Neutropenia

Neutropenia caused by intrinsic defects in myeloid cells or their precursors is uncommon (1, 2). When present, the most common causes include

• Chronic idiopathic neutropenia

• Congenital neutropenia

Chronic idiopathic neutropenia is a type of chronic neutropenia in which the rest of the immune system appears to remain intact. Even when neutrophil counts are < 200/mcL (< 0.2 × 10⁹/L), severe infections are infrequent, probably because neutrophils are produced in adequate quantities in response to infection. It is more common in women.

Severe congenital neutropenia (SCN) is a heterogenous group of rare disorders that are characterized by an arrest in myeloid maturation at the promyelocyte stage in the bone marrow, resulting in an absolute neutrophil count of < 200/mcL (< 0.2 × 10⁹/L) and significant infections starting in infancy. Severe congenital neutropenia is usually inherited in an autosomal dominant fashion but can be recessive, X-linked, or sporadic.

Several genetic abnormalities that cause severe congenital neutropenia have been identified, including mutations affecting neutrophil elastase (ELANE), CLPB, HAX1, GFI1, and very rarely the G-CSF (granulocyte colony-stimulating factor) receptor (CSF3R). Almost all patients with severe congenital neutropenia will respond to G-CSF therapy, but hematopoietic stem cell transplantation may be needed for patients who respond poorly to G-CSF and those who develop myelodysplasia or acute myeloid leukemia.

Cyclic neutropenia is a rare congenital granulocytopoietic disorder, usually transmitted in an autosomal dominant fashion and usually caused by a mutation in the gene for neutrophil elastase (ELANE), that results in apoptosis. It is characterized by regular, periodic oscillations in the number of peripheral neutrophils. The mean oscillatory period is 21 ± 3 days. Cycling of other blood cells is also evident in most cases.

Benign ethnic neutropenia occurs in members of some ethnic groups (eg, some people of African, Middle Eastern, or Jewish ancestry). Patients normally have lower neutrophil counts but do not have increased risk of infection. In some cases, this finding has been linked to the Duffy red blood cell antigen; some experts think neutropenia in these populations is related to protection from malaria.

Rare congenital syndromes (eg, cartilage-hair hypoplasia syndrome, Chédiak-Higashi syndrome, dyskeratosis congenita, glycogen storage disease type Ib, Shwachman-Diamond syndrome, warts, hypogammaglobulinemia, infections, myelokathexis [WHIM] syndrome) can involve bone marrow failure that causes neutropenia.

Neutropenia is also a feature of myelodysplasia, where it may be accompanied by megaloblastoid features in the bone marrow, and of aplastic anemia. Neutropenia can occur in dysgammaglobulinemia and paroxysmal nocturnal hemoglobinuria.

Secondary neutropenia can result from use of certain drugs, bone marrow infiltration or replacement, certain infections, or immune reactions.

The most common causes include

• Drugs

• Infections and immune reactions

• Marrow infiltrative processes

Drug-induced neutropenia is one of the most common causes of neutropenia. Drugs can decrease neutrophil production through toxic, idiosyncratic, or hypersensitivity mechanisms; or they can increase peripheral neutrophil destruction through immune mechanisms. Only the toxic mechanism causes dose-related neutropenia.

Severe dose-related neutropenia occurs predictably after administration of cytotoxic cancer drugs, phenothiazine, or radiation therapy due to suppression of bone marrow production.

Idiosyncratic reactions are unpredictable and occur with a wide variety of drugs, including alternative medicine preparations or extracts, and toxins.

Hypersensitivity reactionshepatitis, nephritis, pneumonitis, or aplastic anemia accompanies hypersensitivity-induced neutropenia.

Neutropenia due to ineffective bone marrow production can occur in megaloblastic anemias caused by vitamin B12 deficiency or folate deficiency. Usually, macrocytic anemia and sometimes mild thrombocytopenia develop simultaneously. Ineffective production can also accompany myelodysplastic disorders and acute myeloid leukemia.

Bone marrow infiltration by leukemia, myeloma, lymphoma, or metastatic solid tumors (eg, breast cancer, prostate cancer) can impair neutrophil production. Tumor-induced myelofibrosis may further exacerbate neutropenia. Myelofibrosis can also occur due to granulomatous infections, Gaucher disease, and radiation therapy.

Hypersplenism of any cause can lead to moderate neutropenia, thrombocytopenia, and anemia.

Infections can cause neutropenia by impairing neutrophil production or by inducing immune destruction or rapid turnover of neutrophils. Sepsis is a particularly serious cause. Neutropenia that occurs with common childhood viral diseases develops during the first 1 to 2 days of illness and may persist for 3 to 8 days. Transient neutropenia may also result from virus- or endotoxemia-induced redistribution of neutrophils from the circulating to the marginal pool. Alcohol may contribute to neutropenia by inhibiting the neutrophilic chemotactic response of the marrow during some infections (eg, pneumococcal pneumonia).

