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RESEARCH ARTICLE
Effect of nanocurcumin supplementation on the severity of
symptoms and length of hospital stay in patients with COVID-
19: A randomized double-blind placebo-controlled trial
Elaheh Honarkar Shafie
1
| Fateme Taheri
1
| Neda Alijani
2
|
Ahmad Reza Okhovvat
3
| Razieh Goudarzi
1
| Nasrin Borumandnia
4
|
Leila Aghaghazvini
5
| Seyed Mahdi Rezayat
6
| Saeidreza Jamalimoghadamsiahkali
7
|
Mohammad Javad Hosseinzadeh-Attar
1
1
Department of Clinical Nutrition, School of
Nutritional Sciences and Dietetics, Tehran
University of Medical Sciences, Tehran, Iran
2
Department of Infectious Disease, Shariati
Hospital, Tehran university of medical
sciences, Tehran, Iran
3
Central Herbarium, Tehran University,
Tehran, Iran
4
Urology and Nephrology Research Center,
Shahid Beheshti University of Medical
Sciences, Tehran, Iran
5
Department of Radiology, Shariati hospital,
Tehran University of Medical Sciences,
Tehran, Iran
6
Department of Pharmacology, School of
Medicine, Tehran University of Medical
Sciences, Tehran, Iran
7
Ziaeian Hospital, Tehran University of
Medical Sciences, Tehran, Iran
Correspondence
Mohammad Javad Hosseinzadeh-Attar,
Department of Clinical Nutrition, School of
Nutritional Sciences and Dietetics, Tehran
University of Medical Sciences, Hodjat Doost
Alley, Naderi St., Keshavarz Blvd, Tehran, Iran.
Email: mhosseinzadeh@tums.ac.ir
Funding information
Tehran University of Medical Sciences and
Health Services, Grant/Award Number: 47473
Abstract
It has been more than a year since the outbreak of COVID-19, and it is still the most
critical issue of the healthcare system. Discovering effective strategies to treat
infected patients is necessary to decrease the mortality rate. This study aimed to
determine the effects of nanocurcumin on the severity of symptoms and length of
hospital stay (LOS) in COVID-19 patients. Forty-eight COVID-19 patients were ran-
domly assigned into nanocurcumin (n=24) and placebo (n=24) groups receiving
160 mg/day nanocurcumin or placebo capsules for 6 days. Mean differences of O
2
saturation were significantly higher in patients who received nanocurcumin supple-
ments (p=0.02). Also, nanocurcumin treatment significantly reduced the scores of
domains 3 and 4 and the total score of Wisconsin Upper Respiratory System Survey
(WURSS-24), indicating milder symptoms in the treatment group (p=0.01, 0.03, and
0.01 respectively). Besides, the LOS in curcumin groups was lower than in the pla-
cebo group, although the difference was not statistically significant (6.31 ± 5.26
vs. 8.87 ± 8.12 days; p=0.416). CBC/differentiate, hs-CRP level and the pulmonary
involvement in CT scan were not different between the two groups. As
nanocurcumin can be effective in increasing O
2
saturation and reducing the severity
of symptoms in COVID-19 patients, it could probably be used as a complementary
agent to accelerate the recovery of patients.
KEYWORDS
COVID-19, CT scan, hs-CRP, nanocurcumin
1|INTRODUCTION
The novel disease generated by Coronavirus (COVID-19) is rapidly
increasing worldwide. Since affecting about 190 countries, the disease
was declared a pandemic by the World Health Organization (WHO)
several months ago (Mahase, 2020). The severe acute respiratory syn-
drome coronavirus 2 (SARS-CoV-2) can infect human cells, especially
lung cells. Furthermore, this virus can affect the kidney, heart, brain,
stomach, oral, and nasal mucosa (Palmeira, Barbuto, Silva, & Carneiro-
Sampaio, 2020). There is a significantly high risk for the development
of severe infection in patients with noncommunicable diseases. The
comorbidities most associated with severe COVID-19 are hyperten-
sion, diabetes, and respiratory diseases (Gold et al., 2020). When
Coronavirus infects a cell, pro-inflammatory cytokine secretion
Received: 22 April 2021 Revised: 2 November 2021 Accepted: 27 December 2021
DOI: 10.1002/ptr.7374
Phytotherapy Research. 2022;36:1013–1022. wileyonlinelibrary.com/journal/ptr © 2022 John Wiley & Sons Ltd. 1013
increases, leading to immune activation (Conti et al., 2020). Excessive
immune activation as a result of systemic hyper-inflammation caused
by SARS-CoV-2 can contribute to cytokine storm. Cytokine storm, the
auto-amplifying cascade of cytokine production because of the
impaired immune response, can result in multiple-organ dysfunction
and has been recognized as the leading cause of severe COVID-19
(Ye, Wang, & Mao, 2020). SARS-CoV-2 is more dangerous in people
with noncommunicable diseases like obesity and diabetes due to
chronic low-level inflammation in these people, which may accelerate
and exacerbate the disease process (Festa et al., 2000).
