INTRODUCTION
The coronavirus disease 2019 (COVID-19) caused by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), first introduces to
world as an outbreak in Wuhan, China, in December 2019, was declared as
a “global pandemic” by World Health Organization (WHO) on March 11,
2020.1 As of July 11, 2020, a total of 12 322 395
confirmed COVID-19 cases and 5 56335 related deaths have been reported
worldwide.2 Acute respiratory distress syndrome (ARDS)
due to hyperinflammation in the lungs and ultimately, respiratory
failure from COVID-19 pneumonia has been reported as the prime cause of
COVID-19-associated mortality3,4 ranging from 1% to
more than 7%.5 Cytokine storm due to the over
production of proinflammatory cytokines, including IL (interleukin)-6,
IL-7, IL-8, etc. in critically ill patients with COVID-19 is a critical
phase of the disease that may lead to acute respiratory failure or
multiple organ dysfunction.6,7 Therefore, early
detection of the COVID-19 infection and prompt management to suppress
the cytokine storm is equally important in the patients with
COVID-19.8
IL-6 plays a pivotal role in exacerbating the cytokine storm as a part
of host’s innate immune response mechanism which is mostly activated by
IL-1 beta, tumor necrosis factor (TNF-alfa), Toll-like receptors (TLRs),
prostaglandins, adipokines and other cytokines.9 High
levels of IL-6 and IL-8 were detected in patients with severe SARS-CoV-1
infection, where high-magnitude of innate inflammatory response in
correspondence to SARS-CoV-1 invasion in the host’s respiratory tract
was extensively induced by IL-6.10 Similarly, high
plasma level of IL-6 along with other proinflammatory cytokines, such as
IL-2, IL-7, IL-8, IL-10, macrophage inflammatory protein (MIP1A),
monocyte chemoattractant protein (MCP1) and TNF-alfa have been found in
critically ill patients with COVID-19 and these cytokines significantly
contribute in the severity of the disease.5,6,8
Receptor-mediated endocytosis is a process through which most viruses
penetrate into the host cells. AP2-associated protein kinase 1 (AAK1) is
a regulator of this endocytosis and inactivation of this enzyme
interrupt the entry of the virus into the host
cells.11 Baricitinib, a janus kinase (JAK) inhibitor,
is an approved drug for rheumatoid arthritis (RA). In effect,
baricitinib specifically prevents the expression of proinflammatory
cytokines, including IL-6 by inhibiting JAK. Interestingly, among the
six highly potent inhibitor of AAK1, baricitinib is one of them which
works by binding with the cyclin G-associated kinase that disrupt
endocytosis, competently leading to reduction in viral
load.11,12 Nowadays, baricitinib at a 4 mg once daily
oral dose has been highlighted as a promising investigational
anti-inflammatory (IL-6 inhibitor) drug therapy in patients with
COVID-19 pneumonia.4,11,12,14 The pharmacokinetics,
pharmacodynamics and safety data of baricitinib at a 4 mg daily dose in
COVID-19 are still under investigation and to date, no standard dosing
of baricitinib in COVID-19 has yet been established
worldwide.11-15 The objective of this study was to
compare the clinical outcomes of patients with moderate-to-severe
COVID-19 pneumonia treated with baricitinib at a 4 mg once daily oral
dose with or without a high oral loading dose.
MATERIALS AND METHODS
Study design and data collection
This prospective case-control study was conducted in the “COVID-19
Unit” of Square hospital ltd., Dhaka, Bangladesh on 37 (N) adult (≥ 18
years) patients with moderate to severe COVID-19 symptoms admitted to
this hospital from May 15-June 13, 2020. All the patients were
Bangladeshi citizen and older than 18 years. Dexamethasone
(corticosteroid) (10-20 mg/day, intravenously) and baricitinib combinely
was started on day one of admission for down-regulating the inflammatory
processes in lungs. Seventeen (n) patients in “no loading dose (LND)
group” (control) received baricitinib 4 mg daily orally for 2 weeks,
where as 20 (n) patients in “loading dose (LD) group” (case) received
baricitinib 8 mg single dose orally as a loading dose on day one and
then, 4 mg daily orally from day 2 to 14. The dose of baricitinib was
taken on empty stomach. Simple random sampling method was used in this
study. The local brand “Baritor 2” (baricitinib 2 mg tablet) of Square
pharmaceuticals ltd., Bangladesh was used in this study. Data of this
study were collected from online patient-wise data archive of this
hospital and directly from patient-prescriptions on daily basis by
participating doctors in COVID-19 unit. Adverse events were routinely
monitored and reported by two clinical pharmacists.
