Ob.Gyn. News

Seven days into his presidency, Joe Biden announced that he is taking new steps to speed vaccines to Americans.

The president said he would increase the supply of vaccines to states from 8.6 million doses to 10 million doses per week, a 16% increase, for at least the next 3 weeks.

He said he was working to give states more advanced notice of their allotments so they could better plan their campaigns. He also said doses would be doled out based on population.

“We will both increase the supply and give our state and local partners more certainty about when doses will arrive,” he said Tuesday.

Finally, Mr. Biden announced that the United States would “soon be able to confirm” the purchase of 200 million more doses of the Pfizer and Moderna vaccines – 100 million of each – to effectively double the nation’s supply by “early summer.” That would increase the nation’s supply enough to fully vaccinate 300 million Americans by fall.

Mr. Biden said he was also working to shift the focus to getting more doses to economically disadvantaged communities and rural areas, which have fallen further behind as the vaccine rollout has faltered.

Even with these steps, Mr. Biden stressed that it would take months for vaccines to curb infections and deaths. He said, for the time being, masks, not vaccines, are the best way to save lives.

“The brutal truth is its going to take months before we get the majority of Americans vaccinated. Months,” he said, adding that wearing masks until at least April could save to save 50,000 lives.

“Let me be clear,” Mr. Biden said, “Things are going to get worse before they get better.

“We didn’t get into this mess overnight. It’s going to take months for us to turn things around. But let me be equally clear we’re going to get through this. We will defeat this pandemic,” he said.

A version of this article first appeared on WebMD.com.

Seven days into his presidency, Joe Biden announced that he is taking new steps to speed vaccines to Americans.

The president said he would increase the supply of vaccines to states from 8.6 million doses to 10 million doses per week, a 16% increase, for at least the next 3 weeks.

He said he was working to give states more advanced notice of their allotments so they could better plan their campaigns. He also said doses would be doled out based on population.

“We will both increase the supply and give our state and local partners more certainty about when doses will arrive,” he said Tuesday.

Finally, Mr. Biden announced that the United States would “soon be able to confirm” the purchase of 200 million more doses of the Pfizer and Moderna vaccines – 100 million of each – to effectively double the nation’s supply by “early summer.” That would increase the nation’s supply enough to fully vaccinate 300 million Americans by fall.

Mr. Biden said he was also working to shift the focus to getting more doses to economically disadvantaged communities and rural areas, which have fallen further behind as the vaccine rollout has faltered.

Even with these steps, Mr. Biden stressed that it would take months for vaccines to curb infections and deaths. He said, for the time being, masks, not vaccines, are the best way to save lives.

“The brutal truth is its going to take months before we get the majority of Americans vaccinated. Months,” he said, adding that wearing masks until at least April could save to save 50,000 lives.

“Let me be clear,” Mr. Biden said, “Things are going to get worse before they get better.

“We didn’t get into this mess overnight. It’s going to take months for us to turn things around. But let me be equally clear we’re going to get through this. We will defeat this pandemic,” he said.

A version of this article first appeared on WebMD.com.

Seven days into his presidency, Joe Biden announced that he is taking new steps to speed vaccines to Americans.

The president said he would increase the supply of vaccines to states from 8.6 million doses to 10 million doses per week, a 16% increase, for at least the next 3 weeks.

He said he was working to give states more advanced notice of their allotments so they could better plan their campaigns. He also said doses would be doled out based on population.

“We will both increase the supply and give our state and local partners more certainty about when doses will arrive,” he said Tuesday.

Finally, Mr. Biden announced that the United States would “soon be able to confirm” the purchase of 200 million more doses of the Pfizer and Moderna vaccines – 100 million of each – to effectively double the nation’s supply by “early summer.” That would increase the nation’s supply enough to fully vaccinate 300 million Americans by fall.

Mr. Biden said he was also working to shift the focus to getting more doses to economically disadvantaged communities and rural areas, which have fallen further behind as the vaccine rollout has faltered.

Even with these steps, Mr. Biden stressed that it would take months for vaccines to curb infections and deaths. He said, for the time being, masks, not vaccines, are the best way to save lives.

“The brutal truth is its going to take months before we get the majority of Americans vaccinated. Months,” he said, adding that wearing masks until at least April could save to save 50,000 lives.

“Let me be clear,” Mr. Biden said, “Things are going to get worse before they get better.

“We didn’t get into this mess overnight. It’s going to take months for us to turn things around. But let me be equally clear we’re going to get through this. We will defeat this pandemic,” he said.

A version of this article first appeared on WebMD.com.

Since the first baby was born after a uterus transplantation in Sweden in 2014, uterus transplantation has been rapidly transitioning toward clinical reality.¹ Several teams in the United States and multiple teams worldwide have performed the procedure, with the total number of worldwide surgeries performed nearing 100.

Uterus transplantation is the first and only true treatment for women with absolute uterine factor infertility – estimated to affect 1 in 500 women – and is filling an unmet need for this population of women. Women who have sought participation in uterus transplantation research have had complex and meaningful reasons and motivations for doing so.² Combined with an accumulation of successful pregnancies, this makes continued research and technical improvement a worthy endeavor.

Most of the births thus far have occurred through the living-donor model; the initial Swedish trial involved nine women, seven of whom completed the procedure with viable transplants from living donors, and gave birth to eight healthy children. (Two required hysterectomy prior to attempted embryo transfer.³)

The Cleveland Clinic opted to build its first – and still ongoing – trial focusing on deceased-donor uterus transplants on the premise that such an approach obviates any risk to the donor and presents the fewest ethical challenges at the current time. Of eight uterus transplants performed thus far at the Cleveland Clinic, there have been three live births and two graft failures. As of early 2021, there was one ongoing pregnancy and two patients in preparation for embryo transfer.

Thus far, neither the living- nor deceased-donor model of uterus transplantation has been demonstrated to be superior. However, as data accrues from deceased donor studies, we will be able to more directly compare outcomes.

In the meantime, alongside a rapid ascent of clinical landmarks – the first live birth in the United States from living-donor uterus transplantation in 2017 at Baylor University Medical Center in Houston,⁴ for instance, and the first live birth in the United States from deceased-donor uterus transplantation in 2019 at the Cleveland Clinic ^– there have been significant improvements in surgical retrieval of the uterus and in the optimization of graft performance.⁵

Most notably, the utero-ovarian vein has been used successfully in living donors to achieve venous drainage of the graft. This has lessened the risks of deep pelvic dissection in the living donor and made the transition to laparoscopic and robotic approaches in the living donor much easier.
 

Donor procurement, venous drainage

Adequate circulatory inflow and outflow for the transplanted uterus are essential both for the prevention of ischemia and thrombosis, which have been major causes of graft failure, and for meeting the increased demands of blood flow during pregnancy. Of the two, the outflow is the more challenging component.

Courtesy Cleveland Clinic

Venous drainage traditionally has been accomplished through the use of the uterine veins, which drain into the internal iliac veins; often the vascular graft will include a portion of the internal iliac vessel which can be connected via anastomoses to the external iliac vein classically in deceased donors. Typically, the gynecologic surgeon on the team performs the vaginal anastomosis and suspension of the uterus, while the transplant surgeons perform the venous and arterial anastomoses.

In the living-donor model, procurement and dissection of these often unpredictable and tortuous complexes in the deep pelvis – particularly the branching uterine veins that lie in close proximity to the ureter, bladder, other blood vessels, and rectum – can be risky. The anatomic variants in the uterine vein are numerous, and even in one patient, a comprehensive dissection on one side cannot be expected to be mirrored on the contralateral side.

Courtesy Cleveland Clinic

In addition to the risk of injury to the donor, the anastomosis may be unsuccessful as the veins are thinly walled and challenging to suture. As such, multiple modifications have been developed, often adapted to the donor’s anatomy and the caliber and accessibility of vessels. Preoperative vascular imaging with CT and/or MRI may help to identify suitable candidates and also may facilitate presurgical planning of which vessels may be selected for use.

Recently, surgeons performing living-donor transplantations have successfully used the more accessible and less risky ovarian and/or utero-ovarian veins for venous anastomosis. In 2019, for instance, a team in Pune, India, reported laparoscopically dissecting the donor ovarian veins and a portion of the internal iliac artery, and completing anastomosis with bilateral donor internal iliac arteries to recipient internal iliac arteries, and bilateral donor ovarian veins to recipient external iliac veins.⁶ It is significant that these smaller-caliber vessels were found to able to support the uterus through pregnancy.

Courtesy Cleveland Clinic

We must be cautious, however, to avoid removing donors’ ovaries. Oophorectomy for women in their 40s can result in significant long-term medical sequelae. Surgeons at Baylor have achieved at least one live birth after harvesting the donor’s utero-ovarian veins while conserving the ovaries – a significant advancement for the living-donor model.⁴

There is tremendous interest in developing minimally invasive approaches to further reduce living-donor risk. The Swedish team has completed a series of eight robotic hysterectomies in living-donor uterus transplantations as part of a second trial. Addressing the reality of a learning curve, their study was designed around a step-wise approach, mastering initial steps first – e.g., dissections of the uterovaginal fossa, arteries, and ureters – and ultimately converting to laparotomy.⁷ In the United States, Baylor University has now completed at least five completely robotic living-donor hysterectomies with complete vaginal extraction.

Published data on robotic surgery suggests that surgical access and perioperative visualization of the vessels may be improved. And as minimally invasive approaches are adopted and improved, the length of donor surgery – 10-13 hours of operating room time in the original Swedish series – should diminish, as should the morbidity associated with laparotomy.

Courtesy Cleveland Clinic

Surgical acquisition of a uterine graft from a deceased donor diminishes concerns for injury to nearby structures. Therefore, although it is a technically similar procedure, a deceased-donor model allows more flexibility with the length, caliber, and number of vessels that can be used for anastomosis. The internal iliac vessels and even portions of the external iliac vessels and ovarian vessels can be used to allow maximum flexibility.⁸

Surgical technique for uterus recipients

For the recipient surgery, entry is achieved via a midline, vertical laparotomy. The external iliac vessels are exposed, and the sites of vascular anastomoses are identified. The peritoneal reflection of the bladder is identified and dissected away to expose the anterior vagina, and the vagina is opened to a diameter that matches the donor, typically using a monopolar electrosurgical cutting instrument.

Courtesy Cleveland Clinic

The vault of the donor vagina will be attached to the recipient’s existing vagina or vaginal pouch. It is important to identify recipient vaginal mucosa and incorporate it into the vaginal anastomosis to reduce the risk of vaginal stricture. We recommend that the vaginal mucosa be tagged with PDS II sutures or grasped with allis clamps to prevent retraction.

Surgical teams have taken multiple approaches to vaginal anastomosis. The Cleveland Clinic has used both a running suture as well as a horizontal mattress stitch for closure. For the latter, a 30-inch double-armed 2.0 Vicryl allows for complete suturing of the recipient vagina – with eight stitches placed circumferentially – before the uterus is placed. Both ends of the suture are passed intra-abdominal to intravaginal in the recipient.⁹

Once the donor uterus is suspended, attention focuses on vascular anastomosis, with bilateral end-to-side anastomosis between the donor anterior division of the internal iliac arteries and the external iliac vessels of the recipient, and with venous drainage commonly achieved through the uterine veins draining into the internal or external iliac vein of the recipient. As mentioned, recent cases involving living donors have also demonstrated success with the use of ovarian and/or utero-ovarian veins. Care should be taken to avoid having tension or twisting across the anastomosis.

Courtesy Cleveland Clinic

After adequate graft perfusion is confirmed, with the uterus turning from a dusky color to a pink and well-perfused organ, the vaginal anastomosis is completed, with the arms of the double-armed suture passed through the donor vagina, from intravaginal to intra-abdominal. Tension should be evenly spread along the recipient and donor vagina in order to reduce the formation of granulation tissue and the severity of future vaginal stricturing.

For uterine fixation, polypropylene sutures are placed between the graft uterosacral ligaments and recipient uterine rudiments, and between the graft round ligaments and the recipient pelvic side wall at the level of the deep inguinal ring.

