Leukocyte adhesion deficiency – Diagnostics – Overview of Information and Clinical Research

Leukocyte adhesion deficiency (LAD) is a rare inherited immune disorder where white blood cells cannot reach infection sites to fight bacteria and fungi, leading to severe recurrent infections that begin from birth.

Introduction: Who Should Seek Diagnostic Testing

Diagnostic testing for leukocyte adhesion deficiency becomes crucial when certain warning signs appear, particularly in newborn infants and young children. Parents and doctors should consider LAD testing when a baby’s umbilical cord stump, which normally falls off within the first two weeks after birth, remains attached for three weeks or longer. This delayed separation is often accompanied by inflammation or infection around the cord area, known as omphalitis, which is a characteristic early sign of this condition.^[1]

Infants and young children who experience repeated severe bacterial or fungal infections should undergo evaluation for LAD. These infections commonly affect soft tissues including the skin, mouth, gums, and mucous membranes. A particularly telling feature is that infected areas fail to produce pus, which is the thick yellowish substance normally produced when the body fights infection. This absence of pus formation is a hallmark of leukocyte adhesion deficiency and should raise immediate concern.^[2]

Children who develop severe inflammation of the gums, called gingivitis, and surrounding tooth tissue, known as periodontitis, at an unusually young age should be considered for LAD testing. These dental problems often result in the loss of both baby teeth and permanent teeth. Additionally, wounds that heal extremely slowly or not at all, leading to persistent sores or infections that spread widely across the skin, are important warning signs that warrant diagnostic investigation.^[4]

Genetic testing is strongly recommended for siblings of a child diagnosed with LAD, even if they show no symptoms. Because this condition follows an autosomal recessive inheritance pattern, brothers and sisters have a higher risk of carrying or having the same genetic mutations. Early detection through family screening allows for prompt treatment initiation before life-threatening infections develop.^[6]

Medical professionals should also maintain a high index of suspicion when blood tests reveal extraordinarily high numbers of white blood cells, sometimes six to ten times higher than normal levels, even when the patient appears relatively well between infection episodes. This persistent elevation of white blood cells, combined with recurrent infections, creates a distinctive pattern that points toward leukocyte adhesion deficiency.^[5]

Classic Diagnostic Methods

The diagnostic journey for leukocyte adhesion deficiency typically begins with a complete blood count (CBC), which is a routine blood test that measures different types of cells in the blood. In patients with LAD, this test reveals a striking and persistent elevation in the number of neutrophils, a type of white blood cell. These numbers can be extraordinarily high, ranging from 50,000 to 100,000 cells per microliter (or 10,000 to 40,000 in LAD type 2), compared to normal levels. What makes this finding particularly suspicious is that these elevated counts persist even when the patient is not actively fighting an infection, unlike the temporary increases seen in healthy people during illness.^[1]

The most definitive diagnostic test for LAD is flow cytometry, which analyzes proteins on the surface of white blood cells. This specialized laboratory technique uses specific markers, called monoclonal antibodies, to detect whether certain proteins are present, absent, or deficient on the cell surface. For LAD type 1, the most common form of the disease, doctors look specifically for proteins called CD11 and CD18. These proteins are part of the beta-2 integrin family, which acts like molecular glue helping white blood cells stick to blood vessel walls and migrate to infection sites.^[3]

In LAD type 1, flow cytometry reveals either a complete absence or severe reduction of CD18 protein expression on white blood cells. The severity of the disease correlates directly with how much CD18 is present. When less than 1% of normal CD18 expression is detected, patients typically have severe disease with life-threatening infections beginning in infancy. When CD18 expression is between 1% and 30% of normal levels, the disease tends to be milder, with fewer serious infections and the possibility of survival into adulthood without transplantation. This correlation between protein levels and disease severity helps doctors predict outcomes and plan treatment strategies.^[3]

⚠️ Important

The absence of pus formation at infection sites is a distinctive diagnostic clue that differentiates LAD from other immune disorders. While most people produce thick, yellowish pus when fighting infections, individuals with LAD cannot form this substance because their white blood cells are trapped in the bloodstream and cannot reach the infected tissue. This unusual finding should prompt immediate consideration of LAD diagnosis.

