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197
Table 8.2
Common regimens for prophylaxis against infections in solid organ transplant recipients
Infection Prophylaxis
Cytomegalovirus
(CMV)
Ganciclovir (IV), Valganciclovir (PO)
D+/R− Lung: 6–12months; some
centers extend >12months
Heart: 3–6months
Liver: 6months or
preemptive therapy in some
centers
Kidney: 6months
R+ (any donor status) Lung: 3–12months
Liver: 3months or
preemptive therapy in some
centers
Heart, Kidney: 3months
D−/R− No prophylaxis (but should
have HSV/VZV
prophylaxis)
HSV If recipient is positive for HSV (1 or 2) and not receiving CMV
prophylaxis, then at least 1month is recommended. (e.g., acyclovir, but
regimens vary)
VZV Provide if recipient is positive for VZV and negative for HSV and CMV,
and not already receiving prophylaxis against CMV or HSV; optimal
duration uncertain
Fungal Invasive (Aspergillus, Candida species):
Varies by transplant center and patient risk factors; prophylaxis against
aspergillus often given in lung transplant recipients; against candida in
liver and kidney transplant recipients
Endemic
Varies by patient risk factors, e.g., history of prior endemic mycotic
disease and donor from endemic area
Pneumocystis
jirovecii
Lung: lifelong
Other organs: 6–12months, may vary if risk factors present
The late post-transplant period typically starts >6–12months after transplant
and continues for the duration of immunosuppression (lifelong generally). By this
time immunosuppression is being tapered and solid organ transplant recipients are
living in their home community under the care of their primary care providers in
conjunction with their transplant center. Community-acquired infections are more
likely and with similar patterns to the general population: viral respiratory infec-
tions including pneumonia, urinary tract infections (UTI), and infectious diarrhea
are common. The risk for opportunistic infections is higher if patients experience
organ rejection and require intensication of immunosuppression. Unique infec-
tions affecting solid organ transplant recipients include late CMV reactivation/
infection, HSV, HBV, and HCV reactivation, and less commonly JC and BK virus
infections. BK virus is a particular concern in kidney transplant recipients in whom
it can be a major cause of graft failure. The above discussed fungal and mycobacte-
rial infections can also occur, but with decreased frequency over time.
8 Infections intheAdult Solid Organ Transplant Recipient
198
Table 8.3
Key considerations in diagnosis of infection in solid organ transplant recipients
compared to the general population
Symptoms and
signs
• Immunosuppression may result in a reduction of the usual signs and
symptoms of inammation that accompany infections, such as fever, pain,
and leukocytosis [3]
Diagnostic
testing
• Immunosuppression reduces the sensitivity of tests that rely on the patient’s
immune system such as serology. Instead, direct detection of pathogens
using culture or polymerase chain reaction (PCR) is preferred
• Diagnosis may more frequently require invasive testing such as biopsy of
affected tissue [16]
• More comprehensive testing is often indicated (e.g., extended respiratory
panel instead of testing only for inuenza and SARS-CoV-2)
• Newer diagnostic approaches, such as next-generation sequencing for
detection of cell-free DNA, are rising in popularity, but must be used and
interpreted with careful consideration
Consultation
• Early discussions with the transplant team and a transplant infectious
diseases specialist are often indicated
Escalation of
care
• While symptoms may be muted, the actual infection may progress rapidly;
therefore, rapid escalation to invasive testing is often appropriate in this
vulnerable population [17]
Case
A 60-year-old woman with a history of bilateral lung transplantation 2years
ago presents to the primary care clinic in the winter season with 3days of
subjective fevers, nasal congestion, rhinorrhea, dry cough, and myalgias. She
is adherent to her immunosuppression regimen and is receiving appropriate
prophylaxis for Pneumocystis jirovecii pneumonia. She has not had any epi-
sodes of rejection in the last year. On exam, her temperature is 38.0°C, heart
rate 98bpm, blood pressure 125/70mmHg, respiratory rate 22 breaths/min,
and oxygen saturation 97% on ambient air. Her exam reveals mild erythema
(continued)
8.2 Diagnostic Approach toSolid Organ Transplant
Recipients withPossible Infection
When considering the causes of symptoms in a solid organ transplant recipient, the
primary care provider should consider a broad differential diagnosis, including
infection, malignancy, and other complications of immunosuppressive medications
(see Chap. 9). In this chapter, we focus on the evaluation of potential infections—
several key considerations that distinguish the evaluation of SOT recipients from the
general population are given in Table8.3.
