Drugs and Eosinophilia


Drugs, prescription and non-prescription,  and nutritional supplements are a common cause of eosinophilia across the world. In regions with a low prevalence of parasitic infestations drugs are the leading cause of eosinophilia.

Clinical Spectrum of Drug Induced Eosinophilia

The spectrum of drug induced eosinophilia extends from an asymptomatic eosinophilia discovered on a routine haemogram to a a serious disorder like drug induced drug reaction with eosinophilia and systemic syndromes (DRESS). Eosinophilia associated with specific organ complications includes

  1. Eosinophilic pulmonary infiltrates associated with the use of sulfadsalazine, nitrofurantoin and non-steroidal anti-inflammatory drugs (NSAID)
  2. Acute interstitial nephritis with eosinophilia  associated with the use of semisynthetic penicillins, cephalosporins, NSAID, sulphonamides, phenytoin, cimetidine and allopurinol
  3. Eosinophilia-myalgia syndrome (EMS) presents with increased eosinophil counts associated with  severe myalgia, neuropathy, skin rash and multi-system complications. The cause of EMS is not known but L-tryptophan has been implemented.
  4. Drug reaction with eosinophilia and systemic symptoms /Drug induced hypersensitivity syndrome (DRESS/DIHS): The syndrome is a form of delayed drug hypersensitivity the presents with fever lymphadenopathy and end organ damage. The spectrum of end-organ damage includes hepetitis, interstitial nephritis, pneumonitis and carditis. The drugs implicated in DRESS/DIHS include
    1. Anti-infective
      1. Antibiotics: Cephalosporins, doxycycline, fluoroquinolone, linezolid, metronidazole, nitrofurantoin, penicillins, tetracycline
      2. Sulfomaides: Sulfasalazine trimethoprim-sulfamethoxozole
      3. Sulfones: Dapsone
      4. Antiviral: Abacavir, Nevirapine
    2. Anti-epileptic: Carbamazepine, lamotrigine, phenobarbital, phenytoin, , valproate
    3. Anti-depressants: Amitriptyline, desimipramine, fluoxetine
    4. Anti-inflammatory: Diclofenac, ibuprofen, naproxen, piroxicam
    5. Antihypertensives: ACE inhibitors, β-blockers, hydrochlorthiazide
    6. Others:  Allopurinol, cyclosporine, ranitidine

Management

The incriminating drug should be withdrawn in symptomatic patients. Asymptomatic eosinophilia does not necessitate discontinuation of therapy. If equally effective therapy is available it is preferable to stop therapy. If this is not the case the drug may be continued with careful monitoring for symptoms.

Advertisements

Morphology of Myeloid Precurssors


The earliest morphologically distinct myeloid cell is a myeloblast. Cell with myeloid commitment at stages of differentiation between the pleuripotant stem cell and myeloblasts have been identified but these lack morphological characters of a myeloid lineage. Myeloid cells share a common precursors with the cells of the monocyte-macrophage system in the form of CFU-GM. CFU-GM matures into CFU-G, a precursor for myeloid cells and CFU-M, a precursor for cells of the monocyte-macrophage series. There are five morphological distinct stages of myeloid precursors, myeloblast, promyelocyte, myelocyte, metamyelocyte and the band form. Only the first three are capable of cell division. Myeloid cells in the peripheral blood are classified into neutrophils, eosinophils and basophils depending on the staining characteristics of the cytoplasmic granules. Morphological evidence of commitment one of the myeloid lines is seen at the myelocyte stage. Electron microscopically commitment can be seen at the promyelocyte stage.

Figure 1. Myeloblast, Myelocyte and Metamyelocyte

Myeloblast (Figure 1, 3 and 4): Cells 10-20μ in size with a large slightly round nucleus with fine chromatin showing no clumping. Fine chromatin gives the nucleus a sieve-like or a finely granular appearance. The nucleus shows 2-5 pale sky-blue nucleoli. The nuclear membrane is exceedingly thin. Lymphoblasts nucleus may be differentiated from myeloblasts by the coarser chromatin, fewer nucleoli and the clumping of chromatin near the nuclear membranes. The cytoplasm of a myeloblast is basophilic but the basophilia is less marked than the lymphoblast or pronormoblast. Of the three types of leukaemic lymphoblasts the L1 (small cells with few nucleoli and a thin rim of cytoplasm) and L3 (strongly basophilic cytoplasm with prominent vacuolation) can be easily differentiated from myeloblasts morphologically. Differentiation of myeloblasts from L2 blasts on morphological grounds alone may not be possible. Perinuclear clearing is a feature of pronormoblasts and is not seen in the myeloblast. By definition myeloblasts have no granules but some classify cells with a few granules as myeloblasts particularly in the presence of abnormal myelopoiesis. In addition to granulation leukaemic myeloblasts may show nuclear furrows and Auer rods. Three stages in the maturation of myeloblasts are recognized

  1. Type I: No granules
  2. Type II: Fewer than 20 granules, Auer rods may be seen
  3. Type III: More than 20 granules seen without a Golgi apparatus

Very immature blasts lack morphological features of any lineage making it impossible to classify them as myeloblast, monoblast, lymphoblast or pronormoblast. Lineage identification in such cases may be aided by the company they keep, immunophenotyping and staining for peroxidase and esterases.

