Int J Basic Sci Med.

2023;8(1):36-41 Original Article

http://ijbsm.zbmu.ac.ir/ doi 10.34172/ijbsm.2023.06

The Effect of Bromelain Combined With Montelukast

in Hospitalized COVID-19 Patients
ID ID ID
Alireza Jahangirifard1 , Kamal Fani2 , Seyed Bashir Mirtajani1*
1
Lung Transplant Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD),
Shahid Beheshti University of Medical Sciences, Tehran, Iran
2
Anesthesiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

ARTICLE INFO Abstract

Article History: Introduction: The activation of bradykinin B1 receptors on endothelial cells in the lung following
Received: November 28, 2022 inflammation is a major cause of the severity and mortality of COVID-19. It has already been
Accepted: March 25, 2023
Published online: March 29, 2023
shown that bromelain and montelukast as two anti-inflammatory agents can be effective in
controlling this condition.
*Correspondence to Methods: Patients with the novel coronavirus (COVID-19) referred to Masih Daneshvari hospital
Seyed Bashir Mirtajani,
Email: bashirmirtajani67@gmail.
in Tehran were included in the study after providing full explanations and obtaining written
com consent. All 40 patients with moderate symptoms were randomly divided into the placebo
(n = 20) and intervention (n = 20) groups. In the sample group, a dose of 200 mg oral bromelain
was given to patients every 8 hours and one tablet of montelukast 10 mg 1 hour before or after
dinner for 5 days. In the control group, placebo capsules were administered exactly at the above
intervals. The results were evaluated using a t test and SPSS21 software.
Results: After treatment, the sample (bromelain and montelukast) group represented significant
improvements in C-reactive protein (CRP), lactate dehydrogenase (LDH), and lymphocyte count
(P < 0.05), while the other factors did not have significant differences with the control group.
Conclusion: Bromelain and montelukast can improve the condition of hospitalized COVID-19
patients by the positive effect on oxygen saturation, lymphocytes, serum levels of CRP, and LDH.
Keywords: Bromelain, Montelukast, COVID-19, Inflammatory response, Clinical symptoms,
Respiratory parameters, Immunological factors

Please cite this article as follows: Jahangirifard A, Fani K, Mirtajani SB. The effect of bromelain combined with montelukast in
hospitalized COVID-19 patients. Int J Basic Sci Med. 2023;8(1):36-41. doi:10.34172/ijbsm.2023.06.

Introduction The excessive activity of coagulation factors can have

With the prevalence of SARS-CoV 2 infection, known devastating effects through thrombotic disorders.12
as COVID-19, the challenge of treating and providing COVID-19-associated coagulation is characterized by
treatment options for patients has always been a priority increased D-dimer, fibrinogen, systemic thrombotic
for treatment teams.1-3 complications in venous and arterial vessels, and
This infection causes localized pulmonary angioedema, decreased prothrombin time.13 Thus, anticoagulants or
which in turn increases the influx of local immune cells thrombotic therapies provide an opportunity to prevent
and proinflammatory cytokines into the edematous or reduce the “excessive” production of thrombin while
area.4,5 This type of bradykinin-dependent angioedema maintaining homeostasis.
via B1 and B2 receptors is an important feature of SARS- Bromelain obtained from raw pineapple extract is an
CoV-2.6,7 anti-inflammatory that is involved in reducing the serum
The expression of bradykinin B1 and B2 receptors can and tissue levels of quinogen and bradykinin.14,15 Due to
be induced by inflammatory mediators (e.g., interleukin its anti-edematous, anti-inflammatory, and inhibitory
[IL-4], IL-13, tumor necrosis factor-α, IL-6, and IL-8) properties, bromelain has been useful for the treatment of
via intracellular mitogen-activated protein kinase and many diseases such as bronchitis, sinusitis, arthritis, and
nuclear factor kappa B (NF-κB) signaling.8-10 BK expresses inflammation reduction.16 More precisely, these effects are
its therapeutic effects, mainly vasodilation, by activating due to increased serum fibrinolytic activity and inhibition
B2 receptors.11 of fibrinogen synthesis, as well as direct degradation of

