity is more likely to suggest TB than sarcoidosis

when biopsy reveals granulomatous disease.[3,22]

Table 3. Demographic, radiographic and lung function

characteristics of the treated group of patients with

sarcoidosis, aer at least 1 month on corticosteroids

Characteristic n (%)*

Patients, N (1 ex-smoker, rest non-

smokers)

Ethnicity and sex (1 BM, 5 BF, 2 IM, 1 IF)

Female 6 (66.7)

Male 3 (33.3)

Biopsy conrmation 9 (100)

Age (years), median (IQR); min - max 54 (49.5 - 65.5);

43 - 79

sACE (U/L), median (IQR); min - max 67 (30.5 - 98.5);

28 - 222

Chest radiograph

Stage I 2 (22.2)

Stage II 1 (11.1)

Stage III 3 (33.3)

Stage IV 3 (33.3)

Lung function tests

FVC <80% 1 (11.1)

FEV1 <80% 4 (44.4)

FEV1/FVC <70% 4 (44.4)

Low DLCO <80% 3 (33.3)

BM = black male; BF = black female; IM = Indian male; IF = Indian female; sACE = serum

angiotensin-converting enzyme; IQR = interquartile range; min - max = minimum and

maximum; FVC = forced vital capacity; FEV1 = forced expiratory volume in 1 second;

DLCO = diusion capacity for carbon monoxide.

*Except where otherwise indicated.

Table 4. Characteristics of patients with active tuberculosis

Characteristic n (%)*

Patients, N10

Ethnicity and sex (all black, 6 HIV positive, 3

on ARVs)

Female 6 (60.0)

Male 4 (40.0)

Conrmation (8 sputum and 1 bone marrow

GeneXpert positive)

9 (100)

Age (years), median (IQR); min - max 36.5 (25 - 45);

18 - 51

ARVs = antiretrovirals; IQR = interquartile range; min - max = minimum and maximum.

*Except where otherwise indicated.

Table 6. Serum chitotriosidase activity (nmol/h/mL) of

patients and controls

Group nMedian (IQR) Min - max

Sarcoidosis

(untreated)

12 600.3 (178.5 - 1

030)*, **

0 - 5 772

Sarcoidosis

(treated)

9 199.0 (102.8 - 1

003)***

72.6 - 1 459

Tuberculosis 10 101.7 (83.5 -

167.0)****

57.7 - 418.9

Controls 12 51.3 (46.3 - 53.4) 23.8 - 147.7

IQR = interquartile range; min - max = minimum and maximum.

*p<0.0009 v. controls, **p<0.0192 v. TB patients, ***p<0.003 v. controls, ****p<0.0007 v.

controls.

Table 5. Characteristics of the healthy controls

Characteristic n (%)*

Controls, N (all non-smokers) 12

Ethnicity and sex (4 BM, 2 BF, 6 WM)

Female 2 (16.7)

Male 10 (83.3)

Age (years), median (IQR); min - max 50 (45.5 - 51.5),

29 - 55

BM = black male; BF = black female; WM = white male; IQR = interquartile range;

min - max = minimum and maximum.

*Except where otherwise indicated.

168 AJTCCM VOL. 30 NO. 4 2024

ORIGINAL RESEARCH: ARTICLES

Serum ACE levels are not only increased in patients with sarcoidosis.

The correlation between chitotriosidase and other serological

sarcoidosis markers, for example sACE, found in other studies has

indicated that sACE levels are oen elevated in various granulomatous

pulmonary disorders, including TB, and are two to three times higher

than normal in ~50% of patients.[23-25] e median sACE level in our

patients before treatment was 105 U/L (Table 2), and aer at least 1

month of corticosteroid treatment it was 67 U/L (Table 3). A correlation

between serum chitotriosidase and sACE was not performed in the

present study, as the patient numbers were small and sACE levels were

not measured in the patients with TB or in the controls.

