6782 Indian Journal of Forensic Medicine & Toxicology, October-December 2020, Vol. 14, No. 4 Review on Covid-19 Disease: Its Outbreak and Current Status

Pankaj Wagh1, Saood Ali1, Ulhas Jadhav2, Babaji Ghewade3, Deepanshu Chawla4

1Assistant Professor, 2Professor and Head, 3Professor, 4Junior Resident, Dept of Respiratory Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India

Abstract Summary: (COVID-19) is diversely found in human beings and wild animals. It is an enveloped RNA virus. There are a total six species which cause disease in humans. They commonly infect respiratory, neurological, enteric, and hepatic systems. There is history of endemic outbreaks in past in the form of Middle East respiratory syndrome coronavirus (MERSCoV) and severe acute respiratory syndrome related coronavirus (SARS-CoV).We have seen another outbreak due to a new strain called the SARS-CoV-2 virus which presented as a pneumonia of unknown etiology in patients in Wuhan,China. The epicenter of infection was linked to seafood and exotic animal wholesale markets in the city. It is highly contagious and has resulted in a rapid pandemic of COVID-19. As the number of cases continue to rise, it is clear that these viruses pose a threat to public health. This review will describe clinical features and treatment of COVID-19 patients and raise awareness among healthcare workers and general population during the current pandemic. This review article aims at giving up-to-date information about the disease and counselling of patients.

Keywords: RNA virus, COVID-19, SARS-CoV-2, MERSCoV, Coronavirus, Pneumonia.

Introduction cases, which led to 858 deaths.[2] In 2002, a severe acute respiratory syndrome related coronavirus (SARS-CoV) Coronavirus (CoV) is a single-stranded RNA virus rapidly spread across Guangdong, China which resulted that belongs to the Nidovirales order. The order includes in 8,000 infections and 774 deaths in 37 countries.[2] The Roniviridae, Arteriviridae, and families outbreak in 2020 has presented in the form of pneumonia which are subdivided into Torovirinae and Coronavirinae of unknown etiology in Wuhan, China. Deep sequencing subfamilies.[1] Coronavirinae is further subclassified studies and lab investigations have identified the culprit into alpha-, beta-, gamma-, and delta- COVs.[1] Viral as a new strain of COV.[3] Initially, this virus was RNA genome ranges from 26 to 32 kilobases in length designated as 2019-nCoV. However, the International and can be isolated from different animal species such Committee on Taxonomy of Viruses designated it as the as birds, livestock, and mammals such as camels, bats, SARS-CoV-2 virus.[4] On February 11, 2020, the World masked palm civets, mice, dogs, and cats.[2] Human Health Organization (WHO) announced the disease pathogenic subtypes of CoV are associated with mild caused by this novel virus as coronavirus disease-2019 clinical symptoms. In 2012, Middle East respiratory (COVID-19). The repeated emergence and outbreaks of syndrome coronavirus (MERS-CoV) was first detected CoVs indicate a public health threat. This suggests the in Saudi Arabia and was responsible for 2,494 confirmed possibility of animal-to-human and human to-human transmission of newly emerging CoVs. The ongoing changes in ecology and climate make future emergence of such infections more likely.[3] Corresponding Author: Dr. Pankaj B. Wagh History of Coronavirus: In 1960 corona virus Department of Respiratory Medicine, Jawarharlal was first identified as a causative agent for common Nehru Medical College, Sawangi, Wardha‑442 001, cold. One study was carried out in Canada in 2001, flu- Maharashtra, India like symptoms were present in more than 500 patient. e-mail: [email protected] Virological analysis by polymerase chain reaction (PCR) Indian Journal of Forensic Medicine & Toxicology, October-December 2020, Vol. 14, No. 4 6783 of these patients showed that 3.6% of these cases were SARS-CoV, leads to severe acute respiratory syndrome positive for the HCoV-NL63 strain. By 2002 Corona (SARS). In 2019, a new dangerous strain was discovered virus was considered as a relatively simple, nonfatal called SARS-CoV-2, causing COVID-19 disease. virus. Corona virus life cycle: After the outbreak in 2002-2003 in Guangdong Steps: province in China, which resulted in spread to many other countries, including Vietnam, Hong Kong Singapore, 1. Attachment and entry Thailand, Taiwan and the United States of America, 2. Replicase protein expression caused severe acute respiratory syndrome (SARS) and high mortality, microbiologists and infectious disease 3. Replication and transcription experts focused on the understanding the pathogenesis 4. Assembly and release. of the disease and discovered that this infection was caused by a new form of corona virus. Corona virus Epidemiology: As of April 27, 2020, the WHO is not a stable virus demonstrated by the evolution of has confirmed 28,78,196 cases globally and of these this virus and can adapt to become more virulent, even confirmed cases,1,98,668 (6.9%) patients have [6] lethal to human. In 2012 in Saudi Arabia, it resulted in succumbed to the virus. In the Europian region out of many deaths and spread first to other countries within 13,59,380 confirmed cases,1,24,525 (9.2%) patients,in the Middle East and then worldwide.[5] the region of America out of 11,40,520 confirmed cases,58,492 (5.1%) patients, in Eastern Mediterranean Types: Corona viruses are the members of subfamily Region out of 1,65, 933 confirmed cases 6991(4.2%) Coronavirinae in the family Coronaviridae. Uptill now patients, in Western Pacific Region out of 1,44, 121 seven types of are recognised that can confirmed cases 5958 (4.1%) patients, in South-East infect humans. Asia Region out of 46,060 confirmed cases,1824 (3.9%) patients, in African Region out of 21,470 confirmed Common types: cases 865 (4.1%) patients have succumbed to the virus. 1. 229E (alpha coronavirus) [6] The majority of cases and deaths have been reported in USA. of the total number of cases, 9,31,698 (32.4%) 2. NL63 (alpha coronavirus) patients have been identified in USA.[6] Likewise, the 3. OC43 (beta coronavirus) majority of fatalities (47,980 [24.2%]) have also been reported in USA.[6] It is important to note that confirmed 4. HKU1 (beta coronavirus) cases are clinically diagnosed and laboratory-confirmed. MERS-CoV strain causes more severe complications Due to the ongoing nature of the pandemic, the number like Middle East respiratory syndrome (MERS), and of cases and involved countries are expected to vary.

