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© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 N. Rezaei (ed.), Coronavirus Disease - COVID-19, Advances in Experimental Medicine and Biology 1318, https://doi.org/10.1007/978-3-030-63761-3_11
Clinical Manifestations
in nature. They are classified into alphacoronavi- ruses and betacoronaviruses, which both have their gene source from bats and are mainly pres- ent in mammals such as bats, rodents, civets, and humans, and gammacoronaviruses and delta- coronaviruses, which both have their gene source from birds and mainly occur in birds (Woo et al.
2005; Lau et al. 2015). Betacoronaviruses have proven to be highly pathogenic and contagious pathogens, leading to respiratory, digestive, hepatic, and nervous system disorders (Weiss and Leibowitz 2011; Chen et al. 2020d).
Two of coronaviruses can cause acute respi- ratory distress syndrome (ARDS), acute respi- ratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome corona- virus (MERS-CoV), which caused two out- breaks in 2002 in China and 2012 in the Middle East, respectively. SARS-CoV-2 is the seventh beta- coronavirus known to infect humans and cause coronavirus disease in 2019 (COVID-19). At the end of the year 2019, it was discovered in Wuhan, China, with the potential of causing acute respiratory distress syndrome (ARDS) and transmission between humans (Cleary et al. 2020; Phan et al. 2020;
Lotfi et al. 2020).
COVID-19 pandemic is the third outbreak of coronavirus in the twenty-first century (Organization 2020; Jabbari et al. 2020).
In December 2019, the first case of COVID- 19 pneumonia was reported in Wuhan, China.
Infection rapidly spread worldwide in almost 3 months, and World Health Organization announced COVID-19 outbreak as a pandemic and a public health emergency of international concern with a total of 63,965,092 confirmed cases and 1,488,120 total death worldwide as of Dec 3, 2020 (Hick and Biddinger 2020; Lotfi and Rezaei 2020; Hanaei and Rezaei 2020;
Organization 2020).
Currently, the source and pathogenesis of the COVID-19 remain unclear, and there are no uni- form diagnostic and treatment standards.
Unfortunately, in certain patients, the disease progresses rapidly, and respiratory failure can occur within a short time, even leading to death (Liu et al. 2020). Thus, early identification of
patients is necessary to prevent and control this outbreak (Zhu et al. 2020d).
The reverse transcription-polymerase chain reaction (RT-PCR) for viral nucleic acid is the current gold standard method to detect and diag- nose COVID-19. However, several studies have reported false-negative results and reduced sensi- tivity for this test (Huang et al. 2020a; Suzuki et al. 2020; Basiri et al. 2020a). For instance, in Wu et al. study with 80 confirmed COVID-19 cases, more than 10% passed 3 tests (with at least 1-day sampling time interval) before they got positive results. Therefore, if the suspected cases are excluded based on even two consecutively negative respiratory pathogenic nucleic acid test results, about 10% of the infected patients will be missed (Wu et al. 2020a). Xu et al. also reported that the detection of the nucleic acid of the SARS- CoV- 2 was still negative in some patients on the sixth to the eighth day after the onset of disease (Xu et al. 2020b). In another study, despite nega- tive nucleic acid test results, all 56 patients showed high specific IgG concentrations, sug- gesting SARS-CoV-2 infection (Dong et al.
2020). It has also been reported that the SARS- CoV- 2 was detected by RT-PCR in the upper respiratory tract, even after full resolution of symptoms (Lescure et al. 2020).
Studies reported the sensitivity of the RT-PCR method on throat swab samples ranging from 30% to 60% (Ai et al. 2020). Moreover, it has been reported that the number of days between symptom onset and positive RT-PCR ranged from 1 to 19 days (median 14 days) (Himoto et al. 2020), which can be due to the testing errors or sample collection method of throat swap (Dong et al. 2020). COVID-19 targets human angiotensin-converting enzyme 2 (ACE2) (Sharifkashani et al. 2020; Ahmadi et al. 2020) and infects intrapulmonary epithelial cells more than cells of the upper airways, which may be the reason for the false-negative results of throat swab specimens for RT-PCR assays (Veeramachaneni et al. 2020).