Inflammation plays a fundamental role in the pathogenesis and
severity of COVID-19 pneumonia, although the mechanism of
COVID-19 is not well understood. Therefore, reducing inflammation
can probably help manage the disease's symptoms. C-reactive protein
(CRP) is one of the most reliable biomarkers routinely used to evaluate
systemic inflammation in different pathophysiologic states (Chen
et al., 2020).
Turmeric as a spice has received much concern from both the culi-
nary and the medical/scientific aspects. The medicinal properties of
turmeric as the source of curcumin have been realized for thousands
of years; however, only recently, the exact mechanisms of action and
its bioactive components have been investigated (Gupta, Patchva, &
Aggarwal, 2013). Curcumin (1,7-bis[4-hydroxy-3-methoxyphenyl]-
1,6-heptadiene-3,5-dione), also called diferuloylmethane, is the major
natural polyphenol found in the rhizome of Curcuma longa (turmeric).
It has been traditionally used in Asian countries as a medical herb due
to its antioxidant, antiinflammatory, antimutagenic, antimicrobial, and
anticancer characteristics (Hewlings & Kalman, 2017). These multiple
health benefits of curcumin have been demonstrated to occur through
modulation of multiple signaling molecules in addition to showing
activity at the cellular level (Sahebkar, 2014).
Considering curcumin as a complementary therapy for COVID-19
can be generally regarded from two aspects: First, curcumin as an
immunomodulatory agent can avert tissue damage and inflammatory
disease (Aggarwal & Harikumar, 2009). Second, it also was effective
against many viruses such as influenza A virus, HIV, enterovirus
71 (EV71), herpes simplex virus (HSV), hepatitis C virus (HCV), and
human papillomavirus (HPV) and SARS-CoV (Zorofchian
Moghadamtousi et al., 2014). Furthermore, molecular docking analyses
have shown curcumin's capability to prevent SARS-CoV-2 main prote-
ase (Khaerunnisa, Kurniawan, Awaluddin, Suhartati, & Soetjipto, 2020).
Despite previous studies reporting curcumin's beneficial effects
via inflammatory and antioxidant mechanisms (Hewlings &
Kalman, 2017; Sahebkar, 2014), one of the most crucial problems with
ingesting curcumin is its poor bioavailability, which appears to be prin-
cipally due to poor absorption, rapid metabolism, and elimination
(Anand, Kunnumakkara, Newman, & Aggarwal, 2007). Different strat-
egies are adopted to conquer these critical pharmaceutical problems
of curcumin to boost its bioavailability, including using analogs of cur-
cumin and formulations such as adjuvants, nano-particles, liposomes,
nano-micelles, and phospholipid complexes (Stohs et al., 2020). A
recent research project revealed that the encapsulation of curcumin
into a specific nanocarrier could augment its therapeutic efficacy
(Moballegh Nasery et al., 2020). This study aimed to assess the effect
of nano-micellar form of curcumin supplementation on the severity of
symptoms and length of hospital stay (LOS) in patients with
COVID-19.
2|METHODS
2.1 |Study population
We conducted a randomized, double-blind, placebo-controlled trial in
48 COVID-19 patients referred to Shariati and Ziaeian Hospitals.
Informed consent was obtained from all patients before participation.
The study was approved by the Research Ethics Committee of
Tehran University of Medical Sciences (IR.TUMS.VCR.REC.1399.287)
and registered at the Iranian Registry of Clinical Trials
(IRCT20131125015536N13).
