1. Introduction

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1. Introduction

The pandemic of the coronavirus disease 2019 (COVID-19) has affected the global population since the first detection in late of year 2019. To date, it has recorded over 86 million confirmed cases and attained a mortality rate of about 4% (as of 9 January 2021) [1,2]. Patients with overt cardiovascular diseases are particularly susceptible to COVID-19 and may have increased mortality rate [3].

The culprit of this disease, namely severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) belongs to the Coronaviridae family, Betacoronavirus genus and Orthocoronaviridae subfamily. The spike glycoprotein at the N-terminal region of SARS-CoV-2 acts as a receptor binding domain which binds to the human angiotensin converting enzyme 2 (ACE2) of the host cell. This leads to fusion between viral and host cell membranes to allow entry of coronavirus into target host cells [4]. Upon being infected with SARS-CoV-2, patients may present without symptoms or with symptoms, ranging from mild, moderate, severe to critical, with clinical classifications outlined by the Chinese National Health Committee [5]. Symptoms commonly presented in COVID-19 patients include fever, fatigue, respiratory symptoms like cough and shortness of breath, and gastrointestinal symptoms like diarrhoea, nausea and vomiting [6]. Although there is a list of symptoms presented in the COVID-19 infected patients, they are quite identical to other normally occurring illnesses such as flu or diarrhoea. This has further made the task of identifying and quarantining infected patients a great challenge.

Interestingly, there is an increasing number of cases that reported a variety of other symptoms that may not be commonly manifested in COVID-19, which might provide some critical useful hints for healthcare personnel to pinpoint those who might be infected and provide the necessary actions accordingly. Moreover, the changes in haematological parameters in SARS–CoV–2-infected patients are imperative to understand the pathophysiology of the disease and useful information as early clues to diagnosis [7]. Since the very first reported case of COVID-19 in late 2019, researchers have been working relentlessly in order to design effective drugs or specific vaccines for this disease; however, the discovery process has faced various great challenges. In actual fact, the World Health Organization (WHO) released a statement very recently stating that there is no silver bullet for this pandemic, which has reflected greatly on the gravity of the situation [8].

As of 9 January 2021, different countries have approved and started COVID-19 vaccinations among their populations using vaccines from Pfizer, Moderna, and AstraZeneca, with large numbers of vaccines at phase three of clinical trials [9–11]. Other management of COVID-19 includes the use of antivirals and antimalarial drugs, immune-based therapy, and supportive oxygen therapy for those who are in severe condition [12]. Previous measures in controlling the pandemic should continue to be practiced in this early phase of vaccinations. These include (1) social distancing, regular hand washing, wearing face masks in public, and (2) testing, isolating, and treating patients besides tracing and quarantining close contacts done by the healthcare facilities. Thus, it is of the utmost importance for healthcare providers to recognize and detect all possible symptoms of COVID-19 when treating patients to allow rapid testing, confirmation, and isolation to be done in a timely manner to prevent an outbreak and protect everyone.

This review focuses on the identification and description of rare and atypical symptoms that may aid targeted screening. Therefore, this article has pinpointed the less common and atypical symptoms that may be presented in infected patients, with its possible mechanism of action, which may shed some light for us in enhancing the effectiveness in the identification and targeted screening processes during this COVID-19 pandemic (Table 1).

Table 1. Prevalence of atypical and rare symptoms of COVID-19.