Current uterus transplantation protocols require removal of the uterus after one or two live births are achieved, so that recipients will not be exposed to long-term immunosuppression.
 

Complications and controversies

Postoperative vaginal strictures can make embryo transfer difficult and are a common complication in both living- and deceased-donor models. The Cleveland Clinic team has applied techniques from vaginal reconstructive surgery to try to reduce the occurrence of postoperative strictures – mainly increasing attention paid to anastomosis tissue–site preparation and closure of the anastomosis using a tension-free interrupted suture technique, as described above.⁹ The jury is out on whether such changes are sufficient, and a more complete understanding of the causes of vaginal stricture is needed.

Other perioperative complications include infection and graft thrombosis, both of which typically result in urgent graft hysterectomy. During pregnancy, one of our patients experienced abnormal placentation, though this was not thought to be related to uterus transplantation.⁵

The U.S. Uterus Transplant Consortium (USUTC) is a group of active programs that are sharing ideas and outcomes and advocating for continued research in this rapidly developing field. Uterine transplants require collaboration with transplant surgery, transplant medicine, infectious disease, gynecologic surgery, high-risk obstetrics, and other specialties. While significant progress has been made in a short period of time, uterine transplantation is still in its early stages, and transplants should be done in institutions that have the capacity for mentorship, bioethical oversight, and long-term follow-up of donors, recipients, and offspring.

The USUTC has recently proposed guidelines for nomenclature related to operative technique, vascular anatomy, and uterine transplantation outcomes.¹⁰ It proposes standardizing the names for the four veins originating from the uterus (to eliminate current inconsistency), which will be important as optimal strategies for vascular anastomoses are discussed and determined.

In addition, the consortium is creating a registry for the rigorous collection of data on procedures and outcomes (from menstruation and pregnancy through delivery, graft removal, and long-term follow-up). A registry has also been proposed by the International Society for Uterine Transplantation.

A major question remains in our field: Is the living-donor or deceased-donor uterus transplant the best approach? Knowledge of the quality of the uterus is greater preoperatively within a living-donor model, but no matter how minimally invasive the technique, the donor still assumes some risk of prolonged surgery and extensive pelvic dissection for a transplant that is not lifesaving.

On the other hand, deceased-donor transplants require additional layers of organization and coordination, and the availability of suitable deceased-donor uteri will likely not be sufficient to meet the current demand. Many of us in the field believe that the future of uterine transplantation will involve some combination of living- and deceased-donor transplants – similar to other solid organ transplant programs.

Dr. Flyckt and Dr. Richards reported that they have no relevant financial disclosures.

Correction, 2/2/21: An earlier version of this article misstated Dr. Richards' name in the photo caption.
 

References

1. Lancet. 2015;14:385:607-16.

2. AJOB Empir Bioeth. 2019;10(1):23-5.

3. Transplantation. 2020;104(7):1312-5.

4. Am J Transplant. 2018;18(5):1270-4.

5. Am J Obstet Gynecol. 2020;223(2):143-51.

6. J Minimally Invasive Gynecol. 2019;26:628-35.

7. Acta Obstet Gynecol Scand. 2020;99(9):1222-9.

8. Fertil Steril. 2018;110(1):183.

9. Fertil Steril. 2020 Jul 16. doi: 10.1016/j.fertnstert.2020.05.017

10 Am J Transplant. 2020;20(12):3319-25.

Since the first baby was born after a uterus transplantation in Sweden in 2014, uterus transplantation has been rapidly transitioning toward clinical reality.¹ Several teams in the United States and multiple teams worldwide have performed the procedure, with the total number of worldwide surgeries performed nearing 100.

Uterus transplantation is the first and only true treatment for women with absolute uterine factor infertility – estimated to affect 1 in 500 women – and is filling an unmet need for this population of women. Women who have sought participation in uterus transplantation research have had complex and meaningful reasons and motivations for doing so.² Combined with an accumulation of successful pregnancies, this makes continued research and technical improvement a worthy endeavor.

Most of the births thus far have occurred through the living-donor model; the initial Swedish trial involved nine women, seven of whom completed the procedure with viable transplants from living donors, and gave birth to eight healthy children. (Two required hysterectomy prior to attempted embryo transfer.³)

The Cleveland Clinic opted to build its first – and still ongoing – trial focusing on deceased-donor uterus transplants on the premise that such an approach obviates any risk to the donor and presents the fewest ethical challenges at the current time. Of eight uterus transplants performed thus far at the Cleveland Clinic, there have been three live births and two graft failures. As of early 2021, there was one ongoing pregnancy and two patients in preparation for embryo transfer.

Thus far, neither the living- nor deceased-donor model of uterus transplantation has been demonstrated to be superior. However, as data accrues from deceased donor studies, we will be able to more directly compare outcomes.

In the meantime, alongside a rapid ascent of clinical landmarks – the first live birth in the United States from living-donor uterus transplantation in 2017 at Baylor University Medical Center in Houston,⁴ for instance, and the first live birth in the United States from deceased-donor uterus transplantation in 2019 at the Cleveland Clinic ^– there have been significant improvements in surgical retrieval of the uterus and in the optimization of graft performance.⁵

Most notably, the utero-ovarian vein has been used successfully in living donors to achieve venous drainage of the graft. This has lessened the risks of deep pelvic dissection in the living donor and made the transition to laparoscopic and robotic approaches in the living donor much easier.
 

Donor procurement, venous drainage

Adequate circulatory inflow and outflow for the transplanted uterus are essential both for the prevention of ischemia and thrombosis, which have been major causes of graft failure, and for meeting the increased demands of blood flow during pregnancy. Of the two, the outflow is the more challenging component.

Courtesy Cleveland Clinic

Venous drainage traditionally has been accomplished through the use of the uterine veins, which drain into the internal iliac veins; often the vascular graft will include a portion of the internal iliac vessel which can be connected via anastomoses to the external iliac vein classically in deceased donors. Typically, the gynecologic surgeon on the team performs the vaginal anastomosis and suspension of the uterus, while the transplant surgeons perform the venous and arterial anastomoses.

In the living-donor model, procurement and dissection of these often unpredictable and tortuous complexes in the deep pelvis – particularly the branching uterine veins that lie in close proximity to the ureter, bladder, other blood vessels, and rectum – can be risky. The anatomic variants in the uterine vein are numerous, and even in one patient, a comprehensive dissection on one side cannot be expected to be mirrored on the contralateral side.

Courtesy Cleveland Clinic

In addition to the risk of injury to the donor, the anastomosis may be unsuccessful as the veins are thinly walled and challenging to suture. As such, multiple modifications have been developed, often adapted to the donor’s anatomy and the caliber and accessibility of vessels. Preoperative vascular imaging with CT and/or MRI may help to identify suitable candidates and also may facilitate presurgical planning of which vessels may be selected for use.

Recently, surgeons performing living-donor transplantations have successfully used the more accessible and less risky ovarian and/or utero-ovarian veins for venous anastomosis. In 2019, for instance, a team in Pune, India, reported laparoscopically dissecting the donor ovarian veins and a portion of the internal iliac artery, and completing anastomosis with bilateral donor internal iliac arteries to recipient internal iliac arteries, and bilateral donor ovarian veins to recipient external iliac veins.⁶ It is significant that these smaller-caliber vessels were found to able to support the uterus through pregnancy.

Courtesy Cleveland Clinic

We must be cautious, however, to avoid removing donors’ ovaries. Oophorectomy for women in their 40s can result in significant long-term medical sequelae. Surgeons at Baylor have achieved at least one live birth after harvesting the donor’s utero-ovarian veins while conserving the ovaries – a significant advancement for the living-donor model.⁴

There is tremendous interest in developing minimally invasive approaches to further reduce living-donor risk. The Swedish team has completed a series of eight robotic hysterectomies in living-donor uterus transplantations as part of a second trial. Addressing the reality of a learning curve, their study was designed around a step-wise approach, mastering initial steps first – e.g., dissections of the uterovaginal fossa, arteries, and ureters – and ultimately converting to laparotomy.⁷ In the United States, Baylor University has now completed at least five completely robotic living-donor hysterectomies with complete vaginal extraction.

Published data on robotic surgery suggests that surgical access and perioperative visualization of the vessels may be improved. And as minimally invasive approaches are adopted and improved, the length of donor surgery – 10-13 hours of operating room time in the original Swedish series – should diminish, as should the morbidity associated with laparotomy.

Courtesy Cleveland Clinic

Surgical acquisition of a uterine graft from a deceased donor diminishes concerns for injury to nearby structures. Therefore, although it is a technically similar procedure, a deceased-donor model allows more flexibility with the length, caliber, and number of vessels that can be used for anastomosis. The internal iliac vessels and even portions of the external iliac vessels and ovarian vessels can be used to allow maximum flexibility.⁸

Surgical technique for uterus recipients

For the recipient surgery, entry is achieved via a midline, vertical laparotomy. The external iliac vessels are exposed, and the sites of vascular anastomoses are identified. The peritoneal reflection of the bladder is identified and dissected away to expose the anterior vagina, and the vagina is opened to a diameter that matches the donor, typically using a monopolar electrosurgical cutting instrument.

Courtesy Cleveland Clinic

The vault of the donor vagina will be attached to the recipient’s existing vagina or vaginal pouch. It is important to identify recipient vaginal mucosa and incorporate it into the vaginal anastomosis to reduce the risk of vaginal stricture. We recommend that the vaginal mucosa be tagged with PDS II sutures or grasped with allis clamps to prevent retraction.

Surgical teams have taken multiple approaches to vaginal anastomosis. The Cleveland Clinic has used both a running suture as well as a horizontal mattress stitch for closure. For the latter, a 30-inch double-armed 2.0 Vicryl allows for complete suturing of the recipient vagina – with eight stitches placed circumferentially – before the uterus is placed. Both ends of the suture are passed intra-abdominal to intravaginal in the recipient.⁹

Once the donor uterus is suspended, attention focuses on vascular anastomosis, with bilateral end-to-side anastomosis between the donor anterior division of the internal iliac arteries and the external iliac vessels of the recipient, and with venous drainage commonly achieved through the uterine veins draining into the internal or external iliac vein of the recipient. As mentioned, recent cases involving living donors have also demonstrated success with the use of ovarian and/or utero-ovarian veins. Care should be taken to avoid having tension or twisting across the anastomosis.

Courtesy Cleveland Clinic

After adequate graft perfusion is confirmed, with the uterus turning from a dusky color to a pink and well-perfused organ, the vaginal anastomosis is completed, with the arms of the double-armed suture passed through the donor vagina, from intravaginal to intra-abdominal. Tension should be evenly spread along the recipient and donor vagina in order to reduce the formation of granulation tissue and the severity of future vaginal stricturing.

For uterine fixation, polypropylene sutures are placed between the graft uterosacral ligaments and recipient uterine rudiments, and between the graft round ligaments and the recipient pelvic side wall at the level of the deep inguinal ring.

Current uterus transplantation protocols require removal of the uterus after one or two live births are achieved, so that recipients will not be exposed to long-term immunosuppression.
 

Complications and controversies

Postoperative vaginal strictures can make embryo transfer difficult and are a common complication in both living- and deceased-donor models. The Cleveland Clinic team has applied techniques from vaginal reconstructive surgery to try to reduce the occurrence of postoperative strictures – mainly increasing attention paid to anastomosis tissue–site preparation and closure of the anastomosis using a tension-free interrupted suture technique, as described above.⁹ The jury is out on whether such changes are sufficient, and a more complete understanding of the causes of vaginal stricture is needed.

Other perioperative complications include infection and graft thrombosis, both of which typically result in urgent graft hysterectomy. During pregnancy, one of our patients experienced abnormal placentation, though this was not thought to be related to uterus transplantation.⁵

The U.S. Uterus Transplant Consortium (USUTC) is a group of active programs that are sharing ideas and outcomes and advocating for continued research in this rapidly developing field. Uterine transplants require collaboration with transplant surgery, transplant medicine, infectious disease, gynecologic surgery, high-risk obstetrics, and other specialties. While significant progress has been made in a short period of time, uterine transplantation is still in its early stages, and transplants should be done in institutions that have the capacity for mentorship, bioethical oversight, and long-term follow-up of donors, recipients, and offspring.

