Granulocytopenia

Granulocytopenia is defined as a decrease of peripheral blood granulocytes below lower limit of normal range. Patients with severe granulocytopenia - agranulocytosis exhibit < 0.5 × 109/l granulocytes in peipheral blood. Granulocytopenia may result from congenital or acquired defective production of granulocyte precursors or it may be a consequence of increased destruction of mature granulocytes, most frequently caused by immune mechanisms. Investigation of origin of granulocytopenia must be connected with exclusion of etiological agents causing secondary neutropenia (infections, autoimmune disorders, drugs, LGL syndrome). Patients with > 0.5 × 109/l of granulocytes usually do not exhibit clinical symptoms unless they do not suffer from a concomitant disease (especially immunodeficiency). Patients with severe granulocytopenia are indicated for supportive treatment and for administration of G-CSF. Children with severe congenital neutropenia (SCN) are at risk of later development of MDS or AML and are candidates for SCT when signs of disease progression appears. Key words: diagnosis - granulocytopenia - growth factors - pathogenesis - transplantation -treatment.

apparent that the finel ~ord has not BB yet been written but that the work of the last five yeers has seemingly accomplished the most toward that end.
In this paper an attempt will be made to correlate the various manifestations of the disease with special refer ence to etiology, pathology and trea,trnent. No attempt is made in this paper to discuss the grBnulopenic syndrome under the various classifications that have been suggested because no classificetion has as yet been advanced which is satisfactory. showing the presence of anemia, and the third a tendency to hemorrhage.
B~cteriologic study has not as yet yielded anything definite. Friedmann isolated Bacillus Pyocyaneus from the blood stream once.
(2) Lovett (12) fout;ld the SBme organism in the throat and determined that the isolated organism in the throat caused a relative lowering of' the granulocyte count in rabbits.
Dasse (13)   The phagocytic activity of the leucocy~e is intimately connected with its amebi sm and a s one-would expect is most pronounced in the heterophils. Phagocytosis is of great biological importance a.s it is one of the meE;ms by which ~he host destroys bacteria.
It has 8.180 been shown tte t the heterophil gr~m ..
ulocytes contain proteolytic and oxidizing enzymes.
The eosinophils display phagocytosis rarley if ever; however their granules give a marked oxidase reaction.
The function of the baso phils and the cherild:cal nature of their granules is unknown.
Roberts ~md Kracke (22) Confusion has existed, and still prevails, among hematologists relative to the origins and relationships of the cells of the blood. Rov/ever it is agreed that !ll take their first beginning from the mesenchymal cells of the mesoderms~l layer in the embryo. But thereafter the theories and hypotheses diverge more or less rs,di-c8.l1y; however the essentia.l differences a.rise more in the interpretation and nomenclature than in opposing . objective observations. In the usual hyperplastic reo. In some levels, the factors may increase together, in others, some may increase while others decrease.
Sabin gives the following explanation of the chart.
Level I is best studied in a completely aplastic adult bone marrow from w'hich 8.cti ve marrow is readily end quickly regenerated. (31) In such a Duiescent marrow, only three types of cells can be seen: fat, endothelium,. and reticulum. Of these three, the fat is but accessory to blood formation. Evidence indicates tha.t the red cells regenerate from the endothelium, while the white cells regenerate from the reticulum.
The reticular cells Bre ea.sl1y found because they are the only cells lying between the fat cells along the reticu18r framework. The nuclie he.ve so Ii ttle chroma tin as to make them scarcely more ba sophilic tha.n the cytoplasm. These cells Bre probably as close to primitive embryonic mensenchyme as occurs in the adult animal. MaTI'cry (36) describes the reticular cells as a type less differentiated than the fibroblast but also says they may differentiate into a fibroblast. These With the concept in mind that bone marrow as an .
organ is the place where two types of cells are made, that it holds a large store of each strain almost ready for delivery, a.nd that its store of immature forms is small in numbers, but of exceedingly high potentiality toward multiplication, growth, and maturation, the question of the mecha.nism whereby a normal structure in both the marrow and blood is maintained becomes the major problem of hematology.
Doan (40) and others have shown that vlhatever con-  Me.dison and Squier (14), Stelhorn and Amolsch (47) They called a.ttention also, to the fact that a temporary leucopenia may be produced by the injection of peptones t'md a large number of other protiens.
Since the works of Ruedeger (52)  In typical cases of malignant neutropenia with myeloid aplasia, the part of the bone ma.rrow that manufa.ctures the granular leUkocytes, level I, has ceased to function, or nearly so. The life of the granular cells of the blood stream being but from 3 to 5 days, when level II and III a.re exhausted, the granulocytes of the blood strea . . m will tota.lly disappear in from 3 to 5 days there ...
after. There is little evidence tp...a t the granulocytes B.re abnormally destroyed in the blood stream. The bulk of the evidence pOints to the fact that the primary lesion, sO far as is known is the granulopoetic area of the bone marrow, and that this condition precedes the c1inica.l symptoms and loca.l infections. She reasons that the primary lesion is not in the bone marrow but in the organ or tissue which give rise to the substance (maturation factor) that keeps the gra . .TIulocytes to a normal blood level or keeps the destruction and production at a constant level. She points out that the text book picture of pernicious anemiB. can very aptly be substituted for that of malignant neutropenia and as a ma-turation factor for erythropoesis has been found. so it rem/olins but to find the maturati on factor for granulocytes. She suggests that a chemical analysis of bacteria known to produce a leucocytosis might let:td to a solution but that it seems more 10gica.l to seBrch within the bocly for the particular organ extJ:'act reguleting granulopoesis.
The other group of patients showing peripheral neutropenia with slight hypoplasia; normal, moderate, or marked hyperplasia of the myeloid tissue, S1:1e considers as due to a lack ~ the chemotactic factor.
The cells my be growing and ma.turing but are net being . called to the circulating-blood. The normal stimulus for calling the granulocytes from the marrow to the circulating bood has been shown by experimental work (42) to be the liberated products (nucliec acid, adenine, guanine, and etc), from disentegrating granulocytes in the blood streB.m. This theory, she points out, could account for failures in the treatment of pa~tients with nucleotides who clinically were similar to those who recovered under such trea.tment. If the maturation factor is absent, a chetnotactic factor would be of Ii ttle value.

