Ricerca


Infections in Thalassemia and Hemoglobinopathies: Focus on Therapy-Related Complications


Bianca Maria Ricerca, Arturo Di Girolamo* and Deborah Rund

Hematology Department, Catholic University, Rome (Italy), *Infectious Diseases Department, G. d’Annunzio University, Chieti-Pescara (Italy), Hebrew University-Hadassah Medical Center, Ein Kerem, Jerusalem, Israel IL 91120

Correspondence to: Bianca Maria Ricerca, Servizio di Ematologia, Policlinico A. Gemelli, Largo A Gemelli 8. 00168 Rome (Italy), Tel:  +39 0630154968, e-mail: bmricerca@rm.unicatt.it

Published: December 28 , 2009
Received: December 6,  2009
Accepted: December 26, 2009
Medit J Hemat Infect Dis 2009, 1(1):e2009028 DOI 10.4084/MJHID.2009.028
This article is available from: http://www.mjhid.org/article/view/5229
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Abstract
The clinical approach to thalassemia and hemoglobinopathies, specifically Sickle Cell Disease (SCD), based on transfusions, iron chelation and bone marrow transplantation has ameliorated their prognosis. Nevertheless, infections still may cause serious complications in these patients. The susceptibility to infections in thalassemia and SCD arises both from a large spectrum of immunological abnormalities and from exposure to specific infectious agents. Four fundamental issues will be focused upon as central causes of immune dysfunction: the diseases themselves; iron overload, transfusion therapy and the role of the spleen. Thalassemia and SCD differ in their pathogenesis and clinical course. It will be outlined how these differences affect immune dysfunction, the risk of infections and the types of most frequent infections in each disease. Moreover, since transfusions are a fundamental tool for treating these patients, their safety is paramount in reducing the risks of infections. In recent years, careful surveillance worldwide and improvements in laboratory tests reduced greatly transfusion transmitted infections, but the problem is not completely resolved. Finally, selected topics will be discussed regarding Parvovirus B19 and transfusion transmitted infections as well as the prevention of infectious risk postsplenectomy or in presence of functional asplenia.


Introduction: Infections are a frequent complication of thalassemias and hemo-globinopathies and they can be fatal. The morbility and mortality rate for infections vary throughout the world depending on differences in the epidemiology of each infection and on the socio-economic level of each country and also vary depending on the preventive and therapeutic strategies adopted. In an Italian multicenter study [1], infections were the second cause of death after heart failure in thalassemia. Similar results were reported in Greece [2] and in Taiwan [3], while in E-beta thalassemia patients in Thailand, infections are the primary cause of morbidity and mortality [4]
Considering infections in sickle cell disease (SCD), the data are much more variable. In an analysis performed on 306 autopsies of SCD patients between 1929 and 1996, infections are the most common cause of death in all age groups (33-48%). The predominant anatomic site involved (72.6%) was the upper respiratory tract [5]. On the other hand, Darbari et al[6], in 141 autopsies in SCD patients  between 1976-2001,  reported a lower mortality rate due to infections (18.4%) and infections were the fourth cause of death after pulmonary hypertension (PHT), the and renal failure. Both of these studies were conducted in USA. Perhaps the difference between these two reports reflects an improved surveillance of infectious complications.  Bacterial infections are the main cause of death in Angolese SCD patients (40.1%)[7]. In France and England infections are the third cause of death and the rate is much lower (19%)[8]. A cohort study on children affected by SCD shows that the therapeutic strategy currently in use (transfusions, bone marrow transplantation, vaccinations and penicillin prophylaxis), decreased the global childhood mortality, in particular that which derived from infections, and it increased the mean age at the time of death [9].
In this review we will compare and contrast the different mechanisms which predispose to infectious complications in thalassemia and in hemoglobinopathies, specifically SCD. We will  distinguish between those aspects deriving from the disease itself and those which are essentially therapy related. Thereafter, we will examine only selected issues from the large amount of data on the clinical management of infectious diseases, trying to determine if there are infections to which these patients are naturally susceptible and others that are primarily due to treatment. Finally, the last point on which we will focus is  how much some clinical aspects of these diseases (for example iron overload (IOL),  and splenic absence (or hypofunction) influence the outcome of certain infection such as Acquired Immunodeficiency Syndrome (AIDS), hepatitis C virus (HCV)  or bacterial infections.

Etiology Of Risks Of Infections In Thalassemia And Hemoglobinopathies: The susceptibility to infections in thalassemia and SCD arises both from a large spectrum of immunological abnormalities and from the exposure to infectious agents.
To simplify the complex scenario of immune system perturbations, four fundamental issues can be addressed: the disease itself, i.e. all those changes inherent to the pathological process which can interfere with the immune systems; IOL, transfusion therapy and the role of the spleen.
Transfusion and chelation therapies represent true progress in the management of these diseases. In fact, they dramatically ameliorated the prognosis of thalassemia and SCD, as epidemiological data clearly demonstrate[1,2,9]. Nevertheless, the benefits offered by allogenic blood transfusions (ABTs) come together with the disadvantages of the high transfusion burden in terms of direct exposure to infectious risks and, indirectly, transfusion related immunomodulation (TRIM) and IOL. Moreover, other therapeutic options (splenectomy, central venous catheters, bone marrow transplantation) or nutritional deficiency (zinc deficiency) contribute to the infectious risks.
Immunological Abnormalities In Thalassemia And SCD: Recently, the immunological abnormalities observed in thalassemic patients were reviewed and listed in two publications [10,11]. The immune alterations concern both the innate and the adaptive immune systems. The CD4/CD8 ratio is lower than normal, neutrophil and macrophage phagocytosis, neutrophil chemotaxis, natural killer (NK) function are compromised;  C3 and C4 are reduced.  High immuglobulins (Ig) were reported and B lymphocytes were found to be increased, activated with impaired differentiation. Table 1 summarizes the most important evidence in the literature (experimental or clinical), indicating, where noted, the relationship between the immune alteration and the ABTs or the IOL. There are few inconsistencies among the various reports.
The role of the disease itself in inducing immune abnormalities can be explained by pathophysiological mechanisms of the disease, as is reported in the literature.
The pathogenesis of thalassemia is based on ineffective erythropoiesis, hemolysis, and a tendency to increased iron absorption, inherent in the disease itself. For the first two reasons, the monocyte/macrophage compartment undergoes gross hyperplasia and is hyperactive in phagocytizing all defective erythroid precursors and erythrocytes [39,40,41]. This increased phagocytic activity very likely reduces the capacity of the phagocytic system to defend against pathogenic microorganisms. For the same reason, the pattern recognition receptors (PRR) are overwhelmed [28]. Moreover, in a study conducted in a mouse model of β-thalassemia, susceptibility to infection by L. Monocytogenes and of S. Typhimurium was demonstrated as a result of low phagocytotic activity [13]. The authors suggest that, in this model, the relationship of this alteration to IOL not caused  by transfusions but results from the disease itself. Finally, in clinical practice, it has been observed that severe anemia, itself, is a risk factor for bacterial infections in thalassemia, predominantly pneumonia [4,43]. The current criteria for transfusion therapy recommend the maintenance of Hb level above 9 g/dl but in some countries with lower socio-economic levels, this optimal regimen is not assured. In these cases, anemia itself represents another risk factor for infections.
As far as SCD disease is concerned, its pathogenesis is quite different from thalassemia. Ineffective erythropoiesis does not play a central role as in thalassemia. HbS polymerization is the trigger, able to initiate the catastrophic chain of events responsible for chronic hemolytic anemia and for vaso-occlusive (VOC) crises. The latter may cause organ damage in all parts of the body and it accounts for the enormous clinical complexity of this disease. Much evidence is consistent with the existence of a chronic inflammatory state in SCD, exacerbated during the VOC episodes [44,45 ]with participation of cells (neutrophils, macrophages platelets), cytokines and adhesion molecules. Many signs of high oxidative stress and decreased anti-oxidant defense are present [46]. Moreover, high interleukin-6 (IL-6) levels were observed in SCD47,[48] in addition to interleukin-4 and interleukin-10 [48,49]. This cytokine elevation suppresses humoral and cell-mediated immune function, increasing infectious risks [49,50]. High values of soluble IL-2 receptors (sIL-2R), observed in a large number of SCD patients, were interpreted as the effect of continuous IL-6 stimulation [51].
Regarding the cellular aspects of the immune system, monocytes are continously activated, as is demonstrated by the upregulation and the atypical expression of CD152. Neutrophil dysfunction was considered a very important functional defect involved in the high susceptibility to infections53. For example, neutrophils from SCD patients show high expression of CD18, a molecule correlated with adhesive properties, and they respond, in vitro, to IL-8 with enhanced sensitivity [54]. This feature renders neutrophils important participants in the initiation of vaso-occlusion (VOCs)  but they are thus less available for defense tasks.
In fact, VOC crises are responsible for  further immune abnormalities which are present to a lesser degree or absent in the steady state of the disease [55]. For example, phagocytic activity rises during VOCs [56].  Neutrophil chemotaxis is normal or clearly reduced in the steady state of the disease but increases during VOC crises [57]. This hyperactivity of the monocyte/macrophage and neutrophil compartments is not committed to defending against pathogens but it contributes to VOCs. Moreover, it is a source of oxidative stress which impairs the immune response (see below).
As a further sign of inflammatory activation, the alternate (pathway of complement (AP50) is reduced for consumption  in SCD patients and has a significant inverse correlation  with the number of crises, while circulating immune complexes are elevated and they directly correlate with the number of complications of the disease [58].
The last factor to consider is that in SCD, VOCs themselves can predispose, locally, to the onset of infectious complications. Respiratory infections, frequently following the acute chest syndromes (ACSs), or osteomyelitis are examples of this mechanism [59].
Another difference between thalassemic and SCD patients concerns splenic function: SCD patients undergo functional asplenia due to recurrent episodes of vaso-occlusion in this organ. Thus, the immunodeficiency observed in thalassemia after splenectomy is often naturally present even early in the life in SCD[60]. This state particularly favors infections by encapsulated bacteria [61].
Finally, we mention that some immune alterations similar to those mentioned for thalassemia were also found in SCD:  CD4 lymphocyte reduction and CD4/CD8 ratio reduction [55, 62-64]; natural killer lymphocyte reduced activity [64]; high serum immunoglobulin [65], and elevated B lymphocytes [55]. On the other hand, the published data are less uniform and there are also some studies reporting the normality of these immunological features [66,67].



