Trajectory of the COVID-19 Pandemic: Chasing a Moving Target

Review Article Page 1 of 13

Trajectory of the COVID-19 pandemic: chasing a moving target

Kamal Kant Sahu1, Ajay Kumar Mishra1, Amos Lal2^

1Department of Internal Medicine, Saint Vincent Hospital, Worcester, Massachusetts, 01608, USA; 2Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota 55902, USA Contributions: (I) Conception and design: All authors; (II) Administrative support: None; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Amos Lal, MBBS, MD. Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota 55902, USA. Email: [email protected]; [email protected].

Abstract: The spread of COVID-19 has already taken a pandemic form, affecting over 180 countries in a matter of three months. The full continuum of disease ranges from mild, self-limiting illness to severe progressive COVID-19 pneumonia, multiorgan failure, cytokine storm and death. Younger and healthy population is now getting affected than before. Possibilities of airborne and fecal oral routes of transmission has increased the concern. In the absence of any specific therapeutic agent for coronavirus infections, the most effective manner to contain this pandemic is probably the non-pharmacological interventions (NPIs). The damage due to the pandemic disease is multifaceted and crippling to economy, trade, and health of the citizens of the countries. The extent of damage in such scenarios is something that is beyond calculation by Gross Domestic Product rate or currency value of the country. Unfortunately, unlike many other diseases, we are still away from the target antiviral drug and vaccine for severe acute respiratory syndrome (SARS- CoV-2) infection. The prime importance of NPIs like social distancing, staying in home, work from home, self-monitoring, public awareness, self-quarantine, etc. are constantly being emphasized by CDC, WHO, health ministries of all countries and social media houses. This is time of introspection and learning from our mistakes. Countries like China and South Korea who were initially the most hit countries could contain the disease spread by liberal testing of their population, stringent quarantine of people under investigation and isolation of the positive cases. Rest of the countries need to act urgently as well to bring an immediate halt in the community transmission.

Keywords: COVID-19; coronavirus; pandemic; infection; vaccine

Submitted Mar 23, 2020. Accepted for publication May 18, 2020. doi: 10.21037/atm-20-2793 View this article at: http://dx.doi.org/10.21037/atm-20-2793

th 1 Introduction world. As of 19 March 2020, there are 244,979 confirmed 7 2 cases in 180 countries with 10,035 deaths (3). Worst hit 8 Wuhan, a city in Hubei province of Eastern China has 3 countries are China, Italy, South Korea, Iran, France, Spain, 9 4 an approximate population of 11 million people. As per Germany and many other European countries (Figure 1). 10 th 5 epidemiologists, this city is considered as an epicenter Italy surpassed China on 19 March 2020 in terms of 11 6 for current COVID-19 pandemic (1,2). Subsequently, it having the highest number of active COVID-19 cases and 12 DEMO involved other parts of China and then to the rest of the more deaths (3). 13

^ORCID ID: 0000-0002-0021-2033.

