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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 221-232

COVID-19: A review of the ongoing pandemic


1 Department of Radiodiagnosis, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Sharma Diagnostic Centre, Wardha, Maharashtra, India
3 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Submission06-May-2020
Date of Decision10-May-2020
Date of Acceptance22-May-2020
Date of Web Publication19-Jun-2020

Correspondence Address:
Abhishek Mahajan
Department of Radiodiagnosis, Tata Memorial Hospital, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_174_20

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  Abstract 


In December 2019, cases of pneumonia of unknown etiology were reported in the Wuhan city in China. In January 2020, the causative agent for this outbreak was discovered to be a novel strain of coronavirus, the severe acute respiratory syndrome-coronavirus-2. With Wuhan being the epicenter, the coronavirus disease 2019 (COVID-19) spread rapidly to other countries and soon took over every continent in the world except Antarctica. As the infection primarily presents as pneumonia, especially in patients with underlying comorbidities, radiological studies play an indispensable role in the early detection and further assessment of the course of COVID-19. The current pandemic is unprecedented with regard to the rate of spread, mortality rate, and palpable lack of our understanding of the mode of transmission and spread of the virus. This review is focused on the etiology, epidemiology, clinical symptoms, diagnosis, complications, and management of COVID-19. It emphasizes the need to integrate symptomatology, social history, and radiological findings, even in the absence of positive serological tests, to identify and isolate infected individuals.

Keywords: Chest X-ray, coronavirus, COVID, COVID-19, computed tomography, imaging, nCOV, severe acute respiratory syndrome-coronavirus-2


How to cite this article:
Pande P, Sharma P, Goyal D, Kulkarni T, Rane S, Mahajan A. COVID-19: A review of the ongoing pandemic. Cancer Res Stat Treat 2020;3:221-32

How to cite this URL:
Pande P, Sharma P, Goyal D, Kulkarni T, Rane S, Mahajan A. COVID-19: A review of the ongoing pandemic. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Sep 18];3:221-32. Available from: http://www.crstonline.com/text.asp?2020/3/2/221/287222




  Introduction Top


The initial outbreak of cases of pneumonia of unknown cause in Wuhan city in China was reported to be linked to the local seafood market. A deep sequencing analysis performed on the lower respiratory tract secretions of the affected individuals led to the discovery of a novel strain of coronavirus, the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). This strain was different from the one that caused the 2003 SARS epidemic. The Chinese New Year ushered in the rapid spread of the coronavirus disease 2019 (COVID-19) from Wuhan to the rest of China. During this period, cases of infection with SARS-CoV-2 were reported for the first time in Thailand and Japan in patients with a travel history to Wuhan.[1],[2] Within no time, the virus spread globally, hitting Europe and the United States of America (USA) harder than China, and countries such as the USA, Italy, Spain, and Iran became the new epicenters of COVID-19. The World Health Organization (WHO) on January 30, 2020, announced that COVID-19 was a Public Health Emergency of International Concern; on March 11, 2020, it was declared a pandemic. As of May 21, 2020, more than 4,893,186 confirmed cases of COVID-19 were reported in over 215 countries, with a total of 323,256 deaths [Figure 1] and [Figure 2].[3] In India, between January 30, 2020, and May 21, 2020, 112,359 cases of COVID-19 were reported, with 3435 deaths. The western state of Maharashtra alone reported 34.58% of the cases.[3] China, through early detection and implementation of strict public health measures, managed to curtail the spread of the infection. However, other countries with delayed preventive responses continue to witness an exponential rise in the number of cases and fatalities. In the absence of targeted antiviral therapy and vaccines, it is vital to promptly identify and isolate the infected individuals from the uninfected ones.[1],[2],[3] Radiological examination, especially the thin-slice computed tomography (CT) scan, has been shown to be a powerful adjunct in the detection of SARS-CoV-2 infection, as it is easy to perform and provides rapid results.[4] This review is focused on the etiology, epidemiology, clinical symptoms, diagnosis, complications, and management of COVID-19.
Figure 1: Frequency chart for the number of cases of coronavirus disease 2019 reported across the world. Source: WHO: https://covid19.who.int/

