Neutrophil dysfunctions in sickle cell disease

The abnormal susceptibility towards certain infections in SCD patients has a partial explanation in the well described functional defects of the spleen and of the alternative complement pathway; such defects probably account for the etiology of fulminant, often fatal, childhood infections with encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae). On the other hand, the frequent systemic infections with enteric organisms in SCD patients, particularly of the salmonella species, and also with Staphylococcus aureus, are more difficult to explain. We therefore reviewed the potential contribution of neutrophil (PMN) dysfunctions to the increased infective tendency of SCD patients and included some previously unpublished data from our laboratory. While notable discrepancies still exist--and need further clarification--a tentative working hypothesis can be extracted from the available data: dysfunctions of neutrophils affect their locomotion (as reflected by decreased chemotaxis and in vivo migration), their phagocytic processes and their bactericidal performance. The latter concerns the ineffective killing of Staphylococcus aureus, Candida albicans, and Streptococcus pneumoniae. Dysfunctional bactericidal activity, in turn, apparently relates to a poor or at times non-existent PMN oxidative activity, which prevents the prompt disposal of microorganisms. Under certain circumstances salmonella species seem to further paralyze the oxidative machinery of PMNs in SCD. Serum from some patients contains a poorly defined inhibitor, or lacks an enhancing factor, and such serum abnormalities aggravate the existing defects just described. Interestingly recent findings suggest that dysfunctional PMNs may originate from the mandatory demargination of leukocytes secondary to the functional asplenia of SCD; a predominance of non-rosetting (EA-) PMNs among such leukocytes could produce the operational explanation for an exaggerated representation of dysfunctional PMNs in SCD patients with leukocytis.