Fimmu 14 1116131

TYPE Review
PUBLISHED 14 August 2023

DOI 10.3389/fimmu.2023.1116131
Pathophysiology and clinical

OPEN ACCESS management of coronavirus
EDITED BY
Severino Jefferson Ribeiro da Silva,
University of Toronto, Canada
disease (COVID-19):
REVIEWED BY
Shangwen Pan,
a mini-review
Huazhong University of Science and
Technology, China
Luiz Gonzaga Francisco De Assis Barros Ying Zhu 1,2, Lokesh Sharma 3* and De Chang 1,2*
D’Elia Zanella,
University of São Paulo, Brazil
1
College of Pulmonary and Critical Care Medicine, 8th Medical Center of Chinese PLA General Hospital,
Beijing, China, 2Department of Pulmonary and Critical Care Medicine, 7th Medical Center of Chinese
*CORRESPONDENCE PLA General Hospital, Beijing, China, 3Section of Pulmonary and Critical Care and Sleep Medicine, Yale
De Chang University School of Medicine, New Haven, CT, United States
changde@301hospital.com.cn
Lokesh Sharma
lokeshkumar.sharma@yale.edu
RECEIVED 05 December 2022 An unprecedented global pandemic caused by a novel coronavirus named SARS-
ACCEPTED 24 July 2023
CoV-2 has created a severe healthcare threat and become one of the biggest
PUBLISHED 14 August 2023
challenges to human health and the global economy. As of July 2023, over 767
CITATION
Zhu Y, Sharma L and Chang D (2023)
million confirmed cases of COVID-19 have been diagnosed, including more than
Pathophysiology and clinical management 6.95 million deaths. The S protein of this novel coronavirus binds to the ACE2
of coronavirus disease (COVID-19): receptor to enter the host cells with the help of another transmembrane protease
a mini-review.
Front. Immunol. 14:1116131. TMPRSS2. Infected subjects that can mount an appropriate host immune response
doi: 10.3389/fimmu.2023.1116131 can quickly inhibit the spread of infection into the lower respiratory system and the
COPYRIGHT disease may remain asymptomatic or a mild infection. The inability to mount a
© 2023 Zhu, Sharma and Chang. This is an strong initial response can allow the virus to replicate unchecked and manifest as
open-access article distributed under the
terms of the Creative Commons Attribution severe acute pneumonia or prolonged disease that may manifest as systemic
License (CC BY). The use, distribution or disease manifested as viremia, excessive inflammation, multiple organ failure, and
reproduction in other forums is permitted,
secondary bacterial infection among others, leading to delayed recovery,
provided the original author(s) and the
copyright owner(s) are credited and that hospitalization, and even life-threatening consequences. The clinical management
the original publication in this journal is should be targeted to specific pathogenic mechanisms present at the specific phase
cited, in accordance with accepted
academic practice. No use, distribution or of the disease. Here we summarize distinct phases of COVID-19 pathogenesis and
reproduction is permitted which does not appropriate therapeutic paradigms associated with the specific phase of COVID-19.
comply with these terms.
KEYWORDS
pathophysiology, clinical management, SARS-CoV-2, COVID-19, prevention
1 Introduction
The ongoing COVID-19 pandemic is entering its fourth year which began with the
identification of a group of patients with unknown pneumonia in Wuhan, China in
December 2019 (1). This is the third major coronavirus outbreak preceded by severe acute
respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), however, both
of these viruses were contained before causing the global pandemic. Since the emergence of
COVID-19, a significant proportion of the human population has been infected with SARS-
CoV-2, the causative virus of COVID-19 (2). The rapid spread of the virus allowed the virus
Frontiers in Immunology 01 frontiersin.org

