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1151
Hemolysis and Infection: Categories and Mechanisms
of Their Interrelationship
Frank E. Berkowitz
From the Department of Pediatrics, Emory University School of
Medicine, Atlanta, Georgia
Anemia is commonly recognized during the course of infections, especially chronic and acute infections in children
[1, 2]. Possible mechanisms for this development of anemia
include failure of iron utilization, bone-marrow suppression,
and shortened duration of red blood cell (RBC) survival
(hemolysis) .
Hemolysis is a well-recognized feature of infections such
as malaria, but it may also occur in a wide variety of other
infections. Recognition of such hemolysis is important not
only because it may require specific management but also because it may provide a clue to the cause of the infectious
process.
The association of hemolytic anemia with infection has been
briefly reviewed by Beutler [3]. The present review will provide a clinically useful classification of different cause-andeffect associations of hemolytic and infectious processes and
examine the mechanisms by which these associations occur.
Case Reports
Case I
A 3-week-old boy was admitted to Baragwanath Hospital,
Johannesburg, with a history of a recent onset of fever. He
had been born by normal vaginal delivery at another hospital. He had received phototherapy and at 2 weeks of age had
received an exchange transfusion for hyperbilirubinemia of
unknown etiology. On admission he was a well-looking baby
with mild fever and no other clinical findings. The hemoglobin concentration was 9.1 g/dl., and the total leukocyte count
was 7.9 x 109/L, with 63% neutrophils, 5% monocytes, and
Received 29 May 1990; revised 27 December 1990.
Reprints and correspondence: Dr. Frank E. Berkowitz, Department of Pediatrics, Emory University School of Medicine, 69 Butler Street SE, Atlanta,
Georgia 30303.
Reviews of Infectious Diseases 1991;13:1151-62
© 1991 by The University of Chicago. All rights reserved.
0162-0886/91/1306-0041$02.00
32 % lymphocytes. The CSF was normal. He was treated for
possible bacteremia with penicillin and gentamicin. On the
third day he was pale and had splenomegaly. A blood smear
showed a high concentration of Plasmodiumfalciparum. He
was treated intravenously with quinine but developed hypoglycemia and shock. He received an exchange transfusion but
died on the following day. Neither the mother nor the donors
of the blood for the original exchange transfusion gave evidence of malaria.
Case 2
An 8-year-old boy from Mozambique was admitted to Johannesburg Hospital with a 3-week history of a high intermittent fever, rigors, vague abdominal pain, and dark urine.
He had been treated with chloroquine for presumed malaria
but did not respond clinically. On examination he was an illappearing child with marked pallor, a temperature of 37.8°C
(which later rose to 40°C), weight of 22.5 kg, a pulse rate
of 134/minute, and a blood pressure of 90/36 mm Hg. He
had mild jaundice but no cyanosis. The other important
findings were a slight distension of the abdomen with a 4-cm
tender hepatomegaly but no splenomegaly, bilateral axillary
lymphadenopathy, and the child's withdrawn but conscious
state and extreme weakness, with brisk deep tendon reflexes.
The results oflaboratory investigations were as follows: hemoglobin concentration, 5.1gldL; mean corpuscular volume,
106 fl; mean corpuscular hemoglobin (MCH), 22.4 pglcell;
MCH concentration, 31.8 g of Hb/dL of red blood cells
(RBCs); total leukocyte count, 30.5 X lQ9/L, with 68% neutrophils, 22 % lymphocytes,S % monocytes, 3 % metamyelocytes, and 1% each of myelocytesand basophils; platelet count,
377 x 109/L; reticulocyte count, 23.2 %; total bilirubin, 6
~mol/L, with a direct component of 1 ~mol/L; aspartate
aminotransferase, 102 units/L; alanine aminotransferase, 76
units/L; and haptoglobin, 0.7 g/L (normal, 1.0-3.0 giL). The
patient was given a blood transfusion.
Blood, urine, and stool cultures were negative for pathogens, and the chest radiograph was normal. Blood smears for
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Different cause-and-effect relationships between hemolytic and infectious processes are categorized in a clinically useful manner as follows: infections causing hemolysis by invasion of red
blood cells (RBCs), by hemolysins, or by immune mechanisms; oxidative damage to RBCs during infections; hemolysis secondary to infection-induced pathologic processes; hemolytic effects
of antimicrobial therapy; and predisposition of an individual to infection caused by an underlying hemolytic disorder or therapy for that disorder. The mechanisms of these interrelationships
are discussed in detail.
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Berkowitz
Infections Causing Hemolysis-No Underlying
RBC Abnormality
Infection of the RBe
Malaria. Malaria is one of the most common human infections and probably the best known and most dramatic example of the association of hemolysis and infection. A
diagnosis of malaria should always be considered in patients
with hemolysis and a fever, as demonstrated by patient 1. Falciparum malaria is the most widespread and potentially harmful type of malaria and that in which anemia is most severe.
Anemia in malaria is due to both hemolysis and defective
erythropoiesis [4]. Hemolysis occurs mainly extravascularly
but may occur intravascularly in severe cases. The mechanisms of hemolysis appear to be both structural and immune.
The structural changes in the RBC include membrane damage and increased membrane rigidity [4]. A review of the sites
on the RBe that potentially expose it to damage by different
malarial parasites has been presented elsewhere [5].
