Cold agglutinins linked to lung transplant complications: Study
Nearly half of recipients test positive for CAD-driving autoantibodies
Nearly half of people without symptoms of cold agglutinin disease (CAD) who undergo a lung transplant test positive for cold agglutinins, the self-reactive antibodies that drive the rare autoimmune condition by targeting red blood cells at low temperatures.
That’s according to new data from the first study of its kind from scientists at the University of Freiburg in Germany, who investigated the impact of these autoantibodies in lung transplant recipients to assess short- and long-term outcomes.
While there was no effect on overall survival, the presence of these antibodies was associated with several short-term post-transplant complications, per the researchers. These included severe graft dysfunction — referring to the impaired function of a transplanted organ — fluid buildup in the lungs, and blood clots.
However, the exact contribution of cold agglutinins to these post-transplant complications remains to be determined, according to the scientists, who noted that “further studies are warranted to evaluate whether regular screening [for cold agglutinins] benefits selected patients.”
Still, these findings further emphasize the importance of immunosuppressive treatments and warming strategies to prevent complications of major surgeries, where the body’s temperature drops, in people with CAD.
The study, “Incidental Cold Agglutinins in Lung Transplant Recipients,” was published in the journal Transplantation Direct.
Cold agglutinins can be detected in people with no CAD symptoms
CAD is marked by high levels of cold agglutinins, which bind to red blood cells at low temperatures, causing them to clump together and marking them for destruction — a process known as hemolysis.
This can result in CAD symptoms such as anemia, characterized by low red blood cells, and fatigue. It also can increase the risk of thromboembolism, or blood clots that block blood flow.
Importantly, researchers note, cold agglutinins can also be detected in people showing no symptoms of CAD. If present at high levels, these antibodies have the potential to cause complications in major surgeries, when the operating room can be cold and the body’s core temperature can get too low under general anesthesia.
In patients with high levels, preoperative strategies like immosuppressive therapies and approaches to eliminate these autoantibodies from blood “have been suggested to reduce antibody [levels] or reactivity, especially in case of a clinically relevant temperature amplitude,” the researchers wrote.
In a lung transplant, the donor lungs are typically kept cold for preservation. After the transplant, incompletely rewarmed lungs can potentially activate cold agglutinins in the recipient and lead to blood vessel injury and blood clots, according to the researchers.
While these self-reactive antibodies have been associated with graft dysfunction following kidney and liver transplants, there is almost no information regarding them or their impact among lung transplant recipients.
To learn more, the research team now examined the presence of cold agglutinins and related complications in 176 people who underwent a lung transplant at their institutions between March 2003 and June 2023. Slightly more than half of the transplant patients were men.
None of the recipients had symptoms of CAD or a history of such symptoms. Still, nearly half (45%) tested positive for cold agglutinins, per the study.
Survival comparable among patients with or without antibodies
More than one year after their transplant, the patients who tested positive for cold agglutinins had comparable survival to those without such antibodies, according to the researchers.
However, those in the cold agglutinin group were significantly more likely to experience fluid buildup in the lungs, known as reperfusion edema, after blood flow restoration (79% vs. 52%), the data showed.
The cold agglutinin group also experienced more severe primary graft dysfunction (51% vs. 26%), as well as worse thromboembolism within 30 days of transplant (16% vs. 5%). Severe primary graft dysfunction is a type of severe lung injury that occurs within the first 72 hours after lung transplant.
In comparison, the rates of chronic lung allograft dysfunction — when the transplanted lung progressively loses its ability to function — were similar between patients with and without cold agglutinins, according to the researchers.
In a statistical analysis adjusted for potential influencing factors, severe primary graft dysfunction, thromboembolism within the first 30 days, and the use of extracorporeal membrane oxygenation, known as ECMO, were independent predictors of reduced survival.
The researchers noted that the number of patients on ECMO — in which a machine takes over heart and lung function during surgery — was similar between patients with and without cold agglutinins (35% vs. 32%).
3 patients underwent blood-cleaning procedure before transplant
In most patients, cold agglutinins were active solely at 4 C (39 F), while 9% had active self-reactive antibodies up to 22 C (72 F).
Two patients (3%) had antibodies active up to 37 C (98.6 F). One of these patients died immediately after transplant, and the other had “a very prolonged postoperative course with multiple thromboembolisms and [red blood cell clumps] being directly visible in blood samples at room temperature,” the researchers wrote.
Additionally, three patients at one institution with high levels of cold agglutinins that acted at a broad temperature range underwent a blood-cleaning procedure — one meant to remove the antibodies from the bloodstream — shortly before their transplants. Two of these individuals were not part of the initial group of patients. As a result of that procedure, cold agglutinins were eliminated for at least two months, and all three patients had good outcomes, the team noted.
There is quite a high prevalence of asymptomatic [cold agglutinins] in patients undergoing [lung transplant]. … Further studies are needed to verify the benefit of regular screening for cold agglutinins [for lung transplant patients].
“To our knowledge, this is the first study analyzing whether the presence of [cold agglutinins] impacts short-term and long-term outcomes in [lung transplants],” the researchers wrote.
Overall, according to the team, “there is quite a high prevalence of asymptomatic [cold agglutinins] in patients undergoing [lung transplant].”
The scientists noted that these antibodies are associated with increased rates of several complications and called for more research.
“Further studies are needed to verify the benefit of regular screening for cold agglutinins” in people undergoing lung transplant, the team wrote.
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