CHINA 61 Total Cases: 80,967 CANADA 62 Total Cases: 943 Recovered:71,150 Recovered:11 EUROPE Deaths: 3,248 63 Deaths: 12 Total Cases: 91,978 Recovered: 54,58 RUSSIA 64 Deaths: 4,148 Total Cases:253 65 Recovered:12 Deaths: 1 66 UNITED STATES 67 Total Cases: 18,121 Recovered:125 68 Deaths: 233 DEMO 69 SOUTH KOREA 70 Total Cases: 8,652 Recovered:2,233 71 Deaths: 3 IRAN 72 Total Cases:19,644 73 SOUTH AMERICA Recovered: 6,745 74 Total Cases: 2140 Deaths: -1,433 Recovered: 15 75 Deaths: 30 AUSTR ALIA 76 SOUTH AFRICA Total Cases: 876 Total Cases:202 Recovered:46 77 Recovered: -2 Deaths: 7 Deaths: -0 78 79 80 Figure 1 COVID-19 pandemic burden worldwide. 81 82 DEMO Disease background most of the COVID-19 cases are as a result of “community 38 83 14 spread” which means SARS-CoV-2 virus seems to be easily 39 84 Coronavirus family 15 sustaining and spreading in the community with most of 40 85 16 Severe acute respiratory syndrome (SARS-CoV-2) belongs the affected population unaware of how or from where they 41 86 17 18 to the family of Beta coronavirus which also has coronaviruses became infected. 42 87 19 responsible for previous outbreaks—SARS and the Middle 43 88 20 East respiratory syndrome (MERS) outbreaks. 44 89 Demographic details of the patients 21 45 90 22 SARS-CoV-2 viral infection can affect any individual 46 91 Possible routes of transmission 23 in a naïve susceptible population. Most retrospective 47 92 24 In the initial phase, most COVID-19 cases in China studies had cohort with age range between 50–80s (8,9). 48 93 25 were found to have a direct or indirect link to Huanan In addition to this, there are also studies reporting no 49 94 26 Seafood Market in Wuhan, possibly due to the zoonotic deaths in those under age 30 from Korea or under age 50 50 95 27 spill over from wild animals to the humans (4). Gradually, from Japan (5). These results were falsely perceived or at 51 96 st nd 28 as the transmission passed beyond 1 and 2 generations, least fail to alert the younger population especially the so 52 97 29 more cases were reported to have no direct link with the called “millennial generation” individuals, most of them 53 98 30 animal exposure and were instead related to community started thinking that they are immune to this virus. The 54 99 31 transmission from person to person (5). Currently, there is sense of false security and illusion did not persist long 55 100 32 enough evidence to suggest that respiratory droplets and enough as now we have concrete data from United States 56 101 33 direct contact with contaminated surfaces are the two most (US) that harbours close to 20,000 COVID-19 cases. As DEMO 102 34 common routes of SARS-CoV-2 transmission. Just like in per The Centres for Disease Control and Prevention 57 103 35 many endemic diseases, other possible routes like airborne (CDC), more younger patients in US are catching SARS- 58 104 th 36 or faecal oral transmission is being explored for SARS- CoV-2 infection. In their report dated 20 March 2020, 59 105 37 CoV-2 transmission (6,7). Now with each passing day, CDC mentions that 20% of the hospitalized patients and 60 106 107

