Immature granulocytes and band forms

Immature granulocytes are produced in reponse to infection or inflammation, where they are released form the marrow prematurely to compensate for the loss of granulocytes at the front line trenches. Band forms are not synonymous with immature granulocytes, but are used interchangeably. A band cell is an immature neutrophil, but not all immature neutrophils are band cells.  Essentially, a "band cell" features an elongated band-like nucleus, as opposed to a multilobed one. These cells are an intermediate step on the way from myelocyte precursor cells to mature segmented neutrophils. At any given time, one should have no more than 3-5% of one's neutrophils represented by such band foms. If there is any more, that represents a "left shift", a change in the immature:mature ratio. According to Wikipedia, the term originates from some sort of "left-most button arrangement of early cell sorting machines", where the least mature cells (myeloblasts) were assigned to the left-most button of the manual counter.

The significance and causes of a "left shift "

The following conditions can give rise to an increased proportion of immature neutrophils:

  • Sepsis
  • Haemorrhage (due to adrenergic mobilisation of marrow neutrophils)
  • Necrosis (of any sort, eg. ischaemia)
  • Bone marrow infiltration (i.e. insufficient space for proper maturation)
  • Anaemia (in an exaggerated haemopoietic reaction, the marrow releases a lot of immature cells, which include neutrophils)

According to a 1997 article by Seebach et al, the utility of this finding in discriminating infectious from non-infectious causes of SIRS is poorer than neutrophil inclusion bodies (such as toxic granules). However, interest in using this parameter in discriminating sepsis from SIRS is still alive (Nierhaus et al, 2013).

Leukoerythroblastic reaction

This had appeared in Question 3.2 from the second paper of 2016. The question expected the candidates to recognise the phenomenon from a blood film with "nucleated red blood cells, immature granulocytes and band forms observed." Four causes were asked for. There are many more than that, but boradly speaking anything which makles the marrow work harder could potentially promote this appearance.

The best source for this is probably the classic 1974 article by Weick et al, but it is not available for the casual Google user. Weick and colleagues reported on a case series of 215 patients with this sort of picture. Of them, the majority (136) had some sort of malignant disease, and the others were either septic or bleeding tod eath (typically from the GI tract). Subsequently, people have published on the finding of leukoerythroblastosis in almost every situation, ranging from pregnancy to the use of granulocyte stimulators.

In summary, the possible causes of leukoerythroblastosis are:

  • Bone marrow inflitration ("myelophthisis")
    • Leukaemia
    • Myelofibrosis
    • Solid tumour infiltration, eg. breast cancer
    • Miliary tuberculosis
  • Extramedullary haematopoiesis
  • States of widespread bone marrow activation
    • Sepsis
    • Inflammatory states, eg. autoimmune disease
    • Severe haemorrhage or haemolysis
    • Use of GM-CSF
    • Marrow recovery following marrow suppression
  • Exotic stuff
    • Still disease
    • Gaucher's disease
    • Myocardial infarction
    • Chronic lung diseases

Döhle bodies

These little peripheral cytoplasmic inclusion bodies in the cytoplasm of neutrophils are thought to be the remnants of the rough endoplasmic reticulum. They appear during leukemoid reactions, but they are also a feature of severe inflammatory states, and are generally considered to be a part of the "toxic" reaction to infection.

The following are scenarios in which one would not be surprised to see some Döhle bodies:

  • Syphilis
  • Typhoid
  • Tuberculosis
  • Sepsis
  • Severe burns
  • Leukemoid reaction
  • May-Hegglin disease, a familial disorder also associated with abnormally large platelets

This has come up only once, in Question 9.3 from the first paper of 2008 - the same question (and the only question) to discuss leukemoid reaction. It is possible that this will never appear again.

If one is for some reason interested in this blood film abnormality, one may pursue it further, knowing well that doing so imperils their time-critical exam preparation. The topic of neutrophil inclusion bodies is so esoteric that there is very little literature published on the subject, and pragmatic exam-oriented sites like LITFL dedicate an appropriately small amount of space to them.  An excellent article about these little lumps was written by Weiner and Topley in 1955. The bodies were fist discovered in 1911. At first Döhle mistook them for spirochaetes, because the cause of syphilis was only recently discovered with great fanfare,  and everybody was seeing spirochaetes everywhere.

References

Bain, Barbara J. "Diagnosis from the blood smear." New England Journal of Medicine 353.5 (2005): 498-507.

Sakka, Vissaria, et al. "An update on the etiology and diagnostic evaluation of a leukemoid reaction." European journal of internal medicine 17.6 (2006): 394-398.

ul Haque, Anwar, and Noor ul Aan. "Leukemoid Reaction: Unusual Causes." International Journal of Pathology 8.1 (2010): 39-40.

Weiner, W., and Elizabeth Topley. "Döhle bodies in the leucocytes of patients with burns." Journal of clinical pathology 8.4 (1955): 324-328.

Kulkarni, M., T. Agrawal, and V. Dhas. "Histopathologic bodies: An insight." Journal of the International Clinical Dental Research Organization 3.1 (2011): 43.

Easton, J. A., and Ch Fessas. "The incidence of Döhle bodies in various diseases and their association with thrombocytopenia." British journal of haematology 12.1 (1966): 54-60.

Cawley, J. C., and F. G. J. Hayhoe. "The Inclusions of the May‐Hegglin Anomaly and Dohle Bodies of Infection: an Ultrastructural Comparison." British journal of haematology 22.4 (1972): 491-496.

Nierhaus, Axel, et al. "Revisiting the white blood cell count: immature granulocytes count as a diagnostic marker to discriminate between SIRS and sepsis-a prospective, observational study." BMC immunology 14.1 (2013): 1.

Seebach, Jörg D., et al. "The diagnostic value of the neutrophil left shift in predicting inflammatory and infectious disease." American journal of clinical pathology 107.5 (1997): 582-591.

Shamdas, Glenn J., et al. "Leukoerythroblastic anemia in metastatic prostate cancer. Clinical and prognostic significance in patients with hormone‐refractory disease." Cancer 71.11 (1993): 3594-3600.

Weick, J. K., A. B. Hagedorn, and J. W. Linman. "Leukoerythroblastosis. Diagnostic and prognostic significance." Mayo Clinic Proceedings. Vol. 49. No. 2. 1974.