Lung Transplant Considerations for the Community Pulmonologist

Lung Transplant Considerations
for the
Community Pulmonologist
Developed by the Transplant NetWork of the
American College of Chest Physicians
Members of the ACCP Transplant NetWork writing committee:
Sangeeta M. Bhorade, MD, FCCP
Kevin M. Chan, MD, FCCP, Co-Chair
Deborah Jo Levine, MD, FCCP
Janet R. Maurer, MD, FCCP, Co-Chair
Maria L. Padilla, MD, FCCP
Rajat Walia, MBBS
© 2007 by the American College of Chest Physicians
Table of Contents
1. Introduction
a. Indications
b. Single lung transplantation
c. Bilateral lung transplantation
d. Survival
2. Community physician visits and concerns
a. Routine office visit
b. Immunosuppression
c. Nonpulmonary concerns
3. Preventive care
a. Immunizations
b. Screening/early detection
4. Physiologic outcomes
a. Pulmonary function
b. Gas exchange
c. Exercise capacity and oxygen utilization
5. Normal posttransplant course
a. Immediate
b. First 24 to 48 h
c. Fiberoptic bronchoscopy
d. Long-term care
6. Acute rejection
a. Clinical presentations
b. Diagnosis
c. Histologic grading
7. Chronic rejection
a. Obliterative bronchiolitis
b. Bronchiolitis obliterans syndrome
c. Risk factors
d. Clinical presentation
e. Management
8. Infectious complications
a. Bacterial
b. Viral
c. Fungal
9. Airway complications post-lung-transplantation
a. Bronchial stenosis
b. Bronchomalacia
10. Malignancy
11. Posttransplantation lymphoproliferative disease
12. Renal failure and hypertension
13. GI complications
a. Gastric ulceration
b. GI motility
c. Gastroesophageal reflux disease
d. Acute abdomen
e. Colonic complications
f. Colonic perforation
g. Infections
h. Distal intestinal obstruction
i. Pneumatosis intestinalis
j. Other GI complications
14. Neurologic/CNS complications
a. Severe headache
b. Seizures
c. Cognitive function/confusion
d. Psychosis/hallucinations
e. Stroke
f. Tremors
g. Peripheral neuropathy
h. Myopathy
i. Myalgias/myositis/rhabdomyolysis
15. Hematologic complications
a. Anemia
b. Hemolytic uremic syndrome
c. Leukopenia
d. Thrombocytopenia
e. Hypogammaglobulinemia
16. Endocrine issues
a. Hyperglycemia
b. Metabolic bone disease
c. Menses/pregnancy
17. Psychologic/psychiatric health
18. Quality of life
19. Deconditioning and physical rehabilitation
20. Nutrition and diet
21. Bibliography
22. Appendix: Lung transplant medications
a. Immunosuppressive
i. Induction agents
(1) Anti-T-cell agents
(2) IL-2 receptor antagonists
ii. Maintenance immunosuppression
(1) Calcineurin inhibitors
(2) Purine synthesis inhibitors
(3) Corticosteroids
(4) Sirolimus
(5) Other/chronic rejection agents
b. Antimicrobial prophylactic medications
i. Pneumocystis jiroveci
ii. Antifungal prophylaxis or treatment
(1) Clotrimazole
(2) Nystatin
(3) Itraconazole
(4) Voriconazole
(5) Inhaled amphotericin B
iii. Cytomegalovirus prophylaxis
iv. Other antiviral prophylaxis
c. Antihypertensives
d. GI medications
e. Endocrine medications
f. Important drug and diet interactions
i. Drugs
ii. Diet
1. Introduction
• Between 1988 and 2005, lung transplants annually in the United States increased from 33 to
• Lung transplants are limited by organ availability.
o Reached a plateau at ~1,000 patients/year in the United States in 2001
o Patients waiting for a lung allograft increased to 3,200
o Median waiting time of more than 2 years
• Lung allocation score was implemented in May 2005.
o Allocates organs based on disease severity rather than on waiting time
o With the implementation of this system, the number of patients currently active and
waiting for lung transplantation has decreased to 940.
o Effect of the lung allocation score on waiting times is yet to be determined.
• This document is designed to serve as a basic reference for the management of lung transplant
recipients with concise presentation of information.
• Concise Community Physician Office Visit Expectations in Community physician visits and
• Communication with the patient’s lung transplant center is necessary when information and
guidance is warranted.
• Emphysema (related to tobacco, environment, alpha1-antitrypsin deficiency)
o 50% of all lung transplants
• Pulmonary fibrosis, primarily idiopathic pulmonary fibrosis
• Sarcoidosis
• Cystic fibrosis and bronchiectasis of any cause
• Pulmonary hypertension (idiopathic pulmonary arterial hypertension, Eisenmenger syndrome)
• Other diagnostic groups
o Lymphangioleiomyomatosis, eosinophilic granuloma (histiocytosis lung disease),
pulmonary fibrosis due to connective tissue diseases (rheumatoid lung; limited
scleroderma), hypersensitivity pneumonitis, pneumoconiosis, and radiation fibrosis
Single lung transplantation
• Suffices in patients without suppurative lung disease (see International Society for Heart and
Lung Transplantation data, which is updated quarterly).
• Advantages
o Increases the organ donor pool
o Shorter, less complex procedure
• Indications
o Mainly emphysema and pulmonary fibrotic diseases
o Pulmonary hypertension in some programs
Bilateral lung transplantation
• Suppurative lung disease
o Cystic fibrosis or bronchiectasis
• Pulmonary Hypertension
o Idiopathic pulmonary arterial hypertension, rheumatologic causes, Eisenmenger
• Preferred in the younger patient (<45 years of age)
• Recently demonstrated to provide improved survival when compared with single lung
• Survival limited by infection and chronic allograft rejection (obliterative bronchiolitis [OB])
• One- and 5-year survival approximates 78% and 49%
o Patients with emphysema have better survival in the first 5 years
o Patients with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial
hypertension generally have worse survival in the first 5 years
o Causes of early mortality
First 30 days: primary graft failure and surgical complications
One year: infection
• Acute allograft rejection rarely a cause of death
o Usually responds to augmented immunosuppression
Greater than 1 year: chronic allograft rejection (manifested by concentric OB)
• Thirty to 50% of patients surviving to 1 year will develop OB by 5
o Frequently refractory to treatment
o Infectious complications often develop during treatment for OB
o Can manifest as bronchiectasis
o Aspergillus fumigatus and pseudomonas aeruginosa colonize
2. Community physician visits and concerns
Routine office visits
• Evaluate with a physical examination, spirometry, chest radiography
o Physical examination
Fever, tachypnea or hypo/hypertension
• Fever or hypotension could indicate infection
o Proceed with infection evaluation, including complete blood
count with differential, blood cultures, if indicated, liver function
tests, chest radiograph, urinalysis and culture, sputum culture, if
o Initial therapy should be with aggressive double Gram-negative
coverage (eg, piperacillin/tazobactam + levofloxacin (avoid
aminoglycosides). Add IV ganciclovir, if cytomegalovirus
infection is suspected (see below). The patient would be
hospitalized at this time.
o If the patient has a history of cytomegalovirus infection or is
cytomegalovirus donor or recipient positive, consider
cytomegalovirus infection
Evaluate with chest radiograph, cytomegalovirus serum
polymerase chain reaction (quantitative), look for
transaminitis, leukopenia
• Hypertension could indicate high cyclosporine/tacrolimus levels or renal
o Check a trough (1 h prior to dose) cyclosporine or tacrolimus
o Check BUN, creatinine, potassium, bicarbonate, chloride,
glucose, phosphorus, magnesium levels
o Evaluate medications as many medications increase the level of
cyclosporine or tacrolimus (eg, fungal azoles increase the levels
of both)
Skin lesions (patients prone to skin carcinomas, rash, etc)
Abnormal breath sounds
• New wheeze or crackles in transplanted lung
o Chest radiograph
Tremor, neurologic changes, neuropathy
• If greater than usual, could be indicative of high cyclosporine or
tacrolimus levels
• Check medication interactions, especially with cyclosporine or
Pneumonia or chest radiograph abnormality
• Focal consolidation
o Likely bacterial pneumonia
Initiate broad spectrum fluoroquinolone + ceftriaxone or
if pseudomonas is suspected, piperacillin/tazobactam or
• Interstitial disease
o As above + cytomegalovirus or viral pneumonitis + Pneumocystis
carinii pneumonia (PCP)
If patient on PCP prophylaxis and compliant, PCP
o Initiate broad spectrum antibiotics as above +
IV ganciclovir, if at risk for cytomegalovirus infection
Trimethoprim/sulfamethoxazole or equivalent, if PCP
Consider treatment for common viral pneumonias:
influenza, respiratory syncytial virus, adenovirus, etc
• Nodular changes
o Consider fungal disease
Initiate voriconazole, if fungus suspected
• Causes severe elevations in calcineurin inhibitors,
therefore dose must be adjusted
• Bronchoscopy as soon as possible, prior to initiation of treatment if
possible, but do not delay therapy if infection is highly suspected
Contact the transplant center if patient does not respond quickly to treatment or if abnormalities or
questions arise.
Immunosuppression over time (For detailed medication information, see Appendix)
• Cyclosporine levels
o <6 months posttransplant, 200 to 300 ng/mL
o 6 to 12 months, 180 to 250 ng/mL
o 12 to 24 months, 150 to 200 ng/mL
o >24 months, 100 to 150 ng/mL
• Tacrolimus levels
o <6 months posttransplant, 10 to 15 ng/mL
o 6 to 24 months, 8 to 10 ng/mL
o >24 months, 6 to 8 ng/mL
• Sirolimus
o 8 to 12 ng/mL
• Prednisone
o Discharge: 3 months, 20 mg daily
o 3 to 6 months, 15 mg daily
o 6 to 12 months, 10 mg daily
o 12 to 18 months, 7.5 mg daily
o >18 months, 5 mg daily
Nonpulmonary concerns
• Hematologyount
o Maintain WBC count >4.0 x 103
Adjust azathioprine or mycophenolate dose
o Pancytopenia can occur most likely due to azathioprine (Imuran®; DSM
Pharmaceuticals, Inc.; Greenville, NC) or mycophenolate mofetil (Cellcept®; HoffmanLaRoche; Nutley NJ; Myfortic®; Novartis Pharmaceuticals; East Hanover, NJ)
o Patients on sirolimus are prone to thrombocytopenia
o Adjust sirolimus dose
If thrombocytopenia persists, discontinue sirolimus. Notify transplant center of
o Valganciclovir can cause thrombocytopenia or anemia
Adjust or hold dose
• Hypertension and renal function
o Patients on calcineurin inhibitors (cyclosporine or tacrolimus) frequently develop
hypertension and renal insufficiency
When new hypertension is discovered, always check medication levels. If
levels are high, hypertension may resolve with a reduction in dosing
Otherwise, the addition of antihypertensive agents is warranted
• Diltiazem, nifedipine, and verapamil increase calcineurin inhibitor
• Amlodipine does not increase calcineurin inhibitor levels.