That the degree of anemia often exceeds the degree of
parasitemia and that anemia may persist or first appear after
clearance of the parasitemia suggests that mechanisms other
than structural changes in the RBC might also operate in
producing hemolysis [6, 7]. Evidence suggests that autoimmune hemolysis affecting nonparasitized RBCs accounts for
some of this anemia, but the involvement of an autoimmune
response remains controversial [8-10]. The prevalence of
hemolysis, as measured by decreased serum concentrations
of haptoglobin, has been used as an indicator of the prevalence of malaria in a community [11].
Babesiosis. Babesiosis is primarily an infection of animals,
but it occasionally affects human beings. The causative organisms, members of the genus Babesia, of which there are
several species, are sporozoans that infect RBCs and that may
be confused on microscopic examination with malarial parasites. Most cases of babesiosis in humans are caused by Babesia microti, which is transmitted to humans by ticks. Most
Table 1. Categories of association of infection and hemolysis.
I. Infection causing hemolysis-no underlying RBC abnormality
A. Infection of the RBC: malaria; babesiosis; bartonellosis
B. Hemolytic toxin: Clostridium perfringens
C. Immune hemolysis
1. Autoantibodies to the RBC
2. Deposition of immune complexes on the RBC
3. Exposure of T antigens in the RBC membrane
D. Congenital infections: unknown mechanism
II. Infection precipitating hemolysis by oxidative stress in individuals
with underlying RBC disorder: G6PD deficiency; unstable
hemoglobins; paroxysmal nocturnal hemoglobinuria
III. Infection-induced pathologic responses causing hemolysis
A. Hemolytic uremic syndrome
B. Cardiac hemolytic anemia
C. Hypersplenism (?)
IV. Hemolysis caused by anti-infective therapy
A. Autoimmune
B. Oxidant stress
C. Toxic, e.g., ribavirin
V. Underlying hemolytic disorder predisposing to infection
A. Hyposplenism: sickle cell disease
B. Ischemia: sickle cell disease
C. Reticuloendothelial blockade (?)
D. Hyperferremia (?)
E. Defect in neutrophil killing: variants of G6PD deficiency
VI. Predisposition to infection by therapy for hemolytic disorders
A. Blood transfusion: transmission of infectious agents
B. Immunosuppressive therapy
C. Splenectomy
D. Iron overload from repeated blood transfusions
E. Deferoxamine therapy: predisposition to systemic yersiniosis,
zygomycoses
VII. Underlying hemolytic disorder, with aplastic crisis precipitated by
infection with parvovirus B19
cases in the United States occur in the northeast, particularly
on the islands off the Massachusetts coast [12]. The disease
resembles malaria clinically, but it is usually self-limited, except in asplenic individuals, for whom it may be fatal.
The mechanism of hemolysis in babesiosis is unclear. However, changes in the RBC membrane, such as protrusions, inclusions, and perforations, suggest that direct parasite-induced
damage to the RBC occurs [13]. Hemophagocytosis in the
bone marrow has also been described [14].
Bartonellosis (Oroyafever). Bartonellosis is caused by the
gram-negative bacillus Bartonella bacilliformis. It is transmitted by the sandfly in the valleys of the Andes in Peru,
Colombia, and Ecuador. The organism initially infects endothelial cells and subsequently becomes attached to the surface of RBCs. The acute phase of the illness is associated with
a severe hemolytic anemia, whereas the chronic (eruptive)
phase is characterized by verrucous skin lesions [15]. The
hemolytic anemia lasts for about 10 days. The mechanical fragility of the RBCs increases, but the Coombs' test is negative.
It has been suggested that the causative organism can be re-
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plasmodia and microfilaria were negative. Agglutinating antibodies to the 0 antigen of Salmonella typhi were present
at a titer of 1:3,200.
A diagnosis of typhoid fever with severe hemolytic anemia
was made, and the patient was treated with amoxicillin at a
dosage of 1 g every 6 hours orally, to which he responded well.
The patient's glucose-6-phosphate dehydrogenase (G6PD)
activity was 72 % of the control value during the acute illness, and 25 % of the control value when measured 3 months
later. He thus had G6PD deficiency and suffered from a hemolytic crisis precipitated by typhoid fever.
These cases are dramatic examples of an infectious process causing hemolytic anemia.
Different categories of association of hemolytic and infectious processes are summarized in table 1.
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Hemolysis and Infection
Hemolytic Toxins
Although many pathogenic bacteria produce hemolytic
toxins (hemolysins) that may be virulence factors [17], the
only bacterial hemolysin known to cause hemolysis in humans is the ex toxin of Clostridium perfringens. This toxin,
when given iv to animals-but not when given im-causes
massive intravascular hemolysis [18, 19]. The toxin reacts with
an RBC surface lipoprotein complex, a reaction that results
in the release oflysolecithin, a potent hemolysin. In humans,
this hemolysinmay produce severeintravascular hemolysis [20].
Immune Hemolysis Due to Infection
There are three basic mechanisms by which infections may
result in hemolysis on an immune basis: antibodies to the
RBCs are produced as a result of the infection (autoimmunity); antibody-antigen complexes specifically related to the
infectious agent coat the RBC, which then acts as an "innocent bystander"; the infectious agent results in exposure of
RBC antigens, which are normally hidden, to naturally occurring antibodies (polyagglutination).
Autoimmune hemolytic anemia. Autoimmune hemolytic
anemia is the result of the formation of antibodies directed
to antigens on the RBC membrane [21]. Infections account
for 1'\.18 % of cases of autoimmune hemolytic anemia overall
[22] and for rv27 % of cases in children [23]. The possible
immunologic bases for the production of these antibodies are
discussed in other reviews [22, 24].