Table 1 Provides a comparison of the epidemiological characteristics of SARSCoV, MERS-CoV, and SARS- CoV-2.

Features SARS-CoV-2 SARS-CoV MERS-CoV Estimated R0 2.68 2.5 >1 Bats are natural Chinese horseshoe bats are natural Bats are natural hosts,dromedary hosts,pangolins are hosts, masked palm civets are Host of virus camels are intermediate hosts, Intermediate hosts, and intermediate hosts, and humans are and humans are terminal hosts humans are terminal hosts terminal hosts Human-to-human through Human-to-human through aerosol Respiratory transmission, fomites, physical contact, droplets,opportunistic airborne zoonotic transmission, Transmission Mode aerosol droplets, nosocomial transmission, nosocomial transmission, nosocomial transmission, transmission, zoonotic fecal-oral transmission,zoonotic limited human-to-human transmission transmission transmission,aerosol transmission Incubation Period 6.4 days (range:0-24 days) 4.6 days 5.2 days

SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SARS-CoV, severe acute respiratory syndrome coronavirus; MERSCoV, Middle East respiratory syndrome coronavirus; R0, reproduction number 6784 Indian Journal of Forensic Medicine & Toxicology, October-December 2020, Vol. 14, No. 4 Table 2: The number of confirmed cases and death of COVID – 19 outbreak according to WHO as of 27 April 2020