Risks Related To Iron Overload: Hereditary hemocromatosis patients represent an ideal model to understand the effects of IOL on immunity. Indeed, many studies have demonstrated that immunological function is largely and negatively influenced by iron excess [68]. Many of the alterations observed in hereditary hemochromatosis were confirmed also in thalassemic patients (Table 1).
To comment on the numerous data, we will outline only some specific aspects: for example the dual and opposing roles of the phagocytic system (monocyte/macrophages and neutrophils). IOL damage derives from a disequilibrium between iron oxidation (through the Fenton reaction) and the effectiveness and availability of those systems able to counteract oxidative stress.  In this sense, in addition to the antioxidant systems, ferritin and the monocyte/macrophage compartment also participate in clearing up toxic iron. Indeed, lysosomes in these cells are able to endocytose both free iron and ferritin and this contributes toward protection from iron [68] (Figure 1). Additional oxidative stress can destabilize the secondary lysosomes of the macrophage, and their protective role is lost. Moreover, phagocytosis of microorganisms, of dyserythropoietic precursors and of senescent or damaged red blood cells (intravascularly and/or extravascularly) causes oxidative stress [69] which compounds that deriving from IOL. Finally, IOL impairs phagocytosis [70] and its negative effect on neutrophil function has been clearly demonstrated [70,71]. Phagocytic function is the center of a vicious cycle, acting as a double edged sword: protective against oxidative stress while also generating oxidative stress on the one hand, and on the other hand, having its own function impaired by the same oxidative stress (Figure 1).
Finally, the scanty detoxifying properties of lymphocyte are the reason for their numerous functional alterations related to IOL.
In addition, regarding IOL, SCD seems to be a different disease. Indeed non transfused SCD patients may present with iron deficiency (due to intravavascular hemolysis)[72] and even in  transfused patients, the organ damage due to iron overload is less severe [73]. Perhaps this difference derives from the significant contribution of inflammation to the pathogenesis of the disease, as recent studies evaluating the role of hepcidin in these diseases have led us to hypothesize [74]. A recent multicenter prospective study [75] seems to support the influence of ABTs and IOL on the prevalence of infections requiring hospitalization, and, in general, on the rate of hospitalization, in SCD patients. Nevertheless, the data analysis shows a very complex scenario and the results suggest that this topic needs further studies to be clarified. Indeed, the transfused SCD are overall adult patients with more severe and advanced disease and, as the authors conclude, the differences observed may be, but not necessarily, attributable to ABTs and to IOL.
We conclude by mentioning that in patients who underwent hematopoietic stem cell transplantation, IOL severity is related to high infectious risk and it negatively influences the outcome of infections in this patient group[76].



