Infections in Patients With Aplastic Anemia

Jessica M. Valdez,a,b Phillip Scheinberg,c Neal S. Young,c and Thomas J. Walshb

Infection is a major cause of death in patients with aplastic anemia (AA). There are differences
between the immunocompromised state of a patient with AA and the patient who is neutropenic
due to chemotherapy and this leads to a difference in the infections that they incur. Prolonged
neutropenia is one of the largest risk factors for the development of infections with the invasive
mycoses and bacteria. Recovery from neutropenia is directly related to survival, and supportive care
plays a large role in protection while the patient is in a neutropenic state. The most common
invasive mycoses include the Aspergillus species, Zygomycetes, Candida spp., and Fusarium spp.
Bacterial infections that are seen in patients with AA include gram-positive coagulase-negative
Staphylococcus species, Enterococcus, Staphylococus aureus, Clostridium spp., Micrococcus,
alpha-hemolytic streptococci, Listeria monocytogenes, and Bacillus cereus. Gram-negative infec-
tions including gram-negative bacilli, Escherichia coli, Salmonella, Bacteroides fragilis, Klebsiella
oxytoca, Klebsiella pneumonia, Aeromonas hydrophilia, Pseudomonas aeruginosa, and Vibrio
vulnificus. Viral infections are much less common but include those that belong to the Herpes-
viridae family, community-acquired respiratory viral infection, and the viral hepatitides A, B, and
C. Evidence of the parasite Strongyloides stercoralis has also been documented. This review
discusses the major invasive fungal infections, bacterial pathogens, parasites, and viral infections
that are found in patients with AA who are treated with immunosuppressive therapy. The specific
immune impairment and current treatment parameters for each of these classes of infection will
also be discussed.
Semin Hematol 46:269 276. 2009 Published by Elsevier Inc.

A plastic anemia (AA) is a bone marrow failure

syndrome characterized by reduction of hema-
topoietic stem and progenitor cells, empty
bone marrow, and pancytopenia. Aplastic anemia,
when severe, is life-threatening and if untreated is fa-
EPIDEMIOLOGY AND
ETIOLOGY OF APLASTIC ANEMIA
AA is rare, with an incidence of two cases per million
in the West but a higher rate in East Asian countries.1,4,5
Severe AA (SAA) is defined by at least two of the following
tal.1,2 Neutropenia associated with AA increases suscep-
peripheral blood count criteria: (1) absolute neutrophil
tibility to infections, particularly those caused by bac-
count (ANC) 500/mL, (2) absolute reticulocyte count
teria and fungi. As neutropenia in patients with AA may
(ARC) 60,000/L, and (3) a platelet count 20,000/
be severe and prolonged, infection is the leading
L.6 AA has been associated with exposures to drugs,
causes of death in these patients.3 This monograph will
chemicals, and toxins, as well as certain viral infections.
review the major invasive fungal infections, bacterial
However, despite the evidence of multiple epidemiologic
pathogens, parasites, and viral infections that are found
associations, the cause of AA remains elusive in the ma-
in patients with AA who are treated with immunosup-
jority of cases7 (Table 1).
pressive therapy (IST).

aHoward Hughes Medical InstituteNational Institutes of Health Re-
search Scholars Program, Bethesda, MD.
bPediatric Oncology Branch, National Cancer Institute, Bethesda, MD.
cHematology Branch, National Heart, Lung and Blood Institute, Be-
thesda, MD.
Address correspondence to Thomas J. Walsh, MD, Chief, Immunocom-
promised Host Section, Pediatric Oncology Branch, National Cancer
Institute, CRC 1-5750, 10 Center Dr, Bethesda, MD 20892. E-mail:
