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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 Aghdam
a, Ramin Hosseinzadeh
b, Behzad Motallebizadeh
c, Mohammadreza Rezaeimehr
d,
Leila Khedmat
e, Zahra Soleimani
f, Mohammad Heiat
g, Mehrdad Moosazadeh Moghaddam
h,
Mohammadali Abyazi
gand Ashraf Karbasi
gSince 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.
Copyrightß2020 Wolters Kluwer Health, Inc. All rights reserved.
Reviews in Medical Microbiology2020,31:000–000 Keywords: COVID-19, nCoV-2019, pathophysiology, SARS-CoV-2
aFaculty 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, andhApplied 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.
Highlights:
COVID-19, an emerging outbreak, has involved millions of people and turned to a global crisis.
This multiorgan involving disease has major effects on pulmonary, cardiac, renal, gastrointestinal and hepatic systems.
Multifaceted property of COVID-19, justifies more investigations in other involved area apart from pulmonary system.
Background
In the last 20 years, the viruses ofCoronaviridaefamily have caused three epidemics. The last epidemic caused by SARS- CoV-2 which is currently happening was started in December 2019 in Wuhan, China. The viruses of Coronaviridaefamily which are morphologically known by a crown like spike on their envelope are RNA viruses with a large genome that makes them very potent for mutations and as a result, they have a great potential to initiate newepidemics [1]. The average incubation period in which the infected individual can infect other people is 5.2 days varying in different patients [2,3]. Clinical manifestations of the disease have a very wide spectrum from asymptomatic to acute respiratory distress syndrome (ARDS); however, the main clinical manifestations are fever, dry cough, dyspnea, muscle pain, diarrhea, nausea and vomiting. Conjunctivitis is also known as a disease symptom [4]. The situation in about 20%
of patients progress to pneumonia after a week which can result in ARDS and death in some of them [5]. Severe-critical cases are usually presented with respiratory, cardiac or renal failure and ARDS ending up with death [6]. The mortality rate of the disease is about 2–3% and 4–11% in those who needed admission [7]. In this review, we have focused on COVID-19 multiorgan involvement and its multiorgan effects on the body.
Methods
Protocol and registration
The current study was designed to provide a compre- hensive view of different and the most vulnerable organs’
involvement during COVID-19 infection including pulmonary system, cardiovascular system, renal tract, gastrointestinal tract and liver. In addition, we discussed obstetrics-related effects of COVID-19. It is worth noting that we aimed not to discuss diagnosis and treatment issues and we only focused on different aspects of body internal organs’ involvement during COVID-19 infection. To achieve this aim, one independent author was assigned to each section. Just pulmonary system
section was done by two authors due to large number of articles discussing its involvement during COVID-19 infection. Also, obstetrics and gynecology section was done by two authors.
Eligibility criteria
Any study discussing the different aspects of respective body internal organs’ involvement during COVID-19 infection was eligible to enter this review. In this review, we specifically discuss multiorgan involvement during COVID-19 infection and studies concerning other coronaviruses such as SARS-CoV and MERS-CoV were not of interest generally.
Information sources
Studies were identified by searching within electronic database of PubMed. No language limit was applied, but articles in other languages were excluded unless there was a useful translated abstract. There was 2019–2020 time period limitation for study selection.
Search
To find all the articles related to the subject of this review, four authors searched PubMed independently using the following search terms. First, we used the search term
‘COVID-19 OR SARS-CoV-2 OR nCoV-2019’ to address all articles related to SARS-CoV-2. Then, we used the following search terms with Boolean operator of
‘AND’ to access the related articles for each section of the review: ‘pathology OR pathogenesis OR characteristics’,
‘imaging or CT or X-Ray OR complication OR prognosis’ and ‘ARDS OR respiratory failure’ for pulmonary system section, ‘GI OR digestive OR fecal’
for gastrointestinal section, ‘liver OR hepatic’ for liver section, ‘myocarditis OR cardiovascular OR cardiomy- opathy OR arrythmia OR heart OR cardiac OR cardiogenic’ for cardiovascular section, ‘renal OR kidney OR nephropathy’ for renal tract involvement and
‘pregnancy OR postnatal OR vertical transmission OR neonates’ for obstetrics and gynecology section.
Study selection
We included any original research concerning about involvement of body’s different organs and systems during COVID-19 infection. Studies concerning other issues related to COVID-19 such as prevention, treatment and COVID-19 in special populations were not of interest and excluded from the review. Eligibility assessment and inclusion and exclusion decisions were performed independently in an unblinded standardized manner by at least two review authors through screening titles, abstracts and full texts. Conflicts between reviewers were resolved by consensus. Some studies have been used in two or more sections.