For LAD type 2, which is extremely rare with fewer than ten cases reported worldwide, diagnosis involves examining glycosylated forms of a protein called transferrin. A key diagnostic marker is the absence of CD15a (also known as sialyl Lewis X) on the surface of white blood cells. This type is also associated with a rare blood type called the Bombay phenotype, where red blood cells lack a specific sugar molecule called the H antigen. Standard blood typing will show these patients as type O, but specialized testing reveals their true rare blood type.^[3]

LAD type 3 presents unique diagnostic challenges because it affects not only the immune system but also blood clotting. Patients with this form have both recurrent infections and bleeding problems similar to those seen in a condition called Glanzmann thrombasthenia. Doctors must look for defects in a protein called kindlin-3, which is critical for activating integrins. The combination of immune deficiency and bleeding tendency helps distinguish type 3 from the other forms of LAD.^[5]

Physical examination findings provide valuable diagnostic information before laboratory results are available. Doctors look for signs of soft tissue infections that lack typical inflammation features, particularly the absence of pus. Examination of the mouth often reveals severe gum inflammation and significant tooth loss at an inappropriately young age. Skin infections may appear extensive but lack the redness and swelling typically associated with bacterial infections in people with normal immune systems. Wounds show delayed healing or complete failure to heal, sometimes leading to large areas of tissue death.^[6]

Genetic testing provides the ultimate confirmation of LAD diagnosis by identifying the specific mutations responsible for the condition. For LAD type 1, doctors test the ITGB2 gene located on chromosome 21, which provides instructions for making the CD18 protein. Scientists have identified numerous different mutations in this gene, including point mutations, frame shift deletions, splicing alterations, and missense changes. Each patient typically carries two different abnormal copies of the gene, making them compound heterozygotes. For LAD type 2, mutations occur in the gene encoding the GDP-fucose transporter. LAD type 3 results from mutations in the FERMT3 gene on chromosome 11.^[1]

Prenatal diagnostic systems have been established for families with a known history of LAD, allowing early detection before birth. When both parents are confirmed carriers of LAD-causing mutations, prenatal testing through amniocentesis or chorionic villus sampling can determine whether the developing baby has inherited both abnormal genes. This early detection allows parents and medical teams to prepare for immediate postnatal care and potentially arrange for early curative treatment such as stem cell transplantation.^[5]

Diagnostics for Clinical Trial Qualification

Clinical trials investigating new treatments for leukocyte adhesion deficiency, particularly gene therapy approaches, require extensive diagnostic testing to determine patient eligibility. The foundation of qualification testing is the confirmation of LAD diagnosis through flow cytometry demonstrating absent or severely reduced CD18 expression, typically less than 1% of normal levels for severe LAD type 1. This criterion ensures that enrolled patients have the form of disease most likely to benefit from experimental interventions.^[3]

Genetic confirmation through DNA sequencing of the ITGB2 gene is mandatory for most clinical trial protocols. Researchers need to identify the specific mutations causing each patient’s LAD to understand how genetic corrections might work and to monitor whether gene therapy successfully introduces functional genetic material into the patient’s cells. Some trials may exclude patients with certain types of mutations that are less amenable to correction through the specific gene therapy approach being tested.^[8]

Age restrictions often apply to clinical trial enrollment, with many studies focusing on infants and young children who have severe disease manifestations but have not yet developed overwhelming infections or organ damage. Trial protocols typically require documentation of the patient’s infection history, including the frequency, severity, and types of infections experienced. This information helps researchers establish baseline disease severity and evaluate whether the experimental treatment reduces infection rates after intervention.^[8]

Complete blood count testing serves as both a diagnostic criterion and a monitoring tool throughout clinical trials. Before enrollment, patients must demonstrate the characteristic persistent elevation of white blood cells that defines LAD. During and after treatment, serial CBC measurements track whether experimental therapies normalize white blood cell counts, which would indicate improved ability of these cells to migrate out of the bloodstream to infection sites.^[1]

Functional assays that test white blood cell behavior are crucial for trial qualification and monitoring. These specialized laboratory tests measure whether white blood cells can properly adhere to surfaces that mimic blood vessel walls, respond to chemical signals that normally attract them to infection sites, and cross barriers similar to those they must traverse in the body. Before treatment, these tests confirm that cells cannot perform these critical functions. After experimental therapies, repeated testing shows whether function has been restored.^[8]

⚠️ Important

Clinical trial eligibility often depends on disease severity and whether patients have suitable donors for standard bone marrow transplantation. Severe LAD type 1 patients with less than 1% CD18 expression who lack matched bone marrow donors may be prioritized for experimental gene therapy trials, as these children face the highest mortality risk without curative treatment.

