Pathogenesis

Information on the pathogenesis of COVID-19 can be obtained from work undertaken by Cao et al (https://pubmed.ncbi.nlm.nih.gov/32346073/) ¹.

Epidemiology

Continuously updated information on the epidemiology of COVID-19 can be obtained from the COVID-19 Dashboard being maintained by the Centre for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU) (https://coronavirus.jhu.edu/map.html).

Clinical features

The clinical spectrum of COVID-19 varies from asymptomatic or paucisymptomatic forms to clinical conditions characterized by respiratory failure that necessitates mechanical ventilation and support in an intensive care unit (ICU), to multiorgan and systemic manifestations in terms of sepsis, septic shock, and multiple organ dysfunction syndromes (MODS)2. The symptoms of COVID-19 infection appear after an incubation period of approximately 5.2 days³.

The clinical manifestations of COVID-19 are classified based on their severity⁴:

Mild disease: non-pneumonia and mild pneumonia; this occurs in 81% of cases. These patients usually present with symptoms of an upper respiratory tract viral infection, including mild fever, cough (dry), sore throat, nasal congestion, malaise, headache, muscle pain, or malaise. New loss of taste and/or smell, diarrhoea, and vomiting are usually observed. Signs and symptoms of a more serious disease, such as dyspnoea, are not present². There could also be respiratory symptoms such as cough and shortness of breath (or tachypnoea in children) without signs of severe pneumonia, thus suggestive of a moderate pneumonia.

Severe disease: dyspnea, respiratory frequency ≥ 30/min, blood oxygen saturation (SpO2) ≤ 93%, PaO2/FiO2 ratio or P/F [the ratio between the blood pressure of the oxygen (partial pressure of oxygen, PaO2) and the percentage of oxygen supplied (fraction of inspired oxygen, FiO2)] < 300, and/or lung infiltrates > 50% within 24 to 48 hours; this occurs in 14% of cases. However, the fever symptom must be interpreted carefully as even in severe forms of the disease, it can be moderate or even absent.

Critical disease: respiratory failure (acute respiratory distress syndrome [ARDS]), septic shock, and/or multiple organ dysfunction (MOD) or failure (MOF); this occurs in 5% of cases. Different forms of ARDS are distinguished based on the degree of hypoxia. The reference parameter is the PaO2/FiO2, or P/F ratio:

• Mild ARDS: 200 mmHg < PaO2/FiO2 ≤ 300 mmHg. In patients who are not undergoing ventilation or in those managed through non-invasive ventilation (NIV) by using positive end-expiratory pressure (PEEP) or a continuous positive airway pressure (CPAP) ≥ 5 cmH2O.
• Moderate ARDS: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg.
• Severe ARDS: PaO2/FiO2 ≤ 100 mmHg.

When PaO2 is not available, a ratio SpO2/FiO2 ≤ 315 is suggestive of ARDS.

Differential diagnoses

These include the following:

• Community acquired pneumonia
• Influenza
• Common cold
• Other viral or bacterial respiratory infections
• Aspiration pneumonia
• Pneumocystis jirovecii pneumonia
• Middle East respiratory syndrome (MERS)
• Severe acute respiratory syndrome (SARS)
• Avian influenza A (H7N9) virus infection
• Avian influenza A (H5N1) vírus infection
• Pulmonary tuberculosis (PTB)
• Febrile neutropenia.

