By Maria Nicola, Niamh O’Neill, Catrin Sohrabi, Mehdi Khan, Maliha Agha, and Riaz Agha
• Published 2020 Apr 11
COVID-19 has now been declared a pandemic. To date, COVID-19 has affected over 2.5 million people worldwide, resulting in over 170,000 reported deaths. Numerous preventative strategies and non-pharmaceutical interventions have been employed to mitigate the spread of disease including careful infection control, the isolation of patients, and social distancing. Management is predominantly focused on the provision of supportive care, with oxygen therapy representing the major treatment intervention. Medical therapy involving corticosteroids and antivirals have also been encouraged as part of critical management schemes. However, there is at present no specific antiviral recommended for the treatment of COVID-19, and no vaccine is currently available. Despite the strategic implementation of these measures, the number of new reported cases continues to rise at a profoundly alarming rate. As new findings emerge, there is an urgent need for up-to-date management guidelines. In response to this call, we review what is currently known regarding the management of COVID-19, and offer an evidence-based review of current practice.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initially named novel coronavirus or 2019-nCoV, is a single-stranded RNA virus which forms one of the seven coronaviridae – 229E, OC43, NL63, HKU1, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) – now known to infect humans. It is the virus responsible for causing coronavirus disease 2019 (COVID-19), a type of lower respiratory tract infection with the potential to cause severe and possibly fatal atypical novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) in humans.
Now labelled a pandemic, COVID-19 has affected over 2.5 million people worldwide, with the majority of cases (n = 793,505) seen in the USA alone, followed by Spain (n = 200,210) and in third place Italy (n = 181,228). There have been over 170,000 reported deaths and at least 663,400 recovered cases. Sohrabi et al. highlighted the extent of the outbreak with the World Health Organization (WHO) declaring the COVID-19 outbreak as a global emergency on January 30, 2020.
Mode of evolution and transmission
To facilitate the characterisation of SARS-CoV-2, comparisons have been made with the better known structure of SARS-CoV. Both viruses share an amino acid sequence similarity of 76.5%  and utilise angiotensin-converting enzyme 2 (ACE2) receptors as a mode of entry into healthy cells. Variations between the receptor-binding domain of the two brought about by mutations, genetic recombination, and natural selection enable SARS-CoV-2 to bind to the receptor more effectively. Furthermore, evidence of genetic recombination as a mechanism of viral evolution has sparked concerns regarding the misdiagnosis of infections by SARS-CoV-2, inaccurate tracking of transmission rates, adaptation of the virus to human immunity, as well as increasing severity of the infection with time.
A study looking into the first 425 confirmed cases of NCIP has provided evidence to support that the main method of viral transmission is human-to-human. To date, a confirmed case of NCIP is defined as at least one of the following obtained from the respiratory tract (ie. pharyngeal swabs, sputum samples, and alveolar lavage) or serological samples:
- ● Isolation of SARS-CoV-2
- ● ≥2 positive real time RT-PCR assays of SARS-CoV-2
- ● Genetic sequence matching of SARS-CoV-2
Recovery and clearance of the virus is thought to be achieved when ≥2 negative oral swabs are confirmed in an infected individual. Emerging evidence, however, has speculated the complete clearance of the virus in such cases as anal swabs and blood cultures may remain positive despite having negative oral swabs and supports that the main modes of spread of the virus include respiratory droplets, bodily fluids, fecal-oral, direct contact, and transmission through environmental surfaces. Current evidence supports that there is no vertical transmission of the virus.
Alarmingly, despite extensive efforts by governments to contain the virus, a recent Chinese study has demonstrated that although 80.9% of sufferers had subclinical or mild symptoms of the disease they still possessed the potential to spread the virus further. Interestingly, they also possessed the same viral load to patients who exhibited symptoms of the disease. As it stands, it has been estimated that an infected individual is likely to spread the disease to an average of 2.2 people.