A total of 2688 studies (up to 15 June 2020), were recognized to be included in this review. Of these, 1386 studies were discarded after screening titles and abstracts
due to the mismatch between them and the inclusion criteria. Full texts of the remaining 1302 studies were reviewed in a detailed manner. Among remaining studies, 1167 studies were excluded from the review because of addressing other aspects of COVID-19 out of the interest of this review or concerning about SARS-CoV and MERS-CoV or low sample size and low quality.
Remaining 135 studies met the inclusion criteria and were eligible to be included in the systematic review. No unpublished relevant studies were obtained (Fig. 1).
Results
The main pathological findings of the involvement of body’s different organs during COVID-19 infection have
been summarized in Fig. 1. These findings have been discussed in detail in the following sections (Fig. 2).
Lungs
Immune system response and microscopic findings Several studies have shown that SARS-CoV-2 uses the same receptor as SARS-CoV (ACE2) [1,8–10]. ACE2 is expressed on alveolar epithelial cells types I and II. Men have greater expression of ACE2 in their alveolar 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 SARS-CoV-2 binds its receptor with a higher affinity than SARS-CoV. With a higher affinity to bind the receptor, the number of viruses needed to infect the alveolar cell is reduced, partly explaining why SARS- Fig. 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram of study selection.
CoV-2 is much more aggressive than SARS-CoV [8,9].
The immune system response has been studied. One study has divided the immune system response into the primary and the secondary responses. Primary inflam- matory response mainly results from active viral replica- tion and ACE2 downregulation which leads to increased production of cytokine/chemokine and cellular damage because of apoptosis and/or pyroptosis [11]. Infection of upper and lower respiratory tract with SARS-CoV-2 leads to production and release of pro-inflammatory cytokines including IL-1band IL-6. IL-1bis responsible
for lung inflammation and fever. ACE2 is an important factor in the renin–angiotensin (Ang) system (RAS) which cleaves Ang II (a potent vasoconstrictor) into Ang [1–7] (a vasodilator). ACE2 downregulation – mediated by SARS-CoV-2 – leads to imbalance in the RAS system and increased levels of ACE and Ang II and this imbalance causes multisystem inflammation [12]. Secondary inflam- matory response begins with the formation of neutraliz- ing antibody (NAb) which reduces replication of the virus [11]. Formation of NAb also causes FcR-mediated inflammatory response leading to further lung injury.
Fig. 2. The main pathological findings of COVID-19.
Virus-NAb complex binds to FcR of macrophages and promotes accumulation of proinflammatory macrophages in the lungs. These macrophages release inflammatory cytokines such as monocyte chemoattractant protein 1 (MCP1) and IL-8, causing further lung damage [11].
It has been shown that in SARS-CoV infection, the formation of antiviral IgG coincides the worsening of respiratory disease in 80% of patients [13]. A possible mechanism is antibody dependent enhancement (ADE).
ADE happens when the antiviral antibodies do not completely neutralize the virus. Instead, the virus-NAb complex binds to the FcR, causing to the endocytosis of the virus into the target cells. Eventually this process results in further replication of the virus and higher disease severity [11]. In a recent study, microscopic features of COVID-19 are described in two patients whom underwent lung lobectomy because of lung adenocarcinoma but later found out to have COVID-19 during hospitalization. In both patients, pulmonary edema and prominent proteinaceous exudates were seen.
Mononuclear inflammatory cells infiltration and multi- nucleated giant cells were noted in the alveoli in both patients. Patchy pneumocyte hyperplasia was seen. No hyaline membranes were seen suggesting early stages of acute lung injury [14]. In a second study histopathological examination of a 50 years old man who died because of confirmed COVID-19 showed diffuse alveolar damage with fibromyxoid exudates. Infiltration of mononuclear inflammatory cells with the majority of lymphocytes was seen in interstitial tissue of both lungs. Giant multinucle- ated syncytial cells with atypical pneumocytes were seen in the alveolar space. Hyaline membranes were seen with pneumocytes desquamation and pulmonary edema indicating ARDS [15].
In addition, peripheral blood was sent for flow cytometry. Results revealed that peripheral CD4 and CD8 T cells were significantly decreased while having hyperactivated status. The hyperactivation of T cells, characterized by increased number of Th17 proinflam- matory cells and enhanced cytotoxicity of CD8 T cells, partially, is responsible for severe immune lung damage [15]. The histopathological examination of three people died of COVID-19 revealed quite similar findings to previous studies indicating ARDS. Infiltration of inflammatory cells and presence of giant multinucleated cells were also similar to previous studies. Under electron microscopy particles of coronavirus in bronchial epithe- lium and type II alveolar epithelial cells were observed.
Immunohistochemical staining revealed that some alveolar epithelial cells and macrophages are positive for SARS-CoV-2 [16].