The USUTC has recently proposed guidelines for nomenclature related to operative technique, vascular anatomy, and uterine transplantation outcomes.¹⁰ It proposes standardizing the names for the four veins originating from the uterus (to eliminate current inconsistency), which will be important as optimal strategies for vascular anastomoses are discussed and determined.

In addition, the consortium is creating a registry for the rigorous collection of data on procedures and outcomes (from menstruation and pregnancy through delivery, graft removal, and long-term follow-up). A registry has also been proposed by the International Society for Uterine Transplantation.

A major question remains in our field: Is the living-donor or deceased-donor uterus transplant the best approach? Knowledge of the quality of the uterus is greater preoperatively within a living-donor model, but no matter how minimally invasive the technique, the donor still assumes some risk of prolonged surgery and extensive pelvic dissection for a transplant that is not lifesaving.

On the other hand, deceased-donor transplants require additional layers of organization and coordination, and the availability of suitable deceased-donor uteri will likely not be sufficient to meet the current demand. Many of us in the field believe that the future of uterine transplantation will involve some combination of living- and deceased-donor transplants – similar to other solid organ transplant programs.

Dr. Flyckt and Dr. Richards reported that they have no relevant financial disclosures.

Correction, 2/2/21: An earlier version of this article misstated Dr. Richards' name in the photo caption.
 

References

1. Lancet. 2015;14:385:607-16.

2. AJOB Empir Bioeth. 2019;10(1):23-5.

3. Transplantation. 2020;104(7):1312-5.

4. Am J Transplant. 2018;18(5):1270-4.

5. Am J Obstet Gynecol. 2020;223(2):143-51.

6. J Minimally Invasive Gynecol. 2019;26:628-35.

7. Acta Obstet Gynecol Scand. 2020;99(9):1222-9.

8. Fertil Steril. 2018;110(1):183.

9. Fertil Steril. 2020 Jul 16. doi: 10.1016/j.fertnstert.2020.05.017

10 Am J Transplant. 2020;20(12):3319-25.

Since the first baby was born after a uterus transplantation in Sweden in 2014, uterus transplantation has been rapidly transitioning toward clinical reality.¹ Several teams in the United States and multiple teams worldwide have performed the procedure, with the total number of worldwide surgeries performed nearing 100.

Uterus transplantation is the first and only true treatment for women with absolute uterine factor infertility – estimated to affect 1 in 500 women – and is filling an unmet need for this population of women. Women who have sought participation in uterus transplantation research have had complex and meaningful reasons and motivations for doing so.² Combined with an accumulation of successful pregnancies, this makes continued research and technical improvement a worthy endeavor.

Most of the births thus far have occurred through the living-donor model; the initial Swedish trial involved nine women, seven of whom completed the procedure with viable transplants from living donors, and gave birth to eight healthy children. (Two required hysterectomy prior to attempted embryo transfer.³)

The Cleveland Clinic opted to build its first – and still ongoing – trial focusing on deceased-donor uterus transplants on the premise that such an approach obviates any risk to the donor and presents the fewest ethical challenges at the current time. Of eight uterus transplants performed thus far at the Cleveland Clinic, there have been three live births and two graft failures. As of early 2021, there was one ongoing pregnancy and two patients in preparation for embryo transfer.

Thus far, neither the living- nor deceased-donor model of uterus transplantation has been demonstrated to be superior. However, as data accrues from deceased donor studies, we will be able to more directly compare outcomes.

In the meantime, alongside a rapid ascent of clinical landmarks – the first live birth in the United States from living-donor uterus transplantation in 2017 at Baylor University Medical Center in Houston,⁴ for instance, and the first live birth in the United States from deceased-donor uterus transplantation in 2019 at the Cleveland Clinic ^– there have been significant improvements in surgical retrieval of the uterus and in the optimization of graft performance.⁵

Most notably, the utero-ovarian vein has been used successfully in living donors to achieve venous drainage of the graft. This has lessened the risks of deep pelvic dissection in the living donor and made the transition to laparoscopic and robotic approaches in the living donor much easier.
 

Donor procurement, venous drainage

Adequate circulatory inflow and outflow for the transplanted uterus are essential both for the prevention of ischemia and thrombosis, which have been major causes of graft failure, and for meeting the increased demands of blood flow during pregnancy. Of the two, the outflow is the more challenging component.

Courtesy Cleveland Clinic

Venous drainage traditionally has been accomplished through the use of the uterine veins, which drain into the internal iliac veins; often the vascular graft will include a portion of the internal iliac vessel which can be connected via anastomoses to the external iliac vein classically in deceased donors. Typically, the gynecologic surgeon on the team performs the vaginal anastomosis and suspension of the uterus, while the transplant surgeons perform the venous and arterial anastomoses.

In the living-donor model, procurement and dissection of these often unpredictable and tortuous complexes in the deep pelvis – particularly the branching uterine veins that lie in close proximity to the ureter, bladder, other blood vessels, and rectum – can be risky. The anatomic variants in the uterine vein are numerous, and even in one patient, a comprehensive dissection on one side cannot be expected to be mirrored on the contralateral side.

Courtesy Cleveland Clinic

In addition to the risk of injury to the donor, the anastomosis may be unsuccessful as the veins are thinly walled and challenging to suture. As such, multiple modifications have been developed, often adapted to the donor’s anatomy and the caliber and accessibility of vessels. Preoperative vascular imaging with CT and/or MRI may help to identify suitable candidates and also may facilitate presurgical planning of which vessels may be selected for use.

Recently, surgeons performing living-donor transplantations have successfully used the more accessible and less risky ovarian and/or utero-ovarian veins for venous anastomosis. In 2019, for instance, a team in Pune, India, reported laparoscopically dissecting the donor ovarian veins and a portion of the internal iliac artery, and completing anastomosis with bilateral donor internal iliac arteries to recipient internal iliac arteries, and bilateral donor ovarian veins to recipient external iliac veins.⁶ It is significant that these smaller-caliber vessels were found to able to support the uterus through pregnancy.

Courtesy Cleveland Clinic

We must be cautious, however, to avoid removing donors’ ovaries. Oophorectomy for women in their 40s can result in significant long-term medical sequelae. Surgeons at Baylor have achieved at least one live birth after harvesting the donor’s utero-ovarian veins while conserving the ovaries – a significant advancement for the living-donor model.⁴

There is tremendous interest in developing minimally invasive approaches to further reduce living-donor risk. The Swedish team has completed a series of eight robotic hysterectomies in living-donor uterus transplantations as part of a second trial. Addressing the reality of a learning curve, their study was designed around a step-wise approach, mastering initial steps first – e.g., dissections of the uterovaginal fossa, arteries, and ureters – and ultimately converting to laparotomy.⁷ In the United States, Baylor University has now completed at least five completely robotic living-donor hysterectomies with complete vaginal extraction.

Published data on robotic surgery suggests that surgical access and perioperative visualization of the vessels may be improved. And as minimally invasive approaches are adopted and improved, the length of donor surgery – 10-13 hours of operating room time in the original Swedish series – should diminish, as should the morbidity associated with laparotomy.

Courtesy Cleveland Clinic

Surgical acquisition of a uterine graft from a deceased donor diminishes concerns for injury to nearby structures. Therefore, although it is a technically similar procedure, a deceased-donor model allows more flexibility with the length, caliber, and number of vessels that can be used for anastomosis. The internal iliac vessels and even portions of the external iliac vessels and ovarian vessels can be used to allow maximum flexibility.⁸

Surgical technique for uterus recipients

For the recipient surgery, entry is achieved via a midline, vertical laparotomy. The external iliac vessels are exposed, and the sites of vascular anastomoses are identified. The peritoneal reflection of the bladder is identified and dissected away to expose the anterior vagina, and the vagina is opened to a diameter that matches the donor, typically using a monopolar electrosurgical cutting instrument.

Courtesy Cleveland Clinic

The vault of the donor vagina will be attached to the recipient’s existing vagina or vaginal pouch. It is important to identify recipient vaginal mucosa and incorporate it into the vaginal anastomosis to reduce the risk of vaginal stricture. We recommend that the vaginal mucosa be tagged with PDS II sutures or grasped with allis clamps to prevent retraction.

Surgical teams have taken multiple approaches to vaginal anastomosis. The Cleveland Clinic has used both a running suture as well as a horizontal mattress stitch for closure. For the latter, a 30-inch double-armed 2.0 Vicryl allows for complete suturing of the recipient vagina – with eight stitches placed circumferentially – before the uterus is placed. Both ends of the suture are passed intra-abdominal to intravaginal in the recipient.⁹

Once the donor uterus is suspended, attention focuses on vascular anastomosis, with bilateral end-to-side anastomosis between the donor anterior division of the internal iliac arteries and the external iliac vessels of the recipient, and with venous drainage commonly achieved through the uterine veins draining into the internal or external iliac vein of the recipient. As mentioned, recent cases involving living donors have also demonstrated success with the use of ovarian and/or utero-ovarian veins. Care should be taken to avoid having tension or twisting across the anastomosis.

Courtesy Cleveland Clinic

After adequate graft perfusion is confirmed, with the uterus turning from a dusky color to a pink and well-perfused organ, the vaginal anastomosis is completed, with the arms of the double-armed suture passed through the donor vagina, from intravaginal to intra-abdominal. Tension should be evenly spread along the recipient and donor vagina in order to reduce the formation of granulation tissue and the severity of future vaginal stricturing.

For uterine fixation, polypropylene sutures are placed between the graft uterosacral ligaments and recipient uterine rudiments, and between the graft round ligaments and the recipient pelvic side wall at the level of the deep inguinal ring.

Current uterus transplantation protocols require removal of the uterus after one or two live births are achieved, so that recipients will not be exposed to long-term immunosuppression.
 

Complications and controversies

Postoperative vaginal strictures can make embryo transfer difficult and are a common complication in both living- and deceased-donor models. The Cleveland Clinic team has applied techniques from vaginal reconstructive surgery to try to reduce the occurrence of postoperative strictures – mainly increasing attention paid to anastomosis tissue–site preparation and closure of the anastomosis using a tension-free interrupted suture technique, as described above.⁹ The jury is out on whether such changes are sufficient, and a more complete understanding of the causes of vaginal stricture is needed.

Other perioperative complications include infection and graft thrombosis, both of which typically result in urgent graft hysterectomy. During pregnancy, one of our patients experienced abnormal placentation, though this was not thought to be related to uterus transplantation.⁵

The U.S. Uterus Transplant Consortium (USUTC) is a group of active programs that are sharing ideas and outcomes and advocating for continued research in this rapidly developing field. Uterine transplants require collaboration with transplant surgery, transplant medicine, infectious disease, gynecologic surgery, high-risk obstetrics, and other specialties. While significant progress has been made in a short period of time, uterine transplantation is still in its early stages, and transplants should be done in institutions that have the capacity for mentorship, bioethical oversight, and long-term follow-up of donors, recipients, and offspring.

The USUTC has recently proposed guidelines for nomenclature related to operative technique, vascular anatomy, and uterine transplantation outcomes.¹⁰ It proposes standardizing the names for the four veins originating from the uterus (to eliminate current inconsistency), which will be important as optimal strategies for vascular anastomoses are discussed and determined.

In addition, the consortium is creating a registry for the rigorous collection of data on procedures and outcomes (from menstruation and pregnancy through delivery, graft removal, and long-term follow-up). A registry has also been proposed by the International Society for Uterine Transplantation.

A major question remains in our field: Is the living-donor or deceased-donor uterus transplant the best approach? Knowledge of the quality of the uterus is greater preoperatively within a living-donor model, but no matter how minimally invasive the technique, the donor still assumes some risk of prolonged surgery and extensive pelvic dissection for a transplant that is not lifesaving.

On the other hand, deceased-donor transplants require additional layers of organization and coordination, and the availability of suitable deceased-donor uteri will likely not be sufficient to meet the current demand. Many of us in the field believe that the future of uterine transplantation will involve some combination of living- and deceased-donor transplants – similar to other solid organ transplant programs.

Dr. Flyckt and Dr. Richards reported that they have no relevant financial disclosures.