• Angiotensin-converting enzyme inhibitors or angiotensin II receptor
blocker require careful titration to avoid deterioration in renal function
o Monitor kidney function, including potassium, magnesium, and phosphorus levels
Over time, kidney function may deteriorate with the development of
Calcineurin inhibitor levels require close monitoring and doses are usually
• Hyperglycemia and lipids
o Common after transplantation due to chronic corticosteroid use and
Tacrolimus associated with hyperglycemia
o Patients frequently on insulin early after transplantation with reduction as
corticosteroid doses fall
o Lipids also elevated due to chronic immunosuppression
Sirolimus is associated with severe elevations in triglycerides and lipids;
cyclosporine more than tacrolimus also associated with hyperlipidemia
Control with diet and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase inhibitors (statins)
• Close monitoring of liver function and creatine phosphokinase required
• Increased risk of rhabdomyolysis when used in conjunction with
antifungal azole agents (eg, itraconazole, voriconazole)
• Osteoporosis
o Common in both men and women, due to chronic immunosuppression
o Annual bone densitometry and aggressive treatment to prevent bone loss required
Vitamin D + calcium
Testosterone, if required, in men
• GI
o Nausea and vomiting
Gastric and bowel dysmotility not uncommon after transplantation
• Improves over time
• Motility agents, such as metoclopramide or erythromycin (off-label),
sometimes helpful
• Can be asymptomatic
• Proton-pump inhibitors used to treat symptomatic patients
• Associated with chronic rejection of the transplanted lung
• Some advocate surgical management either prophylactically or as
treatment in high risk patients
Elevated liver enzymes noted with azathioprine and antifungal azole agents
Pancreatitis is associated with azathioprine, calcineurin inhibitors
o Diarrhea
Check fecal leukocytes and C difficile toxin to eliminate infection as a cause
Often associated with medications, such as mycophenolate mofetil or
Can be seen with alendronate (Fosamax; Merck & Co.; Whitehouse Station;
• Malignancy
o Skin malignancies most common
Avoid excessive sun exposure
• Sunblock at all times
Careful skin examinations
o Malignancy in native lung not uncommon
o Development of posttransplant lymphoproliferative disease (lymphoma)
o Patients who develop malignancy (other than skin) often do poorly due to
immunosuppression requirements. Newer monoclonal antibody treatments are
occasionally successful in posttransplant lymphoproliferative disease.
o Azathioprine or mycophenolate mofetil reduced or discontinued when malignancies are
• Annual health screening
o Extremely important
Pap smear
Prostate examination
Colonoscopy (when required)
Bone density
• Infectious disease
o Annual influenza vaccine is beneficial (inactivated virus only)
o No swimming in nonchlorinated water
o Avoid gardening, working in soil, areas with aerosolized molds
o Wash hands frequently
Contact the transplant center with questions or concerns of any type.
3. Preventive care
• Annual influenza immunization with killed virus is beneficial. An attenuated immune response
is seen; however, this may be protective.
• Pneumococcal vaccination in nonimmunized patients is beneficial.
• Immunosuppressed patients can receive killed (or inactivated virus) vaccines, especially in the
event of exposures or other high-risk situations. The immune response, however, is not
predictable and may be suboptimal.
o Killed virus vaccines include: diphtheria/tetanus/pertussis; eIPV (inactivated polio
vaccine); influenza (not intranasal); pneumococcal; hepatitis A, hepatitis B,
meningococcal, rabies
• In general, immunosuppressed patients should not receive attenuated live viral vaccines.
o Live attenuated vaccines include: measles/mumps/rubella; oral polio vaccine; typhoid
vaccine, yellow fever vaccine, vaccinia and varicella vaccines
o Care should be taken to avoid household contact with persons receiving live-attenuated
viral vaccines until shedding period over
• The role of palivizumab (Synagis®; MedImmune; Gaithersburg, MA), a monoclonal antibody
directed against respiratory syncytial virus, is not yet clear but should be considered in patients
with contact exposure.
Screening/early detection
• Immunosuppressed patients have an increased risk of a variety of cancers, particularly
lymphomas. Cervical cancer and precancerous changes are reported to occur at five times the
rate in a normal population.
• Early data suggest colorectal, and some other cancers occur at a younger age in the organ
transplant population.
• Routine screening, as defined by the US Preventive Services Task Force, should be carried out
in lung transplant patients, and screening should be started at least at the minimum
recommended ages.
• Skin cancers, particularly basal cell and squamous cell, are markedly increased in organ
transplant recipients. Semiannual, full-body skin examinations are beneficial.
• High SPF sunscreen should be worn whenever the patient goes out of doors. Re-educate
patient on each visit.
4. Physiologic outcomes
Pulmonary function
• Improves from a restrictive pattern to maximal function at 3 to 6 months
• Double lung transplants
o Attain normal lung function or mild restrictive defect with or without mild diffusion
• Single lung transplants
o Physiologic function, as determined by underlying disease
• Spirometry reveals initial normal flow from the transplanted lung,
followed by terminal flow from the native emphysematous lung
• Expiratory loop demonstrates this biphasic characteristic (Fig 1)
Figure 1.
• FEV1 improves from 50% to 57% of predicted
• Persistent restrictive component without airway obstruction
o FVC improves from 43% to 69% predicted
o Evidence of airway obstruction could be representative of acute
or chronic rejection
Gas exchange
• Normalizes in 8 to 12 weeks
• Single lung transplants
o Oxygenation improves, but increased alveolar-arterial oxygen gradient remains
o In emphysema, 80% of pulmonary perfusion flows to the transplanted allograft.
o 60% to 70% of flow occurs to the allograft of patients with fibrotic lung disease.
May account for mild exercise desaturation in patients with fibrotic lung
Exercise capacity and oxygen utilization
• Oxygen consumption usually peaks at 40% to 60% of predicted values.
o Limitation in oxygen utilization may be due to calcineurin inhibitor effect on cellular
• No ventilatory or cardiac limitation after transplantation
• Early onset of the anaerobic threshold
• Exercise is symptom-limited by muscle fatigue
o Impaired oxidative capacity of skeletal muscle
o Skeletal muscle dysfunction due to the pretransplant condition
o Effects of pre- and posttransplant medications
5. Normal posttransplant course
Immediate posttransplantation
Prophylactic antibiotics to prevent infection.
IV corticosteroids
Purine analog for immunosuppression.
May add induction therapy with antilymphocyte globulins or with IL-2 receptor antagonists
o These agents “destroy” functioning lymphocytes or block IL-2, which inhibits
lymphocyte activation and proliferation.
• Initiation of a calcineurin inhibitor (cyclosporine or tacrolimus), delayed by 1 to 2 days
postoperatively to prevent renal insult
• Early extubation
Airway frequently examined by flexible fiberoptic bronchoscopy prior to extubation
• Pain control
o Epidural anesthesia effective in preventing postoperative pain and atelectasis
First 24 to 48 h after transplantation
• Primary graft failure or reperfusion injury
o Decreased PaO2/FiO2 ratio
o Alveolar filling opacities in the areas of greatest injury
o Pulmonary hypertension with a reduction in lung compliance
Cold ischemia and reperfusion results in “leaky” endothelium, which leads to
noncardiogenic pulmonary edema
• Diffuse alveolar damage
o Managed by diuresis, inhaled nitric oxide, supportive care, and, occasionally, by
extracorporeal membrane oxygenation
• Physical therapy and activity immediately after extubation
o Maneuvers to encourage cough and pulmonary “toilet”
Aerosolized beta-agonists
Chest physiotherapy
Incentive spirometry
• Additional prophylactic antibiotics
o Antifungal agent itraconazole, inhaled amphotericin B (off-label), or voriconazole to
prevent aspergillus fumigatus colonization
o Ganciclovir or valganciclovir to patients at risk of cytomegalovirus disease
o Aerosolized antibiotics, such as amphotericin B or tobramycin
o Proton-pump inhibitors or H-2 blockers, magnesium, potassium, diuretics, and insulin
are often added
• Chest tubes are discontinued as output decreases
• Transferred to a telemetry unit within 3 to 5 days
• Intensive education
o Medications
“Self-medication” program
o Posttransplant activities
o Home spirometry is recorded by the patient after discharge.
Patient is taught to calculate the percent fall in FEV1 based on peak values
Reduction of 10% or more in this number would alert the patient toward the
possibility of allograft rejection
Signs and symptoms of rejection or infection are discussed with patient (see
section Acute Rejection)
o Contact lung transplant coordinator
Home spirometry falls by greater than 10%
Fever, cough, or dyspnea or generally feel unwell without specific symptoms
Medication additions or changes
• Length of stay
o Single lung recipients 7 days
o Double lung recipients 10 to 14 days
Fiberoptic bronchoscopy
• Sometimes performed prior to discharge to ensure that the anastomosis and airways are clean
and intact
• Surveillance bronchoscopy with transbronchial biopsy and BAL
o Evaluate the allograft for evidence of acute or chronic rejection or infection
o Minimum of 5 to 10 pieces of tissue encompassing both alveoli and small airways
required to reduce sampling error
o BAL studied for bacteria, viruses (especially cytomegalovirus), pneumocystitis
jiroveci, and fungi
o Typical surveillance schedule at 1, 3, 6, 9, 12, 18, and 24 months after transplantation
o Yields results that cause a change in management 25% to 30% of the time
• Also performed when clinically indicated
• Acute rejection: bronchoscopy repeated 4 to 6 weeks following treatment
Long-term care
• Weekly visit is typical for 4 weeks
o Biweekly visits for 1 to 2 months
o Monthly visits until 6 months
o Visits continue every 3 months until 1 year
Then biannual visits
• Any change in patient condition results in an urgent outpatient visit
o Includes a physical examination, spirometry, chest radiography, and laboratory studies,
including calcineurin inhibitor trough levels that are drawn 1 h prior to the next dose
Some programs may monitor cyclosporine levels based on levels drawn 2 h
(C2) after the last dose
Corticosteroid and calcineurin inhibitor dosing also is reduced as the patient
continues to do well after transplantation.
6. Acute Rejection
• Acute rejection is a common complication.
o More than 60% of patients develop at least one episode within the first year
o Histopathological examination demonstrates perivascular lymphocytic cuffing of the
small vessels in the allograft.
Lymphocytic extension into the alveolar space indicates a higher grade of
• Risk is greatest in the first few months after transplantation.
o Most frequent between 10 and 90 days
o Less frequent after the first postoperative year
Related to noncompliance, infection, low immunosuppression
• Majority of episodes (>80%) resolve with treatment
o Increased immunosuppression (methylprednisolone)
• Recurrent (>2 episodes) or persistent (failure to resolve) acute rejection identified as a
significant risk of chronic rejection (bronchiolitis obliterans syndrome [BOS])
Clinical presentation
• Mild cases of rejection may be clinically silent
• Patients present with nonspecific symptoms
o Dyspnea, low grade fever, cough, and malaise
o May be hypoxemic at rest or with exercise
• Spirometry
o Airway obstruction
Reduction in FEV1 and FEF25-75
Persistent >10% to 15% reduction in FEV1
• Consider acute rejection
• Chest radiograph
o Clear, focal alveolar, or interstitial opacities
o Pleural effusion
• Difficult to distinguish from pneumonia when abnormal chest radiograph noted
• Clinical assessment and noninvasive evaluation (radiographic studies and pulmonary function)
do not reliably distinguish between infection and rejection.
