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Epidemiological Research Study Review No. 1

SARS-CoV-2 Infection & Pulmonary Tuberculosis in Children and Adolescents: A Case-Control Study

PMHNP Post-Master

NGR5674-Population Health, Epidemiology, & Statistical Problems

Professor Diane Gullett, RN, PhD, MSN, MPH

July 9, 2023

Epidemiological Research Study Review No. 1

The purpose of the review of “SARS-CoV-2 infection and pulmonary tuberculosis in children and adolescents: A case-control study” (2023) using a critical appraisal tool is to analyze the assertiveness of the study and research through a structured checklist that make an evaluation of the methodology against the set of criteria to provide theoretical and clinical quality. The present review covers the analytical appropriateness of the design and results evaluation.

Citation

Swanepoel, J., van der Zalm, M.M., Preiser, W. et al. (2023). SARS-CoV-2 infection and pulmonary tuberculosis in children and adolescents: a case-control study . BMC Infect Dis, 23, 442. https://doi.org/10.1186/s12879-023-08412-8

Study Design: Observational unmatched case-control study

Level of Evidence: IV

Introduction/Background

Rationale Provided for Study

As a result of the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-Cov-2) pandemic, it is possible that the risk of exposure to the disease can influence in the increase of the occurrence of infection with Tuberculosis (TB) in children and adolescents not only due to the physiologic affectation but also as a consequence of the exposure and the fragmentation of the medical/clinical services. The study pursues to determine if an exposure is associated with such outcome.

Significance of Study Provided

As both diseases are influenced by bio-social determinants where exist probable directional consequences in the risk factors and the incidence of morbidity and mortality, the study is focused on determining whether an association exists between previous SARS-CoV-2 infection and odds of TB to establish a clinical understanding between such relationship.

Current State of Science or Evidence clearly Articulated

The research with emphasis on the correlation between exposure to SARS-CoV-2 and TB has not completely understood and investigated. Not only SARS-CoV-2 is a novel disease which health implications at the long-term demand new study but also TB for child and adolescent has remained as an area neglected by research and programmatic prioritization. Only one cohort study and one clinical study (from same population) have provided some findings which take both different conclusions about the clinical evidence of the immune response in terms of association from the exposure between both diseases.

Problem Statement/Area Identified

According to the authors, “the association between pulmonary TB and past SARS-CoV-2 infection remains understudied.” (Swanepoel, Van Der Zalm, & Preiser et. al., 2023). The reduction of immune responses either due to the infection processes or the effect of pharmacological and/or clinical interventions in combination with risk factors to disease infection reveals that “hyperinflammatory environment, induced by SARS-CoV-2 infection, could potentially accelerate TB disease progression.” (Swanepoel et. al., 2023).

Research Purpose

The purpose has been established as “to determine whether an association exists between previous SARS-CoV-2 infection and odds of pulmonary TB disease in children and adolescents from a high TB burden setting” (Swanepoel et. al., 2023)., including the evaluation of autoimmune response through IgG measures, and the odds of pulmonary TB disease.

Design

Research Question

The research question for the current study is not stated even thought the dissertation seeks for the exploration and explanatory findings that correlate and demonstrate the relationship between the exposure of SARS-CoV-2 infection as risk factor for complication of TB. In this form, the implicit research question pursues the accuracy of relation in terms of infection rather than to establish any prognosis, diagnostic, or treatment. As TB can have a long latency period between an exposure and outcome, the intention for a precise research question to match the study design is placed on the attribute of interest and a single outcome.

Cases

The cases have been clearly defined from previous census of a cohort study in a region and group (Umoya and Teen TB) from the period of one year (November 1st, 2020 to November 1st, 2021). The case definition has been established as “primary diagnosis of newly diagnosed pulmonary TB, with or without HIV co-infection, was made in a hospital or clinic and patients were within the first 14 days since diagnosis.” (Swanepoel et. al., 2023). In this way the cases were based on the prevalence according that the cases consider new and preexisting within the population at the specific time rather than the choice of new cases (incident). For the study, the overall cases are referred, however, from the incidence of TB in the region at 681/100,000 (2015) (Swanepoel et. al., 2023).

	Teen TB	Umoya	Combined
	Cases n (%)	Controls n (%)	Cases n (%)	Controls n (%)	Cases n (%)	Controls n (%)
Overall	50	51	14	48	64	99

From the same population, once the groups have been defined, the cases (and controls) are evaluated using the inclusion and exclusion factors. The sample considered one-hundred-and-one adolescents and 86 children. Among the 86 eligible participants from the Umoya study, 24 children were excluded while the remaining from the total 163 individuals (sixty-four individuals with pulmonary TB and 99 individuals without pulmonary TB were included. were gathered from the Teen TB study. In terms of proportion from the population, it is not provided a data which serve to conclude the real equivalence but referred those cases where pulled from the system which deliver health services to 30% of the regional population (Swanepoel et. al., 2023).

