Non-infectious complications in transplant patients non-infectious complications -One... ·...
Transcript of Non-infectious complications in transplant patients non-infectious complications -One... ·...
Usanarat Anurathapan, MD
Department of Pediatrics
Faculty of Medicine Ramathibodi Hospital
Non-infectious complications in
transplant patients
Outline
• Early complications
• Late complications
Early complications
• Oral mucositis
• Hemorrhagic cystitis
• Endothelial origin:
– Hepatic veno-occlusive disease/sinusoidal obstruction
syndrome
– Engraftment syndrome
– Thrombotic microangiopathy
– Capillary leak syndrome
– Diffuse alveolar hemorrhage
• Idiopathic pneumonia syndrome
Oral mucositis grading
• Grade 0 none
• Grade 1 Erythema, oral pain
• Grade 2 Ulcers, able to eat solids
• Grade 3 Ulcers, able to eat liquids
• Grade 4 Ulcers, oral alimentation impossible
Oral mucositis treatment
• Prevention
– Eliminate local factors & maintain oral hygiene
– Cryotherapy
• Management
– Bland rinses (NSS)
– Viscous lidocaine
– Systemic pain medication
– Diet modifications
Hemorrhagic cystitis (HC)
• Hematuria, symptomatic or asymptomatic
1) Grade I – microscopic
2) Grade II – macroscopic
3) Grade III – with clots
4) Grade IV – requiring instrumentation for clot
evacuation or leading to urinary retention or
requiring surgical intervention
Pathogenesis of HC
• Early (up to 72 hr after conditioning)
– Cyclophosphamide
– Other: ifosfamide, VP-16 or TBI
• Late (usually > 2 wk after SCT)
– BK polyomavirus infection
– GvHD & thrombocytopenia
Prophylaxis for HC
• Hydration: 3L/m2
• Diuresis
• Mesna: 1-1.5 x the daily dose of CY
Treatment of HC
• Forced hydration & intensive platelet support
• Continuous bladder irrigation with saline
• Hyperbaric oxygen or estrogen
• Cidofovir, ciprofloxacin or ribavirin
• Selective embolization of bladder artery
Endothelial origin
Hepatic veno-occlusive disease/
sinusoidal obstruction syndrome
• Reduction of glutathione enzyme level
– Pre-existing liver disease
– Conditioning regimen: BU, BCNU, TBI
• Accumulation of toxic metabolites in area 3
of hepatic acinus (around centrilobular veins)
• Damage to hepatocytes & sinusoidal
endothelium
Risk factors of VOD/SOS
Diagnosis of VOD/SOS
• Baltimore criteria (classical) : the first 21 days after SCT
– Bilirubin >2 mg/dL plus 2 or more of
• Painful hepatomegaly
• Ascites
• Wt gain (>5% basal wt)
• Seattle criteria: the first 20 days after SCT; 2 or more of
– Bilirubin >2mg/dL
– Hepatomegaly or RUQ pain
– Wt gain (>2% basal wt)
EBMT diagnostic criteria
• Late onset (adult only): >21 d
– Classical Baltimore criteria OR
– Histologically proven VOD/SOS OR
– 2 or more of bilirubin >2 mg/dL, hepatomegaly,
ascites, and wt gain >5% AND hemodynamic
and/or U/S evidence of VOD/SOS
Pediatric EBMT criteria: no time frame
• Presence of 2 or more
– Increased bilirubin from baseline for 3 consecutive days
or bilirubin >2mg/dL within 72 h
– Hepatomegaly (best if confirmed by imaging) above
baseline
– Ascites (best if confirmed by imaging) above baseline
– Wt gain on 3 consecutive days or wt gain >5% basal wt
– Transfusion-refractory thrombocytopenia
Other studies help diagnose VOD/SOS
• Hepatic venous gradient pressure >10mmHg
• Liver biopsy
– concentric non-thrombotic narrowing of the lumen of
small intrahepatic veins
• Ultrasonography
– hepatomegaly & attenuated or reversed portal flow
• Biological study: PAI-1, vWF, thrombomodulin
VOD/SOS EBMT grading for adult
Clinical measures Mild Moderate Severe Very severe
Time since first symptoms >7d 5-7d <4d anytime
Bilirubin (mg/dL) >2 and <3 >3 and <5 >5 and <8 > 8
Bilirubin kinetics - - Doubling
within 48 h
-
Transminase (x normal) <2 >2 and <5 >5 and <8 >8
