Primary disorders of phagocyte number and/or function: An overview

INTRODUCTION — Susceptibility to infection from phagocytic dysfunction ranges from mild, recurrent skin infections to overwhelming, fatal systemic infection. Affected patients are more susceptible to bacterial and fungal infections but have a normal resistance to viral infections. Most are diagnosed in infancy due to the severity of the infection or the unusual presentation of the organism, but some escape diagnosis until adulthood. The prompt recognition of the specific defect may allow the correct management, including the prevention and aggressive treatment of serious infections, the management of complications, and the early evaluation for hematopoietic cell transplantation, which may be curative for many of the phagocytic cell defects.

This topic provides a brief overview of the types of defects and typical presentation of primary phagocytic disorders, which is the fifth International Union of Immunological Societies (IUIS) category of inborn errors of immunity (IEI) (table 1) [1] (see "Inborn errors of immunity (primary immunodeficiencies): Classification", section on 'V. Congenital defects of phagocyte number, function, or both'). The major disorders resulting from defects of phagocytic function are also briefly discussed. (Detailed discussions of these disorders are presented separately. See hyperlinks in respective sections below.)

Other IEI can have phagocytic abnormalities in addition to other immune defects, such as Chediak-Higashi syndrome (CHS), Hermansky-Pudlak syndrome type 2 (HPS2), Mendelian susceptibility to mycobacterial disease (MSMD), and warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome. These disorders fall under different categories in the IUIS classification. The full classification of IEI is discussed in greater detail separately. (See "Inborn errors of immunity (primary immunodeficiencies): Classification".)

TYPICAL PRESENTATION

Common features — Primary phagocytic deficiencies characteristically lead to recurrent and severe fungal (eg, Candida and Aspergillus) and bacterial (eg, Staphylococcus aureus, Pseudomonas aeruginosa, Nocardia asteroides, Salmonella typhi) infections [2,3]. Response to nontuberculous mycobacteria (NTM) may also be abnormal, particularly in patients with chronic granulomatous disease (CGD). The most common sites of infection are the respiratory tract, lymph nodes, and skin. Tissue and organ abscesses also occur. Other frequent manifestations include delayed separation of the umbilical cord, abnormal wound healing, dermatitis/eczema, and stomatitis. Many patients have growth failure. Most primary phagocyte disorders are diagnosed in infancy due to the severity of the infection or the unusual presentation of the organism, but some escape diagnosis until adulthood. (See "Recognition of immunodeficiency in the first three months of life", section on 'Phagocyte defects'.)

Features associated with specific disorders — Other findings are unique to each disorder (table 1), including:

●Granuloma formation or inflammatory bowel disease with CGD

●Heart disease/defects in some patients with Barth syndrome, folliculin-interacting protein 1 deficiency (FNIP1) deficiency, and glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency

●Partial albinism in p14/late endosomal/lysosomal adaptor, MAPK and MTOR activator 2 (LAMTOR2) deficiency

●Skeletal abnormalities in SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily d, member 2 (SMARCD2) deficiency

●Psychomotor retardation and microcephaly in Cohen syndrome

●Superficial venous pattern and atrial septal defect in patients with G6PC3 deficiency

●Seizures and psychomotor retardation in some patients with HCLS1-associated protein X-1 (HAX1) deficiency

●Neurodevelopmental delay and/or autistic features in some patients with signal recognition particle 54 (SRP54) deficiency

●Myelofibrosis in patients with vacuolar protein sorting 45 homolog (VPS45) deficiency

●Facial dysmorphisms and mild extrauterine growth retardation in DBF4 zinc finger (DBF4) deficiency [4]

TYPICAL LABORATORY FINDINGS

Overview — Phagocytic cell defects can be divided into quantitative and qualitative defects. Typical laboratory findings are reviewed here and are discussed in greater detail separately. (See "Laboratory evaluation of the immune system" and "Laboratory evaluation of the immune system", section on 'Tests for phagocytic abnormalities' and "Laboratory evaluation of neutrophil disorders".)

Quantitative neutrophil defects — In patients with quantitative defects, the number of circulating neutrophils is decreased. Neutropenia is classified by degree of severity depending upon the absolute neutrophil count:

●Severe neutropenia is defined as <500 neutrophils per microliter.

●Moderate neutropenia is characterized by an absolute neutrophil count between 500 and 1000 neutrophils per microliter.

●Mild neutropenia includes forms with >1000 but <1500 neutrophils per microliter.