The three main types of RBC autoantibodies are the socalled warm antibodies and cold antibodies and the DonathLandsteiner antibodies [21].
Warm antibodies are usually of the IgO class and bind at
37°C to RBC protein antigens-usually those of the Rh sys-
tem. Antibodies of subclasses Ig03 and IgOl may be bound
to Fe receptors of phagocytic cells, resulting in phagocytosis
of the RBC to which such antibodies are attached, a process
that occurs primarily in the spleen.
Cold antibodies are usually of the IgM class. They bind
to RBCs at low temperatures and fix complement. At warm
temperatures (body temperature) the antibody is eluted off
the RBC. The complement remains fixed, however, and may
form the terminal "attack" complex, causing intravascular
hemolysis. Alternatively, the C3b component of complement
may allow the RBC to become attached, via C3b receptors,
to a phagocyte. Phagocytosis in this situation occurs mainly
in the liver. Cold antibodies are generally directed at polysaccharides in the RBC, especially antigens of the Ii system.
The i antigen is found on all human fetal and neonatal RBCs
and is progressively replaced by the I antigen as the individual
gets older [25].
Most infection-induced autoimmune hemolytic anemias are
mediated by cold antibodies (i.e., they cause cold hemagglutinin disease [CHADD [22]. The infectious agents most commonly associated with CHAD are Mycoplasma pneumoniae
(in which the antibody is directed at the I antigen) and EpsteinBarr virus (in which it is directed at the i antigen) [21]. CHAD
has also been described following mumps, cytomegalovirus
infection, Legionnaire's disease, and visceral leishmaniasis
[26-28].
Donath-Landsteiner antibodies, which are IgO, cause paroxysmal cold hemoglobinuria (PCH). These antibodies become
attached to the RBCs at low temperature and fix complement.
When the RBCs are warmed, they are lysed intravascularly
by the complement. The target RBC antigen is the P antigen.
PCH is usually an acute illness, presenting during the convalescent stage of an infection with the sudden onset of pallor,
hemoglobinuria, jaundice, and hepatosplenomegaly [22], and
is usually self-limited. It has been reported following upper
respiratory tract infections, chickenpox, infectious mononucleosis, mumps, measles, measles immunization, and M.
pneumoniae infections [21, 22]. A more chronic form may
complicate secondary syphilis [29].
Autoimmune hemolytic anemia (AIHA) has been reported
following a wide variety of infections, including infection with
human immunodeficiency virus (HN) [30, 31]. The type of
antibody responsible for the disease is not always made clear
in the reports.
Immunizations have also been implicated in AIHA [23, 32].
In most of the reported cases, the role of the immunization
as a cause of the hemolytic anemia was not well demonstrated.
The diagnosis of AIHA depends on the demonstration of
sensitization of the RBCs with antibody (i.e., coated) by showing that the RBCs are agglutinated by an antiglobulin preparation. This is the direct antiglobulin test (DAT) or direct
Coombs' test. The antiglobulin preparation consists of a mixture of antibodies to IgO, IgM, and complement, or of antibody to one of them. To determine the antigen to which the
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moved from the RBC surface by phagocytes without the destruction of the RBC itself [16].
Superinfection with non-typhoid salmonellae is a major
cause of morbidity and mortality during the acute phase of
bartonellosis and is discussed in the section on underlying
hemolytic disorders that predispose to infection.
In addition to infecting the RBC and causing hemolysis,
malaria, babesiosis, and bartonellosis are usually transmitted in specific geographic locations and by specific arthropod
vectors (malaria and babesiosis may also be transmitted by
blood transfusion) and are diagnosed by visualization of the
infecting organism on a Oiemsa-stained blood smear (bartonellosis may also be diagnosed by blood culture).
Therefore, in individuals with evidence of hemolysis and
infection, a history of travel, blood transfusion, iv drug abuse,
and exposure to arthropods must be obtained and consideration must be given to examination of thick and thin blood
smears under an oil-immersion lens.
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Berkowitz
Congenital Infections
Chronic intrauterine infections, e.g., congenital syphilis,
rubella, cytomegalovirus infection, and toxoplasmosis, are
commonly associated with a hemolytic anemia, the mechanism of which is unknown [42-44].
Infection Precipitating Hemolysis by Oxidative Stress
in Individuals with an Underlying RBe Disorder
The normal RBC is frequently exposed to oxidant stresses
that can result in oxidation of the RBC membrane and/or of
hemoglobin. The balance between the severity of the oxidant
stress and the power of the reducing mechanisms of the RBC
will determine whether the RBC will suffer oxidative damage. If such damage occurs, the life span of the RBC will be
reduced [45].
The RBC membrane may undergo lipid peroxidation and
disulfide bonding, reactions that result in increased rigidity
of the cell. Hemoglobin may be oxidized to methemoglobin
and, via the intermediate compound hemichrome, to Heinz
bodies, which are inclusions that bind to the RBC membrane,
contributing to its increased rigidity [45].
The main reducing mechanisms of the RBC consist of four
enzymes: glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase, NADH diaphorase, and glutathione peroxidase (figure 1 [45]). Methemoglobin is reduced primarily
by NADH diaphorase, which is not shown in the diagram.
NADPH methemoglobin reductase, which is shown in the
diagram, plays a role only in the presence of an artificial electron carrier such as methylene blue [46]. Deficiency of these
enzymes is most commonly inherited, the most common and
important deficiency being that of G6PD [45].
