In a matched controlled study, the incidence of bacteremia during the first
30 days post-HCT in the nonmyeloablative recipients was significantly reduced
compared to myeloablative recipients.
168 Moreover, nonmyeloablative HCT
recipients experienced significantly fewer infections attributable to mucositis during
The second or middle (Fig. 101-2) period of infectious risk includes the time from
engraftment to post-transplant day +100. Pathogens such as CMV, adenovirus, and
Aspergillus are common. Adenovirus, CMV, Aspergillus, and P. jiroveci frequently
cause interstitial pneumonitis. Patients undergoing reduced-intensity or
nonmyeloablative preparative regimens that experience acute GVHD and are treated
with corticosteroids have a similar risk of infection during this time period as those
During the late period (after day +100), the predominant pathogens are the
encapsulated bacteria (e.g., S. pneumoniae, H. influenzae, Neisseria meningitidis),
fungi/mold, and varicella-zoster virus (VZV). The encapsulated bacteria commonly
cause sinopulmonary infections. The risk of infection during this late period is
increased in patients with cGVHD as a result of prolonged immunosuppression.
Because of the morbidity associated with opportunistic infection in HCT
recipients, optimal pharmacotherapy for prevention and treatment is critical. In 2009,
the US Centers for Disease Control and Prevention (CDC) published guidelines for
prevention of opportunistic infection in HCT recipients.
constructed from available data by an expert panel from the CDC, the Infectious
Disease Society of America, and the American Society for Blood and Marrow
Transplantation. The following discussion incorporates recommendations from the
CDC guidelines and also provides information on the pharmacotherapy of
opportunistic infections in all types of HCT.
Prevention and Treatment of Bacterial and Fungal
QUESTION 1: S.D. is a 26-year-old woman with Ph
acute lymphocytic leukemia in first complete remission
count less than 20,000/μL. What is the rationale for these supportive measures?
As a result of disease-related immunosuppression, intensive preparative regimens,
and post-transplant immunosuppressive therapy, patients undergoing allogeneic HCT
require careful monitoring for regimen-related toxicities and intensive supportive
care directed at maintaining adequate blood counts, preventing or treating infection,
and providing optimum nutrition.
Placement of a double-lumen or triple-lumen central venous catheter is mandatory
in all patients. The need for administration of chemotherapy, blood products,
antibiotics, parenteral nutrition, and adjunctive medications over a prolonged period
of time precludes the use of peripheral access sites. The use of a central venous
After administration of the preparative regimen and before successful engraftment,
allogeneic myeloablative HCT patients undergo a period of pancytopenia lasting
from 2 to 6 weeks. During this time, patients may require multiple RBC and platelet
transfusions. Packed RBCs and platelets are usually given for a hematocrit less than
25% and a platelet count less than 10,000/μL or 20,000/μL. Transfusions with
multiple blood products put patients at risk for blood product-derived infection (e.g.,
CMV, hepatitis). In addition, sensitization to foreign leukocyte HLA antigens
(alloimmunization) may cause immune-mediated thrombocytopenia. Thus, blood
product support in the myeloablative allogeneic HCT patient must incorporate
strategies that reduce the risk of viral infection and alloimmunization. Effective
methods include minimizing the number of pretransplant infusions, using single-donor
rather than pooled-donor blood products, irradiating blood products, and filtering
blood products with leukocyte reduction filters.
Patients receiving reduced-intensity or nonmyeloablative preparative regimens
may or may not experience neutropenia and generally have reduced requirements for
blood products. In fact, many centers perform reduced-intensity or nonmyeloablative
HCT in the outpatient setting and admit patients to the hospital only for complications
requiring more aggressive management.