Course of disease
Emerging evidence has been collated in an attempt to delineate the course of the disease. The World Health Organisation (WHO) estimates that the incubation time from infection to presentation of symptoms is 5.2 days, with a range of 1–14 days. Furthermore, the mean time from presentation of symptoms to seeking medical advice is 5.8 days, and to hospital admission is 12.5 days. The stages of the disease from onset of symptoms have been classified based on non-contrast enhanced chest computed tomography (CT) findings and can be divided into early (0–4 days), progressive (5–8 days), peak (9–13 days), and absorption stages (≥14 days). Early stage disease consists of subpleural ground glass opacities (GGO) located in the lower lung lobes. The progressive stage demonstrates bilateral distribution of the infective process and diffuse GGO. Presence of dense consolidation, crazy-paving pattern and residual parenchymal bands indicates transition into the peak stage. Finally, the absorption stages, which may last more than 26 days, appears to demonstrate a better controlled disease process on CT, gradual resolution, and signs of recovery.
Signs and symptoms
Data from a report of 72,314 cases published by the Chinese Center for Disease Control and Prevention has revealed that the severity of clinical symptoms can vary between individuals. 81% of cases were described as mild (i.e. non-pneumonia and mild pneumonia). 14% of cases were severe (i.e. dyspnea, respiratory frequency ≥30/min, blood oxygen saturation ≤93%, partial pressure of arterial oxygen to fraction of inspired oxygen ratio <300, and/or lung infiltrates >50% within 24–48 h), and 5% were critical (i.e. respiratory failure, septic shock, and/or multiple organ dysfunction or failure) (Fig. 1 ). Published data from this early, single chinese study does not seem to represent current global percentages. With emerging information, clinicians will more reliably be able to characterise the disease process and clinical presentation of COVID-19. Other studies indicate that patients with multiple comorbidities are prone to severe infection and may also present with acute kidney injury (AKI) and features of ARDS.
There are reports of both adult and paediatric patients being infected with COVID-19. Data pooled from three large case series indicate the following results; The majority of adult patients present with fever (92.8%; n = 258), cough (69.8%; n = 194), dyspnoea (34.5%; n = 96), myalgia (27.7%; n = 77), headache (7.2%; n = 20), diarrhoea (6.1%; n = 17), rhinorrhoea (4.0%), a sore throat (5.1%), and pharyngalgia (17.4%). Data from an European multicentre study indicates that sudden gustatory (88.8%; n = 342) and olfactory (85.6%; n = 357) dysfunctions were also other important symptoms in patients infected with COVID-19. Analysis of data of 1.5 million users from the COVID Symptoms Tracker app developed by King’s College London shows that ageusia and anosmia are stronger predictors of positive COVID-19 diagnosis than self-reported fever. In the paediatric population, symptoms may include fever, fatigue, cough, nasal congestion, runny nose, expectoration, diarrhoea, and headache. As the disease progresses, signs of dyspnoea, cyanosis, in addition to systemic toxic symptoms, including malaise or restlessness, poor feeding, bad appetite and reduced activity may also present. In the most severe situations, these younger patients may progress into respiratory failure unresponsive to conventional oxygen therapy, septic shock, metabolic acidosis, irreversible bleeding, and coagulation dysfunction.
Diagnosis and differential diagnosis
Clinical symptoms must be assessed to aid in the diagnosis of COVID-19. Both the WHO and United States Centers for Disease Control and Prevention (CDC) have issued guidance for key clinical and epidemiological findings suggestive of COVID-19. Extensive laboratory tests should be requested to confirm diagnosis of COVID-19. RT-PCR should be performed in isolated samples of throat swabs, sputum, stool, and blood samples.
Key laboratory results on admission include leucocytes below or above the normal range; neutrophils above the normal range; lymphocytes, haemoglobin and platelets below the normal range. Key liver findings may include elevated alanine aminotransferase, aspartate aminotransferase, C-reactive protein, creatine kinase, lactate dehydrogenase, blood urea nitrogen, and serum creatinine levels. Regarding the infection index, procalcitonin levels may be above the normal range.
