Neutrophil immunodeficiency syndrome

Overview

Neutrophil Immunodeficiency Syndrome refers to a group of rare inherited disorders in which the function or number of neutrophils, a type of white blood cell essential for fighting bacterial and fungal infections is impaired. These syndromes are categorized under primary immunodeficiency diseases and lead to increased susceptibility to recurrent, severe, or unusual infections beginning in infancy or early childhood.

Unlike conditions with complete absence of neutrophils (neutropenia), neutrophil immunodeficiency syndromes often involve qualitative defects meaning the neutrophils may be present in normal numbers but do not function properly. This failure to respond adequately to pathogens can result in life-threatening complications if not diagnosed and managed appropriately.

Causes

Neutrophil immunodeficiency syndromes are typically caused by mutations in genes involved in neutrophil development, movement, signaling, or the ability to kill microbes. These conditions are usually inherited and may be passed down in autosomal recessive or X-linked patterns.

Common Genetic Causes

• Chronic Granulomatous Disease (CGD): Caused by mutations in the NADPH oxidase complex genes (e.g., CYBB, NCF1), leading to defective microbial killing

• LAD (Leukocyte Adhesion Deficiency): Caused by defects in genes like ITGB2, which prevent neutrophils from adhering to blood vessel walls and migrating to sites of infection

• Myeloperoxidase Deficiency: Leads to reduced production of enzymes critical for killing fungi and some bacteria

• Severe Congenital Neutropenia (Kostmann syndrome): Affects neutrophil maturation in the bone marrow

• Specific granule deficiency: Impairs production of granules containing antimicrobial proteins within neutrophils

Symptoms

The symptoms of neutrophil immunodeficiency syndromes typically begin early in life and are characterized by frequent, recurrent infections that are unusually severe or caused by organisms that typically do not affect healthy individuals.

Common Symptoms

• Recurrent skin abscesses or boils

• Recurrent respiratory infections (pneumonia, sinusitis)

• Delayed wound healing

• Gingivitis or severe periodontal disease

• Chronic otitis media (ear infections)

• Gastrointestinal infections or diarrhea

• Lymphadenitis (inflamed lymph nodes)

• Sepsis or systemic infections from common bacteria and fungi

Signs Suggesting Specific Syndromes

• CGD: Granuloma formation, liver abscesses, infections with catalase-positive organisms

• LAD: Delayed umbilical cord separation, lack of pus at infection sites despite high white blood cell counts

• Myeloperoxidase deficiency: Candidiasis and fungal infections more than bacterial infections

Diagnosis

Diagnosis involves a combination of clinical history, laboratory testing, and genetic analysis. Early diagnosis is critical to prevent complications and initiate targeted therapy.

Diagnostic Steps

• Complete blood count (CBC): May show neutropenia or a normal/high neutrophil count with functional defects

• Dihydrorhodamine (DHR) flow cytometry: A standard test to assess neutrophil oxidative burst (used for diagnosing CGD)

• Neutrophil function tests: Include chemotaxis assays, nitroblue tetrazolium (NBT) test, and phagocytosis testing

• Genetic testing: Confirms the exact mutation and helps differentiate among syndromes

• Cultures: From infected sites to identify unusual or recurrent pathogens

Treatment

Management of neutrophil immunodeficiency syndromes is focused on preventing infections, treating them promptly, and addressing the underlying immune defect when possible. A multidisciplinary team is often required, including immunologists, infectious disease specialists, and genetic counselors.

Infection Management

• Antibiotic prophylaxis: Long-term use of trimethoprim-sulfamethoxazole for bacterial infections

• Antifungal prophylaxis: Itraconazole or other agents for CGD or other high-risk syndromes

• Aggressive treatment of infections: Prompt antibiotics or antifungals as soon as infection is suspected

Immunomodulatory and Supportive Therapies

• Interferon-gamma (IFN-γ): Often used in CGD to boost neutrophil function

• Granulocyte colony-stimulating factor (G-CSF): Used in cases of neutropenia to stimulate neutrophil production

Curative Options

• Hematopoietic stem cell transplantation (HSCT): The only curative option for several severe neutrophil immunodeficiencies like CGD or severe congenital neutropenia

• Gene therapy: Experimental but promising for some monogenic forms (e.g., CGD)

Prognosis

The prognosis of neutrophil immunodeficiency syndromes varies widely depending on the specific disorder, severity, and timeliness of treatment. With early diagnosis, prophylaxis, and appropriate care, many patients can lead relatively healthy lives.

Conditions like Chronic Granulomatous Disease and LAD can lead to life-threatening infections if unmanaged, but survival rates have improved with advances in treatment. Hematopoietic stem cell transplantation has been curative in many severe cases, offering long-term survival and normalization of immune function.

Lifelong monitoring is typically required to assess immune function, growth, and development, and to manage complications such as organ damage from chronic infections or inflammatory granulomas.

Genetic counseling is essential for families to understand inheritance patterns and reproductive risks, especially for autosomal recessive and X-linked forms of the disease.