Eri?kin Edinsel ?diopatik N?tropenide Gran?losit Koloni-Stimule Edici Fakt?r?n Olgunla?t?r?c? Etkisi
Hal?k DEM?RO?LU*,? ?uayib YAL?IN**,? Yahya B?Y?KA?IK*, Semra D?NDAR*
?diopatik n?tropeni kal?tsal veya edinsel olabilir. Bu n?tropenik bozukluklar?n ortak ?zellikleri, derin mutlak n?tropeni ve progenit?r h?crelerin promyelosit-myelosit evresinde bir maturasyon blo?udur. ?diopatik n?tropeni ve infeksiyon komplikasyonuyla ba?vuran iki hastam?z? sunmak istiyoruz. Geni? spektrumlu antibiyotiklerle ate?in kontrol alt?na al?namamas? ?zerine n?trofilleri y?kseltmek amac?yla G-CSF 48 milyon ?nite g?nl?k dozda ba?land?. Her iki hastada da n?trofillerin toparlamas?yla birlikte ate? kontrol alt?na al?nd?. Bu t?r n?tropenik hastal?klarda altta yatan esas patoloji bilinmese de elde edilen sonu? bize myelopoezde granulosit yolunda G-CSF?e yan?t veren intrinsik bir bozukluk oldu?unu g?stermektedir.?
Anahtar Kelimeler: N?tropeni, Gran?losit Koloni Stim?le Edici Fakt?r, Diferansiasyon.
Differentiating Effect of Granulocyte Colony-Stimulating Factor in Adult Acquired Idiopathic Neutropenia
Idiopathic neutropenia may be inherited or acquired. The common features of these neutropenic disorders are profound absolute neutropenia and a maturation arrest of marrow progenitor cells at the promyelocyte-myelocyte stage. Here we present two patients with idiopathic neutropenia who were admitted with infectious complications. Since broad spectrum antibiotics failed to control the fever, G-CSF was begun at a dose of 48 million units daily to raise the neutrophil count. With neutrophil recovery, fever was controlled in both patients. Although the basic pathology underlying these neutropenic disorders is unknown, the result we obtained shows that there is an intrinsic defect in myelopoiesis along a granulocytic pathway which is responsive to G-CSF.
Key Words: Neutropenia, Granulocyte Colony-Stimulating Factor, Differentiation.
A group of disorders causing a selective neutropenia of unknown cause are recognised in both children and adults (1). They may be inherited, begin early in childhood and are referred to as Kostmann syndrome (2). On the other hand, idiopathic neutropenia in adults is considered to be an acquired disease, or in occasional cases affected children escape detection until adulthood (3). A remarkable feature of these neutropenic disorders is that, despite a marked decrease in the number of circulating neutrophils, serious infectious complications are rarely observed (1,3). This contrasts strikingly with the frequency of infections seen in neutropenic patients with acute leukaemia, aplastic anaemia and drug-induced agranulocytosis. Nevertheless, in some patients serious infections with Staphylococcus aureus, Escherichia coli and Streptococcus pneumoniae may be encountered (1).? Here we present two cases of adult idiopathic neutropenia presenting with infectious complications, who were successfully treated with recombinant human granulocyte colony-stimulating factor (G-CSF).??
Patient 1: A 35-year-old man was admitted with fever, cough, nausea and vomiting for the last two days. Past medical history was unremarkable. On physical examination, he was tachypneic and tachycardic and fever was 39.2 ˚C. Auscultation of the chest revealed wet rales over the right lower lung region. Lymphadenopathy and splenomegaly were absent. The chest roentgenogram was normal. He had the following CBC values; Hb: 14.7 g/dl, platelets: 318 x 109/l and WBC: 4.8 x 109/l and the differential count showed 10% neutrophils, 12% monocytes and 78% lymphocytes. Sputum examination showed gram positive diplococci. Blood cultures were obtained and he was put on sulbactam+ampicillin to cover streptococci and since he was neutropenic, empiric amikacin+ceftazidime therapy for possible gram negative microorganisms. His bone marrow was normocellular, but there was promyelocytic maturation arrest and blasts consisted %1.2 of the total bone marrow cells. Storage iron was positive, but there was no ringed sideroblasts. Chromosome analysis revealed no abnormality. No microorganism was grown in blood and urine cultures. Fever did not dropped and at the fifth day of therapy amphotericin-B was added for possible fungal infection. However fever could not be controlled and at day seven his WBC was 5.1 x 109/l with 14% neutrophils. He was given G-CSF 48 million units daily and within three days his neutrophil count reached over 1.5 x 109/l and fever dropped; then G-CSF was stopped. On a bone marrow examination, it was seen that promyelocytic maturation arrest was resolved. At this time, his neutropenia was thought to be transient. After a week of G-CSF withdrawal, he was readmitted with papulopustular skin lesions on the chest and arms. On examination, WBC was 4.7 x 109/l with 13% neutrophils and bone marrow examination revealed promyelocytic maturation arrest again. No secondary cause to identify neutropenia could be found despite extensive examination. Myelodysplasia was ruled out since there was no anemia, chromosomal abnormality, ringed sideroblast or increase in blasts. He was diagnosed as chronic idiopathic neutropenia.