Diagnosis

1. Molecular testing: This is the test recommended by WHO for confirmation of COVID-19 (https://www.who.int/publications/i/item/laboratory-testing-strategy-recommendations-for-covid-19-interim-guidance). Specimens are collected from both the upper respiratory tract (naso- and oropharyngeal samples) and lower respiratory tract such as expectorated sputum, endotracheal aspirate, or bronchoalveolar lavage (BAL). The collection of BAL samples should only be performed in mechanically ventilated patients as lower respiratory tract samples seem to remain positive for a more extended period. The samples require storage at 4oC. In the laboratory, amplification of the genetic material extracted from the saliva or mucus sample is through a reverse polymerase chain reaction (RT-PCR), which involves the synthesis of a double-stranded DNA molecule from an RNA mold. Once the genetic material is sufficient, the search is for those portions of the genetic code of the coronavirus (CoV) that are conserved. If the test result is positive, it is recommended that the test be repeated for verification. In patients with confirmed COVID-19 diagnosis, the laboratory evaluation should be repeated to evaluate for viral clearance prior to being released from observation (one at the 14th day and the second at least 24 hours later). The availability of testing will vary based on which country a person lives in.
2. Complete blood count (CBC): In the early stage of the disease, a normal or decreased total white blood cell (WBC) count and a decreased lymphocyte and eosinophil count can be demonstrated. Lymphopenia appears to be a negative prognostic factor. In case of superimposing bacterial infection, there tends to be an increase in the WBC and neutrophil counts⁵.
3. Liver function tests (LFTs): There are noted elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin, as well as a decrease in albumin levels5.
4. Renal function tests: There is an increase in creatinine levels, with a reduced estimated glomerular filtration rate (eGFR) in patients with severe or critical disease^{5, 6}.
5. Coagulation profile markers: Prothrombin time tends to be prolonged, as well as an increase in D-dimer levels, particularly in patients presenting with severe and critical forms of the disease5.
6. Cardiac markers: There are noted increases in cardiac troponin levels, as well as CK-MB levels, particularly in patients with severe and critical forms of the disease⁵.
7. Inflammatory markers: There is a noted increase in the erythrocyte sedimentation rate (ESR), C-reactive protein, lactate dehydrogenase (LDH), and interleukin-6 (IL-6), particularly in severe and critical patients^{5, 6}.
8. Procalcitonin levels: In the absence of a superimposed bacterial infection, the procalcitonin levels are essentially normal⁵.
9. Chest imaging:
   1. Chest radiography: Standard radiographic examination (X-ray) of the chest has a low sensitivity in identifying early lung changes and in the initial stages of the disease². At this stage, it can be completely negative. In the more advanced stages of infection, the chest X-ray examination generally shows bilateral multifocal alveolar opacities, which tend to confluence up to the complete opacity of the lung. Pleural effusion can also occur in this setting.
   2. Chest computed tomography (CT): Given the high sensitivity of the method, chest computed tomography (CT), in particular high-resolution CT (HRCT), is the method of choice in the study of COVID-19 pneumonia, even in the initial stages2. Several non-specific HRCT findings and patterns can be found. The most common findings are multifocal bilateral "ground or ground glass" (GG) areas associated with consolidation areas with patchy distribution, mainly peripheral/subpleural and with greater involvement of the posterior regions and lower lobes.
   3. Lung ultrasound: Ultrasound approach can allow evaluating the evolution of the disease, from a focal interstitial pattern up to "white lung" with evidence often of subpleural consolidations². It should be performed within the first 24 hours in the suspect and every 24/48 hours and can be useful for patient follow-up, choice of the setting of mechanical ventilation, and for indication of prone positioning.
10. Echocardiography: This is useful in ruling out cardiac aetiology of noted pulmonary oedema on chest imaging.
11. Serology: Despite the numerous antibody tests designed, to date serologic diagnosis has limitations in both specificity and sensitivity. Thus, additional research is ongoing to decipher if the IgG antibodies produced provide immunity from future SARS-CoV-2 infection, the protective titer of the produced antibodies, and the duration of the protection.

Clinical management

1. Treatment:

   There is currently no cure for COVID-19. Management predominantly depends on disease severity, and focuses on the following principles: isolation at a suitable location; infection prevention and control measures; symptom management; optimised supportive care; and organ support in severe or critical illness7.