Risks Related To Allogenic Blood Transfusions (ABTs): The data regarding transfusion transmitted infection (TTIs) risks in patients with thalassemia and hemoglobinopathies does not differ from the evidence in the literature regarding multitransfused patients (MTPs) in general. Hepatitis C virus (HCV), Hepatitis B virus (HBV), Human Immunodeficiency virus (HIV) and Syphilis are the most common infection agents transmitted via transfusions and routine screening is performed for these agents throughout the entire world. Other agents are routinely screened for, in different countries, according to epidemiologic alerts but also commensurate with economic resources. In the USA, for example, screening for Human T-cell Lymphotropic virus (HTLV), West Nile virus (WNV), Trypanosoma cruzi and Cytomegalovirus (CMV) is also routinely performed on blood units and screening is performed for bacteria in platelet units [77]. Many other infectious agents are transfusion transmissible. The data in the literature demonstrated that some of these agents do not cause any clinical disease (GBV-C/HGV, SEN-V, TTV, HHV-8) while others represent a transfusional risk according to epidemiologic evidence. Thus, the risk of these agents can vary in different parts of the world. As summarized by Vanvakas et al [77] additional infectious agents which can be transmitted by transfusion include: Parvovirus B19, Dengue fever virus (DFV), Babesia microti, Plasmodia species, Leishmania, Brucella and Creutzfeldt-Jakob disease (vCJD) prions.
The prevention of HBV, HCV and HIV transfusion transmission represented a challenge for transfusion medicine. Two weapons play a fundamental role in the war against these viral agents. The primary preventive measure is the selection of appropriate eligibility criteria for blood donors; the second line of prevention includes testing the units to be transfused by various laboratory methods. Both tools have been and are always in continuous evolution. Health surveillance throughout the world, including rapid information about disease epidemiology and travel patterns of people, as well as the economic and political choices of each country and technological progress, have all contributed in the past and continue contributing to assure transfusion safety. Since the discovery of HBsAg in 1963, diagnostic accuracy has improved progressively. The introduction of Nuclear Amplification Tests (NAT) represented a milestone. A suitable example is transfusion transmitted HCV and HIV. Recently, the centralized data of the American Red Cross blood donor population were reviewed [78] and the prevalence rates of disease marker positivity and the residual risk attributable to the window period were evaluated. A continuous statistically significant decrease (p<0.001) of prevalence rates for infectious disease markers among first-time donors was observed in the period between 1995 and 2001. Examining the data, the effect of the introduction of NAT testing is clear: the estimated risk of collecting blood during the infectious window period for HCV was 1:276,000 and 1:1,935,000 respectively with only antibody determination compared to NAT, respectively. Similarly, the risk for HIV was 1:1,468,000 and 1:2,135,000. The important role of the introduction of NAT is indirectly confirmed by the evidence that a less impressive reduction rate was recorded for HBV for which no relevant diagnostic improvements were achieved (1:205,000). Furthermore, another interesting approach to TTI evaluation is the application of mathematical models to calculate the residual risk of infection. The results obtained in the USA [79] for HCV, HBV and HIV, are similar to those reported by Dodd et al. In England [80] and in Canada [81] the residual risk is substantially lower, in comparison to the USA, for HCV (1: 30 million and 1:13 million respectively) while for HIV only in Canada the residual risk is lower (1:7-8 million). Many clinical reports can be quoted to demonstrate the effect of the more advanced diagnostic tools adopted in transfusion field. For example, in Italy, a recent epidemiologic study of 708 multitransfused children,  showed that HCV hepatitis,  transmitted by transfusion,  disappeared after 199282. Furthermore, in another Italian study, performed retrospectively from 1990 until 2007, HCV-RNA negative thalassemic patients were significantly younger than positive patients (p<0.001)[83]. A survey of 399 patients with thalassemia and SCD  in Turkey [84] reported a prevalence of  0.75%, 4.5% and 0 of positivity to HBsAg, HCV and HIV antibodies respectively but the majority of this positivity (77.7%) was found in patients transfused before the introduction of second generation testing. The most recent data, although encouraging, suggest some considerations: different levels of blood safety are achieved among various countries. It derives that donor screening strategies can be ameliorated. Finally the problem of HCV and also HBV (we will expand on this below) is far from a complete resolution.
As far as the influence of ABTs on immune system is concerned, over 30 years ago, it was noted that patients who had received many ABTs prior to renal transplantation showed a better rate of allograft survival. This was the onset of a long and heated debate focused on understanding the immunomodulation induced by ABTs [85-87]. The debate initially began from the data of approximately 40 studies which indicated that surgical patients receiving perioperative ABTs have a higher risk of bacterial infections, demonstrating the link between multiple transfusions and infectious risk. Recently, Vamvakas and Blajchman [87] reviewed extensive evidence regarding this issue, summarizing the beneficial and deleterious effects of ABTs. TRIM could contribute to all immunological alterations listed above and it also reduces delayed-type hypersensitivy and it induces antiidiotypic and anticlonotypic antibody production. A central role in pathogenesis of  TRIM is played by allogenic mononuclear cells, both for their presence and for the soluble substances they release during storage of blood components. Moreover, the soluble HL-A class I peptides that circulate free in allogenic plasma also contribute to the generation of TRIM. The similarity between donor WBC HLA antigens and those of the recipient is able to induce alloimmunization (if HLA-DR mismatch is high) or tolerance and immunosuppression (if the mismatch is for only one HLA-DR antigen). For these reasons, universal  blood unit leukodepletion in the prestorage phase should be an important measure to prevent TRIM. Thalassemic patients represented an ideal setting to verify the usefulness of ABT leukodepletion. Although leukodepletion reduces non-hemolytic febrile reactions (NHFR)[88-90] and anti-leukocyte antibodies and anti-platelet production [91, 92] it does not modify substantially the immunologic alterations observed in thalassemic patients [92] Probably, their pathogenesis is very complex and TRIM represents only one of the numerous factors interfering with immunity.
Risks Related To Splenectomy Or Functional Asplenia: At the present time, as an effect of the hypertransfusion regimen, fewer thalassemic patients undergo splenectomy [93]. However, when transfusional needs rise excessively, splenic enlargement, or hypersplenism and/or compressive damage occurs, splenectomy is indicated. We already outlined that SCD patients often present with functional asplenia early in life.
The spleen is very important for immunological surveillance. It is an important reservoir of immunocompetent lymphocytes [94]. In asplenia or functional hyposplenia, antibody production in response to new antigens, mediated by CD4 function, is impaired [95]. Efficient phagocytosis depends on splenic macrophages and on the production of many substances (opsonins, properdin, tufsin) which are reduced in asplenic organisms [96, 97]. Chemotaxis  is also impaired [98]. For all these reasons, when the spleen is absent or poorly functioning, sepsis can occur for any pathogen agent. However, encapsulated pathogens (Streptococcus pneumoniae, Haemophilus influenza type B, Escherichia coli, Neisseria menigitidis) are the most fearsome. Hansen et al [99] reviewed the literature regarding overwhelming sepsis in subjects with surgical or functional asplenia. They compared the number of events of sepsis and fatal sepsis in recent reports to the same data obtained in 1973 [100]. In 1973, sepsis occurred in 119 of 2796 cases (4.3%) and fatal sepsis occurred in 71 (2.5%). In the most recent series, sepsis occurred in 270 of 7872 cases (3.5%) and was fatal in 169 (2.1%) The percent reduction of sepsis from 1973 to most recent years was estimated -18 for sepsis and -16 for fatal sepsis. In both series, thalassemia patients have the highest frequency of sepsis and fatal sepsis. No comparison was possible for SCD because data before 1973 were lacking. The preventive strategy based on penicillin prophylaxis and vaccinations (see below) has been fundamental for this reduction of sepsis and fatal sepsis.
Zinc deficiency: The link between zinc deficiency and immunodeficiency is well known [101]. Some reports, concerning SCD patients focus on this aspect and the beneficial role of zinc supplementation [102,103].

Selected Topics Regarding Clinical Aspects Of Infections In Thalassemia And Hemoglobinopathies: The amount of published data on the clinical aspects of infections in thalassemia and hemoglobinopathies is enormous and it is difficult to summarize it. In part, they are recently reviewed by Vento et al11. In the following section, we will focus on some specific aspects or new evidence arising from the literature, concluding by emphasizing the importance of preventive measures in splenectomized patients.
Human Parvovirus B19: Human parvovirus (HPV) B19 is a small, non enveloped, single stranded DNA virus with a terminal hairpin [104]. During replication, two proteins (VP1 and VP2) are produced but also in the absence of replication it can exert its toxic effects. After infection, a transient high titer viremia lasts one week; the HPV DNA disappears during the production of neutralizing antibodies (IgM for 6-8 weeks and afterwards, IgG). This protective reaction can be absent in immunocompromised patients leading to the persistence of viral DNA. The clinical course is characterized by a flu-like syndrome (fever, chills, headache, gastrointestinal discomfort, arthropathy and a typical slapped-cheek rash which, after two days also involves the arms and legs), sometimes complicated by a transient red cell aplasia (TRCA). In fact, HPV B19 it is also called erythrovirus because it has a high and almost specific tropism for erythroid progenitors inducing them to undergo apoptosis by the activation of the caspase pathway. In subjects with high erythroid turn over (such as those with congenital red cell defects) severe anemia with low reticulocyte counts may develop, requiring transfusion or an intensification of a previous transfusion regimen. Moreover, it is presumed that the virus can stay in the bone marrow for lifelong duration, although this point is not completely clarified and there is evidence that persistently infected blood donors can transmit the infection through transfusions [105], although the main route of transmission is always respiratory. For these reasons the course of HPV B19 infection in thalassemia and hemo-globinopathies can be quite different from that in a healthy subject.
A large epidemiological study of 633 children with SCD (older than 12 months) has been reported [106]. They were examined between November 1996 and December 2001. At the start of the study, 187 children (29.5%) had already contracted the disease (HPV B19 IgG+ and IgM-); their mean age was higher than that of serologically negative subjects (p<0.001) and fewer underwent chronic therapies (regular ransfusion or hydroxyurea-HU). The second cohort of patients (446; 70.4%) included those completely negative (IgG and IgM-) and those with a recent infection (IgG-, IgM+). The follow up of 372 children belonging to this group revealed important information: the rate of seroconversion; the features of seroconverted subjects, the prevalence of TRCA (severe or mild) and the variables related to the clinical course.
One hundred-ten children (29.5%) seroconverted during the follow up (incidence rate 11.3 for 100 patient-years; 95% confidence interval [CI] 8.2-14.4). It is very interesting that among them, fewer were receiving transfusions (7 out of 49; 14.3%; incidence rate 5.9 for 100 patients years, 95% CI 1-15) than those treated with hydroxyurea (9 out of 29; 31% ) or not transfused (global incidence rate for non-transfused and HU groups: 11.9 per 100 patients years; 95% CI 7.6-16.2 p<0.06). Moreover, the only risk factor for seroconversion was having a sibling with a recent HPV B19 infection. These data can be important for what we will discuss later. SCD genotype, sex, age at the first serological test did not affect seroconversion.
Sixty-eight TRCA were observed during the study: 3 in the HPV B19 IgG positive group (1.6%) and 65 in the other (59%). The univariate analysis showed a strong association between acute HPV B19 infections with fever and acute splenic sequestration (ASS), while the multivariable analysis identified predisposing factors as ASS and painful episodes. Although the same evidence was not clear for acute chest syndrome (ACS), examining all children admitted with fever and pain, ACS was more common in those with HPV B19 infections. The only risk factor for TRCA was the high reticulocyte count before the infection. This study is rich in information and outlines many aspects of an infectious disease which has some peculiarities in SCD as compared to other diseases with high erythropoietic turnover. Nevertheless, an important debate is taking place in the literature as to whether transfusions are an important source of HPV B19. This hypothesis arises from the detection of HPV B19 DNA in asymptomatic blood donors. In the previous report [106], treated children (transfusion or HU) seemed to have less seroconversion, perhaps because a lower proliferation rate of the erythroid compartment. Other reports coming from the transfusion medicine field [107-109] support the evidence that transmission of HPV B19 through transfusion always plays a secondary role compared to respiratory transmission. As a result, there is currently no consensus regarding the application of preventive measures to blood donors, blood units or to patients.
Yersinia Enterocolitica: The well known problematic of Yersinia enterocolitica sepsis in thalassemia is another area in which some features of the disease combined with the side effects of therapy increase the risk of infection. In fact Yersinia infection is favored by IOL either related to the disease or to transfusions and it can be triggered by deferoxamine therapy. [110, 111]

