Immunology

In Peoria, clinical trials and a new medicine are bringing hope to the sickest COVID-19 patients – News-Press Now

PEORIA -- Immunology researcher Dr. Joseph Kim switched his focus from organ rejection to COVID-19 in the last few months.

Since coming to Peoria in 2018, Kim had been working with OSF HealthCare Saint Francis Medical Center's organ transplant team to develop better treatments for organ rejection, but COVID-19 has brought him a new challenge.

As an infectious disease specialist, Kim is part of the team treating COVID-19 patients at St. Francis. As part of that work, he is gathering information for a clinical trial on a COVID-19 drug in development by I-Mab Biopharma. St. Francis is one of several hospitals across the country participating in the clinical trial to determine if the drug, currently known as TJ003234, is a safe and effective treatment for COVID-19. The drug is designed to treat the cytokine storm some patients suffer when their immune system overreacts to the virus.

"I'm sure you've heard in the news that some people have a lot of consequences from being sick with the virus: shock, acute respiratory distress, blood clots -- these are different things that happen after infection that may be related to the body's own response against the virus," said Kim. "So what's been shown is that people that have serious infection, their body's own immune response can be very dysregulated, it can be very exaggerated, and that can actually cause harm to the body."

TJ003234 works in a similar way as Tocilizumab, a more widely known drug already FDA approved to treat rheumatoid arthritis. Tocilizumab is also in clinical trials at other hospitals around the U.S. to test its efficacy for the treatment of COVID-19 patients. One of the things researchers are keeping a close eye on is side effects.

"If you are using something that's trying to counteract someone's immune response, some of the unintended consequences could be infection, because you obviously need your immune response to function well to fight off infection," said Kim. "So that's a big concern. So that's why these things need to be studied, obviously."

Clinical trials like this are happening all over the world in the race to come up with an effective treatment for COVID-19. Hospitals are enrolling in trials not only to help researchers, but also to be able to provide some hope for patients and their families for a virus that currently has no known treatments.

"So that's what we've been focusing on at OSF, getting in trials that allow us to give treatments to patients that are very, very sick that wouldn't be available otherwise," said Kim.

The trial, which began in mid-April, is in an early stage, where just a few patients have been given the drug to make sure it is safe, said Kim. Once safety is determined, it will be administered to more patients, and results will be recorded to determine if it is helping. Since it is a double-blind trial, with one group getting the drug and another getting a placebo, Kim and other researchers won't know the results until all the data is gathered.

The clinical trial is one of two COVID-19 trials being done at St. Francis. It is also participating in a clinical trial headed by Mayo Clinic on convalescent plasma, anti-body rich blood plasma gathered from recovered COVID-19 patients.

"Your body makes antibodies, and those antibodies can be protective against that virus," said Kim. "So basically what you are trying to do is taking the antibodies that are protective and give them to someone who doesn't have them yet, someone whose body is not making effective antibodies."

The convalescent plasma study is not a blind study, and last month researchers announced that a couple patients who had received the plasma were recovering. But as yet, those happy results are only anecdotal -- researchers are not yet ready to say if convalescent plasma is truly helpful in the treatment of COVID-19.

"With all these studies, you can't draw firm conclusions with such a small sample size and one physician's experience with a patient," said Kim. "That's the problem, and that's what's so hard about being able to treat patients and navigate through this pandemic -- we don't have this type of data yet. For other infections, like influenza, we have different treatments and vaccines. Influenza has definitely been studied well, so we can be confident about the effectiveness of what we are doing. It's just unfortunate that it's just not like that for COVID-19."

Another treatment doctors at St. Francis are using is Remdesevir. Because it has already been studied and has shown enough promise that the FDA gave it emergency-use approval, hospitals don't have to enroll in a clinical trial to get the drug.

"We've used it in Peoria on three patients so far," said infectious disease specialist Dr. Douglas Kasper, a faculty member at the University of Illinois College of Medicine Peoria. "Remdesevir can be used as an antiviral agent, with the idea that you are arresting viral replication as early as possible."

Though it has shown some promise in one study, doctors are still evaluating its worth as a treatment, said Kasper. Another issue with Remdesevir is that it is in very short supply. Area hospitals have only been given enough to treat a few patients.