Sample inclusion criteria were:
- presence of SARS-CoV 2 in the nasal/oral swabs
- no previous history of COVID-19 infection
- having at least 3 of the following symptoms: fever, cough, tiredness,
sore throat, anosmia, respiratory distress, and myalgia
- evidence of pneumonia in radiological diagnosis
Sample exclusion criteria were:
- more than 10 days from onset of symptoms
- patient with pregnancy
- any history of trauma or surgical procedure within the last 3 months
of admission
- any history of acute/chronic autoimmune disease
- evidence of bacterial or fungal coinfection
Definition of moderate and severe COVID-19 pneumonia:
Radiological evidence of bilateral pneumonia with clinical signs (fever,
cough, difficulty breathing, tachypnea), no sign of severe stage of
pneumonia, SpO2 (peripheral capillary blood oxygen
saturation level) ≥ 90% on room air (RA), ratio of arterial oxygen
partial pressure to fractional inspired oxygen
(PaO2/FiO2) 100-300 mmHg; radiological
evidence of severe pneumonia with clinical signs (fever, cough,
difficulty breathing, tachypnea) with at least one of the following
signs: respiratory rate > 30 breaths/min, severe
respiratory distress, and SpO2 < 90% on room
air.16 SpO2 ≥ 95% was considered as
the targeted SpO2 in patients in this study. The
severity of the disease and the progression of the symptoms of COVID-19
were measured on daily basis by assessing physical condition of the
patients and the laboratory investigations, including hematological
tests, tests for liver and kidney functions, inflammation and infection
markers, and arterial blood gas test.
Data analysis and ethical approval
Data were analyzed with SPSS version 22.0 statistical software (SPSS,
Chicago, IL, USA). Descriptive statistics were presented through median
value and interquartile range (IQR). Categorical variables were compared
using Fisher’s exact test, and continuous variables were compared using
Mann-Whitney U test. P values ≤ 0.05 were considered
statistically significant. The Square Hospital Ethical Committee granted
ethical approval (no. 2004SH-OR024) for this study on April 11, 2020.
All patients gave their written consent to participate to the study.
RESULTS
The number of male patients in both the groups was higher than the
number of female patients with a median age of 52 (50.5-62) and 59
(49.8-69) in NLD and LD group, respectively (P = 0.414). Clinical
characteristics, including blood-oxygen saturation profile, respiratory
and cardiac functions, hematological components, and infection markers
of all the patients (N = 37) in the two groups are shown in Table 1 and
compared. On admission, symptoms of moderate/severe COVID-19 pneumonia
and predisposed comorbidities in the two groups were similar.
All patients (N = 37) in both the groups tolerated baricitinib therapy
well with no mild-to-serious adverse events (AEs) during the study
period. No bacterial or fungal or any other opportunistic infections,
hepatic or hematological toxicity were observed in the groups.
The median day to reach the targeted SpO2 (≥95% in RA)
was less in the LD group (case) [3 (IQR: 2-8)] than that in the NLD
group (control) [4 (IQR: 4-5)] (P = 0.180), and the median
day to return in normal breathing function was significantly less in the
LD group [5 (IQR: 4-5)] than that in the NLD group [8 (IQR:
7-10)]. ICU support was required higher in the NLD group with more
requirement of mechanical ventilation support than that in the LD group
[29.4% (n = 17)/10% (n = 20), P < 0.05; 11.8% (n =
17)/5% (n = 20), P = 0.141, respectively] (Table 2). The
median day of hospitalization was lower in the LD group [12 (IQR:
10-14)] than that in the NLD group [15 (IQR: 9-18.5)] and this was
statistically significant. The 30-day all cause mortality rate was
similar in the two groups.