Zhu et al. 10.3389/fimmu.2023.1116131
to evolve quickly to become more infectious. Multiple variants of the (16). In addition to the respiratory droplets and contact with
virus named Alpha, Beta, Gamma, Delta, and Omicron, have contaminated surfaces, infection by fecal-oral route has been
emerged during this pandemic and repeated infections have speculated (17). When SARS-CoV-2 initially infects people, the
become more common. Many of these variants have much higher viral spike (S) protein binds to the angiotensin-converting enzyme 2
infectivity compared to the original strain (3, 4). The continuous (ACE2) receptor, which mediates the entry of SARS-CoV-2 into
evolution of SARS-CoV-2 has caused unprecedented devastating host cells such as nasal, bronchial epithelial cells and pneumocytes
effects on human health and the global economy. As of July 2023, (18). The binding affinity of the S protein of SARS-CoV-2 with
more than 767 million cases of confirmed COVID-19 have been ACE2 is 10-20 folds higher than that of SARS-CoV, potentially
reported and the virus has claimed over 6.95 million lives (5). Beyond explaining the quick spread of this pandemic (19). S protein
the acute disease and death, the COVID-19 pandemic has touched undergoes further priming by type 2 transmembrane serine
every aspect of life including economic well-being, mental health, and protease (TMPRSS2), a cellular protease particularly present in
impaired services for other diseases leading to an increase in alveolar epithelial type II cells, which promotes viral uptake and
mortalities due to other diseases (6). Additional impacts include coronavirus entry. Generally, the ACE2 receptor is expressed in
impaired learning in children and stress among adults leading to multiple tissue cells, including airways, cornea, esophagus, ileum,
increased rates of suicide and self-harm (7). colon, liver, gallbladder, heart, kidney, and testis. TMPRSS2
Individuals infected by SARS-CoV-2 present with a wide range of expression has an even broader distribution implicating that
disease severity ranging from asymptomatic to severe disease that leads ACE2, rather than TMPRSS2, may be a limiting and major factor
to death. While in most of the subjects, COVID-19 manifests as a mild for viral entry at the early stage of the infection (20, 21). Notably,
flu-like disease, a small but significant number of patients develop ACE2 and TMPRSS2 can be targeted for drug intervention to
severe and often life-threatening diseases. A multitude of factors prevent the invasion and transmission of SARS-CoV-2 in host
contributes to the disease severity including viral load, inflammation, cells (22, 23). To further explain the mechanism of viral entry into
and immune response equilibrium. The life-threatening condition host cells, the binding of the S protein to ACE2 in the viral entry
occurs due to excessive inflammation and/or impaired viral clearance process involves several stages:
caused by aging, underlying diseases such as diabetes and hypertension, Attachment: The S protein of SARS-CoV-2 binds to the ACE2
and many other unknown factors (8, 9). Beyond the acute disease, the receptor on the surface of the host cell.
chronic consequences of COVID-19 are being documented that Priming: The S protein is then cleaved by a host protease
include severe life-altering changes such as chronic fatigue, impaired enzyme called TMPRSS2. This cleavage allows the S protein to
memory, and cognitive functions, among others (10, 11). undergo a conformational change, exposing a fusion peptide that
Significant progress has been made in our understanding of the facilitates the fusion of the viral membrane with the host
transmission mechanisms, preventive measures, vaccinations, and cell membrane.
therapeutic approaches to treat COVID-19. Despite these advances, Fusion: The viral membrane fuses with the host cell membrane,
COVID-19 remains one of the foremost healthcare challenges with allowing the viral genetic material (RNA) to enter the host cell.
significant morbidity, mortality, and economic costs each day Replication: Once inside the host cell, the viral RNA is used as a
across the world. Further, the continuous emergence of novel template to produce more viral proteins and RNA.
strains threatens our progress regarding both preventative and Assembly and Release: The newly produced viral proteins and
therapeutic approaches as immune evasion and antiviral RNA assemble into new viral particles, which are then released from
resistance are likely consequences of viral evolution. the host cell to infect other cells. Overall, the binding of the SARS-
The chronic sequelae of COVID-19, known as long COVID CoV-2 S protein to the ACE2 receptor on host cells plays a crucial
occurs in at least 10% of the infected individuals and poses a global role in the viral entry process and the subsequent development of
health challenge (12, 13). More than 200 symptoms have been COVID-19. Understanding the molecular mechanisms underlying
documented affecting multiple organ systems, with many patients this process is crucial for developing effective strategies to prevent
experiencing multiple symptoms simultaneously, affecting their and treat COVID-19 (15–18). More recent evidence has indicated
quality of life including the ability to return to work (14, 15). ACE2 independent entry of SARS-CoV-2 into the cells, especially in
Unfortunately, no validated effective treatments currently exist. the immune cells (24). The pathological consequences of ACE2-
This review provides updated insights into the pathophysiology of independent entry of the SARS-CoV-2 into host cells are not
COVID-19 and available therapeutic avenues to treat this deadly completely understood. Further, it remains unclear if the extra-
disease, with the aim of reducing COVID-19 incidence, pulmonary manifestations such as multi-organ failure are direct
hospitalization, mortality, and long COVID. consequences of viral infection to those tissues or a consequence of
host inflammatory response.
2 Pathophysiology
2.1 Interactions and entry of the 2.2 Early stage of infection
SARS-CoV-2 into the cell
Upon entry into cells in the upper respiratory tract, SARS-CoV-
Confirmed COVID-19 patients with symptoms and 2 starts to replicate and propagate in the nose and upper airways.
asymptomatic carriers are the primary source of new infections Although infected subjects may remain asymptomatic at this stage,

Zhu et al. 10.3389/fimmu.2023.1116131
they are highly infectious with a high viral load, which begins to host is able to mount a strong interferon-mediated response at
peak around symptom onset (25, 26). Subsequently, the virus may this stage, such as seen in children and adults, they may control the
migrate from the nasal epithelium to the upper respiratory tract via viral replication and limit the disease severity at this stage (26, 31,
the ciliated cells in the conducting airways (18, 27). The infected 32). The precise mediators of early viral clearance are not yet
individuals can shed viral particles by not only coughing or sneezing completely understood but given the potent antiviral activity and
but also during their day-to-day activities such as talking, eating, robust upregulation in those with a mild disease show a critical role
and even exhaling. Pre-symptomatic transmission is considered a of interferons in viral elimination (Figure 1) (32, 33).
significant contributor to viral transmission responsible for 9.1%-
62% of positive cases which vary from different literatures among
different populations (25, 28, 29). 2.3 Late stage of infection
The viral transmission also occurs during the symptomatic
disease and may even continue after symptoms are solved (30). Subjects that fail to eradicate the virus in its early stage, may
Infected individuals manifest the symptoms of fever, malaise, cough, progress to the clinical phase or later stage of the infection, which is
and sputum production at the early stage. The host mounts an manifested by COVID-19 symptoms that may vary in severity and
innate response that is mediated by cytokines and antiviral duration (34). It is estimated that 1/5th of the infected patients
interferons and initiates the adaptive immune response. If the progresses to the involvement of the lower respiratory tract that
FIGURE 1
The pathological manifestations of SARS-CoV-2 infection in the human body. Early stage: In the early stage of SARS-CoV-2 infection, the respiratory
epithelial cells were targets of the virus and the virus begins to replicate and spread in the nose and upper respiratory tract. The host mounts an
innate response mediated by cytokines and antiviral interferons that initiates the adaptive immune response. In the early stages, infected people
show the symptoms of fever, malaise, cough and sputum production and can transmit viruses to other people. If the host can mount a strong
interferon-mediated response at this stage and appropriate regulation of the host immunity relative to the viral burden, viral replication would be
arrested and viral clearance initiated to limit disease severity at this stage. Late stage: If the virus can’t be eradicated in a timely manner likely due to
a delayed PAMP-mediated inflammatory/interferon response, the immune response would shift to a nonspecific inflammatory reaction dominated
by damage-associated molecular pattern (DAMP) signaling emanating from damaged or dysfunctional virus-infected host cells. Immune cells
including CD4 helper T cells, and CD8 cytotoxic T cells are sequestered in the lung tissue. The host cells undergo persistent apoptosis or necrosis or
pyroptosis that may amplify the tissue damage. In addition, the inflammatory environment triggers the expression of activated tissue factor on
endothelial cells, macrophages, and neutrophils, thereby enhancing activation of the coagulation cascade in the lungs, causing microcirculatory
thrombi and ARDS and increasing disease severity and mortality.