8.3 Respiratory Infections
J. Hu et al.
199
of the oropharynx but no tonsillar hypertrophy and no exudate. Her lungs are
clear, she has no lymphadenopathy. She received the inactivated inuenza
vaccine 1 month ago; she did not receive her SARS-CoV-2 vaccination
this year.
Comment:
This patient is presenting with symptoms of an upper respiratory tract
infection during viral respiratory season. She has a low-grade fever with mild
tachycardia and an elevated respiratory rate without signicant hypoxemia.
This patient should undergo SARS-CoV-2 testing as well as viral respiratory
PCR panel testing for at least inuenza and RSV.
The absence of lymphadenopathy and pharyngeal exudates make bacterial
pharyngitis unlikely. Community-acquired pneumonia is also less likely with-
out clear signs of lower respiratory tract involvement. Opportunistic infec-
tions due to mycobacterial and fungal etiologies, as well as reactivation of
latent diseases, such as CMV, typically present more gradually and would not
be consistent with the acuity of symptom onset in this case. Nonetheless, a
chest X-ray should be obtained to evaluate for new consolidation or nodules.
Note that viral respiratory tract infections can predispose to secondary bacte-
rial and fungal pneumonia [18, 19].
She is subsequently found to have SARS-CoV-2 infection. The goal of ther-
apeutic management for this patient is to prevent progression to severe dis-
ease, hospitalization, or death; she is at high risk due to incomplete vaccination
[20] as well as receipt of immunomodulatory medications [21].
As of 2024, the preferred therapy in this patient would be remdesivir.
While ritonavir- boosted nirmatrelvir (Paxlovid) is also approved for treat-
ment of non- hospitalized patients with SARS-CoV-2 infection, there are sig-
nicant interactions with calcineurin inhibitors (e.g., cyclosporine,
tacrolimus) as well as mammalian target of rapamycin inhibitors (e.g.,
everolimus, sirolimus). Ritonavir is a strong cytochrome P450 3A4 inhibitor
and a P-glycoprotein inhibitor. The decision to provide ritonavir-nirmatrel-
vir, therefore, should be made in conjunction with the patient’s trans-
plant team.
Should she decompensate and become hypoxemic, she will require hospi-
talization as well as dexamethasone [22]. In certain patients with severe or
critical COVID-19, there are potential roles for combination therapies with
dual antiviral therapy [23] as well as consideration of a second immuno-
modulator (e.g., baricitinib, tocilizumab) [24, 25]. This would occur in an
inpatient setting, and thus is omitted from this book directed toward primary
care physicians.
8 Infections intheAdult Solid Organ Transplant Recipient
200
Respiratory infections after solid organ transplantation are common and account
for signicant morbidity and mortality. Bacterial pneumonia is a common cause of
lower respiratory tract infections, with one study identifying community-acquired
pneumonia (CAP) in 40.7% and healthcare-associated pneumonia (HCAP) in
38.9% of SOT recipients treated for pneumonia [26]. SOT recipients are at higher
risk of developing lower respiratory tract disease from common respiratory viruses
and often develop more severe symptoms than immunocompetent hosts [27]. SOT
recipients are also more likely to develop invasive fungal pneumonia as well as
bacterial and fungal co-infection in the setting of a viral respiratory illness [26].
Primary care providers must be aware of the risk factors and possible presentations
of respiratory infections in SOT recipients to appropriately triage, diagnose, and
treat these patients in the outpatient setting. Table8.4 provides common respiratory
infections in SOT recipients.
