Clinical manifestations, treatment options, and comorbidities in COVID‐19 relapse patients: A systematic review

Abstract Introduction Interest revolving around coronavirus disease 2019 (COVID‐19) reinfection is escalating rapidly. By definition, reinfection denotes severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), PCR redetection, and COVID‐19 recurrence within three months of the initial symptoms. The main aim of the current systematic review was to evaluate the features of COVID‐19 relapse patients. Materials and methods For this study, we used a string of terms developed by a skilled librarian and through a systematical search in PubMed, Web of Science, and Embase for eligible studies. Clinical surveys of any type were included from January 2019 to March 2021. Eligible studies consisted of two positive assessments separated by a negative result via RT‐PCR. Results Fifty‐four studies included 207 cases of COVID‐19 reinfection. Children were less likely to have COVID‐19 relapse. However, the most patients were in the age group of 20–40 years. Asthenia (66.6%), headache (66.6%), and cough (54.7%) were prevalent symptoms in the first SARS‐CoV‐2 infection. Asthenia (62.9%), myalgia (62.9%), and headache (61.1%) were most frequent in the second one. The most common treatment options used in first COVID‐19 infection were lopinavir/ritonavir (80%), oxygen support (69.2%), and oseltamivir (66.6). However, for the treatment of second infection, mostly antibiotics (100%), dexamethasone (100%), and remdesivir (80%) were used. In addition, obesity (32.5%), kidney failure (30.7%), and hypertension (30.1%) were the most common comorbidities. Unfortunately, approximately 4.5% of patients died. Conclusion We found the potency of COVID‐19 recurrence as an outstanding issue. This feature should be regarded in the COVID‐19 management. Furthermore, the first and second COVID‐19 are similar in clinical features. For clinically practical comparison of the symptoms severity between two epochs of infection, uniform data of both are required. We suggest that future studies undertake a homogenous approach to establish the clinical patterns of the reinfection phenomena.


| Inclusion and exclusion criteria
All the studies reported the reactivation or second infection of COVID-19 were considered in the search. Total records were retrieved and entered into EndNote X9 software (Thomson Reuters).
Following duplicate exclusion, a three-stage screening was carried out to exploit the eligible studies based on title, abstract, and full text. The whole eligible studies reported the patients who were recovered from primary infection, but then developed a secondary   same studies, congress abstracts, reviews, systematic reviews and meta-analysis, cellular and molecular studies, and animal studies. All types of manifestations and treatments were regarded without any restriction, and there was no limitation on comorbidities and underlying disorders.

| Data extraction
The following data were acquired from each article: first author's name, location, publication time, type of study, number of relapsed patients, age, gender, interval between two infections, clinical manifestations, treatment, relative status, comorbidities, and outcome. Two investigators independently extracted the data from full text of 54 included studies. Inconsistencies between reviewers were resolved by consensus. The retrieved data are represented in Table 1.

| Quality assessment
The critical appraisal checklist provided by the Joanna Briggs

| Study characteristics
The search strategy yielded 1807 studies from three databases. Thirteen studies were originated from Europe, 11 from the USA, 9 from China, and 6 from Brazil. These articles reported a total number of 207 patients who developed the second infection of coronavirus after a recovery, which was confirmed by a negative RT-PCR test.
Forty-six studies reported the clinical features in the first infection; however, seven articles declared no symptoms. Only one study unrecorded the clinical features in the first infection. In addition, 42 investigations implied the medication and intervention.
In the second phase of infection, 43 articles reported the clinical manifestations, seven articles stated no sign, and four articles did not list any symptoms. Also, 37 studies reported specifically the

| Demographic and general information
Considering the studies included, we reviewed 207 patients pre-

| Clinical manifestations
Some clinical signs were most frequent between the two infections,  were used (Table 2).

| Comorbidities
The evaluating comorbidities and underlying conditions can enlighten some aspects of COVID-19. Based on the extracted data, a number of underlying diseases and conditions had a notable frequency. Obesity was highlighted as a condition in 32.5% of patients by 15 articles, whereas 22 studies stated diabetes with an overall prevalence of 15.15%. Hypertension and heart failure were reported to be 30.16% and 26.09% in 24 and 17 articles, respectively. Neurodegenerative disorders such as Alzheimer's (9.52%) and Parkinson's (9.52%) diseases were found as comorbidities ( Table 2).
However, evidence established an association between these types of comorbidities and COVID-19; further investigations could clarify the detailed mechanisms of these relations.