Reporting Country Total confirmed cases Total deaths Region of America United States of America 931698 47980 Brazil 58509 4016 Canada 45778 2489 Peru 25331 700 African Region South Africa 4546 87 Algeria 3382 425 Cameroon 1621 56 Ghana 1550 11 Eastern Mediterranean Region Iran 90481 5710 Saudi Arabia 17522 139 Pakistan 13328 281 United Arab Emirates 10349 76 South-East Asia Region India 27892 872 Indonesia 8882 743 Bangladesh 5416 145 Thailand 2931 52 European Region Spain 207634 23190 Italy 197675 26644 Germany 155193 5750 The United Kingdom 152844 20732 France 123279 22821 Russian Federation 87147 794 Western Pacific Region China 84341 4643 Singapore 13624 12 Japan 13385 351 Republic of Korea 10738 243 Australia 6713 83 New Zealand 1122 19 Indian Journal of Forensic Medicine & Toxicology, October-December 2020, Vol. 14, No. 4 6785 Table 3: State/UT wise list of COVID confirmed cases (As on 28 April 2020 at 05:00 PM).

State/UT Total Confirmed Cured/Discharged/Migrated Death Andaman & Nicobar 33 11 0 Andhra Pradesh 1259 258 31 Arunachal Pradesh 1 1 0 Assam 38 27 1 Bihar 346 57 2 Chandigarh 40 17 0 Chhattisgarh 37 32 0 Delhi 3108 877 54 Goa 7 7 0 Gujarat 3548 394 162 Haryana 296 183 3 Himachal Pradesh 40 22 1 Jammu & Kashmir 546 164 7 Jharkhand 103 17 3 Karnataka 520 198 20 Kerala 482 355 4 Ladakh 22 16 0 Maharashtra 8590 1282 369 Manipur 2 2 0 Meghalaya 12 0 1 Mizoram 1 0 0 Madhya Pradesh 2368 361 113 Odisha 118 37 1 Puducherry 8 3 0 Punjab 313 71 18 Rajasthan 2185 518 41 Tamil Nadu 1937 1101 24 Telengana 1002 280 26 Tripura 2 2 0 Uttar Pradesh 2043 400 31 Uttarakhand 51 33 0 West Bengal 697 109 20

