key: cord-0894861-ipudfoxv
authors: Dhillon, Rubaid Azhar; Qamar, Mohammad Aadil; Gilani, Jaleed Ahmed; Irfan, Omar; Waqar, Usama; Sajid, Mir Ibrahim; Mahmood, Syed Faisal
title: The mystery of COVID-19 reinfections: A global systematic review and meta-analysis
date: 2021-12-04
journal: Ann Med Surg (Lond)
DOI: 10.1016/j.amsu.2021.103130
sha: 58cab725fa3336691159c118e525c8f07997d5b0
doc_id: 894861
cord_uid: ipudfoxv

BACKGROUND: As the COVID-19 pandemic rages on, reports on disparities in vaccine roll out alongside COVID-19 reinfection have been emerging. We conducted a systematic review to assess the determinants and disease spectrum of COVID-19 reinfection. MATERIALS AND METHODS: A comprehensive search covering relevant databases was conducted for observational studies reporting Polymerase Chain Reaction (PCR) confirmed infection and reinfection cases. A quality assessment tool developed by the National Institute of Health (NIH) for the assessment of case series was utilized. Meta-analyses were performed using RevMan 5.3 for pooled proportions of findings in first infection and reinfection with a 95% confidence interval (CI). RESULTS: Eighty-one studies reporting 577 cases were included from 22 countries. The mean age of patients was 46.2 ± 18.9 years and 179 (31.0%) cases of comorbidities were reported. The average time duration between first infection and reinfection was 63.6 ± 48.9 days. During first infection and reinfection, fever was the most common symptom (41.4% and 36.4%, respectively) whilst anti-viral therapy was the most common treatment regimen administered (44.5% and 43.0%, respectively). Comparable odds of symptomatic presentation and management were reported for the two infections. However, a higher Intensive Care Unit (ICU) admission rate was observed in reinfection compared to first infection (10 vs 3). Ten deaths were reported with respiratory failure being the most common cause of death (7/10 deaths). CONCLUSION: Our findings support immunization practices given increased ICU admissions and mortality in reinfections. Our cohort serves as a guide for clinicians and authorities in devising an optimal strategy for controlling the pandemic. (249 words)

The coronavirus, through its rapid spread and emerging variants, started in Wuhan in December 2019 [1] [2] [3] . It was declared a global pandemic in March 2020 and continues to persist as a public healthcare emergency [4] .Since its onset, the virus has infected more than 237 million individuals globally and has resulted in more than 4.8 million deaths till date [5] .

definition and measurement of outcomes, length of follow-up, statistical methods and results. Studies with score 6-8 were graded to be of good quality, 4-5 considered fair quality and < 4 scores was considered to be of poor quality.

The comprehensive literature search yielded a total of 1039 studies from the databases. Before screening, 69 of these studies were removed due to duplication. The remainder 970 studies from the databases were then screened and a further 893 records were excluded. The remaining 77 records were sought for retrieval and then assessed for eligibility. Six studies were excluded as they either presented with overlapping or missing data (n=5) and/or did not fulfill the inclusion criteria (n=1). Likewise, 10 studies were identified via citation searching. These 10 were sought for retrieval and then assessed for eligibility. None of these were excluded and overall, 81 studies were found to be eligible according to our inclusion criteria [12, . The characteristics of these 81 included studies is shown in S2 Table. An overview of the detailed systematic study selection process is presented in the PRISMA flow diagram (Fig 1) .

Through consultation with a professional librarian, a search was conducted in leading medical journals and through duplication and screening processes, studies were selected.

In terms of study types, 45 studies (55.6%) were case reports, and 36 studies (44.4%) were case series. Studies were reported from 22 countries. Forty-eight out of 81 studies were reported from low-and-middle-income countries (LMICs). More than one-third of the studies were reported from China (28/81, 34.6%); almost one-sixth were from the USA (11/81, 13 3  3  India  4  8  Iraq  1  26  Israel  1  1  Italy  4  4  Iran  1  9  Netherlands  1  1  Pakistan  1  1  Peru  1  1  Portugal  1  1  Qatar  1  1  UK  3  8  USA  11  14  Turkey  2  3  Switzerland  1  1  Korea  1  4  Total  81  577 Demographics and Epidemiology A total of 577 cases with a mean age of 46.2±18.9 years (range 3.0 -91.0 years) were included in the study. The gender of study cases was noted to be 45.8% males and 53.7% females. Of the 577 cases, approximately one-third of the cases (n=179, 31.0%) were reported to have at least one comorbidity. 

