What is Autoimmune and Chronic Neutropenia?
Neutropenia is a condition where the body has fewer than normal neutrophils, a type of white blood cell, less than 1500 per microliter. This can happen for several reasons, like less production, being stored away in the body’s tissues, or being destroyed too quickly.
There’s a particular type of neutropenia caused by autoimmune disorders, known as Autoimmune neutropenia (AIN). In this case, the body has fewer neutrophils because they get destroyed by its own antibodies. These antibodies mistakenly attack parts of the body’s own cells that are usually found on certain receptors.
If AIN lasts for over three months without another identifiable cause, it’s considered chronic neutropenia. This might be idiopathic, meaning we don’t know why it happens, or it might be related to other causes of AIN. AIN falls into two categories: primary or secondary, based on its causes and the processes that lead to it. The primary form is more common in children, where it usually shows up as blood abnormalities and low bone marrow production. The secondary form is more common in adults and can be caused by autoimmune disorders, immune deficiencies, infections, blood cancer, drug exposure, or even after an organ transplant. It’s also found in some neurological diseases.
The symptoms of AIN can range from none at all to severe, life-threatening infections. In children, it can cause recurring infections, blood cancer, and neuropsychiatric disorders.
What Causes Autoimmune and Chronic Neutropenia?
Autoimmune neutropenia is a condition where the body’s immune system attacks its own white blood cells, causing a low white blood cell count. This is usually split into two types: primary, which is mostly in kids, and secondary, which tends to affect adults.
Primary autoimmune neutropenia can range from a blood disorder to severe and potentially deadly infections. Conditions that can cause it include a number of different syndromes like Kostman syndrome, Chediak-Higashi syndrome, Shwachman-Diamond-Oski syndrome, and others. Also, some diseases that impair the immune system, or conditions that prevent the bone marrow from working properly can also cause primary autoimmune neutropenia in children.
The secondary form is more common in adults and can be caused by various things:
1. Diseases where the body’s immune system can attack its own cells like chronic autoimmune hepatitis, rheumatoid arthritis or lupus.
2. Infectious diseases like those caused by Helicobacter pylori, HIV, or Parvovirus B19.
3. Tumors like Wilm’s tumor or Hodgkin lymphoma.
4. Neurological disorders like multiple sclerosis.
5. Organ and tissue transplants such as stem cell, bone marrow, or kidney transplants.
6. Some medicines, like aminopyrine, a type of antibiotic called cephalosporin, and others.
It’s also worth noting that in children, autoimmune neutropenia can occasionally be caused by certain genetic immune system diseases, conditions that cause bone marrow failure and metabolic diseases. Usually, this means they show up with minor blood cell abnormalities, but in some kids, it can lead to severe and repeated infections. Secondary autoimmune neutropenia can also be caused by antibodies that target and destroy white blood cells.
Risk Factors and Frequency for Autoimmune and Chronic Neutropenia
Autoimmune neutropenia (AIN) and chronic idiopathic neutropenia (CIN) are somewhat rare conditions, often showing up as main blood disorders, and therefore are known as “primary” or “isolated” neutropenia. In the United States, a study found that isolated neutropenia was found in 0.44% of Mexican-Americans, 0.84% of whites, and 4.5% of black participants. The same study estimated that chronic severe neutropenia was found in 5 out of every million people in Washington state.
In children, primary AIN typically lasts 3 to 5 years, averaging around 17 months. An Italian study showed that the rates of primary and secondary autoimmune neutropenia were approximately 12.85% and 3.84% in preterm babies, respectively. At the time of the study, primary AIN had cleared up in about 74.9% of cases, while secondary AIN had cleared up in around 7.7% of cases. This led to the conclusion that primary AIN is generally harmless, usually occurs in children under 3 years old, while secondary AIN is more severe, generally happens after 5 years of age, and is more likely to become chronic.
One study found a large ratio of females to males of 8:1 with these conditions, though in children, it was more common in males. According to the Severe Chronic Neutropenia International Registry in North America, these conditions usually begin in early childhood and are more common in females.
Signs and Symptoms of Autoimmune and Chronic Neutropenia
Autoimmune neutropenia (AIN) and chronic idiopathic neutropenia (CIN) are conditions that affect the immune system. AIN is more common in children and typically mild, usually resolving after a few years. CIN, on the other hand, is mainly seen in adults and tends to be a long-term condition. People with AIN and CIN often have a history of:
- Frequent minor upper respiratory infections, especially in children
- Opportunistic infections
- Severe infections, mostly in young infants although this is rare
- Regular use of antibiotics and antifungal medications, with the possibility of developing resistance to them
There are also a number of physical symptoms associated with AIN and CIN, such as:
- Delayed separation of the umbilical cord in patients with Leukocyte Adhesion Deficiency (LAD)
- Gum inflammation (gingivitis)
- Skin infections
- Bloodstream infections (bacteremia) and whole-body inflammation due to infection (septicemia)
- Lung abscess, air-filled cavities in the lungs (pneumatocele), sinus infections, and pneumonia
- Bone and joint infections (osteomyelitis and arthritis)
- Fever, cough, and a general feeling of ill health (malaise)
- Recurrent abscesses and mouth ulcers (stomatitis)
- Skin infections such as those caused by Staphylococci bacteria
- Enlarged spleen (splenomegaly)
- Difficulty healing wounds
- Bacterial infection of the umbilical stump (omphalitis)
- Bleeding complications and granulomas (small areas of inflammation)
- Urinary tract infections, meningitis, and denture abnormalities
- Middle ear infections (otitis media)
- Immune reaction to a transplant (graft versus host reaction)
Testing for Autoimmune and Chronic Neutropenia
Diagnosing immune-related illnesses such as autoimmune neutropenia or chronic idiopathic neutropenia involves a series of tests. Key to these tests is checking for anti-neutrophil antibodies – a type of protein that the body might produce against its own cells. Unfortunately, finding these antibodies can be tough, so doctors use a combination of light-based (immunofluorescence) and bonding (agglutination) tests.