© 2023 The Author(s); Published by Zabol University of Medical Sciences. This is an open-access article distributed under the
terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Jahangirifard et al

fibrin and fibrinogen.13 On the other hand, this drug montelukast 10 mg 1 hour before or after dinner for 5 days.
potentially activates the immune system in connection In the placebo group, in addition to the defined standard
with a rapid response to cellular stress.17 Conversely, treatment of Masih Daneshvari hospital for patients
bromelain reduces the secretion of cytokines when with a moderate form of infection caused by SARS-
immune cells are already stimulated by inflammatory CoV2, placebo capsules were administered at the above
conditions caused by cytokine production. intervals. Then, several variables were measured during
Montelukast is a selective cysteinyl leukotrienes the study period, including oxygen saturation (SaO2),
receptor antagonist which blocks leukotriene-D4- body temperature, mean arterial pressure, respiratory
induced bronchoconstriction that is primarily used as rate, heart rate, C-reactive protein (CRP), and erythrocyte
an FDA-approved asthma-controller drug, exercise- sedimentation rate. The other parameters were aspartate
induced bronchoconstriction prophylaxis, and for aminotransferase, alanine aminotransferase, bilirubin
treatment of allergic rhinitis.6 Of note, not only it does (Bil), blood urea nitrogen, creatinine, white blood cells,
have an inhibitory effect on bradykinin-induced airway lymphocyte, lactate dehydrogenase (LDH), and platelet.
hypersensitivity that is the downstream molecule of The results of the questionnaire design and its completion
angiotensin-converting enzyme 2, but also it modulates were analyzed using a t test and SPSS 25 software.
inflammatory cytokines through the inhibition of NF-κB
activation.18 Moreover, the beneficial anti-viral activity of Results
montelukast against Middle-East respiratory syndrome A total of 51 participants responded to the survey between
coronavirus (MERS-CoV) has been reported recently. 20 August and 20 November 2020, of whom 40 (78.43%),
Therefore, considering the common ancestral origin with an average age of 56.3 years cases, who provided
of SARS-CoV-2 and MERS-CoV, the same effect of complete data on variables, were included in the present
montelukast can be expected in SARS-CoV-2.19 analyses. According to the results in Table 1, 23 (57.5%)
Hence, by carefully studying the pathogenesis and of all individuals were men and 17 (42.5%) cases were
clinical signs of patients with SARS-CoV-2, the use of women. Accordingly, 12 (30.0%) patients had a history
bromelain and montelukast may have a synergic effect of hypertension. However, diabetes with 6 (15%) cases,
on the treatment process of these patients. However, hyperlipidemia with 6 (15.0%), and anemia with 4 (10%)
to determine the type of treatment, the amount of were the next most common underlying diseases.
administration, the duration of action of the drug, and The evaluation of patients’ clinical status (Table 2) at
the possible adverse effects, the implementation of a different time intervals between intervention and placebo
clinical process can play an effective role. groups in most indicators demonstrated no significant
difference between the groups. However, the study of
Materials and Methods blood SaO2 percentage on the fifth day in patients in the
The present double-blind clinical trial study was intervention group was significantly higher than patients
approved by the Ethics Committee in the Biomedical in the placebo group (P = 0.049).
Research of Masih Daneshvari Hospital (No. IR.SBMU. The examination of patients’ laboratory conditions
NRITLD.REC.1399.060) and registered in Iranian such as immunological factors, kidney function tests,
Registry of Clinical Trials (https://en.irct.ir/trial/49112 ). liver function evaluation indices, and coagulation factors
Patients with the novel coronavirus (COVID-19) referred at different time intervals in the intervention and placebo
to Masih Daneshvari hospital in Tehran were included groups indicated significant changes between the two
in the study if they met the inclusion and exclusion groups (Table 3).
criteria after providing full explanations and obtaining The number of lymphocytes in the patients who
written consent. The inclusion criteria were definitive received bromelain and montelukast was significantly
COVID-19 infection based on clinical and para-clinical higher after 72 and 120 hours.
tests, 18 years < age < 65 years, and patients admitted to The results represented that the concomitant use of
the ward with moderate symptoms.20 On the other hand, bromelain and montelukast could significantly change
excluded factors included intubated patients, liver and inflammatory parameters in patients. Thus, CRP
kidney enzymes > 2 times the normal limit, drug allergy, significantly decreased compared to the placebo group
opium or alcohol addiction, and recent corticosteroids (after 120 hours P = 0.043, Figure 2). The examination of
consumption. The research physicians were blinded to LDH changes showed that the serum level of this index
the patient group, and the patients were blinded to the in the intervention group was associated with a decrease
injected drug (double-blind). Eventually, 40 patients with in comparison to the placebo group after 120 hours
COVID-19 were included in the study and randomly (P = 0.0351, Figure 2).
divided into intervention and placebo groups (Figure 1).
In the intervention group, 200 mg oral bromelain was Discussion
given to patients every 8 hours, along with one tablet of Montelukast can inhibit the NF-κB signaling pathway

