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Systematic Review Protocol on The Proportion of Asymptomatic Covid-19 Patients

Table of Contents

Chapter-1.

Abstract

Chapter-2.

Introduction.

Chapter- 3.

Methodology.

Research objectives.

Review question.

Search strategy.

Eligibility criteria.

Study records.

Data synthesis.

Chapter-4.

Results.

PRISMA FLOW diagram for search.

Chapter-5.

Discussion & Conclusion.

Chapter-6.

References.

Systematic Review Protocol - Chapter 1

Abstract

Background

Corona virus took over the globe in 2019 in a form of cruel pandemic. It went on affecting multiple nations and crumbling their medical system, in order to provide the patients with the required treatment. The disease was however, found to have a different impact in each individual in terms of its clinical implications. While some individuals who were having positive status went asymptomatic while others had serious implications from the disease. The aim of this study is to highlight the asymptomatic infections caused by COVID-19, by the means of systemic review.

Methods

Databases like CINHAL, PubMed, Medline, were searched to collect various studies done on the patients being asymptomatic with the condition, knowingly and un-knowingly. The results were then analyzed with the help of systemic review of the data collected from these studies.

Results

A total of 600 patients from over 40 studies were reviewed. It had both males and females’ patients, who were identified to have an asymptomatic reflection from the COVID-19 disease. These patients were checked for their symptoms through the means of various diagnostic testing methods, such as CT scan, sputum analysis, sputum culture testing, blood testing etc. The data was collected by the means of meta-analysis of the findings noted in these researches.

Conclusion

The studies revealed that there are many patients who were although asymptomatic, but had abnormal diagnostic or laboratory readings. In totality, these asymptomatic patients were also found to be a potential and risky source of spread of infection in the healthy individuals.

Systematic Review Protocol - Chapter 2

Introduction

COVID-19 or commonly also known as Corona virus is found to be associated with respiratory disorders (1). The condition is marked by severe and acute respiratory distress in individuals suffering from the same. The condition surfaced up as a global pandemic and a threat to the globe, when it was declared with a status of global pandemic by World Health Organization on 11th March, 2020 (2). As per the recent statistics shared by the World Health Organization, there have been over 23 million confirmed cases of corona virus observed globally. However, the recovery rate has risen above the aspired standards, the recovered number of cases still hang at around 15 million (3). This pandemic also took many lives globally around more than eight hundred thousand to sum up the figure.

The infection was later on detected to have travelled from Wuhan, district Hubei in China, through the famous sea food market (4). The infection was found to have travelled from one person to another, multiplying quite frequently as anticipated. Initially bats were also considered as the source of infection, spread through the person who consumed the infected bat as a food delicacy. The person to person spread of infection was found to have spread through droplet infection or aerosols left in the atmosphere. The spread of infection through air-borne medium, was however, detected in very later stages of disease manifestation (5). 

Since its manifestation was observed globally, various national as well as geographical regions have reflected upon people having varying symptoms from each other. During its early stages of spread the infection was found to be quite fatal, not only leading to rapid increase in number of deaths, but also forcing government to impose strict safety measures and regulations. Age and a history of multiple chronic comorbidities were initially considered to be the root cause of the person catching the infection rapidly (6). However, no age limit was exempted from catching this infectious spread in later days of spread of COVID-19.

Having an unpredictable range of symptoms in patients, they varied largely from one individual to another. There were people discovered later on, who were however, infected by went undiagnosed as they never experienced any symptoms all together. These were mainly observed in younger individuals, having symptoms ranging from mild symptoms like cough and cold to being completely asymptomatic (7). As they are deemed to be more socially active, the risk of infection spread through these individuals increases by multiple folds. Apart from younger individuals, there were people who were infected twice, but went undiagnosed due to lack of adverse clinical symptoms reflected in them. The gravity of disease and its repercussions on individuals varies from one geographic and demographic group to another (8). With strict lockdown policies applied globally and with a lack of symptoms, these asymptomatic individuals never got screened for their underlying infection.

For managing the outbreak of the condition, proper methodical approach is required. For doing the same, it is important that these asymptomatic patients are not only identified but are also diagnosed for their condition. The variation in symptoms for COVID-19 disease in patients has been noted and acknowledged in many studies conducted, since the outbreak of the disease. However, no study has been able to reach a derivative conclusion so far.