Patients aged 30 to 65 with confirmation of COVID-19 (having a
positive PCR test or involved lung CT-scan) who do not require ICU
admission entered the study. Patients with a history of chemotherapy,
coronary artery bypass graft surgery (CABG), malignancies, liver fail-
ure, HIV, organ transplants, dialysis, heart attack and stroke in the past
3 months, respiratory diseases, anemia, known food allergies, uncon-
trolled diabetes (A
1
c > 7.5), people with BMI over 40 and pregnant
and lactating women did not include in the study. Patients were
excluded if the following events occurred: heart rate (HR) > 125
beats/minute, respiratory rate (RR) > 24 breaths/minute,
SpO2 < 90%, D-dimer>1,000 ng/mL, creatinine phosphokinase (CPK)
> twice more than the normal values, CRP > 100, lactate dehydroge-
nase (LDH) > 245 U/I, and ferritin>300 μg/L. Patients who needed
ICU admission, those who lost their consciousness or became hemo-
dynamically unstable, and those with hypercapnia, increased troponin,
or advanced lymphopenia were also excluded from the study.
2.2 |Study design
The eligible patients were randomly assigned to two groups of
nanocurcumin and placebo by permuted block randomization method
with equal block sizes of 4 to certify the balance between the groups.
To blind the participants and the researcher (responsible for entering
participants in the study and assessing the outcomes), the supple-
ments and placebos were prepared in the same shape, size, color,
smell, taste, and packaging. In addition, the packages were identified
with a three-digit number in no particular order to conceal the inter-
vention allocation sequence.
Along with routine medications, the treatment group received
160 mg of nano-curcumin (4 capsules of 40 mg) daily for 6 days, and
the control group received the placebo capsule. In this study, we used
Sina Curcumin, the registered oral nanocurcumin capsule of
curcuminoids in Iran, industrialized in Nanotechnology Research Cen-
ter of Mashhad University of Medical Sciences, and marketed by Exir
Nano Sina Company.
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To assess the patients' compliance and the side effects of the
supplements, we asked the related questions from the participants
during the daily visit. If they had been discharged from the hospital,
we contacted them to ask the relevant questions. In addition, we
asked them to bring the empty drug packages back at the end of the
study.
2.3 |Measurements
2.3.1 | Biochemical measurements
At baseline and after 6 days of intervention, 8 mL of fasting blood
samples were collected in EDTA tubes for CBC/differentiate and hs-
CRP measurements. Enzyme-linked immunosorbent assay (ELISA) kit
of Pars Azmoon (Iran) was used to evaluate hs-CRP levels in the
serum according to the manufacturer's protocol.
2.3.2 | Vital signs and O
2
saturation
Body temperature, HR, RR, systolic and diastolic blood pressure (SBP
and DBP), and O
2
saturation were measured daily.
2.3.3 | Pulmonary CT scan
The CT scan of the respiratory system was done at the baseline and
end of the study. All chest scans were non-enhanced and were
implemented during inspiratory breath-hold at the supine position
according to the categorized protocol (Shiri et al., 2021), using a
16-detector-row CT scanner (Brilliance 16, Philips Medical Systems,
Best, the Netherlands). An expert radiologist performed the image
analysis and grading. The final scores and grading were assigned by
agreement. We used a semi-quantitative scoring system to estimate
the pulmonary involvement of all certain abnormalities based on the
area involved. Each of the 6 lung zones (right and left upper, middle
and lower) was visually separately scored from 0 to 5 as: 0: no
involvement; 1: <25% involvement; 2:26–49% involvement; 3:50–
75% involvement; 4: >75% involvement. The total CT score was the
sum of the individual zonal scores with a maximum possible score of
24 when all the six zones showed more than 75% involvement (Zhou,
Wang, Zhu, & Xia, 2020).
2.3.4 | Questionnaires
Twenty-four-item Wisconsin Upper Respiratory System Survey
(WURSS-24), which is a valid instrument (Barrett et al., 2005) to eval-
uate the illness-specific quality of life and the negative impact of
acute Upper Respiratory Tract Infection symptoms (URTIs), has been
used for assessment in COVID-19 patients (Bahrs et al., 2021). This
questionnaire contains 24 items, each based on 7-point Likert-type
severity scales. It constitutes the same items as an earlier version
(WURSS-21) plus items for headache, body ache, and fever (Barrett
et al., 2005). WURSS-24 contains four domains: Global Cold Severity,
Cold Symptoms, Cold-Specific Functional Impairments, and Change in
Global Cold Severity. The total score was determined by summing
domains 1–4; the maximum score was 168 points, and high scores
indicate poor quality of life. To evaluate the lower respiratory tract
infection symptoms, four symptoms, including sputum, chest pain,
shortness of breath, and wheeze, were selected based on previous
studies (Holmes, Macfarlane, Macfarlane, & Hubbard, 2001). All
patients were asked whether or not they experienced these symp-
toms during the study period.
