A REVIEW ON FUNCTION AND SIDE EFFECTS OF SYSTEMIC CORTICOSTEROIDS USED IN HIGH-GRADE COVID-19 TO PREVENT CYTOKINE STORMS

 
A REVIEW ON FUNCTION AND SIDE EFFECTS OF SYSTEMIC CORTICOSTEROIDS USED IN HIGH-GRADE COVID-19 TO PREVENT CYTOKINE STORMS
EXCLI Journal 2021;20:339-365 – ISSN 1611-2156
                             Received: November 24, 2020, accepted: February 09, 2021, published: February 15, 2021

                                                  Review article:

     A REVIEW ON FUNCTION AND SIDE EFFECTS OF SYSTEMIC
       CORTICOSTEROIDS USED IN HIGH-GRADE COVID-19 TO
                 PREVENT CYTOKINE STORMS
Mohammad Amin Langarizadeh1, 2, Marziye Ranjbar Tavakoli1, Ardavan Abiri1, 2,
Ali Ghasempour1, Masoud Rezaei3, Alieh Ameri2, *
1
    Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran
2
    Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical
    Sciences, Kerman, Iran
3
    Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran

* Corresponding author: Alieh Ameri, Pharm.D., Ph.D., Assistant Prof. at Department of
  Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences,
  Kerman, Iran; Tel: +98-34-31325172 ;
  E-mail: al_ameri@kmu.ac.ir; 60ameri@gmail.com

https://orcid.org/0000-0002-0910-1516 (Alieh Ameri)

http://dx.doi.org/10.17179/excli2020-3196

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0/).

                                                      ABSTRACT
In December 2019, a cluster of pneumonia caused by a novel coronavirus (2019-nCoV), officially known as severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan, Hubei province, China. Cytokine
storm is an uncontrolled systemic inflammatory response resulting from the release of large amounts of pro-inflam-
matory cytokines and chemokines that occurs at phase 3 of viral infection. Such emergence led to the development
of many clinical trials to discover efficient drugs and therapeutic protocols to fight with this single-stranded RNA
virus. Corticosteroids suppress inflammation of the lungs during the cytokine storm, weaken immune responses,
and inhibit the elimination of pathogen. For this reason, in COVID-19 corticosteroid therapy, systemic inhibition
of inflammation is observed with a wide range of side effects. The present review discusses the effectiveness of
the corticosteroid application in COVID-19 infection and the related side effects of these agents. In summary, a
number of corticosteroids, including and especially methylprednisolone and dexamethasone, have demonstrated
remarkable efficacy, particularly for COVID-19 patients who underwent mechanical ventilation.

Keywords: COVID-19, cytokine storm, corticosteroid therapy, SARS-CoV-2, adverse effects

                 INTRODUCTION                                    the gastrointestinal tract, hepatic activity,
                                                                 neurological network, and in particular, the
    Coronaviruses (CoVs) are a diverse group
                                                                 respiratory system (Mao et al., 2020; Wong et
of enveloped viruses of the order Nidovirales
                                                                 al., 2020). In addition to humans, the virus has
and the Coronaviridea family. These posi-
tive-sense viruses with single-stranded RNA                      the potential to infect animals, that is the main
                                                                 reason for transferring of coronaviruses, in-
can manifest themselves by a disturbance in
                                                                 cluding COVID-19 from zoonotic sources

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(Loo et al., 2020). CoVs are divided into four         antiviral medicines or vaccines are yet to be
main genera including alpha, beta, gamma,              approved for COVID-19 infection, but now
and delta. SARS-CoV and MERS-CoV are                   unofficially, more than 30 different drugs are
two new β-CoVs that have caused a series of            being used with experimental or proven ef-
lethal respiratory illnesses in the last two dec-      fects, including herbal compounds, synthetic
ades (Zumla et al., 2016; Xu et al., 2020).            drugs, and traditional Chinese medicine
With the sudden outbreak of the novel coro-            (Rothan and Byrareddy, 2020). Most of the
navirus in the late December 2019 in the Wu-           drugs used by medical staff in different re-
han region and its rapid globalization, human          gions are antiviral drugs that inhibit the vital
society has failed to achieve a consensus cure         proteins of coronavirus, including papain-like
for the disease, and unfortunately, the casual-        protease, RNA dependent RNA polymerase,
ties caused by this pandemic are increasing            3C-like proteinase, and spike protein (or its
daily. Due to the lack of sufficient knowledge         receptor, ACE2), which prevent the progres-
in pharmacotherapy to treat the disease, dif-          sion of the disease (Rismanbaf, 2020). The
ferent treatment processes were implemented            fifth trial version of the Diagnostic-Therapeu-
in terms of drug type, method of use, and du-          tic scheme for controlling the pneumonia-like
ration of treatment around the world (Rothan           symptoms of COVID-19 infection was
and Byrareddy, 2020; Zhou et al., 2020a).              drafted by the China National Health Com-
COVID-19 appears to be more contagious                 mission on February 7, 2020, and provided a
than SARS and MERS, but fortunately, it is             systematic treatment strategy for intense
less lethal, killing only 2.2 % of sufferers           cases of sufferers. Corticosteroids were used
(Rothan and Byrareddy, 2020; Zhou et al.,              as adjunctive therapy in this scheme. More
2020c). Most patients have mild symptoms,              precisely, methylprednisolone, 1–2 mg/kg
but according to the Chinese government,               daily for 3–5 days, was recommended (Zhou
about 13.2-21.3 % of patients experience crit-         et al., 2020c).
ical conditions like septic shock, acute respir-
atory distress syndrome (ARDS), progressive                          METHODOLOGY
pulmonary insufficiency, pulmonary edema,                   This work was done according to focusing
severe pneumonia, or death (Sohrabi et al.,            on the role and manner of effectiveness, clin-
2020; Xu et al., 2020; Zhou et al., 2020c,             ical applications, and side effects of cortico-
2020a). Hydroxychloroquine and chloroquine             steroids in various forms to reduce mortality
were transiently approved by the US Food               of COVID-19. The required searches are done
and Drug Administration (FDA) for emer-                in Google scholar and PubMed search engine.
gency usage in critically-ill patients, which          To search for the clinical application of each
was later revoked. On October 22, 2020, FDA            drug in COVID-19, the combined keywords
confirmed Veklury® (remdesivir) for the                [drug name] + [COVID-19 or SARS-CoV-2]
treatment of COVID-19 patients (FDA,                   have been used. Also, to search for the side
2020c). A bit later, in November 2020, this            effects of each drug, combined keywords in-
organization approved the combination ther-
                                                       cluding [drug name] + [side effects] have
apy of remdesivir with baricitinib for the             been used. PubMed searches were limited to
treatment of suspected or confirmed cases of           advanced search in titles. Other searches have
COVID-19 (patients of two years of age or              been done based on the general focus of the
older) (FDA, 2020a). To date, dexamethasone            content of each section or on an ad hoc basis.
is the only certified corticosteroid medication        The coherence of the text from a scientific and
that is recommended for hospitalized patients          literary point of view was then re-evaluated
requiring supplemental oxygen (including               and then revised accordingly.
those who need high flow oxygen or mechan-
ical ventilation) by a survey conducted in the
University of Oxford (FDA, 2020b). Certain