61 12% of the intensive care patients from US belong to age Blood work and their significance 108 62 range of 20 to 44 years (10). Amongst the comorbidities, DEMO Laboratory studies including complete blood count, renal 63 hypertension, cardiovascular disorders, cerebrovascular 109 function test, liver function test, coagulation profile, D 110 64 disorders and diabetes are the top medical conditions dimer, serum calcitonin are the common lab tests for 111 65 who had more severe disease and required intensive care hospitalised COVID-19 patients. Various inflammatory 112 66 as compared to individuals without these comorbidities markers like C-reactive protein (CRP), procalcitonin, 113 67 (7-16). Specific subset of population like patients suffering ferritin, D-dimer, interleukin 2 (IL-2) are shown to be 114 68 from cancer, transplant recipients or other benign blood elevated in patients with COVID-19 and have been found 115 DEMO disorders need special attention for their underlying to be associated with vital organs dysfunction (38,39). 116 69 disease (17-20). Wang et al. in their case series of 138 hospitalised patients 117 70 reported following laboratory abnormalities: lymphopenia 118 71 Symptomatology and laboratory investigations (70.3%), deranged coagulogram (58%), elevated lactic acid 119 72 dehydrogenase (39.9%) and abnormal imaging findings 120 73 Symptomatology and Mortality rate of COVID-19 cases 74 (100%). Presence of lymphopenia, elevated D dimer values, 121 75 In general, most SARS-CoV-2 affected patients have only deranged renal functions have been reported as poor 122 76 mild symptoms, with approximately 20% developing prognostic factors with high chance of need of intensive care 123 77 moderated to severe illness (21). This means that most with high mortality (7,8). Other hematological parameters 124 78 patients can be managed with home quarantine only like thrombocytopenia has been found to be predicting the 125 79 and hospital isolation is required only for moderate to severity and worst prognosis (40,41). 126 80 sick population. The likelihood of having more severe 127 128 81 disease is multifactorial. Vulnerable population as per the Diagnostic modalities: how to investigate a 82 available literature are older individuals more than 60 years, suspected case? 129 130 38 83 pregnant women, patients with multiple comorbidities COVID-19 RT-PCR testing 131 39 84 and immunosuppressed individuals like cancer patients 132 40 85 (1,20,22-28). With regards to the gender predisposition, Amongst the available investigations, the COVID-19 real- 133 41 86 there are mixed reports with some mentioning that time reverse transcription polymerase chain (RT-PCR) 134 42 87 males have higher chance of acquiring the infection with test is used for the qualitative detection of nucleic acid 135 43 88 higher mortality rates when compared to females. The from SARS-CoV-2 virus. Samples can be used taken from 136 44 89 age subgroup which has the highest mortality are the upper or lower respiratory areas like swabs, sputum, lower 137 45 90 older individuals as compared to the younger population. respiratory tract aspirates, and bronchoalveolar lavage. It is 138 46 91 The Special Expert Group for Control of the Epidemic important to note that a positive COVID-19 result by RT- 139 47 92 of Novel Coronavirus Pneumonia of the Chinese PCR does not rule out the concomitant bacterial infection 140 48 93 Preventive Medicine Association has recently reported the or other viral infections at the same time. Similarly, a 141 49 94 epidemiological characteristics of COVID-19 cases (29,30). negative result does not exclude SARS-CoV-2 infection 142 50 95 As per the report, the overall crude morality rate was 2.3%, altogether and hence must not be used as a sole parameter 143 51 96 with 14.8% in the age group over 80 years old, 2.8% in men for diagnostic purposes. Hence, we emphasize that if 144 52 97 and 1.7% in women. Individuals with HIV, hematopoietic clinical suspicion is high, the ideal approach should be to 145 53 98 stem cell transplantation, pregnancy is always at risk of evaluate the suspected patient based on the combination 146 54 99 acquiring atypical viral infections and hence such patients of clinical symptoms, contact history, and other dynamic 147 55 100 have higher chance to acquire COVID-19 disease (31-35). blood changes to identify COVID-19. CDC as laid down 148 56 101 The most common reported symptoms were high grade guidelines on how to interpret the results and suggested on 149 DEMO 102 fever, dry cough, shortness of breath and fatigue as the most repeating the test in case the of high clinical suspicion after 150 57 103 common presenting features. Nausea, vomiting and other consultation with public health authorities (Table 1) (42). 151 58 104 gastrointestinal symptoms were rarely reported. Recent 152 59 105 reports have shown that patients with severe COVID-19 153 Computed tomography (CT imaging) of the chest 60 106 had higher cardio-cerebrovascular events than the milder 154 107 cases (36,37). As mentioned above, if clinically indicated, imaging studies 155