• Diagnosis dependent on clinical suspicion and histologic findings
o Serial pulmonary function tests are monitored by home spirometry and spirometry
performed at each clinic visit.
o Decline in FEV1 by >10% from baseline, as well as a decline in FEF25-75 of 10% to
15% indicates airway dysfunction, possibly from rejection
o Bronchoscopy with BAL and transbronchial biopsies is the diagnostic method of
choice to evaluate for acute rejection.
• Gram stain and culture, potassium hydroxide stain, fungal cultures,
acid-fast bacilli stain and culture, pneumocystosis jiroveci antibodies
detection (or polymerase chain reaction), and viral rapid antigen assays
and cultures (cytomegalovirus, respiratory syncytial virus [RSV],
Influenza A and B).
o Transbronchial biopsy is the procedure of choice to evaluate lung allograft rejection
Sensitivity >90%
Minimum of 5 to 10 pieces of tissue encompassing both alveoli and small
airways required to reduce sampling error
Samples obtained from multiple segments if no abnormality noted on
o Severity of lung rejection is classified by the extent and distribution of the
mononuclear infiltrates according to the International Society of Heart and Lung
Transplantation standard classification (Table 1).
o Many centers perform scheduled surveillance bronchoscopy to detect clinically silent
rejection or infection. This practice remains controversial and is not practiced
o When a histologic diagnosis cannot be obtained and clinical suspicion for acute
rejection is high, empiric treatment is administered after infection as a cause has been
Histologic grading of acute rejection
• Characterized by perivascular and subendothelial lymphocytic infiltrates
• Acute rejection is graded as a continuum from no rejection (A0) to severe (A4), based on the
histologic findings (Table 1) and treated accordingly.
• Lymphocytic bronchitis and lymphocytic bronchiolitis have been strongly associated with
BOS (Table 2).
• Lymphocytic bronchitis and lymphocytic bronchiolitis does not alone signify acute rejection,
as it can also be present with viral infection.
• Biopsy results should be evaluated by a pulmonary pathologist with experience in lung
• If one is not available, the biopsy slides can be sent to a transplant center for evaluation.
• Follow-up transbronchial biopsies are performed 3 to 5 weeks after treatment to evaluate
resolution of the acute rejection episode.
Table 1–Histologic classification of acute rejection*†
A1 (minimal AR)
A2 (mild AR)
A3 (moderate
A4 (severe AR)
Normal histology
Scattered infrequent perivascular mononuclear infiltrates in alveolar lung
parenchyma that are not obvious on low magnification
Frequent perivascular mononuclear infiltrates surrounding venules and on
arterioles seen easily at low magnification
Dense perivascular mononuclear infiltrates with the extension of inflammatory
infiltrate into perivascular and perialveolar septae and air spaces
Diffuse perivascular and interstitial and air space mononuclear infiltrates and
prominent alveolar pneumocyte damage associated with intra-alveolar necrotic
cells, macrophages, hyaline membranes, hemorrhage, and neutrophils
Not gradable, due to sampling problems
* Reprinted with permission from: Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the
classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant 1996; 15:1-15.
†AR = acute rejection
Table 2–Histologic classification of airway inflammation*
No airway inflammation
Rare scattered mononuclear cells within the submucosa of the bronchi or
Circumferential band of mononuclear cells with occasional eosinophils in the
submucosa of bronchi or bronchioles
Dense circumferential band of mononuclear cells within the submucosa of
bronchi/bronchioles including lymphocytes and eosinophils with
transmigration through the epithelium
Dense circumferential band of mononuclear cells within the submucosa of
bronchi/bronchioles associated with dissociation of epithelium from the
basement membrane, epithelial ulceration, fibropurulent exudates, and
epithelial cell necrosis
Not gradable, due to sampling problems
B2 (Mild)
B3 (Moderate)
B4 (Severe)
*Reprinted with permission from: Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the
classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant 1996; 15:1-15.
• Acute management of acute rejection
o Management of acute rejection is based on the severity of the histologic finding
o Mild (A2), moderate (A3), and severe (A4) acute rejection are universally treated
o Those with minimal or mild rejection (A1 and A2) are dependent on the clinical setting
and vary by center
o Patients with lymphocytic bronchiolitis (B2 or greater) may also receive treatment
based on the number of episodes, clinical conditions, and the transplant center.
Uncomplicated acute rejection
• Treated with steroid pulse therapy, usually three daily doses of 500 to
1,000 mg of methylprednisolone followed by an oral steroid taper (0.5
to 1.0 mg/kg/day) over 2 to 3 weeks
• Symptoms usually resolve within 1 week
• Histologic improvement can be seen within 3 to 4 weeks
Persistent or recurrent acute rejection
• Most centers will repeat a course of high-dose IV steroids
• Modification of maintenance regimen
o Substitute tacrolimus for cyclosporine
o Substitute mycophenolate mofetil (MMF) for azathioprine
• Lympholytic therapy with monoclonal or polyclonal antilymphocyte
• Addition of other therapies
o Methotrexate
o Aerosolized cyclosporine or steroids
o Total lymphoid irradiation
o Photophoresis
7. Chronic rejection
Obliterative bronchiolitis
• OB is the histopathologic finding and endpoint of chronic lung allograft rejection
o Concentric OB seen in the terminal bronchioles
• Main limitation to long-term success in lung transplantation
• Progressive obstructive airway process resulting in graft dysfunction, which affects 30% to
50% of recipients surviving beyond 1 year posttransplant
• Survival of recipients after onset of chronic rejection is 20% to 40% lower than the rate of
survival of those without chronic rejection
• Etiology and pathogenesis of OB appears to be multifactorial, including multiple presumed
risk factors that may result in injury to the allograft
• Definitive diagnosis can only be made histologically, with OB proven by biopsy specimen
o Unlike acute rejection, the diagnosis of chronic rejection is difficult to make with
transbronchial biopsies (20%)
o Usually diagnosed pathologically with open lung biopsies, explant at retransplant, or
Bronchiolitis obliterans syndrome
• BOS is a clinical correlate to OB, and patients are identified by progressive irreversible airway
obstruction, rather then by histology.
o Based on a combination of clinical, radiologic, and functional markers
o Defined in stages based on the percentage decrease in the FEV1 and FEF25-75%,
compared with baseline values posttransplantation (Table 3)
o BOS requires that confounding diagnoses are excluded (ie, infection, acute rejection,
anastomotic stricture, bronchomalacia, and progression of native lung disease
(increased hyperinflation in the native lung in patients with obstructive lung disease)
o Bronchoscopy with transbronchial biopsies useful in excluding other causes of
declining pulmonary function and clinical symptoms
• OB/BOS is often accompanied by recurrent lower respiratory tract infections and
Risk factors
• Alloantigen dependent
o Acute rejection
Risk increased with histologically graded severe acute rejection
Risk increased with persistent or recurrent episodes of acute rejection
Risk increased when acute rejection diagnosed later in posttransplant course
o Lymphocytic bronchiolitis or bronchitis
o Human leukocyte antigen mismatching
o Antihuman leukocyte antigen antibodies
o Positive panel reactive antibody in >10% of cell panels
o Insufficient immunosuppression and/or medication noncompliance
• Alloantigen independent
o Cytomegalovirus infection
o Ischemia-reperfusion injury
o Gastroesophageal reflux disease (GERD) with aspiration or micro-aspiration
o Community respiratory viruses (RSV, parainfluenza virus, adenovirus, influenza A and
Table 3—BOS Clinical Staging System*†
BOS 0p
Potential OB
Mild OB
Moderate OB
Severe OB
>90% of baseline and FEF 25-75 >75% of baseline
81-90% of baseline and/or FEF 25-75 <75% of baseline
FEV1 66-80% of baseline
FEV1 51-65% of baseline
FEV1 <50% of baseline
*Adapted from Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic
criteria. J Heart Lung Transplant 2002; 21:297-310.
†Each stage is divided into a and b, where a is without histologic diagnosis, and b is with histologic diagnosis. Table adapted
from the International Society of Heart and Lung Transplantation staging system.
Clinical presentation
• Dyspnea on exertion, cough, occasional wheeze
• Later stages, progressive sputum production and hypoxemia, especially with exercise
• Clinical pattern is variable. BOS will follow one of three courses:
o Indolent onset with a slow progressive decline in symptoms and pulmonary function
over time
o An initial rapid decline followed by a prolonged period of stability
o Sudden onset with a rapid decline of lung function
Early presentation
• Typically, early symptoms are nonspecific or even absent.
• Symptoms may be consistent with those of an episode of acute rejection or upper respiratory
tract infection.
• Nonproductive cough, dyspnea on exertion, and fatigue are common.
• May present only with asymptomatic drop in pulmonary function (FEV1 or FEF25-75).
• Early in the course of the disease, patients will have clear lung fields on auscultation and no
other specific physical examination findings.
• Chest radiographs are usually normal in the early stages of the disease.
• High-resolution CT scan is more sensitive and may reveal mosaic attenuation consistent with
air trapping.
• BAL may have increased neutrophilia, but likely will not have evidence of pathogenic
Late presentation
• As the disease progresses, symptoms will include a productive cough and dyspnea occurring at
• Patients will have increasing signs and symptoms associated with progressive bronchiectasis
and require frequent courses of antibiotics for recurrent upper and lower respiratory tract
• Patient’s airways are often colonized with pathogenic bacteria (Pseudomonas aeruginosa and
Staphlococcus spp) and/or Aspergillus fumigatus.
• Physical examination findings include progressively worsening hypoxemia and chest
ausculatory examination may include end inspiratory wheezes, squeaks, and crackles
associated with worsening bronchiectasis.
• As the disease progresses, chest radiographs may show decreased peripheral vascular
markings, volume loss, atelectasis, and, sometimes, nodular or alveolar densities.
• High-resolution CT scan may show signs of bronchial wall thickening and bronchiectasis,
along with evidence of air trapping.
• Management centered on prevention and slowing progression of the disease
• Currently no effective pharmacotherapy
• The only definitive treatment is retransplantation. However, retransplantation currently
accounts for only 3% of the total lung transplants being performed.
• Current treatment strategies involve the following:
o Augmenting immunosuppression
o Modifying the maintenance regimen (ie, substituting alternative agents within the same
drug class)
o Adding inhaled agents (eg, inhaled cyclosporine-off label)
o Using immune modulating therapies
• Aggressive immunosuppression will predispose or exacerbate infection.