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   MECHANISM OF IMMUNE CELL                           Adaptive immune response
          RESPONSE                                        The adaptive immune system consists of
                                                      humoral and cellular immunity. This response
Innate immune response
                                                      is confirmed by CD8+, CD4+ T cells, and B
    The entrance of the virus to the body is
                                                      cells that are adapted to specific pathogens.
mediated by ACE-2 receptors on the surface
                                                      This level of immune response happens (IFN-
of the epithelial cells of the respiratory tract
                                                      ɑ or anti-sera) during the non-severe stages to
through spike (S) proteins. The virus will then
                                                      prevent disease advancement to severe stages.
start to replicate, followed by spreading
through the lower respiratory tract that even-        Genetic differences in people make the indi-
tually triggers a robust immune response. The         vidual variation in the adaptive immune re-
infected cells produce inflammatory cyto-             sponse to the virus, including T cells, which
kines in the lungs that attract the nearby mac-       eliminate the infected cells and pathogens,
rophages (Roh and Sohn, 2018; Li et al.,              and B cells, which produce antibodies for spe-
2020). The alveolar macrophages are M1 and            cific pathogen and will be then differentiated
M2 types with pro-inflammatory activity and           to generate immunoglobulin (Ig). All immu-
regulatory functions, serving as innate im-           noglobulins (IgM, IgA, and IgG) have been
munity players in the lung (Li et al., 2020).         seen in the serum of SARS-CoV infected pa-
Coronavirus directly infects macrophages and          tients. Based on the previous surveillances,
T cells. Innate immune cells have pattern             IgM (which is the firstly secreted in response
recognition receptors (PRRs) that can recog-          to acute inflammation) and IgG antibodies
nize the virus invasion by their hallmarks            can remain in the plasma for a while and play
called pathogen-associated molecular pat-             a protective role. Recent studies firmly
terns (PAMPs). Interaction between Toll-like          showed the critical role of T helper 1 (Th1)
receptors (TLRs, one of the most important            type response to limit SARS-CoV and
PRRs) in the lungs and nucleic acid of the vi-        MERS-CoV infections (Dhama et al., 2020;
rus found to activate immune response                 Ye et al., 2020).
                                                          In the following, the mechanism of action,
through the production of antibodies by B
                                                      indications, and side effects of systemic corti-
cells and release of interferons (Dhama et al.,
                                                      costeroids (i.e., those corticosteroids that are
2020; Jamwal et al., 2020). The performed in-
                                                      given orally or by injection (not topically) and
vestigations on patients who survived from
coronavirus have revealed an extreme expres-          are distributed throughout the body) used for
                                                      COVID-19 patients will be explored. The side
sion of IFN-ɑ, IFN-γ, CXCL10, and CCL2.
                                                      effects of inhaled corticosteroids are listed
Furthermore, elicitation of the immune re-
                                                      separately below.
sponse has been also observed via gene ex-
pression analysis. Some studies in Wuhan il-
lustrated an increased level of neutrophils and               MECHANISM OF ACTION
serum IL-6 but decreased levels of lympho-                Corticosteroids can prevent lung injury
cytes. In many patients, the elevated plasma          caused by severe community-acquired pneu-
level of some innate cytokines, such as mon-          monia (sCAP) due to their immunomodula-
ocyte chemo-attractant protein-1 (MCP-1),             tory and anti-inflammatory properties (Stock-
macrophage inflammatory protein 1alpha                man et al., 2006; Zhou et al., 2020c). These
(MIP-1A), and TNF-ɑ, have been observed.              agents restrict the inflammation (which is the
IFN response is the most effective innate im-         leading cause of severe lung damage and de-
mune response to defense, prevents the                layed recovery) by reducing the excessive
spreading of the virus and also induce the de-        production of inflammatory cytokines, chem-
velopment of adaptive immune response, and            okines, and activated lymphocytes (Ni et al.,
promotes macrophage, natural killer (NK), T           2019). Cytokine storm is one of the leading
and B cells’ functions (Dhama et al., 2020).

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causes of disease exacerbation and progres-           body, such as the lungs, may occur, which can
sion to ARDS, which is the main cause of              lead to hypoxia. Bilateral infiltrates, ground-
death in COVID-19 patients. Prior to the              glass opacities in radiography, increasing
coronavirus pandemic, there was evidence of           lymphopenia, and transaminitis may help to
cytokine storms in viral infections. H5N1,            diagnose this stage. At this point, corticoster-
dengue virus, Ebola virus, SARS-CoV, EBV,             oids should be avoided, and antiretroviral
DHAV-1, Zika virus, and human herpesvirus             therapy and supportive measures should be
are among the viruses that cause hemophago-           considered unless the hypoxia ensues. If hy-
cytosis, cell damage, and organ dysfunction           poxia occurs, mechanical ventilation and the
by causing hypercytokinemia (Imashuku,                use of anti-inflammatory drugs such as a low
2002; Huang et al., 2005; Us, 2008; Wu et al.,        to moderate dose of corticosteroids may be ef-
2008; Rothman, 2011; Sordillo and Helson,             fective for the patient (Shang et al., 2020;
2015; Li et al., 2018; Xie et al., 2018;              Siddiqi and Mehra, 2020). The third stage is
Maucourant et al., 2019). The best time to            the most severe stage of the disease, which
prescribe corticosteroids in the treatment of         can lead to ARDS and death. Systemic in-
COVID-19 patients is when the patient’s con-          flammation, increased inflammatory markers,
dition is deteriorating, i.e., progressing to         decreased T lymphocyte count, and lympho-
ARDS. Some patients usually have a sudden             cytopenia are important symptoms of this
worsening 1-2 weeks after the onset. In-              stage that eventually lead to multiple organ
creased resting respiratory rate, drop in oxy-        failure. Anti-inflammatory and immunomod-
gen saturation level when the person is               ulatory agents such as glucocorticoids, immu-
breathing the room air, and multi-lobular pro-        nosuppressants, inflammatory cytokines an-
gression on imaging within 48 h are some              tagonists such as tocilizumab (IL-6 receptor
good indicators of the right time to take glu-        inhibitor) or anakinra (IL-1 receptor antago-
cocorticoids (Zhou et al., 2020b). Meanwhile,         nist), and intravenous immune globulin
the rapid and short-term initiation of anti-in-       (IVIG) can be helpful in this stage while anti-
flammatory therapy during this short period           viral drugs may not be effective (Siddiqi and
of time can most likely lead to an acceptable         Mehra, 2020; Zhang et al., 2020). Timely use
therapeutic response (Ahn et al., 2020; Zhang         of glucocorticoids can improve fever and pro-
et al., 2020). According to the clinical signs        vide better oxygen delivery, but some studies
and findings, the disease is divided into three       have suggested that the use of these agents is
stages with different severity. The first stage       incorrect due to weakened immune response
is related to the early exposure of the body to       and reduced virus clearance (Zhang et al.,
the virus, which is an emerging infection with        2020). Combination therapy with ribavirin
nonspecific symptoms (malaise, fever, and             and corticosteroids has been experimentally
dry cough), all of which are related to the in-       effective and, in fact, has a scientific basis. In
cubation of the virus and the development of          addition to being effective in treating respira-
the disease. Respiratory polymerase chain re-         tory syncytial virus infection, influenza virus
action, serum testing for virus-related IgG and       A and B infections, measles, parainfluenza,
IgM, chest imaging, complete blood count,             and Lassa fever, ribavirin has been found to
and liver function tests are among the diag-          inhibit RNA-dependent RNA polymerase
nostic methods at this stage. Antiretroviral          (Oba, 2003; Elfiky, 2020). In acute viral res-
pharmacotherapies, such as remdesivir or fav-         piratory infections, rapid-acting cytokines
ipiravir, are the best treatment options at this      and inflammatory markers such as IL-1β,
stage which is called early infection or viral        IL1RA, IL-2, IL-4, IL-6, IL-7, IL8, IL9, IL-
response phase (Siddiqi and Mehra, 2020). In          10, TNF-α, CRP, ferritin, D-dimer, IFN-γ, IP-
the second stage (pulmonary phase), virus             10, MCP-1, basic FGF2, GCSF, GMCSF,
multiplication and localization of the disease        MIP1α, MIP1β, PDGFB, and VEGFA medi-
and inflammation in a number of areas of the          ate the lung damage. IL-2, IL-7, IL-10, G-

