Statistical Analysis:
Data analysis was performed using SPSS 21.0 (Statistical Package for
Social Sciences for Windows, Inc, Chicago, Illinois, USA). The
compatibility of the data to normal distribution was investigated by
Kolmogorov Smirnov test. Data showing the characteristics of continuous
variables are expressed as mean ± standard deviation if they are
distributed normally, as median (minimum-maximum) if they are not
normally distributed, and categorical data were expressed as number and
percentage (%). independent groups were compared using Student T test
if the data was normally distributed, and Mann-Whitney U test if it was
not normally distributed. Categorical variables were compared using the
Chi-square test. A p <0.05 value was considered statistically
significant.
RESULTS:
During the observation period, a total of 317 patients were hospitalized
for COVID-19 pneumonia. After data examined, it was found that a HDS was
given to 54 patients whereas 261 patients had LDS therapy. The
methylprednisolone doses of 54 patients were 1000 mg, 500 mg, and 250 mg
for 9, 5, and 40 patients, respectively. The mean age of included
patients was 62.5 (±13.64) years, and 64.7% (n=205) were male. Although
males were more in overall, there was no difference for gender between
the HDS and LDS groups. HDS group was younger than LDS (58.3±13.8 vs
63.4±13.4, p=0.012).
Clinical characteristics between the high and low-dose corticosteroid
groups were spesicified in Table 1. According to demographic features,
the body mass index (BMI) was a little higher in the HDS group (28.
96±4.44 vs 30.28±5.08, p=0.05). Both groups had similar rates of
comorbidities (Hypertension, Chronic obstructive pulmonary disease,
Asthma, Coronary artery disease, Chronic kidney disease, Diabetes
mellitus, Congestive heart failure, Interstitial lung diseases,
Rheumotology, Malignancy; p=0.28). Admission symptoms [fever
(p=0.275), dyspnea (p=0.53), cough (p=0.281)] were found at similar
rates in both groups. When the first treatments at hospitalization were
compared, no difference was found for Favipiravir and
Low-molecular-weight heparin between the groups, whereas the need for
adding antibiotics during the hospitalization and added Plaquenil
(p=0.009), and vitamin C (p=0.002) more in the HDS group
(p<0.001). Bilateral consolidation with ground-glass opacities
were detected higher in HDS than LDS group (88.9% vs 59.7%,
p<0.001). In addition, the oxygen need of patients at
admission and the need for advanced oxygen therapy during
hospitalization were found higher in the HDS group (p<0.001).
Furthermore, 18.5% of patients in the HDS group had need transfer to
the intensive care unit whereas it was 3.8% in LDS (p<0.001).
Additionally, the mortality rate was determined higher in the HDS group
(25. 9% vs 9.9%, p<0.001).
The median (IQR) length of hospitalization was 10 (7-15), and 6 days
(4-9), in HDS and LDS groups, respectively (table 2, p<0.001).
Compared with the LDS group, the HDS group had lower saturated
O2 on ambient air at admission [IQR, 85% (76-89), p
<0.001], and higher ferritin both at admission and before
discharge [IQR, 529.5 (270.0-878.5) p = 0.03] and [IQR, 653.5
(453.6-885.0,) p <0.001] (table 2). However, there was no
difference between the groups for the other laboratory parameters at
admission (C-reactive protein, lymphocytes, neutrophils, neutrophil to
lymphocyte ratio, platelets, D-dimer, troponin and creatinin, table 2).
Median (IQR) time from symptom onset to hospitalization was 5 (4-7) days
in LDS, and 6 (3-10) days in the HDS group (p=0.75). When 317 patients
were evaluated, no treatment change was required in the LDS group, while
the median (IQR) pulse steroid was applied in the HDS group 3 (2-5) days
after hospitalization, and 10 (6-16) days after symptoms appeared. When
the HDS group is examined in more detail, it was found that lymphopenia
deepened and ferritin increased on the third and fifth days, while pulse
steroid was also given on these days (figure 1). Moreover, compared with
the LDS group, a decrease in CRP was also lower in the HDS group (table
3, figure 1).
Of overall 317 patients, when the deaths (n=25) and had no regular
followed were excluded (n=109), 181 patients were examined for
developing fibrosis. All the patients followed up for a mean of 40.2
(±19.38) days after discharge. Of 181 patients, fibrosis was developed
in 78 (43.1%) patients whereas was not in 103 (56.9%). Compared with
the non-fibrosis group, older age (p=0.001), prolonged hospitalization
(p=0.024), the lower saturation at admission (p=0.01), the higher
d-dimer (p=0.014), and increased recurrent hospitalizations (p=0.04)
were identified in the fibrosis group (table 4). There was no difference
in fibrosis development between receive high-dose steroid patients
(15.4% vs 26.2%, p=0.11).
