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Medit J Hemat Infect Dis 2009; 1
; Open Journal System
MEDITERRANEAN JOURNAL OF HEMATOLOGY AND INFECTIOUS DISEASES
Review Article
Infections in Thalassemia a
Therapy-
Related Complications
Bianca Maria Ricerca, Arturo Di Girolamo* and Deborah Rund
Hematology
Department, Catholic University, Rome (Italy)
University, Chieti-Pescara (Italy), °
Hebrew University
91120
Correspondence to: Bianca Maria Ricerca
,
Rome (Italy), Tel: +39 0630154968, e-
mail:
Published: December 28 , 2009
Received: December 6, 2009
Accepted: December 26, 2009
Medit J Hemat Infect Dis 2009, 1(1):
e2009028
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
medium, provided
the original work is properly cited
Abstract:
The clinical approach to thalassemia and hemoglobinopathies
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 infecti
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
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 infe
ctions 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 red
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 postsplenec
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
; Open Journal System
MEDITERRANEAN JOURNAL OF HEMATOLOGY AND INFECTIOUS DISEASES
www.mjhid.org
ISSN 2035-3006
Infections in Thalassemia a
nd
Hemoglobinopathies:
Related Complications
Bianca Maria Ricerca, Arturo Di Girolamo* and Deborah Rund
°
Department, Catholic University, Rome (Italy)
,
*Infectious Diseases Department, G. d’Annunzio
Hebrew University
-
Hadassah Medical Center, Ein Kerem, Jerusalem, Israel IL
,
Servizio di Ematologia, Policlinico A. Gemelli,
Largo A Gemelli 8.
mail:
bmricerca@rm.unicatt.it
e2009028
DOI 10.4084/MJHID.2009.028
http://www.mjhid.org/article/view/5229
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
//creativecommons.org/licenses/by/2.0
),
which permits unrestricted use, distribution, and reproduction in any
the original work is properly cited
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 infecti
ons 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
ctions 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 red
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 postsplenec
tomy or in presence of
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
economic level
of each country and also vary depending on the
preventive and therapeutic strategies adopted. In an
, 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
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
MEDITERRANEAN JOURNAL OF HEMATOLOGY AND INFECTIOUS DISEASES
Hemoglobinopathies:
Focus on
*Infectious Diseases Department, G. d’Annunzio
Hadassah Medical Center, Ein Kerem, Jerusalem, Israel IL
Largo A Gemelli 8.
00168
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
which permits unrestricted use, distribution, and reproduction in any
, 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
ons 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
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
ctions 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 red
uced
greatly transfusion transmitted infections, but the problem is not completely resolved. Finally,
selected topics will be discussed regarding Parvovirus B19 and transfusion transmitted
tomy or in presence of
second cause of death after heart failure in
thalassemia. Similar results were reported in
, while in E
-beta thalassemia
patients in Thailand, infections are the primary
.
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
Medit J Hemat Infect Dis 2009; 1; Open Journal System
most common cause of death in all age groups (33-
48%). The predominant anatomic site involved
(72.6%) was the upper respiratory tract5. On the
other hand, Darbari et al6, 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 death9.
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 demonstrate1,2,9.
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 publications10,11. 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.
Medit J Hemat Infect Dis 2009; 1; Open Journal System
The pathogenesis of thalassemia is based on
Medit J Hemat Infect Dis 2009; 1; Open Journal System
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
erythrocytes39,40,41. 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.
Medit J Hemat Infect Dis 2009; 1; Open Journal System
Finally, in clinical practice, it has been observed
that severe anemia, itself, is a risk factor for
bacterial infections in thalassemia, predominantly
pneumonia4 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 episodes44,45 with
participation of cells (neutrophils, macrophages
platelets), cytokines and adhesion molecules. Many
signs of high oxidative stress and decreased anti-
oxidant defense are present46. Moreover, high
interleukin-6 (IL-6) levels were observed in
SCD47,48 in addition to interleukin-4 and interleukin-
1048, 49. This cytokine elevation suppresses humoral
and cell-mediated immune function, increasing
infectious risks49,50. 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 stimulation51.
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
sensitivity54. 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 crises57. 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 mechanism59.
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 SCD60. This state
particularly favors infections by encapsulated
bacteria61.
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
reduction55, 62-64; natural killer lymphocyte reduced
activity64; high serum immunoglobulin65, and
elevated B lymphocytes55. On the other hand, the
published data are less uniform and there are also
some studies reporting the normality of these
immunological features66,67.
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 excess68. 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
Medit J Hemat Infect Dis 2009; 1; Open Journal System
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
iron68 (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 phagocytosis70 and its negative effect on
neutrophil function has been clearly
demonstrated70,71. 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 severe73. 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 hypothesize74. A recent multicenter
prospective study75 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 group76.
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
Medit J Hemat Infect Dis 2009; 1; Open Journal System
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 units77. 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 reviewed78 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 USA79 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
Turkey84 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 ABTs85-87. 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,
Medit J Hemat Infect Dis 2009; 1; Open Journal System
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 production91, 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 lymphocytes94. In
asplenia or functional hyposplenia, antibody
production in response to new antigens, mediated
by CD4 function, is impaired95. Efficient
phagocytosis depends on splenic macrophages and
on the production of many substances (opsonins,
properdin, tufsin) which are reduced in asplenic
organisms96, 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 al99 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 1973100.
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
supplementation102,103.
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
hairpin104. 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
Medit J Hemat Infect Dis 2009; 1; Open Journal System
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 1 05,
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
reported106. 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 report106, 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
field107-109 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+
Medit J Hemat Infect Dis 2009; 1; Open Journal System
lymphocytes, and renders the individual at risk for
many types of opportunistic infections112. 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 published113 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
publication115 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
inhibitors116, 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
research117, 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
infrequent120.
The influence of IOL on the outcome of
HCV infection was the subject of debate both in
nonthalassemic121,122 and thalassemic patients.
Di Marco et al83 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 link123-128.
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 effects129.
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 encouraging130, 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 safe133.
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
Medit J Hemat Infect Dis 2009; 1; Open Journal System
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 experiences134-136 with this
combination are positive in terms of efficacy on
HCV infection. Inati et al135 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
authors134, 136 reported similar results.
The last point concerns SCD patients;
Teixera et al137, 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 HBV142, 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 necessary142. 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
cirrhosis144.
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 species147. 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 al148, 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
Medit J Hemat Infect Dis 2009; 1; Open Journal System
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 vaccines149, but they should also be
immunized against Streptococcus pneumoniae, H.
influenzae type b, and Neisseria meningitides147,150.
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
bacteria151 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 observation152, 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 period153. 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 sepsis154. 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 reoperation155.
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.
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