Certain inherited abnormalities of hemoglobin, e.g., sickle
hemoglobin; hemoglobin Barts (HbH); and hemoglobins
Zurich, Christchurch, Koln, and Volga, also render the RBC
particularly susceptible to oxidative damage [47].
The main factors causing oxidative stress in RBCs are infections (discussed here) and drugs and toxins (discussed
later). The role of infections as a cause of hemolysis via oxidative stress has been most thoroughly investigated in individuals with G6PD deficiency.
The gene for the enzyme G6PD lies on the X-chromosome
and is polymorphic. The genetic variants-more than 150are produced by one or more genetic mutations [48]. They
have been categorized into five groups according to the activity of the enzyme. A few variant enzymes have a shortened
life span, which results in progressive deficiency in enzyme
activity with increasing age of the RBC. This deficiency
renders the cell susceptible to oxidative damage and hemolysis. The enzyme with standard activity is G6PDB. The most
common variants resulting in deficient activity are G6PDA-,
which is common in blacks in sub-Saharan Africa and in
the United States; G6PDMediterranean, in the Mediterranean
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antibodies are directed, it is necessary to elute the antibodies
off the RBC.
Depositionofimmune complexes on the RBC. This form
of immune hemolysis, in which the RBC acts as an "innocent
bystander;' is one of the most common forms of hemolysis
affecting children because of its frequent occurrence in systemic infections caused by Haemophilus infiuenzae type b.
The high frequency of anemia in children with meningitis
due to H. influenwe, as compared with meningitis due to other
bacteria, was first noted by Schiavone and Rubbo in 1953 [33],
and the association of such anemia with a longer duration of
illness was recognized by Kaplan and Oski in 1980 [34]. In
1986 Shurin et al. confirmed these findings and showed that
polyribose phosphate (PRP, the H. infiuenzae type b capsular antigen) and antibodies to PRP were present simultaneously in the sera of children with systemic infection with H.
influenwe and anemia, as was evidence of recent intravascular hemolysis [35].
These workers showed in vitro that RBCs sensitized with
PRP were lysed when they were incubated together with antibodies to PRP and complement, demonstrating that the
hemolysis that occurs during H. influenwe type b infections
is due to an immune-complex mechanism. PRP-sensitized
RBCs bind antibody to PRP, after which complement is fixed,
a sequence resulting in hemolysis [35]. Whether the RBC is
truly an "innocent bystander" or exhibits specific PRP receptors is unclear.
A similar mechanism is also thought to explain the anemia
that occurs in African trypanosomiasis [36] and to playa role
in the pathogenesis of anemia in malaria [8].
Polyagglutination. Polyagglutination occurs when Thomsen-Friedenreich (T) cryptoantigens within the RBC membrane are exposed to naturally occurring serum antibodies
to T antigens. The T antigen is a precursor substance of the
human MN blood group antigens. It is normally masked but
may become unmasked by exposure of the RBC to neuraminidase, which removes sialic acid from surface glycoproteins.
Most individuals >6 months old have circulating antibodies
to T antigens. If the T antigen is unmasked, these antibodies,
which are mainly of the IgM class, cause agglutination and
subsequent phagocytosis of the RBCs [37].
This phenomenon of polyagglutination has been noted in
young infants with bowel disorders, such as necrotizing enterocolitis, in whom neuraminidase produced by enteric bacteria is thought to cause exposure of the T antigen [38-40].
Such agglutination may be recognized only during attempts
at cross-matching blood [41]. In young infants who lack antibodies to T antigens, exposure of the T antigen will not result
in polyagglutination and hemolysis. However, transfusion of
adult blood containing antibodies to T antigens may result
in hemolysis [39, 40]. Lenz et al. found evidence of polyagglutination in 17 of 53 adults in a surgical intensive care unit. In
12 of these 17 patients, elevated serum levels of neuraminidase,
presumably of microbial origin, could be demonstrated [37].
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Hemolysis and Infection
G6P
NADP
GSH
6PG
N ADPH
GSSG
area; G6PDDebrousse, in North Africa; and G6PDCanton, in
Southern Asia [49].
The role of infection in precipitating hemolysis in individuals with G6PD deficiency was first appreciated during the
1960s·[50, 51]. Pursuing the observation that transient anemia during acute bacterial infection occurred more commonly
in American blacks (30%-40%), in whom G6PD deficiency
is common, than among American whites (5%-10%), in
whom this deficiency is rare, Mengel et al. prospectively studied the association of infection, anemia, and G6PD deficiency
in 206 black patients [52]. Of 69 patients with anemia only,
14 (20%) had G6PD deficiency; of 47 with infection only,
14 (30 %) had this deficiency; and of 18 with both anemia and
infection, 12 (67 %) had this deficiency. Mengel et al. concluded that the likelihood of G6PD deficiency in a patient with
both infection and anemia is high [52]. More recently, Shannon et al. found that infection is the factor precipitating hemolysis in 10 of 14 black children with G6PD deficiency [53].
How does infection impose oxidative stress on the RBC?
A large body of evidence suggests that the stress is accomplished by phagocytic cells, e.g., neutrophils that have been
activated by the infection [54-59]. It is thought that superoxide produced by neutrophils causes oxidation of hemoglobin
to methemoglobin and that H 20 z interacts with the methemoglobin to cause hemolysis. Other evidence indicates that
proteolytic mechanisms account for some of the damage
inflicted on the RBCs by activated neutrophils [59].