   1. Isolation: The following should be considered regarding selection of isolation location and severity of COVID-19:
      • Mild disease: manage in a healthcare facility, in a community facility, or at home. Home isolation can be considered in most patients, including asymptomatic patients.
      • Moderate disease: manage in a healthcare facility, in a community facility, or at home. Home isolation can be considered in low-risk patients (i.e., patients who are not at high risk of deterioration).
      • Severe disease: manage in an appropriate healthcare facility.
      • Critical disease: manage in an intensive/critical care unit.
   2. Symptom management: Fever and pain (through use of either paracetamol or ibuprofen)^{7, 8}, cough (through use of one teaspoon of honey in patients aged ≥1 year)9, and olfactory dysfunction (through use of olfactory training)¹⁰ should be utilized.
   3. Antibiotic use: Empirical antibiotics can be considered if there is sufficient clinical suspicion of bacterial infection or in older people (particularly those in long-term care facilities) and children <5 years of age for possible pneumonia^{7, 9}.
   4. Oxygen therapy: Supplemental oxygen therapy should be instituted immediately in any patient with emergency signs (i.e., obstructed or absent breathing, severe respiratory distress, central cyanosis, shock, coma and/or convulsions), or any patient without emergency signs and SpO₂ <90%7, 9. Target SpO₂ to ≥94% during resuscitation in adults and children with emergency signs who require emergency airway management and oxygen therapy. Once the patient is stable, a target SpO₂ >90% in children and non-pregnant adults, and ≥92% to 95% in pregnant women, is recommended.
   5. Venous thromboembolism prophylaxis: Venous thromboembolism (VTE) prophylaxis in acutely ill hospitalised adults and adolescents with COVID-19 as per the standard of care for other hospitalised patients without COVID-19, provided there are no contraindications^{7, 9, 11, 12}. Low molecular weight heparin (LMWH) or fondaparinux are preferred over unfractionated heparin in order to reduce patient contact. Unfractionated heparin is contraindicated in patients with severe thrombocytopenia. Fondaparinux is recommended in patients with a history of heparin-induced thrombocytopenia. Direct oral anticoagulants are not recommended.
   6. Antiviral therapy: Various clinical trials, including a global effort by the WHO are underway to study effective treatments, mostly geared towards moderate to severe COVID-19 disease (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments). The drug candidates being evaluated in the WHO-supported “Solidarity” trial include chloroquine and hydroxychloroquine; boosted lopinavir with ritonavir (LPV/r); remdesivir; and LPV/r plus interferon beta. So far, remdesivir has shown clinical promise in reducing the period of hospitalization among patients with severe COVID-19, but does not have a substantial effect on mortality¹³, hence the need for more studies.
   7. IL-6 inhibitors: Medications such as tocilizumab have been shown to anecdotally diminish the cytokine release syndrome experienced in patients with severe and critical COVID-19¹⁴. However, clinical trials are underway to assess its true efficacy.
2. Prevention:
   1. Proper personal and respiratory hygiene: This is highly encouraged for not only prevention of COVID-19, but also other respiratory and waterborne infectious diseases. Wash hands often with soap and water for at least 20 seconds or an alcohol-based hand sanitiser (that contains at least 60% alcohol) and practice respiratory hygiene (i.e., cover mouth and nose when coughing or sneezing, discard tissue immediately in a closed bin, and wash hands).
   2. Social distancing: This has been a key policy intervention since the influenza pandemic15, and mostly based on expert opinion. The aim is to slow transmission and the growth rate of infections to avoid overburdening healthcare systems—an approach widely known as flattening the curve. This strategy has been mainly implemented through encouraging avoidance of close contact with people (i.e., maintain a distance of at least 1 metre [3 feet]), bans on public events, the closure of schools, universities and non-essential workplaces, limiting public transportation, travel and movement restrictions, and limiting physical interactions. It is important to note that recommended distances differ between countries (for example, 2 metres is recommended in the US and UK, and one metre in Kenya). Cancelling public gatherings and imposing travel restrictions decreases transmission and morbidity rates, with mixed evidence on the efficacy of school closures^{16, 17}. However, it objectively needs to be quantified how this strategy has fared in the COVID-19 pandemic, as well as innovating newer, less-restrictive social distancing measures¹⁸.
   3. Use of facemasks: This has been demonstrated to be effective with and without hand hygiene in preventing acquisition of coronaviruses and other respiratory transmissible viruses, and both together are more protective^{19, 20}.
   4. Vaccination: No vaccine exists yet for COVID-19, though a number of vaccines are being investigated in trials across the world (https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines). However, it is recommended that people at high risk of either contracting or suffering from adverse outcomes of COVID-19 be vaccinated against other infectious diseases such as influenza and pneumococcal disease.

