Update on Treating Neutropenia

It may seem counterintuitive at first glance (particularly for patients and their families), but a low white-blood count can be as much a sign of infection as a high count, or at the very least a warning of potential infection. 

“Neutropenia” is a broad classification that accounts for several diseases and conditions — all of which are marked by a low count of neutrophils in the blood. Neutrophils are a subset of granulocytes, a type of white blood cell that releases enzyme-packed granules when they detect a bacterial or fungal infection. The most common type of white blood cell in healthy patients (accounting for 50 to 80 percent of all white blood cells), neutrophils first detect invading bacteria, fungi and parasites, and then attack the invaders. The absence of enough neutrophils puts patients at increased risk for bacterial and fungal infections.

It can be a challenging condition to monitor and treat because there are no overt symptoms for neutropenia itself — and it is often only discovered during attempts to diagnose resultant infections. And, because serious cases leave patients’ immune systems compromised, immediate treatment and even hospitalization may be required.

The Different Types of Neutropenia

Neutropenia is classified according to the underlying cause such as infection, genetics, immunological disease or drugs used to fight cancer, to name a few. Within each classification, cases will range from mild to severe; some cases are lifelong, while most will resolve in a matter of weeks.

There are also three manifestations of neutropenia: temporary, chronic and cyclic. Most cases of neutropenia are short-term, caused by an infection or medication, and resolve in three to six weeks. In chronic cases, the low counts of neutrophils are consistent for more than eight weeks.¹ In cyclic, the neutrepenia occurs roughly every three weeks and lasts three to six days at a time; this is most common in children, and usually resolves itself during adolescence.²

Some of the causes of neutropenia are:

• Chemotherapy

• Radiation therapy

• Some cancers

• Congenital (including both Kostmann disease and benign ethnic neutropenia, or BEN)

• Autoimmune disorders

• Some viral or bacterial infections

• Drugs used to treat other diseases

• Nutritional deficiency

• Idiopathic (the cause cannot be determined)

The most common form is chemotherapy-induced neutropenia, a side effect of drugs used to treat cancers. Studies indicate that about half of all patients receiving chemotherapy will develop neutropenia.³ A more serious version of this is neutropenic fever, which affects roughly 30 percent of patients receiving chemotherapy.⁴ 

Fortunately, other forms of neutropenia are relatively rare, with an incidence of less than 1.5 percent of the overall U.S. population.⁵ It is more common in people of African and Middle Eastern heritage,⁶ and affects men and children more than women.

Severe congenital neutropenia is even more rare, occurring about four times per one million births.⁷ Kostmann syndrome was the first congenital neutropenia to be identified and named in 1950.⁸ A series of unrelated genetic abnormalities can prevent the body from creating enough healthy neutrophils: the most widespread mutation (responsible for about half of all congenital neutropenia) affects the ELANE/ELA2 gene, another the HAX1 protein in the mitochondria and a third the AK2 protein, also in the mitochondria.⁹ 

Milder congenital neutropenia is more common, but in many cases is an asymptomatic version (BEN) that for reasons researchers do not fully understand is not associated with an increased risk of infection.⁶ (Canadian researchers note that this form of neutropenia, seen mostly in populations with African or Middle Eastern ancestry, is strongly associated with the presence of red blood cells that protect against malaria.)

Autoimmune disorders can lead to autoimmune neutropenia. It is divided into a primary form, found mostly in children, and a secondary form, which tends to affect adults.¹⁰ Among the autoimmune diseases that can lead to neutropenia in adults are rheumatoid arthritis, Sjögren’s syndrome, granulomatosis with polyangiitis, inflammatory bowel disease, lupus and autoimmune hepatitis. Childhood autoimmune diseases associated with neutropenia include hyper IgM syndrome (HIgM), common variable immunodeficiency and severe combined immunodeficiency.

Malnutrition can also predispose a patient to develop neutropenia, although it is thought to be a contributing factor and rarely the sole trigger.¹¹

Although drugs used to treat cancer can cause neutropenia, some types of cancer can lead directly to neutropenia. This is particularly true of cancers that attack the bone marrow such as leukemia, lymphoma and multiple myeloma. In addition, neutropenia can also be caused by metastatic cancers.³

While neutropenia increases a patient’s susceptibility to infection, it can also result from an infectious disease. It can take the body some time to rebuild its supply of neutrophils after fighting off an infection, and even though this is usually a temporary condition, it still places patients at heightened risk.¹²

Other infections, however, can cause a more serious form of neutropenia by weakening the body’s ability to make new neutrophils. These include not only HIV, but hepatitis (A, B and C), measles, chicken pox, Epstein-Barr and salmonella.¹³

Not only can cancer and drugs used to treat cancer cause neutropenia, but so can radiation therapy. Radiation directed at the bones that create neutrophils is a particular risk for triggering neutropenia.3

There are also drugs other than those used in chemotherapy that can cause neutropenia. Termed non-chemotherapy drug-induced neutropenia, the condition is linked to amoxicillin, carbimazole, cotrimoxazole, ganciclovir, metamizole, penicillin G, quinidine, sulfasalazine, thiamazole, ticlopidine, valganciclovir and others.¹⁴ It is thought to affect fewer than 15 patients out of one million. In addition, drugs used to suppress the immune system following a transplant can also lead to neutropenia.10 And, some patients receiving high-dose intravenous immune globulin (IVIG) therapy have developed neutropenia, although it seems to be mild and short-lived.¹⁵

When patients experience three months or more of neutropenia and no underlying cause can be identified, this is considered to be idiopathic.¹⁵