Clinical signs and symptoms
Clinical signs and symptoms related to the pulmonary system and immune system response are discussed and categorized here. Also, the incubation period of the
disease is discussed below. Generally, considering excep- tions, the median incubation period for COVID-19 is 4–
6.7 days. In a study performed on 50 confirmed cases of COVID-19, the mean incubation period and 95%
confidence interval (CI) was 4.9 (4.4–5.5) days. There was no significant differences between SARS, MERS and COVID-19 incubation periods based on previous reports on outbreaks of SARS (153 patients) and MERS (70 patients) [17]. In a study done on 425 patients with confirmed COVID-19, the mean incubation period and 95% CI was 5.2 (4.1–7.0) days [2]. In a large study performed on 1099 patients with confirmed COVID-19 in 552 hospitals of 30 provinces in China, the median time for incubation was 4 days with interquartile range (IQR) of 2–7 days [18]. In a study performed on 181 confirmed cases of COVID-19 outside of Hubei province, the median incubation period and 95% CI was 5.1 (4.5–5.8) days. This study estimated that less than 2.5% of patients will be symptomatic within 2.2 days of exposure and 97.5% of patients will show symptoms within 11.5 days (95% CI, 8.2–15.6 days). This implies that 101 of 10 000 patients will be symptomatic after 14 days of quarantine [19]. The signs and symptoms related to immune system response and pulmonary system are summarized below. Through all reviewed studies, the most common symptoms of COVID-19, were fever, cough and fatigue or myalgia. Both dry cough [20,21]
and productive cough [14,41,43] were reported. Other uncommon symptoms include dyspnea or chest tightness [14,19], chest pain [4], pharyngalgia and rhinorrhea [5–7]
and hemoptysis.
In a study consisted of 140 laboratory-confirmed and hospitalized patients, which categorized into 82 non- severe cases and 58 severe cases, epidemiological factors and signs and symptoms were compared between these groups. Median age in severe cases was significantly higher than nonsevere cases. Comorbidities such as hypertension and diabetes were more common in severe patients. There was no significant difference in most signs and symptoms between two groups except cough and [31] nausea which were more common in severe patients [29]. The meaningful difference in age and chronic underlying diseases between severe and nonsevere patients was also observed in other studies too [37,48].
In a retrospective case series performed in Tongji Hospital in Wuhan, China, on 799 hospitalized patients with confirmed COVID-19, in which 113 had died and 161 had recovered and been discharged. The remaining was in the hospital and receiving care. The epidemiological and clinical characteristics and laboratory findings of deceased and recovered groups were compared. The median age of deceased group was higher than recovered (68 vs. 51 years). Men were more vulnerable to death than women.
83% of deaths and 55% of recovered were men.
Underlying diseases were more common in deceased group. 63% of patient who had died and 39% who had
recovered had at least one chronic underlying disease.
Hypertension, cardiovascular and cerebrovascular diseases were more common among deceased group. Dyspnea and chest tightness were more frequent in deceased group (62 vs. 31%) [27]. The most common underlying diseases were hypertension [18,22,27,29,33], diabetes [22,29,33], cardiovascular disease [22,27,33], cerebrovascular disease [27], chronic obstructive pulmonary disease [18,33] and chronic liver disease [33].
Laboratory findings
The most common laboratory findings related to pulmonary and immune system include lymphopenia (lymphocyte count <1.0109/l), increased c-reactive protein (CRP) levels, increased D-dimer levels and elevated lactate dehydrogenase (LDH) [18,20–23,25–
30,32–38]. Other frequently found abnormalities in lab tests include prolonged prothrombin time (PT) [21,22,27,38], normal procalcitonin (PCT) [20,22–
24,36,38], thrombocytopenia [20,26,27,35], hypoalbu- minemia [27,28,32,36,38], low hemoglobin [4,38] and elevated erythrocyte sedimentation rate (ESR) [25,30,32,38]. Subpopulations of lymphocytes (such as CD3þ cells, CD3þCD4þ cells and CD3þCD8þ cells) were also decreased [23,33,34].
In a cohort study on 41 hospital-admitted patients with laboratory confirmed COVID-19 in Wuhan, including ICU and non-ICU patients, laboratory findings on admission were also compared between these two groups.
Leukocyte count was significantly higher in ICU patients (11.3109/l vs. 5.7109/l, P value¼0.011). Signifi- cantly, leukocytopenia (white blood cells (WBC) count
<4.0109/l) were more common among non-ICU
patients (Pvalue¼0.041). Neutrophil count was higher among ICU patients (10.6109/l vs. 4.4109/l,Pvalue
<0.001). Lymphopenia was significantly more common in ICU patients (Pvalue¼0.004). PT,D-dimer and LDH were significantly higher in ICU patients than the other group (Pvalue¼0.012, 0.0042 and 0.0044, respectively).
Serum albumin levels were lower in ICU patients significantly (27.9 vs. 34.7 g/l,Pvalue<0.001) [22].