References

1. Cao W, Li T. COVID-19: towards understanding of pathogenesis. Cell Res. 2020; 30: 367‐9. doi:10.1038/s41422-020-0327-4
2. Cascella M, Rajnik M, Cuomo A, et al. Features, Evaluation and Treatment Coronavirus (COVID-19) [Updated 2020 May 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554776/
3. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020; 10.1056/NEJMoa2001316
4. Wu Z, McGoogan JM. Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases from the Chinese Centre for Disease Control and Prevention [published online ahead of print, 2020 Feb 24]. JAMA. 2020;10.1001/jama.2020.2648. doi:10.1001/jama.2020.2648
5. Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clin Chem Lab Med. 2020 Feb 24. doi: 10.1515/cclm-2020-0198
6. Zhang ZL, Hou YL, Li DT, Li FZ. Laboratory findings of COVID-19: a systematic review and meta-analysis [published online ahead of print, 2020 May 23]. Scand J Clin Lab Invest. 2020; 1‐7. doi:10.1080/00365513.2020.1768587
7. World Health Organization. Clinical management of COVID-19: interim guidance. 2020 (https://www.who.int/publications/i/item/clinical-management-of-covid-19) Accessed on 14th June 2020
8. Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Intensive Care Med. 2020; 46: 854-87
9. National Institute for Health and Care Excellence (NICE) in collaboration with NHS England and NHS Improvement. Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines. BMJ. 2020; 369: m1461. Published 2020 Apr 20. doi:10.1136/bmj.m1461 2020 (https://www.bmj.com/content/369/bmj.m1461.long)
10. Whitcroft KL, Hummel T. Olfactory dysfunction in COVID-19: diagnosis and management. JAMA. 2020 May 20 [Epub ahead of print]
11. Barnes GD, Burnett A, Allen A, et al. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the Anticoagulation Forum. J Thromb Thrombolysis. 2020 May 21 [Epub ahead of print]
12. Moores LK, Tritschler T, Brosnahan S, et al. Prevention, diagnosis and treatment of venous thromboembolism in patients with COVID-19: CHEST guideline and expert panel report. Chest. 2020 Jun 2 [Epub ahead of print]
13. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Preliminary Report [published online ahead of print, 2020 May 22]. N Engl J Med. 2020; NEJMoa2007764. doi: 10.1056/NEJMoa2007764
14. Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: A single centre experience. J Med Virol. 2020; 92: 814‐8. doi:10.1002/jmv.25801
15. Glass RJ, Glass LM, Beyeler WE, Min HJ. Targeted social distancing design for pandemic influenza. Emerg. Infect. Dis. 2006; 12: 1671–81
16. Ferguson NM, et al. Strategies for mitigating an influenza pandemic. Nature. 2006; 442: 448–52
17. Germann TC, Kadau K, Longini IM, Macken CA. Mitigation strategies for pandemic influenza in the United States. Proc. Natl Acad. Sci. USA. 2006; 103: 5935–40
18. Block P, Hoffman M, Raabe IJ, et al. Social network-based distancing strategies to flatten the COVID-19 curve in a post-lockdown world [published online ahead of print, 2020 Jun 4]. Nat Hum Behav. 2020; 10.1038/s41562-020-0898-6. doi: 10.1038/s41562-020-0898-6
19. MacIntyre CR, Chughtai AA. A rapid systematic review of the efficacy of facemasks and respirators against coronaviruses and other respiratory transmissible viruses for the community, healthcare workers and sick patients. Int J Nurs Stud. 2020; 108: 103629. doi: 10.1016/j.ijnurstu.2020.103629. Epub ahead of print. PMID: 32512240; PMCID: PMC7191274
20. Stutt ROJH, Retkute R, Bradley M, Gilligan CA, Colvin J. A modelling framework to assess the likely effectiveness of facemasks in combination with ‘lock-down’ in managing the COVID-19 pandemic. Proc R Soc A. 2020; 47620200376.