International Journal of Basic Science in Medicine. Volume 8, Issue 1, 2023 37

Jahangirifard et al

Assessed for eligibility (n=51)

Excluded (n=11)
Not meeting the inclusion criteria (n=7)
Declined to participate (n= 2)
Other reasons (n=2)

Randomized (n=40)

Allocated to intervention (n=20) Allocated to control (n=20)

Received allocated intervention (n=20) Received allocated intervention (n=0)
Did not receive allocated intervention (n=0) Did not receive allocated intervention (n=20)

Lost to follow-up (n=0)

Discontinued intervention (n=0)
Lost to follow-up (n=0)

Analyzed (n=20)
Analyzed (n=20)

Figure 1. Consort Diagram

Table 1. Demographic Information and Patient Records montelukast was assumed to inhibit bradykinin-induced
Indexes Mean ± SD No. (%) tracheal smooth muscle contraction in SARS‐CoV‐2.25
Age 56.3 ± 11.36 -
The related known comorbidities of SARS-CoV-2
encompassing obesity and age were also considered
Gender (male) - 23 (57.5)
to be manageable with montelukast in the context of
Diabetes - 6 (15)
COVID-19. Bromelain as a complex natural mixture of
HTN - 12 (30)
cysteine proteinases with the ability to modulate immune
CVA - 1 (2.5) responses.26 It affects the synthesis of prostaglandins by
Kidney disorder - 3 (7.5) reducing the serum levels and tissues of quinogen and
Liver disorder - 1 (2.5) bradykinin and thus manifests its anti-inflammatory
Anemia - 4 (10) effects.27 It has previously been found that specific
Hyperlipidemia - 6 (15.0)
proteolytic removal of CD128 molecules by bromelain
inhibits the migration of neutrophils to IL-8 and thus
Smoker - 2 (5)
reduces acute responses to inflammatory stimuli.26 The
Note. HTN: Hypertension; CVA: Cerebrovascular accident.
results suggest that the suppression of signaling pathways
by bromelain’s proteolytic activity may contribute to the
and decrease the release of pro-inflammatory cytokines,
anti-inflammatory activity of bromelain.28
which is in agreement with the results of Barré et al,
The results of our study, examining the effects of
indicating that expressing the role of montelukast in
bromelain and montelukast on patients with COVID-19,
inhibiting COVID-19 serious outcomes.20-23 Bradykinin
revealed that they could decrease CRP as an important
is a potent vasoactive mediator that is normally degraded
inflammatory indicator compared to the control group
by the ACE. The dysregulated bradykinin signaling is
in one time period (after 120 hours). A similar result
hypothesized to take part in COVID‐19 respiratory
was observed for the LDH index, and it was lower in the
complications.24 Given the previous evidence of cysteinyl
bromelain and montelukast groups on the fifth day after
leukotriene (cysLT) interaction with bradykinin,

38 International Journal of Basic Science in Medicine. Volume 8, Issue 1, 2023

 Jahangirifard et al

Table 2. Evaluation and Comparison of Clinical Factors of Patients in the Table 3. Evaluation and Comparison of Laboratory Indexes of Patients in the
Intervention Group Compared to the Placebo Group Intervention Group Compared to the Placebo Group

Intervention Group Placebo Group P Value Intervention P

Placebo Group
Group Value
Before 91.0 ± 29.3 89.9 ± 5.3 0.758
Before 1809.3 ± 3810.2 2721.6 ± 4434.6 0.316
After 24 hours 92.1 ± 34.5 87.8 ± 31.1 0.052
SaO2 After 24 hours 4472.2 ± 3532.5 4826.8 ± 4506.1 0.167
After 72 hours 95.3 ± 20.5 93.8 ± 39.1 0.058 WBC
( × 1000) After 72 hours 4190.8 ± 3767.9 6128.1 ± 6039.0 0.075
After 120 hours 97.1 ± 43.5 88.2 ± 41.2 0.049