Around three-fourth of our cases were categorized as being mildly symptomatic with only 10 cases being classified as severe to critical by their respective studies for disease severity in the first infection. The total number of asymptomatic cases during the first infection was 53 (9.2%) with an increase to 184 (31.9%) cases noted during reinfection (S2 Table) . Tian M et al., [81] reported the highest number of asymptomatic cases (20/577, 3.5%) during the first infection whereas An J et al., [26] with 27 cases (4.7%) reported the highest number of asymptomatic cases during reinfection. The presence of antibodies was also reported for the total 577 cases, wherein 323 (56.0%) and 364 (63.0%) cases were detected to be positive during first infection and reinfection, respectively. Regarding the radiological imaging during first infection of the 577 cases, almost one-quarter (146/577, 25.3%) had not reported, or did not have, any kind of chest imaging done. Out of those who reported, only 25 (4.3%) cases had a normal finding, whereas 295 (51.1%) cases reported an abnormality with Chen et al., [36] reporting the highest occurrence of radiological abnormalities (70 out of 81 cases, 86.4%).

The most administered treatment, as reported by the study results, was antiviral therapy accounting for 44.5% (n=257) and 43.0% (n=248) of cases during first infection and reinfection, respectively. Administration of antibiotics was lower at 14.4% (n=83) and 13.2% (n=76) for first infection and reinfection respectively (Fig 3) .

In the study by He et al. [51] , 60% of patients were administered steroids during both infections, which was reported to be the highest use of steroids among studies reported to date. However, in our data, the overall use of steroids was 16.6% (n=96) and 12.1% (n=70) during the respective infections. Traditional Chinese medicine and interferon administration were reported at 13.9% (n=80) and 10.7% (n=62) during the first infection and 26.7% (n=154) and 7.6% (n=44) during reinfections, respectively.

Lastly, our results show that the use of low flow oxygen was reported in 6.1% (n=35) of cases during the first infection, which then doubled to 12.3% (n=71) of cases during reinfection ( Fig  3) . Out of the total studies, reports of ICU admission and mechanical ventilation were relatively low being 0.5% (n=3) and 0.3% (n=2) during first infection, respectively, compared to 1.7% (n=10) and 1.6% (n=9) during reinfection, respectively. This was contradictory to a higher number of asymptomatic cases observed in the reinfection phase, implicating for a possible need of an Individual Patient Data (IPD) analysis in future studies.

Comparable odds of symptomatic presentation (OR:0.93, 95%CI: 0.74-1.17) and management (OR:0.90, 95%CI: 0.63-1.29) were observed in the first infection compared to reinfection when meta-analyzed, as shown in Fig 2 and Fig 3. Although a higher event of management was observed in the first infection, due to the individual weight of the studies, the overall OR favored first infection and was less than 1.

Complete recovery rate after reinfection stood at 97.9% (565 cases) with a total of 10 (1.8%) deaths. The outcome status was unknown for 2 cases (0.3%) (S2 Table) . The eight expired cases were elderly (72-91 years old; 1 male and 7 females) and 2 cases were middle-aged adults (44 and 54 years old; both males). Seven cases had comorbidities involving multiple organ systems whilst three suffered from hypertension and the remaining one had an underlying malignancy. Respiratory failure was the most common cause of death (seven out of ten deaths).

Out of 577 cases, disaggregated data for 24 pediatric (0-18 years) cases was available. Disaggregation reported positive contact histories in 7 cases (29.2%) with only 1 (4.2%) reporting a comorbidity. A total of 7 cases (29.2%) were asymptomatic followed by fever (n= 4, 16.7%) and cough (n= 3, 12.5%) in first infection whereas during reinfection, asymptomatic presentation (n= 7, 29.2%) was followed by cough (n= 4, 16.7%) and then fever (n= 3, 12.5%). With 9 abnormal chest X-ray findings (37.5%), the most frequently used management modalities during first infection and reinfection were anti-viral (n=12) and traditional Chinese Medicine (n=12), respectively. All patient outcomes were reported as recovered.

Seventy-two studies were determined to be of good quality while nine studies were of fair quality (S3 Table) . Studies were primarily downgraded for unclear study objectives [72] , incomplete case definition [25, 37, 57, 75, 76, 79, 86, 92] , non-consecutive subject recruitment [28, 36, 39, 43, 47, 48, 53-55, 58, 80, 88, 89, 95, 99] , incomparable subjects [88] , inadequate length of follow-up [52, 72] , inadequate description of statistical methods [48, 55, 89] and inadequate description of results [48, 87] . The most common cause for downgrading studies was non-consecutive recruitment, which raised concerns that the included sample could be biased towards a more severe presentation or included more individuals undergoing routine screening.

