Periodic Neutropenia – Causes, Symptoms, Treatment

Periodic Neutropenia/Cyclic Neutropenia is a very rare hematological condition and is characterized by regular fluctuations in blood neutrophil counts, leading to periodic neutropenia with a 21-day turnover frequency.[rx][rx] It is now considered an autosomal dominant disease caused by ELANE gene mutations.[rx] The symptoms and clinical manifestation of cyclic neutropenia may range from mild to severe, depending on the degree and duration of neutropenia. The absolute neutrophil count can drop to zero, and these extremely low counts may last for up to three to five days.[rx]

Cyclic neutropenia (CyN) is a rare hematologic disorder and form of congenital neutropenia that tends to occur approximately every three weeks and lasting for few days at a time due to changing rates of neutrophil production by the bone marrow. It causes a temporary condition with a low absolute neutrophil count and because the neutrophils make up the majority of circulating white blood cells it makes the body in severe risk to inflammation and infection. In comparison to severe congenital neutropenia, it responds well to treatment with granulocyte colony-stimulating factor (filgrastim), which increases the neutrophil count, shortens the cycle length, as well decreases the severity and frequency of infections.

Neutrophils play a vital role in our immune defenses by ingesting, killing, and digesting invading microorganisms. Failure to carry out this role results in immunodeficiency, which manifests itself in the form of recurrent infections.[rx] Common causes of neutropenia include autoimmune diseases, drug reactions, chemotherapy, and hereditary disorders.[rx]

Synonyms of Cyclic Neutropenia

• CN
• CyN
• cyclic hematopoiesis
• human cyclic neutropenia
• periodic neutropenia
• cyclic hematopoesis
• cyclic leucopenia
• periodic neutropenia

Pathophysiology

Neutrophils play a pivotal role in the immune defense of the body. Once the neutrophil count is below 1 x 10^9/L, the patient becomes susceptible to recurrent infections.[rx] The exact pathophysiological basis of cyclic neutropenia remains unknown, but several studies in the 1950s by Page and Good concluded that the interrupted cell production by the bone marrow may be the main underlying cause of cyclic neutropenia.[rx] Subsequent studies also showed that there are cyclic fluctuations in all blood cells. This suggests that the intrinsic defect leading to the disorder is in the hematopoietic stem cells.[rx]

Causes of Periodic Neutropenia

Recent research in the field of molecular biology has permitted the discovery of the underlying genetic basis for many inherited diseases.[rx] Genetic sequencing in patients with cyclic neutropenia has highlighted mutations at locus 19q13 in the gene for neutrophil elastase. This gene is now referred to as ELANE, and the mutations are consistently found to be present in all patients suffering from cyclic neutropenia but not in their unaffected family members. Some authorities refer to this condition as ELANE associated neutropenia.[rx][rx]

Mutations in the ELANE gene cause cyclic neutropenia. The ELANE gene provides instructions for making a protein called neutrophil elastase, which is found in neutrophils. When the body starts an immune response to fight an infection, neutrophils release neutrophil elastase. This protein then modifies the function of certain cells and proteins to help fight the infection.

ELANE gene mutations that cause cyclic neutropenia lead to an abnormal neutrophil elastase protein that seems to retain some of its function. However, neutrophils that produce abnormal neutrophil elastase protein appear to have a shorter lifespan than normal neutrophils. The shorter neutrophil lifespan is thought to be responsible for the cyclic nature of this condition. When the affected neutrophils die early, there is a period in which there is a shortage of neutrophils because it takes time for the body to replenish its supply.