Table 1 Interpretation of COVID-19 RT-PCR test based on CDC guidelines 193 2019-nCoV_N1 2019-nCoV_N2 Human RNase Result DEMO Report Actions combined primer combined primer P gene (RP) interpretation 194 Positive Positive Positive or 2019-nCoV Positive 2019-nCoV Report results to CDC and sender 195 negative detected 196 Positive Negative Positive or Inconclusive result Inconclusive Repeat testing of nucleic acid and/ 197 negative or re-extract and repeat rRT-PCR 198 199 If the repeated result remains inconclusive, contact State Public 200 Health Laboratory or CDC for 201 instructions for transfer of the 202 specimen or further guidance 203 Negative Positive Positive or Inconclusive result Inconclusive Repeat testing of nucleic acid and/ 204 negative or re-extract and repeat rRT-PCR 205 If the repeated result remains 206 inconclusive, contact State Public 207 Health Laboratory or CDC for 208 instructions for transfer of the 209 specimen or further guidance 210 Negative Negative Negative Negative Invalid Repeat extraction and rRT-PCR 211 If the repeated result remains 212 invalid, consider collecting a new 213 specimen from the patient 214 Negative Negative Positive 2019-nCoV not Not detected Report results to sender 215 detected Consider testing for other 216 respiratory viruses 217 218 219 220 156 like computed tomography (CT) of the chest should be done Bernheim et al. on 121 symptomatic COVID-19 patients, 174 221 DEMO to evaluate the patient’s low respiratory symptoms (43,44). suggested that 27 (22%) had normal CT findings at initial 175 222 157 Ai et al. did a comparative study involving 1,014 patients, to presentation (48). They studied these patients at follow 176 223 158 compare CT imaging with RT-PCR for their sensitivity (45). up as well with a repeat CT scan and found that with a 177 224 159 They found that 88% (888/1,014) had positive chest CT longer time after the onset of symptoms, more patients had 178 225 160 scans while only 59% (601/1,014) had positive RT-PCR positive CT findings including consolidation, bilateral and 179 226 161 results. Classical positive CT findings included ground- peripheral disease, and GGOs (48). Lastly, this is to note DEMO 227 162 glass opacities (GGOs), local patchy shadowing, bilateral that there are no pathognomonic radiological features that 180 228 can confidently differentiate COVID-19 from other causes 181 163 patchy shadowing, or interstitial abnormalities. Fang et al. 229 of lung infiltrates (49-54). 182 164 also had similar finding in their series of 51 patients, the 230 183 165 sensitivity of CT was 98% compared to RT-PCR of 71% 231 184 166 (P<0.001) (46). While, it is gratifying to know that CT Trajectory of COVID-19 pandemic: how different 232 167 scan could complement RT-PCR for its higher sensitivity, countries are tackling? 185 233 168 however we should also acknowledge that there might 186 234 Rise of the pandemic: when to act and how to act? 187 169 be no radiographic abnormality in less severe cases or in 235 188 170 those cases who present early to hospital (43,47,48). Guan In most cases, a pandemic disease goes through the typical 236 189 171 et al. did not find any CT abnormality in 157 of 877 patients phases of spread from a local outbreak  nationwide 190 237 172 (17.9%) with no severe disease and in 5 of 173 patients epidemic  pandemic worldwide steps. Depending on the 191 238 173 (2.9%) with severe disease. On similar lines, report by region of outbreak, few regions or countries might not get 192 239

