Life-Threatening Infectious Complications in Sickle Cell Disease: A Concise Narrative Review

Abstract

Sickle cell disease (SCD) results in chronic hemolytic anemia, recurrent vascular occlusion, insidious vital organ deterioration, early mortality, and diminished quality of life. Life-threatening acute physiologic crises may occur on a background of progressive diminishing vital organ function. Sickle hemoglobin polymerizes in the deoxygenated state, resulting in erythrocyte membrane deformation, vascular occlusion, and hemolysis. Vascular occlusion and increased blood viscosity results in functional asplenia and immune deficiency in early childhood, resulting in life-long increased susceptibility to serious bacterial infections. Infection remains a main cause of overall mortality in patients with SCD in low- and middle-income countries due to increased exposure to pathogens, increased co-morbidities such as malnutrition, lower vaccination rates, and diminished access to definitive care, including antibiotics and blood. Thus, the greatest gains in preventing infection-associated mortality can be achieved by addressing these factors for SCD patients in austere environments. In contrast, in high-income countries, perinatal diagnosis of SCD, antimicrobial prophylaxis, vaccination, aggressive use of antibiotics for febrile episodes, and the availability of contemporary critical care resources have resulted in a significant reduction in deaths from infection; however, chronic organ injury is problematic. All clinicians, regardless of their discipline, who assume the care of SCD patients must understand the importance of infectious disease as a contributor to death and disability. In this concise narrative review, we summarize the data that describes the importance of infectious diseases as a contributor to death and disability in SCD and discuss pathophysiology, prevalent organisms, prevention, management of acute episodes of critical illness, and ongoing care.

Keywords: children; critical care; infection; prophylaxis; sepsis; sickle cell disease; vaccination.

Figure 1

Number of newborns with Sickle Cell Anemia is Each Country in 2015. Data are based on estimates from Piel et al. Alaska is shown separately from the rest of the United States. Used with permission from Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med (2017) 376:1561-1573.

Figure 2

Hemolysis-associated hemostatic activation. Intravascular hemolysis releases hemoglobin into plasma which quenches nitric oxide (NO) and generates reactive oxygen species (directly via fenton chemistry or via induction of xanthine oxidase and NADP oxidase). In addition, arginase I is released from the red blood cell during hemolysis and metabolizes arginine, the substrate for NO synthesis, further impairing NO homeostasis. The depletion of NO is associated with pathological platelet activation and tissue factor expression. Hemolysis and splenectomy are also associated with phosphatidylserine exposure on red cells which can activate tissue factor and form a platform for coagulation. Used with permission from Gladwin MT, Kato GJ. Hemolysis-associated hypercoagulability in sickle cell disease: the plot (and blood) thickens! Haematologica (2008) 93:1-3.

Figure 3

Common clinical complications of sickle cell disease. Data are from Rees et al. and Serjeant. Acute complications are shown in boldface type. Used with permission from Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med (2017) 376:1561-1573.