Zhu et al. 10.3389/fimmu.2023.1116131
involves infection to the alveolar epithelial type II cells, developing Markers of the coagulation pathway such as upregulation of D-
severe symptoms like acute respiratory distress syndrome (ARDS), dimer are clearly visible at this stage. In an autopsy study,
disseminated intravascular coagulation (DIC), and pulmonary Wichmann et al. demonstrated that 58% of COVID-19 patients
embolism. The clinical phase of SARS-CoV-2 can be have a concurrency of DVT, and 1/3 of the deaths were directly
characterized into three distinct phases: acute or pneumonia caused by pulmonary embolism (PE) (47). The potential role of
phase, viremia phase, and lethal/recovery phase. thrombosis in pulmonary veins distal to the alveolar capillary bed,
The acute phase is characterized by pulmonary disease that is which should act as clot filters, has been pointed out, suggesting that
manifested by pulmonary symptoms such as dyspnea, cough, and it could be SARS-CoV-2-related vasculitis responsible for ischemic
sputum production with imaging evidence of ground-glass opacity manifestations in various organs (48). For this reason, severe
or consolidation in the lung. Diffuse alveolar damage, desquamation COVID-19 is not restricted to the respiratory system but is a
of pneumocytes, and hyaline membrane formation are observed multisystem disease including the development of various
during the development of ARDS in COVID-19 (35). The increased cardiovascular manifestations with myocardial injury, arrhythmia,
permeability of the lung vasculature impairs oxygen diffusion and acute coronary syndrome, and venous thromboembolism. These
contributes to the fatal disease. Factors contributing to lung manifestations are closely related to the disease severity and
permeability during COVID-19 are multifactorial and may progression to lethal disease (49). Based on all these features,
include 1. Direct cytopathic effects of coronavirus in infected anticoagulant therapy and immunomodulatory agents are
endothelium resulting in widespread endothelialitis (36). 2. The probably necessary to attenuate the hyperinflammatory and
reduction of ACE2 activity by SARS-CoV-2 and subsequent prothrombotic states (50). These patients may benefit from
increase in angiotensin indirectly boosting the kallikrein- immune modulators such as steroids while antiviral agents have
bradykinin pathway which promotes vascular permeability (37). limited utility at this stage of the disease. Despite the obvious
3. Inflammatory cytokines and vasoactive mediators secreted by contribution of coagulation pathways in vascular disease, the use
immune cells such as activated neutrophils induce the contraction of anticoagulant therapy may be filled with the risk of increased
of endothelial cells and loosen endothelial tight junctions. 4. bleeding. On the other hand, microcirculatory thrombi in capillaries
Glycocalyx degradation and hyaluronic acid deposition in the and large vessels may already cause extensive damage if
extracellular matrix promote fluid retention (38). The increased administered too late.
lung vascular permeability results in impaired lung function that
manifests into decreased blood oxygenation, a marker of
disease severity. 2.4 The complexity of immune response
The viremic phase begins when the virus enters the peripheral during COVID-19
blood. The molecular mechanisms of viremia in COVID-19 are still
poorly understood, however, ACE2 independent entry of the virus Exacerbated immune response manifested as cytokine storm is
in peripheral monocytes has been shown to promote pyroptotic cell a common pathological event in many infectious diseases. However,
death and disease severity (24). The viremia and subsequent host given the wide range of clinical presentations and extensive studies
response contribute to multiple systemic inflammation and performed on COVID-19, a clearer picture of beneficial and
multiorgan failure. The inflammatory response during severe pathological immune responses started to emerge. Host immune
COVID-19 is mediated by a simultaneous increase in the multiple response, initiated by sensing the pathogen-associated molecular
inflammatory cytokines such as IL-1a, IL-1b, IL-6, IL-8, IL-12, IL- patterns (PAMP) present on the pathogen strives to eliminate the
17), TNF- a, interferons (IFN- b, IFN- l), MCP-1, and MIP-1 a, invading pathogen. A multitude of evidence suggests that the initial
making it difficult to pinpoint the specific mediator of inflammatory host response is dampened markedly in severe COVID-19 patients,
response (39). Additionally, the early inflammatory response may especially those mediated by type I interferon (51, 52). Type I IFNs
help the host to limit viral replication, further complicating the role (IFN- a, IFN- b, IFN- w) are indispensable in viral clearance, and
of cytokines in COVID-19. It is not surprising that therapies this impairment is associated with high blood viral load and
targeting specific cytokines such as IL-6 or TNF- a led to mixed exacerbated inflammatory response (33). Additionally, the
results (40, 41). nucleocapsid (N) protein, one of the four structural proteins of
The lethal phase is mediated by a persistent disease that is CoV, serves as an antagonist of IFN, which appears to be beneficial
manifested both locally and systemically. The inflammatory for viral replication (53, 54). It was speculated that a large spectrum
response in the form of cytokine storm and coagulation factors is of severe clinical presentations could result from a delayed host
significantly elevated in severe patients compared to non-severe response towards a specific pathogen-associated molecular pattern
patients (42–44). In this phase, neutrophils, CD4 helper T cells, and (PAMP), which attenuates the antiviral innate immunity required
CD8 cytotoxic T cells are sequestered in the lung tissue (45). The to eliminate the pathogen. In support of this hypothesis, treatment
host cells undergo persistent apoptosis, necrosis, or pyroptosis, with type I interferon has shown beneficial effects in COVID-
which may amplify the tissue damage. In addition, the 19 (55).
inflammatory environment triggers the expression of activated Moreover, the postponement of the PAMP-mediated response
tissue factor on endothelial cells, macrophages, and neutrophils, shifts the immune response to a nonspecific inflammatory reaction
enhancing activation of the coagulation cascade in the lungs (46). dominated by damage-associated molecular pattern (DAMP)