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CSF, TNFα, IP-10, MCP-1, and MIP-1A                    of secondary infections, including bacterial
were higher in critically-ill patients such as         respiratory infections, due to suppression of
those in intensive care unit (ICU) (Fu et al.,         the immune system. Risks such as shock, car-
2020; Huang et al., 2020; Nile et al., 2020;           diovascular events, fluid retention, premature
Siddiqi and Mehra, 2020; Zhang et al., 2020).          atherosclerotic disease, and arrhythmia are
Glucocorticoids with a genomic mechanism               also more likely to occur in patients treated
inhibit the synthesis of pro-inflammatory cy-          with corticosteroids (Ni et al., 2019). Cortico-
tokines such as IL-1, IL-2, IL-6, IL-8, TNF,           steroids are not recommended in the early
IFN-gamma, COX-2, VEGF, and prostaglan-                stages of the disease owing to delayed recov-
dins (Dinarello, 2010). Prednisolone, for ex-          ery, especially when treatment with antiviral
ample, inhibits the production of TNF, IFN-γ,          drugs has not yet been performed. This rec-
IL-1β, IL-6, IL-17, IL-10, and TGF-β. Dexa-            ommendation is based on a study that vindi-
methasone also significantly reduces the level         cated early consumption of weak corticoster-
of IL-6, which is very problematic in criti-           oids such as hydrocortisone, even at low
cally-ill patients. Corticosteroids also sup-          doses, in more than 80 % of cases, has not
press inflammation by non-genomic mecha-               been able to stop the progression of the dis-
nisms such as i) binding to the membrane-as-           ease (Lee et al., 2004). Thus, corticosteroid
sociated glucocorticoid receptors of T cells           therapy can be effective only in the high
resulting in perturbation of receptor signaling        stages of the disease and in certain conditions
and immune response and ii) interacting with           in combination with antiviral drugs, in which
the exchange of calcium-sodium across the              monitoring the patients’ condition is essential
cell membrane, resulting in a quick downturn           to prevent adverse events.
in inflammation (Levine et al., 1993; Negera               Among all, hydrocortisone and predni-
et al., 2018; Yasir et al., 2020).                     sone have the highest protein binding (Lester
    Therefore, to prevent the progression of           et al., 1998; Czock et al., 2005). Cortisol with
lung disease, corticosteroid therapy is used to        8 to 12 hours has the shortest, and dexame-
suppress the cytokine storm. Previous surveys          thasone and betamethasone with 36 to 54
show that lung opacities in X-ray began to             hours have the longest biological half-life
fade and oxygen delivery started to improve            (Melby, 1977). Some corticosteroids have a
after corticosteroid therapy (Oba, 2003).              number of mineralocorticoid properties, the
Acute lung damage and acute respiratory dis-           potency of which is directly related to some
tress syndrome are partly due to the immune            side effects such as water and sodium reten-
response and inappropriate inflammatory me-            tion, edema, hypocalcemia, fluid-electrolyte
diators in the host. Corticosteroids not only          disturbance, elevated calcium excretion,
suppress the inflammation of the lungs during          weight gain, and hypertension (Melby, 1977;
the cytokine storm, but also, they weaken im-          Lester et al., 1998; Czock et al., 2005).
mune responses and inhibit the elimination of
pathogens. For this reason, in COVID-19 pa-                  GENERAL SIDE EFFECTS OF
tients, corticosteroid therapy (similar to influ-               CORTICOSTEROIDS
enza) systemic inhibition of inflammation is
associated with a wide range of side effects.              In addition to the specific side effects of
Thus, in patients experiencing life-threaten-          each corticosteroid, this category also has a
ing jeopardies in the late stages of COVID-            number of general adverse effects that repre-
19, corticosteroid therapy may be a risk-ben-          sent the typical features of this whole class of
efit option, and it might not be a reliable            medications. Common side effects of cortico-
choice for everyone (Russell et al., 2020). An-        steroids vary, and a wide spectrum of compli-
other reason why corticosteroids are contro-           cations such as fluid retention, changes in glu-
versial is that, according to research, patients       cose tolerance, behavioral and mood altera-
taking corticosteroids may develop a variety           tion, weight gain, high blood pressure, and in-
                                                       creased appetite was recorded. Basically,

