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Infections and thalassaemia
Review
Infections and thalassaemia Sandro Vento, Francesca Cainelli, Francesco Cesario Lancet Infect Dis 2006; 6: 226–33 SV is at the Section of Infectious Diseases, Department of Pathology, University of Verona, Verona, Italy; FCa is a specialist in infectious diseases, Via Vasco de Gama 7, Verona; FCe is at the Infectious Diseases Unit, “Annunziata” Hospital, Cosenza, Italy. Correspondence to: Professor Sandro Vento, Via Vasco de Gama 7, 37138 Verona, Italy. Tel +39 348 7358710; [email protected]
Infections are major complications and constitute the second most common cause of mortality and a main cause of morbidity in patients with thalassaemia, a group of genetic disorders of haemoglobin synthesis characterised by a disturbance of globin chain production. Thalassaemias are among the most common genetic disorders in the world. Predisposing factors for infections in thalassaemic patients include severe anaemia, iron overload, splenectomy, and a range of immune abnormalities. Major causative organisms of bacterial infections in thalassaemic patients are Klebsiella spp in Asia and Yersinia enterocolitica in western countries. Transfusion-associated viral infections (especially hepatitis C) can lead to liver cirrhosis and hepatocellular carcinoma. A unique and challenging infection detected in Asian patients is pythiosis, caused by a fungus-like organism, the mortality rate of which is very high. Because the prognosis for thalassaemia has much improved, with many patients surviving to the fifth decade of life in developed countries, it is mandatory to reduce mortality by recognising and presumptively treating infections in these patients as quickly as possible.
Introduction The term thalassaemia (derived from the Greek “thalassa”, which means “the sea”—referring to the Mediterranean—and “emia”, meaning “related to blood”) indicates a heterogeneous group of genetic disorders of haemoglobin synthesis characterised by a disturbance of the production of globin chains, leading to anaemia, ineffective erythropoiesis, and destruction of erythroblasts in the bone marrow and of erythrocytes in the peripheral blood.1 In individuals that produce normal haemoglobin, two types of polypeptide chains (α and non-α) pair with each other at a ratio close to 1/1 to form normal haemoglobin molecules. In thalassaemic patients, an excess of the normally produced type accumulates in the cell as an unstable product, leading to the destruction of the cell. This imbalance is the hallmark of all forms of thalassaemia. Types of thalassaemia are usually named after the underproduced chain or chains. Thalassaemias are found in all parts of the world, and the often used name “Mediterranean anaemia” is
Malaria Thalassaemia Malaria and thalassaemia
misleading. α-Thalassaemia may be the most common single gene disorder in the world (percentage of gene carriers in the middle east is 5–10%, 20–30% in west Africa, and up to 68% in the South Pacific), although the gene prevalence in northern Europe and Japan is less than 1%.1 In β-thalassaemia, the frequency of the gene is greater than 1% in the Mediterranean basin, India, southeast Asia, north Africa, and Indonesia (figure).4 Clinical severity varies widely, ranging from asymptomatic forms to severe or even fatal entities. In the severe forms of thalassaemia—eg, Cooley’s anaemia or thalassaemia major—the large numbers of abnormal red blood cells processed by the spleen and its haematopoietic response to the anaemia lead to massive splenomegaly and consequent manifestations of hypersplenism, resulting in the need for splenectomy. If chronic anaemia in thalassaemic patients is corrected with regular blood transfusions (with the aim of maintaining the pretransfusional haemoglobin concentration at 9 g/dL or higher), another source of iron is added, which, together with the excessive iron absorption normally present in such cases, leads to a state of iron overload. Iron accumulates in various organs, especially in the heart and the liver, resulting in substantial damage. Morbidity in patients with severe thalassaemia is usually the result of iron-related heart failure, serious infections, or the complications of splenectomy. Bloodborne viral infections (mainly hepatitis C and B), infections with unusual organisms whose presence is favoured by iron overload or by the chelation therapy needed to reduce it, and postsplenectomy infections all contribute substantially to morbidity and mortality in thalassaemic patients, making infections the second most common cause of death after heart failure.5
Factors predisposing to infections Immune abnormalities in thalassaemic patients Figure: Geographic distribution of thalassaemia and malaria in the 1940s (before eradication of malaria in southern Europe) Adapted from references 2 and 3.
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Numerous immune abnormalities have been described in thalassaemic patients (panel 1). As far as T lymphocytes are concerned, greater numbers and activity of CD8 suppressor cells, decreased CD4/CD8 ratio, and reduced http://infection.thelancet.com Vol 6 April 2006
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proliferation have been reported.6–10 B lymphocytes have been found to be increased in numbers, activated, and with impaired differentiation.6,9,11 Increased levels of IgG, IgM, and IgA have also been described,12,13 and neutrophils and macrophages appear to have defects in chemotaxis and phagocytosis.14–16 Finally, reduced levels of the complement components C3 and C412,13 and defective natural killer cell function have been reported. The factors behind these immune alterations are poorly understood, although iron overload may have a prominent role. Long-term receipt of multiple blood transfusions is also thought to be an important cause of immune abnormalities. Indeed, repeated blood transfusions lead to continuous alloantigenic stimulation, and have been associated with autoimmune haemolysis,17 T and B lymphocyte changes,18,19 and modification of monocyte and macrophage functions.14 In a large study done in transfusion-dependent Chinese children with β-thalassaemia, increased T-lymphocyte activation and decreased natural killer cell numbers were found to be prominent features.20 Zinc deficiency, commonly observed in β-thalassaemia, leads to deficient zinc saturation and defective activity of thymulin, a thymic hormone,21 and is thought to cause alterations of lymphocyte subsets and immune deficiency.22 The presence of abnormal erythrocytes with structural changes of the cell membrane in patients with β-thalassaemia is also of importance, since these are continuously cleared by monocytes that are therefore permanently activated.23
Splenectomy-induced immune abnormalities Splenectomy is justified in patients with thalassaemia when the spleen becomes hyperactive, leading to excessive destruction of red blood cells and thus increasing the need for frequent blood transfusions, which in turn results in more iron accumulation. As a result, splenectomy is frequently done, and has been correlated with changes in the immune response. These changes include reduced immune clearance,13 alterations in complement activation, reduced IgM synthesis, lower specific antibody responses,24,25 and further reduced CD4/ CD8 lymphocyte ratio, albeit in the presence of seemingly normal T-cell function. Although all lymphocyte populations are increased in absolute numbers, the percentage of B lymphocytes is higher than normal, while the percentage of T cells is reduced.26–28
Iron overload and bacterial infections Microbial pathogens must obtain growth-essential iron from healthy hosts. Some potential pathogens, however, are so impaired in iron acquisition ability as to be dangerous mainly in hosts with iron loading conditions. Among such organisms are Yersinia enterocolitica, Klebsiella species, Escherichia coli, Streptococcus pneumoniae, http://infection.thelancet.com Vol 6 April 2006
Panel 1: Immune abnormalities underlying susceptibility to infections in thalassaemia ● ● ● ● ● ● ●
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Increased number and activity of CD8 suppressor cells Decreased CD4/CD8 ratio Decreased T-cell proliferation Increased number and activation of B lymphocytes Increased IgG, IgM, and IgA levels Decreased C3 and C4 levels Defective chemotaxis and phagocytosis of neutrophils and macrophages Defective natural killer cell function Increased T-cell activation (blood transfusion-related) Decreased natural killer cell number (blood transfusionrelated) Decreased thymic hormones activity (zinc deficiencyrelated) Decreased antibody response (after splenectomy)
Pseudomonas aeruginosa, Listeria monocytogenes, and Legionella pneumophila, which have increased virulence in vitro in the presence of excess iron.29–32 These organisms’ in-vivo pathogenicity is increased even more by the immune deficiency that results from iron overload. Abnormalities described in conditions characterised by increased iron load (eg, haemochromatosis and thalassaemia) include decreased phagocytosis by the monocyte/macrophage system and by polymorphonuclear leucocytes (due to the deleterious effects of ferritinassociated iron), alterations in T-lymphocyte subsets (increases in the number of CD8 and decreases in CD4 cells), impairment in immunoglobulin secretion, and suppression of complement system function (panel 2).33–36 Although phagocytosis might also be impaired by the development of antiferritin antibodies, which lead to the production of circulating ferritin–antiferritin immune complexes,36 perhaps the most important mechanism by which iron influences immune effector mechanisms is its direct inhibitory effect on the activity of interferon gamma, leading to the loss of ability of iron-loaded macrophages to kill intracellular pathogens via interferon-gamma-mediated Panel 2: Iron overload mechanisms underlying susceptibility to infections in thalassaemia ●