2.3.5 | Sample size calculation
Before initiation of the study, according to the relevant formula and
considering the type I error of 5%, the test power of 80%, attrition of
10%, and effect size of 0.85 based on the previous studies, the sample
size was calculated as 24 per group and totally, 48 subjects entered
the study.
2.3.6 | Statistical analysis
Statistical analyses were performed using the SPSS software (version
21.0; SPSS Inc). The quantitative variables are all expressed as mean
± standard deviation (SD), and qualitative variables were described
using frequency and percent. Quantitative variables were compared
between the nanocurcumin and placebo groups by independent t-test
or Mann–Whitney test. Qualitative variables were compared between
the groups by chi-square test and, if necessary, with Fisher exact
tests. Repeated measures analysis of variance was used to assess the
variables that were measured daily during the study. pvalues <0.05
were considered statistically significant. GLM model with GEE
approach was furtherly used to assess the effect of groups on
repeated measures data. We chose Per Protocol analysis for two rea-
sons: the two groups had identical baseline variables that show ran-
domization has appropriately occurred. Also, we performed GEE
analysis which is strong against data missing.
3|RESULTS
The flowchart of the study participants is illustrated in Figure 1. From
48 subjects who were recruited in this trial, 44 individuals completed
the study. Two patients reported mild stomach pain following
nanocurcumin intake but continued the medication. Demographic
characteristics of the patients are summarized in Table 1. Participants
in both groups were similar in confounding variables at the study
beginning (Table 1).
Among the variables measured daily, O
2
saturation was signifi-
cantly different in nanocurcumin group compared to the placebo
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group during the trial (Table 2, p=0.02). To calculate the amount of
nanocurcumin supplementation on O
2
saturation, a more advanced
statistical analysis was performed. The results showed that O
2
satura-
tion in the nano-curcumin group was on average 2.62 units higher
than the placebo group during the study period. Other daily variables,
including HR, RR, SBP, DBP, and body temperature, were not stati-
cally different over time (data not reported).
The severity of COVID-19 symptoms in the patients was
assessed using the WURSS-24 questionnaire, and the results showed
a statistically significant difference between the studied groups.
Although both groups indicated a decreasing pattern during the inter-
vention, patients in nanocurcumin group reported remarkably lower
scores for domains 3 and 4 and the questionnaire's total score over
time (pvalue =0.01, 0.03, and 0.01 respectively; Figure 2). Among
lower respiratory tract infection symptoms, only dyspnea was margin-
ally significant between the studied groups (pvalue =0.059). How-
ever, it decreased over time in both groups (Table 3).
Although there was no significant difference in the number of
hospitalized days between the two groups, a reduction was observed
in the group who consumed nanocurcumin compared to the placebo
group (6.31 ± 5.26 vs. 8.87 ± 8.12 days; p=0.416).
As shown in Table 4, no statistically significant difference in hs-
CRP nor CBC/differentiates parameters were observed between the
two groups after the supplementation. The total score of pulmonary
involvement (CT scan score) was not significantly different between
the nanocurcumin and placebo groups (13.52 ± 4.8 vs. 14.88 ± 5.44;
p-value =0.41; Table 4).
4|DISCUSSION
The present clinical trial aimed to examine the effects of 160 mg/d of
nanocurcumin supplementation for 6 days in patients with COVID-
19. O2 saturation was significantly higher, and the score of the
FIGURE 1 Flow diagram of the study patients
TABLE 1 Baseline characteristics of
participants in both study groups
Baseline variables
Group
p-value
a
Placebo Nanocurcumin
Sex Male 14 (58.3) 15 (57.7) 0.96
Female 10 (41.7) 11 (42.3)
Smoking (n, %) Yes 1 (4.3) 1 (3.8) 0.7
No 20 (87.0) 20 (76.9)
Quit 2 (8.7) 5 (19.2)
Age mean (SD) 57.79 (11.45) 57.46 (11.61) 0.92
BMI mean (SD) 28.29 (3.52) 28.00 (4.73) 0.81
Abbreviation: BMI, body mass index.
a
p-values are for comparison of the variables between the two groups (all by χ2 test, except for age and
BMI which were analyzed by independent ttest).