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these general side effects are divided into           double-blind study of 647 adults with
twelve categories; cardiovascular system,             COVID-19 in Brazil, the death rate of people
dermatological complications, endocrine               over 60 in the first 28 days of intravenous
glands, fluids, and electrolytes balance, gas-        methylprednisolone was lower than that of the
trointestinal tract, renal system, metabolism,        placebo group (Jeronimo et al., 2020). A vari-
musculoskeletal system, nervous system,               ety of combination therapies also seem to be
ophthalmic complications, reproductive sys-           effective. Due to the important role of inter-
tem, and allergic reactions (FDA, 1955;               leukin-1 (IL-1) in coronavirus inflammation,
Melby, 1977; Berthelot et al., 2013; Yu et al.,       concomitant use of the IL-1 antagonist Ana-
2018). Complications and symptoms associ-             kinra and methylprednisolone reduced mor-
ated with each of these reactions are depicted        tality by 21.7 % compared to the control
in Figure 1.                                          group (Bozzi et al., 2021). Also, the combined
                                                      use of favipiravir and methylprednisolone
     SPECIFIC SIDE EFFECTS OF                         early on 11 cases of COVID-19, all in critical
        CORTICOSTEROIDS                               condition and undergoing oxygen therapy, re-
                                                      sulted in a recovery of 10 patients (~91 %)
Methylprednisolone
     Methylprednisolone has a prominent po-           (Murohashi et al., 2020). Tocilizumab, an IL-
sition among corticosteroids and is used to           6-blocking monoclonal antibody, along with
treat many dangerous illnesses, including nu-         methylprednisolone, has been shown to be ef-
merous autoimmune diseases. Methylpredni-             fective in patients with severe conditions
solone reduces mortality by up to 71 % in pa-         (Sanz Herrero et al., 2021). High dose
tients with COVID-19 and reduces the need             methylprednisolone (a single bolus of 250
for a ventilator (Salton et al., 2020; Papa-          mg, followed by 80 mg on days 2–5) has been
manoli et al., 2021). Also, in patients who           used successfully to rescue critically-ill pa-
were expected to require mechanical ventila-          tients who were hospitalized in the ICU who
tion, the number of days without ventilation          have not responded to azithromycin, hy-
                                                      droxychloroquine, and even two doses of to-
was increased and extubation was more likely
                                                      cilizumab (Conticini et al., 2020). MATH+
(Nelson et al., 2020). In comparison, the effi-
                                                      medication regimen has been suggested as
cacy of methylprednisolone and dexame-
                                                      one of the effective protocols in the pulmo-
thasone has been reported to be the same in
moderate to severe cases (Fatima et al., 2020),       nary phase of the disease, which includes
                                                      methylprednisolone, ("M"), high-dose vita-
however, methylprednisolone is sometimes
                                                      min C infusion ("A"), thiamine ("T"), heparin
better than dexamethasone in preventing mor-
                                                      ("H"), ivermectin, and supplemental compo-
tality due to its better pharmacodynamics and
                                                      nents ("+") such as melatonin, vitamin D,
pharmacokinetics (Liu et al., 2020). On the
                                                      zinc, and magnesium (Turkia, 2020). In clini-
other hand, there have been reports that dexa-
                                                      cal trials, there are a series of certifications for
methasone is more effective in reducing C-re-
                                                      creating rhythmic complications in its inject-
active protein (CRP) and improving P/F ratio
                                                      able dosage form, including sinus bradycar-
(pO2 divided by the fraction of inspired oxy-
                                                      dia, atrial fibrillation, atrial flutter, and ven-
gen (FIO2)) (Rana et al., 2020). Early use of
                                                      tricular tachycardia. Incidents such as hyper-
low-dose methylprednisolone not only pre-
                                                      tension, hyperglycemia, and fluid-electrolyte
vents the progression of the disease in criti-
                                                      disturbances may also occur during low-dose
cally-ill patients, but also reduces the inci-
                                                      methylprednisolone therapy (Darling et al.,
dence of ARDS and death (Yang et al., 2020).
                                                      2013). Unlike cardiovascular events such as
Timely and short-term use of methylpredniso-
                                                      severe hypertension, myocardial infarction,
lone is crucial, as a cohort study propounded
                                                      acute heart failure, angina pectoris, ischemic
that a treatment period of more than 7 days
                                                      stroke, and pulmonary embolism, which oc-
with methylprednisolone can increase the risk
                                                      cur more frequently in lower doses (2.0-5.0 g),
of death in the patients (Ji et al., 2020). In a

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Figure 1: General side effects of corticosteroids with location in the body

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the incidence of unwanted hepatic symptoms            ied in vitro (Sarkar and Sen, 2020). Gastroin-
such as acute liver failure is more probable at       testinal complications, including nausea,
higher doses (> 5.0 g). Intravenous methyl-           vomiting, abdominal distension, and elevated
prednisolone cumulative dose should not ex-           appetite are common. Increased motor activ-
ceed 8 grams due to severe side effects includ-       ity, insomnia, and agitation may also occur.
ing hepatic toxicity and elevated liver en-           Chronic prednisolone can suppress the pitui-
zymes (Walasik-Szemplińska et al., 2019). It          tary-hypothalamic-adrenal pathway. In this
may be necessary to take antibiotics and anti-        case, with discontinuation of the drug, there is
fungals after treatment with methylpredniso-          a possibility of acute adrenal insufficiency,
lone, as several cases have been reported that        which includes symptoms such as shock, an-
by restraining the immune system, a variety           orexia, headache, fever, joint pain, hypoten-
of bacterial and fungal infections of the uri-        sion, nausea, and vomiting. On the other
nary tract, vagina, and mouth may occur. Af-          hand, by changing the distribution of fat in the
ter prescribing methylprednisolone, there is a        body, fat masses in the peripheral areas be-
possibility of early (12 hours to 1 month) or         come reduced and instead accumulate in the
late (even up to 4 years) epilepsy. Due to the        central regions of the body, which causes a
occurrence of glucosuria and hyperglycemia            condition called buffalo hump appearance.
in many patients treated with methylpredniso-         Long-term use of prednisolone also engen-
lone, administration in diabetic and pre-dia-         ders endocrine disorders such as Cushing’s
betic patients should be followed with cau-           syndrome, amenorrhea, and menstrual disor-
tion. Gastrointestinal side effects, such as          ders. The patient’s history and the risk factors
nausea, duodenitis, and persistent pain or            for diabetes must be considered because tak-
heartburn associated with stomach acid, are           ing prednisolone reduces glucose tolerance
possible. Among the psychological side ef-            and causes hyperglycemia, which can lead to
fects, depression or euphoria are most likely         diabetes mellitus. Based on what we expect
to manifest (Lyons et al., 1988). In very rare        about the structure-activity relationship
cases of methylprednisolone administration,           (SAR) of corticosteroids, prednisolone has
severe side effects occur and intense adverse         some mineralocorticoid activity, which is the
events are usually scarce. In a group study re-       reason for complications such as hypocalce-
lated to measuring the effectiveness of intra-        mia, edema, fluid-electrolyte disturbance,
venous methylprednisolone in patients with            fluid retention, elevated calcium excretion,
COVID-19 in Iran, out of 68 patients who en-          and weight gain (Blake, 1990; Robinson et al.,
tered the clinical trial randomly and in a con-       2016). Other disorders observed in patients
trolled manner, only 2 developed severe side          using prednisolone are delineated in Table 1.
effects (Edalatifard et al., 2020).
                                                      Dexamethasone
Prednisolone                                               Dexamethasone was first prescribed to
    Prednisolone has fewer side effects than          patients in COVID-19 by British physicians,
other corticosteroids in a short duration of          and after conducting the necessary research,
therapy with high concentrations or acute             RECOVERY (Randomised Evaluation of
overdoses. In fact, short-term treatment with         COVid-19 thERapY) trial was set. In this
prednisolone is very unlikely to have signifi-        trial, low-dose dexamethasone was injected in
cant side effects. In silico studies based on         a dose of 6 mg daily for 10 days to minimize
molecular docking and dynamics revealed               the incidence of side effects along with proper
that dextromethorphan combined with pred-             effectiveness (Cain and Cidlowski, 2020).
nisolone or dexamethasone could have a syn-           According to this trial, taking dexamethasone
ergistic effect on inhibition of the virus main       will be effective only for people who receive
protease (Mpro), but its efficacy was not stud-       respiratory support. The dexamethasone-re-