Zhu et al. 10.3389/fimmu.2023.1116131
signaling emanating from damaged or dysfunctional virus-infected 3 Clinical management

host cells (56, 57). Although PAMPs and DAMPs can lead to innate
and adaptive immune responses, the latter raises additional damage 3.1 Prevention and self-protection
and dysfunction by releasing various pro-inflammatory cytokines
by activating dendritic cells and other antigen-presenting cells The origin of SARS-CoV-2 including the animal host still needs
(APCs). DAMPs initiate innate immune activation and systemic definitive identification (72). Most of the infections occur through
inflammation, which could further upregulate itself by triggering a human-to-human contact, either directly through droplets emitted
cytokine storm, providing positive feedback to tissue destruction. It from infected objects or indirectly by aerosols suspended in the air (73).
is not surprising that young subjects who remained asymptomatic Preventive measures such as mask/respirator use are highly effective if
post-SARS-CoV-2 infection had elevated levels of inflammatory used appropriately, although the quality of the mask/respirator is
cytokines such as IL-2 while decreasing levels of the anti- critically important. Although infections in healthcare workers have
inflammatory cytokine IL-10 (57). The current clinical challenge been reported, but larger outbreaks in the healthcare workers have been
remains to identify and distinguish the DAMP-driven immune rare, even before the availability of vaccines, due to the efficacy of
response from that driven by PAMPs. personal protective equipment. A nationwide cross-sectional study in
Similar to the innate immune response, the adaptive immune Bangladesh has proved that adequate preventive health measures were
response to SARS-CoV-2 infection has been studied in detail. associated with a lower risk of infection and death from COVID-19
Overall, it appears that the ability of the host to generate an early (74). Among preventive health measures, washing/cleaning hands with
humoral response rather than mounting a stronger humoral soap or hand sanitizer (OR: 0.17, 95% CI: 0.09–0.41), wearing masks
response is critical in protecting the host against severe disease. properly (OR: 0.02, 95% CI: 0.01–0.43), avoiding crowded places (OR:
Both delayed onset of the humoral response and elevated antibody 0.07, 95% CI: 0.02–0.19), and maintaining social distancing in public
titers are associated with severe disease in COVID-19 (58, 59). To places (OR: 0.04, 95% CI: 0.01–0.33), were significantly associated with
support this hypothesis, we have shown that the early onset of the reduced number of cases and deaths (74).
antibody response was associated with asymptotic disease and
patients with severe disease had elevated antibody response (60,
61). Along similar lines, convalescent plasma therapy provided 3.2 Early isolation and treatment settings
limited benefits in COVID-19, leading the World Health
Organization to issue guidelines against plasma therapy for Early isolation and appropriate duration of quarantine are
COVID-19 (62). required to stop or slow down the spread of COVID-19 or its
newly emerging variants. However, given the ubiquitous spread of
COVID-19, the availability of vaccines, effective therapeutic agents,
2.5 Long COVID and an overall decrease in the severe disease by new variants, most
countries are shifting their focus away from extensive quarantine
Despite the widespread prevalence of long COVID-19, the and isolation of suspected individuals. However, the experience
mechanistic understanding of underlying pathophysiology from this pandemic should guide us in future outbreaks to limit
remains limited. There are several suggested hypotheses for the both the disease spread and better deal with the social and economic
pathogenesis of long COVID-19 including the persistent exposure costs associated with the extensive quarantine.
of SARS-CoV-2 in tissues, dysregulation of the immune system,
reactivation of secondary pathogens (eg. EBV, HHV-6, HCMV,
VZV etc.), microbiome dysbiosis in the gastrointestinal system, 3.3 Vaccines
autoimmunity and immune priming from molecular mimicry,
microvascular blood clotting with endothelial abnormalities, and Vaccines are vital cost-effective tools to prevent the disease and
dysfunctional neurological signaling, among others (63–66). limit the disease severity during the COVID-19 pandemic. Effective
Increasing evidence have shown that two third of the population vaccine plays a critical role in preventing the viral spread and limiting
with long COVID is associated with multiple potential risk factors the disease severity (75). Multiple vaccines are currently available
and pre-existing conditions, including female sex, type 2 diabetes, including adenovirus vector vaccines, mRNA, inactivated, and subunit
underlying virus reactivation, the presence of specific vaccines. The initial data shows that among individuals ≥ 18 years of
autoantibodies, and connective tissue disorders (67–69). A higher age, adenoviral vector vaccines were 73% (95% CI = 69- 77) effective
prevalence of long COVID-19 has been reported in certain and messenger RNA (mRNA) vaccines were 85% (95% CI = 82- 88)
ethnicities, including people with Hispanic or Latino heritage (76). Existing adenovirus, mRNAs, and inactivated vaccines can elicit
(13). Lower income and lack of sufficient rest in the early weeks significant immune responses against SARS-CoV-2 RBDs in
after SARS-CoV-2 infection are associated with long COVID-19, vaccinated recipients, and individuals develop neutralizing
which is characterized by postexertional malaise, postural antibodies against the specific area within 30 days of the first and
orthostatic tachycardia syndrome, pain, fatigue, unrefreshing second doses of the vaccine (77). However, the efficacy figures of these
sleep, brain fog, cognitive dysfunction, gastrointestinal symptoms, vaccines are evaluated within the first 6 months post-vaccination. The
neurological symptoms, among others (70, 71). immunity gradually decreases over time, and breakthrough infections

