Pathophysiology of Covid-19 Infection: What Is The Novel Coronavirus (Sars-Cov-2) Doing To Body? A Comprehensive Systematic Review

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Pathophysiology of COVID-19 infection: what is the novel coronavirus (SARS-

CoV-2) doing to body? A comprehensive systematic review
Article in Reviews in Medical Microbiology · August 2020

DOI: 10.1097/MRM.0000000000000247
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Pathophysiology of COVID-19 infection: what is the

novel coronavirus (SARS-CoV-2) doing to body?
A comprehensive systematic review
Mohammadreza Hashemi Aghdama, Ramin Hosseinzadehb,
Behzad Motallebizadehc, Mohammadreza Rezaeimehrd,
Leila Khedmate, Zahra Soleimanif, Mohammad Heiatg,
Mehrdad Moosazadeh Moghaddamh,
Mohammadali Abyazig and Ashraf Karbasig
Downloaded from http://journals.lww.com/revmedmicrobiol by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3q7dCwSUxuLiHU68nY/4ZOhTqgo1EHZt7s2MYtO2FfrI= on 10/04/2020
Since December 2019, an emerging outbreak of a novel coronavirus (SARS-CoV-2) has

begun from Wuhan, China, and spread rapidly throughout the world. This systematic
review aimed to discuss the involvement of the body’s systems during COVID-19
infection comprehensively. PubMed database was used to identify relative studies to be
included in this review. Four authors searched PubMed independently using deter-
mined search terms. Then, the results were merged and duplicates were removed. The
inclusion and exclusion criteria were specified and at least two review authors assessed
the eligibility of the studies. The full texts of included studies were reviewed in detail by
the authors and the relevant content was extracted and summarized. The pulmonary
tract is the most frequent system involved with a wide range of involvement from no
pneumonia to white lung and acute respiratory distress syndrome. Computed tomog-
raphy is the best imaging modality to diagnose COVID-19 infection. Cardiac and renal
system injuries are seen during COVID-19 infection and must be taken seriously.
Gastrointestinal manifestations are frequently observed during the infection and are
probably associated with more severe disease. The placenta acts as an important
physiological and immunological barrier that prevents transplacental vertical transmis-
sion. COVID-19 infection is a multiorgan involving infection which needs a team of
different expertise to diagnose and manage the disease. Although there are many studies
available about COVID-19 infection, most of them are focused on pulmonary involve-
ment and the effects of the virus on many other organs and systems remain unclear that
shows the necessity of further investigations about the disease.
Copyright ß 2020 Wolters Kluwer Health, Inc. All rights reserved.
Reviews in Medical Microbiology 2020, 31:000–000
Keywords: COVID-19, nCoV-2019, pathophysiology, SARS-CoV-2
a
Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran, bFaculty of Medicine, Mashhad University of Medical
Sciences, Mashhad, Iran, cFaculty of Medicine, Alborz University of Medical Sciences, Karaj, Iran, dShiraz Nephro-Urology
Research Center, Shiraz University of Medical Sciences, Shiraz, Iran, eHealth Management Research Center, Iran, fNephrology
and Urology Research Center, Iran, gBaqiyatallah Research Center for Gastroenterology and Liver Diseases, Iran, and hApplied
Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
Correspondence to Ashraf Karbasi, MD, Associate Professor Gastroenterologist, Baqiyatallah Research Center for
Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran.
E-mail: [email protected]
Received: 18 July 2020; accepted: 21 July 2020.
DOI:10.1097/MRM.0000000000000247
Copyright © 2020 Wolters Kluwer

ISSN 0954-139X Health,
Copyright Q 2020Inc. Unauthorized
Wolters reproduction
Kluwer Health, of reserved.
Inc. All rights this article is prohibited. 1
RMM-D-20-00087
2 Reviews in Medical Microbiology 2020, Vol 00 No 00
section was done by two authors due to large number of

Highlights:
articles discussing its involvement during COVID-19
infection. Also, obstetrics and gynecology section was
COVID-19, an emerging outbreak, has
done by two authors.
involved millions of people and turned to
a global crisis.
Eligibility criteria
This multiorgan involving disease has
Any study discussing the different aspects of respective
major effects on pulmonary, cardiac, renal,
body internal organs’ involvement during COVID-19
gastrointestinal and hepatic systems.
infection was eligible to enter this review. In this review,
Multifaceted property of COVID-19, justifies
we specifically discuss multiorgan involvement during
more investigations in other involved area
COVID-19 infection and studies concerning other
apart from pulmonary system.
coronaviruses such as SARS-CoV and MERS-CoV were
not of interest generally.
Information sources
Background Studies were identified by searching within electronic
database of PubMed. No language limit was applied, but
In the last 20 years, the viruses of Coronaviridae family have articles in other languages were excluded unless there was
caused three epidemics. The last epidemic caused by SARS- a useful translated abstract. There was 2019–2020 time
CoV-2 which is currently happening was started in period limitation for study selection.