Transfusion Transmitted Infections (TTI)s: In a manner analogous to the risks of infectious diseases, the course and the outcome of the most common TTIs in thalassemia and hemoglobinopathies are influenced by the pathogenic features of these diseases in terms of immunodysfunction and by IOL.
HIV: Human Immunodeficiency Virus (HIV) disease is a viral- related progressive immune depression that leads to depletion of CD4+ lymphocytes, and renders the individual at risk for many types of opportunistic infections [112]. As previously stated, a low CD4/CD8 ratio is one of the most frequent abnormalities in patients with thalassemias and hemoglobinopathies; thus, HIV disease is an example of negative interactions and bidirectional combination of the hematological with the infectious disease. Similarly, the substantial degree of immunodysfunction related to IOL would influence the outcome of these diseases. However, there are all too few studies dealing the clinical aspects of HIV infection in thalassemia and hemoglobinopahies.
Some years ago a large multicenter study was published [113] which included 79 HIV positive thalassemia patients from various countries (Brazil, Italy, Greece, Spain, France, United Kingdom, Cyprus), the majority of whom were followed in Italy (71%) and Cyprus (16%). The mean age was low enough (12 6.6 years) to presume a prevalent transfusion transmission of HIV infection. The progression to overt AIDS after seroconversion was estimated 1.4% after three years and 9% after five; no significant statistical association was found with age, sex, acute infection, or splenectomy. Two years later, the same investigator focused on the inverse relationship between the rate of progression of HIV and the dose of deferoxamine used: the rate of progression decreases as the mean daily dose of drug increases (p<0.02)[114]. In a further publication [115] reporting the follow-up of the same patients, a multivariate Cox proportional hazard analysis demonstrated a direct relationship between disease progression and ferritin values. These studies, published at the beginning of the nineties, included some patients treated with zidovudine. In subsequent years until the present time, a large spectrum of therapeutic options are available for HIV infected patients: nucleoside analogues (NAs), non nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 (receptor) inhibitors and integrase inhibitors [116], which are used also in patients with thalassemia and hemoglobinopathies. Finally, we mention that the effect in vitro of iron chelators (deferoxamine, deferiprone, deferasirox) on HIV replication is an interesting area of experimental research [117, 118].
HCV: Hepatitis C Virus still represents a fearsome disease, widespread worldwide: it is estimated that one hundred million people are infected throughout the world [119]. It can have a mild presentation, not infrequently asymptomatic, in its acute phase and in a high percentage of cases, the initial infection goes unnoticed. However, the evolution rate to chronic disease of HCV hepatitis is high (at least 80% of acute cases) and the further evolution towards end-stage liver disease, cirrhosis, and hepatocellular carcinoma (HCC) are not infrequent [120].
The influence of IOL on the outcome of HCV infection was the subject of debate both in nonthalassemic[121,122]
and thalassemic patients.
Di Marco et al [83] reported that, in thalassemics, the severity of liver damage (i.e. the finding of fibrosis and histologic signs of cirrhosis) is clearly related to persistent HCV infection (HCV RNA positivity), predominantly for genotypes 1 and 4. In the same study, the data on the influence of IOL on liver damage in HCV RNA positive patients, although less impressive, are however suggestive. Many other authors focused their attention on the relationship between IOL and the outcome of HCV; although these studies may reflect some reporting bias, the results  consistently demonstrate the presence of this negative link [123-128]. Much important evidence was obtained in patients who survived hemopoietic stem cell transplantation: serial liver biopsies, performed to evaluate histology and hepatic iron content, demonstrated that either HCV or IOL are independent risk factors for the progression of  liver fibrosis and they have an additive effects [129].
Since the 1990's, the management of HCV has been characterized by remarkable improvements which initially began with the use of α-Interferon 2a (α-IFN). The first clinical results obtained with α-IFN were encouraging [130, 131]. α-IFN also showed long term efficacy128: 36.5 months (range 25-49 months). Syriopoulou132 reported a complete sustained response after 8 years of therapy in 45% of thalassemic patients. In the first of these two studies, upon multivariate analysis, the absence of cirrhosis, low iron content and infection with non 1b C virus type were independently associated with a complete sustained response. In the second study, younger patients, who were not splenectomized, with a shorter duration of the infection, were more likely to respond to therapy. α-IFN was used also in patients after bone marrow transplantation: it did not adverse engraftment and was demonstrated to be efficacious and safe [133].
Thereafter, treatment options were enriched by the introduction of  pegylated IFN (PegIFN) and ribavirin. There is currently an ongoing debate regarding the use of a combination of α-IFN  (or Peg-IFN) plus ribavirin in the treatment of HCV in thalassemia. This option could be considered at least for patients infected by type 1b virus which results in a more severe disease and it is resistant to α-IFN as a single agent.  On the other hand, it is well known that ribavirin is able to induce hemolysis and so in thalassemic patients the drug could increase the need for transfusions, thus worsening IOL. Although this is a definite possibility, preliminary experiences [134-136] with this combination are positive in terms of efficacy on HCV infection. Inati et al [135] reported a complete sustained response in  62% of patients using  both drugs in comparison to 30% using IFN monotherapy (p=0.19). The patients required more transfusions but no worsening of IOL was observed. After the discontinuation of antiviral therapy, blood consumption  returned to pre-therapy level. Other authors [134, 136] reported similar results.
The last point concerns SCD patients; Teixera et al [137], described the histopathologic features of SCD patients with or without HCV. This work has many limitations, as the authors state. Nevertheless, it gives interesting information: liver damage in SCD was present in subjects infected with HCV. In those not infected, the liver changes were mild and, despite IOL, little fibrosis was present. These observations are consistent with those made by Harmatz et al [138] and they imply that SCD differs from thalassemia in terms of the interaction between iron overload and HCV in SCD.
HBV: The strategies adopted in transfusion medicine as far as the widespread use of vaccination against HBV has reduced the prevalence of this hepatitis among multitransfused patients. Nevertheless, HBV hepatitis is still a serious public health problem. The reasons for this phenomenon are related to several factors. The routes of infection can be different (transfusion as compared to sexual or perinatal); the patients can be  overt (HBsAg+) or occult (HBsAg – or anti HBc+/ HBsAg-) carriers; and the virus can be reactivated in the setting of immunosuppression. Finally, the protection offered by vaccination is not absolute [139]. How can the risks be managed? All transfused patients (who were vaccinated) or those with HBsAg+, must be tested annually for all HBV markers. The appearance of anti HBc positivity is a very important event which mandates careful clinical evaluation
HBV may present as an acute hepatitis with a wide range of manifestations, from mild disease, sometimes asymptomatic, to a severe one which, in some instances, can evolve to fulminant hepatic necrosis which is not uncommonly fatal [140]. Apart from the acute phase, between 2 to 10% of patients evolve to chronic liver disease, and thereafter, end-stage liver disease, cirrhosis and hepatocellular carcinoma (HCC) [141]. The first line treatment, available for chronic HBV disease, is α-IFN. This drug should be used for one year. During this period the goal of therapy should be the complete clearance of HBV [142, 143]. Unfortunately, only 25%-40% of patients are noted to have a good response and the use of other antiviral drugs (adefovir, tenofovir, lamivudine, telbivudine, and entecavir) is often necessary [142]. Unfortunately, the major drawback of such therapies is that they are not “curative”, i.e. these drugs can reduce the viral replication, but they do not achieve complete viral clearance. Nonetheless, treatment is considered effective when liver fibrosis does not progress to cirrhosis [144].
 