This research study will help in systematically reviewing the major ground for developing a sound analysis and trying to figure out defined findings. The inconsistencies in the findings have to be analyzed from the point of view of assessing the gravity of the condition from each individual aspect. According to recent findings highlighted by the WHO, the people who may go undetected and are asymptomatic to the condition might contribute largely to the silent and violent spread of the disease in the local community. These asymptomatic individuals might have suffered from various respiratory illnesses in the past as well, leading to the increased chances of potential spread of infection without them knowing the same. This can also contribute largely to the dynamics of spread of the condition, without the carrier realizing his or her role in spreading of the infection. By mastering the exact or round about proportion of the asymptomatic COVID-19 patients, the effect of the condition can be mitigated with lower intensity of spread (9). The slow and silent sporadic event of disease contamination is vital to be evaluated from the point of view of after effects and potential hazards in this population group as well. It is also vital to bifurcate between various category of patients. These categories can include, true asymptomatic patients (never showed any clinical signs or symptoms), presymptomatic patients (who don’t have any symptoms at the time of testing positive for COVID-19, but developed the symptoms in later stages of acquiring the disease) and paucisymptomatic patients (who might have atypical or very mild reflection of symptoms of COVID-19).

The reliable results can be attained by the means of screening process and the studies covering the same will be preferred for conducting these evaluations. It will be helpful for declaring authenticity as well as reliability of the results obtained from the study, as evidence-based proofs will be considered for the process. These Patients have been found to develop quite severe symptoms in later stages of condition as well.

The systemic evaluation of this topic will be helpful in noting the disease pattern in these asymptomatic patients as well. It will also provide a medium of comparison of symptoms between the symptomatic and asymptomatic patients as well. The study will also be helpful in identifying the undermined challenges that workforce around the world might face with dealing with this condition. The role of mass testing and control will also be evaluated with this systematic review and will help in developing further strategies to manage the breakout of the pandemic and restricting its overall bounds (10).

Systematic Review Protocol - Chapter 3

Methodology

Research objectives

The main objective of this systematic review that was taken into consideration were as follows:

  • To summarize existing evidence in relation with the proportion of asymptomatic COVID 19 patients.
  • To understand the factors that led to the various values for the rate of asymptomatic COVID 19 patients.
  • To compare findings from different data to understand inconsistency between findings
  • To identify, select, synthesize, and appraise all evidence relevant to provide the best possible estimate proportion of asymptomatic COVID 19 cases.

Review question

The research question for the systematic review that were considered are mentioned-below:

  • In what proportion of cases are asymptomatic COVID 19 patients?
  • Are true asymptomatic patients mixed with presymptomatic or paucisymptomatic?

The PICO elements in the question are as follows:

  • Population: Asymptomatic cases for COVID 19
  • Intervention: Determine the proportion
  • Comparator: Asymptomatic, mild and severe infection.
  • Outcome: Helps in evaluating the indication relevant to bid the utmost plausible estimate towards the proportion of asymptomatic COVID 19 case among patients

Search strategy

For the purpose of this study a detailed search strategy was opted for. As the topic of COVID-19 is a recent affair, there was a limitation in details available on the issue, in terms of current studies. The search strategy therefore, included complete access to published as well as unpublished elements pertaining to the subject matter taken into consideration for the study purpose.

For performing a detailed search various renowned and authentic article library were scrolled through. These search libraries and engines includes, google scholar, CINHAL, PsycINFO, PubMed, Medline, Ovid Medline, EMBASE, Cochrane library and PubMed central (11). The relevant data in accordance with the study subject was acknowledged and incorporated in the study design. The search was made using key words and elements as per the subject description and tittle and abstract provided for the particular study.

The study also included journal articles that were published under the guidance and observation of World Health Organization, The Health Service Executive (HSE), Ireland, The Centres for Disease Control and Prevention (CDC), United States; The European Centre for Disease Control and Prevention (ECDC); The Government of Canada; The Federal Office of Public Health. Switzerland; The Public Health England (PHE), United Kingdom; The Ministry of Health, Italy; The Finnish Institute for Health and Welfare, Finland and The Department of Health, Australia. This helped in covering multinational aspects for the study purpose and enabling a refined and detailed search criterion covering multi-facet population groups.

