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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5258_Библиотеки_им_академика_М_И_Перельмана.pdf
257© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
C. J. Wong (ed.), Primary Care of the Solid Organ Transplant Recipient,
https://doi.org/10.1007/978-3-031-98076-3_9
Chapter 9
Common Syndromes intheAdult Solid
Organ Transplant Recipient
KimO’Connor andChristopherJ.Wong
9.1 Introduction
Solid organ transplant recipients often return to the primary care setting after the
rst several months following transplantation, especially if their course has been
free of serious complications. While they will continue to have regular contact with
their transplant team, they may present to primary care when they develop new
symptoms. Patients may be unsure if the new symptoms are related to the trans-
planted organ, their immunosuppression, side effects of transplant-related medica-
tions, or an unrelated illness.
In the USA, the most common reasons for outpatient clinic visits are musculo-
skeletal symptoms (e.g., shoulder, knee), cough, skin problems, and abdominal
symptoms, in addition to chronic disease management (e.g., mental health, hyper-
tension) and wellness/preventive visits [1]. The most common reasons for emer-
gency department visits were abdominal pain, chest pain, dyspnea, cough, fever,
headache, other pain (including back pain), and mental health conditions [2].
This chapter explores several of these common syndromes and offers an approach
to the initial evaluation. As will be discussed, if the patient’s presentation is con-
cerning, close coordination with the transplant team is advised, and often transfer to
an acute care setting (e.g., emergency department or admission to the hospital) may
be indicated for expedited evaluation and treatment.
K. O’Connor (*) · C. J. Wong
Division of General Internal Medicine, Department of Medicine, University of Washington,
Seattle, WA, USA
e-mail: koconnor@uw.edu; cjwong@uw.edu
258
9.2 Respiratory Symptoms
Respiratory symptoms, including shortness of breath and cough, are common con-
cerns of patients presenting to primary care. The following section focuses of
addressing cough and dyspnea in solid organ transplant recipients who present to
care in the outpatient setting.
9.2.1 General Approach: Cough
9.2.1.1 Assess Clinical Stability
• Patients with new-onset hypoxia, severe tachypnea, signs of sepsis, or respira-
tory distress will need rapid evaluation and treatment in an emergency setting.
• Solid organ transplant recipients are at risk of rapid decompensation in cases of
severe infection, and it is generally best to err on the side of caution when con-
sidering whether to transfer to a higher level of care.
9.2.1.2 History
History should be directed toward infectious and non-infectious causes of respira-
tory symptoms.
• Core transplant history: Important initial information to gather includes the time
since transplantation and prior episodes of rejection, as the types of infections to
which a solid organ transplant recipient is more susceptible may vary based on
this history; and CMV and EBV serostatus. (For more in-depth discussion, see
Chap. 8.)
• Medications: A thorough medication history should be taken. The degree of
immunosuppression may be helpful in triaging potential opportunistic infections
as well as risk of decompensation.
• Habits: In most cases solid organ transplant recipients with a prior history of
smoking cigarettes have stopped smoking prior to transplantation. However, a
past history of smoking can lead to complications, including lung cancer and
chronic obstructive pulmonary disease. Patients should be asked about substance
use, including cigarettes, vaping, and marijuana. Inhaled marijuana use has been
associated with pulmonary aspergillosis in renal transplant recipients [3],
although its precise contribution to pulmonary aspergillosis in solid organ trans-
plant recipients overall is uncertain.
• Exposures: As with the general population, recent hospitalization increases the
risk for multi-drug resistant organisms, and recent travel should prompt consid-
eration for infectious illnesses not endemic to the current location. Evaluation of
K. O’Connor and C. J. Wong
259
a chronic, non-infectious cough should include history of environmental expo-
sures associated with interstitial lung disease.
• Associated symptoms:
– Symptoms such as fever and rhinorrhea may point to an infectious source.
Solid organ transplant recipients may contract community-acquired viral
infections such as the common cold. However, one must be careful not to
prematurely narrow the differential diagnosis if the patient is at higher risk for
other opportunistic infections due to increased levels of immunosuppression.
