Citation: Pane, S.; Putignani, L. Cryptosporidium: Still Open Scenarios. Pathogens 2022, 11, 515. https:// doi.org/10.3390/pathogens11050515 Academic Editor: Junhua Wang Received: 8 March 2022 Accepted: 23 April 2022 Published: 26 April 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). pathogens Review Cryptosporidium: Still Open Scenarios Stefania Pane 1 and Lorenza Putignani 2, * 1 Department of Diagnostic and Laboratory Medicine, Bambino Gesù Children’s Hospital, IRCCS, Unit of Microbiology and Diagnostic Immunology, Unit of Microbiomics, 00146 Rome, Italy; stefania.pane@opbg.net 2 Department of Diagnostic and Laboratory Medicine, Bambino Gesù Children’s Hospital, IRCCS, Unit of Microbiology and Diagnostic Immunology, Unit of Microbiomics and Multimodal Laboratory Medicine Research Area, Unit of Human Microbiome, 00146 Rome, Italy * Correspondence: lorenza.putignani@opbg.net Abstract: Cryptosporidiosis is increasingly identified as a leading cause of childhood diarrhea and malnutrition in both low-income and high-income countries. The strong impact on public health in epidemic scenarios makes it increasingly essential to identify the sources of infection and understand the transmission routes in order to apply the right prevention or treatment protocols. The objective of this literature review was to present an overview of the current state of human cryptosporidiosis, reviewing risk factors, discussing advances in the drug treatment and epidemiology, and emphasizing the need to identify a government system for reporting diagnosed cases, hitherto undervalued. Keywords: Cryptosporidium; zoonosis; humans; animals; transmission; epidemiology; treatment; drug; vaccine 1. Introduction In the early 1980s, Cryptosporidium spp. was observed as a pathogen affecting both hu- mans and animals and as a cause of acute gastroenteritis, abdominal pain, and diarrhea [1]. Cryptosporidiosis is mainly transmitted via the fecal-oral, zoonotic, or anthroponotic route, through contaminated water or food [2]. Due to the presence of multiple transmission routes, the epidemiology of cryptosporidiosis is complex (Figure 1). Indeed, the investiga- tion of both sporadic cases and outbreaks has contributed to a better understanding of risk factors and infection sources [3]. For example, cryptosporidiosis is increasingly identified as the leading cause of chronic diarrhea in immunocompromised patients and as a cause of infant malnutrition and premature death in children [4]. Despite this, parasitosis is sub- stantially underdiagnosed and underestimated, lacks standardized preventive protocols, and requires optimal treatment on a large scale. Today, nitazoxanide is the only drug approved by the US Food and Drug Administra- tion (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) for the treatment of cryptosporidiosis in immunocompetent people, but its use is not conclusive in young children and immunocompromised individuals [5–7], thus having a deep impact on public health today. Pathogens 2022, 11, 515. https://doi.org/10.3390/pathogens11050515 https://www.mdpi.com/journal/pathogens