December 2019 in Wuhan, China. The viruses of
Coronaviridae family which are morphologically known by Search
a crown like spike on their envelope are RNA viruses with a To find all the articles related to the subject of this review,
large genome that makes them very potent for mutations and four authors searched PubMed independently using the
asa result,they haveagreatpotential toinitiatenewepidemics following search terms. First, we used the search term
[1]. The average incubation period in which the infected ‘COVID-19 OR SARS-CoV-2 OR nCoV-2019’ to
individual can infect other people is 5.2 days varying in address all articles related to SARS-CoV-2. Then, we
different patients [2,3]. Clinical manifestations of the disease used the following search terms with Boolean operator of
have a very wide spectrum from asymptomatic to acute ‘AND’ to access the related articles for each section of the
respiratory distress syndrome (ARDS); however, the main review: ‘pathology OR pathogenesis OR characteristics’,
clinical manifestations are fever, dry cough, dyspnea, muscle ‘imaging or CT or X-Ray OR complication OR
pain, diarrhea, nausea and vomiting. Conjunctivitis is also prognosis’ and ‘ARDS OR respiratory failure’ for
known as a disease symptom [4]. The situation in about 20% pulmonary system section, ‘GI OR digestive OR fecal’
of patients progress to pneumonia after a week which can for gastrointestinal section, ‘liver OR hepatic’ for liver
result in ARDS and death in some of them [5]. Severe-critical section, ‘myocarditis OR cardiovascular OR cardiomy-
cases are usually presented with respiratory, cardiac or renal opathy OR arrythmia OR heart OR cardiac OR
failure and ARDS ending up with death [6]. The mortality cardiogenic’ for cardiovascular section, ‘renal OR kidney
rate of the disease is about 2–3% and 4–11% in those who OR nephropathy’ for renal tract involvement and
needed admission [7]. In this review, we have focused on ‘pregnancy OR postnatal OR vertical transmission
COVID-19 multiorgan involvement and its multiorgan OR neonates’ for obstetrics and gynecology section.
effects on the body.
Study selection
We included any original research concerning about
involvement of body’s different organs and systems during
Methods COVID-19 infection. Studies concerning other issues
related to COVID-19 such as prevention, treatment and
Protocol and registration COVID-19 in special populations were not of interest
The current study was designed to provide a compre- and excluded from the review. Eligibility assessment and
hensive view of different and the most vulnerable organs’ inclusion and exclusion decisions were performed
involvement during COVID-19 infection including independently in an unblinded standardized manner by
pulmonary system, cardiovascular system, renal tract, at least two review authors through screening titles,
gastrointestinal tract and liver. In addition, we discussed abstracts and full texts. Conflicts between reviewers were
obstetrics-related effects of COVID-19. It is worth resolved by consensus. Some studies have been used in
noting that we aimed not to discuss diagnosis and two or more sections.
treatment issues and we only focused on different aspects
of body internal organs’ involvement during COVID-19 A total of 2688 studies (up to 15 June 2020), were
infection. To achieve this aim, one independent author recognized to be included in this review. Of these, 1386
was assigned to each section. Just pulmonary system studies were discarded after screening titles and abstracts
Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
RMM-D-20-00087
Pathophysiology of COVID-19 infection Aghdam et al. 3
Fig. 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram of study selection.
due to the mismatch between them and the inclusion been summarized in Fig. 1. These findings have been
criteria. Full texts of the remaining 1302 studies were discussed in detail in the following sections (Fig. 2).
reviewed in a detailed manner. Among remaining studies,
1167 studies were excluded from the review because of Lungs
addressing other aspects of COVID-19 out of the interest Immune system response and microscopic findings
of this review or concerning about SARS-CoV and Several studies have shown that SARS-CoV-2 uses the
MERS-CoV or low sample size and low quality. same receptor as SARS-CoV (ACE2) [1,8–10]. ACE2 is
Remaining 135 studies met the inclusion criteria and expressed on alveolar epithelial cells types I and II. Men
were eligible to be included in the systematic review. No have greater expression of ACE2 in their alveolar
unpublished relevant studies were obtained (Fig. 1). epithelial cells than women. Asians have greater expres-
sion of ACE2 in their alveolar cells than African-
American population. It is confirmed that Asian men are
more sensitive to SARS-CoV-2 [10]. It is proved that
Results SARS-CoV-2 binds its receptor with a higher affinity
than SARS-CoV. With a higher affinity to bind the
The main pathological findings of the involvement of receptor, the number of viruses needed to infect the
body’s different organs during COVID-19 infection have alveolar cell is reduced, partly explaining why SARS-
RMM-D-20-00087
Fig. 2. The main pathological findings of COVID-19.
CoV-2 is much more aggressive than SARS-CoV [8,9]. for lung inflammation and fever. ACE2 is an important
The immune system response has been studied. One factor in the renin–angiotensin (Ang) system (RAS)
study has divided the immune system response into the which cleaves Ang II (a potent vasoconstrictor) into Ang
primary and the secondary responses. Primary inflam- [1–7] (a vasodilator). ACE2 downregulation – mediated
matory response mainly results from active viral replica- by SARS-CoV-2 – leads to imbalance in the RAS system
tion and ACE2 downregulation which leads to increased and increased levels of ACE and Ang II and this imbalance
production of cytokine/chemokine and cellular damage causes multisystem inflammation [12]. Secondary inflam-
because of apoptosis and/or pyroptosis [11]. Infection of matory response begins with the formation of neutraliz-
upper and lower respiratory tract with SARS-CoV-2 ing antibody (NAb) which reduces replication of the
leads to production and release of pro-inflammatory virus [11]. Formation of NAb also causes FcR-mediated
cytokines including IL-1b and IL-6. IL-1b is responsible inflammatory response leading to further lung injury.