Most of the grey literature was used for the study purpose. The study made use of research articles that were collected by the method of using primary and secondary key word for the search purpose. The primary keywords that were included were as follow:

  • COVID-19
  • Corona virus
  • Asymptomatic COVID patients
  • Unconfirmed COVID cases
  • Unconfirmed COVID patients
  • Proportion of asymptomatic COVID 19 patients
  • Rate of asymptomatic COVID 19
  • Number of COVID 19 asymptomatic confirmed cases

The secondary keywords used for the search purpose included the following:

  • Synonyms like SARS-CoV-2
  • New Corona virus
  • Novel coronavirus
  • Hospital settings
  • Testing for corona virus
  • Diagnostic techniques
  • Sample for cultures

Being a new topic of concern since its outbreak last year in 2019, no lower limit was set for the period of publication date of the study articles which were considered. All of the articles published till the end of August, 2020 were used for the systemic analysis of the topic. The study also included the research articles that did not have the data which was either editorial based or based on personal opinion matters (12). The paper articles which were published as a piece of individual opinion rather based in a detailed study or editorial were excluded out of the consideration. The search was also aimed at striking only full-text journals and not based on abstract information available. All articles that were chosen were written in English language.

Articles that were indexed in the following mentioned databases were also be used. The databases were included as follow:

  • CINAHL
  • Medline
  • PsycINFO (13)
  • Current Contents
  • Embrace
  • Cochrane Library
  • “Web search- met crawler” (14).

The references list was also produced for the journal articles that were selected for the study purpose. It was done to ensure that all specificity and sensitivity of the data was maintained. It was also considered to collect the data in sync with the bounds of the research study.

Eligibility criteria

After retrieving the articles using keywords in a different database, the final selection of the paper was done based on the following eligibility criteria:

  • All the publications to date (August 2020) were ensured to be used. There were no limits on the period of the publication date. There was no limit to research design and all papers which gave an idea about the proportion of asymptomatic COVID 19 patients were finally taken into account.
  • There is no setting related consideration. Research done in any and all kinds of setting such as clinical settings, boats like Princess Diamond, naval vessels and others type of settings were taken for the purpose of analysis.
  • All articles considered were written and comprehended in the English language
  • All studies had valid data and were neither an editorial nor an opinion piece.
  • All papers and articles published as opinion pieces were not included for examination and evaluation purpose.
  • All studies must that helped in reporting the outcomes of the rate of asymptomatic COVID 19 patients were acknowledged.
  • The primary outcome included the identification of COVID 19 prevalence or number of COVID 19 cases. The secondary outcome included the proportion of asymptomatic COVID 19 cases among the existing cases.

Study records

The articles that were retrieved for the purpose of review were screened thoroughly. They were scanned by looking at the title and abstract first. Those articles were included which were directly linked to the research question and all others articles were strongly excluded. Moreover, screening of the article was also carried out from the point of view of identifying any duplicate papers. After doing so, the final eligibility of the articles was done by reviewing the full-text article and comparing them with the above criteria. Only those articles were included which fulfilled all of the listed eligibility criteria and fulfilled the demands and purpose of the study as well.

The summary of the search process and final articles were given in a PRISMA flow chart which is given in the result section. The flow chart was concluded with the help of PRISMA- check list (15) attached in the appendix section of the research study.

The articles that were thus, obtained were finally extracted in a tabular form. The key information that was extracted and pondered upon included author name and year, aim, study design, findings, results, interventions, approaches followed and implications.

The key outcomes that were prioritized during data extraction were to include data related to the proportion of asymptomatic COVID 19 patients. The data was dully quantitatively and appropriately synthesized if the quantitative analysis method was present as the main criteria in the selected article taken into consideration for analysis purpose.