The pandemic of the coronavirus disease 2019 (COVID-19) has affected the global population since the first detection in late 2019. To date, it has recorded over 86 million confirmed cases and attained a mortality rate of about 4% (as of 9 January 2021) ^[1][2]. Patients with overt cardiovascular disease are particularly susceptible to COVID-19 and may increase the mortality rate ^[3].The culprit of this disease, severe respiratory syndrome coronavirus-2 (SARS-CoV-2) belongs to the Coronaviridae family, Betacoronavirus genus and Orthocoronaviridae subfamily. The spike glycoprotein at the N-terminal region of SARS-CoV-2 acts as a receptor binding domain which binds to the human angiotensin converting enzyme 2 (ACE2) of the host cell. This leads to fusion between viral and host cell membranes to allow entry of coronavirus into target host cells ^[4]. Upon being infected with SARS-CoV-2, patients may present without symptoms or with symptoms, ranging from mild, moderate, severe to critical, with clinical classifications outlined by the Chinese National Health Committee ^[5]. Symptoms commonly presented in COVID-19 patients include fever, fatigue respiratory symptoms like cough and shortness of breath, and gastrointestinal symptoms like diarrhea, nausea and vomiting ^[6]. Although there is a list of symptoms presented in the COVID-19 infected patients, they are quite identical to other normally occurring illnesses such as flu or diarrhoea. This has further made the task of identifying and quarantining infected patients a real great challenge.Interestingly, there are an increasing number of cases that reported a variety of other symptoms that may not be commonly manifested in COVID-19, which might provide some critical useful hints for healthcare personnel to pinpoint those who might be infected and provide the necessary actions accordingly. Moreover, the changes in hematological parameters in SARS–CoV–2-infected patients are imperative to understand the pathophysiology of the disease and useful information as early clues to diagnosis ^[7]. Since the very first reported case of COVID-19 in 2019, researchers have been working relentlessly in order to design the effective drugs or specific vaccine for this disease; however, the discovery process has faced various great challenges. In actual fact, the World Health Organization (WHO) released a statement very recently stating that there is no silver bullet for this pandemic, which has reflected greatly on the gravity of the situation ^[8].As of 9 January 2021, different countries have approved and started COVID-19 vaccinations among their populations using vaccines from Pfizer, Moderna and AstraZeneca, with large numbers of vaccines at phase three of clinical trials ^[9][10][11]. Other management of COVID-19 includes the use of antivirals and antimalarial drugs, immune-based therapy and supportive oxygen therapy for those who are in severe condition ^[12]. Previous measures in controlling the pandemic continue to be practiced in this early phase of vaccinations. These include (1) social distancing, regular hand washing, wearing face masks in public and (2) testing, isolating and treating patients besides tracing and quarantining close contacts done by the healthcare facilities. Thus, it is of the utmost importance for healthcare providers to recognize and detect all possible symptoms in COVID-19 when treating patients to allow testing, confirmation and isolation to be done in a timely manner to prevent an outbreak and protect everyone.

2. Cutaneous Symptoms

Cutaneous features associated with COVID-19 can be categorized by two categories: inflammatory/exanthematous eruptions and vasculopathic/vasculitic lesions ^[13]. Inflammatory/exanthematous eruptions include urticarial lesions, erythema multiforme-like/maculopapular/morbilliform rash and papulovesicular exanthem. Pseudo-chilblain, acro-ischaemia, livedo reticularis, distal necrosis and purpuric/petechiae vasculitis rash fall under the vasculopathic/vasculitic lesions category. Currently, established reviews and systematic reviews that have been found in literature have generally showed that skin lesions are highly varied and may resolve unprompted. A meta-analysis reported that maculopapular rash was the most prevalent skin manifestation with latency of at least 8 days amongst 9.9% of COVID-19-positive patients ^[14]. Two other notable skin lesions are pseudo-chilblain and erythema rashes, which localized mainly at the trunk and extremities of patients. Pruritus is commonly associated with both lesions, followed by pain and burning sensation ^[15][16][17]. Acro-ischaemia found in severe COVID-19 patients were hypothesized due to hypercoagulation, whereas pseudo-chilblain in asymptomatic and mild young patients were due to coagulation disorder or hypersensitivity ^[13][18]. Erythema rashes prevalent in middle-aged adults were suggested to be caused by virus-specific T-cells. The onset of the skin lesions is varied, but under 30 days, can occur as the first symptom or after onset of non-cutaneous COVID-19 symptoms. The mean duration of skin lesions manifestation is around 9 days though the observations done. Matar and colleagues showed that the severity and mortality rates for patients with rashes were significantly higher than chilblains ^[16]. Other atypical skin manifestations that have been reported which require further investigation include atypical erythema nodosum, atypical Sweet syndrome, Kawasaki disease-like presentation and polymorphic patterns ^[19].

Cutaneous features associated with COVID-19 can be categorized into two categories: inflammatory/exanthematous eruptions and vasculopathic/vasculitic lesions [52]. Inflammatory/exanthematous eruptions include urticarial lesions, erythema multiforme-like/maculopapular/morbilliform rash, and papulovesicular exanthem. Pseudo-chilblain, acro-ischaemia, livedo reticularis, distal necrosis, and purpuric/petechiae vasculitis rash fall under the vasculopathic/vasculitic lesions category. Currently, established reviews and systematic reviews that have been found in the literature have generally shown that skin lesions are highly varied and may resolve unprompted. A meta-analysis reported that maculopapular rash was the most prevalent skin manifestation with a latency of at least 8 days amongst 9.9% of COVID-19-positive patients [18]. Two other notable skin lesions are pseudo-chilblain and erythema rashes, which localized mainly at the trunk and extremities of patients. Pruritus is commonly associated with both lesions, followed by pain and burning sensation [53–55]. Acro-ischaemia found in severe COVID-19 patients was hypothesized due to hypercoagulation, whereas pseudo-chilblain in asymptomatic and mild young patients were due to coagulation disorder or hypersensitivity [52,56]. Erythema rashes prevalent in middle-aged adults were suggested to be caused by virus-specific T-cells. The onset of the skin lesions is varied, but under 30 days, can occur as the first symptom or after the onset of non-cutaneous COVID-19 symptoms. The mean duration of skin lesions manifestation is around 9 days through the observations are done. Matar and colleagues showed that the severity and mortality rates for patients with rashes were significantly higher than chilblains [54]. Other atypical skin manifestations that have been reported which require further investigation include atypical erythema nodosum, atypical Sweet syndrome, Kawasaki disease-like presentation, and polymorphic patterns [19].