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Inhibited interferon-gamma activity and loss of macrophage capability to kill intracellular pathogens Decreased phagocytosis by monocytes, macrophages, and polymorphonuclear leucocytes Increased CD8 T-cell numbers Decreased CD4 T-cell numbers Impaired immunoglobulin secretion Suppression of complement system function
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pathways. Part of this loss of ability is related to the reduced formation of nitric oxide in the presence of iron. To prevent excessive iron load and its complications, chelation therapy is administered. Desferrioxamine is the most widely used iron chelator; unfortunately, it predisposes to infections by Yersinia spp. The virulenceenhancing effect of desferrioxamine is caused by at least two factors. First, Y enterocolitica possesses an outer membrane protein called FoxA that acts as a receptor for ferrioxamine, the compound produced following the binding of desferrioxamine with free iron.37 Second, desferrioxamine modulates and/or abolishes the action of specific and non-specific immune cells and inhibits cytokine production by macrophages, leading to partial immunosuppression of the host.38 Thus, strains of Y enterocolitica that are of low pathogenicity and that are usually restricted to the digestive tract can use desferrioxamine to obtain iron molecules and benefit from the induced immune deficiency to disseminate in their host and cause systemic infections. By contrast with desferrioxamine, the iron-chelating agent deferiprone appears to have no immunosuppressive effects,39 and rather normalises the abnormally high levels of some cytokines (eg, tumour necrosis factor α, interleukin 2).40 Iron overload can also have adverse effects on the outcome of viral infections. Indeed, the rate of progression of HIV-1 disease is faster in patients with thalassaemia major on low doses of desferrioxamine and high serum ferritin concentrations and with high bone marrow macrophage iron.41
Specific infectious agents Yersinia enterocolitica Clinical reports of desferrioxamine-treated thalassaemic patients that developed fulminant Y enterocolitica septicaemia are numerous.42–45 However, while common in western countries,42,43 Y enterocolitica is an uncommon cause of severe infections in thalassaemic patients in the east.46–48 The reasons underlying these differences are unknown. Clinical manifestations include enterocolitis (which can cause rectal bleeding and perforation of the ileum), polyarthritis, pharyngitis, and tonsillitis. However, the most serious event is septicaemia, with ensuing hepatic or splenic abscesses, osteomyelitis, endocarditis, or meningitis. Mortality of septicaemia is very high and can reach 50%. Intravenous co-trimoxazole (trimethoprim-sulfamethoxazole) for 7 days (14 days in the case of sepsis) should be used for treatment with the eventual addition of gentamicin. Intramuscular ceftriaxone is an alternative in focal infections (eg, enteritis, pharyngitis, tonsillitis). Other active antibiotics include doxycycline and ciprofloxacin. During invasive Y enterocolitica infections, an immediate discontinuation of desferrioxamine treatment is necessary. 228
Klebsiella spp Klebsiella infections have been reported only from Asia, in five patients from China,49–51 and in 12 from Hong Kong who had 15 episodes of infection.52 Wanachiwanawin46 states that 25% of all severe infections in patients with thalassaemia in Thailand are due to Klebsiella spp. Further studies are needed to assess whether klebsiella infections are under-reported from other regions or truly found only in Asian patients. The clinical spectrum includes sinusitis, intracranial infections, septicaemia, and abscesses of the liver, lung, kidney, and parotid gland. Klebsiella infection is associated with high rates of morbidity and mortality: four of the 17 cases mentioned above died, and four of the remaining 13 had permanent neurological deficits. On univariate analysis, high ferritin levels appear to be a risk factor,52 perhaps due to the role of iron in the growth of Klebsiella spp.30 Prompt treatment with appropriate antibiotics and early surgical intervention are mandatory in Klebsiella spp infections in patients with thalassaemia. Active antibiotics include ceftazidime and gentamicin. In case of resistance, fluoroquinolones, imipenem, or meropenem are used. In Asian countries such as Thailand and Taiwan, antibiotics can be easily obtained without a prescription; the ensuing bacterial resistance could at least partly explain the high prevalence of severe and difficult-to-treat infections.
Post-splenectomy infections In a review of all studies published between 1966 and 1996, it was found that the incidence of severe infections (eg, meningitis, pneumonia, sepsis) caused by encapsulated bacteria (S pneumoniae, Haemophilus influenzae type B, Neisseria meningitidis) was highest among splenectomised patients with thalassaemia compared with those individuals splenectomised for trauma (8·2% vs 2·3%), and mortality rates were also highest in splenectomised thalassaemic patients compared with those splenectomised for trauma (5·1% vs 1·1%).53 Children appear to be at particularly high risk (incidence of sepsis was 11·6% and death rate 7·3%). The shortest time interval from splenectomy to infection was also observed among thalassaemic patients (mean 10·5 months, range 0·5–24).53 Other pathogens responsible for post-splenectomy infections include bacteria such as E coli, P aeruginosa,54 group B streptococci, Enterococcus spp, Ehrlichia spp, and protozoa—eg, Plasmodium spp.
Pythiosis insidiosi Pythiosis insidiosi is a very rare human infection caused by Pythium insidiosum, a fungus-like aquatic organism. The infection is relatively common in horses, cattle, cats, and dogs, and is mostly observed in tropical, subtropical, and temperate regions.55 Successful treatment involves surgery and a therapeutic vaccine composed of pythium http://infection.thelancet.com Vol 6 April 2006
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antigens. Infection is thought to occur by invasion of asexual biflagellate zoospores into injured host tissue after consecutive sequences of attachment, encystment, and germination.56 Human pythiosis was first recognised in Thailand in 1985 and a recent review57 has identified 31 published cases of human pythiosis, 25 of which were in Thai people (almost exclusively farmers). Other cases have been reported in Australia, Haiti, India, New Zealand, and the USA. Arterial infection was present in as many as 17 cases, and association with thalassaemia was very common. Three forms of human pythiosis are recognised: (1) cutaneous or subcutaneous pythiosis affecting the periorbital area, face, or limbs as a granulomatous, ulcerating, abscess-like or cellulitic lesion; (2) ophthalmic pythiosis affecting the eyes as corneal ulcers or keratitis; and (3) systemic pythiosis affecting vascular tissue and resulting in arterial occlusions or aneurysms leading to gangrene or vascular rupture, respectively. High morbidity and mortality rates (most patients die within 6 months) are observed in the latter form (which occurs only in Thailand), particularly in patients with arterial lesions proximal to the superficial femoral artery, causing limb amputation or fatal arterial leakage.57 Serological tests58,59 and PCR assays are being developed to facilitate diagnosis.60 Treatment is very difficult. Antifungal drugs (eg, amphotericin B, ketoconazole) have no therapeutic activity against P insidiosum,61 and medical treatment alone is ineffective against systemic or vascular pythiosis.62 Two vaccines for pythiosis have been prepared from either P insidiosum whole cells or soluble concentrated antigens,63 and both achieve cure in recently infected horses, apparently by eliciting strong inflammatory responses with recruitment of natural killer cells and cytotoxic T lymphocytes to infected tissues.64,65 One case report described the use of the vaccine in a 14-year-old Thai boy with P insidiosum arteritis and thalassaemia who was cured of a very serious infection.63 A subsequent study evaluated the use of the same modified P insidiosumantigen formulation in eight patients with life-threatening vascular pythiosis, six of whom had thalassaemia. The vaccine was administered subcutaneously (except the first injection, given intradermally) in four injections at 14 days intervals. Four patients were cured, two had a partial response, and two no response.66
Hepatitis C virus Hepatitis C virus (HCV) infection is a major problem for thalassaemic patients—antibodies to HCV have been reported in 85% of Italian patients with thalassaemia67 and in 23% of patients treated in the UK.68 Multiple episodes of acute hepatitis C have even been experienced by some thalassaemic patients because of the lack of induction of protective immunity following infection and clearance of the virus.69 Screening of http://infection.thelancet.com Vol 6 April 2006