Several measures are recommended to minimize the risk of infection in autologous
and allogeneic myeloablative HCT patients. Private reverse isolation rooms
equipped with positive-pressure HEPA filters and adherence to strict handwashing
techniques reduce the incidence of bacterial and fungal infections.
exposure to exogenous sources of bacteria in immunosuppressed patients, low
microbial diets (Table 101-10) may be instituted on hospital admission, and visitors
are prohibited from bringing plants or flowers into the patient’s room. Patients are
encouraged to maintain good oral hygiene because the mouth can be a source of
bacterial or fungal infection. Frequent (4–6 times daily) mouth rinses with sterile
water, normal saline, or sodium bicarbonate are effective.
is avoided during periods of thrombocytopenia and neutropenia.
Foods Posing Infection Risk in Neutropenic Patients
High-Risk Foods to Avoid When Neutropenic Infection Risk
Salad Gram-negative bacillus including Pseudomonas
Tomatoes, radishes, celery, and carrots Pseudomonas aeruginosa
Raw eggs Campylobacter jejuni, Salmonella
Unpasteurized cheeses Listeria monocytogenes
Cold, loose meats Listeria, Clostridium perfringens, Campylobacter jejuni
Undercooked meat Salmonella, Listeria, Escherichia coli
Uncooked nuts Aspergillus niger, Aspergillus flavus
Black pepper/uncooked herbs and spices Aspergillus spp.
Raw shellfish/sushi Vibrio vulnificus, Norwalk virus
Bottled water Pseudomonas, Cytophaga, Campylobacter
Prepared foods that are cooked and then eaten chilled Listeria
Ice machines P. aeruginosa, Stenotrophomonas maltophilia
Aggressive use of antibacterial, antifungal, and antiviral therapy, both
prophylactically and for documented infection, is an important aspect of patient
management. Antibiotics with a broad gram-negative spectrum may be instituted
prophylactically once the patient becomes neutropenic (ANC <1,000 cells/μL), or
empirically after the patient is neutropenic and experiences fever (oral temperature
>38°C). Some transplant centers administer a prophylactic fluoroquinolone such as
levofloxacin on admission especially if the neutropenic period is expected to extend
Fluoroquinolone prophylaxis during periods of neutropenia significantly reduces
the incidence of gram-negative bacteremia but generally does not affect mortality.
Concerns regarding prophylactic fluoroquinolone use include the emergence of
resistant organisms and an increased risk of streptococcal infection.
incidence of Viridians group of streptococci has been increasing.
antibiotics (e.g., penicillin, vancomycin) are not recommended due to their lack of
proven efficacy in preventing streptococcal infections and the concern about
antibiotic-resistant bacteria.
4 Regardless of prophylactic strategies, patients who
become febrile during neutropenia should immediately receive broad-spectrum IV
antibiotic(s) (e.g., ceftazidime, cefepime, imipenem, or meropenem) and prophylaxis
Antifungal prophylactic agents are commonly used in HCT recipients. S.D. is
prescribed fluconazole 400 mg/day on admission because prophylactic use until day
+75 post-transplant decreases the incidence of systemic fungal infection and fungal
death in patients undergoing HCT.
178,179 The use of prophylactic fluconazole has been
linked to reports of breakthrough infections with resistant fungi such as C. glabrata
When broader yeast and mold prophylaxis is required, either posaconazole or
voriconazole may be used; however, data are limited in the transplant setting. If S.D.
were to require mold prophylaxis, voriconazole 200 mg twice daily would be a
reasonable choice. Voriconazole 200 mg twice daily was compared to fluconazole
400 mg once daily in a randomized double-blind trial for prevention of invasive
fungal infections in standard risk HCT. No significant differences were seen in
fungus-free survival, relapse-free status, and overall survival at 6 months. Toxicities
were similar, and there was a trend toward reduced aspergillus infections and less
empiric antifungal therapy in the voriconazole arm.
182 Posaconazole has also been
used for mold prophylaxis in HCT based on its efficacy as prophylaxis in
183 However, data in HCT are very limited. Both azoles affect
the CYP3A4 isoenzyme, and their use with calcineurin inhibitors requires judicious
monitoring. The use of broader spectrum azoles has also resulted in the development
of breakthrough zygomycosis infections, particularly with the use of voriconazole.