Both the developing and developed worlds are still battling the spread of COVID-19. A major concern that needs to be addressed is the appearance of reinfections in previously recovered COVID-19 patients.

Our review is the first, and largest, systematic review covering COVID-19 reinfection cases from over 22 countries, raising questions concerning vaccination and exploring a specific set of determinants that can facilitate reinfection in recovered individuals. Similar systematic reviews on COVID-19 reinfection have been conducted previously [101, 102] but none of those studies, or any conducted so far in the literature, have been as extensive as this review in terms of analyzing the clinical information between first infection and reinfection whilst covering a wide range of international and regional databases.

One of the major strengths of this review is the substantial timeframe that it covers: January 2020 to March 2021, spanning a total of 81 studies with a widespread distribution of High-Income Countries (HICs) and LMICs to differentiate features of reinfection cases as per different settings. In addition, adult cases were separated from pediatric cases to differentiate between clinical features and identify the optimal treatment management strategies as per varying age groups. Furthermore, case reports and case series included in our study were quality assessed with 72 out of 81 studies reported to be of good quality. An analysis of only pediatric reinfection cases was also conducted in this review. Good prognosis and lower morbidity were reported in pediatric cases, similar to the general COVID-19 disease course in the pediatric population [103] . Therefore, we suggest public health campaigns targeting people of younger age as they are at similar risk of reinfection as adults, to ensure elimination of complacency and enforcement of protective measures, such as face masks and social distancing.

A broad distribution was seen among severity of the first infection compared to reinfection as well as management and number of symptomatic cases. The most-reported clinical symptoms in our review were fever (41.4%) and cough (34.8%) in first infection, with a frequency of 36.4% cases with fever and 34.8% cases with cough in reinfection, respectively. These findings are similar to a trend observed in the review on reinfections by Gidari et al. [104] In addition, the number of asymptomatic cases in our review increased from 9.2% in first infection to 31.9% in second infection, similar to findings reported in the review by Gidari et al [104] .

On the contrary, a higher requirement of ICU admission and mechanical ventilation was observed during reinfection in our review. A meta-analysis analysis of 123 cases by Vancsa et al [105] showed that the second episode of SARS-COV-2 infection is more severe than the first if it happens within 60 days of the first positive PCR. This deems the necessity of IPD analysis as many of the larger case series report more severe cases which might skew the overall findings. A total of 10 deaths were reported in this review, all among reinfection cases. In all 10 cases, several comorbidities were present and all patients who were classified as the most severe were older, a similar trend seen in a study by Wang et al. [106] . Most of these patients died due to respiratory complications; similar effects of these comorbidities can be seen in other respiratory illnesses such as MERS-CoV [107] . The results from this review suggest that comorbidities and age play a major role in the outcome of critical patients. Another observation made in our review was differences in the presence of antibodies during the first infection and reinfection. A recently published systematic review looked at antibody response following SARS-COV-2 infection across multiple studies [110] . They noted that 80% of patients developed IgM antibodies with antibodies being detected after a mean period of 7 days and declining after 27 days. Total 95% of patients developed IgG antibodies, with antibodies being detectable after a mean period of 12 days and started declining after 60 days. Likewise, IgA levels and neutralizing antibodies started declining after 30 days. In our review, 56.0% and 63.0% of the patients detected positive for antibodies during first infection and reinfection, respectively. Some evidence suggests that waning antibodies places individuals at a risk for reinfection, which may explain our finding of the time duration of first infection and reinfection being a mean of 63 days. The presence of antibodies could provide a protective role, but it does not specifically prevent reinfection as supported by findings in a systematic review by Piri et al. [111] Whilst our review did not analyze the cause of reinfection being due to different variants, they cannot be excluded. A review by Wang et al. [108] concluded that previous COVID-19 reinfection did not confer total immunity and a second infection by a different variant was possible, with the second infection being more severe than the first. Even though most of the studies in our review predate the announcements of the new variants, however, given the ability of the virus to mutate at a rapid pace, some reinfection cases reported in our study could be due to the variants which would have resulted in more severity of reinfection. Whether waning antibodies or new variants were the source of reinfection is a question that should be explored further in future studies.