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Virus-NAb complex binds to FcR of macrophages and disease is discussed below. Generally, considering excep-
promotes accumulation of proinflammatory macrophages tions, the median incubation period for COVID-19 is 4–
in the lungs. These macrophages release inflammatory 6.7 days. In a study performed on 50 confirmed cases of
cytokines such as monocyte chemoattractant protein 1 COVID-19, the mean incubation period and 95%
(MCP1) and IL-8, causing further lung damage [11]. confidence interval (CI) was 4.9 (4.4–5.5) days. There
was no significant differences between SARS, MERS and
It has been shown that in SARS-CoV infection, the COVID-19 incubation periods based on previous reports
formation of antiviral IgG coincides the worsening of on outbreaks of SARS (153 patients) and MERS (70
respiratory disease in 80% of patients [13]. A possible patients) [17]. In a study done on 425 patients with
mechanism is antibody dependent enhancement (ADE). confirmed COVID-19, the mean incubation period and
ADE happens when the antiviral antibodies do not 95% CI was 5.2 (4.1–7.0) days [2]. In a large study
completely neutralize the virus. Instead, the virus-NAb performed on 1099 patients with confirmed COVID-19
complex binds to the FcR, causing to the endocytosis of in 552 hospitals of 30 provinces in China, the median
the virus into the target cells. Eventually this process time for incubation was 4 days with interquartile range
results in further replication of the virus and higher (IQR) of 2–7 days [18]. In a study performed on 181
disease severity [11]. In a recent study, microscopic confirmed cases of COVID-19 outside of Hubei
features of COVID-19 are described in two patients province, the median incubation period and 95% CI
whom underwent lung lobectomy because of lung was 5.1 (4.5–5.8) days. This study estimated that less than
adenocarcinoma but later found out to have COVID-19 2.5% of patients will be symptomatic within 2.2 days of
during hospitalization. In both patients, pulmonary exposure and 97.5% of patients will show symptoms
edema and prominent proteinaceous exudates were seen. within 11.5 days (95% CI, 8.2–15.6 days). This implies
Mononuclear inflammatory cells infiltration and multi- that 101 of 10 000 patients will be symptomatic after 14
nucleated giant cells were noted in the alveoli in both days of quarantine [19]. The signs and symptoms related
patients. Patchy pneumocyte hyperplasia was seen. No to immune system response and pulmonary system are
hyaline membranes were seen suggesting early stages of summarized below. Through all reviewed studies, the
acute lung injury [14]. In a second study histopathological most common symptoms of COVID-19, were fever,
examination of a 50 years old man who died because of cough and fatigue or myalgia. Both dry cough [20,21]
confirmed COVID-19 showed diffuse alveolar damage and productive cough [14,41,43] were reported. Other
with fibromyxoid exudates. Infiltration of mononuclear uncommon symptoms include dyspnea or chest tightness
inflammatory cells with the majority of lymphocytes was [14,19], chest pain [4], pharyngalgia and rhinorrhea [5–7]
seen in interstitial tissue of both lungs. Giant multinucle- and hemoptysis.
ated syncytial cells with atypical pneumocytes were seen
in the alveolar space. Hyaline membranes were seen with In a study consisted of 140 laboratory-confirmed and
pneumocytes desquamation and pulmonary edema hospitalized patients, which categorized into 82 non-
indicating ARDS [15]. severe cases and 58 severe cases, epidemiological factors
and signs and symptoms were compared between these
In addition, peripheral blood was sent for flow groups. Median age in severe cases was significantly
cytometry. Results revealed that peripheral CD4 and higher than nonsevere cases. Comorbidities such as
CD8 T cells were significantly decreased while having hypertension and diabetes were more common in severe
hyperactivated status. The hyperactivation of T cells, patients. There was no significant difference in most signs
characterized by increased number of Th17 proinflam- and symptoms between two groups except cough and
matory cells and enhanced cytotoxicity of CD8 T cells, [31] nausea which were more common in severe patients
partially, is responsible for severe immune lung damage [29]. The meaningful difference in age and chronic
[15]. The histopathological examination of three people underlying diseases between severe and nonsevere
died of COVID-19 revealed quite similar findings to patients was also observed in other studies too [37,48].
previous studies indicating ARDS. Infiltration of
inflammatory cells and presence of giant multinucleated In a retrospective case series performed in Tongji Hospital
cells were also similar to previous studies. Under electron in Wuhan, China, on 799 hospitalized patients with
microscopy particles of coronavirus in bronchial epithe- confirmed COVID-19, in which 113 had died and 161
lium and type II alveolar epithelial cells were observed. had recovered and been discharged. The remaining was in
Immunohistochemical staining revealed that some the hospital and receiving care. The epidemiological and
alveolar epithelial cells and macrophages are positive clinical characteristics and laboratory findings of deceased
for SARS-CoV-2 [16]. and recovered groups were compared. The median age of
deceased group was higher than recovered (68 vs. 51
Clinical signs and symptoms years). Men were more vulnerable to death than women.