Before 37.7 ± 18.0 37.3 ± 18.1 0.182 After 120 hours 5615.6 ± 3435.6 6620.2 ± 7360.1 0.056

After 24 hours 37.4 ± 15.5 37.2 ± 17.5 0.643 Before 0.9 ± 0.4 0.87 ± 0.51 0.187
Temp
After 72 hours 37.7 ± 18.3 37.4 ± 18.5 0.317 After 24 hours 0.96 ± 0.69 0.88 ± .56 0.074
Lymph
After 120 hours 37.7 ± 11.6 37.0 ± 18.5 0.005 (109/L) After 72 hours 1.09 ± 0.59 0.91 ± 0.62 0.041
Before 76.1 ± 45.9 106.9 ± 52.4 0.108
After 120 hours 1.06 ± 0.62 0.90 ± 0.54 0.042
After 24 hours 109.3 ± 51.2 111.6 ± 52.4 0.058
MAP Before 39.5 ± 22.2 48.0 ± 34.0 0.095
After 72 hours 104.1 ± 25.1 103.5 ± 52.7 0.073
After 24 hours 46.1 ± 27.1 77.3 ± 75.0 0.062
After 120 hours 104.4 ± 22.9 105.1 ± 54.9 0.313 BUN
After 72 hours 47.8 ± 13.6 72.8 ± 66.1 0.017
Before 16.6 ± 8.2 22.2 ± 11.0 0.140
After 120 hours 49.3 ± 14.2 70 ± 54.6 0.093
After 24 hours 18.8 ± 8.6 22.6 ± 11.5 0.460
RR
After 72 hours 18.6 ± 6.8 20.4 ± 11.0 0.767 Before 1.4 ± 0.7 1.2 ± 0.3 0.576

After 120 hours 17.7 ± 6.4 21.1 ± 10.4 0.195 After 24 hours 1.4 ± 0.8 1.6 ± 1.1 0.146
Cr
Before 87.1 ± 35.8 88.1 ± 24.0 0.432 After 72 hours 1.5 ± 0.6 1.4 ± 1.0 0.091
After 24 hours 81.3 ± 37.8 83.5 ± 32.5 0.513 After 120 hours 1.4 ± 0.77 1.2 ± 0.7 0.073
HR
After 72 hours 82.5 ± 42.6 87.5 ± 37.1 0.106
Before 37.8 ± 17.1 64.0 ± 29.7 0.192
After 120 hours 82.2 ± 38.4 83.0 ± 31.4 0.218
After 24 hours 32.9 ± 17.0 98.6 ± 70.9 0.106
Note. SaO2: Oxygen saturation; Temp: Temperature; MAP: Mean arterial ALT
pressure; RR: Respiratory rate; HR: Heart rate. After 72 hours 60.2 ± 19.5 89.1 ± 71.1 0.068

After 120 hours 63.171 ± 18.2451 82.2451 ± 60.124 0.071

the initiation of the drug. Before 39.0 ± 16.8 67.4 ± 37.7 0.272
Based on their immune-modulatory characteristics,
After 24 hours 27.0 ± 13.1 90.1 ± 42.6 0.098
bromelain and montelukast can modify immunological AST
responses in patients such as those with COVID-19 After 72 hours 58.2 ± 18.5 59.7 ± 34.4 0.324

who present with the manifestations of lymphocytosis After 120 hours 59.1 ± 18.1 60.5 ± 35.2 0.098
and leukopenia.29 According to the results obtained in Before 0.736 ± 0.346 0.771 ± 0.458 0.069
our study, this effect of bromelain and montelukast was
After 24 hours 0.64 ± 0.29 0.96 ± 0.55 0.027
observed so that patients in the sample group had higher Bili
lymphocytes, thus we are in a better situation in this view After 72 hours 0.725 ± 0.319 0.8 ± 0.458 0.138

between 72 and 120 hours after drug consumption. We After 120 hours 0.9 ± 0.500 0.641 ± 0.361 0.374
have previously shown that the use of bromelain can Before 160057 ± 497789 80752 ± 138242 0.313
reduce inflammation in patients with COVID-19.30
After 24 hours 95391 ± 84909 114235 ± 2276813 0.144
It has previously been shown that the use of bromelain Plt
in animal models reduces airway reactivity, thereby After 72 hours 82284 ± 83489 124862 ± 144469 0.088