Prolonged viral infections may lead to secondary bacterial infection. Due to
immunosuppression, the solid organ transplant recipient may not present with
typical fevers and the absence of a fever is not reliable enough to rule out
infection.
– While a cough may be infectious (e.g., caused by an upper or lower respira-
tory tract infection), it is important not to assume an infectious source.
Interstitial and obstructive lung disease, pulmonary edema, gastroesophageal
reux, and lung cancer all may feature cough as their presenting symptom.
Sputum character does not reliably distinguish one cause from another.
Hemoptysis should always be evaluated further—history should include ask-
ing about other symptoms of infection (including risk factors for tuberculo-
sis), malignancy, and bleeding disorders.
• Time course: Duration and tempo of symptoms cannot solely distinguish among
causes of respiratory symptoms but may nevertheless provide clues to the
diagnosis.
– Acute (1–2days): Consider acute infections more highly on the differential
diagnosis, especially if other infectious symptoms are present. Additionally,
pulmonary embolism should be considered, especially if risk factors are pres-
ent. However, even chronic conditions may present acutely (e.g., a lung can-
cer may present with an effusion that becomes symptomatic, or a decreased
cardiac ejection fraction may be subclinical until it presents with decompen-
sated heart failure).
– Sub-acute (2 weeks): Infections, including opportunistic may still occur.
Pneumocystis jirovecii pneumonia may present sub-acutely with cough and
dyspnea, although more severe cases can occur. Other non-infectious causes
should remain in the differential diagnosis.
– Chronic (weeks-months): In a stable patient with chronic cough, consider tra-
ditional causes such as gastroesophageal reux disease, post-nasal drip, and
reactive airways disease. Medication side effects and interstitial lung disease
should also be considered. For stable outpatients with dyspnea, all causes
should be in the initial differential diagnosis, including anemia, heart disease,
and lung disease.
9 Common Syndromes intheAdult Solid Organ Transplant Recipient
260
• Lung and heart transplant recipients in particular should have additional consid-
erations when presenting with cough or other respiratory symptoms.
– Additional history to obtainfor lung transplant recipients includes baseline
lung function surveillance, whether the lung transplant was single or double,
the indication for transplantation, and whether there have been any prior air-
way complications such as stenosis (See Chap. 7).
– Heart transplant recipients have a denervated donor organ and therefore may
not present with typical angina. Cough may be a symptom of pulmonary
edema. Associated symptoms of heart failure should be asked, including dys-
pnea on exertion, orthopnea, and symptoms of volume excess (See Chap. 6).
9.2.1.3 Examination
• Physical Examination should include vital signs and a thorough upper respira-
tory tract, pulmonary, and cardiovascular exam.
• Note that heart transplant recipients may have a high resting heart rate at baseline
due to loss of vagal nerve input—this can be found by asking the patient as well
as review of prior vital signs.
• Abdominal exam may be useful if an intra-abdominal process leading to pulmo-
nary symptoms is suspected.
• In patients with dyspnea, assessment should include looking for signs of anemia
or other systemic illnesses.
9.2.1.4 Differential Diagnosis (Table9.1)
Infectious:
Infections are reviewed in more detail in Chap. 8 and are briey discussed here.
• Pneumonia: Precise estimates on incidence of pneumonia in solid organ trans-
plant recipients are difcult to obtain. A point-prevalence study in Europe esti-
mated an incidence of 10 per 1000 patients per year [4]. The incidence was
highest in lung transplant recipients. The majority presented late (dened as
>6months from transplantation). Although this sample included outpatient care,
the cases identied were primarily in hospitalized patients. Similarly, prior
single- center studies showed a high mortality rate, but cases were predominantly
nosocomial and early after transplantation [5].