donated blood for HCV—introduced in the early 1990s in developed countries—has considerably reduced the number of infections in young thalassaemic patients. Indeed, data from the registry of the Thalassemia Clinical Research Network indicate that only 5% of patients under the age of 15 years in North America are positive for HCV antibodies or RNA, whereas the prevalence of HCV exposure in those aged over 25 years is 70%.70 Unfortunately, screening of donated blood is not as frequent in low-income countries, where the prevalence of HCV is as high as 63·8% even in young patients with thalassaemia71 and where many patients continue to become infected.72 HCV infection and iron overload are risk factors for cirrhosis and hepatocellular carcinoma. Patients with thalassaemia major or intermediate often experience both of these conditions at a younger age than non-thalassaemic individuals (eg, in the UK, the age at development of hepatocellular carcinoma in thalassaemic patients was found to be lower than the average age of hepatocellular carcinoma development, at 45 years old vs 66 years old).73 Of the two risk factors, iron overload in thalassaemic patients is of greater importance, since a high hepatic iron content favours fibrosis progression and therefore the development of cirrhosis much more than HCV infection per se.74 Borgna-Pignatti and colleagues75 recently presented the only large survey regarding hepatocellular carcinoma in thalassaemic patients, involving 52 centres in Italy. 23 patients (out of an estimated 5000) had hepatocellular carcinoma, and their mean age was 45 years; only one patient had not been exposed to HBV or HCV, and 17 of 19 HCV-exposed individuals had an active (HCV-RNA positive) infection. However, it should be stressed that compliance with desferrioxamine therapy was poor to moderate in all the patients. The survival of patients with hepatocellular carcinoma was negatively associated with tumour size; thus screening of all thalassaemic patients (without or with HBV and/or HCV infections) with liver ultrasound and measurement of serum α-fetoprotein concentrations every 6 months is strongly recommended. What is the rate of spontaneous clearance of HCV in thalassaemic patientss? Data from the registry of the Thalassemia Clinical Research Network indicate a fairly high rate (33%) in North American patients.70 Even if such a considerable rate is correct, the number of patients with chronic infection and liver disease is still very high and therapy needs to be considered. Combination therapy for hepatitis C is based on interferons and ribavirin. However, the latter is contraindicated in thalassaemic patients because haemolysis is a common side-effect of its use, which could lead to increased iron burden and further damage to the liver, outweighing the benefits of clearing HCV. The situation would be even worse in those patients who do not respond to therapy, since they would have both 229
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increased hepatic iron levels and continuing HCV infection. In spite of these considerations and contraindications, studies have been done with combination therapy in patients with thalassaemia major that have shown sustained (6 months after completion of therapy) biochemical and virological response rates of 45·5%76 to 72·2%.77 The increase in transfusion requirements, although variable, may be as high as 152% over baseline.77 Multicentre trials using pegylated interferons (eventually also in combination with ribavirin) in carefully selected individuals are urgently needed to show whether treatment is beneficial not only for liver disease but also for life prolongation. Finally, since the magnitude of hepatic iron overload has been associated with a poor response to antiviral therapy for hepatitis C,78 patients with thalassaemia might respond less to interferon-based therapies. According to one Australian report79 this seems not to be the case; indeed, a durable response can occur in the presence of massive iron overload.
blood units, and more than 25% of infections resolved within 6 years. Active infection did not contribute to hepatocellular damage in patients with β-thalassaemia. It would be interesting to verify whether HGV protects the few coinfected thalassaemic patients from progression of HIV-1 infection, as it does in other patients groups.84
TT virus TT virus (TTV) is a single-stranded, circular DNA virus that is present in a considerable number of individuals and has been proposed to be a factor contributing to fulminant and chronic liver disease. In a study done in Italy,85 69% of thalassaemic patients were found to be infected, the most common TTV genotype being 1b. HCV/TTV-coinfected patients had a significantly higher histological inflammation than patients with HCV monoinfection (p=0·02), but no effect was found on liver fibrosis; by contrast, a French survey86 found no evidence of an influence of TTV infection on chronic liver disease. Further studies with a long-term follow-up are necessary to verify these findings.
Hepatitis B virus Children with thalassaemia have long been considered particularly susceptible to hepatitis B virus (HBV) infection because of their requirement for blood transfusions. The availability of vaccines and the introduction of the screening of transfused blood units for hepatitis B s antigen (HBsAg) have reduced the incidence of this infection, but do not seem to have completely eliminated its occurrence. Indeed, HBV infection is still common in Bangladesh80 and India.72 Interestingly, Singh and colleagues81 reported their experience in 70 patients with β-thalassaemia (median age 6 years), 20 of whom had received transfusions only after vaccination. Four individuals were HBsAg-positive and 14 were positive for antibodies against hepatitis B c antigen. 17 of 70 patients had not responded to vaccination (ie, had a titre of antibodies against HBsAg [anti-HBs] ≤10 IU/L), and 22 patients were HBV DNA-positive in serum. Surprisingly, and worryingly, the frequency of HBV infection was similar in vaccine responders and non-responders and a number of mutations were observed in the hepatitis B s gene that could have influenced acquisition of the infection in the presence of anti-HBs. In those thalassaemic patients with progressive chronic hepatitis B, interferon therapy should be tried,82 although appropriate trials are lacking and no data are available on the use of pegylated interferons.
Hepatitis G virus/GB virus C In a prospective study83 done during the 1990s in multitransfused β-thalassaemic patients, 14·5% of patients were found to have hepatitis G virus (HGV, also known as GB virus C) viraemia at baseline and 10% acquired the infection during follow-up. The risk of infection was estimated to be 5·3 per 10 000 transfused 230
Malaria and α-thalassaemia The suggestion that α-thalassaemia has been selected by malaria has long been put forward on the basis of epidemiological studies and of a largely overlapping geographic distribution (figure). A close altitudedependent and latitude-dependent correlation between the frequency of α-thalassaemia and the endemicity of Plasmodium falciparum was found in the southwest Pacific,87,88 and the markedly decreased incidence of malaria in the Tharu people of southern Nepal was also ascribed to a high incidence of α-thalassaemia.89 In the north coast of Papua New Guinea, α-thalassaemia protects children against both severe malaria and even from non-malarial infectious illnesses.90 Finally, a large case-control study done in children living on the coast of Kenya has most recently demonstrated that α-thalassaemia is associated with a reduced risk of both severe and fatal falciparum malaria.91 Parasite growth is unimpaired in thalassaemic red blood cells,92 and alternative explanations have therefore been sought for the protective effect of thalassaemia from severe malaria, including possible enhanced susceptibility in very young Melanesian α-thalassaemic children to Plasmodium vivax, which would be the basis for protection from severe falciparum malaria later in life.93 In Ghana, where P vivax is virtually absent, pregnant women with α-thalassaemia appear to have increased susceptibility to Plasmodium malariae infection, which might similarly be responsible for the milder courses of falciparum malaria in the same women.94 11 years ago, Carlson and coworkers95 proposed the major protective mechanism from severe malaria was the impaired ability of red blood cells to rosette, an adhesion property in which parasitised erythrocytes bind to unparasitised red blood cells to form clumps of cells http://infection.thelancet.com Vol 6 April 2006
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Search strategy and selection criteria Data for this review were identified by searches of Medline, Current Contents, and references from relevant articles; numerous articles were identified through searches of the authors’ extensive files. Searches were done for the period 1970–2005 combining the terms “thalassaemia” and “infections”, “bacterial infections”, “viral infections”, “fungal infections”, “treatment”, and “immunology”. Papers were selected on the basis of the best level of available evidence for each specific aspect discussed. Only English language papers were included.
that cause microvascular obstruction and impaired tissue perfusion. It now appears that a promoter polymorphism of red cell complement receptor 1 (an essential receptor for rosetting) is significantly associated with protection from severe falciparum malaria (p=0·01), and that α-thalassaemia is independently associated with the reduced expression of this receptor, at least in Melanesian populations.96 An intriguing study of 405 Nigerian children has added an important piece to the puzzle of the relations between thalassaemia and malaria. In vitro, the sensitivity to chloroquine of P falciparum infecting α-thalassaemic erythrocytes is reduced; in vivo, among children with chloroquine in the blood and in spite of comparable concentrations, α-thalassaemic individuals have a higher prevalence of elevated parasitaemia than nonthalassaemic children.97 Hence protection against severe malaria conferred by α-thalassaemia may be obscured in areas of high chloroquine use; in addition, α-thalassaemia may contribute to the spread of chloroquine resistance.