All research is contingent on need, and no one knows what the need will be for COVID-19 treatments going forward.

"To do a clinical trial, you have to have sick people, otherwise you don't have anyone to enroll in the trial," said Kasper. "As the summer goes, and if our rates continue to go down, we won't make progress because we won't have anyone to enroll. That is kind of what happened with the first SARS virus. It was circulating mostly in Asia, causing terrible effects, and there was a huge response into the development of therapeutics and a vaccine. Towards the end of that outbreak, the virus mutated and became weaker, and clinical effects on people were less -- people didn't go to hospital and didn't die, then drive from industry became less. Could that happen with COVID-19? It could, but it's not something you could bet on. We don't know. That's the part of this that is so interesting -- each day, every week, it changes so much. To be able to match all this up and plan is quite a process."

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In Peoria, clinical trials and a new medicine are bringing hope to the sickest COVID-19 patients - News-Press Now

Immunology

Biomarkers of Exacerbation in Severe Asthma – Pulmonology Advisor

High counts of blood eosinophils combined with increased fractional exhaled nitric oxide (FeNO) may serve as biomarkers for a risk for exacerbations in patients with severe asthma, according to study results published in the Journal of Allergy and Clinical Immunology: In Practice.

With this 52-week, prospective, single-arm, longitudinal, noninterventional, multicenter ARIETTA study (ClinicalTrials.gov identifier: NCT02537691) conducted in real-world patients with severe asthma, investigators sought to evaluate the ability of type 2 biomarkers to predict severe outcomes. The primary study endpoint was the asthma exacerbation rate over 52 weeks in serum periostin-high (50 ng/mL at baseline) vs serum periostin-low (<50 ng/mL at baseline) subgroups.

The total number of exacerbations observed over 52 weeks divided by the total patient-weeks was used to estimate the unadjusted exacerbation rate. Secondary study outcomes were: the percentage of patients with treatment failure; the percentage of participants with changes in standard-of care treatments that were considered to be clinically meaningful; the time to initial asthma exacerbation; the time to treatment failure; the change from baseline in FeNO levels; the change from baseline in prebronchodilator forced expiratory volume in 1 second (FEV1); the change from baseline in patient-reported quality of life; and safety over 52 weeks in periostin-high and -low subgroups.

A total of 465 adult patients (median patient age, 54 years; range, 17-83 years; 66.5% women) from 84 sites in 13 countries with severe asthma were enrolled. Participants were receiving daily inhaled corticosteroids (fluticasone propionate 500 g or equivalent) and 1 second controller medication. Biomarker, clinical, and safety data were collected from all of the participants over 52 weeks.

The median time since a diagnosis of asthma was 19.4 years. In the prior year, 42.4% of patients had experienced 1 asthma exacerbation. At baseline, 52.0% of patients were periostin-high and 48.0% of participants were periostin-low. Overall, 87.5% of participants had type 2 inflammation (ie, blood eosinophils 150 cells/L and/or FeNO 25 ppb, and/or positive skin allergen test).

Biomarker levels were found to correlate poorly with each other. Central and local laboratory blood eosinophil and immunoglobulin E measurements, however, were generally in agreement. There was no significant difference reported in asthma exacerbation rates over 52 weeks between periostin-high and periostin-low subgroups (rate ratio, 0.93; 95% CI, 0.67 to 1.28; P =.642). Higher exacerbation rates were observed in participants with blood eosinophils 300 cells/L and FeNO 25 ppb.

[T]here were no clinically meaningful differences in the exacerbation rates between periostin-high and periostin-low subpopulations of patients with severe asthma in this study. Key Type 2 biomarkers, including periostin, blood eosinophils, serum IgE, and FeNO, were not highly correlated with each other, concluded the study authors. [P]ost hoc exploratory analyses suggested a potential clinically relevant predictive and prognostic ability for asthma exacerbation of blood eosinophils and FeNO when used in combination.

Reference

Buhl R, Korn S, Menzies-Gow A, et al. Prospective, single-arm, longitudinal study of biomarkers in real-world patients with severe asthma [published online April 15, 2020]. J Allergy Clin Immunol Pract. pii: S2213-2198(20)30338-X. doi: 10.1016/j.jaip.2020.03.038

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Immunology

Covid-19: ‘We have to assume the virus has attenuated’ – RNZ

Covid-19 has likely become less potent as it mutates over time, and hopefully one day will become a common cold virus, a New Zealand, London-based professor says.

