Abstract
<jats:p>Background: Bromhexine hydrochloride (BRH) is a functional inhibitor of the host serine protease TMPRSS2, a key mediator of viral entry for SARS-CoV-2, influenza A and B viruses, and other respiratory viruses that utilize TMPRSS2-mediated proteolytic activation. While most antiviral strategies aim to prevent infection or suppress viral replication, partial modulation of host-dependent viral entry may represent an alternative approach that attenuates disease severity while preserving sufficient antigen exposure for adaptive immune priming. Methods and Clinical Observations: We describe a 72-year-old man who had received no SARS-CoV-2 vaccination after 2021 and had been taking bromhexine prophylactically (8 mg twice daily) for approximately two weeks before an incidentally diagnosed SARS-CoV-2 infection. The infection remained clinically inapparent apart from mild throat irritation. Despite the absence of clinically significant disease, the patient developed a robust humoral immune response, with an anti-spike antibody concentration of 2,080 BAU/mL three months after infection and persistent anti-spike IgG reactivity nine months later (Vircell anti-S IgG ratio 22.209). A parallel household observation involved his 71-year-old wife, who had multiple established risk factors for severe COVID-19, including chronic obstructive pulmonary disease, previous pancreaticoduodenectomy for pancreatic cancer, severe underweight, and a long history of heavy smoking. Despite continuous bromhexine prophylaxis and presumed household exposure, she remained clinically asymptomatic while demonstrating measurable anti-spike immune reactivity. Additional real-world observations from individuals receiving prolonged bromhexine prophylaxis, including elderly patients with multiple comorbidities, heavy smokers, and a child receiving seasonal prophylaxis, consistently demonstrated favorable tolerability together with absent or markedly attenuated clinically apparent COVID-19 and influenza. Hypothesis and Conclusions: These observations support the hypothesis of pharmacologically attenuated natural immunization, whereby partial inhibition of TMPRSS2 reduces viral entry sufficiently to attenuate disease without completely preventing infection, thereby preserving antigen presentation and promoting durable adaptive immunity. Rather than functioning as a sterilizing antiviral agent, bromhexine may shift the host–virus interaction toward controlled attenuation, reducing tissue injury while maintaining immune memory. These observations are hypothesis-generating and do not establish causality. Prospective controlled studies incorporating documented viral exposure, quantitative virological assessment, neutralizing antibody measurements, and comprehensive cellular immune profiling are required to determine whether TMPRSS2 modulation can reproducibly achieve controlled attenuation of respiratory viral infections while preserving long-term protective immunity.</jats:p>