Conclusions Clinicians must be aware of the potential life-threatening infections of patients with thalassaemia major, especially if splenectomised. Predisposing factors for infections such as severe anaemia and iron overload should be controlled by regular blood transfusions and proper ironchelating therapy in countries that can afford these expensive treatments, and patients should be educated to seek early care when fever develops. Fever without any apparent cause, especially when associated with diarrhoea, should be treated with co-trimoxazole and gentamicin (active against Y enterocolitica), even when culture results are negative. Postsplenectomy risk of sepsis due to encapsulated organisms and of severe malaria98 in endemic areas is a major concern. Presplenectomy immunisations 2 weeks before surgery with pneumococcal vaccines (with boosters every 5–10 years thereafter, as dictated by antibody titres), and H influenzae type B, and meningococcal serogroup C conjugated vaccines are mandatory. Aggressive treatment with antibiotics should always be administered for any febrile illness while http://infection.thelancet.com Vol 6 April 2006
awaiting the results of cultures, and patients travelling to areas endemic for malaria should be especially advised to take appropriate chemoprophylaxis. Hepatitis B must be prevented through vaccination, and treatment with pegylated interferon should be pursued to try to limit the development of cirrhosis and hepatocellular carcinoma in thalassaemic patients with chronic hepatitis B or C. Finally, it must be considered that a number of thalassaemic patients have implantable vascular access devices (commonly placed in younger patients for reliable transfusion access and in older patients to allow 24-hour chelation for heart disease, or because of severe local reactions to desferrioxamine),99 and sepsis due to catheterrelated infections (Staphylococcus spp, Stenotrophomonas spp, E coli, Candida spp, and Enterococcus spp) can occur in a sizeable proportion of these patients.70 It is therefore essential that, at each visit, these patients are asked about symptoms that might indicate a catheter infection (eg, fever, exudate, pain, erythema, swelling), and the port site and catheter track are examined for signs of infection. Optimal treatment for thalassaemia, with advances in erythrocyte transfusion and iron chelation therapy, has greatly increased the probability of a long survival of good quality. Indeed many patients survive to the fifth decade of life. Unfortunately, optimal treatment is expensive and available only for a minority of patients in the world. Haematopoietic stem cell transplantation, the only known curative treatment, is recommended only for selected patients and its outcome is poor in the presence of hepatomegaly, portal fibrosis, and ineffective chelation.100 Infections, albeit largely treatable the world over, still claim the lives of too many thalassaemic patients, and every effort must be made for appropriate prevention and therapy. Conflicts of interest We declare that we have no conflicts of interest. References 1 Higgs DR, Thein SL, Woods WG. The molecular pathology of the thalassaemias. In: Weatherall DJ, Clegg B, eds. The thalassaemia syndromes, 4th ed. Oxford: Blackwell Science, 2001: 133–91. 2 Boyd MF, ed. Malariology. Philadelphia: Saunders, 1949. 3 Silvestroni E, Bianco I, eds. Le emoglobine umane. “De genetica medica”. Rome: Istituto Gregorio Mendel, 1963. 4 Angastiniotis M, Modell B. Global epidemiology of haemoglobin disorders. Ann N Y Acad Sci 1998; 850: 251–69. 5 Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004; 89: 1187–93. 6 Dwyer J, Wood C, McNamara J, et al. Abnormalities in the immune system of children with beta-thalassemia major. Clin Exp Immunol 1987; 68: 621–29. 7 Khalifa AS, Maged Z, Khalil R, et al. T-cell functions in infants and children with beta-thalassemia. Acta Haematol 1988; 79: 153–56. 8 Ezer U, Gulderen F, Culha VK, et al. Immunological status of thalassemia syndrome. Pediatr Hematol Oncol 2002; 19: 51–58. 9 Dua D, Choudhury M, Prakash K. Altered T and B lymphocytes in multitransfused patients of thalassemia major. Indian Pediatr 1993; 30: 893–96.
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Vanittanakom N, Supabandhu J, Khamwan C, et al. Identification of emerging human.pathogenic Pythium insidiosum by serological and molecular assay-based methods. J Clin Microbiol 2004; 42: 3970–74. Sekhon AS, Padhye AA, Garg AK. In vitro sensitivity of Penicillium marneffei and Pythium insidiosum to various antifungal agents. Eur J Epidemiol 1992; 8: 427–32. Wanachiwanawin W, Thianprasit M, Fucharoen S, et al. Fatal arteritis due to Pythium insidiosum infection in patients with thalassemia. Trans R Soc Trop Med Hyg 1993; 87: 296–98. Thitithanyanont A, Mendoza L, Chuansumrit A, et al. Use of an immunotherapeutic vaccine to treat a life-threatening human arteritic infection caused by Pythium insidiosum. Clin Infect Dis 1998; 27: 1394–400. Gudding R, Lund A. Immunoprophylaxis of bovine dermatophytosis. Can J Vet 1996; 36: 302–06. Mendoza L, Villalobus J, Calleja CE, Solis O. Evaluation of two vaccines for the treatment of pythiosis insidiosi in horses. Mycopathologia 1992; 118: 89–95. Wanachiwanawin W, Mendoza L, Visuthisakchai S, et al. Efficacy of immunotherapy using antigens of Pythium insidiosum in the treatment of vascular pythiosis in humans. Vaccine 2004; 22: 3613–21. Prati D. Benefits and complications of regular blood transfusion in patients with beta-thalassemia major. Vox Sang 2000; 79: 129–37. Wonke B, Hoffbrand AV, Brown D, Dusheiko G. Antibody to hepatitis C virus in multiply transfused patients with thalassaemia major. J Clin Pathol 1990; 43: 638–40. Lai ME, Mazzoleni AP, Argiolu F, et al. Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children. Lancet 1994; 343: 388–90. Cunningham MJ, Macklin EA, Neufeld EJ, Cohen AR; Thalassemia Clinical Research Network. Complications of beta-thalassemia major in North America. Blood 2004; 104: 34–39. Ansar MM, Kooloobandi A. Prevalence of hepatitis C virus infection in thalassemia and haemodialysis patients in north Iran-Rasht. J Viral Hepat 2002; 9: 390–92. Irshad M, Peter S. Spectrum of viral hepatitis in thalassemic children receiving multiple blood transfusions. Indian J Gastroenterol 2002; 21: 183–84. Ryder SD; British Society of Gastroenterology. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults. Gut 2003; 52 (suppl 3): 1–8. Angelucci E, Muretto P, Nicolucci A, et al. Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation. Blood 2002; 100: 17–21. Borgna-Pignatti C, Vergine G, Lombardo T, et al. Hepatocellular carcinoma in the thalassaemia syndromes. Br J Haematol 2004; 124: 114–17. Telfer PT, Garson JA, Whitby K, et al. Combination therapy with interferon alpha and ribavirin for chronic hepatitis C virus infection in thalassaemic patients. Br J Haematol 1997; 98: 850–55. Li CK, Chan PK, Ling SC, Ha SY. Interferon and ribavirin as frontline treatment for chronic hepatitis C infection in thalassaemia major. Br J Haematol 2002; 117: 755–58. Fargion S, Fracanzani AL, Rossini A, et al. Iron reduction and sustained response to interferon-alpha therapy in patients with chronic hepatitis C: results of an Italian multicenter randomized study. Am J Gastroenterol 2002; 97: 1204–10. Sievert W, Pianko S, Warner S, et al. Hepatic iron overload does not prevent a sustained virological response to interferon-alpha therapy: a long term follow-up study in hepatitis C-infected patients with beta thalassemia major. Am J Gastroenterol 2002; 97: 982–87. Mollah AH, Nahar N, Siddique MA, Anwar KS, Hassan T, Azam MG. Common transfusion-transmitted infectious agents among thalassaemic children in Bangladesh. J Health Popul Nutr 2003; 21: 67–71.