Wt above baseline (%) >5 >5 and <10 >5 and <10 >10%
Renal function (x baseline at SCT) <1.2 >1.2 and <1.5 >1.5 and <2 >2 or other
signs of MOF
Risk factor adjustment Mild + >2 Mod + >2
Treatment options - Maintain fluid
& sodium
balance
- Careful use of
diuretics
- Avoid
hepatic/renal
toxic drugs
- Analgesia,
oxygen
Mild treatment
plus
- If S&S persist
or progress
after 2d, start
pharmaco Rx
- If HVGP
>10mmHg, start
pharmaco Rx
Moderate plus
pharmaco Rx
Severe plus
hemodialysis/he
mofiltration
VOD/SOS EBMT grading for children
Clinical measure Mild Moderate Severe Very severe
Liver function test (x normal <2 >2 and <5 >5 >5
Persistent thrombocytopenia (d) <3 3-7 >7 >7
Bilirubin (mg/dL) <2 <2 >2 >2
Bilirubin kinetics - - - Doubling
within 48h
Ascites Minimal Moderate Necessity for paracentesis
Coagulation Normal Normal Impaired Impaired wit
need for
replacement
Renal function GFR, ml/min 89-60 59-30 29-15 <15
O2 requirement < 2LPM >2LPM Need for ventilator support
(including CPAP)
CNS Normal Normal Normal New onset
cognitive
impairment
VOD/SOS prophylaxis
• To avoid risk factors
– Delay SCT if acute hepatitis exists; adjust Bu dose;
fractionate TBI; avoid hepatotoxic drugs
– High risk pts, consider RIC allo-SCT
• Pharmacological
– Ursodeoxycholic acid: 4 RCT & 2 HCT
– Defibrotide: 1 RCT in children
– Heparin, LMWH, PGE1: ineffective
VOD/SOS treatment
• Symtomatic:
– Restriction of salt & water intake + diuretics
– Maintain intravascular volume & renal perfusion by
means of albumin, plasma expanders & transfusion
• Specific
– Defibrotide: 6.25 mg/kg IV drip in 2 hr Q6hr x 14 d
• Other measures:
– Analgesia, paracentesis/thoracocentesis, mechanical
ventilation, hemodialysis/hemofiltration
Mechanism of action: defibrotide
Engraftment syndrome (ES)
• Fever, rash & pulmonary edema secondary
to endothelial injury & cytokine production
• Associated with rapid increase in the rate of
appearance of neutrophil
• Skin biopsy showed necrotic keratinocytes &
perivascular invasion by lymphocytes
Clinical manifestations of ES
• Noninfectious fever
• Rash
• Vascular leak: hypotension, wt gain, edema,
ascites, non-cardiogenic pulmonary edema, pleural
effusion
• Organ dysfunction: Renal, hepatic, CNS
• Diarrhea without other cause
Diagnostic criteria of ES
• Major
1. T > 38.3°C with no identifiable infectious etiology
2. Erythrodermatous rash involving >25% BSA not attributable to a
medication
3. Noncardiogenic pulmonary edema, manifestated by diffuse
pulmonary infiltrates & hypoxia
• Minor
1. Hepatic dysfunction with either total bilirubin > 2 mg/dL or
transaminase level > 2 times the upper limit of normal
2. Renal insufficiency with serum creatinine > 2 times the baseline level
3. Weight gain > 2.55 times baseline body weight
4. Transient encephalopathy unexplainable by other causes
Diagnosis of ES
• Presence of all 3 major criteria or 2 major & > 1
minor criteria
• Should occur within 96 hours of engraftment
• Treatment
– Supportive care: antipyretics, O2, topical Rx &
diuretics
– Methylprednisolne 1mg/kg/day IV for 3-5 days
followed by rapid taper
Thrombotic microangiopathy (TMA)
• Generalized endothelial dysfunction from
conditioning regimens & other factors
• Microangiopathic hemolytic anemia & platelet
consumption
• Resulting in thrombosis & fibrin deposition
• ADAMTS13 activity rarely decrease to below 10% of
normal
• Usually around day +60 (day+4 to 2 years)
Clinical features of TMA
• Microangiopathic hemolytic anemia with 2-4%
schistocyte
• Increased LDH & other markers of hemolysis
• Thrombocytopenia or increased requirement of
platelet transfusion
• Renal dysfunction and/or neurological abnormalities
• Hypertension, diarrhea secondary to intestinal TMA,
proteinuria