| DISCUSS ION
To prevent reinfection or reactivation, four criteria can be consid- Several factors influencing reinfection, including the initial load of the virus and the type of genome, are virus-dependent. 16 The average duration of SARS-CoV-2 shedding is 20 days, which in some cases is 37 days. 17

TA B L E 2 (Continued)
factors, such as the level of the individual's immune system or the accuracy of the tests, that affect this time period. Perhaps, the reason for the recurrence of the disease 7-14 days after discharge from the hospital is that the virus is still hidden in exosomes or extracellular vesicles and resumes activity after a period of "silences". 14 In this study, RT-PCR was a necessary inclusion criterion. Thus, patients with only a serologic diagnosis test, without a nasopharyngeal swab RT-PCR were excluded. RT-PCR is the gold standard for diagnosing SARS-CoV-2; however, this test has low sensitivity due to test error or insufficient sample size. 19 The accuracy of RT-PCR is 97%, 20 and the occurrence of false negatives in PCR of SARS-CoV-2 has been reported to be 30%, 21 which in some cases increases due to sampling error. 20 One of the reasons for the error in RT-PCR is the prolonged conversion of nucleic acid, which causes recurrence or "turn positive". 22 In the early stages of infection, the SARS-CoV-2 is readily detected in the upper respiratory tract. As the disease progresses, the virus appears in the lower respiratory tract and other organs such as the intestines and blood. 23 Therefore, it is impossible to identify SARS-CoV-2 in the throat, and some patients may have positive CT scan, despite the negative RT-PCR. 24 Incorrect sampling is another reason for recurrence in improved individuals, 14 although it is unlikely to happen due to the use of devices such as gloves, masks, and caps. 25 As Although studies have shown that underlying conditions cause the severity of COVID-19 disease, but how each of these factors contribute to reinfection should be examined by designing new studies determining these effects separately or in combination. 28,29 The clinical features of patients with reinfection are similar to those of primary infection. The presence of asymptomatic patients among reactivated patients caused the recurrence of the asymptomatic contamination or infection with few symptoms. 14,16 In an earlier study, rhesus macaques became reinfected after recovery, without showing any symptoms. This finding highlights the need for strict protection from SARS-CoV-2 and its control, to hider the development of this severe disease. 30 The second time of infection severity is varied; some cases show mild, and some others indicate more severe symptoms. 10 In a former study, 46.03% of patients had a worse condition, and 39.68% had a better condition in the second than the first infection. One of the reasons for the deteri- In a study performed by Okhuese, the proportion of infected population will continue to grow in the world if unvaccinated. At the same time, the rate of recovery will continue slowly. In other words, in this situation, the mortality rate can be determined based on the ratio of infection to recovery rate. The rate of reinfection with clinical clearance of the virus from the improved population decreases to zero over time. 32 Contrary to the results achieved in Okhuese's study, 33 despite the high prevalence of SARS-CoV-2, the rate of reinfection is still high. Therefore, more experimental and laboratory studies are needed to determine the cause of reinfection and its frequency. Of note, reinfection differs from reactivation.
Reinfection is caused by different variants of SARS-CoV-2 virus, but reinfection occurs with the same strain. The only way to discriminate the reinfection and reactivation is by sequencing and molecular techniques. 34 Regrettably, the first two actions happen only in 5%-10%. 10 Designing studies to sequence the virus genome in the first and second infections is highly recommended. In this way, the cause of COVID-19 recurrence is clarified, and its prevalence in the community is determined.
A number of limitations can be considered in this study. The first is the small number of original articles and short communication. The second is related to case series and case reports studies, which lack sufficient and accurate information on patients and are often reported descriptively. Therefore, accurate meta-analysis calculations were impossible in this study.

| CON CLUS ION
The present study represents a large number of COVID-19 reactivation over different countries. Overall, the recurrence of COVID-19 in

CO N FLI C T O F I NTE R E S T
The authors declare that they have no competing interests.

I N FO R M E D CO N S E NT
Not applicable.

CO N S E NT FO R PU B LI C ATI O N
Not applicable.

DATA AVA I L A B I L I T Y S TAT E M E N T
All the data in this review are included in the study.