Initial plasma cytokine levels including IL-1B, IL-1RA, IL-7, IL-8, IL-9, IL-10, basic fibroblast growth factor, IFNg, MCP1, platelet-derived growth factor, TNFaand vascular endothelial growth factor were significantly higher in all patients – both ICU and non-ICU patients than healthy adult people. Comparison in serum cytokine levels between ICU and non-ICU patients revealed that levels of IL-2, IL-7, IL-10, MCP1 and TNFa were significantly higher in ICU patients than non-ICU patients [22]. In a previously described study, laboratory findings were also compared between these two groups.
Median values of WBC (5.3 vs. 4.5,Pvalue¼0.014),D- dimer (0.4 vs. 0.2,Pvalue<0.001), CRP (47.6 vs. 28.7, P value <0.001), PCT (0.1 vs. 0.05, P value <0.001) were higher in severe cases. Lymphocyte count (median,
0.7 vs. 0.8,Pvalue¼0.048) was lower in severe cases than nonsevere cases [29]. In an already described retrospective case series, the laboratory findings were compared between recovered and deceased patients. Leukocytosis, severe lymphopenia, thrombocytopenia, hypoalbuminemia, pro- longed PT, elevated serum concentrations of LDH, D- dimer, PCT, CRP and ESR were significantly higher in deceased patients than recovered patients. Serum con- centrations of IL-2 receptor, IL-6, IL-8, IL-10 and TNF-a were remarkably higher in deceased patients [27].
Imaging
I Imaging is very frequently used to diagnose COVID-19 and monitor the pulmonary changes and outcomes. Here we discuss different imaging modalities and their possible importance in COVID-19 diagnosis, choosing appropri- ate treatment and follow-up.
Computed tomography (CT) manifestations: Ground glass opacities (GGOs): GGOs are defined as areas of haziness with increased opacity which do not obscure the underlying vessels and bronchi [39–44]. GGOs are the most common and earliest finding in COVID-19 pneumonia cases mostly seen unilaterally or bilaterally with a subpleural and peripheral pattern [39,41,47,50–
52,58–63,73–80].
Consolidations: Consolidations are defined as areas with increased attenuation which conceal the underlying vessels. They are mixtures of fluids, cells and air [39–
41,43,44,55–57]. Consolidations are usual findings in COVID-19 patients. Existence of consolidations often suggests more severe symptoms [59]. Consolidations can be pure or mixed with GGOs. Segmental or patchy consolidations with a subpleural distribution are the common consolidation pattern in COVID-19 patients [40].
Air bronchogram: Air bronchogram is a pattern of bronchi filled up with air on an opaque airless setting (low opacity on high opacity). It is not a common finding in CT scan of COVID-19 patients and usually indicates severe symptoms [39–41]. Another theory is that air bronchograms are a result of filled bronchi with gelatinous mucus which has a low attenuation. The high viscosity of the gelatinous mucus in damaged bronchioles results in lack of sputum motility and dry cough [40].
Crazy paving pattern: Crazy paving pattern is defined as a reticular attenuation superimposed on a ground glass opacity (GCO) reminding of paving stones. This pattern is usually seen in severe cases of COVID-19 infection [39,40]. This pattern is probably caused by alveolar edema accompanied by interstitial inflammation [40].
Reticular pattern and lymphadenopathy: Reticular pattern is referred to interstitial pulmonary changes resulting in interlobular septal thickening [40].
Lymphadenopathy is defined as lymph nodes with more than 1 cm short-axis diameter. This is a rare finding in CT scan of COVID-19 patients seen in almost 4–8% of them [39–41,43]. Although it is not a frequent finding in CT, lymphadenopathy is seen mostly in severe cases and can be a risk factor for developing sever disease in COVID-19 patients [40].
Nodules and fibrosis: Nodules are defined as round opacities below 3 cm in diameter which have poorly or well defined margins. Fibrosis is replacement of cells with scar tissue. Fibrous stripes are defined as irregular lines with high opacity which are not common findings in COVID-19 patients (seen in about 17%) [39–41]. The exact effect of fibrosis in prognosis of COVID-19 patients is unclear. Some studies suggest that fibrosis can be a sign of good prognosis with stabilizing effect on the disease and some others believe that fibrous stripes are a poor prognostic factor [40].
Halo sign, reverse halo sign and pleural changes: Halo sing refers to GCOs surrounding a nodule or density. Reverse halo sign is referred to a GCO surrounded by a consolidation. This sign is probably indicative of progression of the disease. Pleural thickening is an uncommon CT finding in COVID-19 patients (seen in 32%) while pleural effusion is rare (seen in 5%) [40].
Temporal CT changes in COVID-19 patients during the infection:While a patient with COVID-19 infection can be described as mild, moderate, severe and critical clinically [81], the imaging results also can be described in four phases during the time course of illness: early phase, progressive phase, severe phase and dissipative phase which are discussed here.
Early phase: In this phase which patients are mostly in moderate clinical condition, their lesions are supposed to be in single or multiple areas. The distribution of lesions is believed to be subpleural or along bronchi.