193 time to prepare themselves to act efficiently and promptly law breakers which helped them timely mitigate the 240 DEMO unless their taskforce is already on toes by default, while spread of virus. 241 194 other distant countries where the disease has still not  Mitigation strategy and its effectiveness. Singapore 242 195 reached may get some time to prepare themselves. The has a well-established framework in place: the 243 196 damage due to the pandemic disease is multifaceted and MOH Disease Outbreak Response System which DEMO 197 crippling to economy, trade, and health of the citizens of always keeps Singapore on toes and has a generic 244 198 the countries. The extent of damage in such scenarios is preparedness model and response plan against any 245 199 something that is beyond calculation by Gross Domestic outbreak. The Disease Outbreak Response System 246 200 Product rate or currency value of the country. That is why Condition (DORSCON) framework is a colour- 247 201 it is important to learn from past experiences of outbreaks coded alert, risk assessment and response action 248 202 and have a framework/guideline set before hand with protocol which comes into action as soon there is an 249 203 regular mock drilling from time to time to ensure they are outbreak. It was the promptness by this framework 250 204 constantly validated and updated. For instance, countries that Singapore did not require a suppression strategy 251 205 like Singapore, and Japan who have successfully contained and were able to successfully control the pandemic at 252 206 the current COVID-19 pandemic have learned a good stage 2 level itself. 253 207 lesson from SARS epidemic back in 2003 when they made 254 208 stringent guidelines. 255 Italy, conceding the worst hit so far: what went wrong? 209 256 210 As mentioned above, China, South Korea and Singapore 257 How to flatten the curve: “suppression” versus “mitigation”, were able to efficiently implement their personalised 258 211 which one is better? 212 containment measures which could have reduced number of 259 213 Comparing the trajectory of COVID-19 pandemic deaths by thousands at least if not tens of thousands. Italy’s 260 214 of various countries is a litmus test of the extent of health infrastructure is otherwise quite impressive with 3.2 261 215 preparedness of various countries and public awareness. hospital beds per 1,000 people in contrast 2.9 in the United 262 216 An infectious pandemic like COVID-19 can be tackled in Kingdom. 263 217 two ways: (I) suppression strategy, which focuses to reverse Initially, Italy did respond promptly and efficiently to 264 218 epidemic growth; (II) mitigation strategy, which stresses COVID-19 pandemic, but its national health capacity 265 219 more on slowing than stopping epidemic spread. system soon got saturated. Within the first three weeks of 266 st 220  Suppression strategy and its feasibility. Although 1 COVID-19 case detection in Italy, patients flooded the 267 174 221 initially China and South Korea were heavily struck hospitals, occupied the ICU beds and ventilators clogging 268 175 222 by COVID-19, but with their suppression strategy, the healthcare resources (54). The most inflicted regions 269 176 223 which is an intense intervention model, these two are in northern Italy (Figure 2). The northern regions 270 177 224 countries are able to flatten their respective curves like Lombardia (22,264 total COVID-19 cases), Emilia- 271 178 225 of COVID-19 pandemic. China, and South Korea Romagna (5,968 total COVID-19 cases) and Veneto (4,031 272 179 226 have followed the “suppression protocol” by locking total COVID-19 cases) have so far seen the most cases and 273 DEMO 227 down their major cities, social distancing the entire deaths, where overloaded hospitals are groaning to cope 274 180 228 population, case isolation, home quarantine and (55,56). 275 181 229 by closing schools and universities. The most Italy’s death toll is skyrocketing since then and even 276 182 th 230 challenging aspect of suppression strategy is the surpassed China’s numbers on 19 March 2020 (56). 277 183 231 relapse with appearance of new cases as soon as Rosenbaum et al. in his recent report discussed Italy’s 278 184 232 suppression loosens. Probably this is the reason that ground situations at all fronts of Ethics, Logistics, and 279 185 233 we are still seeing the pockets, or a cluster of cases Therapeutics (57). Grasselli et al. from University of Milan, 280 186 234 being reported from these countries. The “generous Italy in their report outlined in detail the actions taken 281 187 235 screening strategy” allowed South Korea to accurately by an emergency task force set up by the Government of 282 188 236 estimate the COVD-19 burden to guide them. They Lombardy, Italy in association with local health authorities 283 189 st 190 237 subsequently took a massive task, implemented a on 21 February 2020, when a cluster of 16 cases were 284 191 238 nationwide public health measures along with strict reported (58). A team of 15 first-responder hub hospitals 285 192 239 lockdown of cities and legal penalties against the were allocated for their expertise in infectious disease 286

Break up of COVID-19 cases in Italy, by region wise Break up of COVID-19 cases, by age group

5000 10000 1.2% 15000 0–18 years

36.5% 25% 19–50 years

51–70 years

37.3% Older than 70 years

Break up of COVID-19 cases, by gender

41% Female 59% Male 331 332 333 334 DEMO Figure 2 Heat map of COVID-19 burden in Italy in various regions with breakdown of cases based on gender and age group. 335 336 337 287 or because they were under part of the Venous-Venous (SIAARTI) issued a modification of triage protocol and 309 338 288 ECMO Respiratory Failure Network (RESPIRA). Extra clinical ethics recommendations to guide Italian physicians 310 339 289 ICU beds were created to accommodate the sick patients. for COVID-19 pandemic: “For the allocation of intensive care 311 340 DEMO However, despite the best efforts, most of the hospitals treatments, in exceptional, resource-limited circumstances” (60). DEMO 341 290 got overwhelmed and ran out of their maximum capacity At present, desperate attempts are being taken with both 312 291 to handle the critical patients. A health resource and non-pharmacological and pharmacological interventions, 313 342 292 service assessment were done by the end of two weeks including lockdown of the whole Italy in order to bring an 314 343 th 293 (dated 7 March 2020) which revealed a huge inequality immediate halt to the community transmission. 315 344 294 between the formulation and actuality faced by Italy 316 345 295 (47,59). As per Grasselli et al.’s report, the patient sickness 317 346 Possible reasons for demographical variation of COVID-19 296 profiles and health resource mobilisation for what Italy 347 amongst Asian, European, American continent 318 297 prepared itself was based on that data from China and 348 319 298 Singapore experiences that witnessed approximately 5% As COVID-19 is evolving across the globe, we are 320 349 299 ICU admission rate amongst the COVID-19 hospitalised noticing variations in the infection rate, mortality, 321 350 300 patients (58). In contrast, when COVID-19 pandemic hit worst hit age group, disease response and so on (Table 2) 322 351 301 Italy, it was found that there were approximately 12% of (23,61-69). Initial reports from China suggested a median 323 352 302 the total COVID-19 cases, and 16% of all hospitalized basic reproduction number (R0) of 2.79, however R0 324 353 303 patients who required ICU admissions. These ICU have been reported as high as 5.7 (70,71). Deshwal 325 354 304 admission numbers were actually 2–3 times of what Italy et al. accumulated a 7-day data for all the new COVID-19 326 355 305 anticipated while formulating its taskforce. Considering cases did a comparative study comparative study of Asian, 327 356 306 the collapsing intensive care infrastructure of almost all European, and American continental countries (72). 328 357 th 307 the hospitals, on 6 March 2020, The Italian College of Amongst the Asian countries, COVID-19 incidence in 329 358 308 Anesthesia, Analgesia, Resuscitation and Intensive Care China has remained almost constant for almost last few 330 359