A recent systematic review by Azam et al. looked at the incidence of SARS-COV-2 positivity in patients who had recovered from COVID-19 [112] . They noted that younger patients and those with a longer initial infection were more likely to have recurrent positivity. A similar systematic review by Manish et al. on the assessment of SARS-COV-2 mutations in reinfections and persistent infections [109] noted it to be challenging to differentiate between reinfection and persistent recurrent infection, concluding that the former happened in immunocompetent individuals and the latter happened in immunocompromised individuals. Furthermore, this phenomenon was associated with a faster viral evolution and mutation resulting in the creation of new variants. Lastly, another systematic review by Hoang on the risk factors associated with repositive viral RNA after recovery from COVID-19 [113] postulated that the re-positive viral RNA seen in their review likely added to the evidence that viral relapse was a cause of COVID-19 recurrence.

At this time, public health initiatives aimed at removing complacency are the need of the hour, and one of the key messages that need to be given is that reinfection is a reality, and vaccines along with social distancing remain the key in fighting the pandemic. A recently published online longitudinal survey [114] in 23 countries of high, middle and low income, across 4 continents with over 1 million participants provides hope in this regard, as it identified that the intention to vaccinate amongst the general public is at an all-time high, with the major issue not being vaccine hesitancy but instead, a shortage of vaccines. A recent report of a 4-month surveillance of mass immunization in Israel [115] notes two doses of the Pfizer BioNTech mRNA COVID-19 vaccine to be highly effective (95.3%; 95% CI 94.9-95.7) against SARS-CoV-2 infection and mitigated COVID-19-related hospitalizations, severe disease, and death, including those caused by variants such as the B.1.1.7 SARS-CoV-2.

Whilst the world is still in the process of getting vaccinated, data needs to be collected on patients, in the long run, to analyze whether vaccination has any correlation with reinfection cases and to further investigate the average time needed by the various vaccines to achieve their desired efficacies. We hope that governments across the world seize this moment and take steps to ensure equitable distribution of vaccines so that the world can finally step out of the long shadow cast by the COVID-19 pandemic.

However, a few questions remain. Firstly, would immunity conferred by the first infection protect individuals from a serious disease process in the reinfection phase? And secondly, does reinfection imply that individuals who are already vaccinated experience a more severe COVID-19 infection? Further studies should be done to answer this very important key facet of reinfection arising in COVID-19 especially in the context of breakthrough infections being reported around the world in vaccinated individuals, with the B.1.617 variant implicated to be the predominant cause [116, 117] .

This review has some limitations, such as the small sample sizes analyzed from each country except for China that had 73% (n=423) of the total included cases. The majority of these cases were reported from Wuhan or the Hubei province, where the gross domestic product per capita is less than half of that of Beijing and Shanghai [118] . Therefore, the findings of studies from China may be generalizable to the socioeconomic and health development status of other middleincome countries and not to high-income nations. This review can be improved by sampling larger series and including IPD, if available, to predict the outcome of COVID-19 illness based off epidemiological trends dramatically reducing hospitalization time, given the lack of sufficient healthcare resources in low-middle income countries. Therefore, a selection bias remains when considering LMICs where admitted hospital patients could be in a more critical state reporting a higher mortality rate. Also, treatment approaches to COVID-19 have altered dramatically over the time of these studies and may have changed many of the outcomes in the first and second infections reported in this study. This may have accounted for some of the differences in ICU treatment or clinical outcome. Likewise, the number of unique outcomes, be it ICU admissions or deaths, were minimal with only about 10 cases or less total in either the primary infection or recurrence (of 577 total). That makes examining differences between first and second infections difficult and clearly predisposes to a type-two error, especially given the variations in case definitions between the studies.

COVID-19 first infections and reinfections observe a similar clinical spectrum and management regimen with a slightly higher severity reported during reinfection in the form of requirement for mechanical ventilation and ICU admission. There lies a need for much closer scrutiny of reinfections globally with individual patient data analysis to derive determinants of reinfection incidence and disposition to a severe infection.

Supplementary Materials: S1 Table: Search Strategy for MEDLINE. S2 Table: Characteristics of included studies (N=81). S3 Table: Quality assessment of case reports and case series (N=81). 

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J o u r n a l P r e -p r o o f Highlights: COVID-19 reinfection is not a phenomenon to be taken lightly.  81 studies from 22 countries reported PCR confirmed infection and re-infection.  The average reported time duration between first infection and reinfection was 63.6 (±48.9) days.  A higher ICU admission rate was observed in reinfection compared to first infection.  Complete recovery rate after reinfection stood at 97.9%.J o u r n a l P r e -p r o o f

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