Several fungal infections can cause pneumonia in solid organ transplant recipi-
ents. Pneumocystis jirovecii is an important cause of opportunistic infections in the
solid organ transplant population, leading to most solid organ transplant recipients
receiving prophylaxis against P. jirovecii within the rst 6–12months after trans-
plantation (protocols vary), with lifelong prophylaxis given to lung transplant recip-
ients. Patients with Pneumocystis jirovecii pneumonia may present acutely with
K. O’Connor and C. J. Wong
261
Table 9.1
Causes of cough in solid organ transplant recipients
Infectious Non-infectious
Upper respiratory tract
infection
• Viral rhinosinusitis
• Bacterial sinusitis
Lower respiratory tract
infection
• Pneumonia
– Bacterial
– Viral (e.g., CMV)
– Fungal (e.g., aspergillus,
P. jirovecii, Candida species,
endemic mycoses)
– Mycobacterial
• Bronchitis
– Viral
– Bacterial
Pulmonary/lung disease
• COPD exacerbation
• Asthma exacerbation
• Interstitial lung disease
• Pulmonary embolism
• Pulmonary hypertension
• Lung transplant recipients: rejection, airway stenosis
Malignancy
• Primary lung cancer
• Lymphoma/PTLD in the lungs or mediastinum
• Pleural effusion associated with malignancy
• Metastatic disease to the lung
• Head and neck cancer/laryngeal
Cardiac
• Heart failure
Medication side effect
• ACE-inhibitors
Gastrointestinal
• Gastroesophageal reux disease
Upper airway
• Post-nasal drip/upper airway cough syndrome
hypoxia and dyspnea, more commonly than in patients with HIV infection, who
often present sub-acutely with several weeks of progressive symptoms. While pro-
phylaxis is credited to dramatic reductions in P. jirovecii pneumonia, cases still
occur, especially after prophylaxis has been discontinued, and have been associated
with episodes of acute rejection (and therefore increased immunosuppression), as
well as CMV viremia; additionally, heart and lung transplant recipients are at higher
risk compared to other solid organ transplant recipients [6, 7].
Aspergillus fumigatus is more common than pneumocystis jirovecii and other
fungal infections in solid organ transplant recipients [8]. Risk factors include lung
and heart transplantation, CMV infection, degree of immunosuppression, and envi-
ronmental exposure [8]. Nosocomial infections may occur early after transplanta-
tion, but late infections (> 6 months post-transplant) also occur. Aspergillus
pulmonary infections may present with cough, fever, hemoptysis, chest pain, and
malaise. Patients may manifest symptoms in other organs if the infection has already
spread at the time of presentation [8]. Prophylaxis is typically administered in the
rst few months post-transplant for lung transplant recipients and in some heart
transplant recipients (protocols vary) [8].
Other fungi such as Candida species, Cryptococcus, Zygomycetes species, the
endemic mycoses coccidioidomycosis and histoplasma all may cause pulmonary
infections. Histoplasmosis tends to occur in the later post-transplant period with
disseminated disease but can have subacute pulmonary symptoms [8]. In contrast,
coccidioidomycosis tends to occur earlier post-transplant and represent re- activation
[8]. Blastomycosis is considered rare even in this population [8].
9 Common Syndromes intheAdult Solid Organ Transplant Recipient
262
Mycobacterial infections can be divided into Mycobacterium tuberculosis and
all non-tuberculous mycobacteria. Pulmonary tuberculosis does occur, and level of
suspicion is dependent on exposure and local epidemiologic risk factors. Non-
tuberculous mycobacterial pulmonary infections are less common than other patho-
gens in the solid organ transplant population, but also do occur and should be
suspected in a patient with chronic cough and especially if systemic symptoms are
also present.
Viral infections. Most solid organ transplant recipients receive prophylaxis
against CMV during the rst 6–12months after transplantation. Although consid-
ered an “early” post-transplant infection, because of effective prophylaxis in the
initial post-transplant period, late cases do occur. While multiple immunosuppres-
sive agents decrease T cell function and increase risk of CMV, mammalian target of
rapamycin (mTOR) inhibitors do not appear to increase risk, and may even lower
risk of CMV infection [9]. CMV may cause a viral syndrome with non-specic
symptoms, but also may cause end-organ damage, including pneumonia. As noted
above, CMV infection increases the risk for subsequent Aspergillus and P. jirovecii
infections.