Controls

Controls have been established as “individuals younger than 20 years of age from similar epidemiological contexts as TB cases who were evaluated closely and found to not have current TB disease” (Swanepoel et. al., 2023). The number of controls also was redefined under the inclusion and exclusion functions and estimated according to similar range to compare with the cases. They were pooled from similar populations and gathered from the same studies as the cases. The proportion of controls are not defined in the relation to the control in an explicit method; however, the independence from the risk factor of exposure seems like the controls have been sampled in a way that their independent of the exposure, from their selection, have not been more (or less) likely if they have the exposure of interest.

Exposures

The exposure to has been ascertained by the detection of quantitative SARS-CoV-2 anti-spike immunoglobulin G (IgG) which means that the individuals have been exposed in the last 14 days to SARS-CoV-2. The results of such exposure to the risk factor are supposed to increase the likelihood of allowing the transition from latent to active TB. The measure is developed through serological assay according to the manufacturer’s protocols (tests) and blinded to clinical characteristics where values≥50 and <50 were defined as positive and negative respectively (Swanepoel et. al., 2023). However, exposure can be linked to facts of misclassification due to the potentiality of other viral infections such as Human Immunodeficiency Virus (HIV), influenza, and measles to an increased risk of TB disease in same population by inducing immunosuppression. The exposure determination is similar for cases and controls considering person, time, and place.

Sampling, Variables, & Level of Significance

The sampling in size is proper for evaluation and contrast against previous studies (cohorts) and for the microbiologic confirmation of pulmonary TB disease against healthy individuals exposed to an infectious case of pulmonary TB in their household. With 164 individuals among cases and control, the sampling satisfies the normal distribution. The samples utilized baseline clinical data collected from the participants, but serum samples are collected as part of the biorepository and stored for later analysis. Nevertheless, the study considers a variable which is not included in the research criteria according to the HIV status of case, control, and environment (with or without HIV co-infection). P value from a likelihood ratio test for trend with a significance level of 95% (Swanepoel et. al., 2023).

Data Management

Data was analyzed using STATA (version 17, College Station, TX, USA). The information was processed under the descriptive analysis to characterize the study population, comparing the case and control groups to identify differences between groups with respect to potential confounders. Univariable logistic regression was performed to calculate unadjusted odds ratios (ORs) and accompanying 95% confidence intervals (CIs) for each covariable. A Mann-Whitney U-test was developed to assess whether the distribution of SARS-CoV-2 IgG

values differed between case and control groups. The analysis plan was established to find any association because of the risk factors combining dataset and different combination of controls (Swanepoel et. al., 2023).

Results/Findings

Comparison of Cases vs Controls

The statistical procedures calculate the relationship between exposures and the likelihood of becoming ill in a given patient with exposure to SARS-CoV-2. Both, cases and controls, are pulled from the same population where bio-social descriptors entail a mixed ancestry, age group, sex, household size, socioeconomic environment, risks of exposure, and comorbidities with diseases (HIV). However, the study recognizes that in the comparison between cases and controls, the outcome comparison was not possible to adjust for sex (differences) or HIV status due to the small number of cases in the model of statistical inference by estimating the distribution of log-transformed viral-specific IgG response values (Swanepoel et. al., 2023). The particular control recruitment functions is different for one group (Teen TB) based on they were recruited to the study later than cases.

Confounders Distribution/Adjustments

The researchers recognize that there is also a risk of residual confounding in this study. SARS-CoV-2 and TB. Potential confounders such as sex and HIV status could not be included in the model examining the association between SARS-CoV-2 IgG due to the small number of IgG seropositive individuals with TB disease. The matching of cases and controls on key confounders such as age and sex were not possible to be estimated during the analysis and no adjustment were developed to measure confounding variables (with the exception of age), making difficulty to determine if both are equally distributed between cases and controls (Swanepoel et. al., 2023).

Sample Size, Power Analysis, & Strength of Association

Based on the sample size, there was no significant difference in the odds of pulmonary TB disease between those with SARS-CoV-2 IgG serology, SARS-CoV-2 IgG for seropositive and seronegative, and seropositive cases and controls median IgG value in the combined dataset. Statistical power in the hypothesis test, as the probability that the test will detect an effect, was determined at p-value of 0.04, 0.09, 0.21, and 0.18 for each sensitivity analysis respectively and in relation with the odds ratios estimated using unconditional logistic regression (Swanepoel et. al., 2023). The study was inadequately powered to investigate the main study associations.