The echinocandins have also been used for broader yeast and mold prophylaxis in
HCT. Micafungin (50 mg IV every 24 hours) and fluconazole (400 mg IV every 24
hours) were compared in a randomized, double-blind study of patients undergoing
HCT. Overall success was defined as the absence of suspected, proven, or probable
systemic fungal infection through the end of therapy and as the absence of proven or
probable systemic fungal infection through the end of the 4-week post-treatment
period. The overall efficacy was greater in the patients who received micafungin
(80.0% vs. 73.5% p = 0.03). Fewer episodes of aspergillosis occurred in patients
Prevention of Herpes Simplex Virus and VaricellaZoster Virus
Up to 70% of HSV-seropositive patients undergoing myeloablative allogeneic
HCT will experience reactivation of HSV.
186 Prophylactic acyclovir is commonly
used in HSV-seropositive patients undergoing allogeneic or autologous HCT to
4,187 Dosing regimens for prophylactic acyclovir vary
widely; the dose of IV acyclovir is typically 250 mg/m2
oral doses of acyclovir range from 600 to 1,600 mg/day.
of acyclovir prophylaxis for HSV varies from day +30 to day +365 post-transplant or
longer, depending on the specific type of HCT and other risk factors. Valacyclovir, a
prodrug of acyclovir with improved bioavailability, provides sufficient blood
concentrations to prevent HSV in patients with mucositis or GI aGVHD.
Prophylactic valacyclovir is commonly used at a dose of 500 mg PO every 12
Varicella-zoster virus (VZV)-seropositive patients are at risk for developing
herpes zoster, particularly after day +100 post-transplant.
reduces the risk of VZV reactivation.
192 As with prophylaxis for HSV reactivation,
the optimum duration of VZV prophylaxis is controversial, often extending to day
+365 post-transplant or longer.
Patients who are HSV-seronegative or VZV-seronegative rarely exhibit primary
HSV or VZV infection and are therefore not administered prophylactic acyclovir. If
HSV does occur, lesions usually appear on the oral mucosa, nasolabial mucous
membranes, or genital mucocutaneous area and can be managed with acyclovir at
Because S.D. is HSV- and VZV-seropositive, she is at risk for viral reactivation
and should receive prophylactic acyclovir 400 mg PO twice daily, beginning 4 days
prior to transplant and continuing until her ANC is greater than 2,500 cells/μL for at
Prevention of Cytomegalovirus Disease
CASE 101-6, QUESTION 3: S.D. is also CMV-seropositive. What is the significance of this finding and
what measures can be taken to prevent reactivation of CMV?
Cytomegalovirus has the ability to establish lifelong latent infection after primary
exposure. In immunocompromised patients, the virus may reactivate, resulting in
asymptomatic shedding or the development of CMV disease. The incidence of CMV
infection (defined as isolation of the virus or detection of viral proteins or nucleic
acid in any body fluid without clinical symptoms) and CMV disease (signs and
symptoms consistent with CMV invasion into a tissue) in HCT recipients is 15% to
60% and 20% to 35%, respectively. The most common manifestations of CMV
disease after allogeneic HCT are pneumonitis, fever, and GI infection.
In the CMV-seronegative HCT recipient, primary CMV infection or disease can be
prevented by selecting a CMV-seronegative donor and using only blood products
from CMV-seronegative donors. No anti-CMV prophylaxis is required in these
morbidity associated with CMV reactivation or secondary infection. Two general
strategies are possible. Universal prophylaxis involves the administration of
disease compared with placebo.
194 However, prophylactic ganciclovir therapy is
associated with neutropenia in 30% of patients, which contributes to an increased
risk of invasive bacterial and fungal infections.