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Figure 2: Frequency chart for the number of deaths due to coronavirus disease 2019 reported across the world: Source: WHO: https://covid19.who.int/

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  Etiology Top


The SARS-CoV-2 is the seventh coronavirus to infect human beings.[1] Mammals such as the ant-eating pangolins and bats are the prime suspects for the transmission of the virus to humans. In addition, it is suspected that the Huanan seafood market facilitated the community spread of the virus via human-to-human transmission.[2] Coronaviruses are the largest known single-stranded, enveloped, positive-sense, ribonucleic acid (RNA) viruses measuring 50–200 nm. They are named so because of their sun-like appearance under an electron microscope due to the 9–12 nm long surface glycoprotein spikes.[5] The virus belongs to the Orthocoronavirinae subfamily of the Coronaviridae family (order Nidovirales). The subfamily is classified into four genera of coronaviruses (CoVs), namely the alpha-CoV, beta-CoV, delta-CoV, and gamma-CoV.[6] Further genomic characterization revealed that bats and rodents are the likely genetic sources of the alpha-CoV and beta-CoV, whereas the avian species are the likely sources of the delta-CoV and gamma-CoV.[7] The SARS-CoV-2 belongs to the genus beta-CoV. It is sensitive to heat, ultraviolet radiation, and lipid solvents such as ether (75%), ethanol, chlorine-containing disinfectants, peroxyacetic acid, and chloroform.[8]

The virus has four major structural proteins embedded in the envelope, namely the spike (S), membrane (M), envelope (E), and nucleoprotein (N), along with a set of accessory proteins unique to each viral species.[9] The protein S with two subunits binds to the angiotensin-converting enzyme 2 (ACE-2) receptor and mediates viral entry into the host cell by fusing the viral envelope with the host cell membrane [Figure 3].[10] ACE-2 confers protection against the inflammatory processes involving the lungs, and the binding of the SARS-CoV-2 protein S to the ACE-2 receptors contributes to diffuse alveolar damage.[11]
Figure 3: Structure of severe acute respiratory syndrome coronavirus 2 and mechanism of binding to the host cell. The virus has four major structural proteins embedded in the envelope, namely the spike (S), membrane (M), envelope (E), and nucleoprotein (N). The S protein with two subunits binds to the angiotensin-converting enzyme 2 (ACE-2) receptor and mediates viral entry into the host cell by fusing the viral envelope with the host cell membranes. Adapted from Estipona et al.[10]

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  Epidemiology Top


The transmissibility of COVID-19 is higher than that of SARS because of its high effective reproductive number (R 0). The R 0 for COVID-19 is reported to be 2.9, whereas that for SARS is 1.77.[12] The R 0 represents the basic reproduction number of a virus and the number of secondary cases that a single infected person can lead to in a homogenous susceptible population at the start of an epidemic. Thus, if one person develops the infection and passes it on to two others, the R 0 is 2. The R 0 is directly proportional to the size of the population and the infectiousness of the organism, and inversely proportional to the rate of removal of individuals by either death or recovery.[13] The concept of R 0 can only be applied to a population with herd immunity to the disease-causing agent. Herd immunity simply represents the resistance to the spread of a contagious disease within a population because a sufficiently high proportion of individuals are immune to the disease. It can either occur when a sufficiently large proportion of the population has been infected or can be induced by vaccination.[13]

The incubation period of SARS-CoV-2 ranges from 2 to 14 days with an average of 7 days,[14] and majority of the infected individuals develop symptoms after 5 days of exposure.[15]

Droplets and fomites are the primary modes of transmission of COVID-19. When the mucosae (mouth and nose) or conjunctivae (eyes) of a person are exposed to infective respiratory droplets because of close contact (<1 m distance) with someone who has respiratory symptoms, there is a chance of droplet transmission. Fomite transmission occurs by indirect contact with surfaces in the immediate vicinity of the infected individual or by touching the objects used by them. No conclusive data are available on the duration for which SARS-CoV-2 remains viable and infective on surfaces, but the factors affecting its stability include the relative temperature, humidity, and surface type.[7],[12],[15]