Assessment of organ function is essential before enrolling patients in clinical trials, particularly those involving intensive treatments like gene therapy or experimental transplantation protocols. Blood tests evaluate liver and kidney function to ensure these organs can tolerate conditioning regimens and process medications used during treatment. Imaging studies may examine the lungs, which are frequently affected by recurrent infections in LAD patients, to document baseline damage and monitor for improvement or complications during trials.^[8]

For gene therapy trials specifically, additional diagnostic procedures collect the cells that will be genetically modified and then returned to the patient. This involves harvesting CD34-positive cells, which are stem cells capable of producing all blood cell types, from the patient’s bone marrow or mobilized into the bloodstream through special medications. The quantity and quality of these collected cells must meet specific criteria for the gene therapy process to succeed. Laboratory testing confirms that adequate numbers of viable stem cells are available before proceeding with genetic modification.^[8]

Infectious disease screening is mandatory before clinical trial enrollment to ensure patients do not have active, untreated infections that could complicate experimental therapies. Blood tests check for viral infections including hepatitis B, hepatitis C, HIV, and cytomegalovirus. Active bacterial or fungal infections must be controlled with appropriate antibiotics or antifungal medications before certain trial interventions can begin, particularly those involving immune system suppression.^[8]

Throughout clinical trials, continuous monitoring through repeated diagnostic testing tracks treatment success and detects complications. Flow cytometry measurements show whether CD18 expression normalizes on white blood cells after gene therapy. Complete blood counts monitor for normalization of white blood cell numbers. Functional tests demonstrate restored ability of white blood cells to migrate and fight infections. Clinical assessments document reduced infection frequency and improved wound healing, which are the ultimate measures of treatment success.^[8]

Prognosis and Survival Rate

Prognosis

The outlook for patients with leukocyte adhesion deficiency varies dramatically depending on the type and severity of the condition. Patients with severe LAD type 1, characterized by less than 1% of normal CD18 protein expression, face the most serious prognosis. Without curative treatment such as hematopoietic stem cell transplantation or gene therapy, these children experience life-threatening bacterial and fungal infections beginning in infancy. The infections become progressively more difficult to control despite aggressive antibiotic treatment, and affected tissues may die from uncontrolled infection. Historical data from 1988 showed that approximately 75% of children with severe LAD type 1 died by age two years when only supportive care was available.^[1]

Patients with moderate LAD type 1, who have CD18 expression between 1% and 30% of normal levels, experience a milder disease course. These individuals have fewer serious infections and can often survive into adulthood without transplantation, though they still require careful medical management and prophylactic antibiotics. However, long-term survival remains compromised even in this milder form, with only about 25% of patients surviving beyond 40 years of age. The prognosis improves significantly for patients who undergo successful hematopoietic stem cell transplantation, which has a success rate of approximately 80% when matched donors are used. Recent advances in gene therapy appear promising, with early trial results showing 100% transplant-free survival at one year and substantial reductions in serious infections.^[3]

LAD type 2 generally has a less severe prognosis regarding infections compared to type 1. Infections are usually non-life-threatening and can often be managed as outpatient cases. However, patients with type 2 face additional challenges including severe intellectual disability, developmental delays, growth problems, and microcephaly (small head size). These neurological complications significantly impact quality of life and long-term outcomes, even when infections are well-controlled. LAD type 3 presents a mixed prognosis because patients face both immune deficiency and bleeding problems, requiring careful management of both complications throughout life.^[3]

Survival Rate

Survival rates for leukocyte adhesion deficiency have improved over recent decades with advances in supportive care and curative treatments. In the severe form of LAD type 1, without hematopoietic stem cell transplantation, historical mortality was 75% by age two years. Most children with severe untreated disease do not survive beyond infancy due to overwhelming infections. Life expectancy is often severely shortened, with many affected individuals not surviving past early childhood without definitive treatment.^[1]

The introduction of hematopoietic stem cell transplantation dramatically changed survival outcomes. When HLA-matched related, haploidentical, or unrelated matched donors are available, transplantation success rates reach approximately 80%. Even reduced-intensity conditioning regimens, which are less toxic than traditional approaches, have shown success in curing LAD. These transplants can provide a complete cure, allowing patients to live normal lifespans without the constant threat of severe infections. However, haploidentical transplants, which use partially matched donors, have lower success rates of approximately 50%.^[3]

Recent gene therapy trials for severe LAD type 1 have shown remarkable early results. In a multinational phase 1-2 study of nine children, all achieved 100% hematopoietic stem cell transplant-free survival at one year following gene therapy. These patients experienced durable engraftment of genetically corrected cells, normalization of neutrophil adhesion function, and a 75-85% reduction in serious infection-related hospitalizations compared to their pre-treatment rates. While longer follow-up is needed to assess lifelong outcomes, these results suggest gene therapy may become a first-line curative option for patients lacking suitable transplant donors.^[8]

Patients with moderate LAD type 1 who have 2-30% of normal CD18 expression have better survival prospects than those with severe disease. Many can survive into young adulthood and some reach middle age with aggressive infection management and prophylactic antibiotics. However, the condition still significantly reduces life expectancy compared to the general population, with studies showing only about 25% survival beyond age 40 years even in this milder phenotype. Continuous medical surveillance, prompt treatment of infections, and excellent wound care are essential for maximizing survival in these patients.^[3]

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