194,195 Neutropenia secondary to
ganciclovir may lead to interruptions in antiviral therapy or necessitate
administration of filgrastim daily or several times per week to maintain adequate
neutrophil counts. The other strategy involves preemptive therapy, or risk-adjusted
188,196 Using this strategy, patients begin therapy only if they have early
reactivation of CMV detected through the assay of blood for CMV antigens (e.g.,
pp65), or viral nucleic acid using polymerase chain reaction (PCR) testing. Using
preemptive therapy selectively administers ganciclovir to only those HCT patients at
greatest risk for development of CMV disease.
197–199 Antigenemia-based preemptive
therapy is as effective as universal ganciclovir prophylaxis for prevention of CMV
disease and is associated with reduced CMV mortality.
195,200–203 The induction dose
of ganciclovir is typically 5 mg/kg IV every 12 hours for 7 to 14 days, followed by a
maintenance dose of 5 mg/kg IV daily until 2 to 3 weeks after the last occurrence of
antigenemia or until day +100 post-transplantation.
4 Preemptive therapy limits patient
exposure to the potential toxicity of ganciclovir and thus reduces overall cost.
Recent data suggest that oral valganciclovir is a safe and effective alternative to
ganciclovir for preemptive therapy.
204,205 Foscarnet may also be administered in lieu
of ganciclovir, but its use is complicated by nephrotoxicity and electrolyte
203,206 Monitoring and correction of electrolyte and fluid imbalances are
essential when foscarnet is initiated.
Cidofovir is used to treat CMV in HCT patients but is reserved for use when
ganciclovir or foscarnet has failed.
207 Dose-related renal dysfunction, which can be
seen after even 1 or 2 doses, limits the number of patients able to receive
207 An advantage of cidofovir is its infrequent dosing making it conducive
to clinic administration. Monitoring renal function, electrolytes, WBC, and
intraocular pressure are essential monitoring parameters.
Autologous HCT recipients who are CMV-seropositive pretransplant should
receive antiviral treatment preemptively as described previously.
Nonmyeloablative or reduced-intensity HCT recipients should also receive
preemptive antiviral treatment. Because host T cells may persist in the peripheral
blood for up to 6 months after reduced-intensity or nonmyeloablative preparative
regimens, their presence may provide some protection against early CMV disease. A
matched controlled study comparing the incidence and outcome of CMV infection in
myeloablative and nonmyeloablative HCT demonstrated that although the time to
onset of CMV antigenemia was similar in the two groups, fewer nonmyeloablative
HCT recipients experienced CMV disease in the early period.
incidence of CMV disease was also similar, suggesting that nonmyeloablative HCT
recipients are at increased risk for exhibiting late CMV disease (>100 days after
transplantation) compared to their myeloablative counterparts.
recommended that nonmyeloablative HCT patients receive preemptive antiviral
therapy and be monitored for development of CMV antigenemia for 1 year after
S.D.’s ANC recovers to greater than 1,000 cells/μL on day +20, and on day +32,
her weekly surveillance blood sample is positive for CMV by PCR. Preemptive
ganciclovir induction is initiated at 5 mg/kg IV every 12 hours for 2 weeks followed
by maintenance dosing of 5 mg/kg daily. After 3 weeks of therapy, S.D.’s
surveillance samples are negative and ganciclovir is discontinued. Weekly
surveillance sampling continues until day +100. If surveillance samples again
become positive for CMV, ganciclovir therapy should be reinstituted.