Accuracy

The accuracy of the estimation through the association between the exposure and outcome was establishes for the unadjusted at 95% CI in each group and combined at 0.14, 0.54, and 0.36 while after the adjusted OR with same significance it remains at 0.81 with combined at 0.9 (Swanepoel et. al., 2023). This represents an issue to validate the correlation from exposure to development of the disease (from latent to active). A case-control study can help to test a hypothesis about the link between a risk factor and an outcome, it is not as powerful as other types of study in confirming a causal relationship.

Bias/Confounders

The researchers were unable to identify all potentially critical confounders, referring that many potential confounders that need to be considered when investigating associations between these two infections. They also pointed out that the risk of selection bias and residual confounding in the study were high due to the biases associated with the types of controls selected. Using inclusion/exclusion criteria was not enough to influence over the appropriate data collection method (selection bias), regardless the data was integrated from cohort studies. Particular assertion is taken from symptomatic controls in the incidence of hospital admission, which increases the risk of acquiring SARS-CoV-2 (information bias) (Swanepoel et. al., 2023).

Implications of Findings/Results

Once the datasets were combined and adjusted for age group, sex, and household size, there was not possible to find evidence of a relationship between previous SARS-CoV-2 infection and pulmonary TB disease. However, by using IgG antibody response, it appears that serological response to SARS-CoV-2 amongst cases with serological evidence of previous infection demonstrated an increased odds of pulmonary TB disease. The potential application, in addition to be the first study in the region which evaluate relationship between risk factors of SARS-CoV-2 and TB, is the generalization of these findings as references in others high TB-burden settings, and how the virulence, dysregulation of immunological responses, and severity of new SARS-CoV-2 infections can increase the risk factor for progression to TB disease or increases susceptibility to infection (Swanepoel et. al., 2023). The researchers´ recommendations not only emphasizes the growing body of knowledge on the association between two infections but adds with the finding the necessity to generalizable same type of study to more settings.

Strengths

A strength of the study includes the use of a serology testing strategy that allows for the interpretation of an exposure-outcome temporal association but has the weakness of evaluation of serum samples from individuals with TB who were within the first 14-day since diagnosis which affect and reduce the chance of detecting IgG antibodies against SARS-CoV-2

acquired after the diagnosis of pulmonary TB disease was made. Another strength is the inclusion of more controls than TB cases from the same cohort study (Swanepoel et. al., 2023).

Limitations

Based on researchers´ analysis, they determine that the study was inadequately powered to investigate the associations, influence probably by the interference of random errors. The Teen TB and Umoya studies provided different control groups, including the ineffective background frequency selection for SARS-CoV-2 IgG seropositivity samples which differ between the control groups and the general population (as the proportion could not be defined). Moreover, the matching of cases and controls on key confounders such as age and sex were not possible evaluated (Swanepoel et. al., 2023). For the data management and analysis methods, the sampling differs in some controls from the Teen TB group in place and time, leading to the occurrence of bias, including the facts that IgG ranges for the cases cannot be generalized due to the differences in SARS-CoV-2 transmission dynamics.

Ethical/Legal

The research accomplishes to follow the Declaration of Helsinki and South African Guidelines for Good Clinical Practice. Ethical approval for the project was obtained from several institutions according to the Committee´s approval and protocols. For samples access, all parents/legal guardians/participants in the studies provided written informed consent for their data and samples, establishing protection of individual´s rights. It was not necessary to receive approval for consent for publication and the authors does reveal any competing interests. The research provides human subject protection during for communication with cases and controls, but it does not address the healthcare orientation for those who tested positive for active TB.

Reflection

The case-control study is fair in the provision of scientific merit for a research report but has a poor applicability to clinical decision making. The study was unable to demonstrate convincing evidence of relationship between the exposure to SARS-CoV-2 for development of active tuberculosis. Several flags were detected in the revision of cases and controls groups, statistical inferences in the tabulation, power analysis, confounders, and bias. It is recognized as the first epidemiologic study which evaluates the relationship between both diseases. Then, the analysis can be conceptualized as being undertaken on a reconstructed source population from which cases and controls stem as well as the matching between the exposure-outcome distribution.

References

Mhaskar, R., Emmanuel, P., & Mishra, S. et. al. (2009). Critical appraisal skills are essential to informed decision-making. Indian J Sex Transm Dis AIDS. 30(2):112-9. doi: 10.4103/0253-7184.62770.

Porche, D. J. (2023). Epidemiology for the Advanced Practice Nurse: A Population Health Perspective. Appendix E: 327-328

Swanepoel, J., Van Der Zalm, M. M., & Preiser, W. et. al. (2023). SARS-CoV-2 infection and pulmonary tuberculosis in children and adolescents: a case-control study. BMC Infectious Diseases, 23(1). https://doi.org/10.1186/s12879-023-08412-8