Correction, 2/2/21: An earlier version of this article misstated Dr. Richards' name in the photo caption.
 

References

1. Lancet. 2015;14:385:607-16.

2. AJOB Empir Bioeth. 2019;10(1):23-5.

3. Transplantation. 2020;104(7):1312-5.

4. Am J Transplant. 2018;18(5):1270-4.

5. Am J Obstet Gynecol. 2020;223(2):143-51.

6. J Minimally Invasive Gynecol. 2019;26:628-35.

7. Acta Obstet Gynecol Scand. 2020;99(9):1222-9.

8. Fertil Steril. 2018;110(1):183.

9. Fertil Steril. 2020 Jul 16. doi: 10.1016/j.fertnstert.2020.05.017

10 Am J Transplant. 2020;20(12):3319-25.

Until the advent of uterus transplantation, there was no restorative procedure available to a woman presenting with an absent uterus or nonfunctioning uterus; that is, absolute uterine factor infertility (AUFI). It is estimated that 1 in 500 women of childbearing age are affected by AUFI.^1,2 An absent uterus may be secondary to uterine agenesis or Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), which occurs in 1 in 4,500 women.^3,4 (Because women with MRKH have a normal karyotype, their children can be normal, without urogenital malformations.⁵)

Given the fact that roughly 240,000 hysterectomies are performed in the United States each year for women aged under 44 years, hysterectomy is the most common cause of acquired AUFI.⁶AUFI may also be secondary to a uterus that will not support a viable pregnancy; that is, a nonfunctional uterus. In this case, medical or surgical treatment is impossible to enable normal physiological uterine function to produce a successful pregnancy. Causal factors include Müllerian anomalies, severe intrauterine adhesions/Asherman syndrome, uterine fibroids not amendable to surgical therapy, and radiation injury not responsive to medical therapy.

Prior to uterus transplantation, parenthood could only be achieved via adoption, foster parenting, or gestational carrier. While utilizing a gestational carrier is legal in most U.S. states, most countries of western Europe as well as Brazil and Japan, to name a few, do not allow the use of gestational carriers. For some women, moreover, the desire is not only to have a baby, but to carry a child as well.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of Rebecca Flyckt, MD, division chief of reproductive endocrinology and infertility at University Hospitals Cleveland Medical Center and associate professor at Case Western Reserve University, Cleveland, and Elliott G. Richards, MD, director of reproductive endocrinology and infertility research at the Cleveland Clinic, to discuss the current and future state of uterus transplantation.

Dr. Flyckt and Dr. Richards have both contributed to the uterus transplantation team at the Cleveland Clinic and are founding members of the U.S. Uterus Transplant Consortium. They are well published in the field of minimally invasive gynecology and reproductive endocrinology and infertility. It is truly a pleasure to welcome them both to this edition of the Master Class in Gynecologic Surgery.

References

1. Fertil Steril. 2014 May;101(5):1228-36.

2. Acta Biomater. 2014 Dec;10(12):5034-42.

3. Hum Reprod Update. Mar-Apr 2001;7(2):161-74.

4. Obstet Gynecol Surv. 2000 Oct;55(10):644-9.

5. Fertil Steril. 1997 Feb;67(2):387-9

6. Am J Public Health. 2003 Feb;93(2):307-12.
 

Dr. Miller is professor of obstetrics & gynecology in the department of clinical sciences, Rosalind Franklin University, North Chicago, and director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. Dr. Miller reported that he has no disclosures relevant to this Master Class. Email him at [email protected].

Until the advent of uterus transplantation, there was no restorative procedure available to a woman presenting with an absent uterus or nonfunctioning uterus; that is, absolute uterine factor infertility (AUFI). It is estimated that 1 in 500 women of childbearing age are affected by AUFI.^1,2 An absent uterus may be secondary to uterine agenesis or Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), which occurs in 1 in 4,500 women.^3,4 (Because women with MRKH have a normal karyotype, their children can be normal, without urogenital malformations.⁵)

Given the fact that roughly 240,000 hysterectomies are performed in the United States each year for women aged under 44 years, hysterectomy is the most common cause of acquired AUFI.⁶AUFI may also be secondary to a uterus that will not support a viable pregnancy; that is, a nonfunctional uterus. In this case, medical or surgical treatment is impossible to enable normal physiological uterine function to produce a successful pregnancy. Causal factors include Müllerian anomalies, severe intrauterine adhesions/Asherman syndrome, uterine fibroids not amendable to surgical therapy, and radiation injury not responsive to medical therapy.

Prior to uterus transplantation, parenthood could only be achieved via adoption, foster parenting, or gestational carrier. While utilizing a gestational carrier is legal in most U.S. states, most countries of western Europe as well as Brazil and Japan, to name a few, do not allow the use of gestational carriers. For some women, moreover, the desire is not only to have a baby, but to carry a child as well.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of Rebecca Flyckt, MD, division chief of reproductive endocrinology and infertility at University Hospitals Cleveland Medical Center and associate professor at Case Western Reserve University, Cleveland, and Elliott G. Richards, MD, director of reproductive endocrinology and infertility research at the Cleveland Clinic, to discuss the current and future state of uterus transplantation.

Dr. Flyckt and Dr. Richards have both contributed to the uterus transplantation team at the Cleveland Clinic and are founding members of the U.S. Uterus Transplant Consortium. They are well published in the field of minimally invasive gynecology and reproductive endocrinology and infertility. It is truly a pleasure to welcome them both to this edition of the Master Class in Gynecologic Surgery.

References

1. Fertil Steril. 2014 May;101(5):1228-36.

2. Acta Biomater. 2014 Dec;10(12):5034-42.

3. Hum Reprod Update. Mar-Apr 2001;7(2):161-74.

4. Obstet Gynecol Surv. 2000 Oct;55(10):644-9.

5. Fertil Steril. 1997 Feb;67(2):387-9

6. Am J Public Health. 2003 Feb;93(2):307-12.
 

Dr. Miller is professor of obstetrics & gynecology in the department of clinical sciences, Rosalind Franklin University, North Chicago, and director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. Dr. Miller reported that he has no disclosures relevant to this Master Class. Email him at [email protected].

Until the advent of uterus transplantation, there was no restorative procedure available to a woman presenting with an absent uterus or nonfunctioning uterus; that is, absolute uterine factor infertility (AUFI). It is estimated that 1 in 500 women of childbearing age are affected by AUFI.^1,2 An absent uterus may be secondary to uterine agenesis or Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), which occurs in 1 in 4,500 women.^3,4 (Because women with MRKH have a normal karyotype, their children can be normal, without urogenital malformations.⁵)

Given the fact that roughly 240,000 hysterectomies are performed in the United States each year for women aged under 44 years, hysterectomy is the most common cause of acquired AUFI.⁶AUFI may also be secondary to a uterus that will not support a viable pregnancy; that is, a nonfunctional uterus. In this case, medical or surgical treatment is impossible to enable normal physiological uterine function to produce a successful pregnancy. Causal factors include Müllerian anomalies, severe intrauterine adhesions/Asherman syndrome, uterine fibroids not amendable to surgical therapy, and radiation injury not responsive to medical therapy.

Prior to uterus transplantation, parenthood could only be achieved via adoption, foster parenting, or gestational carrier. While utilizing a gestational carrier is legal in most U.S. states, most countries of western Europe as well as Brazil and Japan, to name a few, do not allow the use of gestational carriers. For some women, moreover, the desire is not only to have a baby, but to carry a child as well.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of Rebecca Flyckt, MD, division chief of reproductive endocrinology and infertility at University Hospitals Cleveland Medical Center and associate professor at Case Western Reserve University, Cleveland, and Elliott G. Richards, MD, director of reproductive endocrinology and infertility research at the Cleveland Clinic, to discuss the current and future state of uterus transplantation.

Dr. Flyckt and Dr. Richards have both contributed to the uterus transplantation team at the Cleveland Clinic and are founding members of the U.S. Uterus Transplant Consortium. They are well published in the field of minimally invasive gynecology and reproductive endocrinology and infertility. It is truly a pleasure to welcome them both to this edition of the Master Class in Gynecologic Surgery.

References

1. Fertil Steril. 2014 May;101(5):1228-36.

2. Acta Biomater. 2014 Dec;10(12):5034-42.

3. Hum Reprod Update. Mar-Apr 2001;7(2):161-74.

4. Obstet Gynecol Surv. 2000 Oct;55(10):644-9.

5. Fertil Steril. 1997 Feb;67(2):387-9

6. Am J Public Health. 2003 Feb;93(2):307-12.
 

Dr. Miller is professor of obstetrics & gynecology in the department of clinical sciences, Rosalind Franklin University, North Chicago, and director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. Dr. Miller reported that he has no disclosures relevant to this Master Class. Email him at [email protected].

A systematic review suggests at least one-third of SARS-CoV-2 infections occur in people who never develop symptoms, providing strong evidence for the prevalence of asymptomatic infections.

The finding that nearly one in three infected people remain symptom free suggests testing should be changed, the investigators noted.

“To reduce transmission from people who are presymptomatic or asymptomatic, we need to shift our testing focus to at-home screening,” lead author Daniel Oran, AM, said in an interview. “Inexpensive rapid antigen tests, provided to millions of people for frequent use, could help us significantly reduce the spread of the virus.”

The systematic review was published online Jan. 22 in Annals of Internal Medicine.

The findings come at a dire time when the official number of COVID-19 cases in the United States exceeds 25 million for the first time. Public health officials have raised concerns about more transmissible, and possibly more deadly, variants of SARS-CoV-2, while a new presidential administration tries to meet the challenge of improving vaccine distribution and acceptance rates.

The results also build on earlier findings from the same research team – Mr. Oran and senior author Eric Topol, MD – that published a review article looking at asymptomatic COVID-19 cases. Even though initial data were more limited, they likewise suggested a broader scope of testing is warranted, pointing out that asymptomatic individuals can transmit SARS-CoV-2 for up to 14 days. Dr. Topol is also editor in chief of Medscape.

In the current systematic review, the highest-quality evidence comes from large studies in England and Spain. The nationally representative evidence included serologic surveys from more than 365,000 people in England and more than 61,000 in Spain. When analyzed separately, about the same proportion of asymptomatic cases emerged: 32.4% in England and 33% in Spain.

“It was really remarkable to find that nationwide antibody testing studies in England and Spain – including hundreds of thousands of people – produced nearly identical results: About one-third of the SARS-CoV-2 infections were completely asymptomatic,” said Mr. Oran, a researcher at Scripps Research Translational Institute in La Jolla, Calif.

The systematic review included 43 studies with PCR testing for active SARS-CoV-2 infection and another 18 with antibody results that indicated present or previous infection. The studies were published up until Nov. 17, 2020.

An appreciation for asymptomatic transmission of SARS-CoV-2 infection has come a long way from initial dismissals about its importance, Dr. Topol noted via Twitter. “When Dr. @camilla_rothe reported an asymptomatic transmission a year ago, the @NEJM report was refuted and disparaged. She was later named a TIME 100 Person of the Year.”
 

Not symptomatic vs. never symptomatic

The term “asymptomatic” could be misleading because some people in this group do progress to develop signs of infection. This “presymptomatic” group of patients is likely a minority, the authors noted. Longitudinal studies indicate that about three-quarters of people who are asymptomatic with SARS-CoV-2 remain so.

Dr. Topol anticipated the one-third asymptomatic finding could draw some feedback about distinguishing asymptomatic from presymptomatic individuals. He tweeted, “Some will argue that there is admixture with presymptomatic cases, but review of all the data supports this estimate as being a conservative one.”

The heterogeneity of the settings, populations and other features of the studies prevented the authors from performing a meta-analysis of the findings.
 

Home is where the test is

Based on their findings, Mr. Oran and Dr. Topol believe “that COVID-19 control strategies must be altered, taking into account the prevalence and transmission risk of asymptomatic SARS-CoV-2 infection.” They suggested frequent use of inexpensive, rapid home tests to identify people who are asymptomatic or presymptomatic, along with programs and housing provided by the government to offer financial assistance and allow this group of people to isolate themselves.

Further research is warranted to determine if and how well vaccines for SARS-CoV-2 prevent asymptomatic infection.