Diagnosis and Treatment of Aspergillus Infection
QUESTION 1: A.W., a 60-kg, 165-cm, 15-year-old boy, is day +79 after a matched, unrelated,
has chronic low-grade nausea and hypomagnesemia necessitating daily IV hydration with magnesium
supplementation. Relevant laboratory values are as follows:
He was CMV-seropositive and HSV-seropositive before HCT. Oral medications include cyclosporine 275
mg every evening (tapering), trimethoprim–sulfamethoxazole (TMP/SMX) 160 mg/800 mg twice daily on
hours, enalapril 10 mg every 12 hours, and a multivitamin every morning.
and management of presumed Aspergillus infection. What risk factors does A.W. have for developing an
Invasive molds (most commonly Aspergillus spp., but also Fusarium spp.,
Scedosporium, and Zygomycetes) are an increasing cause of morbidity and mortality
after allogeneic and autologous HCT. Factors contributing to this trend include (a)
more effective prevention of bacterial and viral infection which promote mold
overgrowth, as described previously; and (b) the use of fluconazole prophylaxis,
which has reduced the incidence of candidemia and Candida-related
178–180,211,212 Aspergillus infection is reported in up to 26% of HCT
recipients, and the mortality rate of invasive aspergillosis (IA) is 74% to 92%.
Several risk factors for development of invasive fungal infection have been
211,212 Given that neutrophils are critical for host defense, prolonged
neutropenia is considered the single most important predictor of infection at any point
181,211 GVHD (acute and chronic) and treatment with corticosteroids
are also important risk factors, particularly for aspergillosis, presumably as a
result of neutrophil dysfunction.
In addition, the widespread use of
fluconazole prophylaxis (400 mg/day) for prevention of invasive candidiasis in
transplant patients since the early 1990s has led to a substantial increase in the
incidence of invasive aspergillosis and also fluconazole-resistant Candida species
such as Candida krusei and Candida glabrata.
A.W. is receiving corticosteroid treatment for GVHD and fluconazole prophylaxis.
These therapies increase his risk for exhibiting invasive aspergillosis.
CASE 101-7, QUESTION 2: A.W. undergoes bronchoalveolar lavage to identify the organism responsible
Early diagnosis and treatment of invasive aspergillosis, which rely on tissue or
fluid obtained from the infected site followed by aggressive antifungal therapy, may
215 Although the lower respiratory tract is frequently the
primary focus of infection, Aspergillus may invade blood vessels and spread
hematogenously to other organs, including the brain, liver, kidneys, spleen, and
191 Head, chest, abdomen, and pelvic computed tomography scans assist in
assessing the extent of disease, treatment options, and overall prognosis. Cultures of
respiratory tract secretions lack sensitivity for detecting Aspergillus, and the medical
condition of the patient may preclude invasive diagnostic procedures altogether.
Many clinicians have adopted the European Organization for Research and Treatment
of Cancer criteria for diagnosis of proven, probable, and possible invasive
Newer diagnostic tests based on the detection of fungal antigens or metabolites,
such as galactomannan, 1,3-β-D-glucan, and fungal DNA detection by PCR, are being
developed. Galactomannan is a polysaccharide component of the Aspergillus cell
early detection of Aspergillus infection. The test is useful not only for serum samples
but also for bronchoalveolar lavage and cerebrospinal fluid. Concomitant antifungal
therapy may cause false-negative results, whereas antibiotics of fungal origin (e.g.,
piperacillin/tazobactam) have been associated with false positives.
Outcomes for patients with invasive aspergillosis after HCT are often poor, with
approximately 20% of patients alive after 1 year.
211 Treatment success depends not
only on the use of intensive antifungal agents but also on recovery of the host immune
system and/or reduction of immunosuppression.
215,218 Conventional amphotericin B
had traditionally been the gold standard antifungal therapy for invasive aspergillosis
with response rates in the range of 28% to 51%, depending on the severity of the
underlying immunosuppression; however, 65% of responders eventually died of their
215 Fortunately, broad-spectrum triazoles and echinocandins are available as
alternatives. The treatment of invasive aspergillosis has moved away from the use of
amphotericin to the use of broad-spectrum azoles for its treatment.