Symptoms of Periodic Neutropenia

The signs and symptoms of cyclic neutropenia usually appear at birth or shortly after. This condition is characterized by recurrent episodes of neutropenia that recur every 14-35 days (most commonly around 21 days) and last between 3 and 5 days. During times of neutropenia, it may be more difficult for the body to fight bacteria, viruses, and infections. The severity of the resulting infections can vary and are often similar to the severity of the neutropenia itself. Resulting symptoms during periods of neutropenia may include:

• Recurrent fever
• Sore throat (pharyngitis)
• Inflammation of the gums (gingivitis)
• Inflamed and sore mouth (stomatitis)
• Infections in the skin and in other areas of the body]
• Malaise,
• Inflammation of the tissues surrounding the teeth,
• Mouth ulcers,
• Inflammation and bacterial infection of the respiratory tract, digestive tract, skin, and
• Abdominal pain.
• Sores in the mouth
• Recurring gum problems and loose teeth
• Skin infections
• Lung infections
• Digestive system infections
• An overall feeling of not being well
• It is considered that the greatest risk for death is from developing necrotizing enterocolitis (NEC), peritonitis, bacteremia or Clostridium and Escherichia coli sepsis and septic shock, and pneumonia.^[rx][rx][rx]

Diagnosis of Periodic Neutropenia

Cyclic neutropenia presents with a periodically decreased number of neutrophils in the bone marrow and circulation during an attack.[rx] The absolute neutrophil count is usually <.2 x 10^9/L.[rx] Acquired cyclic neutropenia in adults may show a clonal proliferation of large granular lymphocytes.[rx]

History and Physical

Patients with cyclic neutropenia usually have a periodic decrease in absolute neutrophil count (often <.2 x10^9/L), and present with a clinical syndrome characterized by recurrent fever, oral mucosal ulcers, and respiratory infections.[rx] Opportunistic infections appear during a reduction in absolute neutrophil count and manifest clinically as fever, oral ulcers, gingivitis, tonsillitis, pharyngitis, dermatological infections, and swollen lymph nodes.[rx][rx][rx] Patients also exhibit periodontitis with alveolar bone loss during childhood. It has been observed that the systemic symptoms of cyclic neutropenia such as recurrent fevers diminish after adolescence, but even adult patients continue to experience oral ulcers, gingivitis, periodontitis, and other infections.[rx] Infections usually respond well to antibiotics. Severe infections are very rare. However, long-term follow-up of patients showed that the life-threatening complications encountered were the occurrence of spontaneous peritonitis, segmental bowel necrosis, and septicemia.[rx]

Evaluation

Diagnosis and evaluation of cyclic neutropenia are based on clinical symptoms, duration, history of hereditary inheritance, white cell counts, immune function, bone marrow alterations, and weekly differential leukocyte count (DLC). Investigations such as complete blood count, bone marrow biopsy, histopathological studies, tumoral markers, levels of cytokines (granulocyte-colony stimulating factor), chest x-ray, diagnostic ultrasound, and CT scan should be done to rule out other immunodeficiency disorders. DNA studies can be carried out as a confirmatory test for most genetic disorders, including cyclic neutropenia.[rx]

Diagnosis is usually confirmed by monitoring absolute neutrophil (ANC) count three times per week for at least six weeks.^[rx][rx] The confirmation can be assisted with the Lomb periodogram.^[rx] During the condition, which lasts for three to six days and tends to occur approximately every three weeks (but can range from 14 to 36 days),^[rx][rx] the absolute neutrophil count (ANC) is less than 200-500 cells/microL (<0.2-0.5×10⁹/L), with an increase of monocyte counts, and mild oscillations of other cells, including mild anemia.^[rx][rx] Between cycles, the neutrophil count mostly peaks at subnormal or normal values.^[rx]

It is advised genetic testing for mutations in the ELANE and other neutropenia-related genes (like HAX1, G6PC3, GFI1 etc.) to differentiate it from other secondary causes and forms of neutropenia.^[rx][rx] In some cases intervals and oscillations can be lower making the ANC analysis insufficient,^[rx] and since both disorders can have the same mutation variants in ELANE it is preferable to have both ANC and genetic analysis to confirm in the diagnosis whether it is severe congenital or cyclic neutropenia.^[rx][rx]