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Singh H, Pradhan M, Singh RL, et al. High frequency of hepatitis B virus infection in patients with beta-thalassemia receiving multiple transfusions. Vox Sang 2003; 84: 292–99. 82 Uysal Z, Cin S, Arcasoy A, Akar N. Interferon treatment of hepatitis B and C in beta-thalassemia. Pediatr Hematol Oncol 1995; 12: 87–89. 83 Prati D, Zanella A, Bosoni P, et al. The incidence and natural course of transfusion-associated GB virus C/hepatitis G virus infection in a cohort of thalassemic patients. Blood 1998; 91: 774–77. 84 Williams CF, Klinzman D, Yamashita TE, et al. Persistent GB virus C infection and survival in HIV-infected men. N Engl J Med 2004; 350: 981–90. 85 Sampietro M, Tavazzi D, Martinez di Montemuros F, et al. TT virus infection in adult beta-thalassemia major patients. Haematologica 2001; 86: 39–43. 86 Lefrere JJ, Roudot-Thoraval F, Lefrere F, et al. Natural history of the TT virus infection through follow-up of TTV DNA-positive multipletransfused patients. Blood 2000; 95: 347–51. 87 Flint J, Hill AVS, Bowden DK, et al. High frequencies of alphathalassaemia are the result of natural selection by malaria. Nature 1986; 321: 744–50. 88 Yenchitsomanus P, Summers KM, Board PG, et al. Alphathalassemia in Papua New Guinea. Hum Genet 1986; 74: 432–37. 89 Terrenato L, Shrestha S, Dixit KA, et al. Decreased malaria morbidity in the Tharu people compared to sympatric populations in Nepal. Ann Trop Med Parasitol 1988; 82: 1–11. 90 Allen SJ, O’Donnell A, Alexander NDE, et al. α+-thalassaemia protects children against disease caused by other infections as well as malaria. Proc Natl Acad Sci USA 1997; 94: 14736–41. 91 Williams TN, Wambua S, Uyoga S, et al. Both heterozygous and homozygous α+ thalassemia protect against severe and fatal Plasmodium falciparum malaria on the coast of Kenya. Blood 2005; 106: 368–71. 92 Luzzi GA, Torii M, Aikawa M, Pasvol G. Unrestricted growth of Plasmodium falciparum in microcytic erythrocytes in iron deficiency and thalassaemia. Br J Haematol 1990; 74: 519–24. 93 Williams TN, Maitland K, Bennett S, et al. High incidence of malaria in α-thalassaemic children. Nature 1996; 383: 522–25. 94 Mockenhaupt FP, Rong B, Till H, Thompson WNA, Bienzle U. Short report: increased susceptibility to Plasmodium malariae in pregnant α+-thalassaemic women. Am J Trop Med Hyg 2001; 64: 6–8. 95 Carlson J, Nash GB, Gabutti V, al-Yaman F, Wahlgren M. Natural protection against severe Plasmodium falciparum malaria due to impaired rosette formation. Blood 1994; 84: 3909–14. 96 Cockburn IA, Mackinnon MJ, O’Donnell A, et al. A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria. Proc Natl Acad Sci USA 2004; 101: 272–77. 97 Mockenhaupt FP, May J, Bergqvist Y, Meyer CG, Falusi AG, Bienzle U. Evidence for a reduced effect of chloroquine against Plasmodium falciparum in alpha-thalassaemic children. Trop Med Int Health 2001; 6: 102–07. 98 Petithory JC, Khelil A, Galeazzi G, Ardoin F. Malaria in splenectomized patients. Three fatal cases. Presse Med 2005; 34: 519–21. 99 Davis BA, Porter JP. Long-term outcome of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in highrisk beta thalassemia. Blood 2000; 95: 1229–36. 100 Gaziev J, Sodani P, Polchi P, Andreani M, Lucarelli G. Bone marrow transplantation in adults with thalassemia: treatment and long-term follow-up. Ann NY Acad Sci 2005; 1054: 196–205.
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Infections and thalassaemia Sandro Vento, Francesca Cainelli, Francesco Cesario Lancet Infect Dis 2006; 6: 226–33 SV is at the Section of Infectious Diseases, Department of Pathology, University of Verona, Verona, Italy; FCa is a specialist in infectious diseases, Via Vasco de Gama 7, Verona; FCe is at the Infectious Diseases Unit, “Annunziata” Hospital, Cosenza, Italy. Correspondence to: Professor Sandro Vento, Via Vasco de Gama 7, 37138 Verona, Italy. Tel +39 348 7358710; [email protected]
Infections are major complications and constitute the second most common cause of mortality and a main cause of morbidity in patients with thalassaemia, a group of genetic disorders of haemoglobin synthesis characterised by a disturbance of globin chain production. Thalassaemias are among the most common genetic disorders in the world. Predisposing factors for infections in thalassaemic patients include severe anaemia, iron overload, splenectomy, and a range of immune abnormalities. Major causative organisms of bacterial infections in thalassaemic patients are Klebsiella spp in Asia and Yersinia enterocolitica in western countries. Transfusion-associated viral infections (especially hepatitis C) can lead to liver cirrhosis and hepatocellular carcinoma. A unique and challenging infection detected in Asian patients is pythiosis, caused by a fungus-like organism, the mortality rate of which is very high. Because the prognosis for thalassaemia has much improved, with many patients surviving to the fifth decade of life in developed countries, it is mandatory to reduce mortality by recognising and presumptively treating infections in these patients as quickly as possible.
Introduction The term thalassaemia (derived from the Greek “thalassa”, which means “the sea”—referring to the Mediterranean—and “emia”, meaning “related to blood”) indicates a heterogeneous group of genetic disorders of haemoglobin synthesis characterised by a disturbance of the production of globin chains, leading to anaemia, ineffective erythropoiesis, and destruction of erythroblasts in the bone marrow and of erythrocytes in the peripheral blood.1 In individuals that produce normal haemoglobin, two types of polypeptide chains (α and non-α) pair with each other at a ratio close to 1/1 to form normal haemoglobin molecules. In thalassaemic patients, an excess of the normally produced type accumulates in the cell as an unstable product, leading to the destruction of the cell. This imbalance is the hallmark of all forms of thalassaemia. Types of thalassaemia are usually named after the underproduced chain or chains. Thalassaemias are found in all parts of the world, and the often used name “Mediterranean anaemia” is
Malaria Thalassaemia Malaria and thalassaemia
misleading. α-Thalassaemia may be the most common single gene disorder in the world (percentage of gene carriers in the middle east is 5–10%, 20–30% in west Africa, and up to 68% in the South Pacific), although the gene prevalence in northern Europe and Japan is less than 1%.1 In β-thalassaemia, the frequency of the gene is greater than 1% in the Mediterranean basin, India, southeast Asia, north Africa, and Indonesia (figure).4 Clinical severity varies widely, ranging from asymptomatic forms to severe or even fatal entities. In the severe forms of thalassaemia—eg, Cooley’s anaemia or thalassaemia major—the large numbers of abnormal red blood cells processed by the spleen and its haematopoietic response to the anaemia lead to massive splenomegaly and consequent manifestations of hypersplenism, resulting in the need for splenectomy. If chronic anaemia in thalassaemic patients is corrected with regular blood transfusions (with the aim of maintaining the pretransfusional haemoglobin concentration at 9 g/dL or higher), another source of iron is added, which, together with the excessive iron absorption normally present in such cases, leads to a state of iron overload. Iron accumulates in various organs, especially in the heart and the liver, resulting in substantial damage. Morbidity in patients with severe thalassaemia is usually the result of iron-related heart failure, serious infections, or the complications of splenectomy. Bloodborne viral infections (mainly hepatitis C and B), infections with unusual organisms whose presence is favoured by iron overload or by the chelation therapy needed to reduce it, and postsplenectomy infections all contribute substantially to morbidity and mortality in thalassaemic patients, making infections the second most common cause of death after heart failure.5
Factors predisposing to infections Immune abnormalities in thalassaemic patients Figure: Geographic distribution of thalassaemia and malaria in the 1940s (before eradication of malaria in southern Europe) Adapted from references 2 and 3.