Immune defects can cause neutropenia. Neonatal isoimmune neutropenia can occur with fetal/maternal neutrophil antigen incompatibility associated with transplacental transfer of IgG antibodies against the newborn’s neutrophils (most commonly to human neutrophil antigen [HNA-1]). Autoimmune neutropenia can occur at any age and may be operative in many cases of idiopathic chronic neutropenia. Testing for antineutrophil antibodies (immunofluorescence, agglutination, or flow cytometry) is not always available or reliable.

Autoimmune neutropenias may be acute, chronic, or episodic. They may involve antibodies directed against circulating neutrophils or neutrophil precursor cells. They may also involve cytokines (eg, gamma interferon, tumor necrosis factor) that can cause neutrophil apoptosis. Most patients with autoimmune neutropenia have an underlying autoimmune disorder or lymphoproliferative disorder (eg, large granular lymphocyte [LGL syndrome [a clonal disease of large granular lymphocytes], systemic lupus erythematosus, Felty syndrome). Chronic secondary neutropenia often accompanies HIV infection because of impaired production of neutrophils and accelerated destruction of neutrophils by antibodies.

1. 1. Dale DC: How I diagnose and treat neutropenia. Curr Opin Hematol 23(1):1-4, 2016. doi: 10.1097/MOH.0000000000000208

2. 2. Skokowa J, Dale DC, Touw IP, et al: Severe congenital neutropenias. Nat Rev Dis Primers 3:17032, 2017. doi: 10.1038/nrdp.2017.32

The first priority is to determine whether an infection is present. Because infection may be subtle, physical examination systematically assesses the most common primary sites of infection:

• Mucosal surfaces, such as the alimentary tract (gums, pharynx, anus)

• Sinuses

• Lungs

• Abdomen

• Urinary tract

• Skin and fingernails

• Venipuncture sites

• Vascular catheters

If neutropenia is acute or severe, laboratory evaluation must proceed rapidly.

Cultures are the mainstay of evaluation. At least 2 sets of samples for bacterial and fungal blood cultures are obtained from all febrile patients. If an indwelling IV catheter is present, samples are drawn from the catheter and from a separate peripheral vein. Persistent or chronic drainage material is also cultured for bacteria, fungi, and atypical mycobacteria. Mucosal ulcers are swabbed and cultured for herpes virus and Candida. Skin lesions are aspirated or biopsied for cytology and culture. Samples for urinalysis and urine cultures are obtained from all patients. If diarrhea is present, stool is evaluated for enteric bacterial pathogens and Clostridioides (formerly Clostridium) difficile toxins. Sputum cultures are obtained to evaluate for pulmonary infections.

Imaging studies are helpful. Chest x-rays are done on all patients. A chest CT may also be necessary in patients with neutropenia. CT of the paranasal sinuses may be helpful if symptoms or signs of sinusitis (eg, positional headache, upper tooth or maxillary pain, facial swelling, nasal discharge) are present. CT scan of the abdomen is usually done if symptoms (eg, pain) or history (eg, recent surgery) suggests an intra-abdominal infection.

Next, the mechanism and cause of neutropenia are determined. The history addresses family history, presence of other disorders, all medications or other preparations being taken, pets, and possible toxin exposure or ingestion.

Physical examination addresses the presence of splenomegaly, lymphadenopathy, skin lesions (eg, areas of erythema, macules, papules, pustules), and signs of other underlying disorders (eg, arthritis).

If no obvious cause is identified (eg, chemotherapy), the most important test is

• Bone marrow examination

Bone marrow examination determines whether neutropenia is due to decreased marrow production or is secondary to increased cell destruction (determined by normal or increased production of the myeloid cells). Bone marrow examination may also indicate the specific cause of the neutropenia (eg, aplastic anemia, myelofibrosis, a myelodysplastic disorder, acute leukemia, metastatic cancer, marrow necrosis).

Further testing, such as flow cytometry and T-cell receptor gene rearrangement for the LGL syndrome, may be needed to determine the cause of neutropenia, depending on the diagnoses suspected. In patients at risk of nutritional deficiencies, levels of , folate, and vitamin B12 are determined. Testing for the presence of antineutrophil antibodies is done if immune neutropenia is suspected.

Differentiation between neutropenia caused by certain antibiotics and infection can sometimes be difficult. The white blood cell count just before the start of antibiotic treatment usually reflects the change in blood count due to the infection.

Patients who have had chronic neutropenia since infancy and a history of recurrent fevers and chronic gingivitis should have white cell counts with differential done 3 times/week for 6 weeks, so that periodicity suggestive of cyclic neutropenia can be evaluated. Platelet and reticulocyte counts are done simultaneously. In patients with cyclic neutropenia, eosinophils, reticulocytes, and platelets frequently cycle synchronously with the neutrophils, whereas monocytes and lymphocytes may cycle out of phase.