Airborne transmission occurs when the infective agent is present within the droplet nuclei. Droplet nuclei are particles <5 μm in diameter that can remain suspended in the air for a long period of time and be transmitted over distances >1 m.[16] Even though the SARS-CoV-1 was capable of airborne transmission, irrevocable evidence for the airborne transmission of SARS-CoV-2 is yet to be documented.[17] A study on 98 patients with COVID-19 by Wu et al. showed that the fecal samples of 55% of the patients were positive for SARS-CoV-2 RNA. Moreover, the fecal samples remained positive for this RNA for a mean of 11.2 days longer than the respiratory samples.[18] In mothers infected with SARS-CoV-2, neonatal infection with COVID-19 has been reported, with the likely source of infection being the virus in the maternal fluids, although a vertical transplacental maternal to fetal transmission is possible.[19] In view of the cases of sporadic transmission of SARS-CoV-2 from humans to felines, such as domestic cats, tigers, and lions, and the data showing the ease of transmission between domestic cats, a potential for human–feline–human transmission of the virus has also been suggested.[20]

In fatal cases, the duration between the onset of illness and death ranged from 6 to 41 days, with a median of 14 days; this duration depended on the age and immune status of the patient and was shorter in patients above 65 years of age.[21]

It has been observed that infected individuals are most likely to infect others just before the onset of symptoms, a time point that coincides with the highest viral load in the throat swabs. About 44% of the secondary infections occurred during the index cases' presymptomatic stage, emphasizing that the disease control measures should account for a probable substantial presymptomatic transmission.[22]

In China, by February 2020, the overall case fatality rate (CFR) was 2.3% with no reported deaths in the age group of 0–9 years; the CFR was 8.0% for the age group of 70–79 years and 14.8% for those aged 80 years and over.[23] SARS-CoV-2 has caused more deaths than SARS-CoV-1 and MERS-CoV combined. India has reported a CFR of 3.12%, which is much lower than that reported by other developed nations such as Italy (14.16), the United Kingdom (14.12%), and the USA (6.04%), but more than that reported by Russia (0.94%).[3] A higher CFR has been observed in patients with cancer (28%); the CFR in persons with hematological malignancies (37%) is higher than that in persons with solid tumors (25%). This in part appears to be due to the increased comorbidities, underlying neoplastic processes, and treatment-related immunosuppression.[24],[25]


  Pathophysiology Top


As SARS-CoV-2 belongs to the species of SARS-related coronaviruses, it shares with them some defining characteristics. As described earlier, out of the four major structural proteins embedded in the envelope, the spike glycoprotein recognizes and binds to the human host cell receptor, ACE-2. This leads to activation of the transmembrane serine protease 2 (TMPRSS2) and furin, followed by a TMPRSS2-mediated cleavage of both ACE-2 and the spike protein of coronaviruses.[6],[9],[10] The cleavage of ACE-2 is believed to promote viral uptake, whereas the cleavage of the spike protein primes the viral particle for membrane fusion with the host cell. After the uptake of the viral genomic RNA, the cellular machinery is redirected to viral replication. The recruitment of the replicase-transcriptase complex leads to the transcription and synthesis of new genomic RNA. Translation of viral proteins occurs in the ribosomes, and the envelope proteins (M, E, and S) enter the endoplasmic reticulum. The assembly and maturation of the new virus particles take place in the endoplasmic reticulum–Golgi intermediate compartment, following which they are released by exocytosis and can infect other cells.[9],[10] The risk of transmission depends on multiple factors, such as the viral load in the host, the immune status of the susceptible person, presence of comorbidities, and duration of contact. Transmission of COVID-19 seems to be better in cold and dry than in tropical and humid weather.[26]


  Clinical Diagnosis Top


The Chinese Centers for Disease Control and Prevention assessed 44,672 patients with COVID-19 for an estimation of disease severity. As per the report,[23]

  • 81% of the patients had mild illness
  • 14% of the patients had severe illness (hypoxemia, >50% lung involvement on imaging within 24–48 h).
  • 5% of the patients had a critical disease (respiratory failure, shock, multiorgan dysfunction syndrome)
  • The overall CFR was between 2.3% and 5%.