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WURSS-24 questionnaire was considerably lower in the
nanocurcumin group. There were no marked differences in body
temperature, HR, RR, SBP, and DBP between the two groups. Also,
CBC/differentiate, hs-CRP, and CT-scan scores were not different
between the two groups.
Early evidence had demonstrated that hs-CRP as a pro-
inflammatory cytokine is dramatically increased in serum of COVID-
19 patients (Chen et al., 2020). The plasma half-life of CRP is
approximately 19 h and is fixed under all health and disease condi-
tions so that the sole determinant of circulating CRP concentration
is its synthesis rate. Thus, circulating CRP reflects directly the inten-
sity of the pathological process that stimulates CRP production
(Pepys & Hirschfield, 2003). The results of previous studies about
the effect of curcumin on CRP are inconsistent. Some studies
reported that curcumin supplementation could decrease CRP levels
in patients with different diseases (Adibian et al., 2019; Panahi
et al., 2015), while others did not find this effect (Kocher, Bohnert,
Schiborr, & Frank, 2016; Saadati et al., 2019). We also observed no
significant difference in hs-CRP between groups and the values of
hs-CRP after the treatment became normal in both groups. Since
CRP level and its changes during the disease are different in
COVID-19 patients, it may be better to measure its level daily so
that the effect of curcumin on CRP changes can be assessed in more
detail.
Our findings regarding the LOS indicated that patients in the
nanocurcumin group stayed 2 days lower than the placebo group in
the hospital. Although this difference was not statistically significant,
even a small decrease in LOS in the clinical condition is worthy. The
results of a study that estimated the effect of a half-day reduction in
LOS among pneumonic patients in the US indicated a substantial
cost reduction (savings of $500–$900 million annually) (Raut
et al., 2009). In addition to cost–benefit, lower LOS decreases the
healthcare load and provides more healthcare resources for newly
admitted patients.
The analysis of WURSS-24 revealed that the separate score
of domains 3 and 4 of this questionnaire (score for cold specific
functional impairment and change in global cold severity, respec-
tively) and the total score significantly decreased in patients who
consumed nanocurcumin supplements. Previous studies have rev-
ealed the potential efficacy of herbal extracts rich in polyphenols
such as a combination of ginger and goldenrod extracts and vari-
ous species of basil in alleviating symptoms of similar diseases like
common cold measured by WURSS, which is in line with our
results (Guay, Champagne, Guibord, & Gruenwald, 2012; Shelke
et al., 2016).
The radiological findings of our study did not show any signifi-
cant differences in the score of pulmonary involvement by SARS-
CoV-2 between the nanocurcumin and placebo groups. CT findings
obtained from COVID-19 patients have shown that at the early
stages of the disease (0–4 days), mainly the lower zones of the lungs
are involved with ground-glass opacity and its subtypes. Then, the
pulmonary involvement develops and peaks on days 10–13, and
after 14 days absorption phase occurs (Salehi, Abedi, Balakrishnan, &
TABLE 2 Change of O
2
saturation percentage in both groups during the study
Time Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Group effect Time effect
Group Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Beta (95% CI) p-value Beta (95% CI) p-value
Placebo 91.67 (4.51) 92.45 (4.63) 90.24 (4.19) 91.67 (2.74) 91.88 (3.98) 92.33 (4.72) 2.62 (0.38,4.8)
a
0.02 0.22 (0.3,0.74)
a
0.41
Nanocurcumin 93.69 (3.99) 93.58 (3.49) 93 (4.24) 93.11 (4.08) 91.57 (5.00) 90.67 (8.07)
a
Calculated by GLM model (GEE approach).
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Gholamrezanezhad, 2020). Feng Pan et al. (Pan et al., 2020) also
reported that most patients who recovered from COVID-19 pneumo-
nia showed the greatest severity of lung disease in CT approximately
10 days after the initial onset of symptoms and gradual resolution
after ≥14 days. In the present study, patients entered the study and
received nanocurcumin supplements after admission to the hospital,
and the onset of their symptoms may have varied. Besides, the dura-
tion of the study was not probably enough to detect changes in CT
scan scores of the patients, and probably longer follow-up time was
needed to assess CT changes.
Hypoxia is a notable cause of morbidity and mortality in COVID-
19. Also, delays in identifying and correcting hypoxia in pneumonia
will increase disease severity and mechanical ventilation rate (Xie
et al., 2020). As our result demonstrated that the nanocurcumin group
had higher O
2
saturation than the placebo group during the trial,
nanocurcumin supplementation could help decrease hypoxia in
patients with COVID-19.
