Players must establish a better tactic for a plague to be successful in difficulties such as brutal or higher, as the cure can be easily made in a matter of in-game months if the player has not put their disease to effective use. Each respective difficulty becomes harder and harder as the player progresses through them, making the rate of infectivity to their respective plague a greater challenge to pass on in-game, and are at a higher risk for early detection of a plague. The game has four Difficulty levels: Casual, Normal, Brutal, and Mega-Brutal. Time trials, known in-game as Speed Run mode, are also applicable to the game, as these provide how fast the player can affect the world with their plague and whether they are able to beat their previous record if already done so.
These contain certain events that may affect the normal functionality of the world, or present a simulation of a real-life disease that has been previously researched or occurred at some point in time (i.e. Scenarios, another DLC that includes a lot of exclusive gaming material, is also available to the player. The remaining four are special plagues, or add-ons/DLCs, which are the Neurax Worm, Necroa Virus, Simian Flu, and the Shadow Plague. These are, in order of unlocking, Bacteria, Virus, Fungus, Parasite, Prion, Nano-Virus, and Bio-Weapon. Seven of these are the standard plague types, which the player does not have to pay for. There are, currently, a total of eleven basic forms of plagues available to the player. The game holds various forms of diseases, each with their unique traits and capabilities regarding rate of infection, durability in different climates, and transmission. Following the 2022 Monkeypox Outbreak, during the course of May of that year, it was reported that several players were naming their plague "Monkeypox". became one of the most downloaded iOS video games in Colombia during the country's confinement, according to Adsmovil. The game increased in download ranking in the South Korea's Apple App Store, following the outbreak of MERS in the country during 2015, as new cases were reported in the summer of that year. Another example would be that there was an increase in players when the Ebola outbreak started in 2015. was #1 in Japan, it was correlated with outbreaks of bad flu. The game has experienced popularity increases depending on disease outbreaks, an example would be when Plague Inc.
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