According to this pattern, the spread of the disease is believed to be through the air way starting from the bronchioles and the epithelium of the alveoli in the periphery, progressing to the center. The usual morphology of lesions in this phase is patchy or nodular GCOs with reticular changes (thickening of intralobular or interlobular septa) sometimes with the presence of halo sing around the nodules. Events of this phase are due to infiltration of exudates into the alveoli and presence of edema in interstitial space.
Progressive phase: Many of the lesions progress rapidly in this phase and the severe clinical symptoms are seen as a result. The limited lesions of early phase progress in number, density and extent. The morphology of lesions is progressed to a coexistence of GCOs and consolidations and the crazy paving pattern sometimes appears. Events of this phase are seen as a result of large amounts of
exudation into the alveolar cavity and fusion of the alveoli accompanied by dilation of interstitial vessels.
Severe phase: The severe phase which is mostly seen about 14 days after the initiation of symptoms is characterized by peaked number of lesions involving all lung segments bilaterally resulting into the white lung pattern. Pleural effusion can be present. Air broncho- grams can be seen due to massive exudation in the alveolar cavity. Subsegmental atelectasis can also be seen in this phase and the clinical symptoms are severe-critical.
Dissipative phase: The final phase which is described as dissipative usually occurs after 2 weeks from the first illness symptoms. The lesions are gradually absorbed, the clinical symptoms decrease and high-density stripes appear indicating fibrosis [42,45,59,64–72].
CT manifestations in children and pregnant women:Children and infants are usually asymptomatic or present mild clinical symptoms and their CT manifestations are not as typical as adults during COVID-19 infection, so CT scan can be very useful to diagnose children and infants with COVID-19 infection. The common morphology of lesions in children’s CT is believed to be small nodular or patchy GGOs sometimes accompanied by consolidation.
The distribution of lesions is mostly subpleural and peripheral [43,46,48,49,54]. Halo sign is a rare finding and crazy paving pattern is not seen in children [46].
Possible CT differences between pregnant and nonpreg- nant adults were studied by Liuet al.They showed that there is no difference in the distribution of lesions between these groups and they are mostly peripheral.
Consolidations (complete consolidations and consolida- tions mixed with GGOs) were seen more frequently in pregnant women comparing with nonpregnant while GGOs with or without reticulation were seen more in nonpregnant group [43].
Chest X-ray (CXR):Although the main imaging modality to diagnose COVID-19 infection is CT scan, CXRs are also being frequently used. In a meta-analysis by Rodriguez-Morales et al. [32], they showed that the CXR results were mostly GGOs distributed bilaterally. In another study in Korea by Yoon et al. [53] on nine COVID-19 patients, they showed that 33.3% of patients had parenchymal abnormalities on CXR. The lesions were mostly consolidations distributed peripherally in lower lung zones.
Smoking and COVID-19
Smoking is believed to be an important risk factor for ending up with poor outcomes in COVID-19 patients [82,83]. The percentage of former or current smokers is higher among patients, who were admitted to ICU, needed a ventilator or died. Comparing with nonsmo- kers, smokers are 1.4 times more likely to develop severe
symptoms and 2.4 times more likely to need ventilation, ICU admission and dying [83].
Gastrointestinal system Clinical symptoms
COVID-19 infection has also some known gastrointesti- nal manifestations (GIMs) as well. In one retrospective study, of 1141 confirmed COVID-19 cases admitted to Zhongnan Hospital of Wuhan University, 183 (16%) presented with GIMs including, nausea, vomiting, abdominal pain, diarrhea and loss of appetite [84]. These gastrointestinal symptoms were observed in other studies too [85–87,90]. There were also some cases of bloody diarrhea caused by COVID-19 [88]. Yang et al. [89]
found two (4%) cases of nonsurviving gastrointestinal hemorrhage patients among 52 critically ill SARS-CoV-2 pneumonia patients. Some studies report GIMs as early and first symptoms of the disease. For example, in a study consisted of 62 patients with laboratory confirmed SARS-CoV-2 infection, three of which (8%) developed diarrhea at onset of the disease [14]. It’s important to have caution that COVID-19 can present dominantly with gastrointestinal symptoms only. In one study, of 1141 confirmed COVID-19 cases, 183 (16%) presented with gastrointestinal symptoms [84]. Abdominal pain is more frequent among patients admitted to ICUs compared with patients who did not as reported in one study with 138 hospitalized patients with confirmed nonspecific interstitial pneumonia whom 36 (26.1%) of them were transferred to the ICU because of organ dysfunction [48].