The clinical symptoms of the infection are nonspecific as majority of the patients are asymptomatic or have mild symptoms. The most common comorbidities that can cause a severe manifestation of COVID-19 are hypertension and diabetes, followed by cardiovascular and respiratory diseases.[15] Patients with cancer not only have a high risk of infection, but also have a higher risk of severe events (39% in patients with cancer vs. 8% in those without cancer). Moreover, they show more rapid deterioration than those without cancer; the median time to severe events was reported to be 13 days in patients with cancer and 43 days in those without cancer.[25] A study conducted in Wuhan assessed 1099 patients with COVID-19 pneumonia to determine the most common clinical features at the onset of illness.[15] These include fever in 89%, dry cough in 67%, fatigue in 38%, myalgias in 15%, and dyspnea in 19% of the patients. Other symptoms include chills, sore throat, anosmia and/or dysgeusia,[27] headache, and chest pain.

This list is not all inclusive. Recently, about 15% of the cases have been reported to have gastrointestinal symptoms, commonly nausea or vomiting, diarrhea, anorexia, and abdominal pain.[28] In addition, several cutaneous manifestations have been reported, of which maculopapular eruptions are the most common. The others include vesicles or pustules (pseudo-chilblain), other vesicular eruptions, urticarial lesions, and livedo reticularis. A purple/pink discoloration of the tip of the toes with associated papules has been termed “COVID toes” and may result either from impaired blood flow to the toes or pernio/chilblain-like toes.[29]

Severe disease develops in 12% of the patients, who experience dyspnea, tachypnea with respiratory frequency ≥30/min, blood oxygen saturation ≤93%, ratio of partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300, and/or lung infiltrates >50% of the lung field within 24–48 h. About 3.4% of the patients developed acute respiratory distress syndrome (ARDS). The laboratory investigations primarily show leukopenia and elevated C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), D-dimer levels, prothrombin time (PT)/partial thromboplastin time, and fibrinogen, indicating an inflammatory and prothrombotic state.[30] Indications for admission to the intensive care unit (ICU) include the need for mechanical ventilation due to the development of ARDS, vasopressor support for shock, and renal replacement therapy. There were apprehensions regarding the role of invasive mechanical ventilation in patients with COVID-19 because of the initial reports of high mortality rates in the intubated patients (50%–97%).[31] However, a recently published article from the Emory Critical Care Center reported an ICU mortality rate of 28.5% and a hospital mortality rate of 29.7% among patients who received mechanical ventilation. The overall mortality rate in critically ill patients was 25.8%.[32]


  Microbiological Diagnosis Top


The current gold standard for the diagnosis of COVID-19 is a real-time reverse transcription-polymerase chain reaction (rRT-PCR).[33] It can be performed on nasopharyngeal or oropharyngeal swabs, sputum, lower respiratory tract aspirates, bronchoalveolar lavage, nasopharyngeal wash/aspirate, or nasal aspirate collected from the suspected individuals. The test detects three regions in the SARS-CoV-2 N gene using three sets of primers and probes and the human RNase P (RP) using a different set of primers and probe.[33],[34]

A positive result indicates the presence of the virus in the tested biospecimen. However, in addition to the test results, the clinical symptoms and history of the patient are essential to determine the level of infectivity. It is important to understand that negative results do not preclude the presence of infection. Presently, rRT-PCR assay remains the reference standard for the definitive diagnosis of COVID-19.[34] However, it has a high rate of false-negative results (27%), which is likely due to the limited sample collection and transportation or the limitations of kit performance. It is essential to consider clinical symptoms, epidemiology, blood counts, and the results of radiological examinations along with rRT-PCR results when determining the infection status of an individual. The guidelines recommended by the WHO for identifying the infected individuals and their close contacts are presented in [Table 1].[35] The WHO has also set up guidelines for specimen collection and has stressed on the need for collection of serum samples in all suspected cases and their close contacts, regardless of the symptoms [Figure 4].[36]
Table 1: World Health Organization guidelines for identification of cases and close contacts