3. Ocular Symptoms

Although evidence is limited, there are cases of COVID-19 patients who have manifested ocular symptoms. Further studies done by researchers have detailed the proposed mechanism of infection. It is proposed that conjunctiva is the inoculation site of the SARS-CoV-2 from infected droplets. Along with that, viral migration may occur at the upper respiratory tract through the nasolacrimal duct or hematogenous, together with the involvement of the lacrimal gland ^[20]. This is mainly due to the fact of the presence of renin-angiotensin system or ACE2 receptor in the aqueous humour of the human eye ^[21]. However, more evidence is required to support ocular infection of SARS-CoV-2 through ACE2. The overall rate of ocular manifestations among COVID-19 patients is established at a range from 1% to 32% ^[21][22]. Ocular symptoms are varied, some cases are reported as first presentation, whereas others reported as secondary to COVID-19 progression. The most common ophthalmologic symptom reported is conjunctivitis with about 0.7% patients reported as first symptom ^[21][23][24]. Other symptoms reported include chemosis, epiphora, conjunctival hyperaemia, keratoconjunctivitis, haemorrhagic conjunctivitis with pseudomembranous and ophthalmoparesis ^[25][26][27]. Ocular symptoms have been associated with some cases of severe COVID-19, in which patients have higher white blood cells, neutrophils, procalcitonin, C-reactive protein and lactate dehydrogenase comparing to patients without ocular symptoms ^[22][28]. However, another meta-analysis reported that ocular symptoms were not associated with severe disease ^[29]. Inconsistency of PCR positive results for SARS-CoV-2 in tear/conjunctival were observed. Some cases have reported that the virus can be detected in tears and conjunctival secretion sampled from COVID-19 patients with conjunctivitis ^[30][31]. A number of cases have demonstrated that some patients were positive for the virus in tear even without experiencing conjunctivitis, whereas other patients had conjunctivitis with negative PCR tests ^[32]. Only about 2% to 3.5% of ocular samples retrieved from COVID-19-positive patients were tested positive for the virus ^[33][34][21]. Thus, the relation between positive SARS-CoV-2 in tear/conjunctival swab and ocular symptoms including conjunctivitis is still uncertain.

Although evidence is limited, there are cases of COVID-19 patients who have manifested ocular symptoms. Further studies done by researchers have detailed the proposed mechanism of infection. It is proposed that conjunctiva is the inoculation site of the SARS-CoV-2 from infected droplets. Along with that, viral migration may occur at the upper respiratory tract through the nasolacrimal duct or hematogenous, together with the involvement of the lacrimal gland [57]. This is mainly due to the fact of the presence of renin-angiotensin system or ACE2 receptor in the aqueous humour of the human eye [58]. However, more evidence is required to support ocular infection of SARS-CoV-2 through ACE2. The overall rate of ocular manifestations among COVID-19 patients is established at a range from 1% to 32% [58,59]. Ocular symptoms are varied, some cases are reported as the first presentation, whereas others reported as secondary to COVID-19 progression. The most common ophthalmologic symptom reported is conjunctivitis with about 0.7% of patients reported as first symptom [58,60,61]. Other symptoms reported include chemosis, epiphora, conjunctival hyperaemia, keratoconjunctivitis, haemorrhagic conjunctivitis with pseudomembranous and ophthalmoparesis [62–64]. Ocular symptoms have been associated with some cases of severe COVID-19, in which patients have higher white blood cells, neutrophils, procalcitonin, C-reactive protein, and lactate dehydrogenase comparing to patients without ocular symptoms [59,65]. However, another meta-analysis reported that ocular symptoms were not associated with severe disease [66]. Inconsistency of PCR positive results for SARS-CoV-2 in tear/conjunctival was observed. Some cases have reported that the virus can be detected in tears and conjunctival secretion sampled from COVID-19 patients with conjunctivitis [67,68]. A number of cases have demonstrated that some patients were positive for the virus in tear even without experiencing conjunctivitis, whereas other patients had conjunctivitis with negative PCR tests [69]. Only about 2% to 3.5% of ocular samples retrieved from COVID-19-positive patients were tested positive for the virus [21,22,58]. Thus, the relationship between positive SARS-CoV-2 in tear/conjunctival swab and ocular symptoms including conjunctivitis is still uncertain.

