Myeloperoxidase Deficiency

Myeloperoxidase (MPO) deficiency is an inherited or acquired disorder caused by mutations in the MPO gene on chromosome 17, leading to a deficiency of MPO in neutrophils and monocytes. This deficiency particularly impairs destruction of pathogens in phagolysosomes. While the majority of patients are asymptomatic and do not suffer from an increased frequency of infections, a minority (particularly  diabetic patients) can develop serious fungal infections. Histochemical staining of neutrophils for MPO can provide the diagnosis. There is no specific management for MPO deficiency, and prophylactic antibiotics are not indicated.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Epidemiology and Etiology

Epidemiology

  • Myeloperoxidase (MPO) deficiency is the most common primary phagocyte disorder.
  • Incidence: 1 in 1400–2000 individuals in the United States
  • Morbidity:
    • Severe infection occurs in < 5% of cases
    • Generally, infections occur only in patients with concomitant diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus.

Etiology

Genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations:

  • MPO gene: 17q22-23 
  • Normal MPO function: enzyme that generates hypochlorous acid (HOCl) in neutrophils and monocytes

Primary MPO deficiency: 

  • Most common form
  • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables 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)
  • Causes: 
    • Diabetes mellitus
    • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
    • Iron deficiency
    • Renal transplantation
    • Thrombotic diseases
    • Lead poisoning
    • Obstructive jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
    • Hematologic malignancies and disorders
    • Severe infections 
    • Cytotoxic and antiinflammatory medications

Pathophysiology and Clinical Presentation

Pathophysiology

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

MPO-deficient neutrophils:

  • Have variable ability to kill bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview
  • Are unable to kill certain fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview:
    • Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis albicans
    • C. krusei
    • C. stellatoidea
    • C. tropicalis
Respiratory burst diagram

Chemical reactions that occur in phagolysosomes in an effort to kill a pathogen:
Myeloperoxidase deficiency results in an inability to convert hydrogen peroxide to hypochlorous acid.

Image by Lecturio.

Clinical presentation

  • Most individuals are asymptomatic and have no increased frequency of infections.
  • Severe infections are uncommon (< 5% of patients):
    • Usually due to Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis 
    • Increased risk with diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus or malignancy

Diagnosis and Management

Diagnosis

  • Histochemical staining: 
    • Performed on a blood smear 
    • Neutrophils will lack MPO (normally seen as azurophilic granules).
  • Immunohistochemistry
  • Flow cytometry measures reactive oxygen intermediates.

Management

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).

Differential Diagnosis

  • Leukocyte adhesion deficiency type 1 Leukocyte adhesion deficiency type 1 Leukocyte adhesion deficiency type 1 (LAD1) is an inherited condition in which genetic mutations result in a lack of CD18 expression on neutrophils. These mutations lead to a decrease in the ability of neutrophils to migrate from the blood vessels to the site of injury or infection on recruitment, presenting as recurrent infections and delayed wound healing. 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 Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing, and an elevated neutrophil count. Leukocyte adhesion deficiency type 1 Leukocyte adhesion deficiency type 1 Leukocyte adhesion deficiency type 1 (LAD1) is an inherited condition in which genetic mutations result in a lack of CD18 expression on neutrophils. These mutations lead to a decrease in the ability of neutrophils to migrate from the blood vessels to the site of injury or infection on recruitment, presenting as recurrent infections and delayed wound healing. Leukocyte Adhesion Deficiency Type 1 is not associated with oculocutaneous albinism Oculocutaneous albinism Albinism refers to a group of inherited disorders that result in the disruption of melanin production, causing hypopigmentation and visual impairment. The condition is classified according to the clinical phenotype. Oculocutaneous albinism results in hypopigmentation of the skin, eyes, and hair. Ocular albinism affects only the eyes. 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 Chronic Granulomatous Disease Chronic granulomatous disease (CGD), as the name implies, is a chronic disorder that is characterized by granuloma formation. This disorder is a consequence of defective phagocytic cells that are unable to produce bactericidal superoxide because of a defect in nicotinamide adenine dinucleotide phosphate (NADPH), the oxidase responsible for the respiratory burst in phagocytic leukocytes. 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 Severe congenital neutropenia Severe congenital neutropenia (SCN) affects myelopoiesis and has many different subtypes. SCN manifests in infancy with life-threatening bacterial infections. 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 Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of 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 Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder 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 Oculocutaneous albinism Albinism refers to a group of inherited disorders that result in the disruption of melanin production, causing hypopigmentation and visual impairment. The condition is classified according to the clinical phenotype. Oculocutaneous albinism results in hypopigmentation of the skin, eyes, and hair. Ocular albinism affects only the eyes. Albinism. The diagnosis is made by analysis of the patient’s blood or bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin abscesses, pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. 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.

References

  1.  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
  2. 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
  3. Pahwa, R., Modi, P., Jialal, I. (2020). Myeloperoxidase deficiency. [online] StatPearls. Retrieved May 4, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK470278/

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