Photo: Unsplash / Kvin et Laurianne Langlais

Professor Alberto Zangrillo, head of intensive care at Italy's San Raffaele Hospital in Lombardy, says the new coronavirus is losing its potency and has become much less lethal. He told state television the new coronavirus "clinically no longer exists".

But World Health Organisation experts and a range of other scientists said there was no evidence to support his claim.

There is no data to show the new coronavirus is changing significantly, either in its form of transmission or in the severity of the disease it causes, they said.

But New Zealander Gary McLean, a professor in molecular immunology at London Metropolitan University, told Sunday Morning he was inclined to believe Zangrillo, whose claim was backed up by a second doctor from northern Italy who said he was also seeing the coronavirus weaken.

"They've experienced the full gamut of this virus and the effects and I think we have to believe what they're saying, the clinical picture that is. If they're seeing reduced severity there must be something to it.

"It's really difficult to know why exactly at this point, because there's a lot of reasons why it could be and there's no scientific literature, peer-reviewed papers that really document this, but if the clinicians are saying that I have to think it's probably real."

The virus may well have changed or attenuated causing a change in the clinical picture, McLean said.

"I would probably favour that in some way the virus is attenuating itself, just by accumulating mutations over timeand these little mutations accumulate and eventually the virus has had long enough in that host, in humans, it will drift and change slightly," McLean said.

Zangrillo, well known in Italy as the personal doctor of former Prime Minister Silvio Berlusconi, said his comments were backed up by a study conducted by a fellow scientist, Massimo Clementi, which Zangrillo said would be published soon.

Zangrillo said: "We have never said that the virus has changed, we said that the interaction between the virus and the host has definitely changed."

He said this could be due either to different characteristics of the virus, which he said they had not yet identified, or different characteristics in those infected.

The study by Clementi, who is director of the microbiology and virology laboratory of San Raffaele, compared virus samples from Covid-19 patients at the Milan-based hospital in March with samples from patients with the disease in May.

"The result was unambiguous: an extremely significant difference between the viral load of patients admitted in March compared to" those admitted last month, Zangrillo said.

Oscar MacLean of the University of Glasgow's Centre for Virus Research said suggestions that the virus was weakening were "not supported by anything in the scientific literature and also seem fairly implausible on genetic grounds."

Experts and representatives of Johns Hopkins University, Wake Forest Baptist Medical Center, George Washington University and Northwell Health also said they were not aware of evidence suggesting that the virus had changed.

Could Covid-19 become a common cold?

Gary McLean said there were 40 known coronaviruses, including seven which have infected humans, including four which are endemic cold viruses which cause relatively mild symptoms.

"One could argue originally those four might have been similar to SARS1, MERS and SARS2, and they attenuated themselves and became just a mild common cold."

One of the endemic strains, OC43, has been mapped back in time and the common ancestor is a cow coronavirus thought to have jumped into humans in 1890, McLean said.

"And coincidentally in 1890 there was a world-wide pandemic of a respiratory disease that killed one million people. And you can put one and one together and assume OC43 may have come from a pandemic and over the next 130 years it's evolved into a very mild, common cold virus," McLean said.

"And I'm hoping it doesn't take 130 years for this one to get that mild, but let's say it might take a year or so and we're going to have another common cold coronavirus.

"So I'd like to predict that but I don't know for sure if that will happen."

- Reuters/ RNZ

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Covid-19: 'We have to assume the virus has attenuated' - RNZ

Anatomy

The anatomy of a pandemic – BBC News

South Korea, a nation of 51 million people, stands out as one of the most successful countries in the world in managing to contain Covid-19.

Much of this success has been attributed to the countrys ability to mobilise a small army of contact tracers: detectives trained to connect the dots between a positive Covid-19 case and all their most recent contacts. The tracers must then decide who should be instructed to self-isolate, or, in some cases, whether to quarantine an entire building or organisation, such as a hospital, care home or office.

New daily cases of Covid-19 in South Korea

New daily cases of Covid-19 in South Korea

With only a handful of cases throughout January and early February, many South Koreans thought perhaps a large outbreak had been avoided. However, in late February, from a single city, came a sudden escalation of thousands of cases reported within the space of only a few days.