Diagnostic criteria for TMA
A. Microangiopathy diagnosed by tissue biopsy
B. Laboratory & clinical markers: 1-3 -> consider Dx
1. Increased LDH above normal limit
2. Proteinuria: random >30mg/dL
3. Hypertension
4. De novo thrombocytopenia
5. De novo anemia
6. Evidence of microangiopathy: schistocyte
7. Terminal complement activation: elevated sC5-9
TMA risk assessment algoritm
Pathogenesis & potential treatment
Treatment of TMA
• Supportive
– Withdrawal or minimization calcineurin inhibitor
– Treatment of co-existing conditions
– Aggressive treatment of HTN
• Specific
– Antibody reduction: rituximab, plasma pheresis
– Complement blockade: eculizumab
Eculizumab administration & monitoring
Capillary leak syndrome (CLS)
• Injury to capillary probably caused by
cytokines and VEGF
• Risk factors
– Use of G-CSF, GM-CSF
– Unrelated of HLA-mismatched allo-graft
Clinical features of CLS
• Wt gain >3% within 24 h & generalized
edematous syndrome (ascites, pleural
effusion or pericarditis), not response to
diuretics
• Occasionally, tachycardia, hypotension &
renal insufficiency
Treatment of CLS
• Withdraw any growth factor
• IVIG or bevacizumab (anti-VEGF)
• Poor response to corticosteroid
Diffuse alveolar hemorrhage (DAH)
• Disruption of alveolar-capillary basement
membrane by conditioning, immune-mediate
events & return of neutrophil with marrow
recovery
• Dyspnea, non-productive cough, hemoptysis,
hypoxemia require O2 therapy
• Focal or diffuse interstitial or alveolar infiltrate in
middle & lower lungs
Diagnosis of DAH
• Based on BAL findings
– Progressively bloodier
– Not attributable to infection, thrombocytopenia,
fluid overload or heart failure
– Presence of hemosiderin-laden macrophage
• Risk factors: older age, previous thoracic
radiation, TBI, myeloablative conditioning
Treatment of DAH
• High-dose methylprednisolone for 4-5 days
and tapering over 2-4 weeks
• Supportive care
– Mechanical ventilation
Idiopathic pneumonia syndrome (IPS)
• Caused by toxic effects of conditioning,
immunological cell-mediated injury, inflammatory
cytokines, flora-derived LPS
• Median time to onset after allo-SCT on day+18 to
day+21
• Fever, non-productive cough, tachypnea &
hypoxemia
• Diffuse alveolar or interstitial infiltrates
Diagnosis of IPS
• Widespread alveolar injury
– Multilobar infiltration
– Symptoms and signs of pneumonia
– Evidence of abnormal pulmonary physiology
• Absence of active lower respiratory tract infection
– BAL negative for bacteria, viruses & fungi
• Absence of cardiac dysfunction, acute renal failure or
iatrogenic fluid overload
Pathogenesis of IPS
• Risk factors: intensity of conditioning , use of TBI,
allo-SCT, older recipient age, acute leukemia or MDS
& presence of GvHD
Treatment of IPS
• Supportive care
– Non-invasive & invasive mechanical ventilation
– Hemofiltration
– Broad-spectrum antimicrobial agents &
corticosteroids
• Potential targeted therapy: anti-TNF-α
(eternacept)
Late complications
• Ocular effects
• Oral & dental
• Skin & appendages
• Thyroid dysfunction
• Cardiac & Vascular
• Metabolic syndrome
• Chronic kidney disease
• Noninfectious respiratory tract
• Fertility & gonadal dysfunction
• Liver complications & iron overload
• Late complications of bone
• Late hematological malignancies
• Secondary solid tumors
Eye Complications
• Cataract
– Risk factor: TBI, steroids, CY or BU/CY
– Clinical features: decrease in vision, decreased
contrast, altered color perception
– Diagnosis: slit lamp examination
– Treatment: surgical remove
Eye complications
• Kerato-conjunctivitis sicca syndrome
– Risk factor: cGVHD, TBI
– Clinical features: reduced tear flow, dryness &
irritation of eyes, sterile conjunctivitis, corneal
