Acute Respiratory Failure in Immunocompromised Patients · Immunocompromised Patients ÉlieAzoulay,...

Acute Respiratory Failure in

Immunocompromised Patients

Élie Azoulay, Université Paris Sorbonne, Hôpital Saint-Louis, Paris,

Groupe de Recherche Respiratoire en Réanimation Onco- Hématologique (Grrr-OH).

Nine-i Investigators

My last 3 hematology patients

❸ 34yo man, ARF

37,000 leucocytes

❶ 57yo man,

Auto-HSCT Myeloma

HypoGamma

❷ 47yo woman Newly diagnosed AML5Leukemic infiltrates

Meropenem

TMP-SMX

Ambisome

Amikacine

Amoxyciline

Acute Respiratory failure

First acute complication in Hem. Malignancies Pts

❸⓿%

❸❺-❼⓿ %❼⓿ %

ARF Incidence according the type of ID

50

.

.

40

.

.

30

.

.

20

.

.

10

.

.

5

.

.

1

Allogeneic BMT/HSCT, AML

.

.

Prolonged Neutropenia

.

.

Lymphoproliferative disease

SOT (lung)

.

SOT (kidney), ALL, lymphomaLung cancer,

Syst diseases,

SOT heart

Solid tumors

500,000 patients per year in Europe

Early ICU

Admission

Identify ARF

Etiology

Daily Meeting

hematologistsAppropriate

Goals Of CareCritical Care

Training

Improving survival

Standard Oxygen

High Flow OxygenTherapy

Noninvasive Ventilation

Intubation and

MechanicalVentilation

❶ ❷ ❸ ❹

❺

❻ ❼ ❽

❾

Oxygenation Strategy is Unlikely

to Improve Survival

Understanding the Challenge

1. Early ICU admission to improve survival

2. The GPS

3. Identifying the ARF etiology

4. When the ARF etiology remains undetermined

5. Stay Tuned

Improving Survival

❶ Early ICU Admission

Adjusted Survival:

early vs. late intervention

Overall population ICU survivors

early intervention (≤ 1.5 hr)

early intervention (≤ 1.5 hr)

Late intervention (> 1.5 hr)

Late intervention (> 1.5 hr)

ICU MORTALITY 18 42

HOSPITAL MORTALITY 40 68

6 M MORTALITY 56 74

1-Y MORTALITY 66 78

Song, Crit Care Med 2012

Early ICU Admission for Hematology patients

Hourmant & Darmon, Submitted. 2019

Do Not Navigate in the Dark

❷ The GPS

The GPS = clinical stratificationIt assists you to identify the most probable ARF etiologies

❶

Use the GPS to provide early and adequate TTT,

select the appropriate diagnostic strategy and sometimes avoid risky

procedures

❷

Perform the appropriate diagnostic strategy to document and confirm the initial approach. Give priority