8.3.1 Diagnostic Considerations
All SOT recipients who present with a suspected respiratory viral infection should
undergo evaluation with a nasopharyngeal sample tested by PCR for respiratory
viral pathogens [27]. Most respiratory viral infections are restricted to the upper
respiratory tract; however, SOT patients are at higher risk of developing lower respi-
ratory tract infection and subsequent complications, including superimposed bacte-
rial pneumonia, due to impaired cellular and humoral immunity. In lung transplant
recipients, development of lower respiratory tract disease may be associated with
increased risk of chronic lung allograft dysfunction, though the relationship with
episodes of acute rejection has not been established [28]. Identifying common viral
infections, such as coronavirus or rhinovirus, as a cause of lower respiratory tract
infection may reassure the clinician that additional evaluation is not necessary and
improve antibiotic stewardship. We note that prolonged shedding of respiratory
viruses is well documented in transplant recipients, and physicians should consider
reviewing prior PCR results [29, 30].
In a SOT recipient with lower respiratory tract symptoms, the primary care pro-
vider should strongly consider obtaining chest imaging. Focal inltrates on chest
X-ray are most consistent with a bacterial pneumonia, whereas diffuse lung disease
and multifocal inltrates are more likely to represent a viral infection, atypical
organisms such as Pneumocystis jirovecii pneumonia (PJP) or a non-infectious pro-
cess. With a relevant exposure history and characteristic tempo of symptom onset,
nodular opacities on chest X-ray may suggest a fungal etiology, or opportunistic
organisms such as Nocardia spp. [31] Please see Fig.8.1 for classic radiographic
patterns on chest computed tomography imaging and potential next diagnostic steps.
Chest imaging, while helpful, cannot denitively rule in or rule out bacterial,
viral, or fungal etiologies of respiratory symptoms; imaging must be combined
with a thorough history and the provider’s best clinical judgment. The primary
care provider should have a low threshold to consult with an infectious disease
J. Hu et al.
201
Table 8.4 Common respiratory infections in solid organ transplant recipients
Category Common pathogens Common diagnostic evaluation Treatment Prevention
Viral
• COVID PCR-based nasopharyngeal
swab
Severity dependent; for outpatients without
signicant hypoxemia:
• IV remdesivir
• Ritonavir-boosted nirmatrelvir
a
• Molnupiravir
• Emerging antivirals
• Hand hygiene, masking
• COVID-19 vaccination
• Adjunctive pre-exposure
prophylaxis with monoclonal
antibodies, depending on
dominant circulating strain
• Inuenza PCR-based nasopharyngeal
swab
Neuraminidase inhibitor
• Oseltamivir
• Zanamivir
• Peramivir
Cap-dependent endonuclearse inhibitor
• Baxlovir
b
• Hand hygiene, masking
• Inuenza vaccination with either
inactivated inuenza vaccine
(IIV) or recombinant inuenza
vaccine (RIV)
• Prophylaxis with oseltamivir for
close contacts with inuenza
exposure
• RSV PCR-based nasopharyngeal
swab
• Consider reduction in immunosuppression
• +/− ribavirin +/− IVIG, particularly in lung
transplant (mixed data, only in consultation
with an infectious disease specialist)
• Hand hygiene, masking
• RSV vaccination
• Parainuenza
• Human metapneumovirus
PCR-based nasopharyngeal
swab
• Supportive care
• Consider reduction in immunosuppression
• Hand hygiene, masking
• No vaccination or prophylaxis
available
• Adenovirus PCR-based nasopharyngeal
swab
• Supportive care
• +/− cidofovir, only in consultation with an
infectious disease specialist
• Hand hygiene
• No vaccination or prophylaxis
available
(continued)
8 Infections intheAdult Solid Organ Transplant Recipient
202
Table 8.4 (continued)
Category Common pathogens Common diagnostic evaluation Treatment Prevention
• CMV/HSV/VZV In most cases, requires at least
bronchoscopy with BAL for
PCR
Serum CMV, HSV, VZV PCR
c
• IV ganciclovir for CMV pneumonia in consultation
with an infectious disease specialist
• IV acyclovir for conrmed HSV and VZV
pneumonia, in consultation with an infectious
disease specialist
d
• Appropriate antiviral
prophylaxis; duration varies
based on organ and donor/
recipient serostatus
Bacterial Community acquired:
• Streptococcus pneumoniae
• Haemophilus inuenzae
• Moraxella catarrhalis
• MRSA/MSSA
Healthcare associated:
• Pseudomonas aeruginosa
• Klebsiella spp.