Several other tests play a role in identifying these illnesses. These include measuring different types of proteins that the immune system uses to fight infections (IgG, IgM, IgA, and IgE). Doctors will also look at how efficiently cells that gobble up bacteria and viruses (phagocytes) work, both under normal conditions and when exposed to bacteria toxins.
Yet another test assesses how well neutrophils (a type of white blood cell) move, with and without the presence of substances that guide their movement. Doctors also count and assess several other types of immune cells in the blood, included T and B types of lymphocytes.
The complement system is also evaluated. This part of your immune system enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism. It features several proteins that work together and individually to fight infections. Their levels are tested using multiple methods, including immunoprecipitation tests, ELISA, or Western blotting. The functionality of this system is also assessed using multiple unique tests.
Aside from this, antibodies are checked using various disease-specific tests including for HIV, hepatitis B and C, HTLV and dengue. Doctors might also run other basic health checks, like a complete blood count, a bone marrow biopsy, a chest X-ray, and a liver function test among others. These tests may provide additional helpful information for reaching a diagnosis.
Treatment Options for Autoimmune and Chronic Neutropenia
Primary Acute Infected Neutropenia (AIN) mainly occurs in infants and typically gets better on its own over time. It usually doesn’t require intensive treatment. However, secondary AIN is more common in adults and requires antibiotics and a certain kind of drug called granulocyte colony-stimulating factor (G-CSF). This drug can increase both the number and function of a type of white blood cell called neutrophils in patients with low neutrophil counts. G-CSF is also the preferred treatment for a severe condition in newborns called severe congenital neutropenia (SCN).
Hematopoietic stem cell transplant (HSCT) is approved to treat conditions not improved by G-CSF. This is a procedure where a patient receives healthy stem cells to stimulate new bone marrow growth.
Preventive antibiotics can be used for certain inherited conditions like Leukocyte Adhesion Deficiency (LAD) and congenital granulomatous disease. If AIN is associated with other autoimmune diseases and severe, then treatment with steroids, intravenous immunoglobulins, or immunosuppressants such as rituximab should be used.
Another treatment choice for severe congenital conditions that lead to repeated and fatal infections is allogenic bone marrow transplantation from a closely matched family member. Also, gene therapy is recommended for some cases of low neutrophil counts.
What else can Autoimmune and Chronic Neutropenia be?
Neutropenia, or low white blood cell count, can be categorised based on its cause. These causes might include problems with the immune system, such as conditions that affect the proteins our bodies use to fight off infections (called immunoglobulins), problems with the body’s system that helps immune cells to kill germs (the complement system), or issues with the way white blood cells are formed.
There are certain genetic conditions seen mainly in children, like chronic granulomatous disease, leukocyte adhesion deficiency, and reticular dysgenesis, in which neutropenia is often a key feature. On the other hand, adults may experience neutropenia due to immune disorders like systemic lupus erythematosus or inflammatory bowel disease. These lead to the body producing harmful antibodies against its own white blood cells. Testing for these antibodies can help determine if this is causing the neutropenia.
Some people have immunodeficiency conditions, like severe combined immunodeficiency or common variable immunodeficiency, which make them prone to repeated bacterial and fungal infections, particularly in the gut and breathing passages. Checking immunoglobulin levels can rule out these conditions as the cause of neutropenia.
Finally, certain disorders of the complement system, such as C1 esterase inhibitor deficiency, can also lead to severe bacterial infections. Testing for specific complement proteins and enzymes in the blood can rule out these disorders. The symptoms of this condition can look similar to neutropenia.
What to expect with Autoimmune and Chronic Neutropenia
The outcomes for AIN (Acute Interstitial Nephritis), a kind of kidney inflammation, are dependent on the cause and the age when it’s detected. In children, primary AIN often presents with repeated infections, usually harmless and treatable with medications. More severe cases might require bone marrow transplants.
For adults, secondary AIN links with decreased immunity and infections. Treatment options include medications, immunity suppressants, biologic therapies, and in serious cases, a process called plasmapheresis that filters and cleanses the blood. Chemotherapy or drug-induced AIN and CIN (Chronic Interstitial Nephritis) typically get better once the treatment is stopped.
Although some causes lead to less severe infections, certain congenital (present at birth) conditions could be severe and lead to early death. LAD (Leukocyte Adhesion Deficiency), a rare genetic disorder, can cause death in the first year of life, while milder forms of LAD can allow individuals to live into their thirties with recurring infections, manageable with stem cell transplants.
Possible Complications When Diagnosed with Autoimmune and Chronic Neutropenia
The conditions known as AIN and CIN can result in various complications, such as:
- Repeated extreme bacterial and fungal infections
- Early death
- Failing to develop and grow as expected
- Blood poisoning, or septicemia
- The failure of multiple essential organs
- Resistance to antimicrobial medicines
Preventing Autoimmune and Chronic Neutropenia
Couples who are closely related by blood should consider getting genetic testing done before they plan to have a baby. If they already have a child who has been affected by genetic disorders, it’s essential to understand the chances of their next child inheriting the same condition. If possible, they might want to avoid having another child. Parents should also receive guidance and information about how to take care of the affected child, both when they are healthy and when they are unwell.