Prevention Of Bacterial Infections In Splenectomized Patients: The risk of invasive bacterial infection in splenectomized patients is well known. The data collected by Bisharat et al [145] supports this concept. They reviewed 28 studies amounting to 6,942 well-documented patients, 209 of whom developed invasive infection (3%). The incidence of infection was highest among patients with thalassemia major (8.2%), and sickle-cell anaemia (7.3%). Furthermore, the highest mortality rates were observed among patients with thalassaemia major (5.1%), and sickle-cell anaemia (4.8%). Both incidence and mortality were significantly higher in children than in adults. Streptococcus pneumoniae was responsible for the majority of the infections (66%), with a 55.3% mortality rate. It is followed for incidence by H. influenzae type b, Escherichia coli, and Neiserria meningitides146. Less common causative bacteria are Staphylococci, Streptococci, Pseudomonas, and Salmonella species [147]. The highest mortality rates were attributed to gram negative bacteria (62%), and Neisseria meningiditis (58.8%).
Thus the prevention and treatment of bacterial infections in splenectomized thalassemia and SCD patients is a life-saving intervention. Adamkiewicz et al [148], reviewing the records of 1,247 children born after 1983, reported a clear beneficial effect of pneumococcal conjugate vaccine in the reduction of the incidence of invasive pneumococcal disease.
Some issues are of particular interest for clinical practice:  the optimal timing of vaccine administration, the efficacy of various vaccination strategies, the duration of penicillin prophylaxis, and the role of partial splenectomy. Splenectomized and hyposplenic patients must receive routine vaccination, including both live attenuated and killed vaccines [149], but they should also be immunized against Streptococcus pneumoniae, H. influenzae type b, and Neisseria meningitides [147,150]. In the case of elective splenectomy, vaccinations should be completed at least 2 weeks prior to the date of surgery. 
However, vaccination does not completely protect against infection with encapsulated bacteria [151] and prophylactic antibiotics have a role as well. In a prospective multicentre randomized study in pediatric SCD patients aged <3yrs, penicillin prophylaxis reduced the incidence of pneumococcal bacteremia by 84%.  There are no prospective studies in different clinical settings, but in a retrospective observation [152], the incidence of post-splenectomy sepsis (PSS) infection and mortality were reduced, by 47% and 88% respectively, after the introduction of penicillin prophylaxis. The patients had undergone splenectomy for different reasons, but the most relevant characteristic of the series is that 70% of the patients were immunized (54% out of them only against pnemococcus). Consequently, antibiotic prophylaxis is recommended for all children <5 years of age, regardless of immunization status, for all asplenic children <5yrs, for a duration of at least for 2 years following splenectomy, since most series demonstrate that 50% of PSS occurs within this period [153]. The debate about the duration of prophylaxis is still open and the emergence of penicillin-resistant pneumococci indicate that alternate therapy may be warranted.
Notwithstanding the risk of overtreatment, the potential catastrophic clinical course of bacterial sepsis in the splenectomized individual induces the physicians to start antibiotics at the first sign of infection. Patients should carry a medical alert card to improve the speed and appropriateness of treatment of postsplenectomy sepsis.
Subtotal splenectomy may reduce the risk of postsplenectomy sepsis [154]. Nevertheless, there are not, at the moment, specific recommendations for this procedure which has technical drawbacks in this population including regrowth of the spleen and the need for reoperation [155].
Thus, also after a subtotal splenectomy, the guidelines mentioned above for total splenectomy should still be applied.


Conclusions: Thalassemia and SCD each have a different pathogenesis and this implies some differences in the risks factors for infectious complications. The strong inflammatory imprint and the frequent functional asplenia early in life in SCD are the most important, although not the only, differences between the two conditions. Moreover, although transfusions and bone marrow transplantation are important modalities to treat or cure both diseases, the additional problems arising from these procedures or from their adverse effects (for example IOL), have different implications. The knowledge of these differences is essential to efficiently target future research in experimental and clinical fields and also to define the best practical approach in the prevention and in the treatment of infectious diseases in these complex patients.
Although much progress has been made, infectious diseases still represent a major challenge in the efforts for assuring these patients enjoy a good quality of life and prolonged survival. The complexity of infectious complications, involving different regions of the body demonstrates that satisfactory cooperation among specialists in various disciplines (hematology, microbiology, immunology, hepatology), both in experimental and in clinical fields, is fundamental. Moreover, as a consequence of routine use of transfusions in these patients, transfusion medicine plays a central role. Ultimately, infectious diseases in thalassemia and hemoglobinopathies represent an example for which global surveillance, involving countries throughout the world, coupled with an open exchange of information are essential for achieving a high standard of patient care.


