Epidemiology and Etiology
- Myeloperoxidase (MPO) deficiency is the most common primary phagocyte disorder.
- Incidence: 1 in 1400–2000 individuals in the United States
- Severe infection occurs in < 5% of cases
- Generally, infections occur only in patients with concomitant diabetes mellitus.
- MPO gene: 17q22-23
- Normal MPO function: enzyme that generates hypochlorous acid (HOCl) in neutrophils and monocytes
Primary MPO deficiency:
- Most common form
- Variable expression and penetrance
- Most patients are compound heterozygotes, with different mutations on each allele.
Acquired (secondary) MPO deficiency:
- Less common
- May arise from somatic mutations
- Affects only a proportion of neutrophils
- Transient (resolves with improvement of the underlying cause)
- Diabetes mellitus
- Iron deficiency
- Renal transplantation
- Thrombotic diseases
- Lead poisoning
- Obstructive jaundice
- Hematologic malignancies and disorders
- Severe infections
- Cytotoxic and antiinflammatory medications
Pathophysiology and Clinical Presentation
Neutrophils are the 1st line of defense against pathogens:
- During phagocytosis, neutrophils undergo respiratory burst.
- Activation of nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase and superoxide dismutase → production of superoxide, hydrogen peroxide, and other reactive oxygen species (ROS)
- MPO converts hydrogen peroxide to HOCl (amplifies toxicity of ROS)
- Pathogens killed in phagolysosome
- Have variable ability to kill bacteria
- Are unable to kill certain fungi:
- Candida albicans
- C. krusei
- C. stellatoidea
- C. tropicalis
- Most individuals are asymptomatic and have no increased frequency of infections.
- Severe infections are uncommon (< 5% of patients):
- Usually due to Candida
- Increased risk with diabetes mellitus or malignancy
Diagnosis and Management
- Histochemical staining:
- Performed on a blood smear
- Neutrophils will lack MPO (normally seen as azurophilic granules).
- Flow cytometry measures reactive oxygen intermediates.
Because most patients are asymptomatic, no specific treatment for MPO deficiency is required.
- Prophylactic antibiotics are not indicated.
- Prompt treatment of infections, particularly in patients with diabetes
- Avoid unnecessary or prolonged use of antibiotics or steroids (↑ risk of fungal infections).
- Leukocyte adhesion deficiency type 1: inherited condition resulting in a lack of CD18 expression on neutrophils. This deficiency leads to a decrease in the ability of neutrophils to migrate from the blood vessels. Patients with this condition will have recurrent infections, delayed wound healing, and an elevated neutrophil count. Leukocyte adhesion deficiency type 1 is not associated with oculocutaneous albinism. The diagnosis is confirmed with flow cytometry demonstrating a deficiency in CD18. Hematopoietic stem cell transplantation is the treatment of choice.
- Chronic granulomatous disease: consequence of defective phagocytic cells. Patients with this disease will have recurrent infections, abscesses, and granulomatous lesions of multiple organs. Hypergammaglobulinemia may be seen. The diagnosis is made with neutrophil function testing for superoxide production. Antimicrobial prophylaxis, interferon gamma, granulocyte transfusion, and hematopoietic stem cell transplantation are potential management options.
- Severe congenital neutropenia: rare disease resulting from genetic mutations that affect myelopoiesis. This condition manifests in infancy with life-threatening bacterial infections. Neutropenia is found on laboratory evaluation, often with an elevated monocyte count. A bone marrow biopsy will also aid in the diagnosis. Management includes granulocyte colony-stimulating factor and hematopoietic stem cell transplantation.
- Chediak-Higashi syndrome (CHS): autosomal recessive disorder caused by mutations affecting a lysosomal trafficking regulator protein. This protein plays a crucial role in the inability of neutrophils to kill phagocytosed microbes. Patients with CHS exhibit recurrent pyogenic infections, easy bleeding and bruising, and neurologic manifestations. This syndrome is also associated with oculocutaneous albinism. The diagnosis is made by analysis of the patient’s blood or bone marrow smear and genetic testing. The treatment of choice is allogeneic hematopoietic cell transplantation.
- Hyper IgE syndrome: hereditary primary immunodeficiency disease characterized by recurrent skin abscesses, pneumonia with pneumatocele, and eczematous dermatitis. The diagnosis is made by finding elevated serum IgE levels and can be confirmed with genetic testing. Management includes prophylactic antibiotics and interferon-gamma for severe infections.
- Petersen, M.M., Mikita, C.P. (2016). Myeloperoxidase deficiency. In Jyonouchi, H. (Ed.), Medscape. Retrieved March 26, 2021, from https://emedicine.medscape.com/article/887599-overview
- Marciano, B.E., Zerbe, C.S., Holland, S.M. (2021). Myeloperoxidase deficiency and other enzymatic WBC defects causing immunodeficiency. In TePas, E. (Ed.), UpToDate. Retrieved May 4, 2021, from https://www.uptodate.com/contents/myeloperoxidase-deficiency-and-other-enzymatic-wbc-defects-causing-immunodeficiency
- Pahwa, R., Modi, P., Jialal, I. (2020). Myeloperoxidase deficiency. [online] StatPearls. Retrieved May 4, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK470278/