epithelial defect & corneal ulceration
– Diagnosis: Schirmer’s test
– Treatment: systemic treatment of cGVHD, topical
lubricants
Oral complications
• Risk factors: cGvHD, conditioning with TBI
• Clinical features: pain, xerostomia, secondary
oral infection, dental decay
• Prevention: maintaining oral & dental health;
brushing teeth, daily flossing
• Treatment: topical corticosteroid, systemic
treatment regular dental review
Skin complications
• Risk factors: allo-SCT, cGvHD, UV irritation,
physical trauma
• Clinical features: dryness of skin
• Prevention: reduce direct UV skin exposure
• Treatment: topical steroids, calcineurin
inhibitors, phototherapy
Thyroid dysfunction
• Risk factors: TBI, BU/CY
• Clinical features: asymptomatic
compensated hypothyroidism, overt
hypothyroidism, autoimmune thyroid disease
• Prevention: non-TBI conditioning
• Treatment: hormonal substitution
Cardiac complications
• Risk factors: pre-transplant anthracycline
exposure
• Clinical features: dyspnea on exertion,
fatigue, orthopnea, wt gain
• Treatment: manage as non-transplant pts
Vascular complications
• Risk factors: allo-SCT
• Clinical features: TIA, stroke, angina
pectoris, MI, claudication, rest pains
• Prevention: heart-healthy life style, regular
physical activity, maintain healthy weight
• Treatment: as non-transplant pts
Metabolic syndrome
• Risk factors: physical inactivity, smoking, allo-SCT
• Diagnosis: regularly check blood pressure, FBS &
lipid profile
• Prevention: stop smoking, regular exercise,
maintaining healthy weight
• Treatment: control dyslipidemia, diabetes & HTN
Chronic kidney disease
• Risk factors: older age, exposure to CNI,
nephrotoxic drugs used before SCT, during
conditioning & post-transplant
• Diagnosis: regularly check renal function,
blood pressure
• Treatment: as non-transplant pts
Pulmonary Complications
• Chronic obstructive disease
– Risk factor: cGVHD, TBI, older age,
hypogammaglobulinemia
– Clinical features: dry cough, progressive
dyspnea & wheezing, decline of PFT
– Treatment: systemic treatment of cGVHD,
topical steroids, and bronchodilators
Fertility and gonadal dysfunction
• Risk factors: age, TBI, BU
• Clinical features:
– Female: premature menopausal state with
menopausal symptoms, osteoporosis & metabolic
syndrome
– Male: erectile dysfunction, low libido & bone loss
• Treatment: sex-hormone replacement therapy
Liver complication & iron overload
• Risk factors: cGvHD, iron overload, viral
infection
• Clinical features: asymptomatic, liver
function test annually, serum ferritin, MRI
• Treatment: as non-transplant pts, therapeutic
phlebotomy, iron chelation
Bone Complications
• Avascular necrosis
– Risk factor: steroids and TBI, presence of
cGvHD, exposure to CNI & steroids
– Clinical features: pain at hips, knee, wrist &
ankle
– Treatment: analgesia, surgical treatment often
necessary
Bone complications
• Osteoporosis
– Risk factor: TBI, steroids, gonadal failure, length
of CNI treatment
– Clinical features: asymptomatic, non-traumatic
frature
– Treatment: hormonal replacement, Calcium,
vitamin D, bisphosphonates
Late hematological malignancies
• Risk factors: use of akylating agents & high
number of chemotherapy courses before
SCT, prior radiotherapy
• Prevention: tapering immunosuppressive
agents as soon as possible
• Treatment: depends on time of appearance,
type and extent of disease
Risk factor Secondary malignancies
Total body irradiation Melanoma, thyroid, CNS tumor
Limited field irradiation squamous cell CA (SCC), head & neck CA
T-cell depletionPost-transplant lymphoproliferative disorders
(PTLD), melanoma
Chronic GVHD SCC, head and neck CA, skin CA
HLA-mismatch PTLD
ATG, OKT3 PTLD
Acute GVHD PTLD
Secondary malignancies
Questions?