Dr. Topol and Mr. Oran created a short video to highlight the findings from their systematic review.

The study was supported by a grant from the National Institutes of Health.

A version of this article first appeared on Medscape.com.

A systematic review suggests at least one-third of SARS-CoV-2 infections occur in people who never develop symptoms, providing strong evidence for the prevalence of asymptomatic infections.

The finding that nearly one in three infected people remain symptom free suggests testing should be changed, the investigators noted.

“To reduce transmission from people who are presymptomatic or asymptomatic, we need to shift our testing focus to at-home screening,” lead author Daniel Oran, AM, said in an interview. “Inexpensive rapid antigen tests, provided to millions of people for frequent use, could help us significantly reduce the spread of the virus.”

The systematic review was published online Jan. 22 in Annals of Internal Medicine.

The findings come at a dire time when the official number of COVID-19 cases in the United States exceeds 25 million for the first time. Public health officials have raised concerns about more transmissible, and possibly more deadly, variants of SARS-CoV-2, while a new presidential administration tries to meet the challenge of improving vaccine distribution and acceptance rates.

The results also build on earlier findings from the same research team – Mr. Oran and senior author Eric Topol, MD – that published a review article looking at asymptomatic COVID-19 cases. Even though initial data were more limited, they likewise suggested a broader scope of testing is warranted, pointing out that asymptomatic individuals can transmit SARS-CoV-2 for up to 14 days. Dr. Topol is also editor in chief of Medscape.

In the current systematic review, the highest-quality evidence comes from large studies in England and Spain. The nationally representative evidence included serologic surveys from more than 365,000 people in England and more than 61,000 in Spain. When analyzed separately, about the same proportion of asymptomatic cases emerged: 32.4% in England and 33% in Spain.

“It was really remarkable to find that nationwide antibody testing studies in England and Spain – including hundreds of thousands of people – produced nearly identical results: About one-third of the SARS-CoV-2 infections were completely asymptomatic,” said Mr. Oran, a researcher at Scripps Research Translational Institute in La Jolla, Calif.

The systematic review included 43 studies with PCR testing for active SARS-CoV-2 infection and another 18 with antibody results that indicated present or previous infection. The studies were published up until Nov. 17, 2020.

An appreciation for asymptomatic transmission of SARS-CoV-2 infection has come a long way from initial dismissals about its importance, Dr. Topol noted via Twitter. “When Dr. @camilla_rothe reported an asymptomatic transmission a year ago, the @NEJM report was refuted and disparaged. She was later named a TIME 100 Person of the Year.”
 

Not symptomatic vs. never symptomatic

The term “asymptomatic” could be misleading because some people in this group do progress to develop signs of infection. This “presymptomatic” group of patients is likely a minority, the authors noted. Longitudinal studies indicate that about three-quarters of people who are asymptomatic with SARS-CoV-2 remain so.

Dr. Topol anticipated the one-third asymptomatic finding could draw some feedback about distinguishing asymptomatic from presymptomatic individuals. He tweeted, “Some will argue that there is admixture with presymptomatic cases, but review of all the data supports this estimate as being a conservative one.”

The heterogeneity of the settings, populations and other features of the studies prevented the authors from performing a meta-analysis of the findings.
 

Home is where the test is

Based on their findings, Mr. Oran and Dr. Topol believe “that COVID-19 control strategies must be altered, taking into account the prevalence and transmission risk of asymptomatic SARS-CoV-2 infection.” They suggested frequent use of inexpensive, rapid home tests to identify people who are asymptomatic or presymptomatic, along with programs and housing provided by the government to offer financial assistance and allow this group of people to isolate themselves.

Further research is warranted to determine if and how well vaccines for SARS-CoV-2 prevent asymptomatic infection.

Dr. Topol and Mr. Oran created a short video to highlight the findings from their systematic review.

The study was supported by a grant from the National Institutes of Health.

A version of this article first appeared on Medscape.com.

A systematic review suggests at least one-third of SARS-CoV-2 infections occur in people who never develop symptoms, providing strong evidence for the prevalence of asymptomatic infections.

The finding that nearly one in three infected people remain symptom free suggests testing should be changed, the investigators noted.

“To reduce transmission from people who are presymptomatic or asymptomatic, we need to shift our testing focus to at-home screening,” lead author Daniel Oran, AM, said in an interview. “Inexpensive rapid antigen tests, provided to millions of people for frequent use, could help us significantly reduce the spread of the virus.”

The systematic review was published online Jan. 22 in Annals of Internal Medicine.

The findings come at a dire time when the official number of COVID-19 cases in the United States exceeds 25 million for the first time. Public health officials have raised concerns about more transmissible, and possibly more deadly, variants of SARS-CoV-2, while a new presidential administration tries to meet the challenge of improving vaccine distribution and acceptance rates.

The results also build on earlier findings from the same research team – Mr. Oran and senior author Eric Topol, MD – that published a review article looking at asymptomatic COVID-19 cases. Even though initial data were more limited, they likewise suggested a broader scope of testing is warranted, pointing out that asymptomatic individuals can transmit SARS-CoV-2 for up to 14 days. Dr. Topol is also editor in chief of Medscape.

In the current systematic review, the highest-quality evidence comes from large studies in England and Spain. The nationally representative evidence included serologic surveys from more than 365,000 people in England and more than 61,000 in Spain. When analyzed separately, about the same proportion of asymptomatic cases emerged: 32.4% in England and 33% in Spain.

“It was really remarkable to find that nationwide antibody testing studies in England and Spain – including hundreds of thousands of people – produced nearly identical results: About one-third of the SARS-CoV-2 infections were completely asymptomatic,” said Mr. Oran, a researcher at Scripps Research Translational Institute in La Jolla, Calif.

The systematic review included 43 studies with PCR testing for active SARS-CoV-2 infection and another 18 with antibody results that indicated present or previous infection. The studies were published up until Nov. 17, 2020.

An appreciation for asymptomatic transmission of SARS-CoV-2 infection has come a long way from initial dismissals about its importance, Dr. Topol noted via Twitter. “When Dr. @camilla_rothe reported an asymptomatic transmission a year ago, the @NEJM report was refuted and disparaged. She was later named a TIME 100 Person of the Year.”
 

Not symptomatic vs. never symptomatic

The term “asymptomatic” could be misleading because some people in this group do progress to develop signs of infection. This “presymptomatic” group of patients is likely a minority, the authors noted. Longitudinal studies indicate that about three-quarters of people who are asymptomatic with SARS-CoV-2 remain so.

Dr. Topol anticipated the one-third asymptomatic finding could draw some feedback about distinguishing asymptomatic from presymptomatic individuals. He tweeted, “Some will argue that there is admixture with presymptomatic cases, but review of all the data supports this estimate as being a conservative one.”

The heterogeneity of the settings, populations and other features of the studies prevented the authors from performing a meta-analysis of the findings.
 

Home is where the test is

Based on their findings, Mr. Oran and Dr. Topol believe “that COVID-19 control strategies must be altered, taking into account the prevalence and transmission risk of asymptomatic SARS-CoV-2 infection.” They suggested frequent use of inexpensive, rapid home tests to identify people who are asymptomatic or presymptomatic, along with programs and housing provided by the government to offer financial assistance and allow this group of people to isolate themselves.

Further research is warranted to determine if and how well vaccines for SARS-CoV-2 prevent asymptomatic infection.

Dr. Topol and Mr. Oran created a short video to highlight the findings from their systematic review.

The study was supported by a grant from the National Institutes of Health.

A version of this article first appeared on Medscape.com.

Cabenuva (cabotegravir and rilpivirine, a once-per-month injectable formulation) was approved by the Food and Drug Administration as a complete regimen for treatment of HIV-1 infection in adults. It is intended to replace current antiretroviral regimens in those patients who are virologically suppressed with no history of treatment failure and with no known or suspected resistance to either of the two component drugs.

Cabenuva is the first FDA-approved monthly injectable, complete regimen for HIV-infected adults, according to the agency’s announcement.

In addition, the FDA-approved Vocabria (cabotegravir, tablet formulation), a preparatory treatment intended to be taken in combination with oral rilpivirine (Edurant) for 1 month prior to starting treatment with Cabenuva to ensure the medications are well tolerated before switching to the extended-release injectable formulation. The FDA granted the approval of Cabenuva and Vocabria to ViiV Healthcare.

Cabotegravir is as an integrase strand transfer inhibitor that blocks HIV integrase by attaching to the active integrase site and inhibiting retroviral DNA integration, which is necessary in order for HIV to replicate. In contrast, rilpivirine acts as a diarylpyrimidine nonnucleoside reverse transcriptase inhibitor of HIV-1.

Approval of Cabenuva was based upon two randomized, open-label, controlled clinical trials in 1,182 HIV-infected adults who were virologically suppressed (HIV-1 RNA less than 50 copies/mL) before initiation of treatment with Cabenuva. The two pivotal phase three clinical studies were: Antiretroviral Therapy as Long-Acting Suppression (ATLAS; NCT02951052) and First Long-Acting Injectable Regimen (FLAIR; NCT02938520). Patients in both trials continued to show virologic suppression at the conclusion of each study, and no clinically relevant change from baseline in CD4+ cell counts was observed, according to the FDA announcement.

Adverse reactions with Cabenuva included injection-site reactions, fever, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. The FDA warned that Cabenuva should not be used if there is a known previous hypersensitivity reaction to cabotegravir or rilpivirine, or in patients who are not virally suppressed (HIV-1 RNA greater than 50 copies/mL).

Cabenuva and Vocabria were granted Fast Track and Priority Review designation by the FDA. Prescribing information for Cabenuva is available on the ViiV Healthcare website.

[email protected]

Cabenuva (cabotegravir and rilpivirine, a once-per-month injectable formulation) was approved by the Food and Drug Administration as a complete regimen for treatment of HIV-1 infection in adults. It is intended to replace current antiretroviral regimens in those patients who are virologically suppressed with no history of treatment failure and with no known or suspected resistance to either of the two component drugs.

Cabenuva is the first FDA-approved monthly injectable, complete regimen for HIV-infected adults, according to the agency’s announcement.

In addition, the FDA-approved Vocabria (cabotegravir, tablet formulation), a preparatory treatment intended to be taken in combination with oral rilpivirine (Edurant) for 1 month prior to starting treatment with Cabenuva to ensure the medications are well tolerated before switching to the extended-release injectable formulation. The FDA granted the approval of Cabenuva and Vocabria to ViiV Healthcare.

Cabotegravir is as an integrase strand transfer inhibitor that blocks HIV integrase by attaching to the active integrase site and inhibiting retroviral DNA integration, which is necessary in order for HIV to replicate. In contrast, rilpivirine acts as a diarylpyrimidine nonnucleoside reverse transcriptase inhibitor of HIV-1.

Approval of Cabenuva was based upon two randomized, open-label, controlled clinical trials in 1,182 HIV-infected adults who were virologically suppressed (HIV-1 RNA less than 50 copies/mL) before initiation of treatment with Cabenuva. The two pivotal phase three clinical studies were: Antiretroviral Therapy as Long-Acting Suppression (ATLAS; NCT02951052) and First Long-Acting Injectable Regimen (FLAIR; NCT02938520). Patients in both trials continued to show virologic suppression at the conclusion of each study, and no clinically relevant change from baseline in CD4+ cell counts was observed, according to the FDA announcement.

Adverse reactions with Cabenuva included injection-site reactions, fever, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. The FDA warned that Cabenuva should not be used if there is a known previous hypersensitivity reaction to cabotegravir or rilpivirine, or in patients who are not virally suppressed (HIV-1 RNA greater than 50 copies/mL).

Cabenuva and Vocabria were granted Fast Track and Priority Review designation by the FDA. Prescribing information for Cabenuva is available on the ViiV Healthcare website.

[email protected]

Cabenuva (cabotegravir and rilpivirine, a once-per-month injectable formulation) was approved by the Food and Drug Administration as a complete regimen for treatment of HIV-1 infection in adults. It is intended to replace current antiretroviral regimens in those patients who are virologically suppressed with no history of treatment failure and with no known or suspected resistance to either of the two component drugs.