Clinical signs and symptoms related to the pulmonary 83% of deaths and 55% of recovered were men.
system and immune system response are discussed and Underlying diseases were more common in deceased
categorized here. Also, the incubation period of the group. 63% of patient who had died and 39% who had
RMM-D-20-00087
recovered had at least one chronic underlying disease. 0.7 vs. 0.8, P value ¼ 0.048) was lower in severe cases than
Hypertension, cardiovascular and cerebrovascular diseases nonsevere cases [29]. In an already described retrospective
were more common among deceased group. Dyspnea case series, the laboratory findings were compared between
and chest tightness were more frequent in deceased group recovered and deceased patients. Leukocytosis, severe
(62 vs. 31%) [27]. The most common underlying diseases lymphopenia, thrombocytopenia, hypoalbuminemia, pro-
were hypertension [18,22,27,29,33], diabetes [22,29,33], longed PT, elevated serum concentrations of LDH, D-
cardiovascular disease [22,27,33], cerebrovascular disease dimer, PCT, CRP and ESR were significantly higher in
[27], chronic obstructive pulmonary disease [18,33] and deceased patients than recovered patients. Serum con-
chronic liver disease [33]. centrations of IL-2 receptor, IL-6, IL-8, IL-10 and TNF-a
were remarkably higher in deceased patients [27].
Laboratory findings
The most common laboratory findings related to Imaging
pulmonary and immune system include lymphopenia I Imaging is very frequently used to diagnose COVID-19
(lymphocyte count <1.0 109/l), increased c-reactive and monitor the pulmonary changes and outcomes. Here
protein (CRP) levels, increased D-dimer levels and we discuss different imaging modalities and their possible
elevated lactate dehydrogenase (LDH) [18,20–23,25– importance in COVID-19 diagnosis, choosing appropri-
30,32–38]. Other frequently found abnormalities in lab ate treatment and follow-up.
tests include prolonged prothrombin time (PT)
[21,22,27,38], normal procalcitonin (PCT) [20,22– Computed tomography (CT) manifestations: Ground glass
24,36,38], thrombocytopenia [20,26,27,35], hypoalbu- opacities (GGOs): GGOs are defined as areas of haziness
minemia [27,28,32,36,38], low hemoglobin [4,38] and with increased opacity which do not obscure the
elevated erythrocyte sedimentation rate (ESR) underlying vessels and bronchi [39–44]. GGOs are the
[25,30,32,38]. Subpopulations of lymphocytes (such as most common and earliest finding in COVID-19
CD3þ cells, CD3þCD4þ cells and CD3þCD8þ cells) pneumonia cases mostly seen unilaterally or bilaterally
were also decreased [23,33,34]. with a subpleural and peripheral pattern [39,41,47,50–
52,58–63,73–80].
In a cohort study on 41 hospital-admitted patients with
laboratory confirmed COVID-19 in Wuhan, including Consolidations: Consolidations are defined as areas with
ICU and non-ICU patients, laboratory findings on increased attenuation which conceal the underlying
admission were also compared between these two groups. vessels. They are mixtures of fluids, cells and air [39–
Leukocyte count was significantly higher in ICU patients 41,43,44,55–57]. Consolidations are usual findings in
(11.3 109/l vs. 5.7 109/l, P value ¼ 0.011). Signifi- COVID-19 patients. Existence of consolidations often
cantly, leukocytopenia (white blood cells (WBC) count suggests more severe symptoms [59]. Consolidations can
<4.0 109/l) were more common among non-ICU be pure or mixed with GGOs. Segmental or patchy
patients (P value ¼ 0.041). Neutrophil count was higher consolidations with a subpleural distribution are the
among ICU patients (10.6 109/l vs. 4.4 109/l, P value common consolidation pattern in COVID-19 patients
<0.001). Lymphopenia was significantly more common [40].
in ICU patients (P value ¼ 0.004). PT, D-dimer and LDH
were significantly higher in ICU patients than the other Air bronchogram: Air bronchogram is a pattern of
group (P value ¼ 0.012, 0.0042 and 0.0044, respectively). bronchi filled up with air on an opaque airless setting (low
Serum albumin levels were lower in ICU patients opacity on high opacity). It is not a common finding in
significantly (27.9 vs. 34.7 g/l, P value <0.001) [22]. CT scan of COVID-19 patients and usually indicates
severe symptoms [39–41]. Another theory is that air
Initial plasma cytokine levels including IL-1B, IL-1RA, bronchograms are a result of filled bronchi with
IL-7, IL-8, IL-9, IL-10, basic fibroblast growth factor, gelatinous mucus which has a low attenuation. The high
IFNg, MCP1, platelet-derived growth factor, TNFa and viscosity of the gelatinous mucus in damaged bronchioles
vascular endothelial growth factor were significantly results in lack of sputum motility and dry cough [40].
higher in all patients – both ICU and non-ICU patients
than healthy adult people. Comparison in serum cytokine Crazy paving pattern: Crazy paving pattern is defined as a
levels between ICU and non-ICU patients revealed that reticular attenuation superimposed on a ground glass
levels of IL-2, IL-7, IL-10, MCP1 and TNFa were opacity (GCO) reminding of paving stones. This pattern
significantly higher in ICU patients than non-ICU is usually seen in severe cases of COVID-19 infection
patients [22]. In a previously described study, laboratory [39,40]. This pattern is probably caused by alveolar edema
findings were also compared between these two groups. accompanied by interstitial inflammation [40].
Median values of WBC (5.3 vs. 4.5, P value ¼ 0.014), D-
dimer (0.4 vs. 0.2, P value <0.001), CRP (47.6 vs. 28.7, Reticular pattern and lymphadenopathy: Reticular
P value <0.001), PCT (0.1 vs. 0.05, P value <0.001) pattern is referred to interstitial pulmonary changes
were higher in severe cases. Lymphocyte count (median, resulting in interlobular septal thickening [40].
