Abstract

Haider Nulwala*

ABSTRACT

Secondary infections have emerged as a defining yet under-recognized dimension of the COVID-19 pandemic, driven by the profound immunological and clinical disruptions caused by SARS-CoV-2. Beyond direct viral pathology, COVID-19 induces sustained lymphopenia, T-cell exhaustion, impaired interferon signaling, and dysfunctional innate immune responses, collectively weakening host defenses and creating highly permissive conditions for opportunistic, latent, and multidrug-resistant pathogens. These immune alterations enabled several infections to behave with unusual aggressiveness and contributed substantially to clinical deterioration in vulnerable patients. This review synthesizes current evidence on the unusual and clinically significant bacterial, fungal, viral, and protozoal infections that surfaced with unprecedented frequency during the pandemic. Prominent patterns included post-COVID reactivation of Mycobacterium tuberculosis; ICU-associated outbreaks of multidrug-resistant Klebsiella pneumoniae; explosive surges of mucormycosis and COVID-associated pulmonary aspergillosis; global expansion of Candida auris; and increased reactivation of latent viruses such as VZV, CMV, and EBV. Additionally, steroid-triggered Strongyloides stercoralis hyperinfection emerged as a severe complication in endemic regions, underscoring the unintended consequences of widespread immunomodulatory therapy. Together, these infections significantly amplified morbidity and mortality, often presenting diagnostic challenges due to overlap with severe COVID-19. Understanding how SARS-CoV-2 alters pathogen behavior is essential for improving diagnostic vigilance, strengthening ICU infection-control practices, optimizing antimicrobial stewardship, and enhancing preparedness for future respiratory pandemics. The insights summarized here highlight the need for integrated multidisciplinary strategies to prevent, detect, and manage secondary infections in the evolving landscape of COVID-19 and beyond.