Congenital neutropenias (eg. severe congenital neutropenia [SCN] type 1 to 5) typically exhibit a severe quantitative defect (<500 neutrophils/uL).

Qualitative neutrophil defects — A quantitative defect of neutrophils can be associated to monocytopenia, as seen in glycogen storage disease type Ib, which is characterized by fasting hypoglycemia and hepatomegaly, or p14/late endosomal/lysosomal adaptor, MAPK and MTOR activator 2 (p14/LAMTOR2) deficiency, which features growth failure and partial albinism. The number of circulating monocytes and peripheral dendritic cells is markedly decreased in patients with GATA-binding protein 2 (GATA2) deficiency. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'GATA2 deficiency (MonoMAC syndrome)'.)

Features associated with specific phagocytic dysfunction or inborn errors of immunity — Laboratory abnormalities that characterize distinct forms of congenital phagocytic dysfunction include:

●Impaired oxidative burst with defective response to the dihydrorhodamine 123 (DHR) flow cytometry test, which is seen in patients with chronic granulomatous disease (CGD). Complete myeloperoxidase (MPO) deficiency can cause a false-positive result for CGD in the DHR flow cytometric assay. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Neutrophil function tests'.)

●Abnormal expression of adhesion molecules (CD11 a,b,c; CD18), which is observed in leukocyte-adhesion deficiency (LAD). (See "Leukocyte-adhesion deficiency", section on 'Laboratory abnormalities'.)

●Giant lysosomal granules, which are present in the cytoplasm of neutrophils of patients with Chediak-Higashi syndrome (CHS), a disease of immune dysregulation. (See "Chediak-Higashi syndrome", section on 'Laboratory and imaging findings'.)

●Abnormal macrophage function in patients with Mendelian susceptibility to mycobacterial disease (MSMD) due to defects along the interleukin (IL) 12/interferon (IFN) gamma pathway. (See "Mendelian susceptibility to mycobacterial diseases: An overview", section on 'Pathogenesis'.)

●An abundance of senescent, hypersegmented neutrophils in the bone marrow (myelokathexis), a laboratory hallmark of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, another disorder caused by a defect in innate immunity. (See "Epidermodysplasia verruciformis", section on 'WHIM syndrome'.)

Other laboratory findings — Aside from the various specific abnormalities that characterize distinct forms of phagocytic cell disorders, the high susceptibility to infections is typically associated with elevation of inflammatory markers (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]). Hypergammaglobulinemia is also common in patients with CGD and has been reported in patients with C-X-C motif chemokine receptor 2 (CXCR2) deficiency, while hypogammaglobulinemia is seen in patients with p14/LAMTOR2 deficiency.

TYPES OF DEFECTS

Extrinsic and intrinsic defects

●Extrinsic (secondary) defects – Extrinsic defects include opsonic abnormalities secondary to deficiencies of antibody and complement factors [5]. Extrinsic factors may also lead to neutropenia by suppression of granulocyte production or cause a decrease in the number of circulating neutrophils via leukocyte autoantibodies or isoantibodies directed against neutrophil antigens. Defects of phagocytic movement may occur secondary to diabetes mellitus, metabolic storage disease, malnutrition, immaturity, and burns. Acquired autoimmune and isoimmune neutropenias result from antibodies directed against neutrophils. Alloimmune (also called isoimmune) neutropenia in infants is caused by transplacental passage of maternal antineutrophil antibodies. Increased neutrophil destruction is also common in chronic splenomegaly from any cause and certain autoimmune diseases (eg, Felty syndrome, lupus erythematosus). These nonprimary disorders of phagocytic function are discussed in detail separately. (See "Immune neutropenia" and "Drug-induced neutropenia and agranulocytosis" and "Infectious causes of neutropenia".)

●Intrinsic (primary) defects – Intrinsic disorders of granulocytes may be divided into those that result from defects in granulocyte development or exit into the circulation (primary neutropenias), granulocyte-killing ability, or chemotaxis (cell movement). Intrinsic disorders of phagocytic-killing ability include chronic granulomatous disease (CGD), glycogen storage disease type Ib, glucose-6-phosphate dehydrogenase (G6PD) deficiency class I, and neutrophil-specific granule deficiency (SGD) [2,3]. Intrinsic disorders of chemotaxis include glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency, leukocyte-adhesion defects, Ras-related C3 botulinum toxin substrate 2 (Rac2) deficiency, Shwachman-Diamond syndrome (SDS), and syndromes with periodontitis.