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Figure 4: World Health Organization guidelines for specimen collection from suspected COVID-19 cases and close contacts[36]

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A multitude of antibody-based tests are available, but there are several concerns ranging from their quality to interpretation of results. The target antigen (e.g., N protein or S protein) used in the antibody-based tests may differ as there is no consensus on which antibody response is protective and/or sustained. The sensitivity and specificity of these tests are undefined, making it difficult to interpret their results.[30],[36] Despite their shortcomings, these tests can be used in the following scenarios:

  1. Confirmation of negative rRT-PCR test, especially when the presentation is late, viral load is low, and/or when lower respiratory tract sampling is not possible
  2. Identification of convalescent plasma donors who can be counseled for plasma donation, which has shown some efficacy in the treatment of severe cases [37]
  3. Determining the disease prevalence in the community.


Another potential future use is determining the response to a vaccine, once protective antibodies have been identified.


  Radiological Diagnosis Top


A chest CT scan has been proven to play a significant role in the diagnosis of COVID-19, primarily because of the predominant pneumonia-like clinical picture and the more or less characteristic chest CT findings reported in case studies from all over the world.[38] The temporal changes observed in the chest CT scan have been shown to evolve progressively and rapidly in infected patients, which correlate with the severity of the clinical symptoms that peak 6–11 days after the onset.[39] The most common abnormalities observed are the bilateral, pulmonary, parenchymal ground-glass opacities (GGOs), with or without consolidation in the lung periphery, with a basal predominance [Figure 5]. A characteristic 'spiderweb' sign was reported, denoting GGOs that are triangular/angular-shaped under the pleura with net-like thickening of the interlobular septae that pull the adjacent pleura, giving rise to a spiderweb-like appearance.[40] Discrete pulmonary nodules, lung cavities, pleural effusions, and lymphadenopathy were notably absent in almost all the patients.[41]
Figure 5: A 58-year-old hypertensive male presented to the casualty with a 4-day history of high-grade fever, cough, and breathlessness that had progressed over the preceding 3 days. (a) The chest radiograph of the patient revealed bilateral air space opacities, predominantly in the lower lung zones. (b) After a day of symptomatic treatment, the patient experienced further increase in the breathlessness. A computed tomography scan of the chest revealed diffuse bilateral subpleural ground-glass opacities and few smaller patches forming subsegmental consolidation. The real-time reverse transcription-polymerase chain reaction confirmed the presence of severe acute respiratory syndrome-coronavirus-2 infection

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A study evaluated the performance of radiologists in differentiating COVID-19 pneumonia from other pneumonias in 219 patients with positive rRT-PCR results for COVID-19 and abnormal chest CT findings and 205 patients with non-COVID-19 pneumonias. Patients with COVID-19 pneumonia were more likely to have a peripheral distribution, GGOs, fine reticular opacities, and vascular thickening, but less likely to have both central and peripheral distribution, pleural effusion, or lymphadenopathy than those with non-COVID-19 pneumonias.[42] The lung opacities increased in extent and lobar involvement with the formation of crazy-paving patterns and progressive peripheral consolidations as the disease progressed.[42] A study on 121 symptomatic patients confirmed to have COVID-19 determined the time interval between the initial onset of symptoms and the subsequent chest CT imaging [Figure 6].[43] This time interval was accurately known for 94 patients, based on which they were considered to have undergone imaging during the early (0–2 days), intermediate (3–5 days), or late (6–12 days) phases of the illness.[43] Similarly, Pan et al. have described four stages of CT changes in 21 patients who recovered from mild-to-moderate disease [Table 2].[44]
Figure 6: Chest computed tomography findings based on the disease time course (adapted from Bernheim et al.)