walsht@mail.nih.gov
0037-1963/09/$ - see front matter
2009 Published by Elsevier Inc.
doi:10.1053/j.seminhematol.2009.03.008
PATHOPHYSIOLOGY AND TREATMENT
AA can be inherited or acquired. Inherited AA usu-
ally presents in childhood and characteristic physical
anomalies are frequently (but not always) present. Most
AA is acquired and occurs in the first three decades of
life. Clinical evidence and laboratory data suggest that
the marrow failure in AA is due to an immune-mediated
destruction of the hematopoietic compartment by au-
toreactive cytotoxic lymphocytes.2 A primary stem cell
defect may contribute to the marrow failure as short-

Seminars in Hematology, Vol 46, No 3, July 2009, pp 269 276 269

270 J.M. Valdez et al

IST. HSCT from a matched sibling donor is preferred

Table 1. Causes of Severe Aplastic Anemia for children and young adults with a histocompatible
sibling, and IST for those without a matched sibling
Idiopathic donor and in older patients. Long-term survival with
Infections either treatment modality is comparable.1 HSCT from
Hepatitis unrelated donors is usually reserved for patients who
A, B, C, non-serological are transplant candidates and have failed IST. The cur-
Epstein-Barr virus rent standard of IST is a combination of antithymocyte
Cytomegalovirus globulin (ATG) and cyclosporin A (CsA), for which a
Mycobacterial infections response rate of about 60%-70% have been reported
Human immunodeficiency virus across several studies1,8,9 In those with refractory or
Parvovirus B19 relapsed disease, repeat courses of IST have been ben-
Drugs and chemicals eficial in about one third and two thirds of cases,
Gold salts respectively.10 In addition to the natural history of in-
Chloramphenicol fections in AA, treatment modalities may also increase
Carbamazepine the risk of infection.11 Currently, due to improvements
Sulfonamides in salvage therapies, and better transfusional and anti-
Nonsteroidal anti-inflammatory drugs fungal support, the survival rates of patients with SAA
Antiepileptic and psychotropic agents have greatly improved.
Cardiovascular drugs
Penicillamine
Allopurinol IMMUNE IMPAIRMENT AND
Benzene INFLUENCE ON SUSCEPTIBILITY TO INFECTION
Pesticides Profound persistent neutropenia is the dominant
Paroxysmal nocturnal hemoglobinuria risk factor for the development of bacterial and inva-
Graft-versus-host disease sive fungal infections in SAA. Reflecting the predomi-
Pregnancy nance of persistent neutropenia in the natural history
Eosinophilic fasciitis of SAA, invasive pulmonary aspergillosis constitutes a
Pure red cell aplasia major cause of mortality, while pneumocystis pneumo-
Inherited nia, which is associated with defective T-cell responses,
Fanconi anemia is seldom reported.
Dyskeraatosis congenital Some major differences exist between the immuno-
Inevitable compromised state of the AA patient and that of the
Radiation patient who is neutropenic due to chemotherapy,
Chemotherapy which in turn, leads to differences in the infections that
they incur (Table 2). Neutropenia in cancer is usually
due to cytotoxic therapy and the myelosuppression
can lead to defects in the host defense matrix and cause
ened telomeres and mutations in the genes of telomere a breakdown of the mucosal integrity.3 As stated ear-
repair complex have been identified in some patients lier, patients with AA have primarily a decrease in the
with SAA.1 blood counts resulting in neutropenia and increased
Patients with SAA undergo treatment with either susceptibility to recurrent bacterial sepsis or invasive
hematopoietic stem cell transplantations (HSCT) or fungal infection.12 In comparison to patients undergo-

Table 2. Differences in Immune Impairment and Susceptibility to Infection in Patients With Severe
Aplastic Anemia and Cancer
Severe Aplastic Anemia Cancer
Cause of neutropenia Causes of aplastic anemia, as listed in Table 1 Chemotherapy, marrow infiltration
Duration of neutropenia Persistent Reversible
Mucocutaneous Intact Disrupted (chemotherapy-induced
integrity mucositis)
Common pathogens Gram-positive bacteria, filamentous fungi Enterobacteriaciae (eg, E coli,
(eg, Aspergillus spp., Zygomycetes) Klebsiella spp.), Candida spp.
Infections in patients with aplastic anemia
ing chemotherapy, they normally do not have a disrup-
tion of mucocutaneous barriers. The combination of
chemotherapy-induced mucosal disruption and neutro-
penia in a cancer patient leads to invasion and translo-
cation of enteric bacteria (like Escherichia coli) and
gastrointestinal Candida spp. By comparison, the pro-
longed neutropenia in an AA patient predisposes to
respiratory fungal pathogens, such as Aspergillus spe-
cies and Zygomycetes. There have been more reported
episodes of gram-positive bacterial infections in AA,
such as those caused by Staphylococci, suggesting that
vascular catheters may provide a portal of entry.