The outbreak in Daegu city has since been attributed to the movements of one single person, South Koreas superspreader - the now infamous patient 31.

The city of Daegu accounts for more than 60% of all of the country's cases

The city of Daegu accounts for more than 60% of all of the country's cases

Patient 31 tested positive for coronavirus on 17 February. It was only thanks to the work of contract tracers, that all her most recent contacts - which, shockingly, turned out to be more than 1,000 people in the space of 10 days - were tracked down and instructed to self-isolate, thus avoiding an even bigger outbreak.

As deputy of Daegus epidemiology team, Professor Kim Jong-Yeon is responsible for the citys infantry of contact tracers - often former government employees, as well as junior doctors. He says only if people are evasive, do they use more rigorous methods - such as investigating their credit card transactions and their phone or GPS history. People such as patient 31.

Professor Kim Jong-Yeon in Daegu City

Professor Kim Jong-Yeon in Daegu City

Patient 31, at first she didn't tell us she was from the Shincheonji Church. It was us, the contact tracers, who later discovered she was a member, says Prof Kim.

With approximately 300,000 members nationwide, the doctrine of Shincheonji Church of Jesus claims their founder, Lee Man-hee, is the second coming of Jesus Christ and that only he can interpret the Bible. Many mainstream Christian churches in South Korea consider the group to be a cult and have long criticised their aggressive recruitment of young people.

A service at Shincheonji Gyeonggi-doChurch. Source: Shincheonji

A service at Shincheonji Gyeonggi-doChurch. Source: Shincheonji

But patient 31 has not become infamous simply for covering up her affiliation with Shincheonji Church. As contact tracers uncovered, in the 10 days prior to being tested - despite showing symptoms - she travelled around the city of Daegu coming into contact with more than 1,000 people.

After being involved in a car accident on 6 February, patient 31 was admitted to hospital on 7 February, where she came into close contact with an estimated 128 people. She then temporarily discharged herself in order to return home to collect personal belongings, a two-and-a-half-hour round-trip, before returning to hospital. Later that week she discharged herself multiple times, once going for lunch with a friend, and twice in order to attend a a two-hour church service with a 1000-strong congregation.

Due to the secretive nature of the Shincheonji Church, Prof Kim says the hardest part of the investigation was trying to establish who also visited the church during that week.

We finally secured a list of all 9,000 members of the church. At first, we started to call and ask all of them if they had any symptoms. About 1200 people told us they did, but some people refused to get tested and self-quarantine.

With hundreds of individuals reluctant to reveal their association with the secretive church, the professor says they were left with no choice.

It became a matter of how quickly we could separate those church members from the rest of Daegus citizens. So the government issued an executive order for all church members to self-isolate.

Thousands of students of the Shincheonji Church celebrate their in-house graduation. Source: Shincheonji

Thousands of students of the Shincheonji Church celebrate their in-house graduation. Source: Shincheonji

The citys rigorous investigation of all new cases, combined with comprehensive testing, quickly curbed the spread of the virus - and by early April, the city of Daegu reported zero new cases of Covid-19.

However, elsewhere in the world, the virus continued to advance unabated. For the scientific community, it became vital to track the virus, not only over borders, but across continents.

The answer to this problem lay in the genome, clues left behind in the genetic code of the virus as it began to replicate and spread.

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The anatomy of a pandemic - BBC News

Anatomy

Introducing the Anatomage Table Companion App To Visualize Real Human Anatomy with an iPad – PRNewswire

Anatomage created the Anatomage Table Companion App to bring the world's most accurate digital cadaver to the iPad. All of the functionality and content is derived from the award-winning Anatomage Table platform. The Anatomage Table Companion app will introduce a real male cadaver with the functionality and content highlighted below:

Anatomage Table Companion is designed to complement the utilization of the Anatomage Table. The app is a solution to aid Table users who are unable to access their physical Table. By allowing Table users to review anatomy concepts at home, the app supplements in-class lessons that are incorporated with the Anatomage Table. Anatomage Table Companion provides essential anatomy knowledge for all medical disciplines.

For more information about the app, please visit here.