Treatment of Periodic Neutropenia

The mainstay of treatment and management includes regular monitoring of blood counts, prevention and control of infections through judicious use of antibiotics, oral and dental care, and patient education. Alternate-day corticosteroid regimes have been used successfully to treat recurrent signs and symptoms.[rx][rx] Most children suffering from severe congenital neutropenia require the long-term administration of granulocyte-colony stimulating factor (G-CSF).[rx][rx]. G-CSF is now considered a remarkably safe and efficacious treatment for preventing infections and to improve the quality of life in patients suffering from cyclic neutropenia.[rx] A recent study has suggested that the combination therapy of G-CSF and high-dose immunoglobulin might be an effective treatment for cyclic neutropenia.[rx] Hematopoietic stem cell transplantation (HSCT) is still the ultimate radical treatment, which can permanently correct cyclic neutropenia and is the best long term option for patients who do not respond to G-CSF treatment.[rx]

In low-risk patients, oral empiric therapy with a fluoroquinolone plus amoxicillin/clavulanate is recommended in the outpatient setting.[rx] Clindamycin can be used for those with penicillin allergy. If the patient remains febrile for 48 to 72 hours, the patient will require admission.[rx]

For high-risk patients presenting with neutropenic fever, an intravenous antibiotic therapy should be given within 1 hour after triage and be monitored more than 4 hours before discharge. The Infectious Disease Society of America (IDSA) recommends monotherapy with antipseudomonal beta-lactam agents such as cefepime, carbapenems, or piperacillin and tazobactam. [rx] Vancomycin is not recommended for initial therapy but should be considered if suspecting catheter-related infection, skin or soft tissue infections pneumonia, or hemodynamic instability.[rx] If patients do not respond to treatments, coverage should be expanded to include resistant species[rx][rx][rx][rx][rx]:

• Methicillin-resistant Staphylococcus aureus (MRSA): vancomycin, linezolid, and daptomycin
• Vancomycin-resistant enterococci (VRE) – linezolid and daptomycin
• Extended-spectrum beta-lactamase (ESBL) – producing organisms: carbapenems
• Klebsiella pneumonia – carbapenems, polymyxin, colistin, or tigecycline

Recommendation for prevention of infection in neutropenic patients

• Fluoroquinolones as prophylaxis for patients who are high risk
• Antifungal prophylaxis with an oral triazole with patients with profound neutropenia
• Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended treatment for patients receiving chemotherapy regimens associated with greater than 3.5% risk for pneumonia from Pneumocystis jirovecii
• Yearly influenza vaccination is recommended for all patients receiving chemotherapy
• Treatment with a nucleoside reverse transcription inhibitor is recommended for patients who are at high risk of hepatitis B virus reactivation
• Herpes simplex virus- seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive prophylaxis

In the National Comprehensive Cancer Network (NCCN) guidelines, it is recommended that patients that are at a high risk of neutropenic fever can benefit from granulocyte-colony stimulating factors (G-CSFs).[15]

Application of granulocyte-colony stimulating factor (G-CSF) can improve neutrophil functions and numbers.[rx][rx] Prophylactic use of antibiotics and antifungals is reserved for some forms of alteration in neutrophil function such as chronic granulomatous disease CGD).[rx][rx] The utilization of antimicrobials is compulsory if recurrent infections exist. Interferon-gamma has been successfully used to improve the quality of life of the patient suffering from neutropenia. Allogenic bone marrow transplantation from an HLA-matched related donor can cure CGD but has a high mortality rate [rx], and gene therapy is also a therapeutic option for treating disorders with neutropenia. Furthermore, intravenous immunoglobulins can be another option in the management of these disorders.[rx]

Recombinant granulocyte-colony stimulating factor preparations, such as filgrastim^[rx] can be effective in people with congenital forms of neutropenia including severe congenital neutropenia and cyclic neutropenia;^[rx] the amount needed (dosage) to stabilize the neutrophil count varies considerably (depending on the individual’s condition).^[rx]