RELATION BETWEEN INFECTION
AND TYPE OF IMMUNOSUPPRESSION
The treatment of severe aplastic anemia may add
additional burdens of risk. The basis of immunosup-
pressive therapy for AA is ATG and CsA. Corticoste-
roids, which are routinely administered as serum sick-
ness prophylaxis associated to ATG, add to the net
effect of ATG CsA in producing profound T-cell
depletion and dysfunction. Although the data are lim-
ited, the risk for infection caused by DNA viruses,
including varicella zoster virus (VZV), herpes simplex
virus (HSV), cytomegalovirus (CMV), and Epstein-Barr
virus (EBV) are increased, in principle, in patients dur-
ing this vulnerable period of impaired T-cell response.
The use of cyclophosphamide may also deplete T cells
and may cause mucosal disruption, leading to translo-
cation of gram-negative bacteria from the alimentary
tract.
INVASIVE FUNGAL INFECTION
Fungal pathogens contribute importantly to morbid-
ity and mortality in immunocompromised patients13
and invasive fungal infections are the leading cause of
death in patients with AA.3 Invasive fungal infections
are common in patients with hematological disorders,
and infections caused by Aspergillus species are among
the most common infection reported in the literature.
Aspergillus is a thermophilic, aerobic fungus with sep-
tate hyphae and a fruiting body commonly found in the
environment. The organism is usually acquired through
the respiratory tract. Aspergillus fumigatus is the most
common species causing invasive aspergillosis, fol-
lowed by Aspergillus terreus, Aspergillus flavus, and
Aspergillus niger.14 Invasive aspergillosis has reported
mortality rates of 70% to 90%, making it the most
serious fungal infection in patients with SAA.15 There
are multiple aspects of the immune system of a patient
who is pancytopenic that contribute to the inability of
host defenses to evade or overcome an infection
caused by Aspergillus. Macrophages are the first line of
defense in killing the Aspergillus conidia and polymor-
phonuclear leukocytes (PMNs) are the main defense
271
against the mycelial forms.16 A lack of granulocytes
leads to a susceptibility to the invasive fungi and there
is a significant relationship between the prognosis of an
Aspergillosis infection and the duration of granulocy-
topenia.17
The Zygomycetes are the second most common cause
of invasive fungal infection encountered in SAA. Zygomy-
cosis recently has been recognized as an emerging patho-
gen and an increasing cause of invasive fungal infec-
tion.18,19 Clinically reported as mucormycosis, within
the order of Mucorales, in the class of Zygomycetes, the
fungal pathogens include Rhizopus, Mucor spp., and
Cunninghamella bertholletiae. Mucorales have been re-
ported as causing pulmonary, rhinocerebral, dissemi-
nated, gastrointestinal, and cutaneous infections. Dissem-
inated murormycosis in an immunocompromised patient
carries a grave prognosis: death often occurs within
weeks.20 In an immune-competent patient, macro-
phages destroy inhaled sporangiospores and prevent
infection, which is important because the spores of
Mucoraceae may be highly resistant to other immune
response mechanisms.21 This mechanism of protection
is impaired in the patient who is undergoing cortico-
steroid treatment. Corticosteroids suppress macro-
phage function, and thus corticosteroid use is an addi-
tional risk factor in the development of infection.22
Although still uncommon, mucormycosis is an infec-
tion that requires a high index of suspicion within the
AA population. Aggressive treatment measures should
be taken to prevent the evolution of this severe and
often fatal infection.
Candida spp. are common causes of invasive fungal
infections in immunocompromised patients and are
among one of the leading causes of morbidity and
mortality in the oncology population.23 However, Can-
dida species are not as frequently observed in patients
with SAA. Candida albicans is the most well known of
the Candida species and is a normal constituent of the
human flora, a commensal of the skin, gastrointestinal,
and genitourinary tracts, and is responsible for the
majority of Candida bloodstream infections. In addi-
tion, non-albicans Candida species such as Candida
glabrata, Candida parapsilosis, and Candida krusei
are among the current leading causes of invasive can-
didiasis, causing approximately 50% of all bloodstream
infections.13 Disseminated candidiasis is reported in
AA,24 but was not common in the review of Wein-
berger et al.