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Numerous immune abnormalities have been described in thalassaemic patients (panel 1). As far as T lymphocytes are concerned, greater numbers and activity of CD8 suppressor cells, decreased CD4/CD8 ratio, and reduced http://infection.thelancet.com Vol 6 April 2006
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proliferation have been reported.6–10 B lymphocytes have been found to be increased in numbers, activated, and with impaired differentiation.6,9,11 Increased levels of IgG, IgM, and IgA have also been described,12,13 and neutrophils and macrophages appear to have defects in chemotaxis and phagocytosis.14–16 Finally, reduced levels of the complement components C3 and C412,13 and defective natural killer cell function have been reported. The factors behind these immune alterations are poorly understood, although iron overload may have a prominent role. Long-term receipt of multiple blood transfusions is also thought to be an important cause of immune abnormalities. Indeed, repeated blood transfusions lead to continuous alloantigenic stimulation, and have been associated with autoimmune haemolysis,17 T and B lymphocyte changes,18,19 and modification of monocyte and macrophage functions.14 In a large study done in transfusion-dependent Chinese children with β-thalassaemia, increased T-lymphocyte activation and decreased natural killer cell numbers were found to be prominent features.20 Zinc deficiency, commonly observed in β-thalassaemia, leads to deficient zinc saturation and defective activity of thymulin, a thymic hormone,21 and is thought to cause alterations of lymphocyte subsets and immune deficiency.22 The presence of abnormal erythrocytes with structural changes of the cell membrane in patients with β-thalassaemia is also of importance, since these are continuously cleared by monocytes that are therefore permanently activated.23
Splenectomy-induced immune abnormalities Splenectomy is justified in patients with thalassaemia when the spleen becomes hyperactive, leading to excessive destruction of red blood cells and thus increasing the need for frequent blood transfusions, which in turn results in more iron accumulation. As a result, splenectomy is frequently done, and has been correlated with changes in the immune response. These changes include reduced immune clearance,13 alterations in complement activation, reduced IgM synthesis, lower specific antibody responses,24,25 and further reduced CD4/ CD8 lymphocyte ratio, albeit in the presence of seemingly normal T-cell function. Although all lymphocyte populations are increased in absolute numbers, the percentage of B lymphocytes is higher than normal, while the percentage of T cells is reduced.26–28
Iron overload and bacterial infections Microbial pathogens must obtain growth-essential iron from healthy hosts. Some potential pathogens, however, are so impaired in iron acquisition ability as to be dangerous mainly in hosts with iron loading conditions. Among such organisms are Yersinia enterocolitica, Klebsiella species, Escherichia coli, Streptococcus pneumoniae, http://infection.thelancet.com Vol 6 April 2006
Panel 1: Immune abnormalities underlying susceptibility to infections in thalassaemia ● ● ● ● ● ● ●
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Increased number and activity of CD8 suppressor cells Decreased CD4/CD8 ratio Decreased T-cell proliferation Increased number and activation of B lymphocytes Increased IgG, IgM, and IgA levels Decreased C3 and C4 levels Defective chemotaxis and phagocytosis of neutrophils and macrophages Defective natural killer cell function Increased T-cell activation (blood transfusion-related) Decreased natural killer cell number (blood transfusionrelated) Decreased thymic hormones activity (zinc deficiencyrelated) Decreased antibody response (after splenectomy)
Pseudomonas aeruginosa, Listeria monocytogenes, and Legionella pneumophila, which have increased virulence in vitro in the presence of excess iron.29–32 These organisms’ in-vivo pathogenicity is increased even more by the immune deficiency that results from iron overload. Abnormalities described in conditions characterised by increased iron load (eg, haemochromatosis and thalassaemia) include decreased phagocytosis by the monocyte/macrophage system and by polymorphonuclear leucocytes (due to the deleterious effects of ferritinassociated iron), alterations in T-lymphocyte subsets (increases in the number of CD8 and decreases in CD4 cells), impairment in immunoglobulin secretion, and suppression of complement system function (panel 2).33–36 Although phagocytosis might also be impaired by the development of antiferritin antibodies, which lead to the production of circulating ferritin–antiferritin immune complexes,36 perhaps the most important mechanism by which iron influences immune effector mechanisms is its direct inhibitory effect on the activity of interferon gamma, leading to the loss of ability of iron-loaded macrophages to kill intracellular pathogens via interferon-gamma-mediated Panel 2: Iron overload mechanisms underlying susceptibility to infections in thalassaemia ●
●
● ● ● ●
Inhibited interferon-gamma activity and loss of macrophage capability to kill intracellular pathogens Decreased phagocytosis by monocytes, macrophages, and polymorphonuclear leucocytes Increased CD8 T-cell numbers Decreased CD4 T-cell numbers Impaired immunoglobulin secretion Suppression of complement system function
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pathways. Part of this loss of ability is related to the reduced formation of nitric oxide in the presence of iron. To prevent excessive iron load and its complications, chelation therapy is administered. Desferrioxamine is the most widely used iron chelator; unfortunately, it predisposes to infections by Yersinia spp. The virulenceenhancing effect of desferrioxamine is caused by at least two factors. First, Y enterocolitica possesses an outer membrane protein called FoxA that acts as a receptor for ferrioxamine, the compound produced following the binding of desferrioxamine with free iron.37 Second, desferrioxamine modulates and/or abolishes the action of specific and non-specific immune cells and inhibits cytokine production by macrophages, leading to partial immunosuppression of the host.38 Thus, strains of Y enterocolitica that are of low pathogenicity and that are usually restricted to the digestive tract can use desferrioxamine to obtain iron molecules and benefit from the induced immune deficiency to disseminate in their host and cause systemic infections. By contrast with desferrioxamine, the iron-chelating agent deferiprone appears to have no immunosuppressive effects,39 and rather normalises the abnormally high levels of some cytokines (eg, tumour necrosis factor α, interleukin 2).40 Iron overload can also have adverse effects on the outcome of viral infections. Indeed, the rate of progression of HIV-1 disease is faster in patients with thalassaemia major on low doses of desferrioxamine and high serum ferritin concentrations and with high bone marrow macrophage iron.41
Specific infectious agents Yersinia enterocolitica Clinical reports of desferrioxamine-treated thalassaemic patients that developed fulminant Y enterocolitica septicaemia are numerous.42–45 However, while common in western countries,42,43 Y enterocolitica is an uncommon cause of severe infections in thalassaemic patients in the east.46–48 The reasons underlying these differences are unknown. Clinical manifestations include enterocolitis (which can cause rectal bleeding and perforation of the ileum), polyarthritis, pharyngitis, and tonsillitis. However, the most serious event is septicaemia, with ensuing hepatic or splenic abscesses, osteomyelitis, endocarditis, or meningitis. Mortality of septicaemia is very high and can reach 50%. Intravenous co-trimoxazole (trimethoprim-sulfamethoxazole) for 7 days (14 days in the case of sepsis) should be used for treatment with the eventual addition of gentamicin. Intramuscular ceftriaxone is an alternative in focal infections (eg, enteritis, pharyngitis, tonsillitis). Other active antibiotics include doxycycline and ciprofloxacin. During invasive Y enterocolitica infections, an immediate discontinuation of desferrioxamine treatment is necessary. 228
Klebsiella spp Klebsiella infections have been reported only from Asia, in five patients from China,49–51 and in 12 from Hong Kong who had 15 episodes of infection.52 Wanachiwanawin46 states that 25% of all severe infections in patients with thalassaemia in Thailand are due to Klebsiella spp. Further studies are needed to assess whether klebsiella infections are under-reported from other regions or truly found only in Asian patients. The clinical spectrum includes sinusitis, intracranial infections, septicaemia, and abscesses of the liver, lung, kidney, and parotid gland. Klebsiella infection is associated with high rates of morbidity and mortality: four of the 17 cases mentioned above died, and four of the remaining 13 had permanent neurological deficits. On univariate analysis, high ferritin levels appear to be a risk factor,52 perhaps due to the role of iron in the growth of Klebsiella spp.30 Prompt treatment with appropriate antibiotics and early surgical intervention are mandatory in Klebsiella spp infections in patients with thalassaemia. Active antibiotics include ceftazidime and gentamicin. In case of resistance, fluoroquinolones, imipenem, or meropenem are used. In Asian countries such as Thailand and Taiwan, antibiotics can be easily obtained without a prescription; the ensuing bacterial resistance could at least partly explain the high prevalence of severe and difficult-to-treat infections.