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Lymphadenopathy is defined as lymph nodes with more exudation into the alveolar cavity and fusion of the alveoli
than 1 cm short-axis diameter. This is a rare finding in CT accompanied by dilation of interstitial vessels.
scan of COVID-19 patients seen in almost 4–8% of them
[39–41,43]. Although it is not a frequent finding in CT, Severe phase: The severe phase which is mostly seen
lymphadenopathy is seen mostly in severe cases and can be about 14 days after the initiation of symptoms is
a risk factor for developing sever disease in COVID-19 characterized by peaked number of lesions involving all
patients [40]. lung segments bilaterally resulting into the white lung
pattern. Pleural effusion can be present. Air broncho-
Nodules and fibrosis: Nodules are defined as round grams can be seen due to massive exudation in the alveolar
opacities below 3 cm in diameter which have poorly or cavity. Subsegmental atelectasis can also be seen in this
well defined margins. Fibrosis is replacement of cells with phase and the clinical symptoms are severe-critical.
scar tissue. Fibrous stripes are defined as irregular lines
with high opacity which are not common findings in Dissipative phase: The final phase which is described as
COVID-19 patients (seen in about 17%) [39–41]. The dissipative usually occurs after 2 weeks from the first
exact effect of fibrosis in prognosis of COVID-19 patients illness symptoms. The lesions are gradually absorbed, the
is unclear. Some studies suggest that fibrosis can be a sign clinical symptoms decrease and high-density stripes
of good prognosis with stabilizing effect on the disease appear indicating fibrosis [42,45,59,64–72].
and some others believe that fibrous stripes are a poor
prognostic factor [40]. CT manifestations in children and pregnant women: Children
and infants are usually asymptomatic or present mild
Halo sign, reverse halo sign and pleural changes: Halo sing clinical symptoms and their CT manifestations are not as
refers to GCOs surrounding a nodule or density. Reverse typical as adults during COVID-19 infection, so CT scan
halo sign is referred to a GCO surrounded by a can be very useful to diagnose children and infants with
consolidation. This sign is probably indicative of COVID-19 infection. The common morphology of
progression of the disease. Pleural thickening is an lesions in children’s CT is believed to be small nodular or
uncommon CT finding in COVID-19 patients (seen in patchy GGOs sometimes accompanied by consolidation.
32%) while pleural effusion is rare (seen in 5%) [40]. The distribution of lesions is mostly subpleural and
peripheral [43,46,48,49,54]. Halo sign is a rare finding
Temporal CT changes in COVID-19 patients during the and crazy paving pattern is not seen in children [46].
infection: While a patient with COVID-19 infection can Possible CT differences between pregnant and nonpreg-
be described as mild, moderate, severe and critical nant adults were studied by Liu et al. They showed that
clinically [81], the imaging results also can be described in there is no difference in the distribution of lesions
four phases during the time course of illness: early phase, between these groups and they are mostly peripheral.
progressive phase, severe phase and dissipative phase Consolidations (complete consolidations and consolida-
which are discussed here. tions mixed with GGOs) were seen more frequently in
pregnant women comparing with nonpregnant while
Early phase: In this phase which patients are mostly in GGOs with or without reticulation were seen more in
moderate clinical condition, their lesions are supposed nonpregnant group [43].
to be in single or multiple areas. The distribution of
lesions is believed to be subpleural or along bronchi. Chest X-ray (CXR): Although the main imaging modality
According to this pattern, the spread of the disease is to diagnose COVID-19 infection is CT scan, CXRs are
believed to be through the air way starting from the also being frequently used. In a meta-analysis by
bronchioles and the epithelium of the alveoli in the Rodriguez-Morales et al. [32], they showed that the
periphery, progressing to the center. The usual CXR results were mostly GGOs distributed bilaterally. In
morphology of lesions in this phase is patchy or nodular another study in Korea by Yoon et al. [53] on nine
GCOs with reticular changes (thickening of intralobular COVID-19 patients, they showed that 33.3% of patients
or interlobular septa) sometimes with the presence of had parenchymal abnormalities on CXR. The lesions
halo sing around the nodules. Events of this phase are due were mostly consolidations distributed peripherally in
to infiltration of exudates into the alveoli and presence of lower lung zones.
edema in interstitial space.
Progressive phase: Many of the lesions progress rapidly in Smoking and COVID-19
this phase and the severe clinical symptoms are seen as a Smoking is believed to be an important risk factor for
result. The limited lesions of early phase progress in ending up with poor outcomes in COVID-19 patients
number, density and extent. The morphology of lesions is [82,83]. The percentage of former or current smokers is
progressed to a coexistence of GCOs and consolidations higher among patients, who were admitted to ICU,
and the crazy paving pattern sometimes appears. Events of needed a ventilator or died. Comparing with nonsmo-
this phase are seen as a result of large amounts of kers, smokers are 1.4 times more likely to develop severe
RMM-D-20-00087
symptoms and 2.4 times more likely to need ventilation, nCoV RNA was detected in feces in mild patients, virus
ICU admission and dying [83]. RNA shedding in feces lasts for 2 weeks to 1 month [95]
and in another study among 41 patients with confirmed
Gastrointestinal system SARS-CoV-2 infection, one patient had positive fecal
Clinical symptoms sample 33 days after respiratory sample became negative
COVID-19 infection has also some known gastrointesti- [96]. These findings may suggest gastrointestinal tract as a
nal manifestations (GIMs) as well. In one retrospective potential viral replication site [95].