Fusarium spp. also are well-described causes of
invasive fungal infection that have recently emerged as
causes of mortality in neutropenic patients.25-28 Inva-
sive fusarosis in patients with AA has been caused by
Fusarium solani, Fusarium oxysporum, Fusarium
chlamydosporum, and other cases in which the spe-
cies was not noted. Fusarium are soil saprophytes and
plant pathogens that are commonly associated with
keratitis, skin wounds, and nail infections in humans,
272
but they may be highly invasive in patients with SAA.
Unfortunately, the histological appearance of Fusar-
ium can be variable and potentially indistinguishable
from invasive aspergillosis.25 Both produce branched
septate hyphae with similar width range, and both
cause vascular invasion, which leads to thrombosis and
tissue necrosis,26 thus leading to challenges in diagnosis
and treatment. Disseminated fusarosis can present as a
pulmonary infiltrate, cutaneous lesions, and sinusitis.
Disseminated fusarosis has a high mortality and prog-
nosis is associated with recovery from neutropenia.29
Treatment for localized disease can include surgery
that is supplemented with antifungal therapy, while
treatment for disseminated disease is not well defined,
but the literature suggests combination antifungal ther-
apy with the use of cytokine stimulation and granulo-
cyte transfusions.30
Less common but potentially lethal fungal infections
in patients with AA also have been reported. Trichos-
poron spp., which are also widely distributed in nature
and are commensal in the human respiratory and gas-
trointestinal tracts, cause severe infections in patients
with leukemia, AA and HSCT.31 Trichosporon infection
is not as common in patients with AA as in those with
acute leukemia, possibly because a common route of
infection cannot be attributed to mucosal disruption.
Trichosporon is resistant to the fungicidal effects of
amphotericin B.32 Current data support treatment with
fluconazole or voriconazole and granulocyte-macroph-
age colony-stimulating factor (GM-CSF).13
Another uncommon but serious infection caused by
Trichoderma longibrachiatum is reported in the AA
literature.33 Trichoderma is a ubiquitous saprophytic
fungus that is commonly found in soil and has low
pathogenicity. Trichoderma can present as pulmonary,
cerebral, soft tissue, and disseminated disease.
Single case reports of infections caused by dematia-
ceous moulds, Scedosporium inflatum,34 Phaeoacre-
monium inflatipes,35 and Exserohilum rostratum36
are also described. It is important to maintain height-
ened awareness of these rare but serious mycological
causes of human infection in patients with AA.
Because the neutropenia of SAA is chronic, espe-
cially in those unresponsive to IST, prophylaxis against
bacterial and fungal infections is not routinely admin-
istered. The potential for emergence of resistant patho-
gens militates against this strategy. Instead, patients are
monitored carefully and are instructed to report any
signs or symptoms of infection to allow for early and
definitive diagnostic procedures and rapid implemen-
tation of therapeutic interventions. For management of
invasive fungal infections, the use of diagnostic com-
puted tomography followed by bronchoscopy should
be employed in order to determine the presence of a
pathogen and to utilize specific antifungal therapy to
that pathogen. In settings where a diagnosis cannot be
definitively established, empirical therapy should be
J.M. Valdez et al
implemented. The available armamentarium for man-
agement of invasive pulmonary aspergillosis and other
respiratory fungal infections include voriconazole, lipid
formulations of amphotericin B, echinocandins, posacon-
azole, and itraconazole. A review of antifungal therapy is
provided by Groll and colleagues in this issue of Semi-
nars. The completion of a course of antifungal therapy is
predicated upon resolution of pulmonary infiltrates; foci
may require weeks for resolution, and therefore extended
courses of antifungal therapy are not unusual. There is a
propensity for invasive fungal infections to relapse during
periods of extended neutropenia, and secondary prophy-
laxis is recommended.