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lated mortality reduction was about 35 per-            comitant use of dexamethasone with long-act-
cent for people who were being ventilated and          ing beta-2 adrenergic agonists such as salmet-
about 20 percent for people receiving oxygen           erol and formoterol relieves respiratory symp-
therapy (Lester et al., 2020, RECOVERY                 toms and together synergistically improves
Collaborative Group et al., 2020). A very im-          the anti-inflammatory and anticoagulant ef-
portant point about taking dexamethasone and           fects (Hajjo et al., 2020). Also, in a controlled
other corticosteroids is that people may seek          study with a treatment regimen consisting of
self-medication for fear of illness with insuf-        inhaled corticosteroids along with remdesivir
ficient information, which in turn can lead to         and dexamethasone, 5 out of 6 patients sur-
a number of damages related to the side ef-            vived (Yatam Ganesh and Nachimuthu,
fects of these drugs. Therefore, at this time, it      2020). In a special case, a pregnant woman
is necessary for health professionals to be vig-       with COVID-19 was successfully treated with
ilant to minimize the potential harm and be            dexamethasone, remdesivir, convalescent
able to predict the side effects caused by these       plasma, and mechanical ventilation at 26
drugs (Alessi et al., 2020). A prominent ther-         weeks of gestation (Jacobson et al., 2021).
apeutic effect of dexamethasone in COVID-              Measurement of blood ferritin activity in pa-
19 is reduced vascular permeability and pre-           tients can play an important role in determin-
vention of myocardial edema (Rafiee et al.,            ing the time window of dexamethasone ad-
2020). Based on another mechanism, follow-             ministration, because the level of ferritin in
ing viral infection, an increase in pro-resolv-        patients who die is much higher than those
ing lipid mediators such as protectins, re-            who recover, and in fact can be a good crite-
solvins, maresins, and lipoxins is probable            rion for assessing cytokine storm (Burugu et
and dexamethasone may block the activity of            al., 2020). The use of the leukosomal form of
these mediators (Andreakos et al., 2020).              dexamethasone, which is a type of nanovesi-
Also, according to a hypothesis based on               cle, exhibited good results in vitro and in this
computational studies, dexamethasone pre-              formulation dexamethasone had better thera-
vents virus entrance by occupying the SARS-            peutic activity (Molinaro et al., 2020). Dexa-
CoV-2 spike pseudotyped virus binding site             methasone is transported in the body through
in the ACE2 (Zhang et al., 2021). In a ran-            binding to serum albumin. The binding site
domized controlled trial of 2104 hospitalized          for dexamethasone in albumin is the same
patients, dexamethasone was found to reduce            with testosterone and NSAIDs, and therefore
mortality, but this effect only affects patients       this competition should be considered
receiving oxygen and mechanical ventilation            (Shabalin et al., 2020). Dexamethasone is
and does not include people without respira-           well tolerated as a widely used corticosteroid
tory support (RECOVERY Collaborative                   in short-term or single-dose use, but with in-
Group et al., 2020). A similar study in 299            creasing the dose or duration of therapy, a
people in Brazil found that the dexame-                number of side effects appear. Side effects
thasone group had more ventilator-free and             such as glucose intolerance and hyperglyce-
ICU-free days than the placebo group. There            mia, increased risk of infection, especially
were also fewer adverse events and secondary           fungal infections, delayed wound healing, ad-
infections in these individuals (Tomazini et           renal suppression, joint avascular necrosis,
al., 2020). Combination therapies with dexa-           gastrointestinal bleeding and perforation,
methasone can be effective. Due to the weak-           restlessness, flushing, and to a lesser extent,
ening of immune mechanisms and the possi-              nausea and vomiting are possible after taking
bility of reduced virus clearance after dexa-          dexamethasone (De Gans and Van Beek,
methasone, its combined use with intravenous           2002; Thomas and Beevi, 2007; Batistaki et
immunoglobulin and beta interferon may be a            al., 2017). Decreased sleep quality, anxiety,
viable option (Abdolahi et al., 2020). Con-            insomnia, increased sweating, hirsutism, cu-

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taneous purpura, and facial rounding are con-         other related diseases is not recommended.
sidered as minor side effects of dexame-              Also, the dose of the drug, the amount of salt
thasone (Bunim et al., 1958; Dinan et al.,            consumed by the patient, and the serum level
1997). Advanced hypertension, edema, hy-              of the electrolytes should be monitored regu-
perglycemia, and glucosuria are significantly         larly. Allergic reactions and systemic infec-
less likely to occur after dexamethasone con-         tions have been reported in some studies. An-
sumption than other corticosteroids (Bunim et         tibiotic treatment is recommended to prevent
al., 1958). Strongyloidiasis with symptoms of         infections along with fludrocortisone therapy
eosinophilia can be a hyperinfection in pa-           (Glenmark Pharm Eur Ltd, 2017). Cardiac
tients with COVID-19 following the use of             complications include cardiac failure, systolic
dexamethasone, which can be prevented by              hypertension, and stroke. In some cases, evi-
taking ivermectin, which itself has an anti-          dence of depression has been found. Hyper-
coronavirus effect (Stauffer et al., 2020).           kalemia is also a common side effect of long-
Dexamethasone-related information and its             term use of fludrocortisone, but it is not seri-
side effects are classified in Table 1.               ous enough to halt the treatment protocol (Ta-
                                                      ble 1) (Hussain et al., 1996; Taplin et al.,
Hydrocortisone                                        2006).
     Among severe COVID-19 patients, treat-
ment with a 7-day fixed-dose hydrocortisone           Prednisone
or shock-dependent hydrocortisone dose re-                Prednisone along with dexamethasone
sulted in a 93 % and 80 % improvement over            and methylprednisolone are among the drugs
21 days, compared with no hydrocortisone              offered in the RECOVERY trial to reduce
treatment, respectively (Angus et al., 2020;          mortality in patients with hypoxemia. The
Prescott and Rice, 2020). Low-dose hydro-             dose of 0.5-1 mg prednisone per day for 3-4
cortisone treatment in patients experiencing          weeks is considered for patients with COVID-
ARDS has mild positive results compared               19 (Bani-Sadr et al., 2020; Mattos-Silva et al.,
with the placebo group, and most of these tri-        2020). In a special case, a woman with severe
als have been discontinued early (Angus et            Crohn's disease treated with prednisone and
al., 2020; Dequin et al., 2020). Hyperglyce-          adalimumab was exposed to COVID-19 and
mia (glucose > 150 mg/dl) is more likely to           received acceptable results as the two drugs
occur after taking hydrocortisone, but it often       continued to be administered (Vechi et al.,
does not lead to insulin administration. It is        2020). There are other similar results in an-
recommended to take antihypertensive drugs            other COVID-19 patient with autoimmune
to control hypertension, which is likely to be        pancreatitis who was taking a high dose of
followed by hydrocortisone. Secondary infec-          prednisone, which may support the appropri-
tions, muscle weakness, hypernatremia, and            ate efficacy of this drug (Liaquat et al., 2020).
other general side effects associated with cor-       Prednisone has obvious bone complications,
ticosteroids have not been significantly ob-          and a number of recommendations, namely
served in patients who have taken hydrocorti-         lifestyle changes, should be applied to reduce
sone (Keh et al., 2016). The structure and pos-       the risk of osteoporosis (Shah and Gecys,
sible side effects of hydrocortisone are listed       2006). There is a high probability of un-
in Table 1.                                           wanted incidences, but the treatment should
                                                      be continued despite these adverse effects.
Fludrocortisone                                       The main problem with prednisone is fluid re-
    Fludrocortisone is a potent mineralocorti-        tention, which increases the volume or the fre-
coid that retains sodium. Following this event,       quency of urination. Gastrointestinal compli-
edema, weight gain, and hypertension are              cations, including heartburn, diarrhea, and
very likely. Therefore, the use of this drug in       nausea, are also likely to be seen. Minor com-
patients with a history of hypertension and