Guidelines for neutropenia regarding diet are currently being studied.^[rx]

Most cases of neonatal neutropenia are temporary. Antibiotic prophylaxis is not recommended because of the possibility of encouraging the development of multidrug-resistant bacterial strains.^[rx]

Neutropenia can be treated with hematopoietic growth factors, granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). These are cytokines (inflammation-inducing chemicals) that are present naturally in the body. These factors are used regularly in cancer treatment with adults and children. The factors promote neutrophil recovery following anticancer therapy.^[rx]

The administration of intravenous immunoglobulins (IVIGs) has had some success in treating neutropenias of alloimmune and autoimmune origins with a response rate of about 50%. Blood transfusions have not been effective.^[rx]

If neutropenia is caused by medication, your doctor might tell you to stop the medication. If the cause is an underlying disease, that condition must be treated (as in the case of a vitamin deficiency). Your doctor might prescribe corticosteroids if you have an autoimmune disorder.

Patients with neutropenia caused by cancer treatment can be given antifungal drugs. A Cochrane review ^[rx] found that lipid formulations of amphotericin B had fewer side effects than conventional amphotericin B, though it is not clear whether there are particular advantages over conventional amphotericin B if given under optimal circumstances. Another Cochrane review ^[rx] was not able to detect a difference in effect between amphotericin B and fluconazole because available trial data analyzed results in a way that disfavoured amphotericin B.

Complications

• Recurrent and fatal bacterial and fungal infections[rx]
• Bacteremia
• Septic shock
• Premature death
• Failure to thrive
• Protein-energy malnutrition
• Multiorgan failure

How can you prevent infections if you have neutropenia?

Preventing infections if you have or are liable to develop neutropenia is key. These suggestions should help:

• Wash your hands frequently with soap and water. Wash your hands before and after you eat, after you use the toilet, after touching pets or things outside of your house, and after you cough or sneeze.
• Keep and use an alcohol-based hand sanitizer with you when you leave the house.
• Make sure you get the flu shot as early as you can, if your doctor says you can do this.
• Stay away from crowds of people and people who are sick.
• Do not share eating utensils, cups, food or beverages with other people.
• Do not share towels, razors or toothbrushes with other people.
• Wash raw fruits and vegetables.
• Keep raw meats, fish and poultry away from other foods.
• Use hot water and soap to clean the kitchen surfaces before you start cooking.
• Cook foods completely to the proper temperature.
• Use gloves if you are gardening in the dirt or working in the yard.
• It is best to not pick up pet waste. If you have to do so, use gloves. Wash your hands when you are done.
• Use a soft toothbrush to brush your teeth at least two times per day.
• Take a shower each day. Use lotion so your skin does not dry out and crack.
• Eat a healthy diet.
• Tell your doctor if you might need dental work so he or she can prescribe antibiotics before the work is done, if necessary.
• Do not get body piercings or tattoos.
• Do not swim in lakes or ponds.
• Avoid becoming constipated if you can.

Lifestyle precautions for people with neutropenia include:

• cleaning hands regularly, especially after using the toilet
• avoiding crowds and people who are ill
• not sharing personal items including toothbrushes, drinking cups, cutlery, or food
• bathing or showering daily
• cooking meat and eggs thoroughly
• not buying food in damaged packages
• cleaning the fridge thoroughly and not overfilling – doing so can raise the temperature
• carefully washing any raw fruit or vegetables or avoiding completely
• avoiding direct contact with pet waste and washing hands after handling any animals
• wearing gloves when gardening
• using a soft toothbrush
• using an electric shaver rather than a razor
• cleaning any wounds with warm water and soap and using antiseptic to clean the site
• wearing shoes outdoors
• not squeezing spots or picking scabs
• keeping surfaces clean
• getting the flu shot as soon as it becomes available

References