Leukocyte adhesion deficiency is a rare inherited disorder where white blood cells cannot reach infection sites to fight bacteria and fungi. Treatment approaches range from preventive antibiotics to advanced stem cell transplantation and experimental gene therapies, all aimed at reducing life-threatening infections and improving survival in affected children.

How Medicine Fights Back Against a Rare Immune Disorder

Managing leukocyte adhesion deficiency is a complex challenge that requires a team of specialists working together to protect patients from the constant threat of infection. The main goals of treatment are to prevent bacterial and fungal infections before they start, control infections quickly when they do occur, and ultimately restore the immune system’s ability to function normally. Because this is a genetic disorder affecting the fundamental ability of white blood cells to travel to infection sites, treatment must address both immediate threats and the underlying immune defect.^[1]

The approach to treatment depends heavily on how severe the disease is in each patient. Severity is measured by looking at how much of a specific protein called CD18, which is the amount of this protein found on the surface of white blood cells, is present. When less than one percent of normal CD18 is expressed, the disease is considered severe, and these patients face life-threatening infections very early in life, often within the first year. When CD18 expression is between one and thirty percent of normal, patients have a milder form of the disease with fewer serious infections, and they may survive into adulthood without the most aggressive treatments.^[3]

Treatment strategies have evolved significantly since leukocyte adhesion deficiency was first recognized in the 1970s. Medical societies and specialist immunologists now recognize that there are established, proven therapies that can help manage symptoms and prevent complications, alongside cutting-edge research into curative treatments. These newer approaches, many of which are being tested in clinical trials around the world, offer hope for children who might otherwise face a very short life expectancy.^[1]

Standard Medical Care and Prevention Strategies

The cornerstone of managing leukocyte adhesion deficiency has long been the aggressive use of antibiotics to prevent and fight bacterial infections. Because patients with this disorder cannot mount an effective immune response, even minor infections can quickly become dangerous. Many patients, particularly those with severe disease, are prescribed antibiotics on a continuous, long-term basis to prevent infections from occurring in the first place. The most commonly used preventive antibiotic is trimethoprim/sulfamethoxazole, also known as co-trimoxazole. This combination antibiotic works by interfering with the ability of bacteria to produce essential compounds needed for their growth and survival.^[6]

Preventive antibiotics are typically given every day, month after month, for as long as the patient needs this protection. The decision to use continuous antibiotics is not taken lightly, because long-term antibiotic use can lead to side effects and the development of antibiotic-resistant bacteria. However, for patients with leukocyte adhesion deficiency, especially those with severe disease, the risk of life-threatening infection without antibiotics is considered much greater than the risks of long-term antibiotic therapy.^[8]

When infections do break through despite preventive measures, they must be treated immediately and aggressively. First-line treatment typically involves intravenous antibiotics, meaning antibiotics delivered directly into the bloodstream through a vein, rather than pills taken by mouth. This allows higher concentrations of the medication to reach infected tissues more quickly. Patients with leukocyte adhesion deficiency type I are particularly vulnerable to infections with Staphylococcus bacteria and gram-negative bacteria, which are types of bacteria that can cause severe skin, lung, and blood infections. Because these patients frequently need strong, broad-spectrum antibiotics, they are also at increased risk for fungal infections, particularly with Candida species, which are yeasts that can cause infections in the mouth, throat, and other areas.^[8]

After initial diagnosis and stabilization in the hospital, many patients can complete their intravenous antibiotic treatments at home. This home-based care requires careful coordination with healthcare providers, regular monitoring, and often the involvement of home healthcare nurses who can administer medications and check on the patient’s condition. Patients with the milder type II form of leukocyte adhesion deficiency generally do not require preventive antibiotics and can usually be treated as outpatients when infections occur.^[8]