Also, in the same study it is discussed that having gastrointestinal symptoms in patients with COVID-19 may be associated with more severe disease compared with patients without gastrointestinal symptoms. Similar to adults, pediatric patients with COVID-19 had diarrhea and vomiting as gastrointestinal presentations [91]. In Wuhan Children’s Hospital a cohort was performed consisted of 171 confirmed SARS-CoV-2 infection with the median age of 6.7 years. Diarrhea in 15 (8.8%) and vomiting in 11 (6.4%) cases were observed [92]. Other clinical features like milder course of disease and lower respiratory symptoms have been described but gastroin- testinal symptoms appear to be like adults in severity, although more data is necessary to conclude that [91].
Fecal shedding of the virus
Viral RNA can be found in the stool or anal/rectal swabs of COVID-19 patients [91,93]. Surprisingly their stool viral RNA can remain positive even after their respiratory samples became negative as in one study with 73 hospitalized SARS-CoV-2 confirmed patients, were SARS-CoV-2 RNA positive in stool but 17 (23.29%) of them remained positive in stool after respiratory samples became negative [94]. The viral shedding from gastrointestinal tract can be abundant and last for weeks.
In a Case Series with 10 children with confirmed SARS- CoV-2 infection who were admitted to the Children’s Hospital in Shanghai, a high frequency (83.3%) of 2019-
nCoV RNA was detected in feces in mild patients, virus RNA shedding in feces lasts for 2 weeks to 1 month [95]
and in another study among 41 patients with confirmed SARS-CoV-2 infection, one patient had positive fecal sample 33 days after respiratory sample became negative [96]. These findings may suggest gastrointestinal tract as a potential viral replication site [95].
Liver
Liver injury during COVID-19 disease is observed in many patients with COVID-19 [97,98]. The incidence rate of liver injury has been estimated between 14.8 and 53% in various studies [99–101]. In mild cases of COVID-19 liver dysfunction is rare. But, in severe cases, liver damage is common and requires additional attention [98,102]. The most common manifestation of liver involvement in patients with COVID-19 is an increase in liver enzymes and sometimes an increase in bilirubin levels [28,97,98,100,102]. In a retrospectively analyzed study of 40 patients who were admitted to the isolation ward of Tangdu Hospital, China, 55% of them suffered liver damage as elevated liver enzymes in the first week of hospitalization while the albumin dropped in the second week. Liver damage was correlated with the severity of the underlying disease [101]. Furthermore, there was a direct correlation between liver transferase impairments and COVID-19 disease severity in different studies [28,97,102]. In a study of 651 patients with COVID-19 in Zhejiang province, patients with gastrointestinal symp- toms were more likely to have an elevated level of aspartate aminotransferase (AST) rather than alanine aminotransferase (ALT) compared with those without gastrointestinal symptoms. Also, it was observed that in patients with gastrointestinal symptoms ALT is one of the significant risk factors for severe COVID-19 [103].
Various causes for liver involvement have been reported from SARS-COV-2 infection to medications and systemic inflammation [15,97,98,102,104]. Drug toxicity can be one of the possible causes of liver damage, although in many cases, there has been an enzymatic disorder before drug treatment [102]. It is well known that pulmonary congestion in intubated patients with positive end-expiratory pressure or hepatic ischemia can be a cause of abnormal hepatic enzymes, but these conditions are more common in special wards, while the mentioned disorders are seen in all wards. A biopsy of the liver showed a slight lobular and portal involvement and slightly microvesicular steatosis [102,105]. For these reasons, direct liver damage by the virus is less likely. A review study has reported that liver damage may begin with damage to bile duct cells. Because the receptor for the virus is mostly expressed in bile duct cells [99].
Cardiovascular system
One of the relatively common COVID-19 infection complications are cardiac injuries. But the main caveat to study the pure effect of this infection on the cardiovascu- lar system is that in most studies there is not a clear line
between the patients who have cardiovascular disease (CVD) history and comorbidities and the patients who don’t, which leaves the results inconclusive in many cases.
Cardiac biomarkers
Patients with COVID-19 may develop cardiac injuries and therefore elevations of cardiac indicators are expected. In a study by Shi et al. on 416 COVID-19 confirmed cases, patients with cardiac injury had higher creatine kinase (median [IQR], 3.2 [1.8–6.2] vs. 0.9 [0.6–1.3] ng/ml), myohemoglobin (median [IQR], 128 [68–305] vs. 39 [27–65]mg/l), high-sensitivity cardiac troponin I (median [IQR], 0.19 [0.08–1.12] vs.<0.006 [<0.006–0.009]mg/l), N-terminal pro-B-type natri- uretic peptide (NT-proBNP) (median [IQR], 1689 [698–3327] vs. 139 [51–335] pg/ml) and creatinine kinase myocardial band (median [IQR], 3.2 [1.8–6.2] vs.