Table 2 Geographical variation in the mortality reported as mentioned in various recently conducted studies Geographical location of conducting study North/South Author Reported mortality or case fatality rate America Asia Europe

Borba et al. (61) North/South America 15–39%

Arentz et al. (62) North/South America Up to 67%

Basu A. (63) North/South America 1.7–33.3%

Zhou et al. (23) Asia Up to 28.2%

Wu et al. (64) Asia 2.3–49.0%

Yang et al. (65) Asia Up to 61.5%

Odone et al. (66) Europe 6.4–18.3%

La Maestra et al. (67) Europe 10–19%

Livingstone et al. (68) Europe 7.2%

Grasselli et al. (69) Europe Up to 26%

331 weeks. Cases in other Asian countries like India are on 1.0%). In United States, there is huge variation amongst the 360 332 rising trend with evidence of community transmission. Italy, variation states as every state is following its own protocol 361 333 Spain, France, United Kingdom and Netherlands are the as there is no declaration of nationwide lockdown (75). 362 334 worst hit European countries. As per the report by Deshwal 363 DEMO et al., ratio of confirmed cases, death cases and death rate 364 Management strategies 335 per 1,000 confirmed cased were highest in North American 365 336 countries and lowest in Asian countries (72). Non-pharmaceutical interventions (NPIs) DEMO 366 337 There are multiple reasons which we could count on 309 Unfortunately, unlike many other diseases, we still are 367 338 for variation in COVID-19 epidemiology; (I) community 310 still away from the target antiviral drug and vaccine for 368 339 immunity; (II) travel and connectivity across the borders; 311 SARS-CoV-2 infection. The prime importance of NPIs 369 340 (III) population density; (IV) social class disparities; (V) DEMO like social distancing, staying in home, work from home, 370 341 percentage of elderly population and so on. For instance, 312 self-monitoring, public awareness, self-quarantine etc. 371 342 amongst the European nations, Italy has the oldest 313 are constantly being emphasized by CDC, WHO, health 372 314 343 population, with approximately 23% of its citizens more ministries of all countries and social media houses (Figure 3). 373 315 344 than 65 years which probably was one of the major reasons As SARS-CoV-2 infection can easily be transmitted through 374 316 345 for highest morality noted in Italy (73). Contrary to this, respiratory droplets and direct contact, the best way to halt 375 317 346 India which has so far done fairly well despite being the the community transmission is to follow the civic etiquettes 376 347 second most populous nation has more than 50% and and social distancing. Neil M Ferguson and colleagues from 377 318 348 65% of its population below 25 years and below the age of Imperial College London recently submitted their report 378 319 320 349 35 years respectively. on the behalf of Imperial College COVID-19 Response 379 321 350 Another important factor that needs discussion is the Team (76). They studied the epidemiological modelling 380 322 351 variation in the differing strategies used for SARS-CoV-2 microsimulation model on COVID-19 for two countries: 381 323 352 RT-PCR testing. This could be another potential factor the UK (Great Britain specifically) and the US and they also 382 324 353 for difference in country-specific case-fatality rates. For suggested NPIs in their conclusion. 383 325 354 example, Korea adopted the strategy of liberal testing for 384 326 355 SARS-CoV-2, that way many patients with milder disease or 385 Pharmacological interventions: newer strategies and 327 356 symptomatic disease were included in the denominator (74). developments 386 328 357 In contrast, Italy prioritized testing for patients with more 387 329 358 severe symptoms. This could be another reason for a higher Supportive therapy 388 330 359 case-fatality rate in Italy as compared with Korea (7.2% vs. Currently, Physicians across the world are testing for 389