In addition to antibiotics, some medical teams have tried using transfusions of granulocytes, which are a type of white blood cell that includes neutrophils. The idea behind granulocyte transfusions is to temporarily supply the patient with healthy white blood cells from a donor that can travel to infection sites and fight bacteria. However, granulocyte transfusions require very careful donor screening to prevent transmission of infections. They can also cause serious side effects including lung complications and severe febrile reactions, which are reactions causing very high fevers. Additionally, granulocyte transfusions provide only temporary help, as the donated cells do not last long in the body. Because of these limitations and the mixed evidence regarding their benefit, granulocyte transfusions are used with caution and are not considered a primary treatment approach.^[8]

Another medication that has been investigated for leukocyte adhesion deficiency is interferon-gamma. Interferon-gamma is a substance produced naturally by the immune system that helps activate various immune cells. The hope was that this medication might boost the ability of the immune system to fight infections despite the adhesion defect. However, studies have shown limited or no significant benefit from interferon-gamma in patients with this disorder, and it is not routinely recommended as part of standard care.^[8]

For patients with type II leukocyte adhesion deficiency, which is caused by a different genetic defect affecting sugar molecules on cell surfaces, there is a unique treatment option. These patients may benefit from fucose replacement therapy. Fucose is a type of sugar molecule that is missing or deficient in type II leukocyte adhesion deficiency. Fucose can be given orally by mouth or intravenously through a vein. The success of fucose therapy has been variable from patient to patient, with some showing improvement in how well their white blood cells function, while others show little benefit.^[8]

Preventive care for patients with leukocyte adhesion deficiency extends beyond medications. Excellent hygiene is critical, as the skin and mucous membranes like the mouth and nose are major entry points for infections. Patients and their families need education about proper wound care, dental hygiene, and how to recognize early signs of infection such as fever, increased pain, or changes in wound appearance. Because even minor injuries are slow to heal and at high risk for infection, any cut, scrape, or wound should be cleaned carefully and monitored closely. Many healthcare providers recommend that patients with leukocyte adhesion deficiency use preventive antibiotics even for minor injuries that would not normally require such treatment.^[8]

Stem Cell Transplantation as Curative Therapy

While antibiotics and supportive care can help manage symptoms and prevent some infections, they do not fix the underlying immune defect. The only treatment currently recognized as curative for leukocyte adhesion deficiency is hematopoietic stem cell transplantation, also known as HSCT. This is sometimes called bone marrow transplantation, although stem cells can also be collected from circulating blood or umbilical cord blood. Hematopoietic stem cells are the cells in the bone marrow that give rise to all types of blood cells, including white blood cells, red blood cells, and platelets.^[6]

The principle behind stem cell transplantation is to replace the patient’s defective immune system with a healthy one from a donor. When successful, the transplanted stem cells settle into the patient’s bone marrow and begin producing new, healthy white blood cells that have normal adhesion molecules and can therefore travel to infection sites and fight bacteria effectively. This can restore normal immune function and allow patients to live without the constant threat of severe infections.^[5]

Stem cell transplantation is considered the therapy of choice for severe leukocyte adhesion deficiency type I, particularly for patients who have less than one percent CD18 expression. These are the patients who face the highest risk of dying from infections in infancy or early childhood. When performed successfully, stem cell transplantation has a very high success rate in these patients. Without transplantation, the mortality rate for severe leukocyte adhesion deficiency type I was reported as seventy-five percent by age two years in an early research study from 1988. With successful transplantation, many of these children can survive and thrive.^[1][8]

Donors for stem cell transplantation can come from several sources. The best outcomes are typically seen with HLA-matched related donors, meaning a sibling or other close family member whose tissue type closely matches the patient. When a matched related donor is not available, doctors may use unrelated matched donors found through bone marrow registries, or haploidentical donors, who are partially matched family members, typically parents. Advances in transplantation techniques and medications to prevent graft-versus-host disease, a condition where the donor immune cells attack the patient’s body, have improved outcomes even when donors are not perfectly matched.^[8]