• Stepwise treatment usually initiated once OB/BOS identified
o High-dose methylprednisolone followed by a tapering course of oral prednisone with
modification in triple drug maintenance immunosuppression
o Antilymphocyte globulins (antithymocyte globulin [ATG] or OKT3) or IL-2 receptor
antagonists (daclizumab, basiliximab), if there is no clinical response to the
augmentation of steroids
• Modify maintenance immunosuppression
o A single substitution is made usually in conjunction with acute treatment previously
For example, substitute tacrolimus for cyclosporine
For example, substitute mycophenolate mofetil for azathiaprine
o Sirolimus (antiproliferative agent) can be substituted for a calcinurin inhibitor or used
in conjunction with a calcinurin inhibitor
Used only in patients who present >3 months after transplantation
• May cause anastomotic dehiscence if used <3 months after
• Other agents
o Inhaled cyclosporine has been reported to be effective in preventing progression of
Currently not widely available
o Azithromycin three times a week
Antibacterial and immunomodulatory effects may be effective in altering BOS
o Methotrexate, cyclophosphamide, total lymphoid irradiation, photophoresis
All have been used as alternative agents for the treatment of OB/BOS
8. Infectious complications
• Leading cause of morbidity and mortality in the first year
• 60% to 80% involve the transplanted lung; approximately one half are bacterial
• Other serious infections include cytomegalovirus infection, other community-acquired viral
infections, fungi, and mycobacteria
• Approximately 40% of deaths during the first year after lung transplantation are infectionrelated
• Predisposing factors
o immunosuppression; the majority of patients are on at least three different agents
resulting in significant immunocompromise
o Donor and recipient colonization by bacteria prior to transplantation
o Transplanted lungs are nidus for infection due to denervation, decreased mucociliary
clearance, and diminished cough reflex
o Early postoperative state: splinting due to pain, atelectasis, and wound healing
• Bacterial pneumonia diagnosis: radiographic infiltrates, clinical symptoms, isolation of
pathogen from lower respiratory tract
o Diagnosis may be difficult due to similar presentation to rejection: if diagnosis unclear,
bronchoscopy with BAL and transbronchial biopsy required for diagnosis
o Treatment should be based on cultures and susceptibilities of the organisms in the
lower respiratory tract
o In general, broad-spectrum antibiotics that cover for Pseudomonas aeruginosa and
Staphylococcal sp are appropriate pending culture and susceptibilities
• Cytomegalovirus most common posttransplant viral infection
• Cytomegalovirus seropositivity present in more than half the adult US population
• Cytomegalovirus infection in lung transplant recipients
o Infection: presence of cytomegalovirus in blood, BAL or urine; disease: presence of
cytomegalovirus inclusion bodies in tissue
o Infection may occur as one of the following:
De novo transmission from a cytomegalovirus seropositive donor lung (D+)
Reactivation of a latent infection in a seropositive recipient (R+)
Transmission of cytomegalovirus positive blood products
o Rates of occurrence
D+R- lung recipient (79% of susceptible patients)
D+R+ lung recipient (69% of susceptible patients)
D-R+ lung recipient (58% of susceptible patients)
D-R- (10% to 15%)
o Clinical presentations
Asymptomatic (24%) to acute respiratory failure; also colitis, hepatitis, and
Most common symptoms are dyspnea, cough, fevers, and malaise
Leukopenia, transaminitis can be present
o Diagnosis
Polymerase chain reaction, hybrid capture assay or antigenemia most
sensitive/specific methods and can quantify cytomegalovirus DNA in blood
Shell vial cultures no longer commonly used as neither sensitive or specific
o Common measures to prevent/decrease incidence of cytomegalovirus disease
Ganciclovir IV or oral valganciclovir (Valcyte®; Roche Pharmaceuticals;
Nutley, NJ) (occasionally in combination with cytomegalovirus Ig),
posttransplant (length of time and dose varies per center)
Preemptive therapy with ganciclovir IV or valganciclovir in patients indicating
cytomegalovirus viral replication
o Treatment for cytomegalovirus disease
Ganciclovir or valganciclovir (occasionally in combination with
cytomegalovirus Ig)
Alternate agents include foscarnet and cidovir, but use limited by
Recurrent disease: evaluate patient for ganciclovir resistance
• Other viral infections
o Commonly detected respiratory viruses include: parainfluenza, RSV, rhinovirus,
influenza, adenovirus
o Reported in 8% to 23% of lung transplants, most often in first year posttransplant.
o Parainfluenza and RSV lower respiratory tract infections reported to predispose to
chronic rejection (bronchiolitis obliterans)
o Treatment: oseltamivir and zanamivir reported useful in transplant recipients with
influenza; ribavirin often used in RSV cases
Most common fungi in lung transplant recipients are Candida and Aspergillus species.
o Candida colonization is common, but rarely results in invasive pulmonary disease.
o Disseminated Candida infection is most commonly in wound infections or line sepsis
and usually treated with either fluconazole or an amphotericin formulation.
o Aspergillus spp cause most serious fungal infections in lung transplant recipients.
Colonization or disease reported in 20% to 45% of patients
Aspergillus disease spectrum
• Colonization of the bronchial anastomosis
• Necrotizing ulcerative tracheobronchitis
• Invasive parenchymal disease
• Disseminated invasive aspergillosis
o Antifungal prophylaxis commonly used for 3 to 6 months posttransplant, particularly in
high risk patients (eg, those with preoperation colonization, multiple episodes of
rejection, complicated postoperation course, etc)
o Prophylaxis agents: itraconazole, voriconazole, inhaled amphotericin, or caspofungin
o Treatment of infection include these agents or IV amphotericin formulations,
depending on location and severity of disease
9. Airway complications post-lung-transplantation
• Nine to 15% of recipients require treatment/intervention for airway anastomotic problems.
o Risk factors
Airway ischemia, infection, steroid therapy, acute rejection, prolonged
mechanical ventilation, and the recipient’s pretransplant diagnosis (septic lung
o Patient symptoms, physical examination, radiologic and pulmonary function findings
o Direct visualization of the airway with bronchoscopy is required for diagnosis
o Mechanical debridement, balloon dilation, Nd:YAG laser, cryotherapy, brachytherapy
and stent placement are treatment options.
o Rigid bronchoscopy performed by an experienced bronchoscopist is frequently
required for these procedures.
o If dehiscence is detected, surgical re-anastomosis with omental wrap may be required
• Late airway complications
o Progressive strictures or bronchomalacia of the anastomosis or distal to the
anastomosis may occur months or years posttransplantation
o Attributed to ischemia, healing after dehiscence, necrosis, or infection in the early
postoperative period
Bronchial stenosis
• Most frequent airway complication posttransplant
• Present with progressive dyspnea, cough, wheezing, and symptoms of recurrent upper or lower
respiratory disease
• On physical examination, there may be a localized wheeze or rhonchi at the site of narrowing
• Pulmonary function tests will show increasing obstructive defect, and there may be a concave
appearance on both the inspiratory and expiratory flow volume loop.
Radiographic findings
• Chest radiograph findings are nonspecific but may show some air-trapping or atelectasis.
• Chest CT scan may help determine the longitudinal extent of the bronchial narrowing.
Bronchoscopic findings
• Stenosis can be caused by ingrowth of excessive granulation tissue or progressive narrowing
of the airway caused by scar or ischemic changes.
• Lesions can occur at or distal to the anastomosis.
• Most strictures secondary to granulation tissue or circumferential scarring
o Balloon dilatation, along with an additional modality for debridement (cryotherapy,
laser therapy, electrocautery, or a combination)
o Placement of a stent (silicone or expandable wire) is necessary, if there is persistence
or recurrence of airway obstruction.
o Rigid bronchoscopy is used based on the severity of the lesion and the modalities to be
Surgical Therapy
• May be required if persistent complications, including persistent stenosis and recurrent upper
and lower respiratory tract infections
• Sleeve resection of the stenotic segments, bilobectomy, and pneumonectomy have been
successfully performed.
• When stenosis extends to the distal lower airways, surgical procedures may be the only option.
• Retransplantation is the final option in some cases.
• Clinical presentation similar to that of bronchial stenosis
Bronchoscopic findings
• Dynamic collapse during spontaneous exhalation
• Defined as collapse of at least 50% of the airway lumen during expiration, cough, or
spontaneous breathing
o Some have bronchomalacia of the distal airways (distal to the anastomotic site)
• Prolonged or permanent stent placement is required in most cases.
• Retransplantation if diffuse malacia of the lower airways, not amenable to stenting
10. Malignancy
• Incidence between 4% and 19% of surviving lung transplant recipients at 1 and 7 years,
o Contributes to 8% and 12% of deaths in lung recipients surviving greater than 1 year
and 5 years, respectively
• Most common type of malignancies are nonmelanotic skin cancers and lymphoma
• Other reported malignancies in solid organ transplant recipients include Kaposi sarcoma
(associated with human herpes virus 8), vulvar and perineal carcinoma, renal cell carcinoma,
urinary bladder cancer, and various sarcomas.
• Heart and lung transplant patients at higher risk than other solid organs due to increased levels
of immunosuppression
• Lung carcinoma incidence varies between 2.4% and 7%
o Usually non-small cell carcinoma
o Almost always presents in the native lung of previous smokers
o Very aggressive course in this patient population
o Risk factors for primary lung cancer development include increasing age, >60 packyear smoking history, and single vs bilateral lung transplant
• Colon carcinoma
o Adenocarcinoma reported in 0.5% of lung and heart lung recipients
o Increased incidence in patients with cystic fibrosis at younger than expected age
o Mean age at the time of transplantation, 55 years (range 39 to 71 years); and mean age
at the time of cancer diagnosis, 62 years (range 47 to 72 years)
o Average time from transplantation to cancer diagnosis, 92 months (range 3 to 152
o Advanced disease common with mortality rate of 60%
• Health-care screening for skin, breast, and colon carcinoma imperative
o Colon and breast carcinoma much more aggressive due to immunosuppression
• Treatment
o Reduction of immunosuppression
Discontinuation of azathioprine
o Surgical removal
o Radiation therapy
o Chemotherapy poorly tolerated
11. Posttransplant lymphoproliferative disease
Definition and incidence
• Premalignant or malignant polyclonal or monoclonal lymphoproliferation associated with
transplant immunosuppression
• Posttransplantation lymphoproliferative disease (PTLD) reported in 2% to 20% in lung
transplant recipients
o Types of PTLD reported in lung transplant population:
Benign polyclonal polymorphic B cell hyperplasia (55%)
Early malignant transformation of B cell lymphoma (30%)
Monoclonal polymorphic B cell lymphoma (15%)
Risk factors
• Strongest risk factor: transplantation of an Epstein-Barr virus seropositive donor lung into an
Epstein-Barr virus seronegative recipient
• Increased immunosuppression, particularly lympholytic therapy; use of OKT3, a T cell
depleting monoclonal antibody, leads to a higher incidence and an earlier onset of PTLD in
solid organ transplantation
Clinical presentation
• Usually occurs within 1 year of transplantation
• Most common presentation is pulmonary nodules
• GI tract PTLD has been reported
• May be asymptomatic or present with overt constitutional symptoms and respiratory
• Better prognosis has been associated with the following
o Presentation within 1 year of transplant
o Confined to the allograft
o Polymorphic histology
o Donor origin
o Decreased immunosuppression
o No history of cytomegalovirus disease
• Initial treatment includes decreasing current immunosuppressive therapy; however, this often
results in acute and/or chronic rejection.