BACTERIAL INFECTIONS
Patterns of Bacterial
Infections in Aplastic Anemia
Torres and colleagues from the M.D. Anderson Can-
cer Center found that gram-positive bacteria (n 40)
predominated over gram-negative bacteria (n 8) as
causes of infections in patients with AA.37 Coagulase-
negative staphylococci (n 13) were the most com-
mon causes of the 40 cases of gram-positive bacterial
infection, while Stenotrophomonas maltophilia (n
3), a waterborne non-enteric pathogen, was the most
common cause of the eight cases of gram-negative
bacterial infection. Notably, E coli constituted only two
of the eight gram-negative bacterial pathogens. Simi-
larly, Weinberger and coauthors reported that E coli
was a relatively infrequent pathogen occurring in 6
(23%) of 39 gram-negative bacillary infections.3 By com-
parison, E coli was found to cause 361 (43%) of 835
gram-negative bacterial infections in a parallel patient
population of febrile neutropenic cancer patients.
Gram-Positive Infections
The gram-positive bacteria tend to predominate as
being more common than the Enterobacteriaciae (such
as E coli). The predominant gram-positive bacteria in
patients with SAA are coagulase-negative Staphylococ-
cus spp.3,37-39 The fact that the gastrointestinal mucosal
barriers usually remain intact in patients with SAA may
explain the relative paucity of enteric gram-negative
bacillary infections, in contrast to patients with chemo-
therapy-induced mucositis and neutropenia in whom
gram-negative bacteremias are more common. The pre-
dominance of coagulase-negative gram-positive staphylo-
cocci appears to be related to central venous cathe-
ters.37,40-43 In the study of Torres et al, the most frequent
bacterial pathogen was coagulase-negative, gram-posi-
tive staphylococci followed by gram-negative bacilli.
Other gram-positive pathogens that in AA include En-
terococcus spp., Staphylococcus aureus, Clostridium
spp., Micrococcus, alpha-hemolytic streptococci, and Lis-
teria monocytogenes. Notably, multiple cases of Bacil-
Infections in patients with aplastic anemia
lus cereus have been reported in the literature.44-47
Gram-positive infections continue to pose a serious
threat to the health of the AA patient.
Gram-Negative Infections
Gram-negative infections occur in the AA popula-
tion.3,37,48-56 In a patient with a competent immune
system, enteric bacteria are usually non-pathogenic,
part of the normal intestinal flora, and a component of
a normal commensal and symbiotic relationship.57 Due
to the often frequent use of antibiotics in AA patients
and the compromised immune system, an environment
is created that allows otherwise controlled bacteria to
overgrow, potentially leading to bacteremia and/or
bacterial sepsis.58 Recent studies show that certain
gram-negative bacilli, such as Stenotrophomonas mal-
tophilia, can additionally be difficult to treat due to an
increase in multidrug resistance.37,59 An example is
presented in the study by Torres et al, in which S
maltophilia was the most common gram-negative bac-
terium identified, and bacterial sepsis was observed in
40% of patients who died.37 These organisms tend to be
waterborne and may cause catheter-related bacteremia,
pneumonia, and septic shock. Gram-negative rod bac-
teria were also among the most causative agents of
death in the report of Chansumrit et al of 100 pediatric
patients with acquired AA.48 Other gram-negative bac-
terial pathogens that in AA include: E coli, Salmonella,
Bacteroides fragilis, Klebsiella oxytoca, Klebsiella
pneumonia, Aeromonas hydrophilia, Pseudomonas
aeruginosa, and Vibrio vulnificus.3,37,60-63 Pseudomo-
nas aeruginosa is particularly worrisome due to in-
creasing antibiotic resistance and a high rate of patho-
genicity.60,64,65
The appropriate duration of antibacterial therapy in
SAA is not well defined. However, a definitive course of
antibacterial therapy is generally 10-14 days, depending
on the severity of the infection. Upon discontinuation
of antibacterial therapy, patients are monitored, but in
general do not require secondary prophylaxis for bac-
terial infections if the original focus was fully eradi-
cated. A pneumonic process may require more ex-
Table 3. Important Common Pathogens Complicating Severe Aplastic Anemia
Fungal Bacteria
Aspergillus spp. Staphylococcus spp.
Zygomycetes Stenotrophomonas maltophilia
(Rhizopus spp., Mucor spp. Pseudomonas aeruginosa
Cunninghamella bertholletiae) Enterobacteriaciae
Candida spp. (E coli)
Fusarium spp. Klebsiella spp.
Bacillus cereus
273
tended treatment to 3 or more weeks. Following a
careful history and performing a detailed physical ex-
amination, patients are initially managed in a manner
similarly as in acute leukemia, with attention to coverage
of potential gram-negative and gram-positive pathogens.