Post-splenectomy infections In a review of all studies published between 1966 and 1996, it was found that the incidence of severe infections (eg, meningitis, pneumonia, sepsis) caused by encapsulated bacteria (S pneumoniae, Haemophilus influenzae type B, Neisseria meningitidis) was highest among splenectomised patients with thalassaemia compared with those individuals splenectomised for trauma (8·2% vs 2·3%), and mortality rates were also highest in splenectomised thalassaemic patients compared with those splenectomised for trauma (5·1% vs 1·1%).53 Children appear to be at particularly high risk (incidence of sepsis was 11·6% and death rate 7·3%). The shortest time interval from splenectomy to infection was also observed among thalassaemic patients (mean 10·5 months, range 0·5–24).53 Other pathogens responsible for post-splenectomy infections include bacteria such as E coli, P aeruginosa,54 group B streptococci, Enterococcus spp, Ehrlichia spp, and protozoa—eg, Plasmodium spp.
Pythiosis insidiosi Pythiosis insidiosi is a very rare human infection caused by Pythium insidiosum, a fungus-like aquatic organism. The infection is relatively common in horses, cattle, cats, and dogs, and is mostly observed in tropical, subtropical, and temperate regions.55 Successful treatment involves surgery and a therapeutic vaccine composed of pythium http://infection.thelancet.com Vol 6 April 2006
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antigens. Infection is thought to occur by invasion of asexual biflagellate zoospores into injured host tissue after consecutive sequences of attachment, encystment, and germination.56 Human pythiosis was first recognised in Thailand in 1985 and a recent review57 has identified 31 published cases of human pythiosis, 25 of which were in Thai people (almost exclusively farmers). Other cases have been reported in Australia, Haiti, India, New Zealand, and the USA. Arterial infection was present in as many as 17 cases, and association with thalassaemia was very common. Three forms of human pythiosis are recognised: (1) cutaneous or subcutaneous pythiosis affecting the periorbital area, face, or limbs as a granulomatous, ulcerating, abscess-like or cellulitic lesion; (2) ophthalmic pythiosis affecting the eyes as corneal ulcers or keratitis; and (3) systemic pythiosis affecting vascular tissue and resulting in arterial occlusions or aneurysms leading to gangrene or vascular rupture, respectively. High morbidity and mortality rates (most patients die within 6 months) are observed in the latter form (which occurs only in Thailand), particularly in patients with arterial lesions proximal to the superficial femoral artery, causing limb amputation or fatal arterial leakage.57 Serological tests58,59 and PCR assays are being developed to facilitate diagnosis.60 Treatment is very difficult. Antifungal drugs (eg, amphotericin B, ketoconazole) have no therapeutic activity against P insidiosum,61 and medical treatment alone is ineffective against systemic or vascular pythiosis.62 Two vaccines for pythiosis have been prepared from either P insidiosum whole cells or soluble concentrated antigens,63 and both achieve cure in recently infected horses, apparently by eliciting strong inflammatory responses with recruitment of natural killer cells and cytotoxic T lymphocytes to infected tissues.64,65 One case report described the use of the vaccine in a 14-year-old Thai boy with P insidiosum arteritis and thalassaemia who was cured of a very serious infection.63 A subsequent study evaluated the use of the same modified P insidiosumantigen formulation in eight patients with life-threatening vascular pythiosis, six of whom had thalassaemia. The vaccine was administered subcutaneously (except the first injection, given intradermally) in four injections at 14 days intervals. Four patients were cured, two had a partial response, and two no response.66
Hepatitis C virus Hepatitis C virus (HCV) infection is a major problem for thalassaemic patients—antibodies to HCV have been reported in 85% of Italian patients with thalassaemia67 and in 23% of patients treated in the UK.68 Multiple episodes of acute hepatitis C have even been experienced by some thalassaemic patients because of the lack of induction of protective immunity following infection and clearance of the virus.69 Screening of http://infection.thelancet.com Vol 6 April 2006
donated blood for HCV—introduced in the early 1990s in developed countries—has considerably reduced the number of infections in young thalassaemic patients. Indeed, data from the registry of the Thalassemia Clinical Research Network indicate that only 5% of patients under the age of 15 years in North America are positive for HCV antibodies or RNA, whereas the prevalence of HCV exposure in those aged over 25 years is 70%.70 Unfortunately, screening of donated blood is not as frequent in low-income countries, where the prevalence of HCV is as high as 63·8% even in young patients with thalassaemia71 and where many patients continue to become infected.72 HCV infection and iron overload are risk factors for cirrhosis and hepatocellular carcinoma. Patients with thalassaemia major or intermediate often experience both of these conditions at a younger age than non-thalassaemic individuals (eg, in the UK, the age at development of hepatocellular carcinoma in thalassaemic patients was found to be lower than the average age of hepatocellular carcinoma development, at 45 years old vs 66 years old).73 Of the two risk factors, iron overload in thalassaemic patients is of greater importance, since a high hepatic iron content favours fibrosis progression and therefore the development of cirrhosis much more than HCV infection per se.74 Borgna-Pignatti and colleagues75 recently presented the only large survey regarding hepatocellular carcinoma in thalassaemic patients, involving 52 centres in Italy. 23 patients (out of an estimated 5000) had hepatocellular carcinoma, and their mean age was 45 years; only one patient had not been exposed to HBV or HCV, and 17 of 19 HCV-exposed individuals had an active (HCV-RNA positive) infection. However, it should be stressed that compliance with desferrioxamine therapy was poor to moderate in all the patients. The survival of patients with hepatocellular carcinoma was negatively associated with tumour size; thus screening of all thalassaemic patients (without or with HBV and/or HCV infections) with liver ultrasound and measurement of serum α-fetoprotein concentrations every 6 months is strongly recommended. What is the rate of spontaneous clearance of HCV in thalassaemic patientss? Data from the registry of the Thalassemia Clinical Research Network indicate a fairly high rate (33%) in North American patients.70 Even if such a considerable rate is correct, the number of patients with chronic infection and liver disease is still very high and therapy needs to be considered. Combination therapy for hepatitis C is based on interferons and ribavirin. However, the latter is contraindicated in thalassaemic patients because haemolysis is a common side-effect of its use, which could lead to increased iron burden and further damage to the liver, outweighing the benefits of clearing HCV. The situation would be even worse in those patients who do not respond to therapy, since they would have both 229
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increased hepatic iron levels and continuing HCV infection. In spite of these considerations and contraindications, studies have been done with combination therapy in patients with thalassaemia major that have shown sustained (6 months after completion of therapy) biochemical and virological response rates of 45·5%76 to 72·2%.77 The increase in transfusion requirements, although variable, may be as high as 152% over baseline.77 Multicentre trials using pegylated interferons (eventually also in combination with ribavirin) in carefully selected individuals are urgently needed to show whether treatment is beneficial not only for liver disease but also for life prolongation. Finally, since the magnitude of hepatic iron overload has been associated with a poor response to antiviral therapy for hepatitis C,78 patients with thalassaemia might respond less to interferon-based therapies. According to one Australian report79 this seems not to be the case; indeed, a durable response can occur in the presence of massive iron overload.
blood units, and more than 25% of infections resolved within 6 years. Active infection did not contribute to hepatocellular damage in patients with β-thalassaemia. It would be interesting to verify whether HGV protects the few coinfected thalassaemic patients from progression of HIV-1 infection, as it does in other patients groups.84
TT virus TT virus (TTV) is a single-stranded, circular DNA virus that is present in a considerable number of individuals and has been proposed to be a factor contributing to fulminant and chronic liver disease. In a study done in Italy,85 69% of thalassaemic patients were found to be infected, the most common TTV genotype being 1b. HCV/TTV-coinfected patients had a significantly higher histological inflammation than patients with HCV monoinfection (p=0·02), but no effect was found on liver fibrosis; by contrast, a French survey86 found no evidence of an influence of TTV infection on chronic liver disease. Further studies with a long-term follow-up are necessary to verify these findings.
