Coach Roberto Mancini has contracted COVID-19 and - though fortunately asymptomatic - is currently self-isolating, so assistant manager Alberigo Evani will be in charge as a new-look Italy squad take on Karel Voolaid's modest side.
Last week, Mancini called up a remarkable 41 players for the matches against Estonia, Poland and Bosnia-Herzegovina, in order to cope with fixture congestion and mitigate fatigue-related injuries.
Several players from the Serie A clubs involved in European competition were effectively given time off for this game, so have arrived two days late at the Azzurri's Coverciano training ground. Those stars - including first choice goalkeeper Gianluigi Donnarumma - are then set to come into contention for the upcoming Nations League fixtures against Poland and Bosnia.
However, Lazio, Roma and Fiorentina players have since been banned from joining up with their international colleagues, after cases of COVID-19 were discovered within their respective squads.
Local health guidelines in Rome and Florence mean that travel restrictions are in place, thereby jeopardising the involvement of valuable players such as Ciro Immobile and Gianluca Mancini. All of which could mean greater opportunity for fresh faces.
Mancini has issued first call-ups for Atalanta midfielder Matteo Pessina and Milan's Davide Calabria, while Roberto Soriano of Bologna returns to the fold after four years away. They are more likely to be involved in what could be a relatively experimental lineup versus Estonia before more established names return for the Nations League action.
Intriguingly, Monaco's former 'wonderboy' Pietro Pellegri was also recalled to the setup for the first time in two years. The striker, who joined Monaco for a reported £22.5million fee as a 16-year-old, was selected by the Azzurri for the first time in September 2018 but injury forced him to withdraw.
A Genoa youth product, unfortunate Pellegri has only made a handful of appearances for Monaco so far due to a series of fitness issues. Having missed the entire 2019-20 campaign due to hamstring injury, perhaps now - still aged just 19 - is the time for the one-time joint-youngest player in Serie A history to shine.
Italy drew 1-1 against the Netherlands in last month's Nations League fixture after Roma's Lorenzo Pellegrini opened the scoring, but having thumped Moldova 6-0 in their most recent international friendly last month and previously doled out a 9-1 hammering to Armenia, Mancini's men have often proved to be ruthless when facing Europe's minnows.
Underdogs Estonia, meanwhile, also registered a 1-1 result last time out - albeit against opposition of a lower order. Flora Tallinn forward Rauno Sappinen scored the Baltic nation's goal against Armenia, which leaves them rock bottom in League C2. They have mustered just four goals and two points so far in a section also including Georgia, North Macedonia and Armenia.
National team captain Ragnar Klavan, once of Liverpool, plies his trade in Serie A with Cagliari but has not been included in the squad due to injury, while promising 19-year-old midfielder Georgi Tunjov is at Serie B club SPAL, but has featured mostly from the bench.
After 123 caps and 25 goals, veteran midfielder Konstantin Vassiljev is still incredibly influential in former Under-21 manager Voolaid's squad. The coach, who has worked his way up through the age groups to finally manage the senior side, has selected a number of younger players, so the team to take on this formidable challenge will comprise a wide range of experience.
Estonia last faced Italy in 2011, with the Azzurri winning 3-0 and in the six games contested between these nations, Italy have won each and every one. No matter what the side selected by Mancini on Wednesday, gleaning top-level experience and keeping the score respectable will be the height of the visitors' ambitions.
Italy International Friendlies form: WLDDWW
Italy form (all competitions): WDWWDD
Estonia International Friendlies form: LWLWLL
Estonia form (all competitions): LLLLDD
Genoa captain Domenico Criscito and Sassuolo forward Francesco Caputo have already left Italy's training camp and will not be available due to injury. After injuries to West Ham's Angelo Ogbonna and fellow defender Alessio Romagnoli, Italy have promoted Inter defender Alessandro Bastoni from the Under-21 squad and also called up Sassuolo's Gian Marco Ferrari and Mattia Zaccagni of Verona.
Due to the innumerable complications posed by COVID-19 restrictions and Mancini's desire to test out fringe players, little else is certain about the lineup, other than that he is likely to persist with his favoured 4-3-3, affording game time to promising players such as Moise Kean, Sandro Tonali and Bastoni.
Estonia coach Karel Voolaid pits his wits against Mancini's deputy Alberigo Evani on the touchline and is unlikely to deviate from a rigid 4-4-1-1 setup, designed to frustrate more talented opposition.
Seven-time Estonian player of the year Ragnar Klavan is unavailable, so the heart of defence will be manned by Nikita Baranov and Marten Kuusk - ahead of young Arsenal goalkeeper Karl Jakob Hein, who was named as a substitute for the first time in Arsenal's Europa League encounter with Dundalk last month.
Italy possible starting lineup:
Sirigu; D'Ambrosio, Bastoni, Ferrari, Palmieri; Gagliardini, Soriano, Tonali; Bernardeschi, Grifo, Lasagna
Estonia possible starting lineup:
Hein; Teniste, Baranov, Kuusk, Pikk; Liivak, Kreida, Kait, Sinyavskiy; Vassiljev; Sappinen
We say: Italy 4-0 Estonia
A welcome opportunity for Azzurri fans to cast their eye over some promising players who might yet make it into next summer's Euros squad, this Nations League warm-up is set to be a one-sided affair.
Talented youngsters such as Bastoni, Tonali and Kean have already demonstrated enough class to help sweep aside out-of-their depth Estonia, for whom the only real goal is to avoid a 'friendly' thrashing.