How are neutrophils brought into proximity with RBCs in
order to exert their damaging effect? Evidence suggests that
the cells are brought into contact by immune-complex bridges
[60]. The RBC receptors for these complexes are thought to
be their surface receptors for the activated complement components C3b and C4b [61, 62].
Infection-Induced Pathologic Responses Causing
Hemolytic Anemia
Three unrelated syndromes are included in the category of
pathologic responses to infection that result in a shortened
RBC survival time: hemolytic-uremic syndrome, cardiac
hemolytic anemia, and hypersplenism.
Hemolytic-Uremic Syndrome
Hemolytic-uremic syndrome (HUS) consists of a group of
disorders characterized by hemolytic anemia, thrombocytopenia, renal injury, CNS dysfunction, and thrombotic microangiopathy. Its clinical spectrum overlaps with that of thrombotic
thrombocytopenic purpura [63, 64]. The syndrome exhibits
different epidemiologic patterns, i.e., epidemic (typical) and
endemic (atypical). Typical HUS affects primarily, although
not exclusively, infants and young children. It is characterized clinically by a prodromal illness - usually gastroenteritis or an upper respiratory tract infection - followed by the
acute onset of renal failure, hemolytic anemia, and thrombocytopenia. Pathologically it is characterized by thrombotic
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Figure 1. Principal reactions involved in
reduction of oxidized compounds in the red
cell, which involves the enzymes glucose6-phosphate dehydrogenase (1); glutathione
reductase (2); NADPH methemoglobin
reductase Q); and glutathione peroxidase
~). G6P = glucose-6-phosphate; 6PG =
6-phosphogluconate; NADP = nicotinamide adenine dinucleotide phosphate;
GSSG = glutathione (oxidized form); GSH
= glutathione (reduced form); RSSR =
compound with sulfhydryl groups (oxidized
form); RSH = compound with sulfhydryl
groups (reduced form); Hb Fe2+ = hemoglobin with ferrous iron; and HbFe 3+ =
hemoglobin with ferric iron. Reprinted with
permission from W. B. Saunders [45].
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Berkowitz
Cardiac Hemolytic Anemia
The association of hemolysis with disease of native heart
valves was first recognized by Dameshek et al. in 1964 [67].
This type of hemolysis has been called macroangiopathic
hemolysisand is thought to be caused by shear forces exerted
on the RBC by extremely turbulent blood flow. The hemolysis
occurs intravascularly and is characterized by hemoglobinuria,
hemosiderinuria, a decreased plasma concentration of haptoglobin, and the finding of fragmented RBCs on blood smear.
Although most cases occur in patients with prosthetic heart
valves, it also occurs in patients with valvular rheumatic heart
disease, particularly that affecting the aortic valve [68-70].
This type of hemolytic anemia may occur in patients with infective endocarditis but has been reported only rarely in patients with this infection who do not have prosthetic valves
[68, 71-73].
Hypersplenism
Hypersplenism is a syndrome consisting of splenomegaly,
a decrease in one or more cellular elements of blood., a normal amount or hyperplasia of these elements in the bone marrow, and correction of the abnormality following splenectomy.
Many underlying conditions may cause hypersplenism, including infections such as malaria, visceral leishmaniasis,
schistosomiasis, tuberculosis, and brucellosis [74J.
The anemia in hypersplenism is thought to be caused primarily by the sequestration ofRBCs in the spleen and expansion of the plasma volume. Shortened RBC survival and overt
hemolysis are not prominent features of this condition. However, in several of the above-mentioned infections associated
with marked splenomegaly, hemolytic anemia is thought to
be immune-mediated. In these circumstances the splenomegaly may occur partially as a result of chronic hemolysis rather
than as a cause of it [75].
Hemolysis Caused by Anti-Infective Therapy
Hemolytic anemia accounts for rv10 % of the adverse
hematologic effects of drugs. The precise role played by a
specific drug in this hemolysis is not always clear, because
the hemolysis might be caused by the disease being treated,
by an underlying RBC abnormality, or by another drug. Although many different antimicrobial agents have been shown
to cause hemolysis, only a few cases have been reported for
several agents [76].
Drugs may cause hemolysis by immune or oxidative mechanisms. When the mechanism of hemolysis is unknown, the
effect of the drug on the RBC is called toxic.
Immune Drug-Induced Hemolytic Anemia
There are three different immune mechanisms by which
drugs may cause hemolysis: the immune-complex "innocent
bystander" mechanism; the immune-complex drug-adsorption
mechanism; and the autoimmune mechanism [77].
With both immune-complex mechanisms, the drug acts as
a hapten. Since most drugs are small molecules (molecular
weight, <500-1,000) and are non-protein, they are generally
non-immunogenic by themselves. However, when the drugs
are attached to a carrier protein such as an RBC membrane
protein or a serum protein, they may become immunogenic.
Immune-complex "innocent bystander"mechanism. In this
circumstance, the prototype cause of which is quinidine, immune complexes consisting of the drug and antibodies to the
drug become attached to the RBC, usually fixing complement
and resulting in total lysis of the RBC. The direct Coombs'
test is positive with anti-complement antiserum, and the indirect Coombs' test is positive only in the presence ofthe drug
[77]. In some cases a specific RBC receptor antigen appears
to be necessary for binding of the immune complex [78]. In
a patient who has previously been sensitized to the drug, only
a small amount of drug is necessary to cause hemolysis. Clinically, the hemolysis is acute, severe, and often intravascular.
Drugs used in the treatment of infection that have been
implicated in this type of immune hemolysis include acetaminophen, amoxicillin, cephalosporins, isoniazid, p-amino-
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microangiopathy, which primarily affects the renal glomeruli.