Zhu et al. 10.3389/fimmu.2023.1116131
became common. In addition, mutations in the SARS-CoV-2 can other antiviral molecules. These agents vary in efficacy and adverse
subvert the immunity to cause infections in vaccinated subjects. effect profile. Some of the currently available agents are the following:
Boosting host immunity with additional doses of vaccines is
effective in limiting disease severity and death, especially among 3.5.1.1 Remdesivir
older patients. The beneficial effects of boosters among the young Remdesivir was originally developed as an antiviral agent against
subjects are difficult to decipher given low hospitalizations and Ebola, however, the clinical trials failed to show any effectiveness in
mortality in these subjects and potentially due to strong immune reducing the mortality (83). The mechanism by which remdesivir acts
response to initial vaccine doses. However, in patients with against viruses is by acting as a nucleoside analog and inhibiting
carcinomas and other immunosuppressive diseases, currently RNA-dependent RNA polymerase, which elicits the delay of the
available vaccines have shown to trigger sufficient immune response chain termination in the replication of the RNA genome (97). The
(78, 79). Further, variant-specific vaccines have been recently drug was then tested against SARS-CoV-2, where it was found to
developed and approved, however, the precise supremacy of variant- have potent antiviral effects during in vitro testing (98). These studies
specific vaccines in real-life settings is yet to be determined. led to its approval for emergency use in COVID-19. The initial
clinical studies show the clinical benefit of remdesivir in COVID-19
(84). This led to WHO recommending the use of remdesivir for
3.4 Diagnostic evaluation patients without severe or critical illness in April 2022. Subsequent
randomized clinical trials failed to show any beneficial effects of
Reliable clinical or laboratory parameters are of great remdesivir regardless of the severity of the disease (62, 83, 85). This
importance to accurately distinguish between COVID-19 and prompted WHO to recommend against the use of remdesivir in
respiratory infections of other origins. Individuals with typical COVID-19 regardless of disease severity (62).
respiratory symptoms such as fever, cough, and myalgia should
be tested by respiratory nucleic acid amplification test (NAAT) 3.5.1.2 Molnupiravir
through the specimen from bronchoalveolar lavage, sputum, and Molnupiravir is a ribonucleoside prodrug of N-hydroxycytidine
nasopharyngeal swab using real-time fluorescence polymerase (NHC) that effectively inhibits RNA viruses including SARS-CoV-2
chain reaction with reverse transcription (RT-PCR). Since false- (99). Large-scale clinical trials have shown its beneficial effects
negative results occur in the circumstance of low viral load in the during COVID-19 including decreasing hospitalizations and
initial screening, repeated testing should be performed if the mortality (86). Unlike remdesivir, this drug can be used orally,
symptoms continue to persist. Other measures such as computed allowing it to be administered early in high-risk subjects.
tomography (CT) examination can be performed for the auxiliary Subsequent studies have confirmed the beneficial findings, but the
diagnosis of COVID-19 which is manifested as patchy or segmental beneficial effects were limited to a 30% decrease in mortality due to
GGOs (93.3%) and reticular markings distributed by COVID-19 (100, 101). Another major concern is its efficacy against
peribronchovascular and subpleural (80). Although limitations novel variants. Initial data show the clinical benefit of molnupiravir
exist when some imaging signs of COVID-19 were presented as against alpha and beta variants, however, limited clinical data are
the same as those of other lung diseases. Chest CT is easy to perform obtained that molnupiravir exerts activity against delta and
and readily available to quickly detect lung lesions and make omicron variants (86, 102, 103). Recent evidences have indicated
imaging diagnoses at an early stage. Particular attention should be the potential benefit of molnupiravir against the omicron
paid to the final confirmation of a SARS-CoV-2 infection. In variant (104).
addition, patients with fever in the emergency department (ED)
should be monitored for the presence of SARS-CoV-2 (81). While 3.5.1.3 Paxlovid
nucleic acid-based tests or antigen detection tests are used for Paxlovid is one of the most effective and orally available
diagnostic purposes, antibody detection tests may be used to anticoronaviral medication against SAR-CoV-2. Paxlovid is a
assess the overall exposure in the population (82). combination of nirmatrelvir and ritonavir. Nirmatrelvir targets the
main polyprotein protease enzyme of SARS-CoV-2 in the replication
cycle, dramatically decreasing the viral loads (105). Ritonavir is a
3.5 Therapy and clinical management protease inhibitor and a CYP3A4 antagonist, inhibiting nirmatrelvir
breakdown and enhancing its pharmacokinetics (106). A double-blind,
The clinical management and target of currently used randomized, controlled trial with 2246 patients who received paxlovid
therapeutics against SARS-CoV-2 are demonstrated (Tables 1, 2) (300mg of nirmatrlvir and 100mg of ritonavir) showed 89% lower
(96). The clinical management of COVID-19 involves a wide range incidence of hospitalization and deaths attributed to any cause within
of antiviral and immune modulatory drugs that are described 28 days along with decreased viral load (87). Moreover, no obvious
below (Figure 2). safety concerns were observed besides mild generic side effects such as
bitter aftertaste, diarrhea, and fatigue. However, one should be careful
3.5.1 Antiviral drugs about drug-drug interactions and should not be co-administrated with
In the last four years, aggressive research allowed the other medicines that are metabolized by CYP3A4. Further, this is not
development of novel antiviral agents in addition to repurposing indicated in pregnant or breastfeeding patients.

Zhu et al. 10.3389/fimmu.2023.1116131
TABLE 1 Main findings of reported literature.
Authors Journal Year of Study Main findings

