WHO has declared human mpox (formerly known as monkeypox) a global public health emergency since July, 2022. When case numbers were increasing, so did clinicians' exposures to new elements of the disease. Additionally, the burden of mpox is particularly apparent in immunocompromised patients, who can have more variable and severe manifestations of disease across organ systems. In this Grand Round, we report novel and severe oculocutaneous manifestations of mpox in this population, which are both sight and life threatening. Specifically, we highlight two patients with mpox and AIDS who had refractory skin necrosis that progressed to either ocular compromise or panfacial gangrene, or both. Both patients ultimately died due to systemic complications of their infections. Through clinical analogies, we show how past experiences with related orthopoxviruses, such as variola virus (smallpox) and vaccinia virus, can add useful context for understanding and treating these new disease states. We suspect that in patients who are immunocompromised, monkeypox virus can clinically evolve not only via viraemia but also through direct intradermal spread. We propose that intradermal spread occurs by a process clinically and immunologically analogous to progressive vaccinia, a complication previously seen after conventional smallpox vaccination. We share evidence in support of this theory and implications regarding early management and post-exposure prophylaxis for at-risk populations. Content note: this Grand Round contains graphic images of mpox lesions of the eyes and face.
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