Such regimens may include ceftazidime with vancomy-
cin or piperacillin, and tazobactam plus vancomycin.
When an anaerobic process is suspected, metronida-
zole may be added to these regimens or a consolidated
regimen using a carbapenem may be given. A review of
management of resistant bacterial infections is de-
scribed elsewhere in this monograph by Roilides and
colleagues.
VIRAL INFECTIONS
Among the viruses to which patients with AA are
susceptible are various members of the Herpesviridae
family, community-acquired respiratory viral infec-
tions, and the viral hepatitides A, B, and C. However,
the literature reporting infections in patients with AA
seldom describe viral infections from these organisms.
Nevertheless, our clinical experience indicates that pa-
tients may suffer reactivation of oral/labial HSV and
develop dermatomal outbreaks of VZV. These infec-
tions tend to occur during the course of treatment with
ATG and CsA, during which there is general suppres-
sion of T-cell function and numbers. Although EBV and
CMV disease are very rare in AA, subclinical reactiva-
tion of no apparent clinical consequences of these
viruses after ATG is very common, and no specific
antiviral therapy is required as the reactivations are
self-limited.66
As patients with AA are commonly managed as out-
patients, they are at risk for acquiring community-asso-
ciated respiratory viral infections. These infections in-
clude influenza A and B, respiratory syncytial virus, and
parainfluenza viruses 1, 2, and 3, and adenovirus. A
recognition of the patterns of active community-asso-
ciated viral respiratory tract infection is useful in pre-
dicting likely pathogens that patients with AA who
present with upper and/or lower respiratory tract
Viruses Helminths
Hepatitides A, B, C Strongyloides
Herpes simplex virus stercoralis
Varicella zoster virus
Cytomegalovirus
Influenza A, B
Respiratory syncytial virus
Parainfluenza virus
274
symptoms may have contracted. Patients who are re-
ferred from developing countries to tertiary care med-
ical centers may have received blood products for
which screening may not have been optimal, and there-
fore they may have acquired hepatitis B or hepatitis C,
or hepatitis B through other parenteral routes. During
the course of ATG-CsA treatment, these viruses may
reactivate and become aggressive hepatic pathogens,
requiring therapeutic intervention. A more extensive
discussion of antiviral therapy appears in the article by
Jancel et al.
Management of viral infections in general is focused
on those in the Herpesviridae family and is usually
implemented following definitive diagnosis of a reac-
tived or primary infection. Acyclovir and its derivatives
are the main antiviral therapies. A definitive course of
antiviral therapy usually eradicates the herpesvirus in-
fection. However, as HSV tends to recur, a subsequent
course of long-term suppression with prophylactic acy-
clovir may be warranted.
PARASITIC INFECTIONS
Illness of parasitic origin has been documented in
patients with AA. Along with the decrease in neutro-
phils, eosinophils are also reduced. Eosinophils are an
important component of the immune system responsi-
ble for combating infections with parasites. Strongy-
loides stercoralis is a relatively common helminthic
pathogen that may cause disseminated infection and
septic shock associated with polymicrobial bacteremia.
Patients from endemic areas and developing countries
should be screened for enteric parasitic diseases. How-
ever, due to the lack of sensitivity of microbiological
tools in screening for S stercoralis routine administra-
tion of antihelminthic therapy is advised for potentially
infected patients.67,68
CONCLUSION
Infection is the major cause of death in patients with
AA (Table 3). A major risk factor for developing infec-
tion is degree and duration of neutropenia. When the
patient is refractory to traditional therapy or unable to
undergo HSCT, infection is inevitable. Recovery from
neutropenia is directly related to survival, and support-
ive care plays a large role in protection while the
patient is in a state of neutropenia.69 Recent advances
in supportive care have increased the survival of pa-
tients with AA, but advances in the diagnostic methods
of infective pathogens are needed. Invasive aspergillo-
sis remains as the most common and serious fungal
infection in patients with a mortality rate of 80%-90%.15
A multidisciplinary approach should be taken when
caring for this specific patient population. Further ep-
idemiological research will help to elucidate the cur-
J.M. Valdez et al
rent patterns and characteristics of infections in AA
patients.
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