Patient 2: A 27-year-old woman was hospitalized for a fever of 39.3 ˚C. She had an appendectomy three years before and at that time she had the following CBC values: Hb:12.5 g/dl, platelets: 249 x 109/l and WBC: 6.2 x 109/l with 58% neutrophils, 36% lymphocytes, 1% eosinophil and 5% monocytes. Two years ago, she was admitted to another hospital with a fever of 39.5 ˚C and she was found neutropenic with bone marrow promyelocytic maturation arrest. She was treated with broad spectrum antibiotics and at the end of ten days her neutrophil count rose to normal values. Her neutropenia was thought to be secondary to septicemia. She denied any drug, toxin or radiation exposure recently. There was no lymphadenopathy or splenomegaly. Chest X-ray and abdominal ultrasonography were normal. Blood tests showed a Hb: 12.8 gr/dl, platelets: 297 x 109/l and WBC: 1.1 x 109/l with 22% neutrophils. Bone marrow was normocellular and there was a maturation arrest at the promyelocyte stage (Figure 1); karyotypic analysis was normal. As in the first patient there was no increase in blast cells and iron staining was positive without ringed sideroblasts. No focus for fever could be found. After blood and urine cultures were obtained, she was given amikacin+ceftazidime for neutropenic fever. Fever did not drop at the second day of therapy and blood cultures revealed Escherichia coli infection. Although it was sensitive to the given antibiotics fever did not drop. Her WBC was 1.3 x 109/l with 23% neutrophils. As in the first patient, no cause could be found to explain neutropenia. She was given daily G-CSF 48 million units. Within four days her WBC rose to 12 x 109/l with 76% neutrophils and fever dropped; G-CSF therapy was discontinued. Her control bone marrow examination was normal (Figure 2). The patient is still in remission six months after the neutropenic attack with WBC: 8.2 x 109/l and 65% neutrophils.
Whether inherited or acquired, the common features of these neutropenic disorders are profound absolute neutropenia and a maturation arrest of marrow progenitor cells at the promyelocyte-myelocyte stage (4). The basic pathology underlying the block at promyelocytic stage suggests the loss of cells during this maturation process, that is, ineffective granulocytopoiesis (5).
The myeloid growth factors, one of which is G-CSF, are glycoprotein hormones that regulate the proliferation and differentiation of myeloid progenitor cells (6). Their biologic effects are mediated via binding to high affinity receptors on the surface of target cells which include the myeloid progenitor cells. The cellular and molecular mechanisms of neutropenia remain poorly understood. A defect in G-CSF receptor is proposed to be a likely cause of these disorders with maturation arrest (7). This defect may lead to a decreased responsiveness to endogenous G-CSF. We set with the point of view that if pharmacologic doses of G-CSF is administered, a response may be obtained.
In our patients, response to G-CSF was excellent. In the first patient, the response was transient. In general, the story of idiopathic neutropenic patients are alike. They respond to G-CSF and neutropenia recurs following discontinuation of therapy (8). The story of the second patient was more interesting with periods of remissions and exacerbations of the neutropenic state. In her first attack, neutropenia resolved spontaneously. However we had to give G-CSF in the second attack. It is difficult to explain with certainty the mechanism of spontaneous remission as well as the response to G-CSF. To our knowledge, this is the first patient having such long periods of remissions and relapses. Spontaneous resolution of neutropenia with complete remission is well documented in the literature and although a specific antibody has not been demonstrated in states of idiopathic neutropenia, this spontaneous resolution raised the possibility of an immune etiology as suggested by others previously (9).
The result we obtained shows that there is an intrinsic defect in myelopoiesis along a granulocytic pathway which is responsive to G-CSF. The basic defect in idiopathic neutropenia has long been considered at the stem cell level and bone marrow transplantation has been advocated to establish a definite therapy (6). With the development of growth factors, therapy with G-CSF and granulocyte-macrophage colony stimulating factor has replaced bone marrow transplantation (9,10). Many patients have a benign course and even do not require treatment with G-CSF (9). However, in a few patients life threatening infections may occur as it was the case in our patients. G-CSF therapy is a new treatment modality for these group of disorders. In 1990, the first report of phase 1 to 2 trials with G-CSF was published; the preliminary results were excellent (11). In phase 1/2/3 studies, patients were enrolled into long-term maintenance treatment once a response was documented. Favorable responses were obtained with no serious side effects (12). In conclusion, we suggest that G-CSF has a differentiating effect in the treatment of idiopathic neutropenia and it is worth a trial as first line agent if infectious complications develop; otherwise patients may be followed without treatment.
ADDRESS FOR CORRESPONDENCE:
Dr. Hal?k DEM?RO?LU
Ho?dere Cad. 80/19