• Other current therapies include:
o Rituximab, an anti-CD20 antibody
o Chemotherapy
o Surgical therapy
o Radiation therapy
o Extracorporeal photochemotherapy
o Retransplantation (if other therapies fail and disease localized)
12. Renal failure and hypertension
Incidence and prevalence
• Common complication after lung transplantation: as survival improves, risk of renal
insufficiency/failure and hypertension increases
• Renal function decline (measured by glomerular filtration rate) begins within 6 months of
• No uniform definition of post-lung-transplant renal failure, so prevalence rates have ranged
widely from 10% to over 90%
• More formal evaluation of renal failure of patients reported in Scientific Registry of Transplant
Recipients using estimated glomerular filtration rate of 2.9 mL/min/1.73 m2 as marker of renal
failure showed 1-year cumulative incidence of 2.9%; 5-year cumulative incidence of 15.8%
• The International Society of Heart and Lung Transplant registry reported renal failure defined
by abnormal creatinine, requirement of chronic dialysis or renal transplant, in lung transplant
recipients from 1999 to 2003. The 1-year prevalence of renal failure was 28.8% and 36.3%, up
to 8 years posttransplant.
Risk factors
• Major risk factors for both acute and chronic renal failure after solid organ transplantation are
the calcineurin inhibitors, tacrolimus, and cyclosporine A.
o Acute renal failure from these agents is thought to be secondary to direct
vasoconstriction of both the afferent and efferent renal arterioles. This effect appears to
be greater with cyclosporine, compared with tacrolimus.
o Chronic renal failure is related to decreased renal blood flow, increased renal vascular
resistance, and elevated mean arterial pressure.
o Though calcineurin inhibitors often titrated to lower levels after 1 year, chronic renal
failure appears to be irreversible. Renal biopsy results have often shown interstitial
• A multivariate analysis has shown increased risk associated with increasing age, female sex,
hypertension, diabetes mellitus, and postoperative acute renal failure.
• Majority are asymptomatic, with only hypertension and an abnormal creatinine
• Other complications of renal failure include increased risk of cardiovascular disease,
hyperlipidemia, anemia, and hypertension.
• Strategies for preventing progressive renal failure:
o Early perioperative period: optimize fluid management to maintain renal perfusion;
avoid or minimize known nephrotoxic agents, including radiographic contrast, IV
calcineurin inhibitors, and nephrotoxic antibiotics
o Long-term management: minimization of calcineurin inhibitors by adding other
immunosuppressive agents that may help to stabilize or reverse renal function. Several
studies have shown addition of sirolimus or mycophenolate mofetil may enable
lowering of the dose of calcineurin inhibitor in order to preserve renal function.
o Other potential therapies include the use of calcium channel blockers, angiotensinconverting enzyme inhibitors, or angiotensin receptor blockers. All three agents have
been shown to decrease renal failure in small, uncontrolled studies.
• International Society of Heart and Lung Transplantation registry reports prevalence of 53.1%
in lung transplant survivors at 1-year; and 93.7% at 8-years posttransplant.
• Calcineurin inhibitors (cyclosporine more than tacrolimus) are important contributors to
development of hypertension.
• Corticosteroids often contribute to hypertension.
• Hypertension can be both a cause and effect of chronic renal failure in this population.
• Treatment for hypertension:
o Often includes calcium channel inhibitors, angiotensin-converting enzyme inhibitors,
or angiotensin receptor blockers, because these agents may decrease the effect of
calcineurin inhibitor mediated nephrotoxicity.
o Though little data are available in lung transplants, aggressive management to
normal/near normal values is probably important, as, in other populations, it reduces
renal failure progression.
13. GI complications
• GI symptoms/disease occur in >50% of lung transplant recipients
• Significant contribution to morbidity/mortality
• Association with bronchiolitis obliterans
• Pretransplant GI disorders may be aggravated by the transplant procedure/immunosuppressive
• Common GI symptoms (including nausea, vomiting, abdominal discomfort, diarrhea)
o Cause often unclear
May be underlying GI disease, drug toxicity/side effects, drug interactions
o Recent review of immunosuppression-related effects suggests strategies to reduce
toxicity/side effects
Reduction of total dosage, spacing of various drugs
Dose-splitting and changing of drug formulation or agent
Gastric ulceration
• Symptoms include abdominal pain, nausea, loss of appetite or pain with food intake, and
• Causes
o Surgical stress
o Impairment of native gastroduodenal cytoprotection due to azathioprine or
mycophenolate effect on intestinal cell turnover
o Increased gastric acid secretion
o Corticosteroids
• Ulcers may be asymptomatic or their symptoms masked by treatment with corticosteroids
• Giant ulcers (gastric ulcers with a diameter >3 cm)
o Reported in lung transplant recipients, despite use of H2-receptor antagonists
o High morbidity and mortality due to tendency to bleed
• Associated with bilateral lung transplantation, corticosteroids for acute rejection, and
cyclosporine immunosuppression
• Prophylaxis with H2-receptor antagonists, proton-pump inhibitors, coating agents, and
prostaglandins (misoprostol) are indicated.
• Avoid nonsteroidal antiinflammatory drugs
• Endoscopy helpful in diagnosis and treatment
GI motility
• GI motility delay reported in up to one fourth of lung transplant recipients
• May be the result of the following:
o Vagus nerve injury during surgery
o Side effect of the calcineurin inhibitors (cyclosporine, tacrolimus)
• Strong association of gastroparesis and bronchiolitis obliterans
• Symptoms
o Abdominal discomfort, pain, bloating, early satiety, nausea, vomiting
o May be confused with intolerance to or toxicity from the multiple drugs
o There may be delay in establishing the correct diagnosis
• Diagnosis
o Gastric emptying time, nuclear medicine scintigraphy test, evaluates transit time of
bolus of food in the GI tract
• Treatment
o Prokinetic agent (metoclopramide, macrolides)
o Extreme cases may require pyloroplasty and/or jejunal feeding tubes
• Patients with diabetes, scleroderma, or other diseases associated with disturbed GI motility
may manifest this complication more readily.
Gastroesophageal reflux disease
• Contributes to pathophysiology of pulmonary diseases
Cystic fibrosis
Idiopathic pulmonary fibrosis
Mechanism: aspiration of reflux gastric contents, neuroreflex bronchoconstriction
or cytokine upregulation
• Multiple pulmonary diseases associated with GERD are indications for lung transplantation
• Prevalence of gastroesophageal reflux in patients assessed for transplant, 63%
• GERD reported in 87% of patients with idiopathic pulmonary fibrosis
• Gastroesophageal reflux prevalence posttransplant, 76%
o Gastroesophageal reflux linked to bronchiolitis obliterans (chronic allograft rejection)
o Reports suggest treatment of gastroesophageal reflux by fundoplication improves
function and survival in patients with established BOS
• Diagnosis: gastroesophageal reflux can be silent
o Evaluate patients pre- and posttransplant with esophageal pH probe, manometry
o May need impedance studies to detect refluxed bile acids, important contributors to
• Management
o Medications to minimize reflux and neutralize acid
o Consider fundoplication within 3 to 6 months of transplant for patients with established
gastroesophageal reflux
Acute abdomen
• Signs and symptoms of acute abdominal catastrophe in immunosuppressed patients are often
subtle and easily missed
• Corticosteroids, other drugs
o Mask symptoms
o Have permissive effect on development of opportunistic infections that may complicate
acute abdomen
Colonic complications
• Reported in 13% of lung transplant recipients
• Diverticulitis
o Rate higher than nontransplant patients
o Patients tend to have fulminant course and frequently require surgical intervention;
delay may result in death but surgical outcomes are good
o Viscus perforation risk high in lung transplant patients with diverticulitis: mortality
Colonic perforation
• Incidence reported as high as 8.6%; higher than reported for other organ transplants
• High early postoperative rate attributed to hypoperfusion, narcotics, and aggressive diuresis
leading to constipation
• Late postoperation risk factors include invasive fungal, viral infection, mesenteric infarction,
and high prevalence of diverticular disease, especially in older patients
• Colonic perforation can occur at any time after transplantation
o Presentation
Lower abdominal pain, tenderness, leucocytosis
Fever and rebound tenderness may be absent
May not have radiographic evidence of free air
• All lung transplant recipients with complaints of abdominal pain require aggressive workup
and consideration of early laparotomy.
• Cytomegalovirus
o Symptomatic GI manifestations reported in 2% to 16% of all organ recipients and in
9.9% of heart and heart-lung recipients
o Highest risk group: D+R- recipient (naïve recipient of a cytomegalovirus antibody
positive allograft)
o Symptoms
Abdominal pain, anorexia, malaise, diarrhea, nausea, vomiting, and even GI
Cytomegalovirus hepatitis and colitis may also occur
o Diagnosis of disease
Requires histological detection of the virus/inclusion bodies in the affected
o Treatment
IV ganciclovir is usual treatment
Distal intestinal obstruction
• Obstruction in the distal intestine, common manifestation of cystic fibrosis
o In the transplant cystic fibrosis population, incidence reported at 20%, comparable with
that observed in the lifetime of the adult CF population
o Almost always affects pancreatic insufficient patients
o Believed due to mucofeculent impaction of material in the distal ileum
o Risk factors: adynamic ileus from surgery or medications, dehydration, and adhesions
from previous surgeries
o Most frequently seen perioperatively, but can present late especially after the
development of BOS
o Symptoms:
Constipation, bloating
Can mimic an acute abdomen
Important to keep high level of suspicion to avoid unnecessary surgery
o Treatment
Medical with electrolyte GI lavage solution given orally, via nasogastric tube or
through gastrostomy
Preventive and early medical treatment with polyethylene glycol (GoLytely;
Braintree Laboratories; Braintree, MA) has been advocated both preoperatively
and in the immediate postoperative period.
Pneumatosis intestinalis
• Uncommon complication in which gas accumulates in submucosa and/or the subserosa of the
large or small intestine
• Associated with organ and bone marrow transplantation.