Hemoglobinopathy and iron metabolism disorders may seriously
impair the capacity of red blood cells for oxygen transportation
through hypoxia. The possible contribution of blood disorders in
FIGURE 2 Daily median WURRS-24 scores and 95% CIs per study groups. (a) First Domain of WURSS-24 scores (b) Second Domain of
WURSS-24 scores (c) Third Domain of WURSS-24 scores (d) Fourth Domain of WURSS-24 scores (e) Total score of WURSS-24
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TABLE 3 Daily change of lower respiratory system infection symptoms in both groups during the study
Time Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Group effect Time effect
Group Symptoms No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) Odds ratio (95% CI) p-value
a
Odds ratio (95% CI) p-value
a
Placebo Without sputum 18 (66.7) 18 (66.7) 18 (69.2) 22 (91.7) 21 (95.5) 22 (100) 3.14 (0.77–12.84) 0.110 1.32 (1.11–1.58) 0.002
With sputum 9 (33.3) 9 (33.3) 8 (30.8) 2 (8.3) 1 (4.5) 0 (0)
Nanocurcumin Without sputum 25 (80.6) 25 (80.6) 27 (87.1) 27 (87.1) 26 (89.7) 26 (89.7)
With sputum 6 (19.4) 6 (19.4) 4 (12.9) 4 (12.9) 3 (10.3) 3 (10.3)
Placebo Without chest pain 15 (55.6) 15 (55.6) 16 (61.5) 17 (70.8) 17 (77.3) 17 (77.3) 2.37 (0.87–6.45) 0.09 1.28 (1.07–1.54) 0.007
With chest pain 12 (44.4) 12 (44.4) 10 (38.5) 7 (29.2) 5 (22.7) 5 (22.7)
Nanocurcumin Without chest pain 20 (64.5) 25 (80.6) 26 (83.9) 28 (90.3) 25 (86.2) 25 (86.2)
With chest pain 11 (35.5) 6 (19.4) 5 (16.1) 3 (9.7) 4 (13.8) 4 (13.8)
Placebo Without dyspnea 11 (40.7) 16 (59.3) 11 (42.3) 14 (58.3) 13 (59.1) 14 (63.6) 2.33 (0.97–5.59) 0.058 1.23 (1.06–1.42) 0.005
With dyspnea 16 (59.3) 11 (40.7) 15 (57.7) 10 (41.7) 9 (40.9) 8 (36.4)
Nanocurcumin Without dyspnea 18(58.1) 22 (71.0) 23 (74.2) 23 (74.2) 23 (79.3) 25 (86.2)
With dyspnea 13 (41.9) 9 (29.0) 8 (25.8) 8 (25.8) 6 (20.7) 4 (13.8)
Placebo Without wheeze 22 (81.5) 22 (81.5) 22 (84.6) 23 (95.8) 21 (95.5) 21 (95.5) 1.58 (0.36–6.89) 0.53 1.54 (1.11–2.13) 0.01
With wheeze 5 (18.5) 5 (18.5) 4 (15.4) 1 (4.2) 1 (4.5) 1 (4.5)
Nanocurcumin Without wheeze 27 (87.1) 28 (90.3) 29 (93.5) 30 (96.8) 29 (100.0) 29 (100.0)
With wheeze 4 (12.9) 3 (9.7) 2 (6.5) 1 (3.2) 0 (0.0) 0 (0.0)
a
Calculated by GLM model (GEE approach).
