Cyclic neutropenia (CN) is a type of neutropenia in which neutrophil levels follow a 21-day cycle. CN comes both as a congenital and acquired disorder, with basically the same symptoms and signs for both forms.
The main CN symptom is the decreased neutrophil blood count in an episode of neutropenia that follows a 21-day cycle. The episode might vary from 3 to 6 days, according to the particular case, but the general trend of the cycle remains constant and consistent among patients. In addition to neutropenia episodes, it is also possible to observe abnormal levels of other blood cells, such as platelets, erythrocytes and monocytes.
During neutropenic episodes, the affected individuals are particularly exposed to bacterial infections which affect the skin as well as the gastrointestinal and respiratory tract. Infections are usually accompanied by other key symptoms, such as fever, malaise, loss of appetite , inflammations and ulcerations that affect the throat (pharyngitis) and the tissues around the teeth (periodontal diseases).
The diagnosis of CN is based on a series of measurements of the absolute neutrophil count taken daily or at least three times a week for a period varying from four to six weeks . At the minimum neutrophil peak, the absolute neutrophil count is generally lower than 0.2 x 109/L. It should be remembered that there are variations of this general pattern in a small group of patients (less than 5% of them), in which cycles might be longer or shorter of the theoretical 3 week period. Furthermore, CN might be present in the relatives of affected individuals, although with less obvious cycles, and blood cell counts might oscillate more strongly in children than in adults. Oscillating cycles can be seen not just for neutrophils, but also for other blood cells such as lymphocytes, eosinophils, monocytes, and platelets.
Molecular tests can also be used to diagnose CN, as ELANE variants have been found in 100% of the individuals with a clear CN clinical history . Therefore, the current diagnostic approach tends to include neutrophil counts and clinical history as basic diagnostic elements .
It is important to address the infections associated with cyclic neutropenia immediately, in order to avoid further negative consequences. This can be done with the administration of antibiotics, in addition to other preventive measures such as careful oral and dental care or avoiding dangerous activities which might cause injuries.
The severe chronic neutropenia can be treated by using a synthetic drug which stimulates the poor bone marrow’s neutrophil production called recombinant human granulocyte-colony stimulating factor [rhG-CSF]. One of its generic form, Filgrastim, was approved by the Food and Drug Administration back in 1989 , after a series of studies that had proved the efficiency of rhG-CSF in increasing the number of neutrophils and reducing infections and related symptoms in long-term therapies. However, side effects such as mild bone pain and local skin reactions are frequent and therefore the administration of the drug needs careful evaluation prior to treatment and careful checks and evaluations during its administration, to ensure long-term safety and effectiveness.
Other treatments might be considered as supportive and symptomatic strategies, while genetic counseling is strongly suggested to detect inherited forms and start specific preventive measures.
As previously mentioned, the CN phenotypic presentation appears when cell production in the bone marrow is impaired, and this can happen under three different circumstances: the bone marrow no longer produces a sufficiently high number of neutrophils, neutrophils are somehow destroyed during their development, or even though their development has been fully completed, neutrophils do not function in a proper manner.
As previously mentioned, CN can come as an inherited or acquired pathological condition. The inherited form is associated with disruptions or mutations of the ELANE gene, located on the short arm of chromosome number 19 (19p13.3). The ELANE gene is responsible for the production of neutrophil elastase, a serine proteinase which destroys bacteria and host tissues. The inherited form is passed down from generation to generation as an autosomal dominant trait . As in the other types of neutropenia, the acquired form appears in relation to a series of other pathological conditions, such as frequent and prolonged exposure to particular drugs, perhaps as a consequence of a direct stem cell toxic effect or the activation of an immune mechanism, due to causes that have yet to be completely understood.
It has been estimated that CN occurs once every 1 million individuals all around the world . Because of this extremely low prevalence, CN is considered by experts as a rare disease.