improving the state of saturated oxygen (SaO2) in After 120 hours 125075 ± 66425 119437 ± 150733 0.058
the sample population.23 These effects are due to Note. WBC: Withe blood cells; BUN: Blood urea nitrogen; Cr: Creatinine;
reduced sensitivity to stimuli, pneumonia markers, and ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Bili:
Bilirubin; Plt: Platelet.
modulation of local airway safety aspects.24,25 However,
the results of other studies confirmed the positive effect
of montelukast on the respiratory condition of patients Our study had limitations such as a small sample
with asthma and could reduce cough in patients with size, lack of extensive measurement of immunological
pneumonia.31-33 Accordingly, in our results, the intake of factors (e.g., interleukins and cytokines), and lack
bromelain and montelukast caused a significant increase of measurement of further coagulation factors (e.g.,
in SaO2 levels compared to the control group in patients prothrombin time and partial thromboplastin time).
with COVID-19 on the fifth day of treatment. The Meanwhile, due to the severity of the new coronavirus
findings of a previous study demonstrated the positive outbreak, it was difficult to increase the sample size
effect of bromelain use on increasing SaO2.30 in the initial study. On the other hand, due to various

International Journal of Basic Science in Medicine. Volume 8, Issue 1, 2023 39

Jahangirifard et al

LDH CRP
2500 60

50
2000

40
U/L 1500

U/L
30
1000
20

500
10

0 0
Before 24 h 72 h 120 h Before 24 h 72 h 120 h

Intervention Placebo Intervention Placebo

Figure 2. Comparison of the Course of Changes in Inflammatory Factors in Patients in the Intervention Groups Compared to Placebo Group Patients at
Different Times. Note. CRP: C-reactive protein; LDH: Lactate dehydrogenase

limitations, it was impossible to measure immunological taaa037

and coagulation tests extensively. 3. Marjani M, Tabarsi P, Moniri A, et al. NRITLD protocol for
the management of patients with COVID-19 admitted to
hospitals. Tanaffos. 2020;19(2):91-99 .
Conclusion 4. Manolis AS, Manolis TA, Manolis AA, Melita H. The controversy
The results of the present study demonstrated that the use of renin-angiotensin-system blocker facilitation versus
of bromelain and montelukast can improve the clinical countering COVID-19 infection. J Cardiovasc Pharmacol.
and para-clinical condition of hospitalized COVID-19 2020;76(4):397-406. doi:10.1097/fjc.0000000000000894
5. Polycarpou A, Howard M, Farrar CA, et al. Rationale for
patients with moderate symptoms by the positive effect
targeting complement in COVID-19. EMBO Mol Med.
on lymphocytes, serum levels of CRP, LDH, and SaO2. 2020;12(8):e12642. doi:10.15252/emmm.202012642
6. Sharifzadeh K, Farzanegan B, Mirtajani SB, Peyravian F,
Acknowledgments Jahangirifard A. The potential role of bromelain in the
The authors express their sincere thanks to the staff of Masih treatment of SARS-COV-2. J Cell Mol Anesth. 2020;5(4):284-
Daneshvari hospital, Tehran, Iran for their assistance. 285. doi:10.22037/jcma.v5i4.32113
7. Pascarella G, Strumia A, Piliego C, et al. COVID-19 diagnosis
Authors’ Contribution and management: a comprehensive review. J Intern Med.
Conceptualization: Alireza Jahangirifard. 2020;288(2):192-206. doi:10.1111/joim.13091
Data curation: Seyed Bashir Mirtajani. 8. Ricciardolo FLM, Folkerts G, Folino A, Mognetti B.
Formal analysis: Seyed Bashir Mirtajani. Bradykinin in asthma: modulation of airway inflammation
Funding acquisition: Alireza Jahangirifard. and remodelling. Eur J Pharmacol. 2018;827:181-188.
Investigation: Kamal Fani. doi:10.1016/j.ejphar.2018.03.017
Methodology: Alireza Jahangirifard. 9. Dutra RC, Bento AF, Leite DF, et al. The role of kinin B1 and
Project administration: Alireza Jahangirifard. B2 receptors in the persistent pain induced by experimental
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Software: Seyed Bashir Mirtajani. the involvement of astrocytes. Neurobiol Dis. 2013;54:82-93.
Supervision: Kamal Fani. doi:10.1016/j.nbd.2013.02.007
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