Therefore, non-ideal sensitivity and specific- ity of RT-PCR testing of the nasopharyngeal sample, as well as the limited number of RT-PCR kits, call for the necessity of diagnostic algorithm
for patients with suspected COVID-19 pneumo- nia. Effective triage and early detection of COVID-19 are also essential for disease control, isolation, psychological reassurance for patients, and effective treatment. The combining of clini- cal, laboratory, and imaging findings is necessary to assist clinicians anywhere in the globe in sus- pecting the possibility of COVID-19, pretest probability assessment, and accurate interpreta- tion of diagnostic testing. We have tried to address this algorithm in this chapter (Table 11.1).
11.2 Respiratory Manifestations and Constitutional
Symptoms
As reported, patients with COVID-19 develop clinical symptoms after an incubation period ranging from 1 to 14 days, mostly 4 to 7 days
which is longer in milder or early asymptomatic cases and shorter in severe or rapidly progressive cases (Guan et al. 2020; Tian et al. 2020).
Since the diameter of the SARS-CoV-2 is very small, about 60 to 140 nanometers, it can pene- trate the lung terminal structures, including the interlobular and alveolar septum. In healthy lung tissue, ACE2 is mainly expressed by club cells of distal bronchioles and type I and type II alveolar epithelial cells, which are involved in preventing ARDS. Cub cells secrete proteins protective against airway inflammation and oxidative stress, and type II pneumocytes are the defender of the alveolus by synthesizing and recycling all com- ponents of the surfactant (Bombardini and Picano 2020). ACE2 serves as a receptor for SARS- CoV- 2, which plays a crucial role in lung injury.
The binding of COVID-19 spike protein to ACE2, activates the enzyme, thus activating the renin- angiotensin system to cause lung injury, which in turn may contribute to ARDS by triggering vaso- constriction, edema, lymphocyte infiltration, apoptosis, and fibrosis in the lung interstitium (Kuba et al. 2005; Rezaei 2020b; Saghazadeh and Rezaei 2020b).
Therefore, the common symptoms of COVID- 19 patients are consistent with the mani- festation of lower respiratory tract infections. By contrast, upper respiratory tract symptoms are less common in these patients. General symp- toms of viral infection and pneumonia happen in the vast majority of COVID-19-infected patients, including fever, fatigue, cough (mostly without sputum), also chills, dyspnea, nausea, headache, anorexia, and muscle ache. On the other hand, upper respiratory tract signs and symptoms, including rhinorrhea, sneezing, or sore throat, have been rarely reported in COVID-19 cases (Zheng et al. 2020; Zhang et al. 2020d; Tian et al.
2020; Zhang et al. 2020b). In a meta-analysis, including 50,466 patients with COVID-19, fever incidence was 89.1%, 72.2% had a cough, and the incidence of muscle soreness or fatigue was 42.5% (Sun et al. 2020). In another meta-analysis of Overall, 31 articles and 46,959 patients, including 10 English articles and 21 Chinese arti- cles, the most common clinical manifestations were fever (87.3%), cough (58.1%), dyspnea
Table 11.1 Systems involved by COVID-19 and associ- ated clinical findings
System or test Common findings
General Fatigue, fever, chills, headache, and muscle ache
Respiratory Dry cough, dyspnea, and chest distress
CNS and PNS Agnosia, anosmia, altered mental status, acute cerebrovascular disease, epilepsy, central respiratory failure, enhanced tendon reflexes, and ankle clonus
GI Anorexia, nausea, vomiting, diarrhea, and abdominal pain Cardiac Acute myocardial injury, arrhythmia,
and cardiac shock
Cutaneous Petechiae, erythema, vesicles, pustules, papulovesicular exanthem, urticarial, maculopapular eruptions, livedo, and necrosis
Hematologic laboratory tests
Decreased: lymphocyte count and thrombocyte count
Increased: CRP, ESR, PCT, D-dimer, prothrombin time, LDH, serum ferritin, AST, ALT, cardiac troponin I, CK-MB, and NT-proBNP Chest CT scan Multifocal, peripheral, bilateral
ground-glass opacities and
consolidation, air bronchogram sign, crazy-paving pattern, and pleural thickening
(38.3%), muscle soreness or fatigue (35.5%), and chest distress (31.2%) (Cao et al. 2020). In other metal analysis studies of COVID-19 cases, the same symptoms have been reported as the most common symptoms of COVID-19 pneumonia (Zhu et al. 2020b; Li et al. 2020b; Rodriguez- Morales et al. 2020; Zhu et al. 2020a).