4. Cardiovascular Symptoms

Although most evidence are mainly anecdotal with a lack of systematic review, cardiovascular manifestations do exist in some COVID-19 patients regardless of any prior cardiovascular diagnosis. Suggested theories of cardiovascular involvement in ACOVID-19 include direct myocardial injury, cytokine storm, pre-existing cardiovascular disease co-morbidities and the use of ACE inhibitors and angiotensin receptor blockers (limited evidence) ^[35]. Myocardial injury caused by myocardial ischemia and myocarditis were showed as elevation in cardiac troponin-I levels and other inflammatory markers including ferritin, C-reactive protein, interleukin-6, interferon-γ, tumor necrosing factor-α and lactate dehydrogenase ^[36][37]. Patients with elevated cardiac markers had higher prevalence of pre-existing cardiovascular disease and were more likely to be admitted into intensive care unit along with the ventilation support. They normally ended up with poor prognosis and high mortality. Myocardial injury can also result from acute respiratory distress syndrome due to oxidative stress and potentially inflammation-induced myocardial apoptosis ^[35]. Acute myocarditis and ventricular arrythmia may be first presented in COVID-19 with arrhythmia which might occurred due to electrolyte and haemodynamic imbalances. The increase of troponin level would directly correlate with malignant ventricular arrhythmia ^[38]. Thus, continuous electrocardiogram monitoring is highly recommended when drugs that prolong QT intervals like hydroxychloroquine or chloroquine are given as COVID-19 treatment ^[6]. In addition, venous thromboembolism (VTE) is also observed in COVID-19 patients due to inflammatory states, old age, comorbidities, respiratory failure, immobility, low lymphocyte count and high D-dimer count. High levels of D-dimer and fibrin degradation products have been associated with severe infection and mortality ^[38][39]. The incidence of VTE in severe COVID-19 was 25% out of 81 patients, of which 8 of them died ^[40]. Patients with impaired left ventricular and right ventricular function as well as tricuspid regurgitation > grade 1 were significantly associated with higher mortality ^[37]. It is well recognized that development of heart failure is also significantly more prevalent in non-survivors compared to survivors ^[41]. Eventually, cardiovascular manifestations in COVID-19 may overlap and mask with the respiratory symptoms, thus cardiovascular involvement should not be overlooked when treating COVID-19 patients.

Although most evidence are mainly anecdotal with a lack of systematic review, cardiovascular manifestations do exist in some COVID-19 patients regardless of any prior cardiovascular diagnosis. Suggested theories of cardiovascular involvement in COVID-19 include direct myocardial injury, cytokine storm, pre-existing cardiovascular disease co-morbidities, and the use of ACE inhibitors and angiotensin receptor blockers (limited evidence) [70]. Myocardial injury caused by myocardial ischemia and myocarditis were showed as elevation in cardiac troponin-I levels and other inflammatory markers including ferritin, C-reactive protein, interleukin-6, interferon-γ, tumor necrosis factor-α, and lactate dehydrogenase [71,72]. Patients with elevated cardiac markers had a higher prevalence of pre-existing cardiovascular disease and were more likely to be admitted into the intensive care unit along with ventilation support. They normally ended up with a poor prognosis and high mortality. Myocardial injury can also result from acute respiratory distress syndrome due to oxidative stress and potentially inflammation-induced myocardial apoptosis [70]. Acute myocarditis and ventricular arrhythmia may be first presented in COVID-19 with arrhythmia which might occur due to electrolyte and haemodynamic imbalances. The increase of troponin level would directly correlate with malignant ventricular arrhythmia [73]. Thus, continuous electrocardiogram monitoring is highly recommended when drugs that prolong QT intervals like hydroxychloroquine or chloroquine are given as COVID-19 treatment [6]. In addition, venous thromboembolism (VTE) is also observed in COVID-19 patients due to inflammatory states, old age, comorbidities, respiratory failure, immobility, low lymphocyte count and high D-dimer count. High levels of D-dimer and fibrin degradation products have been associated with severe infection and mortality [73,74]. The incidence of VTE in severe COVID-19 was 25% out of 81 patients, of which 8 of them died [75]. Patients with impaired left ventricular and right ventricular function as well as tricuspid regurgitation > grade 1 were significantly associated with higher mortality [72]. It is well recognized that the development of heart failure is also significantly more prevalent in non-survivors compared to survivors [76]. Eventually, cardiovascular manifestations in COVID-19 may overlap and mask the respiratory symptoms, thus cardiovascular involvement should not be overlooked when treating COVID-19 patients.