Abstract: On March 11, 2020, the World Health Organization declared the coronavirus disease 2019 (COVID-19), whose causative agent is the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a pandemic. This virus is predominantly transmitted via respiratory droplets and shed via sputum, saliva, urine, and stool. Wastewater-based epidemiology (WBE) has been able to monitor the circulation of viral pathogens in the population. This tool demands both in-lab and computational work to be meaningful for, among other purposes, the prediction of outbreaks. In this context, we present a systematic review that organizes and discusses laboratory procedures for SARS-CoV-2 RNA quantification from a wastewater matrix, along with modeling techniques applied to the development of WBE for COVID-19 surveillance. The goal of this review is to present the current panorama of WBE operational aspects as well as to identify current challenges related to it. Our review was conducted in a reproducible manner by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews. We identified a lack of standardization in wastewater analytical procedures. Regardless, the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) approach was the most reported technique employed to detect and quantify viral RNA in wastewater samples. As a more convenient sample matrix, we suggest the solid portion of wastewater to be considered in future investigations due to its higher viral load compared to the liquid fraction. Regarding the epidemiological modeling, the data-driven approach was consistently used for the prediction of variables associated with outbreaks. Future efforts should also be directed toward the development of rapid, more economical, portable, and accurate detection devices.

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