Guideline:Infections in β-thalassemia major

Infections are the second commonest cause of death in thalassaemia major. Clinicians involved in the care of thalassaemia will be fully aware of this risk and the importance of any intervention that may limit it (Rahav, Volach et al, 2006). However, all medical and nursing staff, including those with the briefest interaction with patients with thalassaemia, should have the same awareness, as should patients themselves. A basic outline of the effects of infection in thalassaemia and their practical implications are provided in Table 1 (see also Table 2 for more blood-borne infections).

A patient with thalassaemia major must not be considered as immuno-compromised per se, particularly if the disease is well compensated by treatment. On the other hand, many alterations to the body’s immune system have been described in thalassaemia, including reduction in neutrophil numbers, changes in number and function of natural killer cells, increase in number and function of CD8 suppress cells, occurrence of macrophages, chemotaxis and phagocytosis and interferon gamma production.

Even in the absence of any evidence-based data on a direct relationship between these alterations and the development of severe infections in thalassaemia, it is recognised by treating physicians through clinical observations and practice that several factors linked to the disease, its complications and treatment may facilitate or aggravate the severity of infections. Where infection is suspected, the main causes to be considered include:


 * Splenectomy;
 * Transmission of pathogens by blood transfusion;
 * Iron overload and
 * Iron chelation.

Splenectomy
The major long-term risk after splenectomy is overwhelming sepsis. In older studies, the risk of postsplenectomy sepsis in thalassaemia major is increased more than 30-fold in comparison with the normal population (Singer, 1973).

Modern preventative measures (see below) have reduced this risk but the overall impact of these measures is unclear.

The pathogens most commonly associated with post-splenectomy sepsis are encapsulated organisms, particularly:


 * Streptococcus pneumoniae (accounting for more than 75% of documented bacterial infections in asplenic patients);
 * Haemophilus influenzae, and;
 * Neisseria meningitides.

Infections with gram-negative, rod-shaped bacteria, notably Escherichia coli, Klebsiella species (e.g., pneumoniae) and Pseudomonas aeroginosa, occur with increased frequency in asplenic patients and are often associated with high mortality. Other gram-negative organisms have also been implicated in postsplenectomy sepsis.

Protozoan infections due to Babesia have been implicated in a fulminant haemolytic febrile state in splenectomised patients, and

Malaria is repeatedly reported as more severe in asplenic people with an increased risk of death (Boone and Watters, 1995)(for blood-borne infections see Table 2).

Iron overload
''The role of iron load in susceptibility to infection has not yet been fully established in clinical trials. It is clear, however, that a variety of microorganisms are more pathogenic in the presence of iron overload.''

The best-described association between bacterial infection, iron and iron chelators involves Yersinia enterocolitica (see below).

Many other organisms, such as Klebsiella species, Escherichia coli, Streptococcus pneumonia, Pseudomonas aeroginosa, Legionella pneumophila and Listeria monocytogenes, have been shown to have increased virulence in the presence of excess iron. On the other hand, phagocytic efficiency, tested in vitro, is impaired in patients with thalassaemia with iron overload compared with individuals without thalassaemia.

Several observations in vivo indicate that infections are more frequent or severe in patients with iron overload either related to genetic haemochromatosis or to transfusions, as in thalassaemia. The role of iron overload in aggrevating Mucormycosis in bone marrow transplanted patients has been demonstrated.

Iron chelators A potential risk of natural siderophores, as in deferoxamine, is that they may be used by micro-organisms as a source of iron, and so become more virulent. This has been demonstrated in vitro and in vivo for Yersinia enterocolitica, which has a receptor on the outer membrane that efficiently binds ferrioxamine.

A clear relationship between Mucormycosis and desferrioxamine has been reported in dialysis patients but only sporadically in thalassaemia. Similar observations have been reported for Rhizopus infections.

Specific infections

Viral Infections
Human Parvovirus B-19 (HPV B19) Parvovirus B-19 is a common pathogen that may cause a wide range of clinical manifestations: erythema infectiosum or fifth disease in children, mild to severe aplastic crises and myocarditis. During pregnancy severe foetal anaemia and myocarditis may lead to lethal non-immune hydrops fetalis.

In patients with an already shortened red cell lifespan (15-20 days) combined with anaemia due to haematological disorders such as spherocytosis, sickle-cell anaemia,autoimmune haemolytic anaemia and thalassaemia, B-19 infection may cause an acute, life-threatening red cell aplasia, commonly referred to as “transient aplastic crisis”. The cessation of erythropoiesis lasts for 5-7 days and haematologically complicates chronic haemolytic anaemia. The condition is characterised by:


 * A variable fall in haemoglobin;
 * Disappearance of reticulocytes from peripheral blood (< 0.2%);
 * A virtual absence of red blood cell precursors in the bone marrow at the beginning of the crisis and
 * B-19 DNA viraemia.

Following recovery from an acute B-19 infection, patients are typically immune to further infections by the agent. Where patients are immunosuppressed (e.g. transplanted, HIV-infected) and fail to mount an effective antibody response to the virus, the infection may be persistent and may mimic or trigger autoimmune inflammatory disorders.

B-19 may be transmitted via the respiratory system or blood derivates. The incidence of B-19-infected individuals with persistently detectable levels of B-19 DNA, despite the presence of specific IgG, is estimated at 1% of blood donors. The resulting risk of infection is estimated at between 1/625 and 1/50,000, depending on a number of factors (including detection methods, seasonal outbreaks, B-19 DNA load of the donor and co-presence of B-19 IgG antibodies) (Lefrere, Maniez-Montreuil et al, 2006). There is currently no general rule on action to be taken to prevent blood-borne transmission of B-19 in high-risk populations, including thalassaemia major patients.

Management of acute B-19 crises includes close monitoring and adequate blood transfusion adjustment. Immunoglobulin administration may be beneficial in chronic illness.