Radiological findings may also aid the diagnosis of pneumonia in virally infected patients. Bilateral and multi-lobe lung involvement were common in over 75% and 71% of adult patients, respectively. In paediatric patients, the following criteria for rapid respiratory rate should be followed for diagnosis of COVID-19 associated pneumonia: ≥60 times/min for less than 2 months old; ≥50 times/min for 2–12 months old, ≥40 times/min for 1–5 years old, ≥30 times/min for >5 years old (after ruling out the effects of fever and crying).
Differential diagnosis can include other viral respiratory infections caused by SARS virus, influenza virus, parainfluenza virus, adenovirus, respiratory syncytial virus and metapneumovirus. These patients present with similar clinical presentations, except for normal or decreased leukocyte count in some patients. Patients may also present with pneumonia due to bacterial causes, which may be accompanied by high fever and moist rale cough. Mycoplasmal pneumonia is another common type of false presentation. Chest X-ray images for such patients may indicate reticular shadows and small patchy or large consolidations. Mycoplasma-specific IgM are helpful for this differential diagnosis. Epidemiological exposure and blood or sputum culture will be helpful for ensuring the correct diagnosis of COVID-19.
High risk groups
Current reports suggest that all demographics of the global population could be susceptible to infection of COVID-19, however there are some groups that are at higher risk of severe disease. According to the CDC, older adults – further classified as over 65 years of age – are more at risk of severe disease than younger people. Furthermore, patients with serious chronic underlying medical conditions, namely cardiovascular disease, diabetes, cancer (especially of the lung), chronic obstructive pulmonary disease, and hypertension are at an increased risk of severe complications. There is currently no evidence to suggest that children are more susceptible to infection, however, there now appears to be an association between male gender and a severer form of the disease. In one study of patients with confirmed COVID-19 infection, 85.9% (n = 67) stabilised whereas 14.1% (n = 11) continued to deteriorate despite treatment. Of the 14.1% who deteriorated, when compared to the stabilised group (median age 37; range = 32–41), the patients were significantly older (median age of 66; range = 51–70), had a history of smoking, and presented with a higher maximum body temperature on admission.
Occupational risks have also been identified by various authorities. During the preliminary stages of the COVID-19 outbreak, employees of seafood and wet animal wholesale markets in Wuhan were most at risk of contracting the virus in addition to any customers who had visited these markets. This was closely followed by the subsequent epidemic which posed a high risk to healthcare workers who regularly came into contact with patients with suspected COVID-19. As a result, healthcare workers with pre-existing risks such as an increased age or chronic respiratory disease are advised to ask colleagues who are not in high risk groups to care for patients with potential COVID-19 where possible.
Various mild and severe clinical syndromes have been associated with the SARS-CoV-2 infection. Mild uncomplicated illnesses include non-specific symptoms including fever, cough, sore throat, nasal congestion, headache, and muscle pain. Elderly and immunosuppressed individuals may present with atypical findings. Mild and severe pneumonia have also been associated with COVID-19. In adults, the latter is characterised by fever or suspected respiratory infection plus one of either respiratory rate >30 breaths/min, severe respiratory distress, or SpO2 <90% on room air. In children, severe pneumonia is indicated by cough or difficulty in breathing plus at least one of either central cyanosis or SpO2 <90%, severe respiratory distress (e.g. grunting, very severe chest indrawing), signs of pneumonia with a general danger sign (e.g. inability to breastfeed or drink, unconsciousness, or convulsions). ARDS presents with new or worsening respiratory symptoms within one week of known clinical insult, and chest imaging reveals bilateral lung opacities. Sepsis and septic shock are further complications of COVID-19. Notably, long-term complications amongst SARS-CoV-2 survivors are not yet available. The mortality rate for cases globally remains between 1 to 2%.
With a peak of 101,736 new cases confirmed on April 3, 2020 alone, there are fears that these findings could indicate exponential spread of the disease. Implementation and adherence to tighter restrictions of social distancing to suppress and mitigate the spread of COVID-19 will prove to be crucial in the months to come. Up-to-date, evidence-based guidelines for acute management of COVID-19 are imperative to guide clinicians through the rapidly evolving pandemic. As new evidence emerges, it is imperative that current and potential treatment options are frequently re-evaluated in order to offer the best possible care under such unprecedented circumstances.