Table 2. Understanding the burden for CMV–TB interaction.

Question	Knowledge gap (summary)	Potential study designs	Parameters and samples to be evaluated
How prevalent are CMV–TB coinfections, and what are risk factors for these infections?	- Quantifying the burden, timing, and outcome of TB–CMV coinfections across different sites and in different risk groups- Impact of co-factors on CMV–TB prevalence- Identifying individual risk factors associated with TB–CMV coinfection- Identifying individual characteristics associated with poor outcome	- Systematic review of existing literature- Cross-sectional and longitudinal cohorts (observational, diagnostic, and randomised intervention studies in humans nested within well-characterised TB cohorts) to quantify prevalence and risk factors for CMV–TB coinfection- Modelling studies to evaluate the number of deaths from TB–CMV coinfections, given number of cases, the proportion diagnosed, and expected mortality treated and untreated	Acute versus latent infection (CMV)- Viral detection: whole blood (EDTA) for viral load (PCR), respiratory specimen, and others- Serology (plasma/serum): quantitative IgG, IgM, and IgG avidity TB diagnostic workup:- TB microbiology- Immunoassays evaluating T-cell response- Novel biomarkers in blood and urine
How do TB, CMV, and HIV interact?	- Impact of HIV on prevalence of CMV–TB coinfections and disease course- Impact of CMV in HIV-infected on TB progression and clinical presentation- Impact of CMV–TB coinfection on course of HIV	- In vitro models including isolated cell populations and mechanistic models- Observational, diagnostic, and randomised intervention studies in humans- In vivo models including mouse and nonhuman primate coinfection- Longitudinal cohorts from varying geographical areas and with different patient populations	Acute versus latent infection (CMV)- Viral detection: whole blood (EDTA) for viral load (PCR), respiratory specimen, and others- Serology (plasma/serum): quantitative IgG, IgM, and IgG avidity- Evidence for exacerbation of TB disease or activation of latent TB infection in CMV/MTB coinfected animals TB diagnostic workup:- TB microbiology- Immunoassays evaluating T-cell response- Novel biomarkers in blood and urine HIV- Viral detection: whole blood (PCR)- CD4 and CD8 T-cell count (absolute, %)

CMV, cytomegalovirus; PCR, polymerase chain reaction; TB, tuberculosis.