Although the initiative for COVID-19 screen- ing started from fever clinics since fever, cough, and shortness of breath are the most emphasized symptoms, it increases the risk of omitting those patients with other symptoms and average body temperature, mainly middle-aged and elderly patients, or cases at the first days of the infection or immunosuppressed patients (Jazieh et al.
2020; Young et al. 2020). In a study of 1,099 laboratory- confirmed patients, fever presentation increased from 43.8% on admission to 88.7%
during hospitalization (Guan et al. 2020). In another study of 202 hospitalized patients with COVID-19, more than 20% of patients were afe- brile on admission (Huang et al. 2020b). It is noteworthy to mention that not all patients with COVID-19 had high temperature during their first visit, although they have experienced a fever- ish feeling which may be due to the use of over- the- counter antipyretic drugs (Zhu et al. 2020f).
Afebrile cases have also been reported in SARS- CoV and MERS-CoV cases (Zumla et al. 2015).
Thus, since afebrile patients may be missed if the surveillance case definition focuses on fever detection, it should be noted that fever is not a reliable symptom for the suspicion or screening out the COVID-19.
11.3 Central Nervous System Manifestations
Nervous system involvement has been reported in SARS-CoV and MERS-CoV cases. The SARS-CoV-2 may also enter the central nervous system (CNS) through the hematogenous or ret- rograde neuronal route, causing neurological symptoms including headache, altered mental status, anosmia, acute cerebrovascular disease, epilepsy, and central respiratory failure, which have been reported in studies of COVID-19
patients (Mao et al. 2020; Yazdanpanah et al.
2020b; Jahanshahlu and Rezaei 2020a; Saleki et al. 2020). Although the most common brain imaging abnormalities reported in COVID-19 cases were leptomeningeal enhancement and bilateral frontotemporal hypoperfusion, which can be due to the hypoxia (Helms et al. 2020;
Kandemirli et al. 2020; Ebrille et al. 2020), autopsy results of patients with neurological symptoms confirmed COVID-19 nucleic acid existence in the brain tissue and the brain tissue damage including hyperemesis, edema, and degeneration (Mao et al. 2020).
The neurotropism of SARS-CoV-2 explains the potential mechanism behind the neural inva- sion of COVID-19 (Hamming et al. 2004). It might lie in the expression of ACE2 on nervous system cells, cytokine storm syndrome (Mehta et al. 2020; Rokni et al. 2020), microvascular thrombosis, and hypoxemia. Neurological symp- toms reported in a high percentage of COVID-19 patients ranging from 20% to as high as 80% in severe cases admitted to the intensive care unit (ICU) (Kandemirli et al. 2020; Helms et al. 2020;
Mao et al. 2020). Diffuse corticospinal tract signs, including enhanced tendon reflexes and ankle clonus, have also been reported in COVID- 19 patients, which may be due to the existence of the SARS-CoV-2 in cerebrospinal fluid (Arabi et al. 2017; Helms et al. 2020).
Severe cases of COVID-19 are more prone to develop neurological symptoms (Mao et al.
2020). Acute ischemic stroke has been reported in young COVID-19 patients (Beyrouti et al.
2020; Oxley et al. 2020), which may be due to the coagulation disorder since a higher level of D-dimer and large vessel occlusion also have been reported in such patients (Thachil et al.
2020). Moreover, severe COVID-19 cases are more prone to develop intracranial cytokine storms, thus acute necrotizing encephalopathy, which is known as a complication of COVID-19 (Li et al. 2020c). Therefore, due to the high mor- tality rate of neurological injury during COVID- 19, patients should be examined for neu- rological symptoms during the early phase of symptoms, and patients with neurological involvement should be closely monitored and
also receive anticoagulant therapies in the case of coagulopathy.