Three broad-spectrum triazole agents (itraconazole, voriconazole, posaconazole)
are available for patients. In an early compassionate use trial of invasive
aspergillosis unresponsive to amphotericin B, 27% of patients had a complete
response to itraconazole, and another 35% experienced improvement in their
219 Patients who had undergone HCT had response rates similar to patients
who were less immunocompromised. Unfortunately, oral itraconazole capsules
exhibit erratic absorption and the IV form is complicated by the risk of drug
In addition, itraconazole is a potent inhibitor of
common CYP isoforms and also has negative inotropic properties.
Voriconazole is one of the newer broad-spectrum azoles whose advantage is its
excellent (96%) oral bioavailability. Voriconazole has been compared to
conventional amphotericin B in a randomized, unblinded trial as primary therapy for
established invasive aspergillosis in an immunocompromised host.
objective was to demonstrate the noninferiority of voriconazole compared with
conventional amphotericin B after 12 weeks of therapy in patients with definite or
probable invasive aspergillosis. Patients received voriconazole 6 mg/kg IV every 12
hours for two doses followed by 4 mg/kg IV every 12 hours for at least 7 days,
followed by oral voriconazole 200 mg every 12 hours or amphotericin B at a dose of
1 to 1.5 mg/kg/day. Patients refractory to or intolerant of initial therapy could receive
other antifungal drugs. Of 144 evaluable patients who received voriconazole, 76
(52.8%) had a partial or complete response compared to 42 of 133 (31.6%) patients
treated with amphotericin B. The median duration of therapy for patients treated with
voriconazole was 77 days, and 52 of 144 patients switched to an alternative agent. In
contrast, the median duration of therapy for patients receiving amphotericin B was 10
days, and 107 of 133 patients switched to another agent (most commonly, a lipid
formulation of amphotericin B). The survival rate at 12 weeks in the voriconazole
group was 70.8% compared to 57.9% (p = 0.02). These results of initial therapy with
voriconazole indicate superior response and improved survival in
immunocompromised patients, such as allogeneic HCT recipients, with invasive
aspergillosis. Voriconazole-treated patients also experienced fewer drug-related
adverse effects; however, drug interactions due to P450 3A4 inhibition should be
Posaconazole, a newer broad-spectrum triazole, is available as an oral
suspension, oral tablets and an intravenous formulation. The oral suspension has a
more variable absorption as compared to the tablet formulation. In general,
posaconazole has the lowest minimum inhibitory concentration of any available
triazole against Aspergillus spp., including Aspergillus terreus. It is the only triazole
with activity against the Zygomycetes. Published clinical experience with
posaconazole is limited; however, in an open-label externally controlled trial in
patients with invasive aspergillosis refractory to or intolerant of other therapies, the
overall success rate was 42% in posaconazole-treated patients compared to 26% for
Echinocandin antifungal agents (caspofungin, micafungin) inhibit the synthesis of
β-(1,3)-glucan, an important component of the fungal cell wall. No prospective
randomized trials have documented the efficacy of any echinocandin for primary
therapy of invasive aspergillosis, and only caspofungin is approved for salvage
therapy. An open-label, noncomparative trial evaluated the efficacy of caspofungin in
69 patients who had failed or were intolerant of at least 7 days of standard antifungal
224 Patients received 70 mg IV of caspofungin on day 1 followed by 50 mg IV
daily. Of the 63 evaluable patients, 26 (43%) responded favorably to treatment.
Twenty-six of 52 patients (50%) who had received at least 7 days of therapy had a
favorable response. In another open-label, noncomparative trial, Denning et al.
evaluated the safety and efficacy of micafungin (alone or in combination) in patients
with proven or probable aspergillosis. Eighty of 225 patients (35.6%) had a
favorable response. Most patients received combination therapy; the 34 patients
treated with monotherapy had a similar response rate.
225 Amphotericin B is no longer
first-line therapy for the treatment of invasive aspergillosis. It is typically reserved
for patients who develop mold infections, such as cryptococcus, that are resistant to
In summary, the number of agents available to manage invasive aspergillosis has
expanded greatly in the past decade. Although some experts believe that voriconazole
is the drug of first choice, considerable controversy still exists regarding acquiring
resistance, selecting out other species of molds, and side effect tolerance due to the
lack of definitive studies. Therapy should be tailored to the individual patient based
on response, tolerability, and cost.