Cabenuva is the first FDA-approved monthly injectable, complete regimen for HIV-infected adults, according to the agency’s announcement.

In addition, the FDA-approved Vocabria (cabotegravir, tablet formulation), a preparatory treatment intended to be taken in combination with oral rilpivirine (Edurant) for 1 month prior to starting treatment with Cabenuva to ensure the medications are well tolerated before switching to the extended-release injectable formulation. The FDA granted the approval of Cabenuva and Vocabria to ViiV Healthcare.

Cabotegravir is as an integrase strand transfer inhibitor that blocks HIV integrase by attaching to the active integrase site and inhibiting retroviral DNA integration, which is necessary in order for HIV to replicate. In contrast, rilpivirine acts as a diarylpyrimidine nonnucleoside reverse transcriptase inhibitor of HIV-1.

Approval of Cabenuva was based upon two randomized, open-label, controlled clinical trials in 1,182 HIV-infected adults who were virologically suppressed (HIV-1 RNA less than 50 copies/mL) before initiation of treatment with Cabenuva. The two pivotal phase three clinical studies were: Antiretroviral Therapy as Long-Acting Suppression (ATLAS; NCT02951052) and First Long-Acting Injectable Regimen (FLAIR; NCT02938520). Patients in both trials continued to show virologic suppression at the conclusion of each study, and no clinically relevant change from baseline in CD4+ cell counts was observed, according to the FDA announcement.

Adverse reactions with Cabenuva included injection-site reactions, fever, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. The FDA warned that Cabenuva should not be used if there is a known previous hypersensitivity reaction to cabotegravir or rilpivirine, or in patients who are not virally suppressed (HIV-1 RNA greater than 50 copies/mL).

Cabenuva and Vocabria were granted Fast Track and Priority Review designation by the FDA. Prescribing information for Cabenuva is available on the ViiV Healthcare website.

[email protected]

The current COVID-19 vaccines may not be as effective against new coronavirus variants, but they should be powerful enough to still be beneficial, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said during a news briefing on Jan. 21.

Both vaccines from Pfizer-BioNTech and Moderna have such high efficacy rates that it creates a “cushion effect,” he said, meaning that new variants will likely only diminish vaccine efficacy slightly. To slow the spread of the new strains, Dr. Fauci said, people should get vaccinated as soon as possible. If viruses can’t spread as far or as quickly, they won’t mutate as much.

“Bottom line: We’re paying very close attention to it,” he said. “There are alternative plans if we ever have to modify the vaccine.”

The U.S. has reported 144 cases of the B.1.1.7 variant, which was first identified in the United Kingdom, according to the latest update from the CDC. So far, no cases of the variant strain identified in South Africa have been reported in the U.S., but Dr. Fauci said public health officials are looking for it.

“We’re following very carefully the one in South Africa, which is a little bit more concerning, but nonetheless not something that we don’t think we can handle,” he said.

Despite challenges with vaccine distribution and administration, the U.S. “can and should” vaccinate 70% to 85% of adults by the end of the summer, Dr. Fauci told CNN. If that happens, people could begin to return to some sense of normalcy by the fall, he added.

“When you put ... the pedal to the floor, you can get it done,” he said.

If the U.S. administered one million shots per day, it would take until the end of 2021 to fully vaccine 75% of adults, according to a CNN analysis. Dr. Fauci said he believes the U.S. can give more than one million shots per day. An updated tally from the CDC showed that 1.6 million shots were given in the past 24 hours, which was the largest single-day increase yet reported.

“I’d like it to be a lot more,” Dr. Fauci told CNN. “If we can do better than that, which I personally think we likely will, then great.”

A version of this article first appeared on WebMD.com.

The current COVID-19 vaccines may not be as effective against new coronavirus variants, but they should be powerful enough to still be beneficial, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said during a news briefing on Jan. 21.

Both vaccines from Pfizer-BioNTech and Moderna have such high efficacy rates that it creates a “cushion effect,” he said, meaning that new variants will likely only diminish vaccine efficacy slightly. To slow the spread of the new strains, Dr. Fauci said, people should get vaccinated as soon as possible. If viruses can’t spread as far or as quickly, they won’t mutate as much.

“Bottom line: We’re paying very close attention to it,” he said. “There are alternative plans if we ever have to modify the vaccine.”

The U.S. has reported 144 cases of the B.1.1.7 variant, which was first identified in the United Kingdom, according to the latest update from the CDC. So far, no cases of the variant strain identified in South Africa have been reported in the U.S., but Dr. Fauci said public health officials are looking for it.

“We’re following very carefully the one in South Africa, which is a little bit more concerning, but nonetheless not something that we don’t think we can handle,” he said.

Despite challenges with vaccine distribution and administration, the U.S. “can and should” vaccinate 70% to 85% of adults by the end of the summer, Dr. Fauci told CNN. If that happens, people could begin to return to some sense of normalcy by the fall, he added.

“When you put ... the pedal to the floor, you can get it done,” he said.

If the U.S. administered one million shots per day, it would take until the end of 2021 to fully vaccine 75% of adults, according to a CNN analysis. Dr. Fauci said he believes the U.S. can give more than one million shots per day. An updated tally from the CDC showed that 1.6 million shots were given in the past 24 hours, which was the largest single-day increase yet reported.

“I’d like it to be a lot more,” Dr. Fauci told CNN. “If we can do better than that, which I personally think we likely will, then great.”

A version of this article first appeared on WebMD.com.

The current COVID-19 vaccines may not be as effective against new coronavirus variants, but they should be powerful enough to still be beneficial, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said during a news briefing on Jan. 21.

Both vaccines from Pfizer-BioNTech and Moderna have such high efficacy rates that it creates a “cushion effect,” he said, meaning that new variants will likely only diminish vaccine efficacy slightly. To slow the spread of the new strains, Dr. Fauci said, people should get vaccinated as soon as possible. If viruses can’t spread as far or as quickly, they won’t mutate as much.

“Bottom line: We’re paying very close attention to it,” he said. “There are alternative plans if we ever have to modify the vaccine.”

The U.S. has reported 144 cases of the B.1.1.7 variant, which was first identified in the United Kingdom, according to the latest update from the CDC. So far, no cases of the variant strain identified in South Africa have been reported in the U.S., but Dr. Fauci said public health officials are looking for it.

“We’re following very carefully the one in South Africa, which is a little bit more concerning, but nonetheless not something that we don’t think we can handle,” he said.

Despite challenges with vaccine distribution and administration, the U.S. “can and should” vaccinate 70% to 85% of adults by the end of the summer, Dr. Fauci told CNN. If that happens, people could begin to return to some sense of normalcy by the fall, he added.

“When you put ... the pedal to the floor, you can get it done,” he said.

If the U.S. administered one million shots per day, it would take until the end of 2021 to fully vaccine 75% of adults, according to a CNN analysis. Dr. Fauci said he believes the U.S. can give more than one million shots per day. An updated tally from the CDC showed that 1.6 million shots were given in the past 24 hours, which was the largest single-day increase yet reported.

“I’d like it to be a lot more,” Dr. Fauci told CNN. “If we can do better than that, which I personally think we likely will, then great.”

A version of this article first appeared on WebMD.com.

The oral, anti-inflammatory drug colchicine can prevent complications and hospitalizations in nonhospitalized patients newly diagnosed with COVID-19, according to a press release from the ColCORONA trial investigators.

After 1 month of therapy, there was a 21% risk reduction in the primary composite endpoint of death or hospitalizations that missed statistical significance, compared with placebo among 4,488 outpatients enrolled in the global, phase 3 trial.

After excluding 329 patients without a confirmatory polymerase chain reaction test, however, the use of colchicine was reported to significantly reduce hospitalizations by 25%, the need for mechanical ventilation by 50%, and deaths by 44%.

“We believe that this is a medical breakthrough. There’s no approved therapy to prevent complications of COVID-19 in outpatients, to prevent them from reaching the hospital,” lead investigator Jean-Claude Tardif, MD, from the Montreal Heart Institute, said in an interview.

“I know that several countries will be reviewing the data very rapidly and that Greece approved it today,” he said. “So this is providing hope for patients.”

Having been burned by hydroxychloroquine and other treatments brought forth without peer review, the response to the announcement was tempered by a desire for more details.

Asked for comment, Steven E. Nissen, MD, of the Cleveland Clinic Foundation, was cautious. “The press release about the trial is vague and lacks details such as hazard ratios, confidence intervals, and P values,” he said in an interview.

“It is impossible to evaluate the results of this trial without these details. It is also uncertain how rigorously data were collected,” he added. “We’ll need to see the manuscript to adequately interpret the results.”

The evidence in the press release is hard to interpret, but early intervention with anti-inflammatory therapy has considerable biologic appeal in COVID, said Paul Ridker, MD, MPH, who led the pivotal CANTOS trial of the anti-inflammatory drug canakinumab in the post-MI setting, and is also chair of the ACTIV-4B trial currently investigating anticoagulants and antithrombotics in outpatient COVID-19.

“Colchicine is both inexpensive and generally well tolerated, and the apparent benefits so far reported are substantial,” Dr. Ridker, from Brigham and Women’s Hospital in Boston, said in an interview. “We are eager to see the full data as rapidly as possible.”

The commonly used gout and rheumatic disease agent costs about 26 cents in Canada and between $4 and $6 in the United States. As previously reported, it reduced the time to clinical deterioration and hospital stay but not mortality in the 105-patient Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention (GRECCO-19) study.

Dr. Tardif said he’s looking forward to having the data in the public domain and that they acted swiftly because the evidence was “clinically persuasive” and “the health system is congested now.”

“We received the results Friday, Jan. 22 at 5 p.m., an hour later we were in meetings with our data safety monitoring board [DSMB], 2 hours later we issued a press release, and a day later we’re submitting a full manuscript to a major scientific journal, so I don’t know if anyone has done this at this speed,” he said. “So we are actually very proud of what we did.”

ColCORONA was designed to enroll 6,000 outpatients, at least 40 years of age, who were diagnosed with COVID-19 infection within the previous 24 hours, and had a least one high-risk criterion, including age at least 70 years, body mass index of at least 30 kg/m², diabetes mellitus, uncontrolled hypertension, known respiratory disease, heart failure or coronary disease, fever of at least 38.4° C within the last 48 hours, dyspnea at presentation, bicytopenia, pancytopenia, or the combination of high neutrophil count and low lymphocyte count.

Participants were randomly assigned to receive either placebo or colchicine 0.5 mg twice daily for 3 days and then once daily for another 27 days.

The number needed to prevent one COVID-19 complication is about 60 patients, Dr. Tardif said.

Colchicine was well tolerated and resulted in fewer serious adverse events than with placebo, he said. Diarrhea occurred more often with colchicine, but there was no increase in pneumonia. Caution should be used, however, in treating patients with severe renal disease.

Dr. Tardif said he would not prescribe colchicine to an 18-year-old COVID outpatient who doesn’t have any concomitant diseases, but would for those meeting the study protocol.

“As long as a patient appears to me to be at risk of a complication, I would prescribe it, without a doubt,” he said. “I can tell you that when we held the meeting with the DSMB Friday evening, I actually put each member on the spot and asked them: ‘If it were you – not even treating a patient, but if you had COVID today, would you take it based on the data you’ve seen?’ and all of the DSMB members said they would.

“So we’ll have that debate in the public domain when the paper is out, but I believe most physicians will use it to treat their patients.”

The trial was coordinated by the Montreal Heart Institute and funded by the government of Quebec; the U.S. National Heart, Lung, and Blood Institute; Montreal philanthropist Sophie Desmarais; and the COVID-19 Therapeutics Accelerator launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard. CGI, Dacima, and Pharmascience of Montreal were also collaborators.

A version of this article first appeared on Medscape.com.

The oral, anti-inflammatory drug colchicine can prevent complications and hospitalizations in nonhospitalized patients newly diagnosed with COVID-19, according to a press release from the ColCORONA trial investigators.

After 1 month of therapy, there was a 21% risk reduction in the primary composite endpoint of death or hospitalizations that missed statistical significance, compared with placebo among 4,488 outpatients enrolled in the global, phase 3 trial.