• Clinical presentation:
o Asymptomatic to fulminant illness
• Underlying causes include infection (cytomegalovirus, Clostridium difficile), ischemia, bowel
perforation, intestinal obstruction, COPD, surgery, and immunosuppressant drugs (particularly
• Can be perplexing to establish underlying cause, but critical to avoid unnecessary surgery;
challenge is to identify those patients in whom it represents a benign condition in which
conservative management is indicated
• Majority of cases have not required surgical intervention
Other GI complications
• Bezoars
o Concretions of vegetable matter (phytobezoars), hair (trichobezoars), medications
(pharmacobezoars), or other ingested substances
o General population incidence very low; but in cystic fibrosis population after transplant
reported in 11% of patients
o Accumulate over time in GI tract, particularly in the stomach
o Symptoms
Nausea, pain, gastric outlet obstruction
Can be asymptomatic
o Diagnosis
May be suggested by radiologic study; confirmed by upper endoscopy
o Treatment:
Endoscopic treatment followed by a combination prophylactic regimen
consisting of “cocktail” of metoclopramide (10 mg, qid), sodium bicarbonate
(648 mg, bid) and pancrelipase enzymes (powder preparation) administered qid
Colonic carcinoma (see Section 10)
14. Neurologic/CNS complications
• CNS complications have been reported in up to one fourth of patients when CNS infections are
• Calcineurin inhibitors (both tacrolimus and cyclosporine) cause typical and frequent white
matter changes that are best seen on MRI; white matter changes may occur without symptoms
and may be reversible. Almost any type of neurologic complication can occur secondary to
these drugs. Some of the most common are outlined below.
Severe headache
• Can be related to calcineurin-inhibitors, especially (though not necessarily) at high levels;
reducing dose may be helpful if levels high
• Always rule out infection
• Can be related to calcineurin-inhibitors, especially (though not necessarily) at high levels;
reducing dose may be helpful if levels high
• Hypomagnesemia is common posttransplant and may precipitate seizures
• Always rule out infection
Cognitive function/confusion
• In the perioperative period, patients typically have mild-to-moderate cognitive function
impairment that generally resolves over weeks to a few months. This is likely multifactorial
related to multiple medications (especially steroids and calcineurin-inhibitors), the stress of
ICU and hospitalization, etc. During this period, it is important to write down all important
information, eg, medication changes, and/or always relay important information to a caregiver.
• Rarely, patients have been reported to have psychotic symptoms from calcineurin inhibitors.
An alternative drug should be tried to determine if symptoms improve. Antipsychotic
medication may also be required, at least temporarily.
Stroke/stroke syndrome
• Severe neurologic dysfunction manifesting as a typical hemiplegic cerebrovascular accident
or, rarely, coma may occur secondary to calcineurin-induced vasospasm and white matter
changes. The occipital lobe appears particularly susceptible to infarction with resulting
blindness. These lesions may be reversible with a reduction in the calcineurin inhibitor or
change to alternative drug, at least temporarily.
• Tremors occur in many patients taking calcineurin inhibitors in the first few months after
transplant. These often occur in patients on therapeutic doses of drug. No treatment is needed
unless the tremors become severe and then switching to an alternate drug is usually the best
option. Tremors usually disappear over a few months.
Peripheral neuropathy
• Calcineurin-inhibitor induced peripheral neuropathy may vary from mild paresthesias
requiring no treatment to severe pain syndromes that require chronic pain management and
may not resolve even with discontinuation of the drug. Fortunately, while mild symptoms are
common, more severe pain syndromes are not.
• Multiple authors have reported myopathy (probably related to calcineurin-related
mitochondrial dysfunction) that occurs virtually universally in lung transplant recipients. The
myopathy typically does not impact ability to perform day-to-day activities but does limit
exercise capacity to about 50% of normal. There is no specific management.
• Rhabdomyolysis has been reported with the use of statin drugs in patients on calcineurin
inhibitors. Typically, this occurs within the first 3 months after starting the statin. Thus, if a
patient is started on a statin, it should be started at a low dose and careful monitoring for
rhabdomyolysis should be undertaken.
15. Hematologic complications
Chronic normocytic anemia is reported in 18% to 50% of long-term survivors.
• Multifactorial causes: azathioprine and other immunosuppression, particularly tacrolimus,
multiple other drugs, rarely parvovirus infection, other infections, depressed erythropoietin
levels, occasional hemolysis, secondary to renal failure in long term survivors with poor
kidney function
• Not typically associated with iron deficiency or folate deficiency, but these should be
measured in initial evaluation to rule out blood loss or nutritional deficits
• Parvovirus infection should be considered in severe, persistent anemia
• Hemolysis associated with ABO-mismatching, other immune reactions or infections
• Treatment:
o Mild-to-moderate anemia may improve over time and usually requires no treatment
o Parvoviral disease has been successfully treated with IV immunoglobulin
o Erythropoietin has been reported successful in a number of patients
Hemolytic uremic syndrome
• Microangiopathic anemia with thrombocytopenia and renal failure
• Reported in conjunction with calcineurin inhibitor use (especially tacrolimus)
• High death rate, but some treatment success reported with change to a different
immunosuppressive regimen
• Common in posttransplant patients
• Causes may be multifactorial but most often related to immunosuppressive, prophylactic, or
other drugs or infections
o Common offenders: induction agents, azathioprine, mycophenolate mofetil, sirolimus,
• Treatment:
o Remove or decrease doses of offending drugs
o Treat infection
o In cases of agranulocytosis or severe leukopenia, granulocyte stimulating factor is
usually successful
• Occurs commonly in lung transplant recipients and, as with leukopenia, most often related to
drugs or infections
• Seen in association with broad group of drugs (see leukopenia); however, sirolimus more
likely to cause thrombocytopenia than leukopenia
• May be presenting sign of hemolytic uremic syndrome (or microangiopathic hemolytic
anemia) in transplant recipients—rarely reported complications of calcineurin inhibitor
• May be associated with heparin therapy
• Treatment:
o Remove or decrease dosage of offending drug or treat infection
o For hemolytic uremic syndrome or microangiopathic hemolytic anemia, change
immunosuppressives and treat as if not a transplant recipient (eg, usually
plasmapheresis, supportive care, etc)
o In patients on heparin (or with indwelling catheters and heparin flush), always consider
heparin-induced thrombocytopenia, as this is a potentially fatal complication of heparin
Hypogammaglobulinemia (severe lymphopenia)
• Hypogammaglobulinemia occurs in at least half of lung transplant recipients and is related to
severe lymphopenia
• In up to 10% of patients, gamma globulin levels are in severe immunodeficiency range; in
those patients multiple infections are reported
• Hypogammaglobulinemia likely caused by overimmunosuppression with cell cycle inhibitors,
especially azathioprine
• Treatment:
o If possible, reduce dosage of azathioprine or mycophenolate mofetil to allow gamma
globulin levels to rise (increase lymphocytes) into mild/moderately deficient range
o May need to use IV gamma globulin to prevent infections
16. Endocrine issues
• Multiple medications, principally corticosteroids and tacrolimus, can cause hyperglycemia
• Steroid-caused hyperglycemia may improve, as corticosteroid doses are reduced to
maintenance levels by 6 to 12 months posttransplant. If patient is on hypoglycemic agents as
steroids are reduced, be alert/educate for hypoglycemic episodes.
• Hyperglycemia should be managed to maintain HbA1C levels at ADA-recommended levels
(≤7). This may require insulin.
Metabolic bone disease
• Osteopenia and osteoporosis are extremely common in patients with advanced lung disease
and lung transplant.
• Bone mineral loss is greatest in the first 6 months posttransplant.
• All advanced lung disease patients should undergo DEXA scans, and treatment should be
started if patient is osteopenic (T-score = -1 to -2.5 standard deviation) or osteoporotic (Tscore >-2.5 standard deviation).
• Bisphosphonates (antiresorptives) are the most commonly used treatment (and the most
studied treatment) for metabolic bone disease and should be continued in posttransplant
period. IV bisphosphonates, eg, pamidronate have been used successfully in severely
osteoporotic patients or those who cannot tolerate oral drugs. It has not been shown that this
route of delivery is superior to oral drugs.
• An uncommon, but serious, complication of osteonecrosis of the jaw has been reported
following dental procedures in patients taking both oral and IV bisphosphonates.
• Patients who experience multiple fractures in the perioperative period should be considered for
“bone-building” treatment, such as teriparatide.
• The rate of bone loss typically slows or stops as the time from transplant increases. A repeat
DEXA scan can be done at 1 year, but earlier posttransplant scan is unnecessary, as it will not
impact treatment.
• Currently, though length of required treatment has not been well studied, bisphosphonate
treatment is continued indefinitely, unless limited by side effects.
• Very little information has been published about the impact of transplant on the menstrual
cycles/fertility of posttransplant women.
• Renal transplant patients’ data documents menstrual irregularities in a majority of patients
pretransplant, with normalization of menstrual cycles in the majority posttransplant.
• Child-bearing age women should be counseled that they will likely be fertile posttransplant.
• Though little has been published on appropriate contraception, hormonal contraception should
probably be avoided, as posttransplant patients have a high risk of venous thrombosis.
• Successful pregnancy is possible in posttransplant women; however, the patient’s lung
function should be monitored carefully during the pregnancy, along with the other high-risk
aspects of an immunosuppressed patient.
• There has not been reported an excessive rate of fetal malformations with any specific
immunosuppressive medication or any of the common combinations.
• Because of metabolic/physiologic changes in pregnancy, immunosuppressive levels should be
monitored frequently.
17. Psychologic/psychiatric health
• Transplantation outcomes may be related to nonmedical factors, including mental health.
• Estimates of prevalence of anxiety and other psychiatric disorders in patients with end-stage
pulmonary illnesses range from 40% to 70%.
• Psychiatric disorders appear to follow development of severe respiratory disease and may be
the result of dyspnea and chronic illness.
• Data in lung transplant population are limited.
o Anxiety levels found to be substantially elevated. Nearly one half of patients showed
clinically significant distress manifested as anxiety, anger-hostility, or depression.
o Psychological stress posttransplant correlates with physical symptoms and greater
levels of physical impairment; those with high levels of anxiety/depression are
significantly more likely to report more physical symptoms and greater physical
o Treatment results: depressive and anxiety disorders in lung transplants respond well to
Risk factors: pretransplant psychiatric history, educational level, posttransplant
caregiver support, and health concerns
Associations with mental health: low sense of mastery and poorer physical
functional status
Survival of treated patients comparable with recipients without these disorders
Treated patients (pre- and posttransplant) respond both psychologically and
Data suggest patients respond to treatment, and adequate treatment optimizes
the quality of life (QOL) for patients with end-stage illness who do not survive
to be transplanted, as well as improves outcomes posttransplantation
o Recognition and treatment of anxiety/depression is critical.
18. Quality of life
• Lung transplant recipients report significant improvements in QOL.
o Multiple studies review data particularly in first 3 years
o Life-long complex regimen of medications, potentially serious side effects, and fear of
loss of transplant function alter perception of QOL posttransplant
o 76% of patients highly satisfied with outcome, and 92% would opt for procedure again
Cystic fibrosis patients most satisfied (significantly) with their QOL.