DISCUSSION:
Herein, we investigated the efficiency of short-term high-dose steroid
therapy in the course of severe COVID-19 pneumonia outside the intensive
care unit. We did not find a lower mortality rate among high-dose GS
patients statistically. However, it should be kept in mind that this
study was retrospectively designed, and the groups were not homogenous,
and the high-dose steroid group consisted of patients with more severe
pneumonia than the low-dose steroid group.
Today most deaths due to COVID-19 are caused by respiratory failure
(stage 3) from cytokine storms and there is no effective and specific
treatment is not yet for all the stages. A limited effect on the early
stages (stage 1-2) with antiviral agents such as remdesivir,
favipiravir, darunavir, lopinavir/ritonavir has been shown besides with
the randomized controlled studies still continue on (10). Stage 3 is
related to cytokine release syndrome which demonstrates high levels of
interleukins (IL) (IL-1 β, IL-1RA, IL-6, IL-8, IL-9, IL-10, IL-17),
macrophage inflammatory protein, vascular endothelial growth factor,
tumor necrosis factor-alpha (TNF-α), and other pro-inflammatory
chemokines, cytokines, and signaling proteins (11). Corticosteroids are
known to functions anti-inflammatory, anti-allergic, and hypothermic due
to reducing levels of IL-8, MCP-1, and IP-10 and inhibiting the gene
expression of IL-6, IFN-γ, and IL-4 (3,12). Based on the effects on
these cytokines it is suggested that using corticosteroid as adjunctive
therapy in COVID-19 treatment (4,5, 13-20). Due to its immunosuppression
property, potential risks of corticosteroid therapy including secondary
infections, long-term complications, and delayed virus clearance, the
benefits and harms should be carefully weighed before using
corticosteroids, and time to administration should be decided carefully
(21). So there is not a consensus on GC s use and the optimal dose.
Considering that the conflicting results regarding the use of steroids
in the treatment of patients with severe COVID-19 pneumonia so far, we
aimed to demonstrate the benefits of high-dose steroid usefulness in
these patients outside the intensive care unit.
Although there was also not found a lower mortality rate in the HDS
group in our study such as Chen’s and Bartoletti’s studies (15, 22),
more clinical improvement was observed in COVID-19 patients given HDS
than LDS. However, when use a propensity score matching, significantly
lower mortality was found in the Cox regression survival analysis (15).
But there couldn’t apply the propensity score matching for our study due
to technical problems. On the other hand, the time to give steroid is
extremely important to these patients that the early high-dose GCs were
shown to decrease the progression of the disease and improve the
resolution of alterations in the pulmonary structures (20). Concurrent
administration of high doses of steroids to these patients together with
the increase in ferritin levels on the 1st, 3rd, and 5th days of
hospitalization, a slower decrease in CRP value, and the deepening of
lymphopenia, and the prominence of clinical worsening, supports this
information.
In this recent study, similar to the literature, higher BMI, the oxygen
need of patients at admission, and the need for advanced oxygen therapy,
more bilateral subpleural multifocal ground-glass opacities with
consolidation and hyperferritinemia were found significantly different
in the HDS group than LDS group (23). However, unlike the literature,
the patients were younger in the HDS group with higher mortality.
Moreover patients in the HDS group spent 4 days more in the hospital,
although that may be partially explained by a more severe course of the
disease. Physicians should be kept in mind that it also prolongs the
duration of virus clearance (24).
The secondary objective of this study was to investigate whether
fibrosis develops in patients with high-dose steroid therapy on
follow-up in three months. However, as expected, the rate of fibrosis
was not lower among patients receiving high doses of steroids.
Nevertheless, older age, prolonged hospitalization, lower saturation at
admission, higher d-dimer, and increased recurrent hospitalizations were
identified as the indicator for fibrosis in our study. There is not yet
a study for predicting fibrosis in the literature. Although the number
of patients is small, this study can be a guide for future studies.
The limitations of the study were the retrospective design that prevents
randomization, the small number of patients with HDS, and the difference
between groups in baseline characteristics.
In conclusion, the use of HDS in hospitalized COVID-19 patients remains
unclear. Along with this, our study demonstrated the use of high-dose
corticosteroids might not be associated with a lower mortality rate
among hospitalized severe COVID-19 patients. Prospective multicenter
studies with a large number of controlled randomized patients will be
guiding in the future.