The blood smear shows features of microangiopathic hemolysis, i.e., fragmented RBCs, burr cells, helmet cells, and
schistocytes [63].
Several microorganisms have been incriminated in the etiology of this syndrome. Those whose roles have been best
demonstrated are Escherichia coli (verotoxin-producing
strains), Shigella dysenteriae, and Streptococcus pneumoniae
[63, 65].
The pathogenesis of HUS is not completely understood and
may be different in different forms of the syndrome. Endothelial injury seems central to the pathogenesis [63]. The
two main theories of pathogenesis are not mutually exclusive.
According to the first theory, endothelial injury, which is
caused by the inciting agent, e.g., verotoxin, is followed by
platelet aggregation and the formation of microthrombi. The
fibrin strands within the thrombi are thought to cause mechanical disruption of RBCs and platelets. According to the
second theory, the inciting agent causes direct damage to endothelial cells, to RBCs, and to platelets. Other factors thought
to be involved in the pathogenesis of HUS include membrane
lipid peroxidation; changes in blood concentrations of coagulation factors, including an imbalance between thromboxane
A 2 and prostacycline concentrations; and an increase in concentrations of von Willebrand factor multimers. The pathogenesis of HUS associated with shigella infections may involve
endotoxin, while that associated with pneumococcal infections appears to be the unmasking of the T cryptantigen by
neuraminidase [63, 66].
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Hemolysis and Infection
Oxidative Drug-Induced Hemolysis
The balance between oxidative stresses exerted on the RBC
and its reducing ability has been discussed earlier. The role
of drugs in oxidative hemolytic anemia has been discussed
in an excellent review by Gordon-Smith [45]. The best-known
example of this type of hemolysis is that occurring in individuals with G6PD deficiency.
Although hemolytic anemia caused by the antimalarial drug
pamaquine was first recognized in 1926, it was only during
the 1950s that its mechanism - oxidative hemolysis of G6PDdeficient red cells - was appreciated [82]. The clinical course
of this disorder was demonstrated by a study in which primaquine was given to individuals with G6PDA- (the common
deficient variant in African Americans). After 2 to 3 days they
developed signs of acute hemolytic anemia. The hemolysis
continued for about 1 week and then stopped, despite continued administration of the drug. Because the enzyme activity in the RBC decreases as the cell ages, hemolysis primarily
affects the older cells. The younger cells, which have adequate enzyme activity, are not hemolyzed despite the presence of the drug. This has important implications for the
diagnosis of this disorder [82]. When a diagnosis of G6PD
deficiency is suspected on the basis of clinical illness and the
hematologic findings of Heinz bodies and vacuolated RBCs
(bite cells), it should be confirmed by the demonstration of
reduced enzyme activity in the RBC. When this is done during or shortly after the hemolytic episode, the enzyme activity might appear to be normal because a high proportion of
the RBCs will be young. The assay should therefore be
repeated after a few weeks, a necessity well demonstrated with
regard to patient 2 described above.
Many drugs have been incriminated as causing hemolysis
in G6PD-deficient individuals, but in several cases the causative role of the drug in the hemolytic episode has not been
well substantiated. Furthermore, the likelihood of a drug's
causing hemolysis is influenced by the dose of the drug and
the variant of the deficient enzyme [82].
The following antimicrobial drugs have been shown to cause
hemolytic anemia in G6PD-deficient individuals: nalidixic
acid, niridazole, nitrofurantoin, pamaquine, primaquine, sulfacetamide, sulfamethoxazole, sulfanilamide, sulfapyridine,
and thiazolsulfone [82]. The combination trimethoprimsulfamethoxazole has been found to be safe for use in individuals with the G6PDA- variant [83].
The following drugs that are used in treating infections and
that have previously been considered to be contraindicated
for individuals with G6PD deficiency should actually be considered relatively safe: acetaminophen, aspirin, chloramphenicol, chlorguanide, chloroquine, colchicine, diphenhydramine,
isoniazid, probenecid, pyrimethamine, quinidine, quinine, sulfamerazine, sulfamethoxypyridazine, sulfazoxazole, and trimethoprim [82].
Dapsone causes oxidative stress in RBCs and may cause
methemoglobinemia and hemolysis [45]. When used in the
usual dosage, dapsone does not cause significant hemolysis
in individuals with the G6PDA- variant but may do so in individuals with the G6PDMediterranean variant or with variants of
G6PD deficiency associated with chronic nonspherocytic
hemolytic anemia [45]. Other drugs that may cause methemoglobinemia and hemolysis include sulfasalazine, which
is used in the treatment of inflammatory bowel disease, and
phenazopyridine hydrochloride, which is frequently used as
a urinary analgesic [45].
"Toxic" Drug-Induced Hemolysis
The drug-induced hemolysis referred to as "toxic" is that
caused by unknown mechanisms. The prime example of an
antimicrobial drug that produces such hemolysis is the broadspectrum antiviral agent ribavirin, a nucleoside analogue. This
agent is given by aerosol inhalation for treatment of severe
infection with respiratory syncytial virus and intravenously
or orally for treatment of Lassa fever. Ribavirin is concentrated within the RBC, producing a mild hemolytic anemia
that is generally not of clinical significance [84, 85].
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salicylic acid, probenecid, quinidine, guanine, rifampin,
streptomycin, and sulfonamides [77, 79]. Blackwater fever,
a severe form of intravascular hemolysis formerly occurring
with repeated use of quinine in malaria-endemic areas, possibly represents an example of this type of immune hemolysis.