0.9 [0.6–1.3] ng/ml) [106]. In Guoet al.’s [107] study on 187 confirmed COVID-19 patients, troponin T levels had association with NT-proBNP levels (b¼0.613, P<0.001). In a retrospective study by Zhouet al.on 191 COVID-19 patients, 22/168 (13%) had creatine kinase more than 185 U/l (P¼0.038) and high-sensitivity cardiac troponin I more than 28 pg/ml 24/145 (17%) (P0.0001). In another study, by Duet al.[108] among 85 COVID-19 confirmed patients, 31 (36.5%) had increased creatine kinase levels.
Electrocardiography and arrhythmia
Shiet al.’s [106] study contained 14 ECGs taken during elevated cardiac markers among patients with cardiac injury all of which were abnormal compatible with myocardial ischemia findings, including T-wave depres- sion and inversion, ST depression and Q waves. A COVID-19 confirmed 43 years old woman’s ECG had low atrial ectopic rhythm, mildly elevated ST (V1–V2 and augmented Vector Right (aVR)), reciprocal ST depression (V4–V6) and QTc 452 ms with diffuse U waves [109]. Another COVID-19 confirmed 53 years old woman’s ECG with no CVD history, showed low voltage in the limb leads, minimal diffuse ST elevation (more prominent in the inferior and lateral leads), and an ST depression with inverted Twaves (V1 and aVR) [110]. Du et al. [108] found arrhythmia among 51/85 (60.0%) patients and among two of 91 died patients (2.47%), malignant arrhythmia was the cause of death. Patients with elevated troponin T had more frequent malignant arrhythmias [107].
Echocardiography
Transthoracic echocardiography of 43 years old patient mentioned above had mild left ventricular (LV) dysfunction (LVEF 43%) with inferolateral wall hypoki- nesia; there was no ventricular dilation and no pericardial effusion. Further evaluation by dynamic three-dimen- sional volume-rendering reconstruction showed a hypo- kinesia of the LV (mid and basal segments) with normal apical contraction, suggesting a reverse Takotsubo
syndrome (TTS) pattern. Her final diagnosis was acute virus-negative lymphocytic myocarditis associated with SARS-CoV-2 respiratory infection [109]. Transthoracic echocardiography revealed normal LV dimensions with an increased wall thickness (interventricular septum, 14 mm, posterior wall, 14 mm) and a diffuse myocardial echo-bright appearance. Hypokinesia, with an estimated LVEF of 40% was observed. There was no evidence of heart valve disease. LV diastolic function was mildly abnormal with mitral inflow patterns, with anE/Aratio of 0.7 and an averageE/e0ratio of 12. A circumferential pericardial effusion that was most notable around the right cardiac chambers (max 11 mm) with no signs of tamponade was observed [110]. In another case, a 69 years old patient of confirmed COVID-19 infection, echo- cardiography showed a dilated LV (LV end-diastolic diameter 56 mm), severe and diffuse LV hypokinesia (LVEF 34%). LVEF decreased to 25% and the estimated cardiac index was 1.4 l/min/m2 3 h later which is indicative of cardiogenic shock [111].
Cardiac histological changes
In one COVID-19 confirmed 50-year-old man, mono- nuclear inflammatory infiltrates without substantial myo- cardial damage and histological changes have been seen in heart tissue [15]. In another case, a 69 years old COVID-19 confirmed patient [111], cardiac myocytes had nonspecific features like myofibrillar lysis and lipid droplets, but no viral particles were observed in cardiac myocytes, therefore viral cardiotropism remains to be proved. No viral particles in endothelia were observed. Endomyocardial biopsy was clear from significant myocyte hypertrophy or nuclear changes. Interstitial changes were focal, minimal and mainly perivascular. There were low-grade interstitial and endocardial inflammation. Interstitial cells with damaged structure had viral particles inside. Single or small groups of viral coronavirus-like particles (dense round envelope and electron-dense spike-like structures on the surface and with 70–120 nm size) [111]. Also, the aforementioned 43 years old case’s endometrial biopsy had diffuse T- lymphocyte infiltrates (CD3þ >7/mm2) with huge interstitial edema and limited foci of necrosis. No replacement fibrosis identified, suggesting an acute inflammatory process. Molecular analysis showed the absence of the SARS-CoV-2 genome within the myocardium. No contraction band necrosis or TTS- associated microvascular abnormalities were observed [109].
Kidney
Gastrointestinal, kidneys and testes, in addition to the lungs overexpress the ACE2 receptors [112]. The reason for the higher accumulation of ACE2 in renal tubules (and less in glomeruli) based on studies is that the kidney is able to express this enzyme more than 100 times as much as the lungs [38,113–115]. But the question, according to observations, is why the prevalence of ARDS is much higher than that of acute kidney injury (AKI)? By studying
several genetic and protein databases, Guo et al. [114]
showed that the expression of AGTR2 mRNA in lung tissue was much higher than in renal tissue, so further studies are recommended. One of the most important biomarkers to diagnose patients with a complicated condition with COVID-19 is considered an increase in blood urea nitrogen (BUN), Cr and cystatin C [116].