Figure 2. Promyelocytes

Promyelocyte (Figure 2): Slightly larger than a myeloblast (15-25μ), the promyelocyte is the largest cell of the myeloid series. Its nucleus is slightly indented, has a fine chromatin (though coarser than the myeloblast) and has nucleoli. Later stages show a slight chromatin condensation along the nuclear membrane. The cytoplasm is basophilic with prominent primary azurophilic granules. Endoplasmic reticulum is prominent and takes the form of dilated vesicles. Cells have a perinuclear Golgi apparatus that manifests as a perinuclear halo, but only in normal cells. Tough it is not possible to differentiate the promyelocytes of the three granulocytic (neutrophilic, basophilic, eosinophilic) series on light microscopy, electron microscopic difference exist. Leukaemic promyelocytes may be of the hypergranular or the hypogranular variety. The hypergranular variety has numerous small granules and Auer rods. Patients usually present with pancytopenia. Apart from having few or no granules in the cytoplasm the hypogranular variety may have a bilobed or folded nucleus.

Figure 3. Myelocytes – Neutrophilic, Eosinophilic and Basophilic

Myelocytes (Figure 1,3, 4 and 5): Lineage specific granules appear in the myelocyte stage. The cell is slightly smaller (10-20μ) than the promyelocyte and has an eccentric nucleus, round to oval, flattened on one side. Nucleoli are small and are only seen on EM, chromatin is coarse. Primary (azurophilic) granules persist but as no new granules are synthesized their number decreases with each division. The ratio of primary to secondary granules in a mature neutrophil is 2-3:1. Primary granules contain myeloperoxidase. The granulation of the endoplasmic reticulum is lesser than promyelocyte and as myelocytes mature the cytoplasmic basophilia decreases and finally disappears. The myelocyte may be neutrophilic, eosinophilic or basophilic. The granules of neutrophilic myelocytes are lilac, eosinophilic myelocytes are orange-red and basophilic myelocytes are purple. The eosinophilic myelocyte may contain purple staining granules. These are structurally different from granules of basophilic myelocytes. Myelocytes are the last stage to have the capacity to divide.

Granulocyte granules

Table 1. Charecteristics of granulocyte granules. The colour of the letters is the same as that of the granules and the backgroung the colour of cytoplasm of the cell the granules are most prominant in.

Figure 4. Myeloblast, Myelocyte and Eosinophil

Metamyelocyte (figure 1): Myelocytes matures to a metamyelocyte with appearance of nuclear indentation. Metamyelocyte can not divide. Unlike the transformation of a promyelocyte to a myelocyte that is accompanied by distinct morphological changes (disappearance of nucleoli, appearance of secondary granules) the most pronounced change that takes place when a myelocyte transforms into a metamyelocyte is indentation of the nucleus. Time-lapse photography has shown that the myelocyte nucleus can developed pronounced indentation and then revert to an oval shape. The distinction between the two stages is physiological. Metamyelocytes can not synthesize DNA, myelocytes can. Fortunately the distinction between a myelocyte and metamyelocyte is of little clinical importance and the ability of the cell to synthesize DNA is only assayed for research.

Band and Segmented Granulocytes (Figure 3): The indentation of the nucleus characteristic of the metamyelocyte increases and the nucleus becomes ribbon shaped. The nucleus of this cell has parallel borders for most of its length, like a band, and the cell is thus known as the band form. As the cell matures the nucleus becomes segmented. The segments are connected by thin strands of nuclear material. A constriction of more than half or two-third is accepted as segmentation by some. Neutrophils usually have 2-5 segments and eosinophils usually have 2 segments. Segmentations of the basophil nucleus are obscured by the intensely granular cytoplasm. The basophil nucleus ahs 2-3 segments, appearing in the contain few granules

Figure 5. Basophilic Myelocyte and Metamyelocyte

Morphological Characteristics of Myeloid Precursors

Cell Size Nucleus Cytoplasm
Myeloblast 12-20μ Round, fine chromatin, nucleoli Blue usually without granules. Some azurophilic granules may be present
Promyelocyte 15-25μ Slightly indented nucleus often eccentrically placed. Chromatin coarser than a myeloblast. Nucleoli seen Blue cytoplasm with numerous azurophilic granules
Myelocyte 10-20μ Round to oval, indented, chromatin more coarse than promyelocyte, no nucleoli Most immature forms have less basophilia than the promyeloblast. Basophilia disappeaqs as cell matures. Secondary granules appear.
Metamyelocyte 12-18μ Indented, coarse clumped chromatin Pink with secondary granules.
Band Form 10-12μ Band shaped. Borders are parallel for most of the length. May be folded Pink with secondary granules

Relates posts in this site

  1. Morphology of Erythroid Precursors
  2. Megakaryocyte Morphology