References

  1. 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;89:1187-1193.
  2. Ladis V, Chouliaras G Bedousi H et al.  Longitudinal study of survival and causes of death in patients with thalassemia major in Greece. Ann N Y Acad Sci 2005;1054:445-50.
  3. Chern JP, Su S, Lin KH et al: Survival, mortality, and complications in patients with beta-thalassemia major in northern Taiwan. Pediatr Blood Cancer 2007;48:550-554
  4. Wanachiwanawin W. Infections in E-beta thalassemia. Pediatr Hematol Oncol. 2000; 22(6):581-7.
  5. Manci EA, Culberson DE, Yang YM et al. Causes of death in sickle cell disease: an autopsy study.  Br J Haematol. 2003;123(2): 359-365.
  6. Darbari DS, Kple-Faget P, Kwagyan Jet al. Circumstances of death in adult sickle cell disease patients. Am J Hematol. 2006; 81:858-63
  7. Van-Dunem JC, Alves JG, Bernardino L et al. Factors associated with sickle cell disease mortality among hospitalized Angolan children and adolescents. West Afr J Med. 2007;26(4):269-273.
  8. Perronne V, Roberts-Harewood M, Bachir D et al. Patterns of mortality in sickle cell disease in adults in France and England. Hematol J. 2002; 3(1):56-60.
  9. Quinn CT, Rogers ZR, Buchanan GR. Survival of children with sickle cell disease. Blood. 2004;103(11):4023-4027
  10. Farmakis D, Giakoumis A, Polymeropoulo E et al. Pathogenetic aspects of immune deficiency associated with β thalassemia. Med Sci Monit 2003: 9: RA19-22
  11. Vento S, Cainelli F, Cesario F. Infections in talassemia. Lancet Infect Dis 2006; 6:226-233
  12. Sternbach MS, Tsoukas C, Pasquin M et al.  Monocyte-Macrophage functions in asyntomatic and supertransfused hemophiliacs and thalassemics. Clin Invest Med. 1987: 10:275-281.
  13. Ampel HM, van Wyck DM, Aguirre ML et al. Resistance to infection in murine beta thalassaemia. Infect Immun 1989; 57: 1011–1017
  14. Pittis MG, Estevez ME and Diez RA. Decreased phagolysosomal fusion of peripheral blood monocytes from patients with thalassaemia major. Acta Haematol 1994;92: 66–70.
  15. Matzner Y, Goldlarb A, Abrahamov A et al. Impaired neutrophil chemotaxis in patients with thalassemia major. Br J Haematol 1993; 85:153- 158.
  16. Bassaris HP, Lianou PE, Skoutelis AT et al. Defective adherance of polymorphonuclear leucocytes to nylon induced by thalassemic serum.  J  Infect  Dis 1982;  146:52–55.
  17. Van Ashbeck BS, Marx JJM, Struyvenberg A et al.(A) Effect of iron (III) in the presence of various ligands on the phagocytic and metabolic activity of human polymorphonuclear leukocytes. J Immunol 1984;132: 851–856.
  18. Van Ashbeck BS, Marx JJM, Stryvenberg A. et al. (B) Functional defects in phagocytic cells from patients with iron overload.  J Infect Dis. 1984;  8: 232–240.
  19. Skoutelis AT, Lianou E, Papavassilion T et al. Defective phagocytic and bactericidal functions of polymorphonuclear leucocytes in patients with beta-thalassaemia major. J Infect 1984;  8: 118–122.
  20. Cantinieaux B, Hariga C, Ferster A, et al.  Neutrophil dysfunction in thalassaemia major: The role of iron overload.  Eur. J. Haematol. 1987; 39:  28–34.
  21. Grady RW, Akbar, AN., Giardina PJ et al. Disproportionate lymphoid cell subsets in thalassemia major: the relative contribution of transfusion and splenectomy. Br. J. Haematol. 1985; 59: 713-720.
  22. Dwyer J, Wood C, McNamara j et al. Abnormalities in the immune system of children with beta-thalassemia major. Clin Exp Immunol 1987; 68: 621-630
  23. Sen I, Goicoa Ma, Nualart PJ et al. immunological studies in talassemia major. Medicina (B Aires)1989, 49: 31-4
  24. Ezer U, Gulderen F, Culha VK et al. Immunological status of thalassemia syndrome. Pediatr Hematol Oncol 2002;19:51-58
  25. Akbar AR, Fitzgerald-Bocarsly PA, De Sousa M et al. Decreased natural killer activity in thalassemia major: a possible consequence of iron overload. J Immunol 1986; 136:1635-1640.
  26. Sihnlah D, Yadav M. Elevated IgG and decreased complement component C3 and factor B in β thalassemiamajor. Acta pediatr scand 1981; 70: 547-560
  27. Wanachiwanawin W, Wiener E, Siripaniaphinyo  U et al. Serum levels of tumor  Necrosis factor a, interleukin-1 and interferon-g in b-thalassaemia/HbE and their clinical significance.  Interferon Cytokine Res 1999; 19:105–110.
  28. Ozinsky A, Underhill DM, Fontenot  J.D et al.  The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors.  Proc  Natl Acad  Sci  USA 2000; 97: 13766–13771.
  29. Ozturk O, Yaylim I, Aydin M, et al. Increased plasma levels of interleukin-6 and interleukin-8 in beta thalassaemia major, Haematologica 2001; 31: 237–244.
  30. Lombardi G, Matera R, Minervini MM et al. Serum levels  of cytokines and soluble antigens in polytransfused patients with beta talassemia major relationship with immune status. Hematologica 1994; 79:406-412
  31. Umiel T, Friedman E, Luria D et al: Impaired immune regulationin children and adolescent with hemophilia and thalassemia in Israel. Am J Pediatr Hematol Oncol 1984;6: 371-378
  32. Khalifa  AS, Maged Z, Khalil R et al. T-cell function in infants and children with beta-thalassemia. Acta Haematol 1988; 79: 153-156
  33. Dua D, Choundury M, PrakashK. Altered  T and B Limphocytes in multitransfused patients of thalassemia major . Indian pediatr 1993; 30: 893-896
  34. Kaplan J, Sarnaik S, Gitlin J et al. Diminished helper/suppressor lymphocyte ratios and natural killer activity in recipients of repeated blood transfusions. Blood. 1984;64:308-310
  35. Pardalos G, Kanakoudi-Tsakalidis  Iron-related disturbances ofF, Malaka-Zafiriu M et al. Iron-related disturbances of cell-mediated immunity in multitransfused children with thalassemia major. Clin Exp Immunol 1987;  68: 138-145
  36. Hodge G, Lloyd JV, Hodge s et al. Functional lymphocytic immunophenothypes observed in thalasemia and haemophilia patients receiving current blood product preparations. Br J Haematol 1999; 105: 817-825
  37. Speer GP, Gahr M, Schuff- Werner P et al. Immunologic evaluation of children with homozygous beta-thalassemia treated with desferrioxamine. Acta Haematol 1990; 83: 75-81.
  38. Akbar AN, Giardina PJ, Hilgartner MW et al. Immunological abnormalities in thalassemia major. A transfusion related increase in cytoplasmic immunoglobulin positive cells. Clin Experimental Immunol.1985;62:397-404.
  39. Wanachiwanawin W, Siripaniaphinyo U, Fucharoen S et al. Activation of monocytes for the immune clearance of red cellls in b0-thalassaemia/HbE. Br J Haematol 1993; 85: 363–369
  40. Wiener, E, Wanachiwanawin W, Chinprasertsuk, S et al. Increased serum levels of macrophage colony stimulating factor (M-CSF) in a- and b-thalassaemia syndromes. Eur J Haematol 1996; 57:363–369
  41. Wiener E, Allen D, Siripaniaphinyo U et al. Role of FcgRI (CD64) in erythrocyte elimination and its upregulation  in thalassaemia  Br J Haematol 1999; 106: 923–930
  42. Ampel HM, van Wyck DM, Aguirre ML et al. Resistance to infection in murine beta thalassaemia. Infect Immun 1989; 57: 1011–1017
  43. Model B, Berdoukas V. The clinical approach to Talassemia. London: Grune & Stratton. 1984: 140-150.
  44. Moore CM, Ehlayed M, Leiva LE et al. New concepts in the immunology of sickle cell disease. Ann Allergy Asthma Immunol 1996; 70: 385-400
  45. Chies JA, Nardi NB. Sickle cell disease: a chronic inflammatory condition. Med Hypotheses 2001; 57:46-50
  46. Wood Kc, Granger DN Sickle cell disease: role of reactive oxygen nitrogen metabolites. Clin Exp Pharmacol Physiol.2007;34:926-932
  47. Taylor SC, Shacks SJ, Mitchell RA et al. Serum interleukin-6 levels in steady state of sickle cell disease. Interferon Cytokine Res 1995;15: 1061-1064
  48. Taylor SC, Shacks SJ, Qu Z et al. Type 2 cytokine serum levels in healthy sickle cell disease patients. J Natl Med Assoc. 1997;89:753-757.
  49. Raghupathy R, Haider MZ, Azizich F et al. Th1 and Th2 cytokine profiles in sickle cell disease. Acta Hematol 2000; 103:197-202.
  50. Taylor S, Shacks S, Qu Z. Effect of anti Il-6 and anti IL-10 monoclonal antibodies on the suppression of the normal T lymphocyte mitogenic responses by steady state sickle cell disease sera. Immunol Invest 2001; 30: 209-219
  51. Taylor S, Shacks S, Qu Z. In vivo production of type1 citokines in healty sickle cell disease patients, J Natl Med Assoc. 1999; 91; 619-624
  52. Sloma I, Zilber MT, Charron D et al. Upregulation and atypical expression of the CD1 molecules on monocytes in sickle cell disease. Hum Immunol. 2004 Nov;65:1370-6.