Molecular genetic testing for ELANE and other genes is appropriate when congenital causes are considered.

Indwelling vascular catheters can usually remain in place even if bacteremia is suspected or documented, but removal is considered if infections involve S. aureus, Bacillus, Corynebacterium, or Candida or another fungus or if blood cultures are persistently positive despite appropriate antibiotics. Infections caused by coagulase-negative staphylococci generally resolve with antimicrobial therapy alone.

Indwelling Foley catheters can also predispose to infections in neutropenic patients, and change or removal of the catheter should be considered for persistent urinary infections.

If cultures are positive, antibiotic therapy is adjusted to the results of sensitivity tests. If a patient defervesces within 72 hours, antibiotics are continued for at least 7 days and until the patient has no symptoms or signs of infection. When neutropenia is transient (such as that following myelosuppressive chemotherapy), antibiotic therapy is usually continued until the neutrophil count is > 500/mcL (> 0.5 × 10⁹/L); however, if cultures remain negative, stopping antimicrobials can be considered in selected patients with persistent neutropenia, especially those in whom symptoms and signs of inflammation have resolved.

Fever that persists > 72 hours despite antibiotic therapy suggests

• A nonbacterial cause

• Infection with a resistant species

• Superinfection with a 2nd bacterial species

• Inadequate serum or tissue levels of the antibiotics

• Localized infection, such as an abscess

Neutropenic patients with persistent fever are reassessed every 2 to 4 days with physical examination, cultures, and a chest x-ray. If the patient is well except for the presence of fever, the initial antibiotic regimen can be continued, and drug-induced fever should be considered. If the patient is deteriorating, alteration of the antimicrobial regimen is considered (1).

Fungal infections

If fever persists after 3 weeks of empiric therapy (including 2 weeks of antifungal therapy) and the neutropenia has resolved, then stopping all antimicrobials can be considered and the cause of fever reevaluated.

For afebrile patients with neutropenia,⁹/L) for > 7 days. Prophylaxis is usually started by the treating oncologist. Antibiotics are continued until the neutrophil count increases to > 1500/mcL (> 1.5 × 10⁹/L). Also, antifungal therapy can be given for afebrile patients with neutropenia who are at higher risk of fungal infection (eg, after hematopoietic stem cell transplantation or intensive chemotherapy for acute myeloid leukemia or who have a myelodysplastic disorder or a history of prior fungal infections). Selection of the specific antifungal drug should be guided by an infectious disease specialist. Antibiotic and antifungal prophylaxis is not routinely recommended for afebrile patients with neutropenia and no risk factors who are anticipated to remain neutropenic for < 7 days on the basis of their specific chemotherapy regimen.

Myeloid growth factors (ie, granulocyte colony-stimulating factor [G-CSF]) are widely used to increase the neutrophil count and to prevent infections in patients after hematopoietic stem cell transplantation or intensive cancer chemotherapy. If the risk of febrile neutropenia is ≥ 30% (as assessed by neutrophil count < 500 mcL [< 0.5 × 10⁹/L], presence of infection during a previous cycle of chemotherapy, associated comorbid disease, or age > 75), growth factors are indicated (2

Neutrophil production and deployment in congenital neutropenia, cyclic neutropenia, and idiopathic neutropenia is usually increased with administration of G-CSF 1 to 10 mcg/kg subcutaneously once a day, beginning with a low dose and increasing to maintain a level of about 1000/mcL (1 × 10⁹/L) (3). Effectiveness is maintained with daily or intermittent G-CSF for months or years.

In the past, splenectomy was used to increase the neutrophil count in patients with splenomegaly and splenic sequestration of neutrophils (eg, Felty syndrome); however, because growth factors and other newer therapies are often effective, splenectomy should be avoided. Splenectomy can be considered for patients with persistent painful splenomegaly or with severe neutropenia (ie, < 500/mcL [< 0.5 × 10⁹/L]) and serious problems with infections in whom other treatments have failed. Patients should be vaccinated against infections caused by Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae before splenectomy because splenectomy predisposes patients to infection by encapsulated organisms.

1. 1. Pizzo PA: Management of patients with fever and neutropenia through the arc of time: A narrative review. Ann Intern Med 170(6):389-397, 2019. doi: 10.7326/M18-3192

2. 2. Becker PS, Griffiths EA, Alwan LM, et al: NCCN guidelines insights: Hematopoietic growth factors, version 1.2020. J Natl Compr Canc Netw 18(1):12-22, 2020. doi: 10.6004/jnccn.2020.0002

3. 3. Dale DC, Bolyard AA, Shannon JA, et al: Outcomes for patients with severe chronic neutropenia treated with granulocyte colony-stimulating factor. Blood Adv 6(13):3861-3869, 2022. doi: 10.1182/bloodadvances.2021005684