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plications of prednisone in long-term con-            enhanced risk of developing COVID-19 and
sumption are myalgia, dermatologic events,            even reduced the related risks in asthmatic pa-
insomnia, mood changes, bloating, hot                 tients (Choi et al., 2020). This article supports
flashes, joint swelling, depression or eupho-         the inhibitory effects of inhaled corticoster-
ria, elevated appetite, tremor, dizziness, swol-      oids for several reasons. First of all, these
len fingers, and changes in fat distribution          compounds significantly reduce the risk of
(Table 1) (Lozada et al., 1984; Ton et al.,           disease recurrence and progression to ARDS
2005).                                                due to their regulatory role in inflammatory
                                                      and immune responses (Halpin et al., 2020;
Cortisone                                             Nicolau and Bafadhel, 2020). More im-
    A number of gastrointestinal side effects         portantly, inhaled corticosteroids have been
have been reported with cortisone, including          shown to be associated with decreased gene
constipation, abdominal cramps, nausea,               expression of proteins ACE2 and TMPRSS2
vomiting, elevated appetite, gastric ulcer, and       in the epithelial cells of the oral mucosa and
diarrhea. Insomnia, mental stress, schizophre-        type 2 alveolar cells, thereby reducing the rep-
nia, and talkativeness are among the psycho-          lication of coronaviruses, including SARS-
logical side effects of cortisone. Other com-         CoV-2. ACE2 and TMPRSS2 are associated
plications including hyperglycemia, moon-             with the entry of the virus into the cell and are
shaped face, mild acne, dizziness, glycosuria,        involved in the binding of the spike protein
headache, palpitations, weakness, edema, so-          and the beginning of the viral infection cycle
dium retention, hypokalemia, hypertension,            (Choi et al., 2020; Nicolau and Bafadhel,
weight gain, osteoporosis, diabetes, infec-           2020). Complications of inhaled corticoster-
tions, and atrophy of the adrenal gland are           oids can be divided into local and systemic.
likely to appear (Table 1) (Schwartz et al.,          Local complications versus systemic compli-
1952; Silltzbach, 1952; Nagai, 1969).                 cations are minor problems but cannot be ig-
                                                      nored (Roland et al., 2004).
INHALED CORTICOSTEROIDS (ICSS)
                                                      Local side effects of inhaled corticosteroids
    Today, corticosteroids, like many other               Local side effects are one of the most
drugs, come in a variety of dosage forms in           commonly reported problems with inhaled
the pharmaceutical market. Corticosteroids in         corticosteroids following the accumulation of
the form of inhaled aerosols and powders are          particles in the upper respiratory tract (Barnes
also suitable dosage forms for patients with          and Pedersen, 1993; Hanania et al., 1995).
lung diseases like COPD and asthma, which             About 60 % of people treated with inhaled
are marketed in three forms of metered-dose           corticosteroids experience at least one local
inhaler (MDI), dry powder inhaler (DPI) and           complication (Dubus et al., 2001). In the fol-
nebulizers. High-volume spacer is also an             lowing, we will examine the common local
auxiliary device that could be related to MDIs        side effects of inhaled corticosteroids.
(Barnes and Pedersen, 1993; Roland et al.,
                                                      Oropharyngeal candidiasis
2004; Irwin and Richardson, 2006). As men-
                                                           Oropharyngeal candidiasis is a dose-de-
tioned earlier, there are ambiguities about the
                                                      pendent complication that depends on the
types of inhaled corticosteroids and their use
                                                      both total dose and the frequency of use. Tak-
in COVID-19. Some sources claimed that res-
                                                      ing it twice a day is less likely to cause can-
piratory patients with COVID-19 that take in-
                                                      didiasis than taking the same dose four times
haled corticosteroids had more severe conse-
                                                      a day (Barnes and Pedersen, 1993; Hanania et
quences than other patients (Nicolau and
                                                      al., 1995; Toogood, 1998). This complication
Bafadhel, 2020). Conversely, according to a
cohort study, inhaled corticosteroids in              is up to 70 % likely to occur and seems to be
                                                      less likely in children (Barnes and Pedersen,
COPD patients were not associated with an
                                                      1993; Hanania et al., 1995; Roland et al. 2004).

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Table 1: Corticosteroids used in COVID-19 with their specific side effects
                                            Types of com-
  Drug (dose; rout of administration)                                          Side effects
                                              plications
                                                                Sinus bradycardia, atrial fibrillation, atrial
                                                                flutter, ventricular tachycardia, hyperten-
                                            Cardiovascular
         Methylprednisolone                                       sion, myocardial infarction, acute heart
  (0.5-2 mg/kg daily for 7-14 days; in-                          failure, angina pectoris, ischemic stroke
              travenous)                       Hepatic                        Acute liver failure
                                               Cerebral                     Early or late epilepsy
                                              Pulmonary                     Pulmonary embolism
                                                                       Nausea, duodenitis, persistent
                                           Gastrointestinal
                                                                                  heartburn
                                            Psychological                   Depression, euphoria
                                                                 Hyperglycemia, fluid-electrolyte disturb-
                                                Others              ances, fungal or bacterial infections,
                                                                         glucosuria, hyperglycemia
                                                                Facial flushing, disturbance of taste, dis-
                                                                  tal paresthesia, insomnia, weight gain,
                                           Minor complica-
                                                                exacerbation of acne, Ankle edema, heel
                                                tions
                                                                  blister and bedsore, subcutaneous ne-
                                                                        crosis, deep vein thrombosis
                                                                Nausea, vomiting, abdominal distension,
                                           Gastrointestinal     elevated appetite or anorexia, gastric irri-
             Prednisolone                                          tation, increased risk of peptic ulcers
          (5-60 mg daily; oral)                                  PHA suppression, acute adrenal insuffi-
                                                Adrenal
                                                                                     ciency
                                           Other endocrine           Cushing's syndrome, amenorrhea,
                                              disorders                      menstrual disorders
                                                                 Increased motor activity, insomnia, rest-
                                                                lessness, Buffalo hump appearance, hy-
                                                                     perglycemia, mellitus diabetes, hy-
                                                                pocalcemia, edema, fluid-electrolyte dis-
                                                Others            turbance, fluid retention, elevated cal-
                                                                     cium excretion, weight gain, mood
                                                                changes, hypopigmentation or hyperpig-
                                                                  mentation of the skin, increased risk of
                                                                                  infections
           Dexamethasone                                         Gastric ulcers, gastrointestinal bleeding
                                           Gastrointestinal
    (8-10 mg every 6 hours; intrave-                               and perforation, nausea and vomiting
          nously for 4-6 days)                                  Glucose intolerance and hyperglycemia,
                                                                increased risk of infection especially fun-
                                                Others            gal infections, delayed wound healing,
                                                                 adrenal suppression, joint avascular ne-
                                                                        crosis, restlessness, flushing