• Enterobacter spp
• Escherichia coli, and other
Enterobacteriaeceae
• Stenotrophomonas
maltophila
• Acinetobacter spp, and so
on
Zoonoses
• Chlamydia psittaci
• Francisella tularensis
• Coxiella burnetti
• Rhodococcus equi
• Pasteurella multocida
Other
• Nocardia spp.
• Actinomyces spp.
• Sputum culture
• Blood culture
e
• MRSA swab
f
• Consider Legionella and S.
pneumoniae urine antigen
tests
g
• Antibiotics tailored to causative agent
• If no pathogen identied, treat empirically
with:
• Respiratory uoroquinolone, or
• Amoxicillin-clavulanate + macrolide
• Hand hygiene
• Vaccination for Haemophilus
inuenzae (Hib) and
Streptococcus pneumoniae
(PCV20, PCV21)
• In SOT recipients who have
received eculizumab, penicillin
prophylaxis for encapsulated
organisms (protocol and
durations vary)
(continued)
J. Hu et al.
203
Table 8.4 (continued)
Category Common pathogens Common diagnostic evaluation Treatment Prevention
• Mycobacterium
tuberculosis
• Non-tuberculous
mycobacterium (NTM)
• AFB sputum stain and culture
• MTB PCR and NTM PCR
h
• Antibiotics tailored to causative agent, in
consultation with an infectious disease
specialist
• Pre-transplant testing and
appropriate treatment for latent
TB
Fungal
• Aspergillus species • Sputum stain and culture
• Galactomannan assays on
sputum and serum samples
• Aspergillus and fungal PCR
h
• Antifungal therapy, typically voriconazole, in
consultation with an infectious disease
specialist
• Prophylaxis with voriconazole
early in post- transplant course
(protocols vary)
• Mucorales species • Typically diagnosed via
bronchoscopy or biopsy
with frozen section analysis,
histopathology, PCR, and
culture
• Evolving role for
metagenomic next-
generation sequencing
• Surgical intervention and antifungal therapy,
often amphotericin +/− posaconazole or
isavuconazole, in consultation with infectious
diseases specialist
(continued)
8 Infections intheAdult Solid Organ Transplant Recipient
204
Table 8.4 (continued)
Category Common pathogens Common diagnostic evaluation Treatment Prevention
• Endemic mycoses
(Histoplasmosis,
coccidioidomycosis,
blastomycosis)
• Sputum or BAL culture or
histopathologic/
cytopathologic identication
of organisms
• PCR testing
• Serologic assays for
coccidioidomycosis less
sensitive in SOT recipients
• Antifungal therapy, often uconazole or
itraconazole, in consultation with an infectious
disease specialist
i
• Pre-transplant evaluation
• In locales where there is
endemic Coccidiodomycosis or
Histoplasmosis, certain
transplant centers utilize
universal azole prophylaxis
• Pneumocystis jirovecii • Immunouorescence stain
on induced sputum or
bronchoscopy sample
• Serum beta-D-glucan
• Trimethoprim-sulfamethoxazole (TMP- SMX)
+/− steroids depending on degree of
hypoxemia
• Prophylaxis with TMP- SMX
preferred, variable duration
depending on organ
transplanted; lifelong after lung
+/− heart transplantation
a
Has interaction with immunosuppressive medications
b
Not as monotherapy in SOT recipients
c
Detection of CMV in peripheral blood does not necessarily indicate end organ disease, and by itself is not an indication for treatment
d
Isolation of HSV/VZV/CMV in respiratory samples such as bronchial washings or BAL by itself is not necessarily indication for treatment
e
Yield of blood culture is generally low but should consider if patient febrile or requiring hospitalization
f
MRSA swab may be helpful for de-escalation of therapy, this test is more applicable for inpatient care
g
Limited sensitivity; note urine legionella antigen only tests for L. pneumophila serogroup 1
h
Typically on bronchoscopy specimens
i
Also consult with transplant team due to common drug interactions between azoles and immunosuppressant medications