Etiology: CoVs are a large family of RNA viruses that families.[3] The Coronaviridae family can be classified are found diversely in animal species and known to cause into four genera of alpha-COV, beta-COV, delta-COV, diseases of the respiratory, hepatic, nervous system, and and gamma-COV.[4] Furthermore, beta-COV can be gastrointestinal systems in humans.[3] They have crown- sub-divided into 5 lineages.[7] Bats and rodents are like appearance under the electron microscope, due to the the gene source of alpha-COV and beta-COV, while presence of envelope spike glycoproteins.[4] CoVs belong avian species are the gene source of delta-COV and to the Roniviridae, Arteriviridae, and Coronaviridae gamma-COV.[4] CoVs causes about 5-10% of acute 6786 Indian Journal of Forensic Medicine & Toxicology, October-December 2020, Vol. 14, No. 4 respiratory infections.[3] Some common human CoVs of patients include fever (98.6%), fatigue (69.6%), dry include HCoV-OC43, HCoV-HKU1, HCoV-229E, cough, and diarrhea.[11] and HCoV-NL63.[4] CoVs clinically present with self limitimg respiratory infections and in Mild Disease: These patients may present with immunocompetent individuals.[4] In the old age and symptoms of an upper respiratory tract viral infection immunocompromised idividuals, they can involve the which includes dry cough, mild fever, nasal congestion, [4] lower respiratory tracts.[4] Other human CoVs such as sore throat, headache, muscle pain, and malaise. MERS-CoV, SARS-CoV, and SARS-CoV-2 present Dyspnea is not present in such cases. The majority (81%) [4] with pulmonary and extra-pulmonary features.[4] of COVID-19 cases are mild in severity. Radiological changes are also absent in such cases.[11] But these cases SARS-CoV-2, which is responsible for the can quickly deteriorate into severe or critical cases. COVID-19 pandemic, is a type of beta-COV. Genomic characterization studies of the new strain have Moderate Disease: These patients present with indicated an 89% nucleotide match with bat SARS- respiratory symptoms of cough, shortness of breath, and [4] like CoVZXC21.[3,8] and 82% nucleotide match with tachypnea. However, signs and symptoms of severe the human SARS virus. [8] Therefore it is to be called disease are absent. SARS-CoV-2. SARS-CoV-2 is sensitive to ultraviolet Severe Disease: These cases present with severe [4] light and heat. The Virus binds to their target cells pneumonia, acute respiratory distress syndrome (ARDS), through angiotensin-converting enzyme 2 (ACE2), sepsis, or septic shock[4]. These cases are diagnosed on which is expressed in the lungs. These viruses can be the basis of clinical findings and radiographic studies. destroyed with the use of ethanol (60%), ether (75%), Clinically these cases are presented with severe dyspnea, and chlorine-containing disinfectants. tachypnea (respiratory rate > 30/minute), respiratory Transmission: The initial cases of Covid 19 were distress, SpO2 ≤ 93%, PaO2/FiO2 < 300, and/or greater [4] associated with direct exposure to infected animals than 50% lung infiltrates within 24 to 48 hours. Fever [4] (animal-to-human transmission) at a seafood market in can be absent or moderate even in these cases. Wuhan, China. But human-to-human transmission of the About 5% of patients can develop respiratory virus is also possible and human-to-human transmission failure, RNAaemia, cardiac injury, septic shock, or is now considered the main form of transmission. multiple organ dysfunction.[4,11] Chineese Centres data [4] Asymptomatic individuals could also transmit the virus. for Disease Control and Prevention (CDC) suggest However, the symptomatic people are the most common that the case fatality rate for critical patients is 49%. [4] source of infection .Most commonly transmission occurs Patients with pre-existing co-morbidities like diabetes from the spread of respiratory droplets through coughing (7.3%), (6.5%), cardiovascular [4] or sneezing. But close contact between individuals can disease (10.5%), hypertension (6%), and oncological [9] also result in transmission. There are more chances of complications (5.6%) have a higher case fatality rate and transmission in closed spaces due to elevated aerosol those without co-morbidities (0.9%).[11] concentrations.[4] Acute Respiratory Distress Syndrome: It occurs SARS-CoV-2 has a basic reproduction number within one week as a complication of known infection [4] of 2.2. This suggests that a patient can transmit which indicates worsening respiratory failure. PaO2/ the infection to two other individuals. Current data FiO2 values are used to distinguish ARDS based on suggest that the virus has an incubation period of three varying degrees of hypoxia. PaO2/FiO2 ≤ 100 mm Hg [10] to seven days. These findings are based on initial is indicative of severe ARDS, between 100-200 mm Hg cases. Therefore, further studies are needed to address are diagnostic for moderate ARDS and between 200- transmission dynamics and incubation times. 