publication type
Zhou F Lancet 2020 Retrospective Potential risk factors such as older age and markers of disease severity such as high SOFA score, and
et al. (1) study elevated d-dimer could identify poor prognosis at an early stage.
Zhu N et al. N Engl J 2019 Descriptive Isolation of the virus and designated it as a novel beta coronavirus belonging to the sarbecovirus
(2) Med study subgenus of the Coronaviridae family. Further, described its specific cytopathic effects and morphology.
Wiersinga JAMA 2020 Systemic Described detailed aspects of transmission, infection, and treatment.
WJ et al. review
(34)
Spinner CD JAMA 2020 Randomized Investigated the effects of Remdesivir on clinical status at 11 days in moderate COVID-19 patients.
et al. (83) Clinical Trial Compared with standard care, patients in a 5-day course of remdesivir administration had a statistically
significant difference in clinical status, while patients treated in a 10-day regimen of remdesivir did not
have a statistically significant difference.
Beigel JH N Engl J 2020 Randomized Remdesivir was superior in shortening the time to recovery in adults who were hospitalized with
et al. (84) Med Clinical Trial COVID-19.
Wang Y Lancet 2020 Randomized Remdesivir was not associated with statistically significant clinical benefits in adult patients admitted to
et al. (85) Clinical Trial hospital for severe COVID-19.
Jayk Bernal New Eng 2021 Randomized Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated
A et al. (86) J Med Clinical Trial adults with COVID-19.
Hammond J N Engl J 2022 Randomized Treatment of symptomatic COVID-19 with nirmatrelvir plus ritonavir resulted in an 89% reduction in
et al. (87) Med Clinical Trial the risk of progression to severe COVID-19 than that with a placebo. No major safety concern was
reported.
Dougan M N Engl J 2021 Randomized In high-risk outpatients, bamlanivimab plus etesevimab resulted in a lower incidence of COVID-19-
et al. (88) Med Clinical Trial related hospitalizations and deaths than placebo and accelerated the decline in SARS-CoV-2 viral load.
Weinreich N Engl J 2021 Randomized The REGN-COV2 antibody cocktail reduced viral loads, with greater effect in patients whose immune
DM et al. Med Clinical Trial response had not yet started or who had high viral loads at baseline. Safety results were similar in the
(89) REGN-COV2 combined dose groups and the placebo group.
Chen P N Engl J 2021 Randomized Evaluated the quantitative virologic end points and clinical outcomes in patients receiving a single
et al. (90) Med Clinical Trial intravenous infusion of neutralizing antibody LY-CoV555 in one of three doses (700 mg, 2800 mg, or
7000 mg) or placebo. This interim analysis of a phase 2 trial showed that one of three doses (2800 mg)
of neutralizing antibody LY-CoV555 appeared to accelerate the natural decline in viral load by day 11.
Cohen MS JAMA 2021 Randomized Among residents and staff in skilled nursing and assisted living facilities, treatment during August-
et al. (91) Clinical Trial November 2020 with bamlanivimab monotherapy reduced the incidence of COVID-19 infection (8.5%
vs 15.2%; odds ratio, 0.43 (95% CI, 0.28-0.68); P < .001; absolute risk difference, -6.6 (95% CI, -10.7 to
-2.6) percentage points).
Guimaraes New Eng 2021 Randomized Among patients hospitalized with COVID-19 pneumonia, tofacitinib led to a lower risk of death or
PO, et al. J Med Clinical Trial respiratory failure on day 28 than placebo (18.1% vs 29.0%; risk ratio, 0.63; 95% confidence interval
(92) (CI), 0.41 to 0.97; P = 0.04).
Cao Y et al. J Allergy 2020 Randomized Ruxolitinib recipients had a numerically faster clinical improvement at day 14 (90% from the ruxolitinib
(93) Clin Clinical Trial group showed computed tomography improvement compared with 61.9% in control group; P =0.0495).
Immunol Significant chest computed tomography improvement, a faster recovery from lymphopenia, and
favorable side-effect profile in the ruxolitinib group.
Shen C JAMA 2020 Case series In this preliminary uncontrolled case series of 5 critically ill patients with COVID-19 and ARDS,
et al. (94) administration of convalescent plasma containing neutralizing antibody was followed by improvement in
their clinical status with decreasing the SOFA score and increasing the Pao2/Fio2 within 12 days. The
limited sample size and study design preclude a definitive statement about the potential effectiveness of
this treatment, and these observations require evaluation in clinical trials.
Simonovich N Engl J 2021 Randomized No significant differences were observed in clinical status (odds ratio, 0.83; 95% confidence interval (CI),
VA, et al. Med Clinical Trial 0.52 to 1.35; P = 0.46) or overall mortality (10.96% in the convalescent plasma group and 11.43% in the
(95) placebo group, 95% CI, -7.8 to 6.8) between patients treated with convalescent plasma and those who
received placebo.
3.5.2 Monoclonal antibodies Klank et al. reported that monoclonal antibodies (mAbs) such as
Neutralizing antibodies targeting the spike protein of the Bamlanivimab can be used in both preventive and treatment settings
coronavirus is another important pillar in the fight against SARS- (108). In addition, casirivimab and imdevimab also showed a positive
CoV-2 infection, especially in immunocompromised patients (107). protective effects, as SARS-CoV-2 negative individuals who received

Zhu et al. 10.3389/fimmu.2023.1116131
TABLE 2 Indications and contraindications of drugs in the treatment of COVID-19.
Drugs Indications Contraindications

Antiviral drugs
Paxlovid is a combination therapy for the treatment of mild to

Paxlovid is contraindicated in patients with a known hypersensitivity to any
Paxlovid moderate COVID-19 in patients who are at high risk of progression
component of the medication.
to severe COVID-19.
Molnupiravir is contraindicated in patients with a known hypersensitivity to

any component of the medication.
Molnupiravir is an antiviral medication for the treatment of
Also, Molnupiravir is not authorized for use in patients aged <18 years; not
Molnupiravir COVID-19 in adults who are at risk of progression to severe
authorized for initiation of treatment in patients requiring hospitalization
COVID-19 and/or hospitalization.
owing to COVID-19; not authorized for use for >5 consecutive days
Not authorized for preexposure or postexposure prophylaxis of COVID-19.
Remdesivir is an antiviral medication for the treatment of COVID-

Remdesivir is contraindicated in patients with a known hypersensitivity to any
Remdesivir 19 in adults and pediatric patients (12 years of age and older and
weighing at least 40 kg) requiring hospitalization.
Monoclonal antibodies
Bamlanivimab and etesevimab are monoclonal antibodies indicated

Bamlanivimab for the treatment of mild to moderate COVID-19 in patients who
There are no known contraindications for Bamlanivimab and etesevimab.
and etesevimab are at high risk of progression to severe COVID-19 and/or
hospitalization.
Casirivimab and imdevimab are monoclonal antibodies indicated

Casirivimab for the treatment of mild to moderate COVID-19 in patients who
There are no known contraindications for Casirivimab and imdevimab.
and imdevimab are at high risk of progression to severe COVID-19 and/or
hospitalization.
IL-6R inhibitor/Immune Modulators
Tocilizumab is an immunosuppressive medication used to treat

Tocilizumab is contraindicated in patients with a known hypersensitivity to
moderate to severe rheumatoid arthritis, juvenile idiopathic arthritis,
Tocilizumab any component of the medication. For all immunosuppressive treatments,
giant cell arteritis, and cytokine release syndrome caused by CAR T-
secondary bacterial and fungal infections should be closely monitored.
cell therapy or COVID-19.
Sarilumab is an immunosuppressive medication used to treat

Sarilumab is contraindicated in patients with a known hypersensitivity to any
Sarilumab moderate to severe rheumatoid arthritis and cytokine release
syndrome caused by CAR T-cell therapy or COVID-19.
Baricitinib is an immunosuppressive medication used to treat