IUIS classification — The International Union of Immunological Societies (IUIS) classification divides the category of primary disorders of phagocytes into four subcategories: congenital neutropenias, defects of motility, defects of respiratory burst, and other nonlymphoid defects (table 1) [1]. These subcategories are discussed below. (See "Inborn errors of immunity (primary immunodeficiencies): Classification", section on 'V. Congenital defects of phagocyte number, function, or both'.)

Several diseases that have other defining features in addition to defects in phagocytic-killing ability (eg. Chediak-Higashi syndrome [CHS]), in neutrophil chemotaxis (eg. hyperimmunoglobulin E syndrome [HIES] due to signal transducer and activator of transcription 3 [STAT3] pathogenic variants and warts, hypogammaglobulinemia, infections, and myelokathexis [WHIM]), or in the interleukin (IL) 12/interferon (IFN) gamma pathway that regulates interactions between macrophages and T cells (eg, Mendelian susceptibility to mycobacterial infections [MSMD]) are classified as belonging to other categories of inborn errors of immunity (IEI) by the IUIS and are discussed in detail separately. (See "Autosomal dominant hyperimmunoglobulin E syndrome" and "Chediak-Higashi syndrome" and "Mendelian susceptibility to mycobacterial diseases: An overview" and "Epidermodysplasia verruciformis", section on 'WHIM syndrome' and "Mendelian susceptibility to mycobacterial diseases: Specific defects".)

OVERVIEW OF SPECIFIC CATEGORIES OF PHAGOCYTIC DISORDERS

Congenital neutropenias — Neutropenia (eg, circulating neutrophils <1500 cells/microL) is associated with a number of primary disorders [3]. Patients with congenital neutropenia have severe neutropenia (<500 cells/microL) and infections but no other syndromic features. Congenital neutropenias include infantile agranulocytosis (Kostmann syndrome and various other forms of severe chronic neutropenia), cyclic neutropenia, and glycogen storage disease type Ib. (See "Congenital neutropenia" and "Cyclic neutropenia" and "Myeloperoxidase deficiency and other enzymatic WBC defects causing immunodeficiency", section on 'Glycogen storage disease Ib'.)

Neutropenia is also common in several inborn errors of immunity (IEI) that also affect lymphoid cells, including X-linked hyperimmunoglobulin M syndrome, X-linked agammaglobulinemia, reticular dysgenesis, and warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome. (See "Hyperimmunoglobulin M syndromes" and "Agammaglobulinemia", section on 'X-linked agammaglobulinemia' and "Severe combined immunodeficiency (SCID): Specific defects", section on 'Reticular dysgenesis' and "Epidermodysplasia verruciformis", section on 'WHIM syndrome'.)

Further discussion of neutropenia appears separately. (See "Laboratory evaluation of neutrophil disorders" and "Overview of neutropenia in children and adolescents".)

Defects of motility — The most common defects of motility are the leukocyte-adhesion deficiency (LAD) syndromes. Other rare disorders include autosomal dominant Rac2 deficiency with leukocytosis and poor wound healing (see "Leukocyte-adhesion deficiency", section on 'Other syndromes of defective neutrophil adhesion'); beta-actin deficiency associated with intellectual disability and short stature; WD repeat domain (WDR) 1 deficiency (with mild neutropenia, poor wound healing, and severe stomatitis that may even impede opening of the mouth and oral feeding); Papillon-Lefevre syndrome with periodontitis and palmar-plantar hyperkeratosis; megakaryoblastic leukemia 1 (MKL1) deficiency with combined immunodeficiency and thrombocytopenia; and localized juvenile periodontitis.

Leukocyte-adhesion deficiencies — LAD type I results from an inability of neutrophils to leave the circulation in response to infection due to mutation of the leukocyte integrin beta 2 (CD18). Patients may present with delayed separation of the umbilical cord, recurrent bacterial sinopulmonary and skin infections, and poor wound healing. Circulating neutrophils may reach levels as high as 100,000/mm³ during infections [6]. (See "Leukocyte-adhesion deficiency", section on 'LAD I'.)

LAD type II results from an inability to appropriately glycosylate the leukocyte adhesion molecule sialyl-Lewis-X (sLeX or CD15s) due to a defect in a fucose transferase enzyme [6]. Thus, the disorder is also known as congenital disorder of glycosylation 2c. Patients with LAD type II have small stature, abnormal facies, and severe cognitive impairment. Recurrent bacterial sinopulmonary and skin infections are characteristic, although less severe than that observed with type 1 disease. Some patients may respond to treatment with high-dose fucose supplementation. (See "Leukocyte-adhesion deficiency", section on 'LAD II'.)

