Complications after HSCT. ICU Fellowship Training Radboudumc

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1 Complications after HSCT ICU Fellowship Training Radboudumc

2 Type of HSCT

3 HSCT Improved outcome due to better HLA matching, conditioning regimens, post transplant supportive care Over one-third have pulmonary complications Both infectious and noninfectious Preengraftment(< 30 D), immediate postengraft-ment ( D) and late postengraftment (> 100 D) phase

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5 Stem cell transplantation ICU complications usually explained by Toxicity of conditioning Immunosuppression with opportunistic infections Graft-versus-host-disease

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7 Pulmonary diseases Repopulation syndrome 7-35%, < 96 hrs after granulocytes > 500/cm3, fever/rash/diarrea/aki/noncardiogenic pulmonary edema/mods, symptomatic treatment + corticosteroids Diffuse alveolar bleeding 5%, usually within 30 days after HSCT, risk factors are intensive chemotherapy before HSCT/total body radiation, often at the time of bone marrow recovery, dyspnea/fever/cough/hypoxemia/rarely hemoptysis, BAL best diagnostic, symptomatic treatment ± corticosteroids - more recent installation of FVIIa 50 μg/kg

8 Pulmonary diseases Idiopatic pneumonia syndrome COP 10%, usually within first 2 month, diffuse alveolar infiltrates with exclusion of infection and diffuse alveolar bleeding by BAL, usually after previous high dose chemotherapy oj acute GVHD, symptomatic treatment ± corticosteroids 1.5% especially after allogenic HSCT, usually 1-3 months HSCT and related to chronic GVHD, dyspnea/dry cough/fever/hypoxemia, diagnosis by open lung biopsy, treatment with corticosteroids - must be differentiated from bronchiolitis obliterans (slowly progressive/no reaction to steroids)

9 CMV infection Control of primary infection Cytotoxic T- and NK cells Primary CMV infection Lifelong CMV latency Immunosuppression Recurrent CMV infection Childhood Usually asymptomatic Saliva Sexual contact Placental transfer Breast feeding B-, T- and Memory cells Seroconversion Neutrophilic granulocytes CD 14 monocytes Dendritic cells Megakaryocytes Depends on Viral load Infection route Immunocompromised state Pneumonitis Hepatitis Retinitis Myocarditis Colitis Encephalitis Negative transplant Positive donor

10 CMV pneumonitis Incidence decreasing with valganciclovir prophylaxis in high risk patients and early treatment based on PCR Incidence ± 6% in first 3 months after BMT, after this 15% especially related to GVHD Diagnosis via BAL (culture +/- direct FA/PCR +) or inclusion bodies with biopsy

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12 CMV in general ICU patients PCR does not predict or proof CMV induced disease nor does culture Rising or high CMV DNA load (> 10 3 copies) makes further investigations necessary Characteristic pathological changes in organ biopsies are essential for diagnosis

13 CMV in general ICU patients Kalil AC. Crit Care Med 2009;37:

14 CMV in general ICU patients Kalil AC. Crit Care Med 2009;37:

15 CMV reactivation and mortality 81% higher mortality with active CMV infection lso associated with increased duration of MV and LOS Kalil AC. Crit Care 2011;15:1

16 CMV pneumonia Treatment with ganciclovir and immunoglobulines Adverse effects ganciclovir may be important neutropenia, nefrotoxicity, convulsions and retinal detachment

17 Prevention of CMV reactivation in ICU patients N = 156 No effect on IL-6 levels (primary outcome) or clinical outcome (except more VFD s) Limaye AP. JAMA 2017;318:

18 Aspergillus infection Bimodal peak During mucosal breakdown/prolonged granulocytopenia and during treatment for GVHD 1 year incidence after allogeneic HSCT of 12% and mortality of 50-80% Positive culture of tracheal aspirate and/or BAL + antigen rise sufficient to start empirical treatment in right clinical/radiological circumstances

19 Epidemiology (1) Increased use of HSCT practices with high risk of GVHD (HLA mismatch and reduced intensity conditioning) T-cell-depleted and CD34-selected stem cells reduce GVHD but have higher risk of delayed immune reconstitution Antifungal prophylaxis in preengraftment period Fewer early fungal infections - increasing late infections

20 Diagnosis of IA in critically ill patients Not suited for the critically ill

21 Radiology in the ICU is aspecific Vandewoude KH. Crit Care 2006;10:R

22 Alternative Blot SI. Am J Respir Crit Care Med 2012;186:56

23 Galactomannan antigen Serum levels of little value in nonneutropenic patients (sensitivity 42%) BAL levels > 0.5 have a sensitivity of 88% and specificity of 87% in diagnosing proven IA in ICU patients In 11 out of 26 proven IA cases BAL culture and serum GM were negative N = 110 Meersseman W. Am J Respir Crit Care Med 2008;177:2

24 Epidemiology (2) Classical radiological signs in neutropenic patients are now often absent Serum galactomannan test less sensitive in non-neutropenic patients Increased incidence of non-aspergillus moulds

25 Nodular infiltrate Halo sign

26 PJP Mortality in patients with PJP and acute respiratory failure 50-80% Difficult to predict in non-hiv patients Definitive diagnosis by silver/immune staining or PCR with β-d glucan in serum as a diagnostic adjunct

27 Risk score Hematological patients with ARF Variables Odds Ratio (95% CI) P Value Score Points Age,0.0001,50 yr yr 0.51 ( ) yr 0.32 ( ) 22.5 Lymphoproliferative disease 2.79 ( ), No prophylaxis 1.50 ( ) Days between respiratory symptom onset and ICU, admission,3 d d 4.35 ( ) 13.5 d 4.98 ( ) 13 Shock at ICU admission 0.47 ( ), Chest X-ray: not alveolar 3.31 ( ), Pleural effusion 0.38 ( ) Definition of abbreviation: CI = confidence interval. Derivation cohort 1092 Validation cohort 238 Best threshold 3 Sensitivity 86.7% Specificity 67.7% NPV 97.9% Azoulay E. Am J Respir Crit Care Med 2018;198:

28 Cardiac complications Congestive heart failure Pre-existent EF < 50%, iv infusion policy, renal failure, VOD, chemotherapy (cyclosfosfamide > 120 mg/kg, ARA-C, paclitaxel, etoposide, cisplatinum) Pericardial effusion cyclofosfamide toxicity, viral infections, chronic GVHD, renal failure Endocarditis (1-1.5%)

29 GI complications GVHD Often together with hepatitis and skin lesions, diagnosis by biopsy, intensify immunesuppression Intestinal pseudo-obstruction Exclude underlying GVHD, perforation rare, conservative therapy including neostygmine Pancreatitis (3.5%) Enteritis GVHD, clostridium difficile, viral, typhlitis

30 GI complications Blood loss (often diffuse mucosal bleeding) GVHD, chemoradiotherapy, viral infections (CMV/adenovirus) Hepatic sinusoidal obstruction syndrome usually due to his dose conditioning regimens, usually < 3 weeks. weight gain/ enlargement of liver/jaundice, diagnosis based on clinical picture/doppler, therapy symptomatic, often acute renal insufficiency

31 Renal complications Transplant AKI % Autologous (myeloablative) 10% Allogeneic (reduced intensity) 50% Allogeneic (myeloablative) 70-75% Median time to onset AKI 33-38D Early AKI or severity: mortality With RRT mortality %

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33 Analysis Complete urinalysis Urine albumin-to-creatinine ratio Complete blood count with blood smear Level of LDH, haptoglobin and calcineurin inhibitor PCR for BK and adenovirus Renal ultrasound and (renal biopsy)