Protecting patients with sickle cell disease from pneumococcal infection after transplant

A lesser-known but serious complication of sickle cell disease is an impaired ability to fight certain infections. The disease’s trademark crescent-shaped red blood cells can become trapped in the spleen, damaging an organ that plays an important role in clearing bacteria from the bloodstream. Compromised spleen function can increase vulnerability to high-risk Streptococcus pneumoniae infections.

Bone marrow transplantation can cure the underlying sickle cell disease, but whether it also restores enough spleen and immune function to reduce that infection risk has remained unclear. To investigate, St. Jude scientists worked with the Sickle Cell Transplant and Advocacy Research Alliance (STAR) to examine health records from 182 patients with sickle cell disease who had received a transplant. Published in Transplant Infectious Disease, the study tracked pneumococcal infections during the first year after transplantation. 

“We found both good and bad news,” said co-corresponding author Akshay Sharma, MBBS, MSc, Department of Bone Marrow Transplantation & Cellular Therapy. “We saw that very few patients had pneumococcal infections after transplant — that’s the good news. The bad news is that those that did have pneumococcal infection had very severe disease.”

“Only three patients had invasive pneumococcal disease, equating to less than 2% of the whole group,” said first and co-corresponding author Diego Hijano, MD, MSc, Department of Infectious Diseases. “However, all three had infection in their blood, requiring hospitalization, with one also having infection of the brain, meningitis.”

The low number of infections was encouraging and suggests that invasive pneumococcal disease is uncommon during the first year after transplantation. However, the severity of the infections that did occur showed how vulnerable this population is if infection takes hold, even after potentially curative treatment.

Uncommon, but potentially devastating

While infection duration and intensity were not tracked in the study, physicians know that pneumococcal disease in these patients looks different from cases in healthy peers. Hijano and Sharma both care for patients with sickle cell disease and other conditions requiring bone marrow transplantation and have seen that danger firsthand.

“These are serious infections, and they tend to progress very rapidly,” Sharma said. “The infection can be so overwhelming that it causes septic shock and death within the first 24 to 48 hours. There just isn’t enough time for the treatments to work in that time frame for some patients.”

In the study, all three patients with pneumococcal infection required hospitalization. One patient developed meningitis, while another died from septic shock caused by the infection. The speed and intensity of the illness caused by this bacterium emphasize that prevention is likely more effective than just trying to intervene once severe disease has taken hold.

Spleen function improves in some

The researchers initially wanted to know whether transplantation restores spleen function enough to protect patients from pneumococcal disease. The presence of infections showed that transplantation alone does not guarantee improved spleen and immune function in all patients. When the scientists directly observed spleen function in a subset of patients, they found it was even less recovered than they had expected.

“Before transplant, more than three out of every four patients had a spleen that was not working,” Hijano said. “After transplant, it was a little over one half, so it improves, but not in everyone, leaving many potentially vulnerable to pneumococcal infection.”

That created another puzzle. If impaired spleen function alone determined infection risk, the researchers might have expected substantially more pneumococcal disease, since many patients continued to have reduced splenic function after transplant. Instead, infections remained rare. The discrepancy suggested that additional protective factors were at work.

Timely pneumococcal vaccination may be an important layer of protection 

The scientists questioned what protective factor infected individuals lacked by looking more closely at their health records. One finding stood out — none of the three patients had received a post-transplant pneumococcal vaccination before developing invasive disease.

Patients undergoing bone marrow transplantation must rebuild their immune systems afterward and are recommended to receive pneumococcal vaccination during that recovery period. The study was not designed to measure the impact of vaccination. However, the fact that all three infections occurred in patients who had not yet received post-transplant pneumococcal vaccination strengthens the case for timely immunization as an important layer of protection.

“Our results emphasize the importance of starting pneumococcal vaccination early after transplant, as recommended by current guidelines,” Hijano explained.

If post-transplant vaccination is one of the most important ways to protect these patients from infection, the scientists made an unsettling finding. The median time to vaccination after transplant was more than nine months, and some patients were never vaccinated during the study period. That delay may leave a window of avoidable vulnerability.

“Our findings show that even one patient with sickle cell disease who dies of pneumococcal infection after undergoing transplant is one too many,” Hijano said. “These patients have been through so much to cure their underlying disease, including all the hardships of transplant. We need to make sure we are using the preventive tools we already have, including pneumococcal vaccination, while we continue to learn how best to protect them.”

Protecting patients as curative therapies expand

The findings also raise questions that will become increasingly important as potentially curative approaches for sickle cell disease expand to include gene therapy and gene editing. Transplantation has traditionally been limited in part by the need for an appropriate donor. Newer gene therapy and gene-editing approaches instead use a patient’s own blood stem cells, potentially allowing more people to receive these treatments. These therapies also involve periods when patients may be more vulnerable to infections. Understanding how infection risk and prevention may differ across these approaches will become increasingly important as their use expands.

“No matter what transplant techniques, gene therapies or gene editing we use, vaccines remain the most effective public health measure to reduce infections,” Sharma said.

Although the researchers began by asking how transplantation affected spleen and immune function, their findings suggest that protection likely depends on several factors working together, including partial recovery of splenic function and vaccination.

“There is still so much we do not know about how to protect these patients,” Hijano said. “We have a lot to learn about the optimal timing of vaccination after transplant and how gene therapies and other emerging approaches will interact with our current methods. With this study, we’ve taken a first step toward understanding how best to prevent these devastating infections.”