One interesting aspect of stem cell transplantation for leukocyte adhesion deficiency is that the absence of certain adhesion molecules on the patient’s own lymphocytes, a type of white blood cell, may actually make the transplantation more likely to succeed. This is because the patient’s existing immune cells are less able to attack and reject the donor cells. This same defect may also reduce the risk of graft-versus-host disease, where the donated immune cells would attack the patient’s tissues. However, not all patients are candidates for stem cell transplantation, particularly if they have severe active infections at the time or other medical complications.^[8]

The process of stem cell transplantation is intensive and carries significant risks. Before the transplant, patients must undergo conditioning regimens, which involve powerful chemotherapy drugs and sometimes radiation to destroy the patient’s existing bone marrow and immune system. This makes room for the donor stem cells and prevents the patient’s immune system from rejecting them. However, this process leaves patients extremely vulnerable to infections for weeks to months until the donor cells engraft and begin producing new immune cells. Patients must be closely monitored in specialized transplant centers, often requiring prolonged hospitalization. Success has been reported with the use of reduced intensity conditioning regimens, which use lower doses of chemotherapy and may cause fewer side effects, though they may also carry a higher risk of the transplant failing.^[8]

For patients with moderate leukocyte adhesion deficiency, where CD18 expression is two to thirty percent of normal, the decision about whether to pursue stem cell transplantation is more complex. These patients have fewer serious infections and may survive into adulthood with supportive care alone. However, they still face significant health challenges and shortened life expectancy, with only about twenty-five percent of patients with the milder form surviving beyond age forty years. Doctors must weigh the risks of the transplant procedure against the ongoing risks of living with a compromised immune system.^[8]

Innovative Approaches in Clinical Trials

While stem cell transplantation can be curative, it is not without risks, and not all patients have suitable donors or can tolerate the intensive conditioning required. This has driven researchers to explore novel therapeutic approaches, particularly gene therapy, which aims to correct the genetic defect in the patient’s own cells. Gene therapy for leukocyte adhesion deficiency is currently under active investigation in clinical trials and represents one of the most exciting areas of research for this rare disease.^[6]

The concept behind gene therapy is relatively straightforward, though the execution is highly complex. Scientists take stem cells from the patient’s own body and, in a laboratory, insert a correct, working copy of the gene that is mutated in leukocyte adhesion deficiency. For type I disease, this would be the ITGB2 gene, which provides instructions for making the CD18 protein. The corrected stem cells are then transplanted back into the same patient. Because the cells come from the patient’s own body, there is no risk of rejection or graft-versus-host disease, and the conditioning regimen required can be less intensive than what is needed for donor transplantation.^[8]

To insert the correct gene into the patient’s stem cells, researchers use lentiviral vectors. These are modified viruses that have been engineered to be safe and to efficiently deliver genetic material into cells. The lentiviral vector carries the correct ITGB2 gene into the patient’s stem cells, where it integrates into the cell’s DNA. Once integrated, the cell can produce normal CD18 protein, and this ability is passed on to all the blood cells that develop from that corrected stem cell.^[8]

A groundbreaking multinational Phase I-II clinical trial has tested this gene therapy approach in children with severe leukocyte adhesion deficiency type I. In this trial, nine children received autologous CD34-positive stem cells, which are the specific stem cells that give rise to blood cells, that had been transduced with a self-inactivating lentiviral vector encoding the ITGB2 gene. This investigational treatment is sometimes referred to as marne-cel. The results have been remarkable. One hundred percent of treated children achieved HSCT-free survival at one year, meaning all the children survived for at least a year without needing a traditional stem cell transplant from a donor. The gene-corrected cells showed durable engraftment without graft failure, meaning the cells successfully established themselves in the bone marrow and continued to produce new blood cells over time.^[8]

