A review of the role of infections in the aetiology of haemolysis in patients with sickle cell diseases: pathogenesis, management, and prevention

ABSTRACT

Background: Sickle cell disease (SCD) is associated with chronic haemolysis, immuno-suppression and susceptibility to infections, which may trigger infection-associated haemolysis (IAH). SCD patients are vulnerable to anaemic effect of IAH due to vicious interaction between pre-existing 'inherited' chronic haemolysis and 'acquired' IAH. IAH in SCD manifests as febrile haemolytic crisis with clinical and laboratory features of severe anaemia or pancytopenia. Clinico-pathological perspectives of IAH in SCD are fragmented. This review presents a comprehensive but concise overview of pathogenesis, management and prevention of IAH in SCD. Methodology and results: Online literature search using search terms such as 'sickle cell disease, viral, bacterial, parasitic, fungal, infections, hyperhaemolytic crisis, haemophagocytic syndrome, severe anaemia, pancytopenia' in various combinations was done on PubMed/Medline, Google, Google-Scholar and Bing. Overall, 112 relevant publications were retrieved, which included 109 peer reviewed journal articles, 2 World Health Organization (WHO) technical reports, and 1 edited text book. A range of bacterial (Bartonella spp, Mycoplasma spp., Mycobacterium avium complex), viral (Dengue, SARS-CoV-2, Parvovirus-B19, Cytomegalovirus, Epstein-Barr virus), parasitic (Plasmodium spp., Babesia spp.), and fungal (Histoplasma spp.) infections were associated with IAH in SCD. There are two broad types of IAH in patients with SCD; infection associated extra-medullary haemolysis (IAEMH) and infection associated intra-medullary haemolysis (IAIMH). While IAEMH is associated with severe anaemia due to intravascular haemolysis caused by red cell invasion, oxidative injury, auto-antibodies, and/or pathogen-haem interaction, IAIMH is associated with haemophagocytic tri-lineage destruction of haematopoietic precursors in the bone marrow. Conclusion: Various microbial pathogens have been associated with IAH in SCD. SCD patients with fever, severe anaemia or pancytopenia should be investigated for early diagnosis and prompt treatment of IAH, which is a lifethreatening haematological emergency for which transfusion therapy alone may not suffice. Prompt and sustainable termination of IAH may require therapeutic combination of transfusion, anti-microbial chemotherapy, and immune modulation therapy. SCD patients should also receive counselling on hygiene, barrier protection against vectors, routine chemoprophylaxis for locally endemic diseases, and immunization for vaccine-preventable infections as a long-term preventive strategy against IAH.