DISCUSSION
This study found that a single 8 mg oral loading dose of baricitinib
added to its daily 4 mg maintenance dose for up to 2 weeks exhibited
better clinical outcomes in patients with moderate-to-severe COVID-19
than 4 mg daily oral dose regimen without having a loading dose. The
targeted SpO2 (≥95%) was gained earlier in patients
received an early 8 mg of loading dose of baricitinib than the patients
treated without a loading dose of baricitinib. Similarly, the
requirement of supplement oxygen support was significantly reduced
earlier in patients treated with an extra 8 mg of loading dose of
baricitinib that the patients received only 4 mg daily maintenance dose.
Study showed that around 80% of patients with COVID-19 develop acute
lung inflammation due to massive cytokine storm3,5-7resulting in hypoxemia, impaired hypoxic pulmonary vasoconstriction, and
high altitude pulmonary edema leading to acute respiratory distress
syndrome (ARDS)3,8,17 which may result death in
2%-7% of patients with COVID-19 pneumonia18 Janus
kinases, a tyrosine kinase, play its major anti-inflammatory role in the
cytokine signaling pathways by constitutively binding to cytokine
receptors. To potentiate a cytokine storm, proinflammatory cytokines
need to transmit more signals through signaling pathways. In-role, more
than 40 different types of cytokines transmit signals through JAKs,
including JAK1, JAK2, JAK3, and tyrosine kinase-2
(TyK2).13,18 Baricitinib has an oral bioavailability
of approximately 79%, plasma protein binding ability up to 50%, mean
half-life of approximately 12.5 h (in RA), and shows serum drug level of
approximately 100-300 nM following a 4 mg oral
dose.13,19 The low molecular weight baricitinib
concentration-dependently inhibits JAK1 and JAK2 with high
target-specificity.13
In addition, baricitinib suppresses the production of Type-I interferons
(IFNs) from plasmacytoid dendritic cells (pDCs), inhibits the synthesis
of interleukin (IL)-6 from B cells,20 and possesses
strong anti-viral property by inhibiting
endocytosis.21 Therefore, down-regulation of signal
transmission of proinflammatory cytokines through JAKs, and suppression
of other intrinsic inflammatory pathways makes baricitinib a suitable
anti-inflammatory drug therapy in the treatment of COVID-19 pneumonia.
The additional strong anti-viral property of baricitinib along with its
selective anti-inflammatory ability has attributed its superiority to
other oral investigational anti-inflammatory drugs in the treatment of
COVID-19 pneumonia.
The plasma drug concentration of baricitinib at 2-4 mg daily oral dose
is sufficient to exhibit its anti-inflammatory roll (JAKs inhibition) in
RA11,12 but, a standard dose of baricitinib to achieve
its optimum therapeutic outcome in COVID-19 pneumonia is still under
investigation. In a recent study with a small sample size showed an
improved clinical outcome of patients with COVID-19 with baricitinib at
4 mg per day of oral dose for 2 weeks.14 In this
study, a 2-fold higher (2 × 4 mg) single loading dose of baricitinib
followed by 4 mg daily dose showed better therapeutic response in the
management of moderate-to-severe COVID-19 pneumonia, and a superior
clinical outcome was attributed in patients (case group) within 2 weeks
of therapy with reduced hospitalization time and mortality rate. The
major limitation of this study were small study sample size, short
duration of study, no proven justification of using 8 mg loading dose of
baricitinib, and unavailability of serum cytokines monitoring facility
in the study setup.
CONCLUSION
Severe pneumonia associated with COVID-19 is a major cause of mortality
in COVID-19 infection. No anti-inflammatory drug, including baricitinib
for the treatment of COVID-19 pneumonia has yet been recommended. In
this study, 2-week-long 4 mg once daily oral maintenance therapy of
baricitinib following a single 8 mg loading dose in moderate-to-severe
COVID-19 pneumonia showed faster return to normal respiratory function
with reduced requirement of ICU and ventilator support, length of
hospital stay, and mortality rate than a loading dose-less 4 mg once
daily oral dose of baricitinib.