After excluding 329 patients without a confirmatory polymerase chain reaction test, however, the use of colchicine was reported to significantly reduce hospitalizations by 25%, the need for mechanical ventilation by 50%, and deaths by 44%.

“We believe that this is a medical breakthrough. There’s no approved therapy to prevent complications of COVID-19 in outpatients, to prevent them from reaching the hospital,” lead investigator Jean-Claude Tardif, MD, from the Montreal Heart Institute, said in an interview.

“I know that several countries will be reviewing the data very rapidly and that Greece approved it today,” he said. “So this is providing hope for patients.”

Having been burned by hydroxychloroquine and other treatments brought forth without peer review, the response to the announcement was tempered by a desire for more details.

Asked for comment, Steven E. Nissen, MD, of the Cleveland Clinic Foundation, was cautious. “The press release about the trial is vague and lacks details such as hazard ratios, confidence intervals, and P values,” he said in an interview.

“It is impossible to evaluate the results of this trial without these details. It is also uncertain how rigorously data were collected,” he added. “We’ll need to see the manuscript to adequately interpret the results.”

The evidence in the press release is hard to interpret, but early intervention with anti-inflammatory therapy has considerable biologic appeal in COVID, said Paul Ridker, MD, MPH, who led the pivotal CANTOS trial of the anti-inflammatory drug canakinumab in the post-MI setting, and is also chair of the ACTIV-4B trial currently investigating anticoagulants and antithrombotics in outpatient COVID-19.

“Colchicine is both inexpensive and generally well tolerated, and the apparent benefits so far reported are substantial,” Dr. Ridker, from Brigham and Women’s Hospital in Boston, said in an interview. “We are eager to see the full data as rapidly as possible.”

The commonly used gout and rheumatic disease agent costs about 26 cents in Canada and between $4 and $6 in the United States. As previously reported, it reduced the time to clinical deterioration and hospital stay but not mortality in the 105-patient Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention (GRECCO-19) study.

Dr. Tardif said he’s looking forward to having the data in the public domain and that they acted swiftly because the evidence was “clinically persuasive” and “the health system is congested now.”

“We received the results Friday, Jan. 22 at 5 p.m., an hour later we were in meetings with our data safety monitoring board [DSMB], 2 hours later we issued a press release, and a day later we’re submitting a full manuscript to a major scientific journal, so I don’t know if anyone has done this at this speed,” he said. “So we are actually very proud of what we did.”

ColCORONA was designed to enroll 6,000 outpatients, at least 40 years of age, who were diagnosed with COVID-19 infection within the previous 24 hours, and had a least one high-risk criterion, including age at least 70 years, body mass index of at least 30 kg/m², diabetes mellitus, uncontrolled hypertension, known respiratory disease, heart failure or coronary disease, fever of at least 38.4° C within the last 48 hours, dyspnea at presentation, bicytopenia, pancytopenia, or the combination of high neutrophil count and low lymphocyte count.

Participants were randomly assigned to receive either placebo or colchicine 0.5 mg twice daily for 3 days and then once daily for another 27 days.

The number needed to prevent one COVID-19 complication is about 60 patients, Dr. Tardif said.

Colchicine was well tolerated and resulted in fewer serious adverse events than with placebo, he said. Diarrhea occurred more often with colchicine, but there was no increase in pneumonia. Caution should be used, however, in treating patients with severe renal disease.

Dr. Tardif said he would not prescribe colchicine to an 18-year-old COVID outpatient who doesn’t have any concomitant diseases, but would for those meeting the study protocol.

“As long as a patient appears to me to be at risk of a complication, I would prescribe it, without a doubt,” he said. “I can tell you that when we held the meeting with the DSMB Friday evening, I actually put each member on the spot and asked them: ‘If it were you – not even treating a patient, but if you had COVID today, would you take it based on the data you’ve seen?’ and all of the DSMB members said they would.

“So we’ll have that debate in the public domain when the paper is out, but I believe most physicians will use it to treat their patients.”

The trial was coordinated by the Montreal Heart Institute and funded by the government of Quebec; the U.S. National Heart, Lung, and Blood Institute; Montreal philanthropist Sophie Desmarais; and the COVID-19 Therapeutics Accelerator launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard. CGI, Dacima, and Pharmascience of Montreal were also collaborators.

A version of this article first appeared on Medscape.com.

The oral, anti-inflammatory drug colchicine can prevent complications and hospitalizations in nonhospitalized patients newly diagnosed with COVID-19, according to a press release from the ColCORONA trial investigators.

After 1 month of therapy, there was a 21% risk reduction in the primary composite endpoint of death or hospitalizations that missed statistical significance, compared with placebo among 4,488 outpatients enrolled in the global, phase 3 trial.

After excluding 329 patients without a confirmatory polymerase chain reaction test, however, the use of colchicine was reported to significantly reduce hospitalizations by 25%, the need for mechanical ventilation by 50%, and deaths by 44%.

“We believe that this is a medical breakthrough. There’s no approved therapy to prevent complications of COVID-19 in outpatients, to prevent them from reaching the hospital,” lead investigator Jean-Claude Tardif, MD, from the Montreal Heart Institute, said in an interview.

“I know that several countries will be reviewing the data very rapidly and that Greece approved it today,” he said. “So this is providing hope for patients.”

Having been burned by hydroxychloroquine and other treatments brought forth without peer review, the response to the announcement was tempered by a desire for more details.

Asked for comment, Steven E. Nissen, MD, of the Cleveland Clinic Foundation, was cautious. “The press release about the trial is vague and lacks details such as hazard ratios, confidence intervals, and P values,” he said in an interview.

“It is impossible to evaluate the results of this trial without these details. It is also uncertain how rigorously data were collected,” he added. “We’ll need to see the manuscript to adequately interpret the results.”

The evidence in the press release is hard to interpret, but early intervention with anti-inflammatory therapy has considerable biologic appeal in COVID, said Paul Ridker, MD, MPH, who led the pivotal CANTOS trial of the anti-inflammatory drug canakinumab in the post-MI setting, and is also chair of the ACTIV-4B trial currently investigating anticoagulants and antithrombotics in outpatient COVID-19.

“Colchicine is both inexpensive and generally well tolerated, and the apparent benefits so far reported are substantial,” Dr. Ridker, from Brigham and Women’s Hospital in Boston, said in an interview. “We are eager to see the full data as rapidly as possible.”

The commonly used gout and rheumatic disease agent costs about 26 cents in Canada and between $4 and $6 in the United States. As previously reported, it reduced the time to clinical deterioration and hospital stay but not mortality in the 105-patient Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention (GRECCO-19) study.

Dr. Tardif said he’s looking forward to having the data in the public domain and that they acted swiftly because the evidence was “clinically persuasive” and “the health system is congested now.”

“We received the results Friday, Jan. 22 at 5 p.m., an hour later we were in meetings with our data safety monitoring board [DSMB], 2 hours later we issued a press release, and a day later we’re submitting a full manuscript to a major scientific journal, so I don’t know if anyone has done this at this speed,” he said. “So we are actually very proud of what we did.”

ColCORONA was designed to enroll 6,000 outpatients, at least 40 years of age, who were diagnosed with COVID-19 infection within the previous 24 hours, and had a least one high-risk criterion, including age at least 70 years, body mass index of at least 30 kg/m², diabetes mellitus, uncontrolled hypertension, known respiratory disease, heart failure or coronary disease, fever of at least 38.4° C within the last 48 hours, dyspnea at presentation, bicytopenia, pancytopenia, or the combination of high neutrophil count and low lymphocyte count.

Participants were randomly assigned to receive either placebo or colchicine 0.5 mg twice daily for 3 days and then once daily for another 27 days.

The number needed to prevent one COVID-19 complication is about 60 patients, Dr. Tardif said.

Colchicine was well tolerated and resulted in fewer serious adverse events than with placebo, he said. Diarrhea occurred more often with colchicine, but there was no increase in pneumonia. Caution should be used, however, in treating patients with severe renal disease.

Dr. Tardif said he would not prescribe colchicine to an 18-year-old COVID outpatient who doesn’t have any concomitant diseases, but would for those meeting the study protocol.

“As long as a patient appears to me to be at risk of a complication, I would prescribe it, without a doubt,” he said. “I can tell you that when we held the meeting with the DSMB Friday evening, I actually put each member on the spot and asked them: ‘If it were you – not even treating a patient, but if you had COVID today, would you take it based on the data you’ve seen?’ and all of the DSMB members said they would.

“So we’ll have that debate in the public domain when the paper is out, but I believe most physicians will use it to treat their patients.”

The trial was coordinated by the Montreal Heart Institute and funded by the government of Quebec; the U.S. National Heart, Lung, and Blood Institute; Montreal philanthropist Sophie Desmarais; and the COVID-19 Therapeutics Accelerator launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard. CGI, Dacima, and Pharmascience of Montreal were also collaborators.

A version of this article first appeared on Medscape.com.

Full-dose anticoagulation was superior to low, prophylactic doses in reducing the need for vital organ support such as ventilation in moderately ill patients hospitalized for COVID-19, according to a report released Jan. 22 by the National Institutes of Health (NIH).

“This is a major advance for patients hospitalized with COVID. Full dose of anticoagulation in these non-ICU patients improved outcomes and there’s a trend toward a reduction in mortality,” Judith Hochman, MD, director of the Cardiovascular Clinical Research Center at NYU Langone Medical Center, New York, said in an interview.

“We have treatments that are improving outcomes but not as many that reduce mortality, so we’re hopeful when the full dataset comes in that will be confirmed,” she said.

The observation of increased rates of blood clots and inflammation among COVID-19 patients, which can lead to complications such as lung failure, heart attack, and stroke, has given rise to various anticoagulant treatment protocols and a need for randomized data on routinely administering increased doses of anticoagulation to hospitalized patients.

Today’s top-line findings come from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – examining the safety and efficacy of full-dose anticoagulation to treat moderately ill or critically ill adults hospitalized with COVID-19 compared with a lower dose typically used to prevent blood clots in hospitalized patients.

In December 2020, all three trials paused enrollment of the critically ill subgroup after results showed that full-dose anticoagulation started in the intensive care unit (ICU) was not beneficial and may have been harmful in some patients.

Moderately ill patients with COVID-19, defined as those who did not require ICU care or organ support, made up 80% of participants at enrollment in the three trials, Dr. Hochman said.

Among more than 1,000 moderately ill patients reviewed as of the data cut with the data safety monitoring board, full doses of low molecular weight or unfractionated heparin were superior to low prophylactic doses for the primary endpoint of need for ventilation or other organ supportive interventions at 21 days after randomization.

This met the predefined threshold for 99% probability of superiority and recruitment was stopped, Dr. Hochman reported. “Obviously safety figured into this decision. The risk/benefit ratio was very clear.”

The results do not pertain to patients with a previous indication for anticoagulation, who were excluded from the trials.

Data from an additional 1,000 patients will be reviewed and the data published sometime in the next 2-3 months, she said.

With large numbers of COVID-19 patients requiring hospitalization, the outcomes could help reduce the overload on intensive care units around the world, the NIH noted.

The results also highlight the critical role of timing in the course of COVID-19.

“We believe that full anticoagulation is effective early in the disease course,” Dr. Hochman said. “Based on the results so far from these three platform trials, those that were very, very sick at the time of enrollment really didn’t benefit and we needed to have caught them at an earlier stage.

“It’s possible that the people in the ICU are just different and the minute they get sick they need the ICU; so we haven’t clearly demonstrated this time course and when to intervene, but that’s the implication of the findings.”

The question of even earlier treatment is being examined in the partner ACTIV-4B trial, which is enrolling patients with COVID-19 illness not requiring hospitalization and randomizing them to the direct oral anticoagulant apixaban or aspirin or placebo.

“It’s a very important trial and we really want to get the message out that patients should volunteer for it,” said Dr. Hochman, principal investigator of the ACTIV-4 trial.

In the United States, the ACTIV-4 trial is being led by a collaborative effort involving a number of universities, including the University of Pittsburgh and New York University.