Hepatitis B virus Children with thalassaemia have long been considered particularly susceptible to hepatitis B virus (HBV) infection because of their requirement for blood transfusions. The availability of vaccines and the introduction of the screening of transfused blood units for hepatitis B s antigen (HBsAg) have reduced the incidence of this infection, but do not seem to have completely eliminated its occurrence. Indeed, HBV infection is still common in Bangladesh80 and India.72 Interestingly, Singh and colleagues81 reported their experience in 70 patients with β-thalassaemia (median age 6 years), 20 of whom had received transfusions only after vaccination. Four individuals were HBsAg-positive and 14 were positive for antibodies against hepatitis B c antigen. 17 of 70 patients had not responded to vaccination (ie, had a titre of antibodies against HBsAg [anti-HBs] ≤10 IU/L), and 22 patients were HBV DNA-positive in serum. Surprisingly, and worryingly, the frequency of HBV infection was similar in vaccine responders and non-responders and a number of mutations were observed in the hepatitis B s gene that could have influenced acquisition of the infection in the presence of anti-HBs. In those thalassaemic patients with progressive chronic hepatitis B, interferon therapy should be tried,82 although appropriate trials are lacking and no data are available on the use of pegylated interferons.
Hepatitis G virus/GB virus C In a prospective study83 done during the 1990s in multitransfused β-thalassaemic patients, 14·5% of patients were found to have hepatitis G virus (HGV, also known as GB virus C) viraemia at baseline and 10% acquired the infection during follow-up. The risk of infection was estimated to be 5·3 per 10 000 transfused 230
Malaria and α-thalassaemia The suggestion that α-thalassaemia has been selected by malaria has long been put forward on the basis of epidemiological studies and of a largely overlapping geographic distribution (figure). A close altitudedependent and latitude-dependent correlation between the frequency of α-thalassaemia and the endemicity of Plasmodium falciparum was found in the southwest Pacific,87,88 and the markedly decreased incidence of malaria in the Tharu people of southern Nepal was also ascribed to a high incidence of α-thalassaemia.89 In the north coast of Papua New Guinea, α-thalassaemia protects children against both severe malaria and even from non-malarial infectious illnesses.90 Finally, a large case-control study done in children living on the coast of Kenya has most recently demonstrated that α-thalassaemia is associated with a reduced risk of both severe and fatal falciparum malaria.91 Parasite growth is unimpaired in thalassaemic red blood cells,92 and alternative explanations have therefore been sought for the protective effect of thalassaemia from severe malaria, including possible enhanced susceptibility in very young Melanesian α-thalassaemic children to Plasmodium vivax, which would be the basis for protection from severe falciparum malaria later in life.93 In Ghana, where P vivax is virtually absent, pregnant women with α-thalassaemia appear to have increased susceptibility to Plasmodium malariae infection, which might similarly be responsible for the milder courses of falciparum malaria in the same women.94 11 years ago, Carlson and coworkers95 proposed the major protective mechanism from severe malaria was the impaired ability of red blood cells to rosette, an adhesion property in which parasitised erythrocytes bind to unparasitised red blood cells to form clumps of cells http://infection.thelancet.com Vol 6 April 2006
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Search strategy and selection criteria Data for this review were identified by searches of Medline, Current Contents, and references from relevant articles; numerous articles were identified through searches of the authors’ extensive files. Searches were done for the period 1970–2005 combining the terms “thalassaemia” and “infections”, “bacterial infections”, “viral infections”, “fungal infections”, “treatment”, and “immunology”. Papers were selected on the basis of the best level of available evidence for each specific aspect discussed. Only English language papers were included.
that cause microvascular obstruction and impaired tissue perfusion. It now appears that a promoter polymorphism of red cell complement receptor 1 (an essential receptor for rosetting) is significantly associated with protection from severe falciparum malaria (p=0·01), and that α-thalassaemia is independently associated with the reduced expression of this receptor, at least in Melanesian populations.96 An intriguing study of 405 Nigerian children has added an important piece to the puzzle of the relations between thalassaemia and malaria. In vitro, the sensitivity to chloroquine of P falciparum infecting α-thalassaemic erythrocytes is reduced; in vivo, among children with chloroquine in the blood and in spite of comparable concentrations, α-thalassaemic individuals have a higher prevalence of elevated parasitaemia than nonthalassaemic children.97 Hence protection against severe malaria conferred by α-thalassaemia may be obscured in areas of high chloroquine use; in addition, α-thalassaemia may contribute to the spread of chloroquine resistance.
Conclusions Clinicians must be aware of the potential life-threatening infections of patients with thalassaemia major, especially if splenectomised. Predisposing factors for infections such as severe anaemia and iron overload should be controlled by regular blood transfusions and proper ironchelating therapy in countries that can afford these expensive treatments, and patients should be educated to seek early care when fever develops. Fever without any apparent cause, especially when associated with diarrhoea, should be treated with co-trimoxazole and gentamicin (active against Y enterocolitica), even when culture results are negative. Postsplenectomy risk of sepsis due to encapsulated organisms and of severe malaria98 in endemic areas is a major concern. Presplenectomy immunisations 2 weeks before surgery with pneumococcal vaccines (with boosters every 5–10 years thereafter, as dictated by antibody titres), and H influenzae type B, and meningococcal serogroup C conjugated vaccines are mandatory. Aggressive treatment with antibiotics should always be administered for any febrile illness while http://infection.thelancet.com Vol 6 April 2006
awaiting the results of cultures, and patients travelling to areas endemic for malaria should be especially advised to take appropriate chemoprophylaxis. Hepatitis B must be prevented through vaccination, and treatment with pegylated interferon should be pursued to try to limit the development of cirrhosis and hepatocellular carcinoma in thalassaemic patients with chronic hepatitis B or C. Finally, it must be considered that a number of thalassaemic patients have implantable vascular access devices (commonly placed in younger patients for reliable transfusion access and in older patients to allow 24-hour chelation for heart disease, or because of severe local reactions to desferrioxamine),99 and sepsis due to catheterrelated infections (Staphylococcus spp, Stenotrophomonas spp, E coli, Candida spp, and Enterococcus spp) can occur in a sizeable proportion of these patients.70 It is therefore essential that, at each visit, these patients are asked about symptoms that might indicate a catheter infection (eg, fever, exudate, pain, erythema, swelling), and the port site and catheter track are examined for signs of infection. Optimal treatment for thalassaemia, with advances in erythrocyte transfusion and iron chelation therapy, has greatly increased the probability of a long survival of good quality. Indeed many patients survive to the fifth decade of life. Unfortunately, optimal treatment is expensive and available only for a minority of patients in the world. Haematopoietic stem cell transplantation, the only known curative treatment, is recommended only for selected patients and its outcome is poor in the presence of hepatomegaly, portal fibrosis, and ineffective chelation.100 Infections, albeit largely treatable the world over, still claim the lives of too many thalassaemic patients, and every effort must be made for appropriate prevention and therapy. Conflicts of interest We declare that we have no conflicts of interest. References 1 Higgs DR, Thein SL, Woods WG. The molecular pathology of the thalassaemias. In: Weatherall DJ, Clegg B, eds. The thalassaemia syndromes, 4th ed. Oxford: Blackwell Science, 2001: 133–91. 2 Boyd MF, ed. Malariology. Philadelphia: Saunders, 1949. 3 Silvestroni E, Bianco I, eds. Le emoglobine umane. “De genetica medica”. Rome: Istituto Gregorio Mendel, 1963. 4 Angastiniotis M, Modell B. Global epidemiology of haemoglobin disorders. Ann N Y Acad Sci 1998; 850: 251–69. 5 Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004; 89: 1187–93. 6 Dwyer J, Wood C, McNamara J, et al. Abnormalities in the immune system of children with beta-thalassemia major. Clin Exp Immunol 1987; 68: 621–29. 7 Khalifa AS, Maged Z, Khalil R, et al. T-cell functions in infants and children with beta-thalassemia. Acta Haematol 1988; 79: 153–56. 8 Ezer U, Gulderen F, Culha VK, et al. Immunological status of thalassemia syndrome. Pediatr Hematol Oncol 2002; 19: 51–58. 9 Dua D, Choudhury M, Prakash K. Altered T and B lymphocytes in multitransfused patients of thalassemia major. Indian Pediatr 1993; 30: 893–96.
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