to NIT

❸

Use innovative tests, oMICs technology and integrative biology to

distinguish colonization from infection

DIAGNOSIS

EARLIEST PHASE INTERMEDIATE PHASE

1-2 days 1 month

Bacterial infection, fluid overload, Pulmonary oedema, alveolar haemorrhage

PRE-TREATMENT PHASE TREATMENT INDUCTION CONSOLIDATION

1 year

EARLY PHASE

❶

❷

❸

Eosinophilic lung Diseases, Hairy cell leukaemia receiving

2-chlorodeoxyadenosine

Lysis pneumopathyAML4, day 6

Alveolar proteinosisNewly diagnosed CML

Leukemic infiltration Newly diagnosed AML5

LeukostasisNewly diagnosed AML2

MucormycosisAML5, day 21

Pneumocystis pneumoniaNewly diagnosed T-ALL

GeotrichumInfection, T-ALL

RSV infectionB-ALL

1-2 weeks

Influenza infectionNewly diagnosed B-ALL

VZV pneumoniaNK)/T-cell lymphoma

Pneumococcus pneumoniaDiffuse B-cell lymphoma

Cardiogenic edemaAML4

Cytarabine-related Infiltrates. AML2, day 4

CMV pneumoniaNK)/T-cell lymphoma inAn VIV-infected patient

Nocardia infectionB-cell lymphoma,

Invasive aspergillosisAML1, day 24

Fusarium infectionT-cell lymphoma

Pleural infiltrationBurkitt Lymphoma

Para-Influenzae virus pneumonia, MDS

CONSOLIDATION

ARDS, neutropenia Recovery, AML

Septic shock (UTI)Aplastic anemia

Leukemic infiltrationALL

TuberculosisAML 2

DIAGNOSIS


1-2 days 1 month



1 year

EARLY PHASE

❶

❷

❸










RSV infectionB-ALL

1-2 weeks












CONSOLIDATION




TuberculosisAML 2

DIAGNOSIS


1-2 days 1 month



1 year

EARLY PHASE

❶

❷

❸










RSV infectionB-ALL

1-2 weeks












CONSOLIDATION




TuberculosisAML 2

DIAGNOSIS


1-2 days 1 month



1 year

EARLY PHASE

❶

❷

❸










RSV infectionB-ALL

1-2 weeks












CONSOLIDATION




TuberculosisAML 2

Earliest Phase Early Phase Intermediate Phase ConsolidationDIAGNOSIS


1-2 days 1 month



1 year

EARLY PHASE

❶

❷

❸










RSV infectionB-ALL

1-2 weeks












CONSOLIDATION




TuberculosisAML 2

Azoulay et al. Lancet Respir Med. 2018DxTTT

1-2

days

1-2

weeks

• Gram negative bacteria

• Gram positive bacteria

• Candida

• Aspergillus

• Herpes Virus

• Nocardia

• Salmonella

NEUTROPHILS

• Mycobacteria

• Salmonella, Listeria, Legionella, Histoplasma, Brucella

• HSV, VZV, PIV, RSV,

• Candida

• S. pneumoniae, S. aureus, E. faecalis, P aeruginosa

• Pneumocystis jirovecii

MACROPHAGES

• Encapsulated bacteria (S. pneumoniae, S. pyogenes, H influenzae, and S aureus)

• Giardia lamblia

• Mycoplasma

• Enterovirus

• Recurrent infections

B LYMPHOCYTES

• Pneumocystis jiroveci, Aspergillus, CMV,

• Mycobacterial infection,

• Candida

• Diarrhoea (rotaviruses, adenoviruses….).

T LYMPHOCYTES

• Encapsulated bacteria (S. pneumoniae, S. pyogenes, H influenzae, and S aureus)

• Mycoplasma,

• Mycobacteria

HUMORAL (antibody) IMMUNITY

DISEASES: Acute leukaemia;

Myelodysplastic syndrome;

Aplastic anaemia;

Chemotherapy and drug-

related neutropenia;

DISEASES: Multiple myeloma

Chronic lymphoid leukemia

TREATMENTS: Ibrutinib; Rituximab

DISEASES: T-cell leukaemia;

Hodgkin disease;

TREATMENTS: Steroids; Fludarabin;

Cyclophosphamide;

Methotrexate; Azathioprine;

Mycophenolate mofetil;

Ciclosporin; Tacrolimus.

DISEASES: Multiple myeloma;

B-cell lymphoma;

Chronic lymphocytic

leukaemia;

TREATMENTS: Chemotherapy;

Steroids;

Asplenia;

Rituximab

DISEASES: Hairy cell leukemia; Aplastic

anemia; Allogeneic BMT;

Malignant histiocytosis; AML;

CML; Solid tumours; HLH

TREATMENTS: Steroids; Basiliximab; ATG;

Alemtuzumab; Tacrolimus;

Cyclosporine; MMF; Betalacept;

mTOR inhibitors (sirolimus)

Infectious risk and immunologic dysfunctions

Azoulay et al. Lancet Respir Med. 2018

http://www.bioscience.org/1997/v2/d/longwort/2.htm

Portion of the lung between epithelial

and endothelial membranes

Ground Glass

Consolidation

Ill defined Nodules

Linear Opacities

Cavitation

Effusion

Heussel et al. JCO 1999GGO

Hemoptysis, acute

anemia? DAH

High Pneumocystis

score? PjP

Viral, Heart,

Leukemia, DRPTCrazy-Paving

PjP

Heart

DRPT

DAH

(CMV)

Alveolar

consolidation with

bronchogram

Tumor

Bacterial pneumonia

Nodular consolidation

Metastasis,

Fungal infection

Tuberculosis, septic

embolism

34yo man, T-cell leukemia. Acute respiratory failure

214 PCP cases

A 49a yo man with fever, pancytopenia, spleen

enlargement: diagnosis of HCL

Are we

at day 0?