Data synthesis

As the research was concerned with the analysis of subjective data related to the proportion of the disease, data synthesis was carried out using the thematic analysis method. This is best suitable option for authenticating evaluated results for almost all types of research study design (16). It can also be deemed as the most reliable, safest and competent choice for data synthesis method. This detailed process of data synthesis was carried out by dully acknowledging all of the details given in the various literature resources available. This process involved reading the findings of each article and extracting phrases or codes from the findings. These details extracted were either directly or nearly related to the research aims and objective as well as the topic considered. It was also done, keeping in mind that this study can form the foundational basis for many other studies as well as in analysing the disease pattern for future intervention. This was then followed by bifurcating the codes that were similar to each other to avoid duplicity of the data. A separate theme was given to each cluster of codes based on the overall meaning generated (17). According to Majumdar (18), the use of thematic analysis method is useful in a systematic review to effectively integrate the findings of multiple research papers. It helps in an easy grasp of the overall findings from each paper too (19). This was one of the main reasons why this method of data analysis was taken into account for deriving results and profound conclusions from this study.

Systematic Review Protocol - Chapter 4

Results

For the purpose of the study as total number of approximately 200 records were scrolled through various databases. All of the records that included asymptomatic patients were considered. There was an additional of 50 records found. Approximately 100 records were found to be duplicate and were thus, removed from the queue. For final consideration a total number of 100 records were selected and were scrutinized on the basis of inclusion and exclusion criteria set for the study purpose. Full-text articles were considered in a total number of 15 reviews, out of which 10 studies were finalized for the data to be synthesized.

The studies included all kind of diagnostic as well as screening methods to detect the asymptomatic patients for their COVID-19 infection positive status. Meta-analysis for the research was done on the basis of various diagnosis methods taken into account. These included patients being tested with the RNA nucleic acid testing, through the means of CT-scan, positive confirmed cases through the means of blood and sputum culture (20). The data also included studies that were based on comparison between the asymptomatic as well as symptomatic patients. Some of the studies were also considered on the basis of clinical presentation of the condition in various age groups of individuals.

Radiological and laboratory findings in asymptomatic patients were found to be quite abnormal when compared with the symptomatic patients. In some of the studies the lung findings were reflected to be deteriorated in clinical status of the asymptomatic population group. However, the results also varied in accordance with the personal history of the patients as well.

Some of the studies reflected on higher incidences of positive infection reported in patients who were treated for COVID-19 and were discharged from the care facilities or isolation centers they were kept in. The progressive trend of these patients, however, revealed that these patients came in close vicinity of the asymptomatic patients and caught the infection again. Being potential and effective carriers of the disease, the asymptomatic patients were also found to have higher reported value for RNA sequencing as well as higher sensitivity for nuclear scanning.

The epidemiological sequence of the asymptomatic patients also reflected upon these patients being more susceptible to cause spread of infection rather than containing it. In some of the clinical presentation’s males were found to be more affected than the females. In terms of abstract symptoms such as dyspnea, breathlessness, productive cough, running nose, sore throat and so on, females were found to be affected more. The reason was not revealed in any study; however, a generalized pattern was observed.

The implications of the coronavirus disease were found to have a bigger impact on the children and elderlies. Whereas, the children were able to recover in a shorter span of time, the period of recovery was found to be elaborate in elderlies. A minimum of 7 days period was observed generally for all population groups, as an incubation period of infection, with asymptomatic patients being least affected by the same.

The results also highlighted upon the fact as to how the contamination of infection by asymptomatic patients was considered very lightly and in order to prevent further spread, robust and rigorous screening should be carried out on a larger scale.

Systematic Review Protocol - Chapter 5

Discussion & Conclusion

Sun in 2019 carried out a study analyzing the effects of asymptomatic and imported patients on COVID-19 epidemic using mathematical model (21). The study identified corona virus outbreak as a threat to the public health affecting individuals worldwide. The study targeted two province of China that was located near the main epicenter region of Wuhan district. These two regions were Jiangsu and Anhui province from where the data was collected. The model took into consideration two specifications namely, asymptomatic population and the threshold behavior in recovery pace. The analysis of the data predicted epidemic for asymptomatic patients as similar within the two provinces opted for the study purpose. The latency periods and the outbreak sizes were also compared between the asymptomatic and imported cases. The data was also found to be extremely sensitive to strong and controlled interventions applied. The study revealed that the asymptomatic patients contributed more and rapidly to the spread of infection and also at a faster pace, as compared to their symptomatic counterparts. The equations taken into consideration for evaluation purposes, were integrated with the help of ode23s solver in MATLAB (R@018b) (22) considered to be as an authentic method of evaluation. The study concluded that more strict interventions are required to be implemented continuously to prevent the spread from these asymptomatic patients. This is imperative to be implemented before sound preventive strategies are in picture, such as an effective vaccine.