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Table 2: Temporal changes in the chest computed tomography imaging findings during different stages of coronavirus disease 2019

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As mentioned earlier, the rRT-PCR test has the drawback of a high rate of false-negative results; therefore, a second test may be deemed necessary in cases with persistently high clinical and epidemiological suspicion.[45],[46],[47] It can take up to 4 days for an initial negative rRT-PCR test to become positive in a SARS-CoV-2-infected patient.[47] In such a situation, chest CT imaging can pitch in as a primary screening tool.[46],[47] A Wuhan-based study on 1014 patients who underwent both rRT-PCR testing and chest CT imaging, compared the performance of CT imaging with rRT-PCR as the reference standard. There was a concordance of 60%–93% between the initial positive CT scans and rRT-PCR results, and 42% of the cases showed improvement in the follow-up chest CT scans before the RT-PCR results turned negative.[46] Other similar studies have also inferred that chest CT imaging is highly sensitive for detecting COVID-19. [Table 3] summarizes the CT scan findings in 62 patients with COVID-19 in the study by Zhou et al.[48]
Table 3: Summary of the chest computed tomography findings in patients with coronavirus disease 2019

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The Fleischner Society has proposed the following guidelines for the imaging of suspected COVID-19 cases.[49]

  • If the individual suspected to have COVID-19 is only mildly symptomatic, imaging is not advised, unless he/she belongs to the high-risk group and is prone to disease progression
  • If a patient with COVID-19 has worsening symptoms, then imaging is indicated
  • Imaging can be used for triaging patients suspected to have COVID-19 because of the presence of moderate-to-severe clinical features in a resource-constrained environment.


Even though some CT findings are characteristic of COVID-19, none are confirmatory. Few conditions could present with symptoms similar to those of a lower respiratory tract infection and could mimic COVID-19 on imaging [Figure 7], [Figure 8], [Figure 9]. Therefore, a thorough recording of history and clinical correlation are of paramount importance to rule out other conditions that can cause GGOs in the lungs or diffuse alveolar damage. [Figure 10] illustrates an efficient imaging protocol to be followed during the COVID-19 pandemic.[50],[51] Thus, in view of the invaluable information provided, especially in cases with a strong clinical suspicion and negative rRT-PCR results, CT imaging should be considered when the findings could alter disease management, weighing the risk of exposure to other patients and health-care workers.[50],[51]
Figure 7: A 29-year-old patient with acute myeloid leukemia post-induction therapy presented with acute-onset shortness of breath, mild fever, malaise, and non-productive cough that persisted for 3 days. The computed tomography scan of the chest showed localized patchy areas of subpleural ground-glass opacities, forming subsegmental consolidation in a peribronchiolar distribution, suggestive of cryptogenic organizing pneumonia. A short course of steroids led to resolution of the symptoms

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Figure 8: A human immunodeficiency virus seropositive 45-year-old male with metastatic right hilar adenocarcinoma on a palliative chemotherapy presented with insidious onset of breathlessness and acute exacerbation of non-productive cough for 5 days. The computed tomography scan of the chest revealed diffuse bilateral ground-glass opacities, with few patches showing subpleural sparing along with few patchy areas of subsegmental consolidation and septal thickening, giving rise to a “crazy paving pattern.” Bronchoalveolar lavage was positive for Pneumocystis jiroveci

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Figure 9: A 36-year-old woman presented with high-grade fever and malaise with non-productive cough since 2 days. She had no history of travel or contact with a suspected/proven case of COVID-19. Coronal computed tomography section of the lung shows few nodules with surrounding ground glass opacities in the right lower lung lobe with a tree-in-bud pattern. Nasopharyngeal swab was negative for severe acute respiratory syndrome coronavirus 2 and she was treated symptomatically for non-COVID-19 viral pneumonia