                                                                Decreased sleep quality, anxiety, insom-
                                           Minor complica-
                                                                nia, increased sweating, hirsutism, cuta-
                                                tions
                                                                   neous purpura and facial rounding

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                                        Types of com-
Drug (dose; rout of administration)                                         Side effects
                                          plications
          Hydrocortisone                Cardiovascular                      hypertension
(200mg daily; continuous IV infusion    Major complica-
                                                               Hyperglycemia, urinary tract infection
for 5 days followed by dose tapering         tions
             until day 11)              Major complica-
                                                                Osteoporosis, headache, epistaxis
                                             tions

                                                              throat discomfort, dizziness, light-head-
                                                              edness, sleepiness, flushing of the face
                                        Minor complica-        and trunk, lack of appetite, nasal irrita-
                                             tions           tion, sneezing, nasosinus discomfort and
                                                                dryness of the mucous membranes,
                                                                       weight loss, infections

         Fludrocortisone                                       cardiac failure, systolic hypertension,
                                         Cardiovascular
       (50-200 μg/day; oral)                                                    stroke

                                                              Sodium retention, edema, weight gain,
                                             Others            hypertension, allergic reactions, sys-
                                                                   temic infections, depression

           Prednisone                      Skeletal                        Osteoporosis
      (2.5-7.5 mg daily; oral)          Gastrointestinal            Heartburn, diarrhea, nausea
                                            Renal                    Fluid retention, urination

                                                             myalgia, dermatologic events, insomnia,
                                                               mood changes, bloating, hot flashes,
                                        Minor complica-       joint swelling, depression or euphoria,
                                             tions             elevated appetite, tremor, dizziness,
                                                                swollen fingers and changes in fat
                                                                             distribution

           Cortisone                                          Constipation, abdominal cramps, nau-
      (100-150mg/day; oral)             Gastrointestinal     sea, vomiting, elevated appetite, gastric
                                                                         ulcer, diarrhea
                                                             Insomnia, mental stress, schizophrenia,
                                         Psychological
                                                                          talkativeness
                                            Skeletal                      Osteoporosis
                                         Cardiovascular                   Hypertension
                                            Adrenal                Atrophy of the adrenal gland

                                                             Hyperglycemia, moon shaped face, mild
                                                              acne, dizziness, glycosuria, headache,
                                             Others           palpitations, weakness, edema, sodium
                                                             retention, hypokalemia, weight gain, dia-
                                                                          betes, infections

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This complication is most often oral, and             day, even in high doses, is less likely to cause
esophageal types are rarely seen. People with         dysphonia and candidiasis (Toogood, 1998).
diabetes are much more prone to develop               Cough, bronchospasm, and throat irritation
esophageal candidiasis (Irwin and Richardson              Cough is one of the most common com-
2006). The main causes of this complication           plications of inhaled forms of corticosteroids,
are actually a decrease in local immunity and         which is mostly due to the presence of excip-
an increase in salivary glucose levels, both of       ients such as propellants and surfactants in the
which can lead to oral thrush (Roland et al.,         drug dosage form (Barnes and Pedersen,
2004). This complication is often self-limit-         1993; Hanania et al., 1995; Roland et al.,
ing, but the cumulative dose or frequency of          2004). These additives are found in MDIs,
use can be reduced to minimize candidiasis. It        and because DPI products do not contain
has also been shown that rinsing the mouth            these excipients, throat irritation and cough
and gargling after each use of the drug and us-
                                                      with DPI is less common (Barnes and
ing high-volume spacers can reduce the risk           Pedersen, 1993; Roland et al., 2004). To re-
of thrush (Barnes and Pedersen, 1993;                 duce the risk of this complication, spacers or
Hanania et al., 1995; Roland et al., 2004).           bronchodilators such as beta-agonists can be
Amphotericin B and nystatin are also good             used as a pre-treatment. Also, changing the
pharmacological treatments. Oral thrush is            MDI to DPI and reducing the respiration rate
usually well-tolerated and there is no need to        can be highly effective (Hanania et al., 1995;
stop the course of treatment (Barnes and              Irwin and Richardson, 2006). However, in a
Pedersen, 1993; Hanania et al., 1995).                group study on the local effects of corticoster-
Dysphonia and hoarseness of the voice                 oids on children, it was found that cough was
    Hoarseness is also a dose-dependent com-          the most probable side effect (40 % of the
plication of inhaled corticosteroids, but unlike      treated population) and most often occurred
candidiasis, it is not frequency-dependent. It        with a spacer (Dubus et al., 2001).
is very common and about one third to half of         Perioral dermatitis and changes in tracheo-
patients experience it (Barnes and Pedersen,          bronchial epithelium
1993). Not only does the use of high-volume                Corticosteroids cause noticeable changes
spacers not reduce this complication but also         in the skin due to inhibition of fibroblasts ac-
it increases the likelihood of hoarseness             tivity and reduced collagen synthesis, but due
(Barnes and Pedersen, 1993; Irwin and                 to structural differences in the epithelium of
Richardson, 2006). Dysphonia is up to 50 %            the mouth and respiratory tract compared with
likely to occur and usually presents with can-        the skin, these effects are negligible and insig-
didiasis (Hanania et al., 1995; Roland et al.,        nificant in inhaled corticosteroids (Hanania et
2004; Irwin and Richardson, 2006). The main           al., 1995). The probability of this side effect
reason is the movement disorder caused by             depends on the type of device and its accesso-
the effect of steroids on the muscles that con-       ries; so that in use with spacer and a face mask
trol the vocal cords (Hanania et al., 1995).          about 5 % and in use with a nebulizer (regard-
There are reports that dysphonia is less likely       less of the presence or absence of face mask)
to occur with DPI than MDI (Barnes and                up to 14 % of the population might get in-
Pedersen, 1993; Roland et al., 2004). This            volved (Dubus et al., 2001; Roland et al.,
complication is usually reversible after the          2004; Irwin and Richardson, 2006). To treat
end of treatment period, but to reduce the like-      this problem in severe cases, topical formula-
lihood of its occurrence, strategies such as re-      tions of erythromycin or metronidazole can be
ducing the dose, reducing vocal stress, and           used (Roland et al., 2004).
rinsing the mouth can be used (Barnes and
Pedersen, 1993; Hanania et al., 1995; Roland          Thirst
et al., 2004; Irwin and Richardson, 2006). It             Thirst is one of the most obvious effects
seems that taking budesonide DPI twice a              of inhaled corticosteroids, with a 20 % chance

