Continuing Education Activity

Neutropenia is a decreased number of neutrophils less than 1500/microliter and can be idiopathic, congenital, autoimmune, or cyclic. Those lasting more than three months without underlying etiology are idiopathic chronic neutropenia. Autoimmune and chronic neutropenia are serious conditions that can lead to a variety of infections. This activity describes the evaluation and management of autoimmune and chronic neutropenia. It highlights the role of the healthcare team in evaluating, treating, managing, and improving care for patients with this condition.

Objectives:

• Identify the etiology of autoimmune and idiopathic neutropenia.

• Assess the evaluation of autoimmune and idiopathic neutropenia.

• Determine the treatment of autoimmune and idiopathic neutropenia.

• Communicate the strategies for improving coordination between the interprofessional team in caring for patients with autoimmune and idiopathic neutropenia.

Introduction

Neutropenia is defined as a number of neutrophils in the body, a granulated white blood cell type, less than 1500/microliter. It is multifactorial in origin, either by decreased production, sequestration from endothelium and tissues, or increased peripheral destruction. Autoimmune neutropenia (AIN) is a reduced number of neutrophils resulting from increased peripheral destruction by antineutrophil antibodies from autoimmune disorders.[1] These autoantibodies are directed against cell membrane antigens present on IgG Fc receptors.[2] AIN can be considered chronic neutropenia if it lasts more than 3 months and is unrelated to any etiology. Chronic neutropenia can be either idiopathic or involve other etiologies of AIN. AIN is categorized as primary and secondary according to etiology and pathogenesis. The primary form of AIN is dominant in children, and it presents commonly as a hematologic abnormality and bonemarrow hypoplasia. The secondary form of AIN is present in adults as autoimmune disorders, primary immune deficiencies, infections, hematologic malignancies, or drug exposure. AIN is also prevalent in post-transplant patients as well as in some neurological diseases. AIN's clinical manifestations may vary from asymptomatic to life-threatening infections in individuals. In the pediatric population, it can lead to recurring infections, hematologic malignancies, and neuropsychiatric disorders.

Etiology

AIN is divided into primary and secondary forms according to the origin, age distribution, and etiopathology.[2][3] The primary form is most prevalent in children and ranges from sole hematological disorders to severe life-threatening infections.

• Kostman syndrome (Severe infantile agranulocytosis)
• Chediak - Higashi syndrome 
• Cyclic neutropenia
• Shwachman-Diamond-Oski syndrome
• Reticular dysgenesis
• Dyskeratosis congenita
• LAD
• Chronic granulomatous disease
• Hyper IgM syndrome 
• Common variable immunodeficiency
• Sever combiner immunodeficiency

The secondary form is more prevalent in adults and divided into the following categories according to etiologies;

1. Systemic autoimmune disorders

•  Chronic autoimmune hepatitis (Primary biliary cirrhosis)
•  Granulomatosis with polyangiitis 
•  Inflammatory bowel disease
•  Rheumatoid arthritis (Felty syndrome)
•  Sjogren syndrome
•  Systemic sclerosis
•  Systemic lupus erythematosus

2. Infectious disorders

• Helicobacter pylori
• HIV 
• Parvovirus B19 

3. Malignancies

• Wilm tumor 
• Hodgkin lymphoma

4. Neurological disorders

• Multiple sclerosis

5. Posttransplant

• Stem cell
• Bone marrow 
• Kidney

 6. Medications

• Aminopyrine
• Cephalosporin
• Fludarabine 
• Hydralazine
• Heavy metals
• Procainamide
• Propylthiouracil
• Quinidine 
• Rituximab
• Sulfonamides

Along with these disorders, certain congenital immunological diseases, bone marrow failure syndromes, and metabolic diseases in the pediatric population can also lead to chronic neutropenia and recurring infections through different mechanisms. Usually, in the pediatric population, AIN presents with a minor hematological abnormality in the majority, but it presents in a few patients, it leads to life-threatening and recurrent infections. One of the causes of the secondary form of AIN is antineutrophil antibodies, which lead to neutropenia by peripheral destruction, bonemarrow inhibition, or apoptosis of cells.[4][5][2]

Epidemiology

AIN and chronic idiopathic neutropenia (CIN) are relatively rare conditions that can sometimes present as primary hematological disorders, and that's why they are referred to as "primary" or "isolated" neutropenia. According to a U.S. study, the prevalence of isolated neutropenia was reported to be 0.44% among Mexican-Americans, 0.84% among whites, and 4.5% among black participants. According to the same study, the prevalence of chronic severe neutropenia was estimated to be 5 cases per million in the Washington state of the USA. The primary AIN lasts for 3 to 5 years in children, with an average of 17 months. The frequency of primary and secondary AIN is 12.85% and 3.84%, respectively, in preterm babies, according to a study done in Italy. At the time of analysis, 74.9% of primary AIN and 7.7% of secondary AIN had recovered from neutropenia. So, the study concluded that primary AIN is benign and occurs in children under 2 to 3 years of age, and secondary AIN is more severe and occurs after 5 years of age with a greater tendency to be chronic.[6] A study concluded a striking predominance of females to males as evidenced by an 8:1 ratio, while in children, more male predominance was seen. The patients with CIN or AIN enrolled in the Severe Chronic Neutropenia International Registry in North America (SCNIR) suggested an early childhood peak with female predominance was seen.[7]