ANTIFUNGAL TOXICITIES AND LENGTH OF ANTIFUNGAL THERAPY
AND COMBINATION ANTIFUNGAL THERAPY
CASE 101-7, QUESTION 3: A.W. is started on voriconazole 6 mg/kg IV every 12 hours for two doses,
should the patient be monitored? How long should A.W. receive antifungal therapy?
Common toxicities reported with voriconazole include reversible visual
disturbances (blurred vision, altered color perception, photophobia, visual
hallucinations), skin reactions (rash, pruritus, photosensitivity), elevations in hepatic
transaminase enzymes and alkaline phosphatase, nausea, and headache.
Caspofungin has fewer adverse effects. Vein irritation and headache are most
common; dermatologic reactions related to histamine release (flushing, erythema,
wheals) have also been reported. Increased hepatic transaminase enzymes occur in
approximately 6% of patients treated with caspofungin.
for changes in liver function and counseled regarding the potential visual side effects
of voriconazole. The azoles are also known inhibitors of the CYP3A4 isoenzyme;
therefore, drug interaction monitoring is imperative. The major interaction seen in
patients undergoing allogeneic HCT is an increase in calcineurin inhibitor levels.
Careful monitoring is warranted.
Data supporting improved outcomes with two-drug combinations of triazoles,
echinocandins, and polyenes in patients with aspergillosis are sparse. However, in
vitro and animal data suggest that an echinocandin plus voriconazole or a polyene
228–231 Given the overall poor prognosis of invasive aspergillosis
in severely immunocompromised patients, many practitioners choose to treat patients
with two-drug combination therapy. Voriconazole in combination with caspofungin is
thus a reasonable alternative for A.W.
The optimum duration of antifungal therapy for treatment of invasive aspergillosis
Important considerations include the status of the
patient’s immune system and the extent of response to treatment. Many clinicians
continue aggressive antifungal therapy until the infection has stabilized
radiographically and then proceed with less aggressive “maintenance” therapy (e.g.,
single-agent oral voriconazole) until restoration of the immune system has taken
place. It is not uncommon for a patient to require several months of antifungal therapy
for effective management of invasive aspergillosis.
Prevention of Pneumocystis jiroveci Pneumonia
CASE 101-7, QUESTION 5: A.W. is receiving TMP/SMX, one double-strength tablet PO BID on Monday
and Thursday. What is the rationale for its use?
Pneumocystis jiroveci is a common pathogen that causes Pneumocystis pneumonia
(PCP) in patients who have undergone allogeneic HCT. PCP is a potentially lethal
infection, and prophylaxis is routinely administered. The optimum prophylactic
regimen has not been established, but most centers administer TMP/SMX for PCP
4 Dapsone and aerosolized pentamidine are alternatives for patients who
are allergic to sulfonamides or do not tolerate TMP/SMX for other reasons such as
hematologic toxicities. PCP prophylaxis is usually begun after neutrophil recovery
because (a) PCP most commonly occurs after engraftment and (b) TMP/SMX is
potentially myelosuppressive. Patients should be closely monitored for unexplained
neutropenia or thrombocytopenia.
HEMATOPOIETIC CELL TRANSPLANTATION
10 years ago, is disease-free, and has not had chronic GVHD for 9 years. Her only medication is one
multivitamin tablet daily. What issues of cancer survivorship are of concern to H.O.?