CN can be ascribed to variations of neutrophil production by the bone marrow. Post-mitotic neutrophil cells are absent from the bone marrow at the beginning of CN development. Furthermore, as shown by electron microscopy studies carried out during the entire neutropenic cycle, it is possible to observe the appearance of developing cells which contain membrane blebs and nuclear condensations, the typical signs of an intense apoptotic activity going on. The death of the developing neutrophils through apoptosis is further suggested by flow cytometry studies, which reveal the presence of an increased number of annexin V-stained cells. The dead neutrophils are subsequently removed from the bone marrow by macrophages . These changes are also accompanied by other oscillatory variations of the erythroid precursors, perhaps due to varied erythropoietin levels throughout the bone marrow, and this further supports the hypothesis that CN arises due to interruptions or variations of cell production .
It is worth remembering the results of recent investigations conducted with the use of purified bone marrow progenitor cells. According to these studies, CD34 cells from CN patients tend to form higher portions of high proliferative potential colony-forming cells (HPPC), even though these colonies remained much less differentiated in later developmental phases. These data seem to suggest that the early hematopoietic progenitor cells might proliferate normally, but the proliferative capacity is then lost before differentiating into the neutrophil lineage as the developing cells undergo apoptosis.
The therapy with rhG-CSF has proved to improve symptoms and reduce infections in almost all affected individuals. This should be coupled with a good and constant dental care. Individuals affected by severe congenital neutropenia might consider hematopoietic stem cell transplantation as further therapeutic strategies, especially when they have become refractory to high doses of rhG-CSF or when malignant transformation in the bone marrow has started.
Cyclic neutropenia (CN) is mainly characterized by its typical 21-day pattern, in which neutrophil counts vary in a cyclical manner . The details of the cycle vary from patient to patient, with the neutropenic phase lasting almost the entire cyclical period in some cases, while only a few days in others. During neutropenic phases, neutrophil blood levels might be lower than 200 cells/µl (0.2 x 109/l), and can be accompanied by low levels of other blood cells such as platelets or erythrocytes. Obviously, this also affects the frequency of infections, as those who experience longer neutropenic phases are more exposed to infections than those experiencing shorter ones. As a consequence, infections tend to follow the neutropenic pattern and this should be used as an important element for the diagnosis .
CN is a consequence of the fluctuations of cell production in the bone marrow, which in turn changes its cytological appearance according to the phase concerned. The condition frequently appears as an inherited form, with many cases where it is passed down from generation to generation within the same family. However, it is also possible to diagnose an acquired form with basically the same pathological presentation of the inherited one. CN often comes as a result of a series of genetic defects which, if studied, might lead to the discovery of new therapeutic approaches.
Cyclic neutropenia is a rare type of neutropenia in which neutrophil levels oscillate cyclically, alternating minimum and maximum peaks in a cycle that usually lasts for around 21 days. The minimum neutrophil levels in the blood generally last for 7 days. The disorder is due to impaired neutrophil production by the bone marrow, which comes as a direct consequence of a series of mutations occurring in a gene known as ELANE or of the occurrence of other associated pathological conditions. For this reason, cyclic neutropenia has an acquired and an inherited form.
In addition to cyclic variations in the blood levels of neutrophils and other particles such as eosinophils, monocytes or platelets, the symptoms of cyclic neutropenia include other key signs such as fatigue, weakness, malaise and several forms of infections. Counting the neutrophil levels in the blood (absolute neutrophil count) is the main diagnostic strategy for cyclic neutropenia, which can eventually be coupled with genetic testing, especially in those individuals with a well-documented family history.
The treatment for cyclic neutropenia is mainly based on the administration of granulocyte colony-stimulating factor, a drug which restores neutrophil production in the bone marrow. Granulocyte colony-stimulating factor has been proved to be effective in both the acquired and inherited form of the disorder, even though its use is frequently associated with side effects such as mild bone pain and local skin reactions. For this reason, treatment should be carefully considered prior to start administration, and patients should be carefully monitored and evaluated throughout it.