study, of 1141 confirmed COVID-19 cases admitted to
Zhongnan Hospital of Wuhan University, 183 (16%) Liver
presented with GIMs including, nausea, vomiting, Liver injury during COVID-19 disease is observed in
abdominal pain, diarrhea and loss of appetite [84]. These many patients with COVID-19 [97,98]. The incidence
gastrointestinal symptoms were observed in other studies rate of liver injury has been estimated between 14.8 and
too [85–87,90]. There were also some cases of bloody 53% in various studies [99–101]. In mild cases of
diarrhea caused by COVID-19 [88]. Yang et al. [89] COVID-19 liver dysfunction is rare. But, in severe cases,
found two (4%) cases of nonsurviving gastrointestinal liver damage is common and requires additional attention
hemorrhage patients among 52 critically ill SARS-CoV-2 [98,102]. The most common manifestation of liver
pneumonia patients. Some studies report GIMs as early involvement in patients with COVID-19 is an increase in
and first symptoms of the disease. For example, in a study liver enzymes and sometimes an increase in bilirubin
consisted of 62 patients with laboratory confirmed levels [28,97,98,100,102]. In a retrospectively analyzed
SARS-CoV-2 infection, three of which (8%) developed study of 40 patients who were admitted to the isolation
diarrhea at onset of the disease [14]. It’s important to have ward of Tangdu Hospital, China, 55% of them suffered
caution that COVID-19 can present dominantly with liver damage as elevated liver enzymes in the first week of
gastrointestinal symptoms only. In one study, of 1141 hospitalization while the albumin dropped in the second
confirmed COVID-19 cases, 183 (16%) presented with week. Liver damage was correlated with the severity of
gastrointestinal symptoms [84]. Abdominal pain is more the underlying disease [101]. Furthermore, there was a
frequent among patients admitted to ICUs compared direct correlation between liver transferase impairments
with patients who did not as reported in one study with and COVID-19 disease severity in different studies
138 hospitalized patients with confirmed nonspecific [28,97,102]. In a study of 651 patients with COVID-19 in
interstitial pneumonia whom 36 (26.1%) of them were Zhejiang province, patients with gastrointestinal symp-
transferred to the ICU because of organ dysfunction [48]. toms were more likely to have an elevated level of
Also, in the same study it is discussed that having aspartate aminotransferase (AST) rather than alanine
gastrointestinal symptoms in patients with COVID-19 aminotransferase (ALT) compared with those without
may be associated with more severe disease compared gastrointestinal symptoms. Also, it was observed that in
with patients without gastrointestinal symptoms. Similar patients with gastrointestinal symptoms ALT is one of the
to adults, pediatric patients with COVID-19 had diarrhea significant risk factors for severe COVID-19 [103].
and vomiting as gastrointestinal presentations [91]. In Various causes for liver involvement have been reported
Wuhan Children’s Hospital a cohort was performed from SARS-COV-2 infection to medications and
consisted of 171 confirmed SARS-CoV-2 infection with systemic inflammation [15,97,98,102,104]. Drug toxicity
the median age of 6.7 years. Diarrhea in 15 (8.8%) and can be one of the possible causes of liver damage, although
vomiting in 11 (6.4%) cases were observed [92]. Other in many cases, there has been an enzymatic disorder
clinical features like milder course of disease and lower before drug treatment [102]. It is well known that
respiratory symptoms have been described but gastroin- pulmonary congestion in intubated patients with positive
testinal symptoms appear to be like adults in severity, end-expiratory pressure or hepatic ischemia can be a
although more data is necessary to conclude that [91]. cause of abnormal hepatic enzymes, but these conditions
are more common in special wards, while the mentioned
Fecal shedding of the virus disorders are seen in all wards. A biopsy of the liver
Viral RNA can be found in the stool or anal/rectal swabs showed a slight lobular and portal involvement and
of COVID-19 patients [91,93]. Surprisingly their stool slightly microvesicular steatosis [102,105]. For these
viral RNA can remain positive even after their respiratory reasons, direct liver damage by the virus is less likely. A
samples became negative as in one study with 73 review study has reported that liver damage may begin
hospitalized SARS-CoV-2 confirmed patients, were with damage to bile duct cells. Because the receptor for
SARS-CoV-2 RNA positive in stool but 17 (23.29%) the virus is mostly expressed in bile duct cells [99].