Pathophysiology

Mature neutrophils are derived from precursor cells in the bone marrow. The total neutrophil count is divided into bone marrow, blood, and tissues. In blood, neutrophils are divided into either peripheral or circulating compartments. The peripheral neutrophils are attached to vascular endothelium, and circulating neutrophils are present through the bloodstream. AIN is a heterogeneous group of disorders that destroy neutrophils from producing IgG antibodies against Fc receptors of neutrophils, leading to peripheral destruction and splenic clearance.[8] 

In primary neutropenia, a decrease in the number of neutrophils leads to several infections with bacteria and fungi, but it is usually a milder form than chemotherapy-induced neutropenia. The peripherally attached neutrophils to vascular endothelium play a vital role in the inflammatory response to a foreign antigen leading to an inflammatory response. For this, they must attach to the vessel wall, which is done by certain adhesion molecules called beta-2 integrin and spectrin. These molecules are deficient in a congenital disorder called leukocyte adhesion deficiency (LAD) and lead to a disease ranging from recurrent infections to severe life-threatening infections and delayed cord prolapse, etc.[9] 

Chronic granulomatous disease is another congenital abnormality that leads to recurrent infections with catalase-positive organisms: Staphylococcus, Serratia, Burkholderia, Aspergillus, etc. The absence of NADPH oxidase enzyme complex helps form reactive oxygen species during the respiratory burst phenomenon.[10] Another congenital form of primary AIN is Chediak Higashi syndrome, an autosomal recessive disease characterized by abnormal chemotaxis and failure of lysosomes to fuse with phagosomes.[11] The evidence for inflammatory bowel disease suggests that the immune system's dysfunctioning innate and adaptive immunity pathways correspond to an aberrant inflammatory response. It was divided into 2 major types: Crohn disease has been considered to be associated with T-helper cells I response and ulcerative colitis is considered to be driven by non-conventional T-helper cells II response.[12]

Histopathology

In the case of LAD, the biopsy of inflammatory tissue shows the absence or paucity of neutrophils. The remains of the umbilical cord show a decreased number of neutrophils and less inflammatory response, showing decreased edema.[9] Chediak Higashi syndrome histologically shows giant lysosomal granules in the cells.[11] In ulcerative colitis, there is a presence of inflammatory infiltrate in lamina propria with an absence of neutrophils, crypt abscesses, and cryptitis. In UC, plasma cells are abundant at the base of crypts, and muscularis mucosa is exposed due to ulceration or may be covered in granulation tissue. 

History and Physical

AIN and CIN are multifactorial in etiology. The primary form is seen in children, and in adults, the secondary form is seen. The primary form in children is mild and resolves after a few years of life in the majority, while in adults, it represents a chronic entity. The history of the following is seen in both:

• Recurrent respiratory infections in children that are usually minor and upper
• Opportunistic infections 
• Rare serious invasive infections, mostly in young infants
• Recurrent use of antibiotics and antifungal agents and developing resistance[13][3] 

In AIN and CIN, the physical examination findings are:

• Delayed separation of the umbilical cord in LAD patients
• Gingivitis
• Skin infections
• Bacteremia 
• Septicemia 
• Lung abscess
• Pneumatocele
• Sinus infections
• Pneumonia 
• Osteomyelitis
• Arthritis 
• Fever 
• Cough 
• Malaise 
• Recurrent abscess 
• Stomatitis 
• Cutaneous infections (eg, Staphylococci)
• Splenomegaly 
• Poor wound healing 
• Omphalitis
• Bleeding complications 
• Granuloma 
• Urinary tract infections 
• Meningitis 
• Denture abnormalities 
• Otitis media 
• Graft versus host reaction[14][13][9] 

Evaluation

The investigation of AIN and CIN includes immunoglobulins, complement systems, inflammatory markers, and phagocyte functions. For the diagnosis of AIN, the detection of antineutrophil antibodies is important. Still, because detecting antineutrophil autoantibodies is difficult, a combination of immunofluorescence and agglutination tests for screening is used.[9][15][12] 

Quantitative Serum Immunoglobulins

• IgG
• IgM
• IgA
• IgE

Phagocytic Function

Nitroblue tetrazolium (NBT) test (before and after stimulation with endotoxin)

• Unstimulated
• Stimulated

Neutrophil mobility

• In medium alone
• In the presence of chemoattractant
• In vivo and in vitro chemotaxis of granulocytes

Blood Lymphocyte Subpopulations

• Total lymphocyte count
• T lymphocytes (CD3, CD4, and CD8)
• B lymphocytes (CD19 and CD20)
• CD4/CD8 ratio

Lymphocyte Stimulation Assays

• Phorbol ester and ionophore
• Phytohemagglutinin
• Antiserum to CD3
• Chemotaxis of human lymphocytes