Baricitinib is contraindicated in patients with a known hypersensitivity to any
Baricitinib moderate to severe rheumatoid arthritis and COVID-19 in
combination with remdesivir.
Ruxolitinib is an immunosuppressive medication used to treat

Ruxolitinib is contraindicated in patients with a known hypersensitivity to any
Ruxolitinib certain types of bone marrow disorders and cytokine release
Tofacitinib is an immunosuppressive medication used to treat

Tofacitinib is contraindicated in patients with a known hypersensitivity to any
Tofacitinib moderate to severe rheumatoid arthritis and cytokine release
Systemic corticosteroids
Dexamethasone is contraindicated in patients with a known hypersensitivity to

Dexamethasone is a corticosteroid medication used to treat a variety
any component of the medication. It should also be used with caution in
Dexamethasone of inflammatory and autoimmune conditions, as well as to reduce
patients with certain infections, such as systemic fungal infections, due to the
inflammation in certain types of cancer.
risk of exacerbating the infection.
the specific mAbs appear to have a lower risk of developing COVID- receiving the drug showed a lower hospitalization rate (2.1% vs. 7.0%;
19 after contact with an infected individual (1.5% versus 7.8%; p<0.001) and a significant reduction in viral load at day 7. Other
P<0.001). Further, the symptom duration of patients suffering from commercially available mAbs such as casirivimab and imdevimab
COVID-19 was shown to be shorter than that of patients on placebo have also shown a positive effect in protecting against reducing viral
(109). Given these promising protective effects, a combination of loads and hospitalization rates and thereby reducing mortality (89,
bamlanivimab and etesevimab could be a potential treatment option 90). mAbs probably have the greatest beneficial effects in the early
for immunocompromised patients. In a phase 2/3 study, a phase of coronavirus infection, where viral replication plays an
combination of bamlanivimab and etesevimab was given to patients important role (110, 111). Serious adverse effects, including allergic
with malignancies or to those who were in an immunosuppressive reactions and cardiac issues such as atrial fibrillation, have occurred
status with COVID-19 (88). Compared to the placebo group, patients and require caution following mAbs infusion (91).

Zhu et al. 10.3389/fimmu.2023.1116131
FIGURE 2
The clinical management and target of currently used therapeutics against SARS-CoV-2. Prior to clinical infection with coronavirus, effective
vaccines including adenovirus vector vaccines, mRNA, inactivated, and subunit vaccines play critical roles in preventing virus spread and limiting the
severity of the infection. The clinical management and target of currently used therapeutics against SARS-CoV-2 are shown based on the disease
severity. Monoclonal antibodies including casirivimab & imdevimab and bamlanivimab & etesevemab have been used in non-severe cases. Likewise,
antiviral drugs such as Paxlovid (nirmatrelvir & ritonavir), molnupiravir and remdesivir, which target the virus replication in the infected cells have
been used in mild-to-moderate patients. For severe to critically illness, corticosteroids and CRS management including IL-6R inhibitor and JAK
inhibitors were administrated to control the excessive inflammation. Anticoagulants have been used to prevent and treat DVT. Supportive respiratory
managements have been primary measures to treat patients with low blood oxygenation including ARDS. DVT, deep venous thrombosis; ARDS,
acute respiratory distress syndrome.
In general, monoclonal antibody therapy is recommended for Since IL-6 is identified as the key propagator of the cytokine storm
patients with mild to moderate COVID-19 who are at high risk for reaction, blocking the two forms of the IL-6 receptor, a membrane-
disease progression. High-risk factors include older age, obesity, bound and a soluble IL-6 receptor was considered. IL-6 receptor
diabetes, chronic kidney disease, or immunosuppression. When it blockers, including tocilizumab and sarilumab, are recommended to
comes to the choice of dose, the specific monoclonal antibody and be used intravenously for severe or critical illness patients of COVID-
the patient’s weight are taken into consideration. For example, for 19 based on evidence of mortality reduction and decreased
the monoclonal antibodies bamlanivimab and etesevimab, the requirement of mechanical ventilation (112, 113). However, this is
recommended dose is 700mg bamlanivimab and 1400mg only effective in those with severe disease.
etesevimab administered together intravenously for patients
weighing at least 40 kg (83, 97). The decision to use monoclonal 3.5.3.2 Janus (JAK) kinase inhibitors
antibodies and the choice of dose should be made by a healthcare Janus kinases are important mediators of cytokine storm and
professional based on the individual patient’s clinical situation. inflammation and serve as a potential target for limiting cytokine
storm during COVID-19. Baricitinib, ruxolitinib and tofacitinib are
3.5.3 Management of cytokine release syndrome three major JAK inhibitors tested for severe or critical COVID-19
A number of therapies targeting a specific or broad range of patients (92, 93, 114). The three JAK blockers are considered
cytokines have been tested in COVID-19. Here we describe major nonspecific despite evident differences. Baricitinib is mainly
approaches to reduce the cytokine storm to alleviate the disease severity. described as a JAK1/2 inhibitor while ruxolitinib also presents the
weak suppression of TYK2 except from JAK1/2, while tofacitinib
3.5.3.1 IL-6 receptor blocker showed more inhibitory potential on JAK1/3 than JAK2/TYK2
Cytokine storm responses pose a significant risk in infectious (115, 116). Although large randomized clinical trials have been
diseases including COVID-19. IL-6 is a pleiotropic cytokine limited, our meta-analysis demonstrated the overall beneficial
stimulating and regulating the immune response during infections. effects of JAK inhibitors in COVID-19 (55).