300 mmHg indicative of of mild ARDS.[4] Higher levels Clinical features: COVID-19 manifests as a of AST (aspartate transaminase) and ALT (alanine spectrum ranging from asymptomatic patients to septic transaminase) at the time of admission result in rapid shock and multiorgan failure.[4] COVID-19 is classified clinical deterioration to ARDS. on the basis of severity of presentation as mild, moderate, In addition to this chest imaging modalities such [4,11] severe, and critical. The most common symptoms as chest X-ray, computed tomography (CT) scan, and Indian Journal of Forensic Medicine & Toxicology, October-December 2020, Vol. 14, No. 4 6787 lung ultrasound can be used to support the diagnosis. for persons under investigation (PUI).[4] If a person is The most frequent finding on CT scan includes ground- considered a PUI, immediate prevention and infection glass opacity (86%), consolidation (29%), crazy control measures are undertaken. Epidemiological paving (19%), bilateral disease distribution (76%), and factors which are used to assess the requirement of peripheral disease distribution (33%).[12] It is important testing include close contact with a laboratory-confirmed to note that a chest X-ray has a lower sensitivity (59%) patient within 14 days of symptoms or travel history to to detect subtle opacities. A CT scan can further detect an infected area within 14 days of symptom onset.[4] mediastinal lymphadenopathy, nodules, cystic changes, and pleural effusion. According to WHO recommendations the samples should be collected from both the upper and lower Sepsis and Septic Shock: Sepsis and septic shock respiratory tracts which includes expectorated sputum, are considered to be the most critical of them all. The bronchoalveolar lavage, or endotracheal aspirate.[4] By accompanying multi-organ dysfunction results as a using polymerase chain reaction (PCR) these samples are consequence of dysregulated host response to infection. then assessed for viral RNA. If the test is positive then Signs of multi-organ dysfunction include severe dyspnea, it is recommended to repeat the test for re verification low oxygen saturation, reduced urine output, tachycardia, purpose and if the test is negative with a strong clinical hypotension, cold extremities, skin mottling, and altered suspicion, CDC recommends repeat testing. sensorium.[4] Laboratory evidence of other homeostatic dysregulation includes acidosis, high lactate levels, Management: Isolation and social distancing hyperbilirubinemia, thrombocytopenia, and evidence remains the most effective measure for containment of coagulopathy[4].Patients with septic shock are of COVID-19. Neither specific antiviral medication [4] persistently hypotensive despite volume resuscitation. nor vaccine is currently available for treatment. They may also have an accompanying serum lactate Hence, the treatment consists of symptomatic care level of >2 mmol/L. and oxygen therapy. Patients with mild infections require early supportive management which includes Laboratory Features: Laboratory findings use of acetaminophen, external cooling, oxygen include elevated prothrombin time, LDH (lactate therapy, nutritional supplements, and anti-bacterial dehydrogenase), D-dimer, ALT, C-reactive protein therapy.[11] Critical patients require high flow oxygen, (CRP), creatine kinase and the early stages of the extracorporeal membrane oxygenation (ECMO), disease shows marked reduction in CD4 and CD8 glucocorticoid therapy, and convalescent plasma.[11] The lymphocytes.[11] Patients in the intensive care unit use of systemic corticosteroid is not recommended to have shown higher levels of interleukin (IL) 2, IL-7, treat ARDS.[4] Unnecessary administration of antibiotics IL-10,GCSF (granulocyte colony-stimulating factor), should also be avoided. ECMO should be considered in IP10 (interferon gamma-induced protein 10),MCP1 patients with refractory (monocyte chemotactic protein 1), MIP1A (macrophage inflammatory protein alpha),and TNF-α (tumor necrosis hypoxemia despite undergoing protective [4] factor-α).[13] They also displayed other abnormal findings ventilation. Intubation, mechanical ventilation, indicative of coagulation activation, cellular immune high-flow nasal oxygen, or non-invasive ventilation deficiency, myocardial injury, renal injury, and hepatic is recommended in patients with respiratory failure. injury.[11] In critical patients, amylase and D-dimer Hemodynamic support with the administration of levels are significantly elevated and blood lymphocyte vasopressors is requires in patient of septic shock. counts progressively decreased.