Olfactory and taste disorders have been reported in COVID-19 patients, even in some patients, as the only presenting symptoms (Hjelmesaeth and Skaare 2020). ACE2 is also expressing on cells in nasal and oral tissue (Xu et al. 2020a; Hamming et al. 2004; Fini 2020), and seems to be the potential mechanism of this finding. Although in magnetic resonance imaging studies of patients with anosmia, the olfactory bulb was found to be normal (Galougahi et al.
2020), but the first cranial nerve branches dys- function can’t be rolled out as the potential cause of anosmia. Since necrotic changes was present in olfactory bulb and cranial nerve tracts of COVID-19 patients (Han et al. 2020).
FDG-PET scan also showed redused meta- bolic activity in the orbitofrontal cortex of COVID-19 patients (Karimi- Galougahi et al.
2020). Moreover, smell loss in these patisnts hap- pens in the absence of mechanical nasal obstruc- tion and lasts longer than common viral rhinitis (Akerlund et al. 1995).
It seems that the virus reaches the brain through peripherally located olfactory dendrites within receptor cells, thus inducing central anos- mia (Brann and Firestein 2014). In transgenic mice, SARS-CoV entered the brain through the olfactory bulb since couple hours following infection, viral antigen was detected and was most abundant in the regions of the brain that are connected with the olfactory bulb, including piri- form and infralimbic cortices, basal ganglia, and midbrain (Baig et al. 2020; Brann et al. 2020).
These findings suggest that impaired neural func- tion due to direct neurotropism of COVID-19 is the main cause of anosmia and probably also agnosia (Hjelmesaeth and Skaare 2020; Karimi- Galougahi et al. 2020).
Anosmia or agnosia has been reported mostly in the mild form of COVID-19. In a study of a total of 417 mild-to-moderate COVID-19 patients, 85.6% and 88.0% of patients reported olfactory and gustatory dysfunctions, respec- tively (Lechien et al. 2020; Yan et al. 2020). Even it has been reported that using the presence of smell or taste change with fever and muscle ache
in outpatient mild-to-moderate cases can give a high sensitivity up to 90% for COVID-19 diagno- ses (Menni et al. 2020; Roland et al. 2020).
However, it should be noted that smell loss related to COVID-19 is mostly presented sud- denly and in the absence of nasal obstruction and rhinitis symptoms (Vaira et al. 2020).
11.4 Gastrointestinal System Manifestations
Some patients with COVID-19 are presented with gastrointestinal (GI) symptoms, including nausea, vomiting, and diarrhea as the initial symptom (Wang et al. 2020a; Zhou et al. 2020;
Zhang et al. 2020b). Even abdominal pain in some patients was the only symptom of COVID- 19, which may be due to pneumonia affecting lower lobes and/or pleural effusion (Dane et al. 2020). Also in other Coronavirus infections inclusding MERS-CoV and SARS- CoV, GI symptoms have been reported in up to 30% of patients (Assiri et al. 2013; Zhou et al.
2017). GI symptoms in COVID-19 can be explained by the fact that ACE2, as the receptor of the SARS-CoV-2, is also present in the GI tract, including epithelial cells of the tongue, oral cavity, esophagus, and enterocytes in the ileum and colon epithelium (Wan et al. 2020; Xu et al.
2020a).
In a study of 1,141 confirmed COVID-19 cases, 183 (16%) presented with just GI symp- toms (Luo et al. 2020). In a meta-analysis of 4,243 COVID-19 patients from 6 countries, the pooled prevalence of all GI symptoms was 17.6%; anorexia was the most common GI symp- tom (26.8%), followed by diarrhea (12.5%), nau- sea/vomiting (10.2%), and abdominal pain/
discomfort (9.2%) (Cheung et al. 2020). Overall GI symptom presentation varies from 3% to 40%
of COVID-19 patients (Zhu et al. 2020a; Li et al.