  53. Humbert JR, Winsur EI, Githens JM et al Neutrophil dysfunctions in sickle cell disease. Biomed Pharmacother 1990; 44:153-158.
  54. Lum AF, Wum T, Staunton  D et al. Inflammatory potential of neutrophils detected in sickle cell disease. Am J Hematol 2004;76:126-133.
  55. Adedeji MO. Lymphocyte subpopulations in homozygous sickle cell anemia. Acta Hematol 1985;74:10-13
  56. Mendoza E, Gutgsell N, Temple JD et al. Nonocytic phagocitic activity in sickle cell disease. Acta haematol 1991;85: 199-201
  57. Lachant NA, Oseas RS. Vaso-occlusive crisis-associated neutrophils dysfunction in patients with sickle-cell disease. Am J Med Sci 1987;294:253-257.
  58. Anyaegbu CC, Okpala IE, Aken'ova AY et al. Complement haemolytic activity, circulating immune complexes and the morbidity of sickle cell anaemia. APMIS. 1999 Jul;107(7):699-702
  59. Agua P, Castello-Herbreteau B. Severe infections in children with sickle cell disease: clinical aspects and prevention. Arch Pediatr 2001; 8(S4): 732s-741s
  60. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. N Engl J Med 1986;314:1593–1599
  61. Overturf G, Powers D. Infections in sickle cell anemia pathogenesis and control. Tex Rep Biol Med 1980; 40: 283-292.
  62. Glassman AB, Deas DV, Berlinsky FS et al. Lymphocyte blast transformation and lymphocyte percentage in patients with sickle cell disease. Ann Clin Lab Sci 1980; 10: 9-12.
  63. Ballester OF, Abdallah JM, Prasad AS. Lymphocyte subpopulation abnormalities in sickle cell anemia: a distinctive pattern from that of AIDS. Am J Hematol 1986, 21:23-27
  64. Rivero RA, Macaas C, Del Valle L et al. Immunnologic changes in sickle cell anemia. Sangre 1991; 36:15-20.
  65. Wang W, Herrod H, Presbury g et al. Lymphocyte phenotype and function in chronically transfused children eith sickle cell disease. Am J Hematol 1985;20:31-3
  66. Hendriks J, De Ceulaer K, Williams E et al. Mononuclear cells in sickle cell disease: subpopulations and in vitro response to mitogens. J Clin Lab immunol 1984; 13. 129-32.
  67. Cetiner S, Akoazlu TF, kilina Y et al. Immunological studies in sickle cell disease: comparison of homozygote mild and severe variants. Clin Immunol Immunopathol 1990; 55: 492-497.
  68. Walker EM, Walker SM. Effects of iron overload on immune system. Ann Clin Lab Sci 2000;30: 354-365.
  69. Fibach E, Rachmilewitz E. The role of oxidative stress in hemolytic anemia. Curr Mol Med. 2008;8:609-619
  70. Wiener E. Impaired phagocyte antibacterial effector functionsin b-thalassemia: a likely factor in the increased susceptibility to bacterial infections. Hematology, 2003; 8:  35–40
  71. Amer J, Fibach E. Chronic oxidative stress reduces the respiratory burst response of neuthrophils from beta thalassemia patients. Br J Haematol 2005;129:435-441
  72. Koduri PR. Iron in sickle cell disease: a review why less is better. Am J Hematol 2003; 73:59-63.
  73. Vichinsky E, Butensky E, Fung E et al. Comparison of organ dysfunction in transfused patients with SCD or beta thalssemia. Am J Hematol. 2005;80:70-4.
  74. Kroot JJ, Laarakkers CM, Kemna EH et al. Regulation of serum hepcidin levels in sickle cell disease. Haematologica 2009;94:885-887
  75. Fung EB, Harmatz P, Milet M et al. Morbidity and mortality in chronically transfused subjects with thalassemia and sickle cell disease: a report from a multicenter study on iron overload. Am J Hematol 2007;82:255-265.
  76. De Witthe T: the role of iron in patients after bone marrow transplantation. Blood Rev 2008;22(S2):S22-S28
  77. Vanvakas  E, Bajchman MA. Transfusion related mortality: the ongoing risks of allogenic blood transfusion and the available strategies for their prevention. Blood 2009;113:3406-3417
  78. Dodd RY, Notari IV, Stramer SL. Current prevalence and incidence of infectious disease markers and estimated window-period risk in the America Red Cross blood donor population. Transfusion. 2002: 42:975-979
  79. Busch, MP, Glynn SA, Stramer SL et al. A new strategy for estimating risks of transfusion transmitted viral infections based on rates of detection of recently infected donors. Transfusion 2005; 45: 254–264.
  80. Soldan K, Barbara JA, Ramsay ME et al. Estimation of the risk of HBV, HCV and HIV infectious donations entering the blood supply in England, 1993–2001. Vox Sanguinis  2003; 84: 274–286
  81. O’Brien SF, Yi QL, Foon W et al. Current incidence and estimated residual risk of transfusion transmitted infections in donations made for Canadian Blood Service. Transfusion 2007; 47, 316–325.
  82. Bortolotti  F, Iorio R, Resti M et al.Epidemiological profile of 806 Italian children with hepatitis C virus infection over a 15-year period. J Hepatol. 2007;47:311-17.
  83. Di Marco V, Capra M, Gagliardotto F et al. Liver disease in chelated transfusion-dependent thalassemic: the role of iron overload and chronic epatitis C. Haematologica 2008;93:1243-1246.
  84. Ocak S, Kaya H, Cetin M, Gali E et al. Seroprevalence of hepatitis B and hepatitis C in patients with thalassemia and sickle cell anemia in a long-term follow-up. Arch Med Res. 2006;37(7):895-898.
  85. Rouger P. Transfusion induced immunomodulation: myth or reality? Transf  Clin Biol 2004; 11:115-116.
  86. Blumberg N. Deleterious effect of transfusion immunomodulation: proven beyond a reasonable doubt. Transfusion 2005; 45S:S33-39
  87. Vamvakas EC, Blajchman MA. Transfusion related immunomodulation (TRIM): an update. Transfusion 2007; 21:327-348.
  88. James J, Matthews RN, Holdsworth R et al. The role of filtration in the provision of leukocyte poor red cells to multitransfused patients. Pathology. 1986;18:127-130.
  89. Tan KK, Lee WS, Liaw LC et al. A prospective study on the use of leucocyte-filters in reducing blood transfusion reactions in multi-transfused thalassemic children. Singapore Med J. 1993; 34:109-111
  90. Cabibbo S, Fidone C, Antolino A et al. Clinical effects of different types of red cell concentrates in patients with thalassemia and sickle cell disease. Transfus Clin Biol. 2007;14:542-550.
  91. Sirchia G, Rebulla P, Mascaretti L et al. Effectiveness of red blood cells filtered through cotton wool to prevent antileukocyte antibody production in multitransfused patients. Vox Sang. 1982;42:190-197
  92. Sirchia G, Rebulla P, Mascaretti Let al. The clinical importance of leukocyte depletion in regular erythrocyte transfusions. Vox Sang. 1986;51 (S 1):2-8.
  93. Rebulla P, Model B. Transfusion requirement and effects in patients with thalassemia major.  Lancet 1991; 337: 277-280.
  94. Amlot PL, Hayes AE. Impaired human antibody response to the thymus-independent antigen, DNP-ficoll, after splenectomy. Lancet 1985;1:1008–1011.
  95. Wolf  HM, Eibl MM, Georgi E, et al. Long-term decrease of CD41 CD45 RA1 T cells and impaired primary immune response after post-traumatic splenectomy. Br J Haematol 1999;107:55–68.
  96. Constantopoulos A, Najjar VA, Smith JW. Tuftsin deficiency: a new syndrome with defective phagocytosis. J Pediatr 1972;80:564–572.
  97. Hashimoto T, Mahour GH, Church JA, Lipsey AI. Plasma fibronectin levels after splenectomy and splenic autoimplantation in rats with and without dietary ascorbic acid supplementation. J Pediatr Surg 1983;18:805–810.
  98. Simon M Jr, Djawari D, Hohenberger W. Impairment of polymorphonuclear leukocyte and macrophage functions in splenectomized patients. N Engl J Med 1985;1089–1092.
  99. Hansen K, Singer D. Aspenic-hyposplenic overwhelming sepsis:postsplenectomy sepsis revisited. Ped Develop Pathol 2001; 4:105-121
  100. Singer DB. Postsplenectomy sepsis. Perspect Pediatr Pathol 1973;1:285–311
  101. Fraker PJ, King LE, Laakko T  et al. The dynamic link between the integrity of the immune system and zinc status. J Nutr. 200;130(5S):1399S-406S.
  102. Prasad AS, Kaplan J, Brewer GJ et al.  Immunological effects of zinc deficiency in sickle cell anemia (SCA). Prog Clin Biol Res. 1989;319:629-47
  103. Prasad AS, Beck FW, Kaplan J et al. Effect of zinc supplementation on incidence of infections and hospital admissions in sickle cell disease (SCD). Am J Hematol. 1999 Jul;61(3):194-202.
  104. Cotmore SF,Tattersal P. Characterization and molecular cloning of human parvovirus genome. Science 1984;226:1161-1165
  105. Cassinotti P, Siegl G. Quantitative evidence for persistence of human parvovirus B19 medicine.Summary of a workshop. Transfusion.2001;41:130-135.DNA in an immunocompetent individual. Eur J Clin Microbiol Infec Dis 2000;19:886-895
  106. Smith-Whitley K, Zhao H, Hodinka RL et al. Epidemiology of human parvovirus B19 in children with sickle cell disease. Blood 2004;103:422-427.
