INDIANAPOLIS – For so long, it was a formula to rely on.

Take care of the football.

Take the football away.

From 2018-2021, the Indianapolis Colts were a plus-28 in one of the NFL’s most influential categories: turnover differential.

While Frank Reich’s offense was taking care of the football – 79 turnovers, tied-9th fewest in the league over that span – the defense was taking it away at an impressive rate. Matt Eberflus’ unit generated 107 takeaways, second only to New England’s 116. That included 33 last season. The Colts were the only defense with at least one takeaway in each of the first 14 games.

No longer. Contributing to the Colts’ 1-2-1 start as they head into Thursday night’s meeting with the Broncos in Denver is a lopsided turnover differential.

The Colts have never had a negative differential under Reich. They were tied-1st last season (plus-11) and 2nd in 2020 (plus-10).

Through four games, they’re a minus-6. Only New Orleans (minus-7) is worse.

“It’s the perfect storm in the wrong way,’’ Reich said.

The offense already has suffered nine turnovers, in large part because of Matt Ryan’s lack of ball security. He’s fumbled a league-high nine times, losing three, and had five interceptions.

“The ball is in my hand every snap,’’ Ryan said, “so it starts with me.’’

His eight turnovers are the most by a Colts QB in the first four games since Andrew Luck piled up that many in 2015; Luck did it in three games, missing the fourth with an injury. Ryan’s nine fumbles are the most since Kurt Warner’s nine in Arizona’s first four games of 2006.

“Turnovers are . . . one of, if not the, most important one or two most critical stats when it comes to winning ballgames or at least giving yourself a chance to win,’’ Ryan said following Sunday’s loss to Tennessee. “I’ve got to do a better job of protecting it.’’

His two turnovers against the Titans – a fumble when Denico Autry whipped left guard Quenton Nelson for a sack; an interception when defensive tackle Teair Tart tipped a pass and secured it – occurred in Colts’ territory and gifted Tennessee 14 points.

And that’s what’s exacerbating the spate of turnovers. Opponents have capitalized with touchdowns on six of the nine. Of the 85 points allowed by Indy, 42 have followed turnovers.

It’s hard enough to win the NFL. The difficulty increases exponentially for the Colts when 22% of their drives (9 of 41, excluding three end of half/game situations) end with turnovers. A key stat: the offense has nine turnovers, and six TDs.

And let’s make one thing clear: this isn’t happening in a vacuum. Erratic pass protection too often has forced Ryan to work out of a chaotic pocket – or deal with free blitzers – and a suddenly unreliable run game is placing a heavy onus on that passing game.

Reich and Ryan analyze every facet of the offense, especially the turnovers. How did this one occur? What contributed to that one?

Ryan wasn’t a serial fumbler before relocating to Indy. He hit double digits three times in 14 seasons with the Atlanta Falcons with a career-high of 12 in 2015. Three of the nine came on center snaps at Houston.

“You try to find reasons why certain things have happened,’’ Ryan said Tuesday. “At the same time, you want to stay aggressive, you really do.

“So, it’s a double-edged sword. It’s the ‘Let’s clean things up. Let’s be tighter with it.’ But we’ve also done a great job of extending plays and making things happen late in plays, too. I’ve got to do a better job in the pocket of making sure I’m securing it as best I can and just protecting it as I’m going to the ground at different times.

Overshadowed by the flurry of turnovers are Ryan’s 1,125 passing yards (4th in the league), 66.2% completion rate (11th) and 7.3 yards per attempt (14th).

There’s no denying the debilitating nature of the turnovers, but the defense could mitigate things by returning to its takeaway days.

It was 2nd in the NFL a year ago with 33. Four games in, the Colts have three, and one was a muffed punt by Kansas City. The only ones generated by the defense are E.J. Speed’s sack/fumble of Houston quarterback Davis Mills and Rodney McLeod’s game-sealing interception of Kansas City’s Patrick Mahomes, which was tipped by Stephon Gilmore.

The prolonged absence of Shaquille Leonard has had a dramatic impact. The All-Pro linebacker had four interceptions and a league-high eight forced fumbles in 2021, but is in the midst of a frustrating season. He missed the first three games while recovering from offseason back surgery, returned against Tennessee but suffered a concussion and broken nose in the second quarter.

The concussion/nose issues might force Leonard to miss several more games.

The defense still features playmaking talent in Gilmore, cornerback Kenny Moore II, tackle DeForest Buckner and end Yannick Ngakoue.

At some point, Reich noted, the offense and defense must return to their complementary ways.

“We’re turning it over more than normal on offense and we’re getting fewer turnovers on defense,’’ he said. “It’s not a winning formula. We know that and we have to change it.’’

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You can follow Mike Chappell on Twitter at @mchappell51.