key: cord-0805798-sxj2nzac
authors: Joshi, Rupa; Singla, Rubal; Mishra, Abhishek; Kumar, Mukesh; Singh, Rahul Soloman; Singh, Ashutosh; Bansal, Seema; Sharma, Amit Raj; Sarma, Phulen; Prakash, Ajay; Medhi, Bikash
title: A systematic review on SARS-CoV-2 remission: an Emerging challenge for its management, treatment, immunization strategies and post-treatment guidelines
date: 2022-01-07
journal: New Microbes New Infect
DOI: 10.1016/j.nmni.2022.100949
sha: 75e559e8a6d269b2265f515618343ea4375fd94a
doc_id: 805798
cord_uid: sxj2nzac

The COVID-19 disease caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2) has posed as a major health concern for people all across the globe. Along with the increasing confirmed patients being readmitted with complaints for fever, cough, cold, the effective monitoring of ‘relapse’ of the SARS-CoV-2 virus in the previously discharged patients have become the next area of focus. However, availability of limited data on reactivation of SARS-CoV-2 makes the disease prognosis as well as the effective control of re-infection an immense challenge. Prompted by these challenges, we assessed the possibility of re-infection in discharged patients and the risk of the transmission, proficiency of RT-PCR results and approximate period required for the quarantine and the real challenges for the development of vaccine. In the present review, the published literature on all the possible cases of re-infection from February to July were reported, thereby selected 142 studies from a hub of overall 669 studies after full text screening. The incomplete virus clearance, poor sensitivity of the present diagnostic testing, emergence of mutant strains, insufficient mucus collection from the throat swab etc. are some of the possible causes of re-infection. The new protocols for management of COVID-19 discharged patients should be revised in the guidelines.

The infection of SARS-CoV-2 has made the whole world feeble. Population of many countries got infected by this virus which was claimed to be originated from Wuhan, China. All the scientists over the globe are engaged in researching the best treatment options and immunization strategies against the SARS-CoV-2 infection. Although a tremendous understanding of the virus, its types have been done in the last five months but still many questions related to its immunity, mutations, relapse and vaccination need to be explored. The fate of infection of this virus is still a mystery for scientists.

On one side various antiviral drugs, steroids, monoclonal antibodies, anti-microbials, convalescent plasma therapy etc. had been tried for its treatment, on the other side numerous vaccines have also been developed to combat this COVID-19 pandemic [1, 2] . In spite of all these concepts, the incidence of relapse of COVID-19 patients has produced another challenge for the treating physicians as well as the researcher scientists and policymaker organizations all over the world. The conception of immunity to coronaviruses is not yet clear. However, the immunity to common cold viruses is not long-lasting but immunity to the previous outbreaks of coronaviruses like SARS-CoV in 2012 has been found to be long lasting but SARS-CoV-2 is not comprehensive [3, 4] . The reports of re-infection or remission of SARS-CoV-2 infection are rising day by day from the last few months. The relapse cases were very few in the month of March 2020 but had been increased suddenly till the second week of July, 2020. The published reports of re-infection cases from all over the globe were collected and summarized to find out the trend of re-infection. Moreover, the time of reoccurrence of the infection has also found to be unpredictable. Although a number of reasons for re-infection were discussed in few reports however, the actual cause of re-infection is not clear. In this review, the different reported cases are critically analyzed to accomplish the exact cause and treatment strategies to control the cases J o u r n a l P r e -p r o o f of re-infection. This would help in monitoring the COVID-19 patients for re-infection and to decide the quarantine or isolation period for the infected patients. The risk of spread of further infection from these relapse cases has also been discussed.

 To evaluate the possibility of re-infection of COVID-19 in recovered/discharged patients and the risk of transmission of infection from re-infected patients  To determine the certainty of the number of negative tests done on the COVID-19 patients to declare them safe or discharged proficiency  To re-evaluate the proficiency of the results of RT-PCR to decide the chances of re-infection or remission of the disease  To decide the approximate quarantine period required for the COVID-19 patients after its first discharge

The published literature for the present review was obtained by searching the articles published from Feb to 20 July, 2020. This literature search was conducted on 1 st April, 2020, using databases like PubMed, Science Direct, Google Scholar, Google), with the search terms: pandemic. The summary of all the included studies has been discussed in Table 1 .

The reasons for relapse of COVID-19 infection can be explained by many theories i.e. re- Another cause of re-infection may be due to the induction of antibody-dependent enhancement of infection due to the presence of anti-S non-neutralizing or sub-neutralizing antibodies. So, the production of low levels of antibodies in a patient may lead to higher chances of re-infection with exacerbation of the disease.

can also cause re-infection. These variants used to escape the immune system and can cause reinfection in patients already recovered from Covid-19. The incidence of cases of new strain of SARS-CoV-2 originated from UK also leads to another challenge for the management of J o u r n a l P r e -p r o o f COVID-19. In the UK, there has been a rapid increase in COVID- 19 

England, leading to enhanced epidemiological and virological investigations. Analysis of viral genome sequence data identified that a large proportion of cases belonged to a new single phylogenetic cluster. This strain is re-infecting the people already infected with SARS-CoV-2 in many countries. This variant strain is upto 70% more transmissible [12] . In India, the incidence of re-infection was reported with the new strain i.e. N440K in health care workers [13] . Thus, the emergence of new mutant strains could be among the various contributing reasons to reinfection. nucleic acid should be included [15] .

Moreover, FDA has granted emergency use authorization for tests that identify antibodies i.e. IgG and IgM, against SARS-CoV-2 in serum or plasma. It has been found that serologic screening can be an important tool to understand population immunity and distinguish individuals who are at lower risk for re-infection. In some individuals, viral RNA can be detected from the respiratory tract months after the initial infection. Detectable viral RNA, however, does not always indicate the presence of infectious virus, and there appears to be a threshold of viral RNA level below which infectiousness is unlikely [16] .

Another cause may be the variation in the clearance of the virus in co-morbid conditions like hypertension, diabetes, etc. Chest congestion in critically ill and elderly patients might also lead to delay in virus clearance [17] . In Shenzhen, 14.5% (38/262) of the patients were again found to be positive after discharge from hospitals without having any history of contact with positive patients. These studies are questioning the importance of herd immunity as well as the individual variations in the immunity against this virus [18] .

The coronavirus replication is seething for an unusual long time and can also cause late reactivation. The length of virus detection also varied from person to person. It has been found that some patients showed positive RT-PCR tests after 1-2 weeks of discharge from the hospital after their first COVID-19 infection [19] . These patients may remain as virus carriers for a long time after their discharge. One of the major issue discussed by most of the experts as the possible cause of re-infection may be the insufficient quarantine period for the people before discharge. 

Various reports all over the globe came with re-infection after discharge from the hospitals.

The latent period of re-infection varied from 7-28 days. It has been found that the symptoms after re-infection in most of the cases were not severe and did not perpetuate to death. In these re-infected patients, although the RT-PCR results were positive but anti-viral therapy was not required. However, the risk of transmission of the virus from these re-infected patients is low but there is no firm evidence that these patients can not transmit the infection further. Thus, the risk Shedding time of virus longer in respiratory tract than in GIT. Possibility of induction of delayed inflammatory response by the presence of SARS-CoV-2 in the gut.

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