Virus-associated apoptosis of blood neutrophils as a risk factor for invasive meningococcal disease

Abstract

Aims: To quantify a range of haematological indicators of viral infection (leucocyte apoptosis, cytopenia of normal lymphocytes, reactive lymphocyte increase, neutropenia) in patients with recent onset invasive meningococcal disease (IMD), with a view to test the association of viral infection with IMD and identify possible haematological risk factors for its development.

Subjects and methods: 88 patients with recent onset IMD, classified on clinical severity as fatal (n=14), septic shock survived (n=26) and no shock (n=48), and 50 healthy controls were studied. Blood film microscopy and leucocyte counts were used to quantify the virus-associated indicators. Cocci-containing neutrophils were also quantified.

Results: All viral parameters were significantly more frequent or higher in patients than controls, with leucocyte apoptosis found only in the patients. A significant gradient in accord with clinical severity was found for neutrophil and lymphocyte apoptosis, neutropenia and cocci-containing neutrophils. Crucially, apoptotic neutrophils did not contain cocci, and cocci-containing neutrophils were not apoptotic.

Conclusions: The correlation between magnitude of neutrophil apoptosis and severity of IMD suggests a cause-effect relationship. We propose that neutrophil apoptosis is more likely a facilitator rather than an effect of IMD for these reasons: (1) apoptotic neutrophils did not contain cocci and cocci-containing neutrophils were not apoptotic, (2) leucocyte apoptosis is a recognised viral effect and (3) Neisseria meningitidis is incapable of producing a Panton-Valentine type leucocidin. The lymphocyte apoptosis which accompanies neutrophil death may contribute to risk by impairing the generation of microbicidal antibody. Leucocyte apoptosis is a morphological expression of viral immunosuppression and, we suggest, is a likely contributor to a range of viral effects.

Keywords: Apoptosis; Leucocytes; Virus.

Figure 1

Apoptotic neutrophil (left), apoptotic lymphocyte (right), blood film, neonatal herpes simplex viraemia. Reproduced, with permission, from Smith H. Diagnosis in Paediatric Haematology 1996. Churchill-Livingstone ©, Elsevier.

Figure 2

Degenerate neutrophil adherent to monocyte, earlobe blood film, infectious mononucleosis. Reproduced, with permission, from Smith H. Diagnosis in Paediatric Haematology 1996. Churchill-Livingstone ©, Elsevier.

Figure 3

Inclusions of lymphocyte, erythrocyte and neutrophil in advanced degeneration (arrow) in monocyte, earlobe blood film, infectious mononucleosis. Reproduced, with permission, from Smith. Churchill-Livingstone ©, Elsevier.

Figure 4

Neisseria meningitidis within neutrophil, which is well preserved, blood film, invasive meningococcal disease. Courtesy of RG Wells.