Zhu et al. 10.3389/fimmu.2023.1116131
3.5.4 Systemic corticosteroids and outcomes (135). In addition, it is recommended that negative
Systemic corticosteroids are generally recommended in treating pressure rooms be used to reduce the risk of the coronavirus spread
severe and critical COVID-19 patients to control the over-activated in the ambient air (45). A large, international systematic review and
inflammatory response despite confounding results (117, 118). meta-analysis was conducted to examine global case fatality rate
Patients younger than 70 years with persistent symptoms for more (CFR) reports in adult patients with COVID-19 who received
than seven days and who required mechanical ventilation are shown invasive mechanical ventilation (IMV). The results showed that
to benefit from dexamethasone therapy (119). In contrast, no clinical the overall estimate for the initial CFR in IMV was 45%. Reported
improvement was observed in patients with a shorter duration of CFR was higher in elderly patients and in early pandemic
symptoms and without supplemental oxygen, even in COVID-19- epicenters, which may be impacted by limited ICU resources
induced mild to moderate ARDS (120). The optimal timing of the (136). However, IMV is used for crucial supportive care and to
therapy from symptom onset is still a matter of debate. Theoretically, provide additional time for patients with severe hypoxemic
it can be speculated that systemic glucocorticoid use should be respiratory failure in the ICU. Further, invasive mechanical
avoided until viral replication is under control by the immune ventilation may increase the risk of secondary bacterial infections
system or through effective antivirals. The consensus is arising that in COVID-19 patients by either directly breaching the host defense
corticosteroids should be administered in patients with severe or or through coronavirus-impaired host immunity (137).
critical COVID-19, even within seven days of symptoms onset, and
non-severe cases should not be treated with corticosteroids even
though symptoms occur longer than a week (62). 4 Conclusion
Our understanding of COVID-19 pathology, clinical
3.5.5 Convalescent plasma therapy
management, and treatments has improved significantly in the
Convalescent plasma therapy is one of the experimental
last four years. However, the persistent emergence of variants
treatments for SARS-CoV-2 infection. The antiviral neutralizing
poses a serious challenge to the effectiveness of both preventive
antibodies collected from the plasma of recovered patients are
and therapeutic approaches. The clinical management of these
transfused into the COVID-19 patients with an active infection to
infections faces several problems, including failure to administer
enhance the immune response (94, 95, 121). Such plasma therapy has
early antiviral agents, high false-negative diagnosis rates, mixed
shown a promising recovery rate in H5N1 influenza and Ebola viral
reports on certain therapeutic drug efficacy, and rapid progression
disease (122–124). However, due to different methodologies,
to severe conditions such as ARDS, pulmonary embolism,
appropriate antibody titers ranging from 1:100 to 1:2560 have been
disseminated intravascular coagulation, sepsis, and cytokine
reported in the existing studies from donor to recipient (125, 126). The
storm. The global fight against COVID-19 is likely to continue
range is confusing and the uncertainty of the definitive dose lies in the
for a long time until we develop effective and clinically proven
different limit values (127, 128). WHO living guidelines recommend
antiviral therapeutics or vaccines that completely prevent
this therapy applied to patients with severe illness, but only in research
transmission of the disease. Further, as we emerge from the
settings or clinical trial, for the reasons that convalescent plasma
pandemic, special emphasis should be given to the chronic
therapy has no significant effect on the indicators such as time to
consequences such as long COVID-19, which may become a
symptom improvement, length of hospital stay, duration of
serious healthcare challenge in upcoming years.
mechanical ventilation, or mortality (62, 129).
3.5.6 Supportive respiratory management Author contributions

Mechanical ventilation and supplemental oxygen are the
primary measures for addressing those who present with low YZ wrote the initial draft, prepared the figures, and tables. LS
blood oxygenation. High flow nasal cannula (HFNC), Non- and DC edited the manuscript and provided guidance. All authors
invasive ventilation (NIV), and lung-protective invasive contributed to the article and approved the submitted version.
mechanical ventilation (IMV) are widely used to support
respiration (130, 131). Given the rapid decompensation due to
early intubation strategies, HFNC was selected early in the Funding
pandemic and used in the populations with hypoxemic
respiratory failure and patients often respond well (132, 133). This work was supported by funding from The National Key
However, HFNC and other NIV devices, including non-invasive Research and Development Program of China (DC;
bi-level positive pressure ventilation (BPAP) and continuous No.2021YFC2302300), Three Talents One Team Project of The
positive airway pressure (CPAP), may pose a potential risk of Joint Logistic Support Force (DC; 2021-439), Beijing Nova Program
aerosolization of the virus. For further safety in HFNC use, Interdisciplinary Cooperation Project (DC; No. 20220484197),
evidence has supported the use of a surgical mask (134). CPAP Three and One Innovation Talents from Chinese PLA General
via a mask covering the mouth and nose or helmet NIV is Hospital (DC; No. 20230315, The grant of Eight Medical Center of
recommended to minimize room air contamination and to better Chinese PLA General Hospital (DC; NO. YQ202211001,
contain aerosol leakage, providing superior oxygenation, pressure, No MS202211014, the National Natural Science Foundations of

Zhu et al. 10.3389/fimmu.2023.1116131
China (No. 81700069), and Major Project of Eighth Medical Center Publisher’s note
of Chinese PLA General Hospital (No.2021ZD005).
All claims expressed in this article are solely those of the authors
Conflict of interest and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
The authors declare that the research was conducted in the reviewers. Any product that may be evaluated in this article, or
absence of any commercial or financial relationships that could be claim that may be made by its manufacturer, is not guaranteed or
construed as a potential conflict of interest. endorsed by the publisher.
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Pathophysiology and clinical

pathophysiology, clinical management, SARS-CoV-2, COVID-19, prevention

Frontiers in Immunology 01 frontiersin.org

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signaling emanating from damaged or dysfunctional virus-infected 3 Clinical management

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TABLE 1 Main ﬁndings of reported literature.

Authors Journal Year of Study Main ﬁndings

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TABLE 2 Indications and contraindications of drugs in the treatment of COVID-19.

Drugs Indications Contraindications

Paxlovid is a combination therapy for the treatment of mild to

Molnupiravir is contraindicated in patients with a known hypersensitivity to

Remdesivir is an antiviral medication for the treatment of COVID-

Bamlanivimab and etesevimab are monoclonal antibodies indicated

Casirivimab and imdevimab are monoclonal antibodies indicated

IL-6R inhibitor/Immune Modulators

Tocilizumab is an immunosuppressive medication used to treat

Sarilumab is an immunosuppressive medication used to treat

Baricitinib is an immunosuppressive medication used to treat

Ruxolitinib is an immunosuppressive medication used to treat

Tofacitinib is an immunosuppressive medication used to treat

Dexamethasone is contraindicated in patients with a known hypersensitivity to

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3.5.6 Supportive respiratory management Author contributions

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