About Anatomage

A market leader in medical imaging technology, Anatomage enables an ecosystem of 3D anatomy hardware and software, allowing users to visualize anatomy at the highest level of accuracy. Through its highly innovative products, Anatomage is transforming standard anatomy learning, medical diagnosis and treatment planning.

Media Contact:Jack Choi CEO Anatomage Inc. Phone: 1-408-885-1474, Email:[emailprotected]www.anatomage.com

SOURCE Anatomage

Table

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Introducing the Anatomage Table Companion App To Visualize Real Human Anatomy with an iPad - PRNewswire

Anatomy

Shonda Rhimes: 7 Interesting Things To Know About The Grey’s Anatomy Creator – CinemaBlend

Since it was founded in 2005, Shondaland, the name of Shonda Rhimes' production company, has become synonymous with the moving stories that she has brought to television. However, in recent year, it has become synonymous with the moving stories that she has given real people a venue on which to share them. In 2017, Rhimes launched shondaland.com, a lifestyle website that offers tips on health, social living, and cultural awareness through various mediums and is open for contributions from anyone who, like Rhimes, aims to make a difference in the world through inspiration and positive change.

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Anatomy

‘Grey’s Anatomy’: 3 Meredith and Cristina Moments That Will Make You Miss Their Friendship – Showbiz Cheat Sheet

In all honesty, we didnt know Greys Anatomy could survive without Meredith Grey (Ellen Pompeo) and Cristina Yangs (Sandra Oh) friendship. Fans were devastated when the Cardio God left in season 10. And while the Shondaland series continues to thrive, we still miss the MerTina Twisted Sisters. So here are a few Meredith and Cristina moments from Greys Anatomy that will seriously make you want to dance it out.

RELATED: Greys Anatomy: The Real Reason Fans Are Nostalgic For the Early Seasons

The first few seasons of Greys Anatomy formally established Meredith and Cristina as soulmates. In the season 2 episode titled Raindrops Keep Falling On My Head, Meredith finds out Cristina is pregnant with Preston Burkes (Isaiah Washington) baby. Then at the end of the episode, Cristina reveals she wants an abortion. She also put Meredith down as an emergency contact at the clinic.

Thats why I told you Im pregnant. Youre my person, Cristina says.

This revealed how close Meredith and Cristina became after meeting. Its also the first time the two women used Youre my person, which was used many times throughout the series.

Now, the phrase has somewhat retired, as Meredith became her own person following Cristina and Alex Karevs (Justin Chambers) exit. But we have no doubts Meredith is still the first person Cristina would call if she murdered someone and needed help dragging the corpse across the living room floor.

RELATED: Greys Anatomys Ellen Pompeo Shares One of Her Most Memorable Scenes With Her Person Sandra Oh

Cristinas departure from Greys Anatomy was one of the most heartbreaking moments in the shows history. In the season 10 finale, the cardio surgeon left for a big opportunity in Switzerland. But before her exit, Cristina and Meredith danced it out for one last time to Where Does the Good Go by Tegan and Sara.

Then right before walking out the door, Cristina left Meredith with one solid piece of advice.

You are a gifted surgeon with an extraordinary mind. Dont let what he wants eclipse what you need, Cristina said. He is very dreamy, but he is not the sun. You are.

RELATED: Greys Anatomy: Kevin McKidd Wants to Call Up Sandra Oh for Owen and Cristinas Reunion

Throughout Greys Anatomy Season 16, viewers have noticed Cristinas presence via text messages with Meredith. The two friends continue to keep in touch and Cristina even delivered a hot new package Cormac Hayes (Richard Flood) to Grey Sloan Memorial.

But nothing got us quite like Cristinas letter to the medical commission during Merediths medical license hearing in My Shot. The letter also referenced her final goodbye.

People who know me would describe me as selfish to a fault, Cristina wrote. After that, theyd say, honest. I can honestly tell you that if I were dying and a surgery stood between me and death, Dr. Greys hands are the only ones Id want inside my body.

She continued, Taking away her license is signing the death certificates of countless future patients. She is a light in a broken system that she will fix, whether you want her to or not. She is the sun and she is unstoppable.

Cristinas letter about Merediths character proved the women still have each others backs, even after all these years. And if that doesnt touch your heart, we dont know what will.