Symptoms and Progression

While neutropenia itself is asymptomatic, it can lead to recurring infections, and the symptoms of those infections often represent the first indication of neutropenia. The most common infections associated with neutropenia are skin infections, pneumonia and, in the most serious cases, sepsis.¹⁶ Skin infections are often caused by opportunistic pathogens, including streptococci or staphylococci. Other symptoms that may present can include painful swallowing, frequent sinus infections, swollen gums, general fatigue or a low-grade fever.¹⁷ 

If neutropenia is left untreated, the patient is likely to suffer a series of increasingly more severe infections, which can lead to life-threatening sepsis, organ failure and death. With children, even milder cases can slow growth and development.¹⁸

Diagnosis and Treatment

Diagnosis of neutropenia is made strictly on the results of a blood test looking at the neutrophil count:¹⁶

• 1,000-1,500 mcL = mild neutropenia

• 500-1,000 mcL = moderate neutropenia

• <500 mcL = severe neutropenia

However, neutrophil counts are not as stable as other blood cells, and can vary over days or weeks. A diagnosis of chronic neutropenia can be made if the levels are consistently low for more than three months. Cyclic neutropenia will, as noted above, manifest with a count that varies regularly in a roughly three-week pattern. Also, patients with an African or Middle Eastern ancestry will naturally have a lower count, which should be accounted for.¹⁶ 

Before considering the cause of neutropenia, the seriousness of a patient’s condition must be considered. An acutely ill patient with a positive diagnosis of neutropenia should be treated as a medical emergency.¹⁹ Any infection will have to be addressed, either before the underlying condition or simultaneously.¹⁷

Diagnosis of the underlying cause of the neutropenia will be made by considering the patient’s overall health and associated risk factors. If the patient has cancer and is undergoing chemotherapy or radiation therapy, the oncologist may temporarily suspend treatment until the neutrophil count increases. The oncologist may also prescribe the bone marrow stimulant filgrastim (Neupogen) to maintain or increase the neutrophil levels.²⁰ In general, the neutrophil count will hit its lowest point, or nadir, in one week to 10 days after chemotherapy begins.

Patients with a newly discovered cancer that may be causing or contributing to neutropenia will need to have their cancer treatment balanced against their neutropenia and any resultant infections.

In addition to any other treatment, cancer patients with neutropenia should also be taught how to protect themselves from infection through good hygiene:²¹

• Avoiding large crowds

• Wearing a mask when out in public

• Washing hands often

• Delaying some vaccines, if possible

• Keeping pets from licking their face

• Not sharing utensils or toothbrushes 

Congenital neutropenia can be diagnosed via genetic testing to look for one of the 20 known mutations that can cause the condition.²²  Most children with the cyclic form of congenital neutropenia will grow out of it after puberty; treatment will consist of monitoring and treating infections. More serious cases will not only require antibiotics to treat any infections, but physicians will also want to try to prevent future infections. This may be attempted with a daily dose of sulfamethoxazole/trimethoprim sulfate (Bactrim), possibly combined with metronidazole.⁸ 

As with patients on chemotherapy, it may be useful to try blood marrow stimulants such as the granulocyte colony-stimulating factor (G-CSF), including filgrastim or lenograstim. In severe cases where other treatment options have failed, a bone marrow transplant or stem cell therapy may be considered.² 

Autoimmune neutropenia (AIN) occurs when the body’s own immune system attacks white blood cells. Primary AIN mostly affects infants and young children, and generally resolves within a few years. Secondary AIN tends to show up in older children and adults, and will most often be chronic.

AIN will be diagnosed with a battery of tests:

• Flow cytometry

• Indirect granulocyte immunofluorescence

• Granulocyte agglutination

Flow cytometry uses a laser to measure the chemical characteristics of cells — often used to check the health of bone marrow. The other two are blood tests that look for specific antibodies known to attack neutrophils.

Treatment will differ for primary vs. secondary AIN. Since primary AIN tends to be milder, treatment may consist of monitoring the patient and prescribing prophylactic antibiotics to prevent infections. With secondary AIN, the physician may be more aggressive in treating the autoimmune disease itself, including corticosteroids to reduce the attacks on the neutrophils. Other treatments that have shown success in fighting secondary AIN are rituximab, alemtuzumab and IVIG.²³

Post-infectious neutropenia is more common in children, and is more highly associated with viral infections than bacterial infections. However, brucella, rickettsial and mycobacterial infections have also been linked with subsequent neutropenia. In most cases, excepting HIV and Epstein-Barr, neutropenia will disappear in a few weeks. With HIV and Epstein-Barr, neutropenia is likely to be chronic and require treatment similar to that in autoimmune cases: close monitoring and treatment for any infections.

If no other cause has been established, then consideration should be given to a drug being the culprit. If possible, all prescriptions should be halted to see if that helps bring the neutrophil count back up.²⁴ 

Some specific nutritional deficiencies are suspected of contributing to neutropenia: Vitamin B-12, folate and copper deficiencies have appeared in some patients with neutropenia, but usually with another correlating condition.¹⁹ These deficiencies can be addressed through dietary changes.

In cases in which no underlying cause is ever identified, yet the conditions for a diagnosis of chronic neutropenia are present, a diagnosis of chronic idiopathic neutropenia can be made; treatment will consist of ongoing monitoring and, if recurring infections are noted, low doses of G-CSF to prevent future infections.¹⁹

Looking Ahead

Due to the varied causes of neutropenia, a single cure or vaccine is highly unlikely. Stand-alone cases of isolated neutropenia are extremely rare and, in most instances, can be readily controlled with antibiotics. For those cases caused by autoimmune disease, several effective treatments are available, as outlined above.

While untreated neutropenia remains a life-threatening condition, current treatment options offer physicians the tools to treat the overwhelming majority of cases.