Even more importantly, the gene therapy resulted in normalization of neutrophil adhesion, meaning the white blood cells could finally stick to blood vessel walls and travel to infection sites as they should. This translated into real clinical benefit, with a seventy-five to eighty-five percent reduction in serious infection-related hospitalizations compared with the rates these children experienced before treatment. These promising results suggest that gene therapy could become a first-line curative option for severe leukocyte adhesion deficiency type I.^[8]

One important finding from research on gene therapy is that even partial restoration of CD18 expression appears sufficient to restore meaningful immune function and protect against severe infections. This is encouraging because it means that the gene therapy does not have to achieve one hundred percent correction in every cell to provide clinical benefit. Since patients who naturally have residual CD18 expression of one to thirty percent already have much milder disease than those with less than one percent expression, achieving even modest levels of correction through gene therapy can make a dramatic difference in patient outcomes.^[8]

Preclinical studies, which are laboratory and animal studies conducted before testing in humans, have also shown promising results. Research published on lentiviral-mediated gene therapy for leukocyte adhesion deficiency type I has demonstrated both safety and efficacy in preclinical models. These studies help establish that the gene therapy approach is safe enough to move forward into human trials and provide important information about how well the approach might work.^[6]

The development of gene therapy for leukocyte adhesion deficiency represents years of collaborative work between immunologists, gene therapy specialists, hematologists, and many other experts. Clinical trials like these are typically conducted at specialized medical centers with expertise in both rare immune disorders and advanced cellular therapies. In the case of leukocyte adhesion deficiency, important work has been done at centers like the California Institute for Regenerative Medicine and other leading research hospitals in the United States, Europe, and elsewhere.^[23]

Participation in clinical trials for gene therapy requires meeting specific eligibility criteria. Trials typically enroll children with severe disease who have a confirmed diagnosis based on genetic testing showing mutations in the ITGB2 gene and flow cytometry demonstrating absent or severely reduced CD18 expression. Patients usually need to be stable enough to undergo the stem cell collection and transplantation procedures. Families considering trial participation undergo extensive counseling to understand what the trial involves, including multiple trips to the trial center, the procedures required, potential side effects, and the fact that the long-term effects of gene therapy are still being studied.^[8]

Beyond gene therapy for type I leukocyte adhesion deficiency, researchers are also working to better understand and develop treatments for the less common type II and type III forms of the disease. Management of type III leukocyte adhesion deficiency is particularly challenging because this form affects not only immune function but also causes bleeding problems similar to those seen in Glanzmann thrombasthenia, a rare bleeding disorder. Some patients with type III disease have been managed long-term without hematopoietic stem cell transplantation, using careful supportive care for both their infection and bleeding risks, though this approach requires expertise and intensive monitoring.^[12]

Most Common Treatment Methods

• Antibiotic Therapy
  • Continuous prophylactic antibiotics, typically trimethoprim/sulfamethoxazole, to prevent bacterial infections
  • Aggressive intravenous antibiotics for active infections, particularly targeting staphylococcal and gram-negative bacteria
  • Prophylactic antibiotics for any injuries or surgical procedures
  • Management of secondary fungal infections, particularly Candida, that may develop due to broad-spectrum antibiotic use
• Stem Cell Transplantation
  • HLA-matched related donor transplantation from siblings or close family members
  • Unrelated matched donor transplantation from bone marrow registries
  • Haploidentical transplantation from partially matched family members
  • Reduced intensity conditioning regimens to reduce side effects while allowing engraftment
• Gene Therapy (Experimental)
  • Lentiviral-mediated gene therapy with autologous CD34-positive cells transduced with ITGB2 gene
  • Treatment with marne-cel in Phase I-II clinical trials
  • Self-inactivating lentiviral vectors for safe gene delivery
• Supportive Care
  • Granulocyte transfusions from healthy donors for severe active infections
  • Fucose replacement therapy for type II leukocyte adhesion deficiency
  • Interferon-gamma therapy (limited evidence of benefit)
  • Careful wound care and hygiene practices
  • Regular monitoring for infections and complications