J. Hu et al.
205
specialist or pulmonologist when interpreting chest X-ray ndings in a SOT recip-
ient with a suspected infectious respiratory illness. Chest CT and even bronchos-
copy may be indicated to differentiate infection from non-infectious causes of
respiratory symptoms such as drug reactions and rejection (in lung transplant
recipients) [2]. Lung transplant recipients in particular should receive consulta-
tion with the transplant pulmonologist, both to expedite the appropriate workup
and to avoid empiric treatment that may make subsequent diagnostic tests less
accurate (See Chap. 7). Patients who present to clinic with signs of impending
respiratory failure, hypoxemia, or any other unstable vital signs due to a suspected
respiratory infection should be admitted to the hospital for inpatient evaluation
and treatment. Because SOT recipients can decompensate quickly, even patients
who appear clinically stable may benet from an emergency department evalua-
tion or inpatient stay if they have higher risk for severe infection, including being
in the earlier time period since transplantation, having a higher level of immuno-
suppression, history of organ failure or chronic illness.
Fig. 8.1 Etiologies of pulmonary infections and CT radiographic patterns. CMV cytomegalovirus,
GM galactomannan, HSV herpes simplex virus, IF immunouorescence, PCR polymerase chain
reaction, VZV Varicella Zoster virus. (Reprinted with permission from Azoulay etal. [32])
8 Infections intheAdult Solid Organ Transplant Recipient
206
See Chap. 9 for a broader discussion of differential diagnoses of respiratory
symptoms, including non-infectious causes. Specic infectious entities are dis-
cussed below.
8.3.2 Respiratory Viral Illnesses
8.3.2.1 Severe Acute Respiratory Syndrome Coronavirus 2
(SARS-CoV-2)
Coronaviruses are enveloped, positive sensed, single-stranded RNA viruses that are
well known causes of infection in humans. SARS-CoV-2 was rst described in late
2019in Wuhan, China, and subsequently caused a major global pandemic. Other
notable coronaviruses include HCoV-229E, HCoV-HKU1, HCoV-NL63, and
HCoV-OC43; these are estimated to cause 15–30% of mild upper respiratory infec-
tions [33]. Other rapidly spreading coronaviruses include severe acute respiratory
syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome (MERS),
both of which have been successfully contained.
Clinical Presentation
The spectrum of symptomatic infection with SARS-CoV-2 is highly variable, with
different circulating variants conferring varying risks of severe disease. Among
SOT recipients, the Omicron variant appears to be associated with less severe dis-
ease compared to earlier variants [34]. Overall, the clinical presentation mirrors the
general population, with fever (61–83%), cough (45–75%), and diarrhea (22–57%)
being the most common symptoms reported [35].
Risk factors for severe COVID-19 infection include lung transplantation, older
age, rituximab treatment, chronic lung disease, chronic kidney disease, and diabe-
tes. Early treatment and ≥3 vaccine doses are associated with reduced severity [36].
Maintenance immunosuppression may also have an effect, with some studies sug-
gesting increased risk of COVID-19 related hospitalization for SOT recipients
receiving mycophenolic acid, sirolimus, and steroids [21].
It is important to note that persistent shedding of SARS-CoV-2 can occur despite
resolution of symptoms, particularly in lung transplant recipients [29, 37].
Treatment
This chapter focuses on outpatient management for primary care providers. In addi-
tion to symptomatic management with over-the-counter antipyretics, analgesics, or
antitussives for fever, headache, myalgias, and cough, SOT recipients are at high
risk for progression to severe disease, and thus benet from additional therapy.
J. Hu et al.