SARS-CoV-2 continues to change worldwide as of the writing of this book.
SARS-CoV-2 infection in solid organ transplant recipients may present similarly to
the general population, with a wide range of symptoms, including asymptomatic
(tested for other reasons); upper respiratory (nasal congestion, cough, and changes
in taste and smell); lower respiratory (dyspnea, pneumonia), constitutional (mal-
aise, fever); and gastrointestinal symptoms (diarrhea).
A multitude of other viruses may cause respiratory infections—those that may
cause lower respiratory tract symptoms include inuenza and respiratory syncytial
virus (RSV).
• Upper respiratory tract infections: Solid organ transplant recipients are suscepti-
ble to the respiratory viruses that cause the common cold, similar to the general
population, including rhinovirus and other coronaviruses. Patients with rhinorrhea
and other upper respiratory tract infection (URI) symptoms, without evidence of
bacterial sinusitis or lower respiratory tract disease, may be considered to have an
isolated URI.However, any patient with a cough or dyspnea should have a broader
differential considered in the evaluation. For lung transplant recipients, even mild
respiratory viral infections may be associated with a decline in graft function, and
therefore the lung transplant team should be notied (see Chap. 7).
Non-infectious:
Other conditions that may present with cough also have a higher prevalence in
the solid organ transplant population.
• Cancer: Solid organ transplant recipients have an increased overall risk of malig-
nancy compared to the general population as well as higher mortality when can-
cers occur [10]. While studies vary, there is an increased incidence of cancers
that may present with pulmonary symptoms, including lung cancer, lymphoma,
melanoma, and kidney cancer in all solid organ transplant recipients. [11, 12]
K. O’Connor and C. J. Wong
263
Primary lung cancer, metastatic cancer to the lung, and lymphoma in the lung
may present with cough and/or hemoptysis (See Chap. 10).
• Interstitial lung disease: Interstitial lung disease typically presents with a variety
of chronic to subacute symptoms, including dyspnea and cough [13]. In addition
to exploring traditional risk factors for ILD, in the solid organ transplant recipi-
ent there have been case reports of ILD associated with immunosuppressive
medications, including the mammalian target of rapamycin (mTOR) inhibitors
sirolimus and everolimus [14–16].
• Lung transplant recipients (see Chap. 7):
– Lung transplant recipients may present with acute and chronic rejection.
Acute symptomatic rejection may present with acute dyspnea and cough.
Symptoms may be subtle, and therefore lung transplant centers routinely
monitor lung function. In cases of suspected acute rejection, consultation
with the transplant pulmonologist is critical, and other causes of dyspnea
such as airway stenosis and infection will often need to be evaluated
urgently.
Chronic Lung Allograft Dysfunction (CLAD) is a form of chronic rejection
and manifests as a decline in FEV1 and may present with chronic dyspnea
and cough. It has obstructive and restrictive subtypes.
– The risk of lung cancer is higher in lung transplant recipients compared to
other solid organ transplant recipients (see Chap. 10).
– Airway complications can occur post-lung transplantation, of which bron-
chial stenosis is the most common, with an estimated prevalence of
2–18% [17].
– Single lung transplant recipients: In single lung transplant recipients, the
native lung may still be diseased—for example, in a patient with a single lung
transplant for smoking-related COPD, the native lung remains at increased
risk for infection, malignancy, and other complications such as
pneumothorax.
– Gastroesophageal Reux Disease (GERD): While GERD is a common cause
of chronic cough in the general population, its impact in lung transplant recip-
ients is greater due to the risk of lung injury. Many lung transplant recipients
are treated routinely with proton pump inhibitors.
