The pandemic from the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) led to >170,000 deaths, including >14,500 in New York City (NYC) alone. This pandemic highlighted a pressing clinical and public health need for rapid, scalable diagnostics that can detect SARS-CoV-2 infection, interrogate strain evolution, and map host response in patients. To address these challenges, we designed a fast (30 minute) colorimetric test to identify SARS-CoV-2 infection and simultaneously developed a large-scale shotgun metatranscriptomic profiling platform for nasopharyngeal swabs. Both technologies were used to profile 338 clinical specimens tested for SARS-CoV-2 and 86 NYC subway samples, creating a broad molecular picture of the COVID-19 epidemic in NYC. Our results nominate a novel, NYC-enriched SARS-CoV-2 subclade, reveal specific host responses in ACE pathways, and find mediation risks associated with SARS-CoV-2 infection and ACE inhibitors. Our findings have immediate applications to SARS-CoV-2 diagnostics, public health monitoring, and therapeutic development.