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Figure 10: Imaging protocol to be followed during the COVID-19 pandemic. CXR: Chest X-ray; CT: Computed tomography; POCUS: Point of care ultrasound; RT-PCR: Reverse transcriptase polymerase chain reaction; SOB: Shortness of breath; ARDS: Acute respiratory distress syndrome. Adapted from Ahuja and Mahajan and Mahajan and Sharma

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  Complications Top


The data on the complications of COVID-19 are emerging rapidly, with ARDS being the most common one. Advanced age and the presence of elevated levels of lactate dehydrogenase (LDH) and D-dimer increase the risk of developing ARDS. A striking aspect of the natural history of the disease is elevated levels of interleukin-1β (IL-1β), interferon-gamma (IFN-γ), IFN-γ-inducible protein-10 (IP-10, CXCL10), and monocyte chemoattractant protein 1 (MCP-1), commonly referred to as a “cytokine storm.” This can lead to a virus-induced secondary hemophagocytic lymphohistiocytosis (HLH) that can be fatal.[52],[53] As a result of the high inflammatory burden and prothrombotic coagulopathy associated with the disease, there is a high incidence of cardiovascular complications. In patients with severe COVID-19 requiring ICU admission, venous thromboembolism has been reported in 20%–69% of patients and is associated with a poor prognosis. Some authors have suggested the use of the term “microvascular COVID-19 lung vessels obstructive thrombo-inflammatory syndrome” (MicroCLOTS) to designate COVID-19-associated acute pulmonary embolism, as it is primarily caused by local thrombus formation in the pulmonary vasculature due to local inflammatory processes rather than conventional embolization from another site. Microvascular inflammation can lead to diffuse microangiopathy with thrombosis, myocarditis, and acute coronary syndrome, all of which contribute to morbidity and mortality.[52],[53]

It has been observed that acute kidney injury can develop any time before or during hospital admission in a patient with COVID-19. Older age along with other renal comorbidities, such as chronic kidney disease due to diabetes mellitus and hypertension, prior history of acute kidney injury, and hemodynamic and thrombotic changes due to the microangiopathy are contributing factors. SARS-CoV-2 has also been detected in the brain and cerebrospinal fluid, and patients with severe illness commonly develop neurologic complications, indicating neurovirulence. In pediatric patients, a multisystem inflammatory state akin to Kawasaki disease and toxic shock syndrome has also been reported. There have been reports of fetal distress, premature labor, respiratory distress, thrombocytopenia, and abnormal liver function, but their mechanisms are yet to be elucidated. Currently, no information is available on the teratogenic potential of the virus. Other rare but clinically significant complications include warm or cold autoimmune hemolytic anemia, rhabdomyolysis, mild pancreatic injury, and secondary infections.[52],[53],[54]


  Prognostic Factors Top


COVID-19 involves an inflammatory prothrombotic state. An initial viral load and presence of comorbidities such as cancer not only lead to higher susceptibility to the infection but also to relatively poor outcomes. Early evidence suggests that some markers can be used for prognostication. Lymphopenia and eosinopenia are features of higher levels of severity. Peripheral CD4+ and CD8+ T-lymphocytes and B-lymphocytes are significantly decreased in severe and critically ill patients. Liver function test profiles with elevated aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, and LDH and decreased albumin indicate hepatocellular injury. The inflammatory markers, CRP, ESR, and ferritin, are elevated in patients with severe disease. IL-6 levels are also higher, indicating that the presence of a hyperimmune inflammatory state portends higher morbidity and mortality. CD8+ T lymphocyte counts and D-dimer are also shown to be independent predictors of disease severity.[55],[56],[57]


  Management Top


Whenever a pandemic occurs, it is a mammoth task to develop timely, targeted treatment regimens, mainly because most of the trials are single-arm intervention trials without concurrent control cohorts, which are not enough to determine efficacy and safety.[58] Isolation of cases with supportive treatment and preventing the spread of the infection are currently the basis of management of COVID-19. Although many drugs have shown in vitro activity against coronaviruses, the in vitro activity may not necessarily translate to clinical efficacy. Administering such drugs often does more harm than good. In the absence of targeted antiviral drugs, the current mainstay of treatment is supportive therapy. Patients can be stratified depending on the severity of symptoms. Asymptomatic patients and those with mild or moderate illness can be isolated and usually recover at home with supportive care.[59],[60]