The REMAP-CAP, ACTIV-4, and ATTACC study platforms span five continents in more than 300 hospitals and are supported by multiple international funding organizations including the National Institutes of Health, Canadian Institutes of Health Research, the National Institute for Health Research (United Kingdom), the National Health and Medical Research Council (Australia), and the PREPARE and RECOVER consortia (European Union).

A version of this article first appeared on Medscape.com.

Full-dose anticoagulation was superior to low, prophylactic doses in reducing the need for vital organ support such as ventilation in moderately ill patients hospitalized for COVID-19, according to a report released Jan. 22 by the National Institutes of Health (NIH).

“This is a major advance for patients hospitalized with COVID. Full dose of anticoagulation in these non-ICU patients improved outcomes and there’s a trend toward a reduction in mortality,” Judith Hochman, MD, director of the Cardiovascular Clinical Research Center at NYU Langone Medical Center, New York, said in an interview.

“We have treatments that are improving outcomes but not as many that reduce mortality, so we’re hopeful when the full dataset comes in that will be confirmed,” she said.

The observation of increased rates of blood clots and inflammation among COVID-19 patients, which can lead to complications such as lung failure, heart attack, and stroke, has given rise to various anticoagulant treatment protocols and a need for randomized data on routinely administering increased doses of anticoagulation to hospitalized patients.

Today’s top-line findings come from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – examining the safety and efficacy of full-dose anticoagulation to treat moderately ill or critically ill adults hospitalized with COVID-19 compared with a lower dose typically used to prevent blood clots in hospitalized patients.

In December 2020, all three trials paused enrollment of the critically ill subgroup after results showed that full-dose anticoagulation started in the intensive care unit (ICU) was not beneficial and may have been harmful in some patients.

Moderately ill patients with COVID-19, defined as those who did not require ICU care or organ support, made up 80% of participants at enrollment in the three trials, Dr. Hochman said.

Among more than 1,000 moderately ill patients reviewed as of the data cut with the data safety monitoring board, full doses of low molecular weight or unfractionated heparin were superior to low prophylactic doses for the primary endpoint of need for ventilation or other organ supportive interventions at 21 days after randomization.

This met the predefined threshold for 99% probability of superiority and recruitment was stopped, Dr. Hochman reported. “Obviously safety figured into this decision. The risk/benefit ratio was very clear.”

The results do not pertain to patients with a previous indication for anticoagulation, who were excluded from the trials.

Data from an additional 1,000 patients will be reviewed and the data published sometime in the next 2-3 months, she said.

With large numbers of COVID-19 patients requiring hospitalization, the outcomes could help reduce the overload on intensive care units around the world, the NIH noted.

The results also highlight the critical role of timing in the course of COVID-19.

“We believe that full anticoagulation is effective early in the disease course,” Dr. Hochman said. “Based on the results so far from these three platform trials, those that were very, very sick at the time of enrollment really didn’t benefit and we needed to have caught them at an earlier stage.

“It’s possible that the people in the ICU are just different and the minute they get sick they need the ICU; so we haven’t clearly demonstrated this time course and when to intervene, but that’s the implication of the findings.”

The question of even earlier treatment is being examined in the partner ACTIV-4B trial, which is enrolling patients with COVID-19 illness not requiring hospitalization and randomizing them to the direct oral anticoagulant apixaban or aspirin or placebo.

“It’s a very important trial and we really want to get the message out that patients should volunteer for it,” said Dr. Hochman, principal investigator of the ACTIV-4 trial.

In the United States, the ACTIV-4 trial is being led by a collaborative effort involving a number of universities, including the University of Pittsburgh and New York University.

The REMAP-CAP, ACTIV-4, and ATTACC study platforms span five continents in more than 300 hospitals and are supported by multiple international funding organizations including the National Institutes of Health, Canadian Institutes of Health Research, the National Institute for Health Research (United Kingdom), the National Health and Medical Research Council (Australia), and the PREPARE and RECOVER consortia (European Union).

A version of this article first appeared on Medscape.com.

Full-dose anticoagulation was superior to low, prophylactic doses in reducing the need for vital organ support such as ventilation in moderately ill patients hospitalized for COVID-19, according to a report released Jan. 22 by the National Institutes of Health (NIH).

“This is a major advance for patients hospitalized with COVID. Full dose of anticoagulation in these non-ICU patients improved outcomes and there’s a trend toward a reduction in mortality,” Judith Hochman, MD, director of the Cardiovascular Clinical Research Center at NYU Langone Medical Center, New York, said in an interview.

“We have treatments that are improving outcomes but not as many that reduce mortality, so we’re hopeful when the full dataset comes in that will be confirmed,” she said.

The observation of increased rates of blood clots and inflammation among COVID-19 patients, which can lead to complications such as lung failure, heart attack, and stroke, has given rise to various anticoagulant treatment protocols and a need for randomized data on routinely administering increased doses of anticoagulation to hospitalized patients.

Today’s top-line findings come from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – examining the safety and efficacy of full-dose anticoagulation to treat moderately ill or critically ill adults hospitalized with COVID-19 compared with a lower dose typically used to prevent blood clots in hospitalized patients.

In December 2020, all three trials paused enrollment of the critically ill subgroup after results showed that full-dose anticoagulation started in the intensive care unit (ICU) was not beneficial and may have been harmful in some patients.

Moderately ill patients with COVID-19, defined as those who did not require ICU care or organ support, made up 80% of participants at enrollment in the three trials, Dr. Hochman said.

Among more than 1,000 moderately ill patients reviewed as of the data cut with the data safety monitoring board, full doses of low molecular weight or unfractionated heparin were superior to low prophylactic doses for the primary endpoint of need for ventilation or other organ supportive interventions at 21 days after randomization.

This met the predefined threshold for 99% probability of superiority and recruitment was stopped, Dr. Hochman reported. “Obviously safety figured into this decision. The risk/benefit ratio was very clear.”

The results do not pertain to patients with a previous indication for anticoagulation, who were excluded from the trials.

Data from an additional 1,000 patients will be reviewed and the data published sometime in the next 2-3 months, she said.

With large numbers of COVID-19 patients requiring hospitalization, the outcomes could help reduce the overload on intensive care units around the world, the NIH noted.

The results also highlight the critical role of timing in the course of COVID-19.

“We believe that full anticoagulation is effective early in the disease course,” Dr. Hochman said. “Based on the results so far from these three platform trials, those that were very, very sick at the time of enrollment really didn’t benefit and we needed to have caught them at an earlier stage.

“It’s possible that the people in the ICU are just different and the minute they get sick they need the ICU; so we haven’t clearly demonstrated this time course and when to intervene, but that’s the implication of the findings.”

The question of even earlier treatment is being examined in the partner ACTIV-4B trial, which is enrolling patients with COVID-19 illness not requiring hospitalization and randomizing them to the direct oral anticoagulant apixaban or aspirin or placebo.

“It’s a very important trial and we really want to get the message out that patients should volunteer for it,” said Dr. Hochman, principal investigator of the ACTIV-4 trial.

In the United States, the ACTIV-4 trial is being led by a collaborative effort involving a number of universities, including the University of Pittsburgh and New York University.

The REMAP-CAP, ACTIV-4, and ATTACC study platforms span five continents in more than 300 hospitals and are supported by multiple international funding organizations including the National Institutes of Health, Canadian Institutes of Health Research, the National Institute for Health Research (United Kingdom), the National Health and Medical Research Council (Australia), and the PREPARE and RECOVER consortia (European Union).

A version of this article first appeared on Medscape.com.

Physician burnout remains at a critical level, at 42% overall – the same percentage as last year – but COVID-19 has changed the specialties hit hardest, according to Medscape’s Death by 1,000 Cuts: Physician Burnout & Suicide Report.

Critical care physicians now top the list of those experiencing burnout, at 51%, up from 44% last year, followed by rheumatologists (50%, up from 46%) and infectious disease specialists (49%, up from 45%). Forty-nine percent of urologists reported burnout, but that was a reduction from 54% last year.

Last year, the specialties burdened most by burnout were urology, neurology, nephrology, endocrinology, and family medicine.
 

Women hit particularly hard

Women in medicine traditionally have experienced higher levels of burnout than men, and the pandemic seems to have widened that gap, with the divide now at 51% for women and 36% for men.

“Many women physicians are in families with children at home,” said Carol Bernstein, MD, psychiatrist at Montefiore Medical Center, New York. “It’s already known that women assume more responsibilities in the home than do men. The pressures have increased during COVID-19 – having to be their child’s teacher during home schooling, no child care, and the grandparents can’t babysit. In addition, all doctors and nurses are worried about bringing the virus home to their families.”

Data were collected from Aug. 30 through Nov. 5, 2020. More than 12,000 physicians from 29 specialties responded.

For many, (79%) burnout has been building over years, but for some (21%), it started with the pandemic. Factors cited include lack of adequate personal protective equipment, grief from losing patients, watching families suffer, long hours, and difficult working conditions.

More than 70% of those who responded feel that burnout has had at least a moderate impact on their lives.

“One-tenth consider it severe enough to consider leaving medicine,” survey authors wrote, “an unexpected outcome after having spent so many years in training to become a physician.”

Tragically, an estimated 300 physicians each year in the United States are consumed by the struggle and take their own lives.
 

One percent have attempted suicide

In this survey, 13% of physicians had thoughts of suicide, and 1% have attempted it; 81% said they had no thoughts of suicide; and 5% preferred not to answer.

By specialty, obstetricians/gynecologists were most likely to have thoughts of suicide (19%), followed by orthopedists (18%) and otolaryngologists and plastic surgeons (17%).

“I yell all the time, I am angry and frustrated all the time. I think about quitting all the time,” said an internist who admitted having suicidal thoughts. “No one in my organization cares about doing the right things for patients as much as I do.”

Yet, many with such thoughts tell no one. By age group, 32% of millennials, 40% of generation X physicians, and 41% of baby boomer physicians who had had thoughts of suicide said they had told no one about those thoughts.

Fear of being reported to the medical board, fear of colleagues finding out, and other factors perpetuate a cycle of burnout and depression, and most don’t seek help.

Top reasons physicians listed for not seeking help for burnout and depression include “symptoms are not severe enough” (52%); “I can deal with without help from a professional” (46%); and feeling “too busy” (40%).
 

Administrative tasks fuel burnout

The top driver of burnout continues to be “too many administrative tasks.” This year, 58% put it at the top. The next highest categories (named by 37%) were “spending too many hours at work” and “lack of respect from administrators/employers, colleagues or staff.” Others mentioned lack of control or insufficient compensation and government regulations.

Notably, only 8% said stress from treating COVID-19 patients was the top driver.

An internist said, “I’m working 6 days a week, nights, weekends, holidays!”

A general surgeon said, “Being forced to see four patients an hour when complicated patients and procedures are involved” was the biggest contributor to burnout.

One physician in the survey summarized it: “It’s all of these causes; it’s death by 1,000 cuts.”
 

Exercise tops coping list

Asked how they cope with stress and burnout, physicians put exercise at the top (48%). Next was talking with family and friends (43%), though 43% said they cope by isolating themselves.

Drinking alcohol and overeating junk food were up slightly in the past year: for alcohol, 26%, up from 24%; for junk food, 35%, up from 33%.

The action respondents said would help most to reduce burnout was “increased compensation to avoid financial stress,” chosen by 45%. Next, at 42%, was “more manageable work and schedule,” followed by greater respect from employers, colleagues, and staff (39%).

Asked whether their workplace offered programs to reduce stress and/or burnout, almost half (47%) of physicians said no; 35% said yes; and 18% didn’t know.

Participation in such programs has been low. Almost half (42%) of physicians in this survey said they would be unlikely to attend such a program. Thirty percent they would be likely to participate; 28% said they were neutral on the idea.

“Anti-stress/burnout programs focus on individual approaches to much larger problems,” Wendy K. Dean, MD, psychiatrist and president of Moral Injury of Healthcare, said in an interview. “The programs offer temporary symptomatic relief rather than lasting systemic change. Many physicians are frustrated by these approaches.”

A study last year by the Mayo Clinic found that “the most efficacious strategy to alleviate physician burnout will target organization-directed changes rather than the level of the individual.”

A version of this article first appeared on Medscape.com.