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TABLE 4 Biochemical variables of the both groups at baseline and after intervention (Mean values and standard deviations)
Variables
Placebo Nanocurcumin
p-value
a
Baseline After the intervention Baseline After the intervention
hsCRP (mg/L) 55.6 (36.65) 3.8 (1.52–7.84) 53 (37.83) 7.84 (1.44–13.00) 0.41
WBC (K/μL) 6,000 (4800–8,700) 9,491 (2139) 6,305 (4830–7,870) 10,933 (4029) 0.13
RBC (M/μL) 4.9 (0.6) 4.97 (0.53) 4.92 (0.6) 5.01 (0.65) 0.8
HGB (g/dL) 13.95 (1.82) 14.27 (1.31) 13.74 (0.65) 14.01(1.65) 0.56
HCT (%) 40.55 (4.87) 42.3 (40.5–44.7) 39.9 (3.56) 40.05 (38.3–43.6) 0.35
MCV (fL) 82.85 (81.5–86.75) 83.3 (80.8–85.4) 82.15 (80.9–84.5) 82.55 (79.6–85.3) 0.5
MCH (pg) 28.9 (27.85–30.35) 28.7 (27.50–30.6) 28.4 (27.3–29.3) 28.5 (28–29.2) 0.4
MCHC (g/dL) 34.32 (1.14) 34.32 (1.32) 34.40 (1.13) 34.34 (1.12) 0.95
PLT (K/μL) 204 (154.5–272.5) 320 (220–406) 235 (189–311) 377.5 (231–428) 0.28
Neutrophil (%) 77.58 (8.65) 71.33 (12.88) 77.72 (8.81) 72.34 (11.30) 0.78
Lymphocyte (%) 15.96 (7.20) 21.31 (11.38) 15.88 (8.04) 19.04 (8.47) 0.45
Pulmonary involvement score 13.05 (4.6) 14.88 (5.44) 14.68 (4.18) 13.52 (4.8) 0.41
Note: Data are reported as mean (SD) or median (IQR).
Abbreviation: hs-CRP, high-sensitivity C-reactive protein.
a
As there was no statistically significant difference in the baseline characteristic of groups, the value of variables after the treatment were compared by independent t test or Mann-whiney test (pvalues are for
comparison between the two groups after the intervention).
1020 HONARKAR SHAFIE ET AL.
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COVID-19 has recently been considered. Whether the process starts
in the lungs and then causes hypoxia or vice versa needs further
investigation. SARS-CoV-2 infection is highly dependent on the virus
interaction with host cell receptors and proteases. CD147 is an addi-
tional receptor in red blood cells that can be the entry point of the
virus in immature bone marrow cells. On the other hand, curcumin
could increase heme oxygenase activity and inhibit some adverse
effects of coronavirus, such as hemoglobin oxidation and SARS-
CoV-2 attachment to bone marrow (Cavezzi, Troiani, & Corrao, 2020).
Therefore, significant improvement in blood oxygen levels in the inter-
vention group, while patients' CT-scan did not show any considerable
progress, could confirm the hypothesis that curcumin may improve
iron metabolism and oxygen delivery through other mechanisms. The
possible mechanisms noted to be beneficially affected by
curcuminoids are: i) hemoglobin oxidation and lipoperoxidation, ii)
cytokine storm and inflammation promotion, iii) activation of SARS-
CoV-2 protease, iv) SARS-CoV-2 attachment to bone marrow, v)
hepcidin and ferroportin regulation (Cavezzi et al., 2020).
Our study had some limitations. Since we entered only the
milder cases of COVID-19 patients in the study and their baseline
hs-CRP level was not very high, the hs-CRP level of both groups
returned to the normal level at the end of the study. Therefore, the
better choice was tracking the daily changes of hs-CRP level in the
participants. Moreover, because the pulmonary resolution phase of
COVID-19 is a gradual event and mainly occurs after 14 days from
the onset of the disease, we should have been repeated CT-scan
after a more extended period, but it was not ethically possible in
our study.
5|CONCLUSION
In conclusion, this study suggests that nanocurcumin supplementation
could probably be a complementary agent in COVID-19 patients to
accelerate the recovery of COVID-19 demonstrations through
improvement in O
2
saturation, the severity of symptoms, and LOS.
Further and longer investigations are required to discover the effects
of nanocurcumin in COVID-19.
ACKNOWLEDGEMENTS
This study was supported by Tehran University of Medical Sciences
and Health Services (grant No.: 47473). The authors also thank Nano-
technology Research Center of Mashhad University of Medical Sci-
ences and Exir Nano Sina Company for providing nanocurcumin
supplements (Sina curcumin) and the placebos.
CONFLICT OF INTEREST
The authors declared no conflicts of interest.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
ORCID
Fateme Taheri https://orcid.org/0000-0002-8993-7945
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How to cite this article: Honarkar Shafie, E., Taheri, F., Alijani,
N., Okhovvat, A. R., Goudarzi, R., Borumandnia, N.,
Aghaghazvini, L., Rezayat, S. M., Jamalimoghadamsiahkali, S., &
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supplementation on the severity of symptoms and length of
hospital stay in patients with COVID-19: A randomized
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36(2), 1013–1022. https://doi.org/10.1002/ptr.7374
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