9.2.1.5 Testing andTreatment
• Imaging: In general, one should have a lower threshold to obtain imaging in solid
organ transplant recipients who present with cough due to the increased risk of
infection and malignancy as well as their potentially blunted inammatory
response to infection. A chest X-ray is a reasonable rst imaging test, but in
patients with concerning symptoms a chest CT is more sensitive.
• Specic tests for respiratory pathogens: While testing for respiratory viruses
other than inuenza is uncommonly performed in the general population, when
9 Common Syndromes intheAdult Solid Organ Transplant Recipient
264
evaluating solid organ transplant recipients presenting with potentially infectious
respiratory symptoms it is recommend to obtain a nasopharyngeal swab to send
for PCR-based tests for viral pathogens. Interpretation of PCR test results should
be interpreted in context of the patient’s prior testing and clinical presentation, as
some patients have persistently positive PCR results for viral pathogens includ-
ing SARS-CoV-2 despite clinical resolution of symptoms [18]. Infectious dis-
ease consultation is indicated when there is diagnostic uncertainty.
• Additional testing: Solid organ transplant recipients with serious illnesses such
as pneumonia frequently require additional testing such as sputum samples,
bronchoscopy, and in some cases biopsy depending on the presentation, imaging
ndings, and response to treatment.
• If CMV is considered, consultation with an infectious disease specialist is appro-
priate. Imaging ndings are typically bilateral, patchy, and may include ground
glass opacities, air-space disease, and small nodules—however most imaging
studies of CMV pneumonitis are limited by small numbers of SOT recipients
[19, 20]. CMV disease (in any organ) is diagnosed denitively by tissue sample.
The CMV antigenemia assay is not sufciently sensitive in the SOT population
[21] and has been replaced by PCR [9]. Serology should be determined from
reviewing the transplantation history, as CMV negative hosts who receive organs
from CMV positive donors are at highest risk, but it is not helpful to recheck
these tests in the acute setting. While in some cases if other causes are ruled out
or are deemed of low likelihood, pneumonitis with CMV viremia may prompt
initial treatment for presumed CMV disease, followed by invasive testing if the
patient does not respond to initial treatment. However, if other causes are also
likely and unable to be ruled out, then early invasive testing with bronchoalveolar
lavage may be indicated both to assess for the cytopathic presence of CMV in the
lung, as well as investigate other causes of the patient’s symptoms. In lung trans-
plant recipients in particular, bronchoscopy may be especially important to
assess for rejection—consultation with the transplant pulmonologist is indicated.
• Early consultation is generally recommended for patients with higher risk or
more serious presentations. The primary care provider should have a low thresh-
old to consult with the transplant specialist, an infectious disease specialist, and
transfer to a higher level of care if necessary.
– Lung transplant recipients presenting with dyspnea or cough should have
their workup coordinated with the lung transplant specialist, as the transplant
team will often recommend an urgent workup for rejection, re-evaluate graft
function, and also may perform additional tests for infection.
• Empiric treatment: If inuenza is suspected, treatment should be initiated while
waiting for conrmatory testing. For suspected community-acquired pneumonia,
patients should be triaged for consideration of hospitalization for inpatient treat-
ment. If deemed stable for outpatient treatment for community-acquired pneu-
monia, then empiric treatment should be initiated based on infectious disease
guidelines, with appropriate assessment of potential drug interactions and
whether the patient is at risk for drug-resistant organisms. Empiric treatment
K. O’Connor and C. J. Wong
265
should generally not be started in stable patients in whom opportunistic infec-
tions are suspected, as guidance by an infectious disease specialist is usually
warranted to identify appropriate testing and management. As noted above, for
lung transplant recipients, the transplant team should be contacted prior to
empiric treatment, as they may have recommendations to guide choice of treat-
ment and what testing should be performed to help assess for both infection and
rejection. (See Chaps. 7 and 8).
• Corticosteroids: Corticosteroids for obstructive lung disease exacerbation and
reactive airways should be used with caution, as it may affect evaluation of organ
rejection—in lung transplant recipients in particular, corticosteroids should not
be given (unless emergent) without rst consulting the transplant
pulmonologist.