Renal damage intensity in COVID-19 patients could vary from mild to severe. Mild injury associates with little increase in serum BUN, Cr with mild microscopic proteinuria and hematuria. Severe injury can be diagnosed by drastic increase in BUN, Cr and decrease of renal output indicative of AKI. There are different statistics on kidney damage caused by COVID-19 according to different studies, ranging from no sever injury to the occurrence of AKI in 15% of hospitalized patients. There are different findings about the relationship between acute renal impairment and severity and mortality of COVID-19.
Study by Wang et al. [117] in Wuhan on 116 patients showed that there was no significant relationship between COVID-19 and acute kidney impairment. Whereas Li et al.in a multicenter study in Wuhan on 193 patients found that kidney impairment, was observed in 7% of patients with COVID-19 and Renal dysfunction, including increased creatinine or urea (BUN) as well as acute kidney impairment, compared with the absence of renal impairment, causes a 5.3-fold increase in mortality in patients with COVID-19. Proteinuria, hematuria, increased BUN, Cr and serum uric acid levels were observed in 60, 40, 31, 22 and 20% of patients with COVID-19, respectively [118].
Zhaoet al.in a systematic review and meta-analysis found that chronic kidney disease is highly associated with severe COVID-19 [119]. Chenget al.[120] in Wuhan in a study on 710 patients found that there is a high risk of death in hospital with renal failure (proteinuria, 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 presence of underlying diseases, such as chronic renal failure [122,123].
Obstetrics and gynecology
The COVID-19 infection in women during pregnancy develops obstetric complications and perinatal adverse outcomes with moderate-to-severe clinical symptoms.
Apart from usual respiratory problems such as dyspnea or tachypnea, dry cough, nasal congestion and runny nose [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 have been observed [124,126]. Zhuet al.[124] reported that the onset of clinical symptoms among 9 mothers with COVID-19 pneumonia was before (1–6 days, four cases), during (two cases) and after (1–3 days, three cases)
delivery. In general, mothers with COVID-19 after an emergency cesarean section had lower symptoms than before the delivery. A case with COVID-19 revealed lower lymphopenia and higher neutrophilia than the normal range [128]. In a case–control study, this viral disease conversely reduced the count of white blood cells and neutrophils [129]. Mild thrombocytopenia and increase of creatine phosphokinase levels were reported in pregnant women with COVID-19 [130–132].
According to the data obtained from liver enzymes, the liver injury may occur in these patients during COVID-19 infection. It was shown that 33% of pregnant women with COVID-19 showed remarkable levels of ALT and AST [133]. Compared with healthy controls, a notably lower ALT amount was obtained in blood samples taken from pregnant patients with COVID-19 [128].
Most of these patients showed low levels (<40.0–55.0 g/
l) of serum albumin [130,134,135] and high levels (>10 mg/l) of C-reactive protein [130,133,136]. Even though the high serum level of PCT (0.5 ng/ml) in adults was considered as a key indicator to clinically diagnose COVID-19, this biomarker could not ade- quately differentiate healthy and patient pregnant women [22]. The placenta is another organ to express ACE2 and acts as an alternative organ for lungs, kidneys, heart and liver for fetuses during pregnancy. Accordingly, this temporary endocrine organ as an important physiological and immunological barrier prevents maternal–fetal transmission of pathogens. As the expression rate of ACE2 receptors in most cells of the early maternal–fetal interface is meager, the new coronavirus cannot pass from mothers to fetuses through transplacental vertical transmission [136]. It was evidenced with no detection of SARS-CoV-2 in amniotic fluid or in the neonatal blood collected from the umbilical cord. Also, the presence of this virus in breastmilk, gastric juice and neonatal throat swabs was also negative [130,134,136].
Conclusion
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 involvement and the effects of the virus on many other organs and systems remain unclear that shows the necessity of further investigations about the disease.
Acknowledgements
The authors would like to thank the Clinical Research Development Unit of Baqiyatallah Hospital, Tehran, Iran, for guidance and advice.
Authors’ contributions: M.H.A.: Data gathering, article writing at pulmonary section and coordination between sections. R.H.: Data gathering, article writing at pulmonary section and coordination between sections.
B.M.: Data gathering, article writing at gastrointestinal and cardiovascular section. M.R.: Data gathering and article writing at nephrology and urology section. L.K.:
Data gathering and article writing at pregnancy section.
Z.S.: Data gathering and article writing at pregnancy section. M.H.: Collaboration with idea development and study design, article editing. M.M.M.: Data gathering and article writing at cardiovascular section. M.A.A.:
Collaboration with idea development, data gathering and article writing at liver section. A.K.: Idea development and project management.
Ethics approval and consent to participate: Not applicable.
Consent for publication: Not applicable.
Availability of data and materials: All data and materials used on this article are available on PubMed.
The current article was not funded.
Conflicts of interest
The authors declare that they have no competing interests.
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