[4,13] Common to non- Patients with multiple organ dysfunction require Organ [4] survivors are the elevations in serum ferritin, neutrophil function support. [14] count, D-dimer, blood urea, and creatinine levels. Therapeutically, suggested drugs are aerosol Elevations in procalcitonin levels are not a feature of administration of alpha-interferon (5 million units COVID-19. Therefore, an elevated level of procalcitonin twice daily), chloroquine phosphate, and lopinavir/ may suggest an alternative diagnosis such as bacterial ritonavir. [4] Other suggested anti-virals include ribavirin pneumonia. Levels of CRP correlate directly with and abidor.[11] The use of three or more anti-viral drugs disease severity and progression. simultaneously is not recommended. Ongoing clinical Diagnosis: The U.S. CDC has developed criteria studies suggest that remdesivir (GS5734) can be used 6788 Indian Journal of Forensic Medicine & Toxicology, October-December 2020, Vol. 14, No. 4 for prophylaxis and therapy.[4] The antiviral drug, called 2015, 1282:1-23. favipiravir or Avigan, has been used in Japan to treat 2. Lu Ret al. Genomic characterisation and influenza, and the drug was approved as an experimental epidemiology of 2019 : treatment for COVID-19 infection. So far, reports implications for virus origins and receptor binding. suggest that the drug has a high degree of safety and Lancet. 2020, 395:565-574.2020 is clearly effective in treatment. Furthermore, a fusion 3. Chen Yet al. Emerging coronaviruses: genome inhibitor targeting the HR1 domain of spike protein is structure, replication, and pathogenesis. J Med reported to have the potential to treat COVID-19. Virol. 2020, 92:418-423. Prevention: Preventive measures must focus on 4. Cascella Met al. Features, Evaluation and Treatment optimizing infection control protocols, self-isolation, Coronavirus (COVID-19). StatPearls Publishing, and patient isolation during the provision of clinical Treasure Island, FL; 2020. care. The WHO has advised against close contact 5. Al-Osail Aet al. The history and epidemiology of [4] with patients, farm animals, and wild animals. Middle East respiratory syndrome corona virus. Patients and the general public must cover their mouth Multidisciplinary respiratory medicine, 2017 Dec while coughing and sneezing to help prevent aerosol 1; 12(1): 20. transmission. Frequent hand washing with soap and 7. Chan Jet al. Interspecies transmission and water is also required and hand sanitizers can also be emergence of novel viruses: lessons from bats and used. It is very important to avoid public gatherings birds. Trends Microbiol. 2013, 21:544-555. by immunocompromised individuals. Strict hygiene measures for the control of infections must be applied by 8. Chan Jet al. Genomic characterization of the 2019 emergency medicine department. Healthcare personnel novel human-pathogenic coronavirus isolated from must use personal protective equipment (PPE) such as a patient with atypical pneumonia after visiting N95 masks, FFP3 masks, gowns, eye protection, gloves, Wuhan. Emerg Microbes Infect. 2020 and gowns. 9. Ghinai Iet al. First known person-to-person transmission of severe acute respiratory syndrome Conclusions coronavirus 2 (SARS-CoV-2) in the USA. Lancet. 2020; 10.1016/S0140-6736(20)30607-3 The COVID-19 pandemic is spreading across the globe at very fast rate. It is considered as more infectious 10. Li Qet al. Early transmission dynamics in Wuhan, than SARS or MERS and responsible for more infections China, of novel coronavirus-infected pneumonia. N and deaths as compared with SARS or MERS. Old age Engl J Med. 2020, 10.1056/NEJMoa2001316 and immunocompromised patients are at the greatest 11. Wang Yet al. Unique epidemiological and clinical risk of infection. Due to rapid spread of disease there features of the emerging 2019 novel coronavirus is need for intense surveillance and isolation protocols pneumonia (COVID-19) implicate special control to prevent further transmission. Neither confirmed measures. J Med Virol. 2020, 10.1002/jmv.25748 medication nor vaccine has been developed. Currently 12. Kanne JP: Chest CT findings in 2019 novel treatment strategies include symptomatic care and coronavirus (2019-nCoV) infections from oxygen therapy. For the future prevention of COV- Wuhan,China: Key points for the radiologist. related epidemic or pandemic prophylactic vaccination Radiology. 2020, 295:16-17. 10.1148/radiol. is required. 2020200241 Ethical Clearance: Taken from institutional ethics 13. Huang Cet al. Clinical features of patients infected committee. with 2019 novel coronavirus in Wuhan, China. Lancet. 2020, 395:497-506. 10.1016/S0140- Source of Funding: Self. 6736(20)30183-5

Conflict of Interest: Nil. 14. Wang Det al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus- References infected pneumonia in Wuhan, China. JAMA. 2020, 323:1061-1069.10.1001 1. Fehr A et al. Coronaviruses: an overview of their replication and pathogenesis .Method Mol Biol.