of them remained positive in stool after respiratory
samples became negative [94]. The viral shedding from Cardiovascular system
gastrointestinal tract can be abundant and last for weeks. One of the relatively common COVID-19 infection
In a Case Series with 10 children with confirmed SARS- complications are cardiac injuries. But the main caveat to
CoV-2 infection who were admitted to the Children’s study the pure effect of this infection on the cardiovascu-
Hospital in Shanghai, a high frequency (83.3%) of 2019- lar system is that in most studies there is not a clear line
RMM-D-20-00087
between the patients who have cardiovascular disease syndrome (TTS) pattern. Her final diagnosis was acute
(CVD) history and comorbidities and the patients who virus-negative lymphocytic myocarditis associated with
don’t, which leaves the results inconclusive in many cases. SARS-CoV-2 respiratory infection [109]. Transthoracic
echocardiography revealed normal LV dimensions with
Cardiac biomarkers an increased wall thickness (interventricular septum,
Patients with COVID-19 may develop cardiac injuries 14 mm, posterior wall, 14 mm) and a diffuse myocardial
and therefore elevations of cardiac indicators are echo-bright appearance. Hypokinesia, with an estimated
expected. In a study by Shi et al. on 416 COVID-19 LVEF of 40% was observed. There was no evidence of
confirmed cases, patients with cardiac injury had higher heart valve disease. LV diastolic function was mildly
creatine kinase (median [IQR], 3.2 [1.8–6.2] vs. 0.9 abnormal with mitral inflow patterns, with an E/A ratio
[0.6–1.3] ng/ml), myohemoglobin (median [IQR], 128 of 0.7 and an average E/e0 ratio of 12. A circumferential
[68–305] vs. 39 [27–65] mg/l), high-sensitivity cardiac pericardial effusion that was most notable around the
troponin I (median [IQR], 0.19 [0.08–1.12] vs. <0.006 right cardiac chambers (max 11 mm) with no signs of
[<0.006–0.009] mg/l), N-terminal pro-B-type natri- tamponade was observed [110]. In another case, a 69 years
uretic peptide (NT-proBNP) (median [IQR], 1689 old patient of confirmed COVID-19 infection, echo-
[698–3327] vs. 139 [51–335] pg/ml) and creatinine cardiography showed a dilated LV (LV end-diastolic
kinase myocardial band (median [IQR], 3.2 [1.8–6.2] vs. diameter 56 mm), severe and diffuse LV hypokinesia
0.9 [0.6–1.3] ng/ml) [106]. In Guo et al.’s [107] study on (LVEF 34%). LVEF decreased to 25% and the estimated
187 confirmed COVID-19 patients, troponin T levels cardiac index was 1.4 l/min/m2 3 h later which is
had association with NT-proBNP levels (b ¼ 0.613, indicative of cardiogenic shock [111].
P < 0.001). In a retrospective study by Zhou et al. on 191
COVID-19 patients, 22/168 (13%) had creatine kinase Cardiac histological changes
more than 185 U/l (P ¼ 0.038) and high-sensitivity In one COVID-19 confirmed 50-year-old man, mono-
cardiac troponin I more than 28 pg/ml 24/145 (17%) nuclear inflammatory infiltrates without substantial myo-
(P 0.0001). In another study, by Du et al. [108] among cardial damage and histological changes have been seen in
85 COVID-19 confirmed patients, 31 (36.5%) had heart tissue [15]. In another case, a 69 years old COVID-19
increased creatine kinase levels. confirmed patient [111], cardiac myocytes had nonspecific
features like myofibrillar lysis and lipid droplets, but no viral
Electrocardiography and arrhythmia particles were observed in cardiac myocytes, therefore viral
Shi et al.’s [106] study contained 14 ECGs taken during cardiotropism remains to be proved. No viral particles in
elevated cardiac markers among patients with cardiac endothelia were observed. Endomyocardial biopsy was
injury all of which were abnormal compatible with clear from significant myocyte hypertrophy or nuclear
myocardial ischemia findings, including T-wave depres- changes. Interstitial changes were focal, minimal and
sion and inversion, ST depression and Q waves. A mainly perivascular. There were low-grade interstitial and
COVID-19 confirmed 43 years old woman’s ECG had endocardial inflammation. Interstitial cells with damaged
low atrial ectopic rhythm, mildly elevated ST (V1–V2 structure had viral particles inside. Single or small groups of
and augmented Vector Right (aVR)), reciprocal ST viral coronavirus-like particles (dense round envelope and
depression (V4–V6) and QTc 452 ms with diffuse U electron-dense spike-like structures on the surface and
waves [109]. Another COVID-19 confirmed 53 years old with 70–120 nm size) [111]. Also, the aforementioned 43
woman’s ECG with no CVD history, showed low voltage years old case’s endometrial biopsy had diffuse T-
in the limb leads, minimal diffuse ST elevation (more lymphocyte infiltrates (CD3þ >7/mm2) with huge
prominent in the inferior and lateral leads), and an ST interstitial edema and limited foci of necrosis. No
depression with inverted Twaves (V1 and aVR) [110]. Du replacement fibrosis identified, suggesting an acute
et al. [108] found arrhythmia among 51/85 (60.0%) inflammatory process. Molecular analysis showed the
patients and among two of 91 died patients (2.47%), absence of the SARS-CoV-2 genome within the
malignant arrhythmia was the cause of death. Patients myocardium. No contraction band necrosis or TTS-
with elevated troponin T had more frequent malignant associated microvascular abnormalities were observed
arrhythmias [107]. [109].