• IV uids: IV uids should generally not be given to solid organ transplant recipi-
ents in the primary care setting. If the patient is ill enough to require IV uids,
then transfer to an acute care setting is indicated. In particular, IV uids should
be administered with caution and only in a well-monitored setting for lung trans-
plant recipients, as the disruption in the lymphatic system makes these patients
more susceptible to pulmonary edema. Heart transplant recipients should also
generally not be given IV uids without consultation with the transplant cardi-
ologist, as their volume status and graft function will likely need more urgent
assessment.
• Follow up: As with any patient, if the solid organ transplant recipient being
treated for a pulmonary condition does not improve, one should re-consider the
initial diagnosis as well as consider co-infection with more than one organism.
9.2.2 General Approach: Dyspnea
Dyspnea alone (for example, absent symptoms such as rhinorrhea, cough, angina,
fever) should lead to a similar differential diagnosis as in the general population,
including cardiovascular disease (e.g., congestive heart failure, angina), pulmonary
disease (e.g., pulmonary embolism, pulmonary hypertension, interstitial lung dis-
ease, obstructive lung disease), and systemic conditions such as anemia. However,
one should also consider infection (e.g., pneumonia with fewer classically infec-
tious symptoms such as fever) and malignancy (e.g., lung cancer presenting with a
malignant pleural effusion).
9.2.2.1 Assess Clinical Stability
• Patients with new-onset hypoxia, severe tachypnea, signs of sepsis, or respira-
tory distress will need rapid evaluation and treatment in an emergency setting.
• If dyspnea is suspicious for acute coronary syndrome, then transfer to an emer-
gency setting is indicated even if vital signs are stable.
9 Common Syndromes intheAdult Solid Organ Transplant Recipient
266
9.2.2.2 History
As with history-taking for cough described above, history should be directed toward
infectious and non-infectious causes of dyspnea, including the core transplant his-
tory, medications, habits, exposures, associated symptoms, and time course.
Additional considerations for dyspnea without prominent other infectious symp-
toms include:
• Venous thromboembolism risk factors: immobility, known malignancy, long-
distance travel, a personal or family history of hypercoagulable state all increase
the risk of venous thromboembolism (VTE).
• Risk factors for lung disease: prior lung disease, exposures.
• Risk factors for heart disease: diabetes, hypertension, hyperlipidemia, smoking.
Solid organ transplant recipients have an increased risk of metabolic conditions
(see Chap. 11).
• Associated symptoms:
– Infectious symptoms such as fever, cough, rhinorrhea may increase the suspi-
cion for an infectious cause of dyspnea, as discussed above.
– As with the general population, chest pain or pressure should raise suspicion
for coronary artery disease.
– Exertional symptoms are concerning for cardiac and pulmonary disease,
including angina, VTE, heart failure, and COPD.
– Unintentional weight loss, chronic fevers, night sweats, and decreased appe-
tite all may be symptoms of malignancy.
– Symptoms of volume overload: peripheral edema, weight gain, orthopnea.
– Symptoms of blood loss that may lead to signicant anemia: hematuria, vagi-
nal bleeding, melena, rectal bleeding.
• Anxiety and panic attacks may present with dyspnea as a prominent symptom.
• Type of transplant:
– Lung transplant recipients presenting with dyspnea should have their workup
coordinated with the transplant team, as the transplant team will often recom-
mend an urgent workup for rejection and re-evaluate graft function. The
patient’s surveillance lung function testing should be reviewed.
– Heart transplant recipients have a denervated donor organ and therefore may
not present with typical angina. Surveillance testing should be reviewed. As
with lung transplant recipients, the heart transplant team should be involved
early in the evaluation of dyspnea due to the potential for graft dysfunction as
a cause.
9.2.2.3 Examination
• Vital signs: in addition to heart rate, blood pressure, respiratory rate, tempera-
ture, assess pulse oximetry and comparison to prior weights to assess for unin-
tentional weight loss as well as possible uid overload.
K. O’Connor and C. J. Wong