Severely symptomatic patients need hospitalization. All measures should be taken to prevent the spread of infective droplets, including wearing a surgical mask, using appropriate personal protective equipment, and exercising caution when performing procedures that might generate aerosols, such as endotracheal intubation, extubation, noninvasive ventilation, bronchoscopy, airway suctioning, nebulization of medication, use of high-flow nasal cannulae, and manual ventilation with a bag-mask device. As the respiratory-system compliance in patients with severe COVID-19 is similar to that in patients with ARDS, the present guidelines recommend that clinicians follow the treatment paradigm developed for ARDS.[59],[60],[61]

Glucocorticoids have been tried for COVID-19-associated cytokine storm and respiratory failure, but they may result in prolonged viral shedding and secondary infections. Empirical antibiotic therapy is usually given to prevent secondary infections. To tackle the prothrombotic state associated with the disease, prophylactic low-dose heparin should be used to reduce the risk of venous thrombosis, but despite optimal heparin thromboprophylaxis, cases of life-threatening thrombosis have surfaced. The benefits and risks of more intense anticoagulation or using direct thrombin inhibitors in patients with severe COVID-19 are unknown.[59],[60],[61] The off-label drugs used for treating COVID-19 are summarized in [Table 4].
Table 4: List of the currently available drugs for off-label use

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Drugs such as chloroquine/hydroxychloroquine,[62] azithromycin, and lopinavir-ritonavir can have serious adverse cardiac and other systemic effects. Therefore, the compassionate and off-label use of such drugs in this time of crisis could lead to erroneous interpretations of the disease outcomes. For instance, the death of a patient could be wrongly attributed to the disease, while their survival could be wrongly attributed to the drug. Clinical trials for targeted vaccine development are time-consuming and need to be so to ensure adequate efficacy and safety before administering the vaccine to humans. The National Institutes of Health (NIH) has proposed treatment guidelines to help the clinicians take care of patients with COVID-19. As the clinical information about the optimal management of COVID-19 is evolving quickly, these guidelines will be updated frequently as published data and other authoritative information become available. The most recent set of guidelines can be accessed online from the websites of the NIH and the Centers for Disease Control and Prevention.[63]

Closer home, the Ministry of Health has proposed guidelines for the isolation of suspected/confirmed cases of COVID-19,[64] and the clinical management of patients.[65] Remdesivir is a nucleoside analog that inhibits the RNA polymerase. It is an investigational drug that was not earlier approved for any indication. Considering its activity against SARS-CoV, MERS-CoV, and SARS-CoV-2 in cell culture and animal models and early reports of efficacy in patients with severe COVID-19, and that the known potential benefits of remdesivir outweigh the risks, the Food and Drug Administration approved the drug for the treatment of patients hospitalized with severe COVID-19 on May 1, 2020.[66]

Recently, there have been growing concerns regarding reinfection following recovery. Confirmation of reinfection typically requires a culture-based documentation of a new infection following the clearance of the preceding infection or evidence of reinfection with a molecularly distinct form of the same virus. Even though sporadic cases have been reported to date, no human reinfections with SARS-CoV-2 have been confirmed.[67]


  Conclusion Top


Tackling COVID-19 is full of uncertainties, and in the present time, it largely relies on the prevention of spread of the infection more than any other currently available management strategy. Knowledge of the etiopathogenesis and prompt diagnosis of the disease with an appropriately raised index of suspicion are essential along with all the possible preventive strategies implemented by individuals, institutions, societies, nations, and the world, to stop the spread and curb the effects of this global pandemic.

Acknowledgments

The authors would like to acknowledge:

  1. Dr. Syeeda Showkat, MD, Associate Professor, Department of Radiology and Imaging, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
  2. Dr. Anuradha Shukla, MBBS, Tata Memorial Hospital, India.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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