436 Travel restriction Be up to date with Public-private partnership CDC & WHO 437 Self monitoring: fever, dry cough, sore throat 438 DEMO 439 440 Public awareness 441 Work from home 442 How to stop 443 444 445 COVID-19? 446 Setting up drive through 447 “testing centers” Social distancing, and staying 448 home 449 450 451 Telemedicine Release of funds for cushioning 452 Stay away from Adequate health/economic crisis 453 rumors, do not panic COVID-19 Kits 454

Figure 3 Pictorial representation of the expected non-pharmacological interventions and decisive actions required by the administration to 455 stop COVID-19. 456 457 458

DEMO COVID with RTPCR testing for patients presenting with regards to time to clinical improvement, duration of DEMO 459 390 with respiratory symptoms. It is particularly important to oxygen therapy, duration of hospitalization, and time from 413 460 391 recognise the importance of keeping in mind the other randomization to death. However, they did find a shorter 414 461 392 local endemic disease like malaria, dengue, and so on (77). ICU stay (median, 6 vs. 11 days), a shorter hospital stay 415 462 393 Similarly, the common cardiopulmonary diseases like from date of randomisation (median, 12 vs. 14 days), and a 416 463 394 congestive heart failure, community acquired pneumonia, higher percentage of clinical improvement at day 14 (45.5% 417 464 395 pulmonary thromboembolism, COPD asthma exacerbation vs. 30.0%) in the lopinavir–ritonavir group than in the 418 465 396 are few of the common differentials that need simultaneous standard-care group. However, all these benefits were non- 419 466 397 testing and exclusion (78). significant between the two groups. 420 467 398 Once confirmed, the standard of care of the treatment 421 468 399 of COVID-19 struck patients involves supportive care that Newer antiviral agents 422 469 400 includes adequate oxygenation, blood pressure support, and Recently National Medical Products Administration of 423 470 401 if needed the life support systems like invasive ventilation, China, China approved first anti-viral drug, Favilavir against 424 471 402 Extracorporeal membrane oxygenations (ECMOs) and COVID-19 (80). Another drug, named remdesivir which is 425 472 403 renal replacement therapy as needed. There is no approved a nucleoside analogue and originally developed during the 426 473 404 antiviral drug for COVID-19. Worldwide, in a desperate Ebola outbreak is being studied at Nebraska medical centre, 427 474 405 attempt to save lives, doctors have been trying conventional Omaha for its effectiveness in COVID-19 (81). 428 475 406 antiviral agents like oseltamivir, lopinavir/ritonavir 429 476 407 combination with variable results. Cao et al. studied Other drugs 430 477 408 effectiveness of Lopinavir–Ritonavir drug combination Anti-malarial agent, hydroxychloroquine (HCQ), an 431 478 409 and randomised their 199 COVID-19 patients to the analogue of chloroquine is also commonly used in 432 479 410 lopinavir–ritonavir group (99 patients) versus standard- rheumatoid arthritis, lupus, Q fever, and Whipple’s disease. 433 480 411 care group (100 patients) (79). They did not find any It has recently gained limelight for its anecdotal reports 434 481 412 benefit of using lopinavir–ritonavir over standard care of effectiveness in COVID-19 patients (82,83). Doing 435 482