CHEMICALS:
It has long been known that various chemicals wil], depress the bone lJI'rrow function, resulting in partial or complete inhibition of one or all cel- Beck (1) says that the usual mode of onset is marked by fever, chill 1:md sore throat, which may be sudden or gradual. To these may be added hea.dache, marked palpitation with a tumultus heart beat, general aching, drowsiness and occasionally delirium. Some patients are nauseated end vomit, and, as a rule, there is dysphagia.
There is an,_offensive, fetid odor to the bree.th, and the tongue is often h3avily coated.
1'he patients a.re wilted in appearance; the skin is pale, but the mucous membranes e~re of goad color.
The weakness, marked prostration end toxic appearance are out of all proportion to the few physical signs.
Jaundice is rare in typical cases. The liver and spleen may be enlarged. The patients are characterized by weakness, easy fatigue, drowsiness and tendency to infection, especially in the oral cBvity. Beck states tb.t there is evidence that just mere lack of neutrophile will CBuse euch symptoms as fever, wea.kness, inertia and mentel and physical collppse. Roberts and Kra.ck (72)  In one the blood picture had tHready become norma.l too late, however, to be of avail.
The classical clinical description given above is a-

In a series of 103 cases reported by Jackson and
P~rker they ~ound the following blood counts. (71) The white count was rarely as high as 2500 per cmm. and is often 1000 or less. Frequently it is in the hundreds. The prognosis of agranulocyts,is is extre~fiely grave", per cent for first ~ttack with recurrences the usual thing~ nearly always terminating fatally. Kastlin (7) in 1927 gave the mortality as 95 per'cent.
Harkins (9)  Jackson and Parker (7!1), even go so fa.r as to state that it is not an uncommon! experience to find the peripheral whi te blood count lowier after transfusion than before. I They state that the' ~ortality in their series was the same for the group rejcei ving both transfusions B.nd pentnucleotide and fOr these receiving only pentnucleotide.
In the last three Or f.our years the enthusiasm of the efficacy of blood transfusions has been lost in the greater enthusiasm for pentnuc1eotldes (71), (88), (89), 0.7 grems is then given daily until the white count has been normel for severel days. In cases which are extremely sick, and e~pecially in those in which the total white count is below 1000, 40 cc. should b e given dAily until the white count has definitely risen and young neutropal1s ere present. Fifty cc. may be given even more advantageously. The drug may also be administered intravenously, well diluted in saline, by the continuous drip method, the speed of injection being such that no untoward readtion occurs. Usually 50 to 100 drops may be given per minute when 20 cc. ere diluted in 100 cc. of normal saline solution. The drug should be continued in larger doses until the white count has definitely risen and in some-wha~ shaller amounts until it has been normal for several days •. If there has been no response in ten days, most authors consider further therapy useless.
Fitz-Hugh and associates (46) report a reaction of 81arming character but do not sta.te 'Nhether· the drug wa.s given intramuscularly or intravenously. They also say that one of their patients reacted violently with fever up to 104 degrees with e8ch intramuscular dose bvt tolerated the same doee intravenously without reactidn. In some, there is a transient sense of discomfort at the site of injection. In others there may be precordial distress, dyspnea and nausea. Very rarely are the symptoms alarming. If however they are sufficiently severe syrr:ptoms to upset, the patient, Jackson and Parker (71) suggest that smeller doses of the drug be given at more . frequent intervals until the required amount is given daily_ They also point out that the drug should never be giv~n to an anaphylaotic individual nor to one with severe cardla.c damage.
Doan (80) pOints out that the first sign of a favora.ble reaction to pentnucleotide is evidenced by the a.ppearance of myelocytes in the blood stream. These cells may reach twenty per cent of the total white cells. This change, he says, usually occurs about the fourth day following treatment and corresponds in some measure to the reticulocytic rise in pernicious anemia. Shortly thereafter the temperature fells, the total white count rises, and more mature neutrophils tpke the pla,oe of the immature cells.
Pentnucleotlde has been used successfully by many and at present is the treatment advocated by "!lost guthors. From this study, the following facts seem to be of primary importance: Whether granulocytopenia is to be regarded as a disease entity or a syndrome, cannot as yet be dogmatically steted, but it is probable that such a disease entity does exist. The etiology of the disease is as yet uncertain, however those particuls_r drugs containing the benzamine nucleus undoubtedly-do have much to do with the development of certain cases. The