2020b). However, recall bias may be the reason behind the relatively low percentage of GI symp- tom reporting in some studies. Moreover, most studies reported hospitalized COVID-19 patients, and GI presentation may have a higher preva- lence in milder outpatient cases, since it has been
reported that GI symptoms in COVID-19 was associated with longer illness duration but lower ICU admission rate and lower mortality rate (Nobel et al. 2020).
Viral replication was seen in stool samples of patients with MERS-CoV infection (Zhou et al.
2017). COVID-19 virus also could be detected in the stool samples of patients during the first week of symptoms (Young et al. 2020; Zhang et al.
2020a). In a meta-analysis of 60 studies includ- ing 4,243 patients, up to 50% of COVID-19 patients tested of viral RNA in stool samples reported positive for viral RNA (Cheung et al.
2020) regardless of GI symptoms or even when the throat swap testing was negative (Qian et al.
2020; Zhang et al. 2020a). In Ling et al. study, the viral RNA could be detected in the stool of 81.8%
(54/66) cases with the negative results for throat swabs (Magrone et al. 2020). Therefore, routine RT-PCR testing of stool in patients with COVID- 19, especially those presenting with digestive symptoms, is recommended since it also seems to be a safer sample for medical staff compared to a throat swap sample.
Moreover, it should be noted that viral pres- ence in stool samples could raise a serious con- cern on the isolation policy for the COVID-19 patients, particularly during the recovery phase, since patients with GI symptoms also presented higher rates of familial clustering, which may be due to the aerosols generated from the toilet flushing of the shared toilets (Jin et al. 2020;
Zhou et al. 2020). Therefore, toilet isolation should be implemented in households with posi- tive cases of COVID-19, and fecal-oral route transmission should be considered for prevention strategies.
Patients with GI symptoms are more likely to present elevated liver tests, such an aspartate ami- notransferase (AST) and alanine aminotransfer- ase (ALT), thus liver injury (Jin et al. 2020; Zhou et al. 2020). However, it seems to be a result of systemic inflammatory response rather than a direct viral invasion to liver cells since ACE2 is highly expressed in bile duct cells but not liver cells (Chai et al. 2020). Moreover, COVID-19 patients with liver damage had higher inflamma- tory indexes, such as elevated C-reactive protein
(CRP) and procalcitonin (PCT), and more likely to have a fever and severe pneumonia, which may be related to the severe immune response (Wang et al. 2020a; Huang et al. 2020a; Bahrami et al.
2020; Yazdanpanah et al. 2020a; Saghazadeh and Rezaei 2020a; Nasab et al. 2020). Liver enzymes need to be monitored in COVID-19 patients regardless of the GI symptoms since liver injury was reported to be significantly higher in COVID- 19 patients compared to other respira- tory virus infections (Jin et al. 2020; Zhao et al.
2020). Moreover, liver damage was reported to be associated with a significantly higher risk of ICU admission and death in COVID-19 patients (Hajifathalian et al. 2020).
These findings suggest that viral shedding from the intestinal tract can be a potential route for infection transmission. Thus, toilet isolation and washing hands after anal hygiene should be considered to reduce fecal-oral route viral trans- mission, especially in patients with GI symp- toms. Moreover, a stool sample can be another way of diagnosis of COVID-19, especially when the throat swab results are negative despite highly suspicious of infection or when the medi- cal stuff protection is not adequate for the throat swap sample. It should be noticed that an unex- plained abdominal pain or GI symptoms could be criteria for COVID-19 testing for reducing missed cases.
11.5 Cardiovascular System Manifestations
Cardiac involvement has been reported in viral infections such as influenza, parvovirus B-19 (Fung et al. 2016), and COVID-19 as well (Shamshirian and Rezaei 2020). In COVID-19, up to 12% of patients were reported to have car- diac injury presenting as abnormal cardiac enzyme level, acute myocardial injury (AMI), and arrhythmia-induced cardiac shock (Ebrille et al. 2020; Kir et al. 2020). In a meta-analysis, including 50,466 patients with COVID-19, 49.4% of the patients presented with myocardial enzyme spectrum abnormalities, which mani- fested as an increase in cardiac enzymes or lac-