Complement System Evaluation

Measurement of individual components by immunoprecipitation tests, ELISA, or Western blotting

• C3 serum levels
• C4 serum levels
• C1 inhibitor serum levels

Hemolytic assays

• CH50
• CH100

Complement system functional studies

• Classical pathway assay (using IgM on a microtiter plate)
• Alternative pathway assay (using LPS on a microtiter plate)
• Mannose pathway assay (using mannose on a microtiter plate)

Antibody Activity

• Test for heterophile antibody
• Anti-streptolysin O titer
• Immunodiagnosis of infectious diseases (HIV, hepatitis B and C, HTLV, and dengue)
• Serum protein electrophoresis

Other Investigations of an Immunodeficiency Disorder

• Complete blood cell count
• Bone marrow biopsy
• Blood chemistry
• Histopathological studies
• Fluorescent in situ hybridization (FISH)
• Tumoral markers
• Levels of cytokines
• Chest X-ray
• Diagnostic ultrasound
• Liver function test

Treatment / Management

Primary AIN is mainly seen in infants, and it is self-limiting over time and does not require extensive measures. Still, secondary AIN is common in adults and requires antibiotics and G-CSF. Implementing granulocyte colony-stimulating factor (G-CSF) has improved neutrophil count and function in certain patients with neutropenia.[16] Also, G-CSF is a treatment for severe congenital neutropenia. Hematopoietic stem cell transplant (HSCT) has been approved for treatment when the condition does not improve with G-CSF. Prophylactic antimicrobial agents can be used for congenital conditions like LAD and congenital granulomatous disease. If AIN is associated with other autoimmune diseases and is severe, treatment with corticosteroids, intravenous immunoglobulins, or immunosuppressants such as rituximab should be indicated.[8] Allogenic bone marrow transplantation from an HLA-matched related donor is the therapy of choice for severe congenital conditions with recurrent and fatal infections. Gene therapy is also recommended for some cases of neutropenia.

Differential Diagnosis

Neutropenia can be differentiated according to the etiology as either immunoglobulin disorders, complement system disorders, or disorders of neutrophil formation. Primary AIN is seen in the pediatric population with congenital disorders like CGD, LAD, and reticular dysgenesis. Secondary AIN is more commonly seen in the adult population with disorders like systemic lupus erythematosus, inflammatory bowel disease, etc, with pathogenesis involving antineutrophil antibodies affecting the immune system, which antibody levels can rule out. Certain immunoglobin disorders involving severe combined immunodeficiency and common variable immunodeficiency also present with recurrent bacterial and fungal infections involving mainly the GI and respiratory system, which Ig levels can rule out. Some complement system disorders like C1 esterase inhibitor deficiency can also lead to extracellular bacterial infections, which can be ruled out by testing laboratory complement and enzyme levels. In clinical manifestations, it resembles neutropenia as well.[9][17][18]

Prognosis

The prognosis of AIN depends on the etiology and age at presentation. Primary AIN in the pediatric population is suggested by recurrent infections, which are usually benign and can be treated with antimicrobial agents and, if severe, with G-CSF and bone marrow transplant in cases such as granulomatous disease and LAD. Secondary AIN in the adult population is associated with decreased immunity and infections, which can be treated with antimicrobial agents, immunosuppressants, biological agents, and in severe cases, plasmapheresis. AIN and CIN, as a result of chemotherapy or drugs, resolve immediately after cessation of the treatment. While certain etiologies present with less severe mucosal infections, severe congenital conditions result in death at a young age. LAD can present with death in the first year of life, or patients with less severe LAD can live till the third decade with recurrent infections and can be managed with a hematopoietic stem cell transplant.[19][13]

Complications

AIN and CIN can lead to the following complications:

• Recurrent severe bacterial and fungal infections 
• Premature death
• Failure to thrive 
• Septicemia
• Multiorgan failure 
• Antimicrobial resistance[9][13][14] 

Deterrence and Patient Education

Consanguinous couples should get genetic testing before conception. If known to have affected children, they should be educated regarding the likelihood of their second child and, if possible, avoid pregnancy at all. Parents should be counseled regarding the affected child's care in good health and disease.

Enhancing Healthcare Team Outcomes

AIN and CIN are rare conditions with a disease spectrum extending from minor infections to severe life-threatening infections leading to death. Thus, interprofessional teams, including physicians, nurses, and pharmacists, can manage these conditions with the best approach. A specialist team, including immunologists, geneticists, infectious disease specialists, and pediatricians, can manage these conditions with prophylactic antimicrobial agents or G-CSF. These patients should be monitored closely with the complete blood cell count, blood chemistry, inflammatory markers, and immunoglobulins. Healthcare providers should advise these patients regarding infection warning signs and symptoms and appropriate precautions. Patients undergoing chemotherapy should watch for signs of infections and, if possible, wear masks in public and follow handwashing measures. Pharmacists should advise of possible side effects of medications prescribed for these patients by providers. Hence a team effort is essentially required for the well being of these patients and their quality of life.