A greater proportion of HCT recipients are surviving their cancer diagnosis
without evidence of their primary malignancy, but they are at risk for long-term
physical and emotional sequelae of their cancer treatments.
survivors are no longer under the care of an HCT center and their healthcare
providers may be unfamiliar with the complications of HCT. To facilitate the clinical
care of long-term HCT recipients, recommendations for screening and preventive
practices have been created for adult and pediatric HCT survivors.
guidelines should facilitate the provision of health care to HCT recipients. The
following paragraphs describe various concerns associated with the morbidity of
232–234 Long-term HCT survivors should be regularly
screened for the development of secondary malignancies, complications of GVHD
that affect the oral mucosa, liver, respiratory, endocrine, ocular, skeletal, nervous
system, kidney, and vascular systems. The psychosocial health of HCT survivors
Immune function can take more than 2 years to recover, even after discontinuation
235 Treatment of GVHD exacerbates immune system defects,
necessitating prophylaxis and vigilant monitoring for infectious complications.
Fevers should be rapidly assessed and treated to prevent fatal infections. Recipients
of HCT also lose protective antibodies to vaccine-preventable diseases; therefore,
HCT survivors need to be revaccinated for selected infectious diseases with due
consideration for the risk of vaccination.
Hematopoietic cell transplant survivors have a greater risk of secondary malignant
2 An increased incidence of cancer of the skin, oral mucosa, brain,
thyroid, and bone is observed after allogeneic HCT, and an increased incidence of
myelodysplasia and acute leukemia can occur after autologous HCT for NHL.
Survivors should avoid carcinogens (e.g., tobacco) and be screened for secondary
malignant neoplasms indefinitely.
2 Long-term impairment of end-organ function may
be due to the preparative regimen, infectious complications (either autologous
or allogeneic grafts), and post-transplant immunosuppression (allogeneic grafts
232,234 Endocrine dysfunction, specifically of the thyroid, gonads, and growth
232,233 Adrenal insufficiency can result from long-term
corticosteroid therapy used to treat GVHD. Infertility is commonly observed after
myeloablative HCT secondary to the high doses of alkylating agents and radiation
administered. Frequently, men become azoospermic, and chemically induced
2 However, pregnancies have occurred after HCT.
Up to 60% of HCT recipients have osteopenia, most likely resulting from gonadal
dysfunction and corticosteroid administration; avascular necrosis due to
corticosteroids can also occur.
236 A significant portion (15%–40%) of HCT
survivors exhibit pulmonary dysfunction with variable symptoms (e.g., restrictive,
chronic obstructive lung disease) from multiple causes.
occur in HCT recipients through blood transfusions or, more commonly, because
recipients or donors have a latent hepatitis viral infection. The prevalence of chronic
hepatitis C ranges from 5% to 70% in long-term HCT survivors.
cirrhosis and its complications may become an important late complication of
237 Hepatic dysfunction can also result from iron overload, which may occur
secondary to multiple red blood cell transfusions administered during aplasia after
myeloablative preparative regimens and before HCT. Alopecia is a common late
effect with BU/CY, as are cataracts with CY/TBI.
H.O. should be routinely monitored for signs of relapse and chronic GVHD. To
lower the risk of infectious complications, she should be counseled to obtain prompt
medical care for fevers or signs of an infection, and she should be revaccinated if she
assessed at regular intervals. In addition, her bone mineral density should be
determined, and H.O. should be counseled on preventive measures for osteopenia
(e.g., calcium supplementation). In addition to standard cancer screening tests, H.O.
should be closely monitored for secondary malignant neoplasms.
A full list of references for this chapter can be found at
http://thepoint.lww.com/AT11e. Below are the key references and websites for this
chapter, with the corresponding reference number in this chapter found in parentheses
Appelbaum FR et al. Haematopoietic cell transplantation as immunotherapy. Nature. 2001;411:385. (4)
Copelan EA et al. Hematopoietic stem-cell transplantation. N EnglJ Med. 2006;354:1813. (2)
Slides. Center for International Blood and Marrow Transplant Research.
http://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/pages/index.aspx. Accessed
Health Resources and Services Administration (HRSA). http://www.hrsa.gov/. Accessed July 7, 2015.
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COMPLETE REFERENCES CHAPTER 101
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