Immune-complex drug-adsorption mechanism. In this circumstance, which most commonly occurs with penicillin, the
drug binds to the RBC membrane. If antibodies to the drug
are formed, they become attached to the drug on the RBC
membrane. These antibodies are of the IgG class and do not
fix complement. Ifmany antibody molecules become attached,
extravascular hemolysis ensues. Although penicillin can frequently be found to coat RBCs, hemolysis of this type occurs
only when large doses of this drug are administered. With
cephalosporins, however, hemolysis may occur with the usual
doses. The direct Coombs' test is positive with antiserum to
IgG, and the indirect Coombs' test is positive only if drugsensitized RBCs are used in the test [77].
Antimicrobial agents that have been shown to cause hemolysis by this mechanism include the penicillins, several cephalosporins, erythromycin, tetracycline, isoniazid, quinidine,
and streptomycin [76, 77, 80, 81].
Cephalosporin-coated RBCs may bind to non-immunoglobulin serum proteins. If the reagents used in the Coombs'
test contain antibodies to these proteins, the Coombs' test may
be positive in the absence of a setting for immune-mediated
hemolysis [77].
Drug-induced autoimmune hemolyticanemia. In this circumstance, the prototype cause of which is a-methyldopa,
the drug induces the formation of antibodies to RBCs without itself playing a role in the hemolytic process [77].
1157
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Berkowitz
Underlying Hemolytic Disorders Predisposing
to Infection
The most common hemolytic disease predisposing to infection is sickle cell disease. This predisposition is due primarily to the hyposplenism that follows the development of
microinfarctions of the spleen, but a defect in C3b fixation
to bacterial surfaces also is involved [101]. Hyposplenism may
be detected in children with sickle cell disease who are as
young as 4 months old and is usually present by the age of
1 year. This defect in host defense predisposes these individuals to infections - especially bacteremia - with encapsulated
bacteria, particularly S. pneumoniae and H. irfiuenzae [87].
In Saudi Arabia and in tropical Africa.ienteric bacilli, e.g.,
E. coli and salmonellae, are also common causes of bacteremia in such individuals [102, 103]. In tropical Africa the
most common infectious cause of death in individuals with
sickle cell disease is malaria. Although individuals with sickle
cell trait (heterozygous) are provided some protection against
infection with P. falciparum, hyposplenic homozygotic individuals are particularly susceptible to severe infections with
this parasite [l 02] .
Persons with sickle cell disease are also particularly susceptible to osteomyelitis caused by non-typhoid salmonellae.
Adeyokunnu and Hendrickse, in their study of 63 Nigerian
children with salmonella osteomyelitis, found that 57 had
sickle cell disease [104]. They postulated that the following
sequence of events produces this infection. (1) Poor sanitation results in frequent gastrointestinal infections with
salmonellae. (2) Bowel ischemia, which results from vasoocclusive episodes, facilitates hematogenous spread of these
organisms. (3) The host defenses against salmonellae might
be further compromised by hepatic dysfunction and hemolysis itself (see above). (4) Bone infarctions predispose to osteomyelitis and persistence of the organism in the affected area
[104].
Another hemolytic disease in which there appears to be a
specific predisposition to infection is G6PD deficiency. The
evidence for this is both clinical and epidemiologic. G6PD
deficiency primarily affects the RBC, resulting in hemolysis.
However, the enzyme is also necessary for the production of
the oxidative metabolites, e.g., H 20 2 , necessary for bacterial
killing by phagocytes. G6PD activity of leukocytes is generally normal in individuals with G6PD deficiency in RBCs,
but with rare variants of the enzyme deficiency, the leukocyte
is affected. Individuals with these variants have presented with
severe or recurrent infections, which often resemble those seen
in patients with chronic granulomatous disease [105-107].
G6PD deficiency also appears to predispose to a particularly
severe clinical course in patients with rickettsial infections
[108, 109].
The epidemiologic evidence suggesting that G6PD deficiency predisposes to infection is provided by studies showing a higher prevalence of G6PD deficiency in infected than
in noninfected individuals or a higher prevalence of infection
in G6PD-deficient than in otherwise normal individuals. In
1975 Lampe et al. showed a higher prevalence of G6PD
deficiency in children with typhoid fever, pneumococcal in-
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It has been known for many years that certain conditions
in which hemolysis occurs predispose to bacterial infections,
e.g., bartonellosis to systemic salmonellosis and sickle cell
disease to pneumococcal bacteremia [86, 87]. Although the
specific reasons why different underlying hemolytic diseases
predispose to infection may vary (see below), two possible
mechanisms are responsible: reticuloendothelial blockade and
increased availability of hemoglobin or iron for microbial
growth.
Experimental work in mice has shown that infusion of sensitized RBCs results in an increase in the fatality rate for
Salmonella typhimurium infection [88], and infusion ofRBC
stroma results in a decrease in the clearance function mediated by the hepatic macrophage complement receptor and an
increase in the fatality rate for pneumococcal infection [89].
In vitro studies have shown that macrophages exposed to
sensitized RBCs demonstrate decreased rates of bacterial killing [88-91]. This work suggests that ingestion of RBCs by
the reticuloendothelial system, which is exaggerated in hemolytic states, may interfere with other clearance functions of
the reticuloendothelial system, such as the removal of bacteria from the bloodstream. However, no decrease in reticuloendothelial clearance activity could be shown in studies of
humans with thalassemia [92, 93].