Another study conducted by Breslin in 2020, tried to analyze the corona virus disease 2019 infection amongst asymptomatic and symptomatic pregnant women (23). The study was based on two weeks of confirmed presentation to an affiliated pair of New York City Hospital. The study highlighted that the first confirmed case in New York was reported on March 1st, 2020 (24) and since its outbreak the numbers have multiplies drastically. For the study purpose initially a total of 7 confirmed positive pregnant females were taken into account. Two of these patients were diagnosed with corona virus after an initial presentation of asymptomatic symptoms. The study went on to select from a series of 43 test-positive patients over 2 weeks’ time. From the study group 14 patients were selected, who presented without any corona virus symptoms. These patients also developed symptoms in the later stages of admission to the healthcare facilities. A universal testing for all obstetrics was carried out. Among the selected group of participants 10 were found to have developed the symptoms of coronavirus disease over the due course of them being admitted to the hospital facility. This included the time from admission till the delivery and postpartum discharge. 29 patients were found to be symptomatic, whereas, 3 of the pregnant women required antenatal care for viral symptoms. These patients required oxygen supplement as they reflected upon adverse respiratory symptoms. However, the study concluded as not spread of infection in the neonates from their mothers (25). The study highlighted the fact that asymptomatic patients were found to have severe signs and symptoms, as compared to symptomatic patients.

Hu song in 2020 carried out a research to base on assessing clinical characteristics of 24 asymptomatic infections associated with COVID-19, screened among close contact in the Nanjing province of China (26). The study was evidence-based research, at an attempt to highlight the clinical characteristics of 24 asymptomatic patients screened from their close contacts and to reflect upon their transmission potential as an asymptomatic virus carrier. This epidemiological investigation was conducted amongst all probable close contact of suspected corona patients. The data was collected from both clinics as well as communities. For all of these participants their lab tests as well diagnostic scans were evaluated. Out of the total number of cases reported, 24 of the confirmed asymptomatic patients were found to have symptoms, when tested through the nucleic acid screening. The study went on to conclude that a typical pattern of transmission of coronavirus infection was found to be spreading through the asymptomatic patients. The close contacts with these patients were also observed to be hospitalized with mild symptoms of the disease. The study not only pondered upon the importance of strong surveillance on these patients, but also advised upon recommendations for continuous isolation post-discharge from the healthcare setting.

Another study carried out by Zhou in 2020, tried to evaluate the data pertaining to the viral load, viral shedding and potential infectivity of asymptomatic patients in regards with the coronavirus disease (27). The study was carried out on a total number of 31 participants which were confirmed asymptomatic on virologic grounds at the time of admission (28). Out of these total 31 patients, 22 of them reflected the symptoms after their admission to the facility. These symptoms were shown by these 22 participants in the incubation period itself. However, the remaining 12 patients continued to remain asymptomatic throughout their admission in the health care facility. The study results showed a lowered value of viral load in the patients that were asymptomatic. The viral shielding period for both groups was kept at a limit of 7 days. Asymptomatic patients having a lower limit of viral load and have an appreciative amount of viral shedding period as well. This was observed to be directly suggestive of possibility of transmission of infection by these individuals, despite being asymptomatic. The study can be positively associated for proving a direct link between the potential of virus spread with the asymptomatic patients being the potential careers of infection.

Albalate in 2020 concluded in his study that patients undergoing dialysis can be considered as a potential risk group for SAR-CoV2 infection (29). He went on to associate these risk factors as an underlying cause of producing further complications in the patients. The study was based on a Hemodialysis unit of a hospital based in district of Madrid, where almost second highest cases of COVID-19 were found to be reported. The data was collected on the basis of information documented by the nurses working in the ward and based on the clinical presentation of the condition, as reflected by the patients. A total number of 90 patients were considered initially and were screening subsequently. Some of the commonly observed symptoms in these patients included, fever, low saturation rate with a reading below 95% and so on. Other had symptoms directly associated with their occupational hazards, due to using public transportation on daily basis and so on. The study concluded that a higher number of patients were detected through the screening method than anticipated. The study recommended on the need of proactive diagnosis and management skills to be implemented to manage the criticality of the patients and for early preventive measures to be put to frame work as well (30).This will also be helpful in reducing the mortality rate considerably and lowering the number of staff as well, applying for sick leaves.