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of occurring. Thirst can occur following              shorter the drug is in the bloodstream and the
throat irritation or candidiasis, but the most        sooner it is cleared from the blood, the less
important risk factor is concomitant treatment        systemic side effects it will have. Budesonide,
with inhaled corticosteroids and long-acting          for example, has fewer side effects than be-
beta-agonists (Dubus et al., 2001; Roland et          clomethasone due to its high clearance rate
al., 2004). Budesonide has been shown to be           and rapid hepatic metabolism (Hanania et al.,
safer than beclomethasone in many local side          1995). Lipophilic corticosteroids such as
effects, including thirst and cough (Irwin and        fluticasone and mometasone have a low clear-
Richardson, 2006).                                    ance rate due to high tissue uptake. Also, the
                                                      higher the protein binding of the drug and its
Tongue hypertrophy
                                                      hepatic first-pass metabolism, the less it is
    Tongue hypertrophy is one of the rarest
                                                      likely to cause side effects (Irwin and
side effects of inhaled corticosteroids with a
                                                      Richardson, 2006). Several recommendations
0.1 % chance of occurring, most commonly
                                                      can be made to reduce the systemic side ef-
associated with nebulizer use (Dubus et al.,
                                                      fects of inhaled corticosteroids. Poor inhala-
2001). The main cause of this complication,
                                                      tion techniques cause the drug to remain in the
which is more common in children and in-
                                                      mouth and throat, and as the drug enters the
fants, is the hypertrophy of the tongue muscle
                                                      bloodstream from the gastrointestinal tract,
and the local accumulation of fat in this area
                                                      the risk of systemic complications increases.
(Roland et al., 2004).
                                                      To solve this problem, a spacer can be used to
Respiratory infections                                strengthen the breathing technique. Also,
     At normal doses of inhaled corticoster-          rinsing the mouth and throat area after each
oids, there is no evidence of viral or bacterial      inhalation has a positive effect (Hanania et al.,
infection or an increase in the number of path-       1995). As the delivery of the drug to the
ogens present in the sputum. Higher doses re-         depths of the respiratory tract increases the ef-
quire further evaluation and study (Hanania et        ficacy of the drug and its systemic side effects
al., 1995).                                           increase. Therefore, the best solution is to re-
                                                      duce the dose of the drug so, it continues to
Systemic side effects of inhaled                      have its maximum effect. For example, the
corticosteroids                                       use of formulations that use hydrofluoroal-
    Inhaled corticosteroids enter the systemic        kane (HFA) instead of chlorofluorocarbon
bloodstream after taking two different routes.        (CFCs) allows the drug to be placed better in
Most of the drug is delivered to the lungs and        the lungs and so, the dose can be reduced
enters the bloodstream based on the rate and          (Irwin and Richardson, 2006). However, in-
extent of pulmonary absorption. Some por-             haled corticosteroids have fewer systemic
tion of the drug remains in the mouth and             side effects than systemic corticosteroids, and
throat and enters the gastrointestinal tract, in      this is a great advantage (Dahl, 2006b). In the
which case, after gastrointestinal absorption,        following, we will examine the systemic side
the drug undergoes the first-pass effect and          effects of inhaled corticosteroids.
then the rest enters the circulation (Barnes and
                                                      Hypothalamic–pituitary–adrenal (HPA) axis
Pedersen, 1993; Irwin and Richardson, 2006).
                                                      suppression
Systemic effects of inhaled corticosteroids of-
                                                          It has been shown that the use of oral and
ten occur over a long period of time and de-
                                                      injectable corticosteroids can cause adrenal
pend on several different factors including
                                                      suppression by reducing the production of
dose, frequency of use, site of absorption, lip-
                                                      ACTH in the pituitary gland, and thus, reduc-
ophilicity, individual differences, age, phar-
                                                      ing the secretion of cortisol in the adrenal
macogenetics,       and      pharmacodynamics
(Barnes and Pedersen, 1993; Hanania et al.,           gland. If this process continues, adrenal atro-
                                                      phy may be seen (Barnes and Pedersen,
1995; Irwin and Richardson, 2006). The
                                                      1993). Many studies have shown that this

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complication is also possible for inhaled cor-         Glaucoma
ticosteroids and in fact, it is the most serious           Because intraocular pressure does not
complication (Hanania et al., 1995; Dahl,              change much after inhaling corticosteroids,
2006b). This complication depends on the               the risk of glaucoma is substantially low but
dose, duration of treatment, frequency of use,         should be monitored for long-term use (Dahl,
route of administration, and time of use               2006b). In a review article on the side effects
(Barnes and Pedersen, 1993; Dahl, 2006b).              of inhaled corticosteroids, it was explained
The lower the dose and frequency, the less ad-         that primary open-angle glaucoma can be ex-
renal suppression will occur. Also, the closer         acerbated by inhaled corticosteroids, even at
the consumption time is to 08:00 am, the less          low doses, so the history of patients' family
ACTH will be inhibited (Barnes and                     should be checked (Toogood, 1998).
Pedersen, 1993). Beclomethasone and bude-              Effects on bone metabolism
sonide suppress the HPA pathway at doses
                                                            Corticosteroids play an important role in
greater than 1,500 and 400 micrograms per              bone formation by having a direct effect on
day, respectively, but ciclesonide appears to          osteoblasts and osteoclasts. Systemic cortico-
have no effect on cortisol secretion (Hanania          steroids have been shown to cause osteoporo-
et al., 1995; Dahl, 2006b). The degree of sup-         sis by increasing bone resorption and decreas-
pression of HPA axis by corticosteroids (de-           ing bone formation (Barnes and Pedersen,
termined by assessing changes in cortisol lev-         1993; Dahl, 2006b). Therefore, biochemical
els at different times of a day) is a good meas-       changes due to conversion in bone formation
ure of the severity of other systemic compli-          and resorption following the use of inhaled
cations (Dahl, 2006b).                                 corticosteroids can be expected (Hanania et
Cataracts                                              al., 1995). However, research studies show
     There are disagreements about this com-           that common doses in children are not associ-
plication in various studies. In general, poste-       ated with a decrease in bone density, and there
rior subcapsular cataracts are possible follow-        is no significant reduction in bone mass den-
ing steroid use. One report stated that there is       sity (BMD) in adults; but in long-term use, es-
a risk of posterior subcapsular cataracts (PSC)        pecially for people prone to osteoporosis such
following the use of inhaled beclomethasone            as postmenopausal women, this risk should be
and dexamethasone, but this is considerably            monitored regularly (Toogood, 1998; Dahl,
less likely than when these corticosteroids are        2006b; Irwin and Richardson, 2006). The risk
taken systemically (Barnes and Pedersen,               of fracture for users of inhaled corticosteroids
1993). Another study claims that taking in-            is minimal and there is no approved guideline
haled corticosteroids has a very low risk of           to prevent such side effects. Beclomethasone
cataracts, even at high doses (Hanania et al.,         has more adverse effects on bone than other
1995). In a review on the systemic effects of          corticosteroids and is not considered safe at
inhaled corticosteroids, it was stated that the        this point (Toogood, 1998).
risk of developing cataracts in children is            Growth
minimal and increases with age, but there was              Corticosteroids alter the growth process
no established link between them (Dahl,                by inhibiting the synthesis of type 1 collagen,
2006b). Unlike others, another review article          which is locally present in bones (Toogood,
stated that taking inhaled corticosteroids can         1998). In asthmatic children who use long-
double the risk of developing PSC (Toogood,            term inhaled corticosteroids, growth retarda-
1998). It also links this risk to current and cu-      tion is likely, especially in the lower leg.
mulative doses. More detailed studies are              However, children's height growth is a multi-
needed to determine the relationship between           factorial phenomenon, and this theory cannot
inhaled corticosteroid use and the incidence           be generalized (Dahl, 2006b). In fact, inhaled
of PSC.                                                corticosteroids alter a child's growth pattern,

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