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?