LAD type III is characterized by severe infections and a thromboasthenia-like bleeding disorder. It is caused by pathogenic variants of the fermitin family (drosophila) homolog 3 (FERMT3) gene, leading to impaired activation of beta-integrins [7]. (See "Leukocyte-adhesion deficiency" and "Leukocyte-adhesion deficiency", section on 'LAD III'.)

In patients with cystic fibrosis, a pathogenic variant in the gene for cystic fibrosis transmembrane conductance regulator (CFTR) can lead to adhesion deficiency in monocytes but not in lymphocytes or neutrophils. This is categorized as LAD type IV. Although integrins are expressed normally, they are not activated. This defect may play an important role in the severe inflammatory process in the lungs in these patients. (See "Leukocyte-adhesion deficiency", section on 'LAD IV' and "Cystic fibrosis: Genetics and pathogenesis".)

Periodontitis syndromes — Several syndromes of severe periodontitis with chemotactic defects due to deficiency of beta 2-integrins have been described, including localized juvenile periodontitis, rapidly progressive periodontitis, acute-necrotizing ulcerative gingivitis, and Papillon-Lefèvre syndrome (early-onset periodontitis with palmar-plantar hyperkeratosis) [8]. Each syndrome has a characteristic oral location, bacterial flora, and hereditary pattern. Oral antibiotics and intensive dental hygiene may aid some patients, but most experience loss of all teeth at an early age. (See "Periodontal disease in children: Associated systemic conditions".)

Neutrophil-specific granule deficiency — Neutrophil-specific granule deficiency (SGD) is a rare congenital disorder characterized by delay in the separation of the umbilical cord; increased susceptibility to pyogenic infections, especially of the skin, lungs, ears, and lymph nodes; and skeletal and dental abnormalities [2]. Two defective genes have been identified. Defects in the cytosine-cytosine-adenine-adenine-thymine (CCAAT)/enhancer-binding protein epsilon (CEBPE) gene cause SGD type 1, and pathogenic variants in SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2 (SMARCD2) genes cause SGD type 2. The diagnosis is made by examining neutrophils in a peripheral blood smear for the pathognomonic laboratory findings of paucity or absence of specific granules and predominantly bilobed nuclei (pseudo Pelger-Huet anomaly). This syndrome is discussed in greater detail separately. (See "Neutrophil-specific granule deficiency".)

Shwachman-Diamond syndrome — Shwachman-Diamond syndrome (SDS) is a rare, autosomal recessive disorder with severe congenital neutropenia [3]. Most patients have a pathogenic variant in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. Patients with SDS have pancreatic insufficiency, malabsorption, dyschondroplasia, eczema, and recurrent infection due to both decreased neutrophil chemotaxis and neutropenia. This syndrome is discussed in greater detail elsewhere. (See "Shwachman-Diamond syndrome".)

Defects of respiratory burst — Patients with reduced neutrophil oxidative burst, as measured by a dihydrorhodamine 123 (DHR) assay, suffer from recurrent infections. The most common disorder in this category is chronic granulomatous disease (CGD).

Chronic granulomatous disease — CGD is a genetically heterogeneous condition, with both X-linked and autosomal recessive forms. It is characterized by recurrent, life-threatening bacterial and fungal infections and granulomata formation [9]. Inflammatory manifestations, especially colitis, are also common. CGD is caused by defects in phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (phox). These genetic defects impair respiratory burst and consequently result in the inability of phagocytes (neutrophils, monocytes, and macrophages) to destroy microbial organisms once phagocytosed. The diagnosis is made by neutrophil function testing and mutation analysis. The cornerstones of CGD management are early diagnosis of infections, antimicrobial and immunomodulatory prophylaxis, and aggressive management of infectious complications. Survival of patients with CGD has dramatically improved, with many now living well into middle age. CGD is discussed in detail elsewhere. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis" and "Chronic granulomatous disease: Treatment and prognosis".)