  107. Brown KE, Young NS, Alvin BM et al. Parvovirus B19: implications for transfusion medicine. Summary of a workshop.Transfusion. 2001 Jan;41(1):130-5.
  108. Kleinman S, Glynn SA, Lee T et al. A linked donor-recipient study to evaluate parvovirus B19 transmissionby blood component transfusion. Blood 2009;114:3677-3683.
  109. Lefrre JJ, Servant-Delmas A, Candotti D et al. Persistent B19 in immunocompetent individuals: implications for transfusion safety. Blood 2005;106:2890-2895
  110. Baumler AJ, Hantke K. Ferrioxamine uptake in Yersinia enterocolitica: characterization of the receptor protein FoxA. Mol Microbiol 1992; 6: 1309–1321.
  111. Autenrieth IB, Bohn E, Ewald JH et al. Deferoxamine B but not deferoxamine G1 inhibits cytokine production in murine bone marrow macrophages. J Infect Dis 1995; 172: 490–96.
  112. Nowak MA, Anderson RM, Boerlijst MC et al. HIV-1 evolution and disease progression. Science. 1996;8:1008-11.
  113. Costagliola DG, Girot R, Rebulla P et al. Incidence of AIDS in HIV1 infected talassemia patients. Br J Haematol 1992;81:109-112.
  114. Costagliola DG, deMontalembert M, Lefrere JJ et al. Dose of desferrioxamine and evolution ofHIV-1 infection in thalassaemic patients. Br J Haematol. 1994;87:849–52
  115. Salhi Y, Costagliola D, Rebulla P, et al. Serum ferritin, desferrioxamine, and evolution of HIV-1infection in thalassemic patients. J Acquired Immune Defic Syndr Hum Retrovirol. 1998;18:473–8
  116. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. November 3, 2008;1-39. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf 
  117. Georgiou NA, van der Bruggen T, Oudshoorn M et al. Inhibition of human immunodeficiency virus type 1 replication in human mononuclear blood cells by the iron chelators deferoxamine, deferiprone, and bleomycin. J Infect Dis. 2000;181:484-490.
  118. Debebe Z, Ammosova T, Jerebtsova M et al.  Iron chelators ICL670 and 311 inhibit HIV-1 transcription. Virology. 2007;367:324-333.
  119. (no Author) Hepatitis C-global prevalence (update).Wkly Epidemiol Rec 2000;75:18-19
  120. Burra P. Hepatitis C. Semin Liver Dis. 2009;29:53-65.
  121. Shedlofsky SI. Role of iron in the natural history and clinical course of hepatitis C disease. Hepatogastroenterology. 1998;45:349-55.
  122. Fujita N, Sugimoto R, Urawa N, et al. Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic epatitis C. J Gastroenterol Hepatol. 2007;22:1886–1893
  123. Li CK, Chik KW, Lam CWK et al. Liver disease in transfusion dependent thalassaemia major. Arch Dis Child 2002;86:344-7.
  124. Ardalan FA, Osquei MR, Toosi MN et al. Synergic effect of chronic hepatitis C infection and beta thalassemia major with marked hepatic iron overload on liver fibrosis: a retrospective cross-sectional study. BMC Gastroenterol 2004;4:17.
  125. Cunningham MJ, Macklin EA, Neufeld EJ et al. Complications of  beta-thalassemia major in North America. Blood 2004;104:34-39.
  126. Prati D, Maggioni M, Milani S et al.  Clinical and histological characterization of liver disease in patients with transfusion-dependent beta-thalassemia. A multicenter study of 117 cases. Haematologica 2004;89:1179-86.
  127. Perifanis V, Tziomalos K, Tsatra I et al. Prevalence and severity of liver disease in patients with beta-thalassemia major. A single-institution fifteen-year experience. Haematologica 2005;90:1136-1138.
  128. Di Marco V,Lo Iacono P, Almasio P et al. Long-term efficacy of α-Interferon in β-thalassemics  with chronic hepatitis C. Blood 1997;90:2207-2212.
  129. 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.
  130. Di Marco V, Lo Iacono O, Capra M et al. Alpha-interferon treatment of chronic C hepatitis of young  patients with homozygous β-thalassemia. Haematologica 1992;77:502-506
  131. Donohue SM, WonkeB, Hoffbrand AV et al. Alpha interferon in the treatment of chronic Hepatitis C in fection in Thalassemia major. Br J Haematol 1993;83:491-497
  132. Syriopoulou V, Daikos GL, manolaki N et al. Sustained response to interferon α-2a in thalassemic patients with chronic hepatitis C. A prospective 8-years follow-up study. Haematologica 2005; 90:129-131
  133. Giardini C, Galimberti M, Lucarelli G et al. α-Interferon treatment of chronic hepatitis C after bone marrow transplantation for homozygous β-thalassemia. Bone Marrow Transpl;.1997;20:767-772
  134. Li CK, Chan PKS, Ling S et al. Interferon and ribavirin as frontline treatment for chronic hepatitis C infection in thalassemia major. Br J Haematol 2002;117:755–758
  135. Inati A, Taher A, Ghorra S et al. Efficacy and tolerability of peginterferon alpha2a with or without ribavirin in thalassemia major patients with chronic hepatitis C infection. Br J Haematol 2005; 130: 644-646.
  136. Harmatz P, Jonas MM, Kwiatkowski JL et al. Safety and efficacy of pegylated interferon α-2a and ribavirin for the treatment of hepatitis C in patients with thalassemia. Haematologica 2008:93:1247-1251.
  137. Teixera AL,  Borato Viana M, Valadares Roquete ML et al Sicke cell disease: a clinica and histopathologic study of the liver in living children.  J Pediatr Hematol Oncol. 2002;24.125-129
  138. Harmatz P, Butensky E, Quirolo K et al. Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusions. Blood 2000; 96:76-79.
  139. 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.
  140. Liang TJ. Hepatitis B: the virus and disease. Hepatology. 2009;49:S13-21.
  141. McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology. 2009;49:S45-55
  142. Papatheodoridis GV, Manolakopoulos S, Archimandritis AJ. Current treatment indications and strategies in chronic hepatitis B virus infection. World J Gastroenterol. 2008;14:6902-10.
  143. 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.
  144. Feld JJ, Wong DK, Heathcote EJ. Endpoints of therapy in chronic hepatitis B. Hepatology. 2009;49:S96-S102.
  145. Bisharat N, Omari H, Lavi I et al.  Risk of Infection and Death Among Post-splenectomy Patients. Journal of Infection 2001; 43:182-186
  146. Lynch AM, Kapila R. Overwhelming postsplenectomy infection. Infect Dis Clin North Am 1996;10:693–707.
  147. Sumaraju V, Smith LG, Smith SM. Infectious complications in asplenic hosts. Infect Dis Clin North Am 2001;15:551–565.
  148. Adamkiewicz TV, Silk BJ, Howgate J et al. Effectiveness of the 7-valent pneumococcal conjugate vaccine in children with sickle cell disease in the first decade of life. Pediatrics 2008;121:562-569.
  149. British Committee for Standards in Haematology. Davies JM, Barnes R, Milligan D. Working Party of the Haematology/Oncology Task Force. Update of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen. Clin Med 2002;2:440–443.
  150. American Academy of Pediatrics. Immunocompromised children-Asplenic children. The red book, report of the committee on infectious diseases, 25th edn. Elk Grove Village, IL, USA: American Academy of Pediatrics; 2000
  151. American Academy of Pediatrics. Committee on Infectious Diseases. Policy statement: Recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis. Pediatrics 2000;106:362–366
  152. Jugenburg M, Haddock G, Freedman MH et al. The morbidity and mortality of pediatric splenectomy: Does prophylaxis make a difference? J Pediatr Surg 1999;34:1064–1067
  153. Price VE, Dutta S, Banchette VS et al. The prevention and treatment of bacterial infections in children with asplenia or hyposplenia: practice considerations at the hospital for sick children, Toronto. Pediatr Blood Cancer 2006;46:597-603
  154. Resende V, Petroianu A. Functions of the splenic remnant after subtotal splenectomy for treatment of severe splenic injuries. Am J Surg 2003;185:311–315.
  155. Rice HE, Oldham KT, Hillery CA, Skinner MA, O'Hara SM, Ware RE : Clinical and hematologic benefits of partial splenectomy for congenital hemolytic anemias in children. Ann Surg. 2003 Feb;237(2):281-8



Abstract views:
151

Views:
PDF
177
HTML
3015

Article Metrics

Metrics Loading ...

Metrics powered by PLOS ALM


Copyright (c) 2016 Mediterranean Journal of Hematology and Infectious Diseases

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

 

The Mediterranean Journal of Hematology and Infectious Diseases [eISSN 2035-3006] is owned by the U.C.S.C. and it is published by PAGEPress®, Pavia, Italy. All credits and honors to PKP for their OJS.
 
 
© PAGEPress 2008-2017     -     PAGEPress is a registered trademark property of PAGEPress srl, Italy.     -     VAT: IT02125780185