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Anatomy

3 ‘Grey’s Anatomy’ Deaths We Will Never Get Over – Showbiz Cheat Sheet

Lets face it, Greys Anatomy is laced with tragic deaths. It all started when Dylan Young (Kyle Chandler) aka the bomb squad guy exploded right in front of Meredith Grey (Ellen Pompeo). Then eventually, the characters nicknamed the hospital Seattle Grace Mercy Death. And now, fans are always wondering who is next. So here are some of the most memorable deaths on Greys Anatomy if you handle reliving the heartbreak.

RELATED: Greys Anatomy: Where Is George O Malley Now, and Why Did He Leave the Show?

Were not crying, youre crying. George OMalley (T.R. Knight) went out like a hero and well never forget it.

In the Greys Anatomy episode titled Now or Never, Owen Hunt (Kevin McKidd) told George he was a natural for trauma. So he decided to join the army. Of course, everyone wanted to stop the character from going. But before they were able to, a John Doe was brought in after being hit by a bus, saving a womans life in the process.

John Doe was unrecognizable and unable to speak. Then he seemingly wrote 007 on Merediths hand. Instantly realizing this was Georges nickname, Meredith and the rest of the doctors rushed to save his life.

All the while, his best friend, Izzie Stevens (Katherine Heigl), was also dying. Then in a dream sequence, Izzie went on the elevator to heaven in the pink dress she wore when Denny Duquette (Jeffrey Dean Morgan) died. Once she reached the top, George was on the other side in his U.S. Army uniform. Finally, in the next episode, the doctors confirmed George was gone and he wasnt coming back.

RELATED: Greys Anatomy Fans Still Wish Mark and Lexie Could Have Lived Happily Ever After

Lexie Grey (Chyler Leigh) and Mark Sloan (Eric Dane) died when they finally realized they were meant to be. And if thats not heartbreaking, we dont know what is.

In the Greys Anatomy Season 8 finale titled Flight Lexie, Mark, Meredith, Cristina Yang (Sandra Oh), Arizona Robbins (Jessica Capshaw), and Derek Shepherd (Patrick Dempsey) experienced a plane crash together. Then toward the start of the episode, everyone discovered Lexie was crushed by a piece of the plane.

Lexie was still alive when they found her. But realizing it was too late, Mark promised her the best life together. Then he held her hand as she died, sobbing, I love you.

In the next episode, Going, Going, Gone, Greys Anatomy revealed Mark survived long enough to make it back to Seattle Grace Mercy West. He also seemed to bounce back for a short period of time. However, Mark eventually died because of his injuries from the crash. But his friends were able to say goodbye as he was taken off life support.

RELATED: Why Greys Anatomy Hasnt Seen a Major Death for Some Time

Meredith and Dereks love story was at the center of Greys Anatomy. So when Derek died in season 11, everything changed.

In the episode called How to Save a Life, Derek was hit by a semi-truck. He wasnt brought to Grey Sloan Memorial. Rather, he went to Dillard, which was closer to the accident.

Upon arrival, Derek was rushed into surgery. Penelope Blake (Samantha Sloyan) noticed Derek needed a CT scan because of a blown pupil. However, she was dismissed by her attending because Derek was bleeding into his chest. Meanwhile, the neurosurgeon on call came in too late. So by the time the doctors at Dillard were able to do anything for the brain bleed, Derek was pronounced brain dead.

Eventually, Meredith arrived at Dillard and she had to say goodbye to her husband and the father of her children. You go, Meredith said. Well be fine. Now please excuse us as we sob for the rest of eternity.

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Anatomy

4 ‘Grey’s Anatomy’ Couples That Deserved to Be Endgame – Showbiz Cheat Sheet

Greys Anatomy has been around for over 15 years, and you could say the Shondaland series knows a thing or two about romance. The ABC medical drama has spawned epic loves like Meredith Grey (Ellen Pompeo) and Derek Shepherd (Patrick Dempsey). Its also given us marriages to aspire to like Ben Warren (Jason George) and Miranda Bailey (Chandra Wilson). But the show has also delivered a number of fiery romances that, for some reason, just didnt work out. So here are the best Greys Anatomy couples that deserved to end up together but didnt.