Immunosuppression side effects and development of BOS major factors
influencing QOL
Longer-term transplant survivors and patients with transplantation further in
their history reported more frequent and problematic symptoms commonly
associated with immunosuppression, including depression, headaches, and
changes in physical appearance
Development of BOS adversely impacted QOL 10 years after transplantation
Prevention of BOS becomes critical to the successful outcome of lung
transplant recipients, as it has been associated with impaired physical, mental
health, and QOL
19. Deconditioning and physical rehabilitation
• Posttransplant patients have substantial improvements in pulmonary function and exercise
capacity; however,
o Peak exercise remains reduced to 40% to 60% of predicted values, even up to 2 years
after transplantation.
o At 3 months postoperation, peak oxygen consumption (VO2 max) is 46% and 50% of
o At 1 to 2 years after transplantation, maximal work capacity remains impaired, despite
return to regular activities (ie, school or work)
o Rationale for ongoing impairment:
No evidence of ventilatory limitation found
Peripheral factors likely implicated and multifactorial
• Deconditioning, chronic anemia, loss of muscle mass, muscle atrophy
• Most important factor may be drug-related: cyclosporin A may impact
muscle blood flow or changes in potassium flux. Altered potassium
homeostasis documented in transplant recipients and linked to limitation
in exercise capacity. Chronic corticosteroid may contribute via steroid
• Peripheral factors need to be considered in design of appropriate
posttransplantation rehabilitation program.
20. Nutrition and diet
• Nutritional recovery
o Negatively impacted early postoperation by gastroparesis, gastroesophageal reflux,
nausea vomiting, diarrhea, and distal intestinal obstruction syndrome
o Most patients demonstrate nutritional recovery by 6 to 12 months after transplantation.
o Long-term goal of nutritional recovery: prevent or ameliorate the complications of
therapy, such as obesity (corticosteroids), diabetes (corticosteroids, tacrolimus
[Prograf; Astellas Pharma, US, Inc.; Deerfield, IL]), hypertension (corticosteroids,
calcineurin inhibitors), osteoporosis, hyperlipidemia (corticosteroids, cyclosporine,
sirolimus) and hyperkalemia (cyclosporine, tacrolimus)
o Diet frequently needs to be altered and supplements or treatment provided in order to
optimize the management of these patients and offset impact of medications.
o Encouragement of exercise and avoidance of destructive behavior need to be
emphasized at each patient encounter.
21. Bibliography
Section 1-5
Grady, Denise. Lung patients see a new era of transplants. New York Times, September 24, 2006.
Accessed December 28, 2006
Organ Procurement Transplant Network 2006 news. Accessed August 1, 2006
Orens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant
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Studer SM, Levy RD, McNeil K, et al. Lung transplant outcomes: a review of survival, graft
function, physiology, HRQOL, and cost effectiveness. Eur Respir J 2004; 24:674-685
US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant
Recipients annual report 2005. Accessed August 1, 2006
Section 6
Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the
classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung
Transplant 1996; 15:1-15
Section 7
Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the
diagnostic criteria. J Heart Lung Transplant 2002; 21:297-310
Section 8
Maurer JR, Tullis E, Grossman RJ, et al. Infectious complications following lung transplantation.
Chest 1992; 101:1056-1059
Monforte V, Roman A, Gavalda J, et al. Nebulized amphotericin B prophylaxis for Aspergillus
infection in lung transplantation: study of risk factors. J Heart Lung Transplant 2001; 20:12741281
Palmer SM, Henshaw NG, Howell DN, et al. Community respiratory viral infection in adult lung
transplant recipients. Chest 1998; 113:944-950
Trulock EP. Lung Transplantation. Am J Respir Crit Care Med 1997; 155:789
Zamora MR. Cytomegalovirus and lung transplantation. Am J Transplant 2004; 4:1219-1226
Section 9-10
Amital A, Shitrit D, Raviv Y, et al. Development of malignancy following lung transplantation.
Transplantation 2006; 81:547-551
Dickson RP, Davis RD, Rea JB, et al. High frequency of bronchogenic carcinoma after singlelung transplantation. J Heart Lung Transplant 2006; 25:1297-1301
Penn I. Incidence and treatment of neoplasia after transplantation. J Heart Lung Transplant 1993;
Reams BD, McAdams HP, Howell DN, et al. Posttransplant lymphoproliferative disorder:
incidence, presentation, and response to treatment in lung transplant recipients. Chest 2003;
Stagner LD, Allenspach LL, Hogan KK, et al. Bronchogenic carcinoma in lung transplant
recipients. J Heart Lung Transplant 2001; 20:908-911
Swinnen LJ, Costanza- Nordin MR, Fisher SG, et al. Increased incidence of lymphoproliferative
disorders after immunosuppression with the monoclonal antibody OKT3 in cardiac transplant
recipients. N Engl J Med 1990; 323:1723-1728
Trulock EP, Edwards LB, Taylor DO, et al. Registry of the International Society for Heart and
Lung Transplantation: 23 official adult lung and heart lung transplantation report-2006. J Heart
Lung Transplant 2006; 25:880-892
Section 11
Bloom RD, Doyle AM. Kidney disease after heart and lung transplantation. Am J Transplant
2006; 6:671-679
Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and
Lung Transplantation: twenty-second official adult heart transplant report. J Heart Lung
Transplant 2005; 24:945-982
Section 12
Berkowitz N, Schulman LL, McGregor C, et al. Gastroparesis after lung transplantation: potential
role in postoperative respiratory complications. Chest 1995;108:1602-1607
Boyle MP, Orens JB. Distal intestinal obstruction syndrome after surgery in cystic fibrosis. Chest
2003; 124:2408-2912
Cantu E III, Appel JZ III, Hartwig MG, et al. Maxwell Chamberlain memorial paper: early
fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux
disease. Ann Thorac Surg 2004; 78:1142-1151
Dellon ES, Morgan DR, Mohanty SP, et al. High incidence of gastric bezoars in cystic fibrosis
patients after lung transplantation. Transplantation 2006; 81:1141-1146
D'Ovidio F, Mura M, Tsang M, et al. Bile acid aspiration and the development of bronchiolitis
obliterans after lung transplantation. J Thorac Cardiovasc Surg 2005; 129:1144-1152
D'Ovidio F, Singer LG, Hadjiliadis D, et al. Prevalence of gastroesophageal reflux in end-stage
lung disease candidates for lung transplant. Ann Thorac Surg 2005; 80:1254-1260
Gilljam M, Chaparro C, Tullis E, et al. GI complications after lung transplantation in patients with
cystic fibrosis. Chest 2003; 123:37-41
Helderman JH, Goral S Gastrointestinal complications of transplant immunosuppression. J Am
Soc Nephrol 2002; 13:277-287
Ho LM, Mosca PJ, Thompson WM. Pneumatosis intestinalis after lung transplant. Abdom
Imaging 2005; 30:598-600
Maurer JR. The spectrum of colonic complications in a lung transplant population. Ann
Transplant. 2000; 5:54-57
Palmer SM, Miralles AP, Howell DN, et al. Gastroesophageal reflux as a reversible cause of
allograft dysfunction after lung transplantation. Chest 2000; 118:1214-1217
Qasabian RA, Meagher AP, Lee R, et al. Severe diverticulitis after heart, lung, and heart-lung
transplantation. J Heart Lung Transplant 2004; 23:845-849
Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal
reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006; 27:136-142
Sections 13-15
Lynch JP, Ross DJ, eds. Lung and heart lung transplantation. New York, NY: Taylor & Francis
Group, LLC, 2006
Sections 16-20
De Vito Dabbs A, Dew MA, Stilley CS, et al. Psychosocial vulnerability, physical symptoms, and
physical impairment after lung and heart-lung transplantation. J Heart Lung Transplant 2003;
Mathur S, Reid WD, Levy RD. Exercise limitation in recipients of lung transplants. Phys Ther
2004; 84:1178-1187
Schwaiblmair M, Reichenspurner H, Muller C, et al. Cardiopulmonary exercise testing before and
after lung and heart-lung transplantation. Am J Respir Crit Care Med 1999; 159:1277-1283
Smeritschnig B, Jaksch P, Kocher A, et al. Quality of life after lung transplantation: a crosssectional study. J Heart Lung Transplant 2005; 24:474-480
Stilley CS, Dew MA, Stukas AA, et al. Psychological symptom levels and their correlates in lung
and heart-lung transplant recipients. Psychosomatics 1999; 40:503-509
Woodman CL, Geist LJ, Vance S, et al. Psychiatric disorders and survival after lung
transplantation. Psychosomatics 1999; 40:293-297
Section 22
Banner NR, Polak JM, Yacoub MH, eds. Lung transplant. New York, NY: Cambridge University
Press, 2003
Hertz MI, ed. Manual of lung transplant medical care. Minneapolis, MN: Fairview Press, 2000
22. Appendix: Lung transplant medications
Immunosuppressive medications
Induction agents
Agents used at the time of transplant surgery and in the immediate postoperative period
50% of programs in North America use induction therapy
• Anti-T-Cell agents
o Antithymocyte globulin-rabbit (ATG, Thymoglobulin®; SangStat Medical Corp;
Freemont, CA)
Pasteurized preparation of rabbit immunoglobulin IgG from
animals immunized with human thymocytes
Main immunosuppressive effect is depletion of circulating T lymphocytes
Given by IV infusion through a central line
Usual dose is 1.5 mg/kg/day times 5 to 7 doses.
Requires premedication
• Acetaminophen, diphenhydramine, methylprednisolone
• “First dose” or “cytokine release” syndrome
o Chills, fever, rigors, headache, and hypotension
o Leukopenia, anemia and thrombocytopenia
o Serum sickness
o Increased incidence of infection
Particularly cytomegalovirus
• Cytomegalovirus prophylaxis for 30 days
o Alemtuzumab (Campath®; Genzyme Corp; Cambridge, MA)
Very limited experience published from the University of Pittsburgh
Humanized monoclonal antibody against the CD52 antigen
• CD52 antigen is expressed on the surface of malignant B-lymphocytes,
T-lymphocytes, NK cells, monocytes, macrophages, and platelets
• Proposed mechanism
o antibody-dependent lysis of target cells
3 mg/dose IV over 2 h, once daily
When the 3 mg dose tolerated, the daily dose to 10 mg IV
When 10 mg dose is tolerated, the maintenance therapy at 30 mg/day
• Diphenhydramine 50 mg, acetaminophen 650 mg
Fatal, infusion-related reactions
IL-2 receptor antagonists
o Basiliximab (Simulect®; Novartis Pharmaceuticals Corp.; East Hanover, NJ) or
daclizumab (Zenapax®; Hoffman-LaRoche; Nutley, NJ)
Antibodies genetically engineered from mouse anti-Tac antibodies
Basiliximab is a chimeric human-mouse antibody
Daclizumab is a fully humanized antibody where only 10% mass is of murine
o Bind to IL-2 receptors
Limit IL-2 driven T-cell proliferation
o Basiliximab = 20 mg IV 2 h before surgery and 20 mg IV day 4
o Daclizumab = 1 mg/kg IV prior to surgery and then qd 2 weeks times 5
o Toxicity
Hypersensitivity reactions described
Maintenance immunosuppression
• Calcineurin Inhibitors (Table 4)
o Cyclosporine (CsA, Neoral®; Novartis Pharmaceuticals Corp.; East Hanover, NJ;
Gengraf®; Abbott Laboratories, North Chicago, IL)
CsA-cyclophilin complex binds to calcineurin
• Key enzyme in transcription of IL-2
• Specific and reversible inhibition of T-cell activation
(Cyclosporine) microemulsion better absorbed in the GI tract
Dosed 12 h apart at 4 mg/kg
Can be given via a continuous infusion, usually one third the oral dose
For oral dosing a 1 h, predose trough level is monitored
Target levels: 150 to 300 ng/mL
• Nephrotoxicity
o Hypertension
o Renal insufficiency
• Neurotoxicity
o Headaches, tremors, paresthesias, seizures may occur
• Hirsutism, gingival hyperplasia, hemolytic-uremic syndrome/thrombotic
thrombocytopenic, hepatotoxicity
Hyperkalemia, hypomagnesemia
o Tacrolimus (FK506, Prograf®; Astellas Pharma, US, Inc.; Deerfield, IL) (Table 4)
Binds to a FK-binding protein
• Complex prevents the elaboration of IL-2
Dosed 12 h apart at a starting dose of 0.05 to 0.1 mg/kg
For oral dosing, a 1-h predose trough level is monitored
Target levels: 8 to 15 ng/mL
• Nephrotoxicity
o Hypertension
o Renal insufficiency
• Neurotoxicity
o Headaches, tremors, paresthesias; seizures may occur
• Hemolytic-uremic syndrome/thrombotic thrombocytopenic,
Hyperkalemia, hypomagnesemia
Table 4—Comparison of Cyclosporine and Tacrolimus Toxicity*
Side Effect
Glucose intolerance and
diabetes mellitus
Gingival hypertrophy
Hyperuricemia and gout
Hyperkalemia and
Liver dysfunction
GI symptoms
*Adapted from Banner NR, Polak JM, Yacoub MH, eds. Lung transplant. New York, NY: Cambridge University
Press, 2003.