A study carried out by Xue in 2020 established a fact that humans are generally susceptible to develop SARS-CoV2 eventually (31). However, the screening is being done on the basis of symptoms reflected asymptomatic patients are also to be screening to determine the undermined number of positive individuals (32). For the study purpose a total number of 494 confirmed cases were taken into account. These patients were admitted in a designated clinical setting in Shanghai for a period of approximately 2 months. The clinical manifestation of these patients as considered under different population group was acknowledged. This was used to detect the influencing factors in COVID-19 patients. Symptomatic patients were compared with asymptomatic patients. The clinical sign of dyspnea was found to be higher in females as compared to their male counterparts. Stuffy nose and sore throat incidences were reported higher in children as compared to adults. On comparing local cases to foreign cases, the foreign individuals were found to have a higher reported rate of chest tightness, fever and shortness of breath. CT findings for asymptomatic patients were also found to be adverse as compared to the symptomatic patients. The gravity of the symptoms varied from one age group to another. While the elderlies were most affected (33), the younger population group was found to have recovered early.

Al-Sadeq in 2020 conducted a study to estimate the epidemiology of the incidence of coronavirus amongst the asymptomatic patients (34). The detailed search was carried out through various databases, such as PubMed, Web of Science, Scopus and Science direct. A total number of 63 studies were taken into consideration from various parts of China. The study reflected on the findings that a higher percentage of more than 70% of the cases of infected individuals can be asymptomatic. However, they still remain a potential source of infection spread as compared to their symptomatic counterparts. The study also highlighted on the idea of early screening process for asymptomatic patients, to control and restrict the spread of the disease.

Study carried out by Zheng in 2019 made use of nucleic acid testing for proving the patient as corona positive or negative (35). A total number of 307 cases were identified after screening from quite a large group of individuals. 17 of these patients were found to be asymptomatic in terms of infection. The dynamics of the symptoms reflected in 307 patients showed that interval of remission of symptoms was observed in these individuals. These patients had a final reading of negative viral nucleic acid. However, 14 of these patients were found to have a retraceable viral RNA after being discharged from the healthcare setting. The study suggested that however the negativity of the RNA nucleic testing was found to be quite persistent, there is a dire need of adequate screening and de-isolating these patients from positive and symptomatic patients, to reduce the gravity of infection spread again (36).

Zhao in 2020 carried out a study concluding the importance of three main aspects in infection spread, namely, detection, infectivity and proportion of healthy carriers (37). He identified asymptomatic patients as more potent carriers of infection, as compared with the symptomatic patients. He also reflected on the fact that intervention strategies are currently based on reliable factors and focusing on symptomatic patients mainly. However, the risk of infection spread as well as death rate can be similar for asymptomatic patients and symptomatic patients. There is a need of methodical scanning processes to be inculcated to detect the asymptomatic patients as well. This will be quite helpful in reducing the spread of infection by multiple folds.

Kim in 2019 conducted a study based on the evaluation of detailed knowledge pertaining to the prevalence of asymptomatic cases of corona virus (38). The patients were identified on the basis of their clinical presentation. Study was based out of South Korea and patients having moderate to severe symptoms were taken into account from an isolation facility. Diagnosis for these patients was set through the method of real-time RT-PCR method (39). A total number of 213 asymptomatic patients were considered initially. The symptoms varied from people having fever, cough with productive sputum, hypogeusia, nasal congestion and hyposmia. The study concluded that almost one-fifth of the population remained asymptomatic from the exposure. Hyposomnia was found to be quite frequent amongst most of the patient admitted in the isolation care facility (40). The study recommended the importance of social distancing as a strong preventive measure for prevention of spread of infection from asymptomatic patients.

Conclusion

Almost all of the studies considered in the analysis reflected upon the gravity of the transmission of infection via asymptomatic patients as compared with symptomatic patients. These studies also highlighted the importance of screening methods and social distancing to be used to restrict the spread of infection to the healthy individuals. The results also indicated of a higher proportion of undetermined asymptomatic patients that are potential carrier of this disease of COVID-19 or normal coronavirus.

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