436 clinical trials on humans was based on the vitro studies that mistakes. Psychological wellness of front-line workers and 483 437 showed an anti-SARS-CoV activity for HCQ (84). Gautret rest of the healthcare team is another consideration that 484 438 et al. studied the effectiveness of combination of HCQ should not be ignored during these times (92-95), and 485 DEMO and azithromycin versus HCQ alone versus standard care countries like China and South Korea who were initially DEMO 439 (twenty patients in total). The dose used in this study was the most hit countries could contain the disease spread by 486 440 oral HCQ 200 mg three times a day for 10 days (83). The liberal testing of their population, stringent quarantine of 487 441 primary endpoint was to evaluate for virologic clearance at people under investigation and isolation of the positive 488 442 day-6 post-inclusion which showed a significant reduction cases. Rest of the countries need to act urgently as well to 489 443 of the viral carriage in the combination group than control bring an immediate halt in the community transmission. 490 444 group. The small patient number is the major limitation of Also, this is an evolving pandemic, the literature regarding 491 445 the study but has given a good platform to work. The Food therapeutics and strategies to monitor the trajectory are 492 446 and Drug Administration (FDA) is currently investigating still evolving. Our manuscript highlights the importance of 493 447 if HCQ can reduce the symptom duration, or “viral the above two point. This review, in no way is a complete 494 448 shedding”, which might be helpful in mitigating the disease guide to the management and public health policy but an 495 449 spread (85). Recently, there has been conflicting reports on overview. 496 450 the use of cardiac medications like ACE inhibitors, ARB’s, 497 451 and other RAAS antagonists on patients with COVID-19. Acknowledgments 498 452 For instance, Goldstein et al. suggested that use of ARB 499 Funding: None. 453 might facilitate the viral entry by increasing the expression 500 501 454 of ACE 2 receptors. However, this needs confirmation by 502 455 conducting larger studies (86-88). Footnote 456 503 457 Investigational vaccines Peer Review File: Available at http://dx.doi.org/10.21037/ 504 458 Development of vaccine is a tedious and time taking atm-20-2793. 505 process. NIH has initiated a clinical trial at Kaiser 506 DEMO 459 Permanente Washington Health Research Institute Conflicts of Interest: All authors have completed the ICMJE 507 413 460 uniform disclosure form (available at http://dx.doi. 508 414 461 (KPWHRI) in Seattle (89). This trial involves 45 volunteers org/10.21037/atm-20-2793). AL serves as an unpaid section 509 415 462 who will be receiving an investigational vaccine (mRNA- editor for Annals of Translational Medicine from November, 510 416 463 1273), two sessions of injections over 28 days apart. These 2019 to October, 2021.The other authors have no conflicts 511 417 464 patients will be subsequently followed for vaccine’s potency. of interest to declare. 512 418 465 Unfortunately, the result will be available approximately 513 419 466 after a year. Ethical Statement: The authors are accountable for all 514 420 467 aspects of the work in ensuring that questions related 515 421 468 Revisiting old therapy: using convalescent serum for to the accuracy or integrity of any part of the work are 516 422 469 COVID-19 susceptible population appropriately investigated and resolved. All authors have 517 423 470 Immunologists at John Hopkins centre are working on participated in the preparation of this manuscript and have 518 424 471 setting up a lab which aims for using the concept of taking approved the final version. 519 425 472 the serum from the patients who have recovered from 520 426 473 COVID-19 disease and injecting them to the individuals Open Access Statement: This is an Open Access article 521 427 474 who have high susceptibility to acquire infection, vulnerable distributed in accordance with the Creative Commons 522 428 475 population like old individuals, and health care providers Attribution-NonCommercial-NoDerivs 4.0 International 523 429 476 who are always at high risk of acquiring the infection (90,91). License (CC BY-NC-ND 4.0), which permits the non- 524 430 477 478 commercial replication and distribution of the article with 525 431 Conclusions the strict proviso that no changes or edits are made and the 526 432 479 original work is properly cited (including links to both the 433 480 COVID-19 pandemic has already costed lives of more than 527 434 481 250,000 individuals, mostly elderly and fragile population. formal publication through the relevant DOI and the license). 528 435 482 This is time of introspection and learning from our See: https://creativecommons.org/licenses/by-nc-nd/4.0/. 529

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