Myeloperoxidase (MPO) is an enzyme found in the azurophilic granules of neutrophils and monocytes [2]. It catalyzes the production of microbicidal hypohalous acid in the presence of halide ions and hydrogen peroxide. The overwhelming majority of patients with MPO deficiency are clinically normal, even though this enzyme drives an important cytotoxic system capable of killing bacteria, fungi, parasites, and tumor cells. This disorder is discussed in detail separately. Complete MPO deficiency can cause a false-positive DHR test and therefore should be excluded in patients with possible CGD [10]. (See "Myeloperoxidase deficiency and other enzymatic WBC defects causing immunodeficiency".)

G6PD deficiency class 1 — Rarely, patients with severe glucose-6-phosphate dehydrogenase (G6PD) deficiency (less than 5 percent of the enzyme activity in neutrophils) have increased susceptibility to infections due to impairment of the neutrophil respiratory burst. (See "Myeloperoxidase deficiency and other enzymatic WBC defects causing immunodeficiency", section on 'Glucose-6-phosphate dehydrogenase deficiency'.)

Other nonlymphoid defects — Patients in this category have phagocyte function that is defective, but neutrophil oxidative burst testing (DHR assay) is normal.

GATA-binding protein 2 deficiency — Haploinsufficiency of GATA-binding protein 2 (GATA2) causes a broad spectrum of clinical manifestations, including mycobacterial infections, viral infections, bone marrow failure, and leukemia. Most commonly, GATA2 deficiency leads to the syndrome of monocytopenia and mycobacterial disease (MonoMAC), which is characterized by late childhood or adult onset of disseminated nontuberculous mycobacterial (NTM) disease. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'GATA2 deficiency (MonoMAC syndrome)'.)

Pulmonary alveolar proteinosis — Hereditary pulmonary alveolar proteinosis is due to recessive variants of the granulocyte-macrophage colony stimulating factor (GM-CSF) receptor alpha and beta genes (CSF2RA and CSF2RB). Genetic variants in the GM-CSF receptor impair signaling by intact GM-CSF, resulting in decreased production and clearance of surfactant. Decreased activity is often the initial symptom in infants and younger children. Weight loss or failure to gain weight is common. A mild, nonproductive cough may be present. Hypoxemia is typically noted. The primary presenting symptom in older children and adults is shortness of breath, usually with exercise. (See "Pulmonary alveolar proteinosis in children" and "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults" and "Treatment and prognosis of pulmonary alveolar proteinosis in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Chronic granulomatous disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical manifestations – Patients with primary phagocytic disorders are more susceptible to bacterial and fungal infections but have a normal resistance to viral infections. Other frequent manifestations include abnormal wound healing, dermatitis/eczema, and stomatitis. (See 'Typical presentation' above.)

●Sites of infection – The most common sites of infection are the respiratory tract and skin. (See 'Typical presentation' above.)

●Common organisms – Fungal infections are primarily Candida and Aspergillus species. The most common bacterial infections are Staphylococcus aureus, Pseudomonas aeruginosa, Nocardia asteroides, and Salmonella typhi. (See 'Typical presentation' above.)

●Laboratory findings – Laboratory findings may include neutropenia or neutrophilia (depending on the nature of the disease), impaired oxidative burst (in patients with chronic granulomatous disease [CGD]), and elevation of inflammatory markers. (See 'Typical laboratory findings' above.)

●Types of defects – Phagocytic disorders can be caused by extrinsic or intrinsic defects. Extrinsic defects include opsonic abnormalities secondary to deficiencies of antibody and complement factors, suppression of granulocyte production, and leukocyte autoantibodies or isoantibodies that decrease the number of circulating neutrophils. Intrinsic disorders of granulocytes may be divided into those that result from defects in granulocyte development, killing ability, or chemotaxis (cell movement). (See 'Types of defects' above.)

●International Union of Immunological Societies (IUIS) classification – The four categories of primary disorders of phagocytes are congenital neutropenias, defects of motility, defects of respiratory burst, and other nonlymphoid defects (table 1). (See 'IUIS classification' above and 'Congenital neutropenias' above and 'Defects of motility' above and 'Defects of respiratory burst' above and 'Other nonlymphoid defects' above.)

●Importance of prompt diagnosis and treatment – The prompt recognition of the defect may allow the correct management, including the prevention and aggressive treatment of serious infections, the management of complications, and the early evaluation for hematopoietic cell transplantation, which may be curative for many of the phagocytic cell defects. (See 'Introduction' above and 'Overview of specific categories of phagocytic disorders' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert L Roberts, MD, PhD and Francisco A Bonilla, MD, PhD, who contributed to earlier versions of this topic review.

The UpToDate editorial staff also acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.