It is not known what mechanisms lead to increased activity of

chitotriosidase in sarcoidosis. is rise is hypothesised to be due

to increased activation of macrophages.[26] Chitotriosidase activity

may be increased in the serum of sarcoidosis patients as a result of

an unidentied antigen, probably containing chitin, that induces

activation of macrophages to produce many mediators, including

chitotriosidase.

ere is proof that macrophage stimulation with tumour necrosis

factor alpha and interferon gamma (IFN-g) results in an increase

in chitotriosidase activity, as well as facilitating the expression of

chitotriosidase genes.[26] In earlier research,[2] enhanced serum and

BAL chitotriosidase activity in stage II - III sarcoidosis patients was

noted, especially in chronic disease, where type 2 helper T-cell (2)

cytokine response predominates, and this is believed to be responsible

for brosis, with reparative or alternatively activated macrophages.[27,28]

Elias et al.[27] likewise revealed that chitinases and chitinase-like

proteins may add to 2-type inammation by a mechanism related

to interleukin (IL)-13. 2 cytokines induce activation of the so-called

alternative activated macrophages involved in pulmonary brotic

processes via the production of bronectin and dierent mediators

(e.g. IL-1 receptors, IL-10, C-C motif chemokine ligand 18, and

perhaps chitotriosidase), as well as induction of broblast collagen

synthesis.[28]

In MTB infection, the immune response is characterised by

macrophage activation, IFN-g and type 1 helper T-cell (Th1)

lymphocyte production.[29] High 2 cytokine and low 1 expression,

for example IL-4, was associated with an inadequate response to TB

treatment.[30] An imbalance in 1/2 responses has been reported

in both sarcoidosis and TB, concomitant with macrophage activation,

although the chitotriosidase activity in the two diseases may rely on

entirely dierent macrophage activation mechanisms or distinctive

cytokine responses.

e present study has several limitations, the major one being the

small sample size. Moreover, the groups were fairly heterogeneous

for ethnicity, age and sex. ere was signicant clinical phenotypic

variation among the sarcoidosis patients. e patients with TB were

mainly HIV positive, and we should have included a comparison

group of HIV-positive patients without TB. ere were few controls,

and a signicant portion of this group were white. In addition, very

high chitotriosidase activity levels, as seen in the present study, are not

typical ofsarcoidosis; however, there was no evidence of Gaucher’s

disease or other associated conditions in these patients.

The results should be interpreted with caution, and should be

validated by further investigations in a multicentre study with

larger patient numbers with specic disease phenotypes. Whether

chitotriosidase could be a sensitive and precise biomarker in

sarcoidosis and TB, and whether it could have other roles in these

diseases, are interesting possibilities, yet at the same time need to be

claried.

Conclusion

is is the rst report of analysis of chitotriosidase activity in the

serum of sarcoidosis and TB patients in SA. Chitotriosidase activity

was higher in sarcoidosis patients compared with TB patients, and

also compared with controls. Although the mechanisms leading to

increased chitotriosidase activity in sarcoidosis are unknown, this

enzyme may be involved in the disease pathogenesis. Investigations

with larger numbers of patients are required to validate these ndings.

It remains to be established whether chitotriosidase can be a biomarker

of diagnosis in sarcoidosis, and whether it has a role in prognosis.

Data availability. e datasets generated and analysed during the present

study are available from the corresponding author (RM) on reasonable

request. Any restrictions or additional information regarding data access

can be discussed with the corresponding author.

Declaration. None.

Acknowledgements. None.

Author contributions. RM contributed to the conception, design and

execution of the study, data acquisition and analysis, and draing of the

manuscript. IS performed the chitotriosidase enzyme assays for the study.

CF contributed to the conception and design of the study, supervised, and

substantially revised and critically reviewed the manuscript.

Funding.None.

Conicts of interest.None.

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Received 8 January 2024. Accepted 17 October 2024. Published 10 December 2024.