Echocardiography Kidney
Transthoracic echocardiography of 43 years old patient Gastrointestinal, kidneys and testes, in addition to the
mentioned above had mild left ventricular (LV) lungs overexpress the ACE2 receptors [112]. The reason
dysfunction (LVEF 43%) with inferolateral wall hypoki- for the higher accumulation of ACE2 in renal tubules
nesia; there was no ventricular dilation and no pericardial (and less in glomeruli) based on studies is that the kidney is
effusion. Further evaluation by dynamic three-dimen- able to express this enzyme more than 100 times as much
sional volume-rendering reconstruction showed a hypo- as the lungs [38,113–115]. But the question, according to
kinesia of the LV (mid and basal segments) with normal observations, is why the prevalence of ARDS is much
apical contraction, suggesting a reverse Takotsubo higher than that of acute kidney injury (AKI)? By studying
RMM-D-20-00087
several genetic and protein databases, Guo et al. [114] delivery. In general, mothers with COVID-19 after an
showed that the expression of AGTR2 mRNA in lung emergency cesarean section had lower symptoms than
tissue was much higher than in renal tissue, so further before the delivery. A case with COVID-19 revealed
studies are recommended. One of the most important lower lymphopenia and higher neutrophilia than the
biomarkers to diagnose patients with a complicated normal range [128]. In a case–control study, this viral
condition with COVID-19 is considered an increase in disease conversely reduced the count of white blood cells
blood urea nitrogen (BUN), Cr and cystatin C [116]. and neutrophils [129]. Mild thrombocytopenia and
Renal damage intensity in COVID-19 patients could vary increase of creatine phosphokinase levels were reported
from mild to severe. Mild injury associates with little in pregnant women with COVID-19 [130–132].
increase in serum BUN, Cr with mild microscopic According to the data obtained from liver enzymes,
proteinuria and hematuria. Severe injury can be diagnosed the liver injury may occur in these patients during
by drastic increase in BUN, Cr and decrease of renal output COVID-19 infection. It was shown that 33% of pregnant
indicative of AKI. There are different statistics on kidney women with COVID-19 showed remarkable levels of
damage caused by COVID-19 according to different ALT and AST [133]. Compared with healthy controls, a
studies, ranging from no sever injury to the occurrence of notably lower ALTamount was obtained in blood samples
AKI in 15% of hospitalized patients. There are different taken from pregnant patients with COVID-19 [128].
findings about the relationship between acute renal Most of these patients showed low levels (<40.0–55.0 g/
impairment and severity and mortality of COVID-19. l) of serum albumin [130,134,135] and high levels
Study by Wang et al. [117] in Wuhan on 116 patients (>10 mg/l) of C-reactive protein [130,133,136]. Even
showed that there was no significant relationship between though the high serum level of PCT (0.5 ng/ml) in
COVID-19 and acute kidney impairment. Whereas Li adults was considered as a key indicator to clinically
et al. in a multicenter study in Wuhan on 193 patients found diagnose COVID-19, this biomarker could not ade-
that kidney impairment, was observed in 7% of patients quately differentiate healthy and patient pregnant women
with COVID-19 and Renal dysfunction, including [22]. The placenta is another organ to express ACE2 and
increased creatinine or urea (BUN) as well as acute kidney acts as an alternative organ for lungs, kidneys, heart and
impairment, compared with the absence of renal liver for fetuses during pregnancy. Accordingly, this
impairment, causes a 5.3-fold increase in mortality in temporary endocrine organ as an important physiological
patients with COVID-19. Proteinuria, hematuria, and immunological barrier prevents maternal–fetal
increased BUN, Cr and serum uric acid levels were transmission of pathogens. As the expression rate of
observed in 60, 40, 31, 22 and 20% of patients with ACE2 receptors in most cells of the early maternal–fetal
COVID-19, respectively [118]. interface is meager, the new coronavirus cannot pass from
mothers to fetuses through transplacental vertical
Zhao et al. in a systematic review and meta-analysis found transmission [136]. It was evidenced with no detection
that chronic kidney disease is highly associated with of SARS-CoV-2 in amniotic fluid or in the neonatal
severe COVID-19 [119]. Cheng et al. [120] in Wuhan in blood collected from the umbilical cord. Also, the
a study on 710 patients found that there is a high risk of presence of this virus in breastmilk, gastric juice and
death in hospital with renal failure (proteinuria, neonatal throat swabs was also negative [130,134,136].
hematuria and increased BUN and Cr) in patients with
COVID-19. Just as in patients with SARS, acute kidney
damage can increase mortality [121]. One of the causes of
increased mortality in patients with COVID-19 is the Conclusion
presence of underlying diseases, such as chronic renal
failure [122,123]. COVID-19 infection is a multiorgan involving infection
which needs a team of different expertise to diagnose and
Obstetrics and gynecology manage the disease. Although there are many studies
The COVID-19 infection in women during pregnancy available about COVID-19 infection, most of them are
develops obstetric complications and perinatal adverse focused on pulmonary involvement and the effects of the
outcomes with moderate-to-severe clinical symptoms. virus on many other organs and systems remain unclear
Apart from usual respiratory problems such as dyspnea or that shows the necessity of further investigations about
tachypnea, dry cough, nasal congestion and runny nose the disease.
[124–128], GIMs including vomiting and diarrhea may
occur in pregnant women infected by COVID-19
[124,128]. Also, skin rash in the abdominal region,
pneumothorax and abnormal liver function in patients Acknowledgements
have been observed [124,126]. Zhu et al. [124] reported
that the onset of clinical symptoms among 9 mothers with The authors would like to thank the Clinical Research
COVID-19 pneumonia was before (1–6 days, four cases), Development Unit of Baqiyatallah Hospital, Tehran, Iran,
during (two cases) and after (1–3 days, three cases) for guidance and advice.
RMM-D-20-00087
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Fig. 2. The main pathological findings of COVID-19.

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