The role of iron in host defenses and microbial growth has
been reviewed by Bullen [94] and Finkelstein et al. [95]. They
reviewed several reports in which iron therapy given for iron
deficiency resulted in an increased incidence of severe infections, particularly those caused by enteric bacilli [94, 95].
Bullen demonstrated that blood facilitates the development
of an infection in an enclosed space, e.g., the peritoneal cavity,
by providing iron for microbial growth [94].
It is not clear if hemolytic conditions predispose to infections by providing iron to microorganisms. However, repeated
blood transfusions resulting in iron overload, together with
the use of deferoxamine, an iron chelator, undoubtedly predispose to severe infections. This effect of iron chelators has
been observed in experimental animals with S. typhimurium
infection and in humans with thalassemia with Yersinia enterocolitica infection [96, 97]. Yo' enterocolitica differs from
many other bacteria in that it does not elaborate siderophores.
When these organisms are present together with other bacteria, e.g., in the colon, they can assimilate iron by utilizing
the siderophores produced by the other bacteria. In individuals with iron overload who are being treated with deferoxamine (a siderophore derived from Streptomyces pilosis) Y.
enterocolitica present in a nonpermissive site, e.g., the bloodstream, can use deferoxamine as its siderophore and thus can
multiply at such a site [98]. Deferoxamine also appears to
predispose patients who are receiving it as therapy for iron
or aluminum overload to infections with Zygomycetes [99,
100].
RID 1991;13 (November-December)
RID 1991;13 (November-December)
Hemolysis and Infection
fection, and tuberculosis than in uninfected children [110].
In a study of 33,943 neonates in Saudi Arabia, Abu-Osba et
al. showed that the incidence of bacteremia in infants with
G6PD deficiency was significantly higher than that in otherwise normal infants. This increase was particularly significant
for bacteremia caused by catalase-positive organisms (Le.,
those organisms capable of destroying leukocyte H2(h) [111].
Predisposition to Infection by Therapy for
Hemolytic Disorders
Blood Transfusion
Blood transfusion is the primary supportive measure in the
treatment of anemia, and transmission of infection is a major
potential complication of this form of therapy. Although many
different infectious agents can be transmitted by blood transfusion, the most important are the viral agentscausing hepatitis
(non-A, non-B hepatitis and hepatitis B) and cytomegalovirus
and HIV [112]. In malarial endemic areas, malaria is also an
important transfusion-transmitted disease [112, 113] as is infection with Trypanosoma cruzi in areas where this parasite
is endemic [112]. Infectious agents that may be transmitted
by blood transfusion are listed in table 2 [114]. Many different bacteria have been reported to cause transfusion-acquired
infections as a result of contamination of the blood after its
collection from the donor [114].
Immunosuppression
Corticosteroids are used for immunosuppression primarily for the treatment of autoimmune hemolytic anemias. If
used in high doses for prolonged periods they predispose the
patient to the infectious complications of chronic immunosuppression.
Splenectomy
Splenectomy is frequently performed in patients with
hereditary hemolytic anemias such as hereditary spherocytosis and thalassemia major. Splenectomy renders the patient
particularly susceptible to fulminating bacteremia with encapsulated organisms, in particular S. pneumoniae, H. irifluenzae type b, and Neisseria meningitidis [115].
Precipitation of an Aplastic Crisis by Parvovirus B19
in Individuals with Underlying Hemolytic Disorder
Parvovirus B19 infects erythroid progenitor cells in the bone
marrow, resulting in a transient decrease in the production
ofRBCs. In normal individuals a transient decrease in hemoglobin concentration can be demonstrated, but usually this
has little clinical consequence. However, in individuals with
a chronic hemolytic anemia, whose RBCs have a shortened
life and erythropoiesis is accelerated, this infection may result in the development of severe anemia, called an aplastic
crisis. This infection has been reviewed elsewhere [116, 117].
Conclusion
The wide variety of clinical situations in which hemolytic
and infectious processes may be associated are described and
categorized in a manner useful to the clinician.
When a patient is suspected of having an infectious illness
as well as a hemolytic process, it is essential to obtain a
detailed history and to perform a thorough physical examination. Each pathologic process may necessitate the performance of several laboratory investigationsfor elucidation, e.g.,
cultures of different body fluids and various hematologic tests.
However, attention to the following specific historical and laboratory information is of particular importance: (1) family
or personal history, i.e., consanguinity, genetic diseases, gallstones, dark urine, chronic leg ulcers, recurrent episodes of
anemia (especially after drug ingestion), and anemia unresponsive to hematinics [21, 118]; (2) epidemiologic history,
i.e., geographic and travel history, blood transfusions, recreational activities, and other possible exposures to infectious
agents; and (3) blood smear, which should include the examination of not only thin smears for RBC morphology, but
also thick and thin smears for parasites.
Table 2. Infectious agents transmitted in blood.
Group
Specific agents
Viruses
Hepatitis B, hepatitis A, hepatitis non-A non-B,
cytomegalovirus; HIV; Epstein-Barr virus; HTLV-I
Rickettsia prowazeki
Treponema pallidum, Brucella, Yersinia enterocolitica;
others associated with contamination of blood after
its collection
Plasmodium species; Trypanosoma cruzi; Trypanosoma
brucei; Babesia species; Toxoplasma gondii
Filaria
Rickettsiae
Bacteria
Protozoa
Nematodes
NOTE.
HTLV-I = human T cell Iymphotrophic virus I.
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