RELATED: Greys Anatomy Fans Still Wish Mark and Lexie Could Have Lived Happily Ever After

Say what you want, but the way Mark Sloan (Eric Dane) and Lexie Grey (Chyler Leigh) finally got together was absolutely devastating. At the start, the pair had a few things going against them and they were never really on the same page. Nevertheless, Mark and Lexie always found themselves drawn to one another. But on Greys Anatomy, love isnt enough.

When we all thought the couple would get together, the cruel Shondaland gods dropped the airplane crash episode. In Flight, Mark and Lexie were able to confess their love, finally acknowledging they were meant to be. But sadly, this happened as Lexie was dying. Mark also passed in the next episode. And just like that, Greys Anatomy shattered our dreams of a Slexie endgame.

RELATED: Why Greys Anatomy Fans Might Never See Callie Again After All

Ask any Greys Anatomy fan and they will tell you Callie Torres (Sara Ramirez) and Arizona Robbins (Jessica Capshaw) deserved better. They were the shows first prominent LGBTQ couple and had some extraordinary moments together. But whatever came their way, it seemed Callie and Arizona always fought for their relationship in the early days. Then things started to shift.

After a brief breakup and the birth of Sophia (via Mark), Callie and Arizona got married. However, the plane crash episode ruined yet another relationship. Following the crash, Arizona lost her leg, which led to a lot of resentment. Then Arizona cheated on Callie, and even after therapy, the couple decided to divorce.

Arizona and Callie found a way to co-parent following their split. But after a difficult custody battle, Callie moved to New York with her new girlfriend, Penelope Blake (Samantha Sloyan). However, that may not be the last of the couple.

In Greys Anatomy Season 14, Arizona left for New York for Sofia. Coincidentally, Callie and Penny broke up. So does this mean Callie and Arizona got back together? Calzonas final ending was never shown on-screen. But after everything they went through, we hope so.

RELATED: Greys Anatomy: Will April and Matthew Ever Return? The Door Is Still Open

Greys Anatomy fans are still not over Jackson Avery (Jesse Williams) and April Kepners (Sarah Drew) relationship. Fans were first introduced to the characters when Seattle Grace and Mercy West merged. The two sparked up a friendship before finally hooking up. Then suddenly, everyone could see the couples chemistry.

As things progressed, fans saw Jackson and Aprils devotion to one another. Even when they decided to stop hooking up, the red string of fate kept them closeby. Then finally, it happened and it happened in the most Greys Anatomy way.

In the middle of Jackson and Matthew Taylors (Justin Bruening) wedding, Jackson got up and professed his love. Everyone was shocked including the audience. Then April and Jackson ran off together and eloped.

Nonetheless, it wasnt happily ever after. Jackson and April faced plenty of challenges, including the death of their newborn, Samuel. Then as time went on, the couple started to unravel and they ended up getting divorced. And when the former lovers signed the papers, April found out she was pregnant with Harriet.

Despite everything, Japril was not endgame on Greys Anatomy. April rekindled her love for Matthew the man she left at the altar and married him. She also continues to co-parent with Jackson offscreen. So technically, its possible April and Jackson could magically end up together. But as much as it pains us to say it, were not holding our breath.

RELATED: Greys Anatomy: Krista Vernoff Reveals Why Alex Karev Didnt Die in Season 16

Before season 16, Jo Wilson (Camilla Luddington) and Alex Karev (Justin Chambers) were on the fast-track to becoming one of Greys Anatomys endgame couples. The pair just knew how to support one another, particularly because their backgrounds were similar. Heck, Jo and Alex even got married twice to prove how much they loved each other.

Even so, that all came tumbling down when Izzie Stevens (Katherine Heigl) came back into the picture. In Greys Anatomy Season 16, Alex disappeared and ghosted Jo. Then in a letter, Alex revealed he reconnected with Izzie, who had his children from the embryos they made when she had cancer. So he decided to leave Jo for his ex-wife in Kansas, mailing her signed divorce papers.

For a couple that delivered so much promise, it was disappointing to see JoLex split so quickly. And seeing as the couple just remarried in season 15, Alexs betrayal has us questioning whether or not true love exists.

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4 'Grey's Anatomy' Couples That Deserved to Be Endgame - Showbiz Cheat Sheet