†HUS/TTP = hemolytic-uremic syndrome/thrombotic thrombocytopenic.
• Purine Synthesis Inhibitors
o Azathioprine (AZA, Imuran®; DSM Pharmaceuticals, Inc.; Greenville, NC)
Metabolized to 6-mercaptopurine (6-MP)
• Converted to thioinosinic acid
o Inhibits DNA synthesis and cell division of activated
• Available as 50 mg scored tablets, as a suspension, and IV
• Dose is 1.5 to 2 mg/kg/daily, titrated to WBC count between 4,000 and
6,000 per mm3
• Toxicity
• Anemia, leukopenia, thrombocytopenia
• Hepatotoxicity
• Pancreatitis
• Nausea, rash
o Mycophenolate mofetil (MMF, Cellcept®; Hoffman-LaRoche; Nutley, NJ) or
mycophenolate sodium (Myfortic®; Novartis Pharmaceuticals; Hanover, NJ)
Active metabolite mycophenolic acid (MPA)
• Inhibits de novo purine synthesis
• Selective to late-stage T-cell activation and proliferation
MMF available as 250 mg and 500 mg capsules, oral suspension, and IV
• 1,000 to 1,500 mg, orally, bid
Mycophenolic acid (Myfortic®; Novartis Pharmaceuticals; Hanover, NJ)
available as 180 mg and 360 mg capsules
• 360 to 720 mg, orally, bid
• Bone marrow suppression (maintain WBC >4,000 per mm3
• Nausea, vomiting, and diarrhea
• Teratogenicity
o Alter T-cell proliferation
Inhibit cytokine production (IL-2 and IL-6)
Suppress macrophage function
Reduce expression of adhesion molecules
Induce lymphocyte apoptosis
o Oral: prednisone, methylprednisolone, or equivalent; IV: methylprednisolone,
hydrocortisone, or equivalent
o Dosing: Methylprednisolone IV intraoperatively (varies per center)
0.25 mg/kg bid tapered over 6 months posttransplant to 0.1 to 0.2 mg/kg daily
Treatment of acute rejection: methylprednisolone IV at 15 mg/kg/day
(maximum 1,000 mg) times 3 days
o Toxicity:
Glucose intolerance, Cushing syndrome, increased appetite, weight gain
Sodium and fluid retention, hypertension
Cataracts, glaucoma
Mood alterations, psychosis
Gastritis, candidiasis
Myopathy, cramps, osteoporosis
Acne, hirsutism, photosensitivity, delayed wound healing, striae, bruisability
Sirolimus (Rapamune®; Wyeth; Madison, NJ)
o Binds to FK-binding protein
o Complex binds to and inhibits mammalian target of sirolimus
Suppression of cytokine-driven T-cell differentiation
• Prevents progression of cell cycle from G1 to S
o Oral 1 mg tablets or liquid
4 mg loading, followed by 2 to 4 mg/daily
Titrate to trough concentration of 5 to 15 ng/mL
o Toxicity:
Hypertriglyceridemia, hypercholesterolemia
Leukopenia, thrombocytopenia
Interstitial pneumonitis
Bronchial dehiscence
• Not be used in the first 3 months posttransplant
Impaired wound healing
• Sirolimus should be stopped 2 weeks before any planned surgery
• Other/chronic rejection agents
o Azithromycin
Immunomodulatory effects may benefit and prevent progression of OB
• 250 mg, orally, three times a week
o HMG CO-A reductase inhibitors, statins
Atorvastatin and other agents may prevent fibrotic proliferation and, therefore,
progression of OB
Antimicrobial prophylactic medications
Pneumocystis jiroveci pneumonia prophylaxis
• Trimethoprim/sulfamethoxazole (Bactrim®; Hoffman-LaRoche; Nutley, NJ; Septra®; Monarch
Pharmaceuticals; Bristol, TN)
o Single strength, one tablet, three times a week
• Alternative agents include dapsone (100 mg, orally, three times a week), atovaquone (750 mg,
orally, daily), or inhaled pentamidine
Antifungal prophylaxis or treatment
• Clotrimazole (Mycelex®; Bayer; Morristown, NJ)
o Prevention and treatment of oropharyngeal candidiasis
o 10 mg, orally, sucked (not swallowed), bid-tid
• Nystatin
o 5 mL, swish-and-swallow tid
• Itraconazole (Sporanox®; Ortho-McNeil; Raritan, NJ)
o Suspension more reliable absorption
o Requires acidic medium for absorption
o 100 mg, orally, bid
o Strong elevation in calcineurin inhibitor and sirolimus levels
• Voriconazole (VFend®; Pfizer; New York, NY)
o Treatment of aspergillosis
o 200 mg bid
o Marked elevation in calcineurin inhibitor levels and relative contraindication with
o More prominent liver toxicity than itraconazole or fluconazole
• Inhaled amphotericin B (off-label)
o Used to prevent Aspergillus infection
o Routine use in the immediate posttransplant period
o Prophylaxis during therapy with ATG
o Asymptomatic airway colonization or bronchial anastomotic infection
o 20 mg inhaled via nebulizer bid
o Premedication with an inhaled bronchodilator
Cytomegalovirus prophylaxis
• Ganciclovir (IV)
o Used to treat or as prophylaxis
o 5 mg/kg IV qd 12 h times 3 weeks or 5 mg/kg IV three times a week, used for
Adjusted in renal insufficiency
Causes thrombocytopenia, anemia, and renal insufficiency
• Valganciclovir, oral (Valcyte®; Roche Pharmaceuticals; Nutley, NJ)
o 450 mg capsules
o Treatment 900 mg, orally, bid or 900 mg, orally, daily for prophylaxis
o Adjusted in renal insufficiency
• Cytomegalovirus hyperimmune globulin (Cytogam®Intravenous; MedImmune ; Gaithersburg,
o Used for prophylaxis in high risk patients (cytomegalovirus D+/R-)
o Used in patients with severe cytomegalovirus infection
Other antiviral prophylaxis
• Acyclovir
• Valacyclovir
• Calcium-channel blockers
o Diltiazem, verapamil, and nifedipine will increase calcineurin inhibitor levels
o Amlodipine does not affect levels
• Angiotensin-converting enzyme inhibitors
• Beta-blockers
GI medications
o H2-blockers or proton-pump inhibitor
• Gastroparesis
o Metoclopramide or erythromycin
Increase calcineurin inhibitor levels
• Diarrhea
o Usually medication-related, especially mycophenolate
• Special GI considerations for the patient with cystic fibrosis
o At risk for development of distal intestinal obstruction syndrome
o Ensure proper pancreatic enzyme supplementation
o May not absorb medications adequately from the GI tract
o Often require higher doses of calcineurin inhibitors to attain therapeutic levels
Endocrine medications
• Diabetes
o Insulin and sulfonylureas are commonly used
o Avoid biguanides
• Osteoporosis
o Exercise, calcium, and vitamin D supplementation
o Bisphosphonate therapy
• Hyperlipidemia
o Common after transplant and related to medications
o Diet and statins
Myopathy and rhabdomyolysis side effects
Pravastatin interaction with cyclosporine is minimal
Important drug and diet interactions
• Common drugs that increase levels of calcineurin inhibitors
o Calcium-channel blockers
Diltiazem, verapamil, and nifedipine increase calcineurin levels
Amlodipine does not affect significantly
o Imidazole antifungals
o Macrolides
Azithromycin usually does not affect significantly
• Common drugs that decrease levels of calcineurin inhibitors
o Barbiturates
o Phenytoin and other anticonvulsants
Levetiracetam (Keppra; UCB Pharma, Inc; Rochester, NY) is a safe
anticonvulsant of choice
o Rifampin
• Important interactions with sirolimus
o Timing with cyclosporine
Take 4 h after oral cyclosporine
o Voriconazole
Contraindicated with sirolimus
o Other interactions similar to calcineurin inhibitors
• Oral contraceptives and hormone replacement therapy
o May decrease cyclosporine metabolism resulting in increased blood levels
o Use preparations that provide constant dose
• Statins
o Combined use of statins and cyclosporine result in increased risk of myopathy and
o Use low doses of statins and monitor patients closely
o Pravastatin maybe safer than others because of minimal interaction with cyclosporine
• Allopurinol
o Inhibits xanthine oxidase, which metabolizes azathioprine; combined use may result in
serious bone marrow suppression
o A safe alternative is to switch patient to mycophenolate, which has no interaction with
o If allopurinol needs to be used, decrease dose of azathioprine by 75% to avoid severe
• Grapefruit and grapefruit juice
o Should not be taken by patients after lung transplant
o Grapefruit juice increases oral bioavailability of cyclosporine
o Similar interaction may occur with lime and lime juice
• Raw foods
o Sushi and uncooked meats are prohibited
• Herbs
o St. John’s Wort induces a decrease in cyclosporine bioavailability
o Avoid cat’s claw and Echinacea
• Itraconazole
o Suspension has more reliable absorption
o Capsules require acid in the stomach for absorption
Should be given after meals and with cola
• Valgancyclovir hydrochloride tablets (Valcyte®; Roche Pharmaceuticals; Nutley, NJ)
o Taken with food
• Over-the-counter medications
o Nonsteroidal antiinflammatory drugs, which may precipitate renal failure
o Consult with transplant center to avoid potential interactions
• Avoid foods high in potassium and fats
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