Are we

at day 15?

Diagnostic strategy

❸ Identify the ARF etiology

You may prefer this one

Causes of pulmonary infiltrates in immunocompromised patients with ARF

Azoulay et al. Lancet Respiratory Medicine 2018

Azoulay et al. Lancet Respiratory Medicine 2018

A place for bronchoscopy and BAL?

A place for bronchoscopy and BAL?

N BAL / N Total Patients = quality indicator

DAY-28 SURVIVAL

Ventilation

Diagnosis +

Outcomes

NS

BAUER

Substudy of Efraim

Diagnosis and Outcome of Acute Respiratory Failure in

Immunocompromised after Bronchoscopy

Bronchoscopy was performed in 618/1611 (39%) patients

more likely with hematologic malignancy and a higher severity of illness score.

Adjusted diagnostic yield = 27%

Therapeutic yield 38%

Worsening of respiratory status in 11%.

Bronchoscopy was associated with higher ICU (40 vs. 28%, p<0.0001) and

hospital mortality (49 vs. 41%, p=0.003).

After propensity score matching, bronchoscopy remained associated with

increased risk of hospital mortality (OR 1.41, 95% CI 1.08-1.81).

Airway

Invasive

vs.

Vascular

Invasive

Pulmonary

Aspergillosis

No BAL

ALL, PFratio=60,

nasal swabNeutropenia 35 days + T cell defect + Steroids

Skin biopsy, pus

BAL mandatory

Eosinophilic pneumonia Alveolar Proteinosis

&Probably

Pneumocystis pneumonia

Interstitial lung disease

Non-neutropenic patients

…

Diagnostic strategy

❹ When the ARF etiology remains undetermined

The Price of Undertermined ARF etiology

Authors Reference Population Prevalence Impact on outcomes

Masur Medicine 1991 AIDS / (autopsy study)

Ewig ERJ 1998 Hematology 31% Not evaluated

Gruson ERJ 1999 BMT 58% Increased mortality

Rano Thorax 2001 All IC patients 19% Not evaluated

Rano Chest 2002 All IC patients 22% Increasd mortality if

time to diagnosis > 5d

Danès JCM 2002 All IC patients 16% Not evaluated

Azoulay Medicine 2004 Cancer 21% Increased mortality

Contejean AIC 2016 Hematology 12.9% Increased mortality

Azoulay ICM 2017 All IC patients 13.2% Increased mortality

ARF: Acute Respiratory Failure; HFNC: High Flow Oxygen; NIV: NoninvasiveVentilation

915 (57%)

Azoulay et al. The Efraim Study. Intensive Care Medicine 2017

INTUBATION

MORTALITY

Age

Direct ICU admission

SOFA score at Day 1

P/F ratio

Intubation

Undetermined ARF etiology

Autopsy findings (2003-2018) in 59 AML pts

>50%of patients had missed major diagnoses found at autopsy,

95% of lungs displaying abnormal findings.

In the patients with ARF of unknown etiology (85% without disease control)

- Malignant lung infiltration was 27%

- Bacterial pneumonias (29%),

- Fungal pneumonias 8%,

- isolated alveolar damage or pulmonary edema were the only findings in 32% of patients.

80% of patients with malignant lung infiltration had ARF of unknown etiology.

90% of malignant infiltration and fungal infections if no remission.

EFRAIM II

Microbiota Microbiome

Meta-Omics

Bacteria/Archea/

Protists/Fungi/Viruses

Composition

Genes/enzymes

Diversity

Culture/ uncultured

Microbiota area

Ecological niches

Host

Crosstalk/Network

Metabolites

Metagenome Metatranscriptome Metabolome

DNA/RNA mRNA Metabolites

Vir-OH study: the pre-oMICs era

PCR testing in 747 hematology patientys

Le Goff J, Zucman N, et al. GRRR-OH AJRCCM 2018

Vir-OH study

(Multiplex)

Le Goff J, et al. GRRR-OH AJRCCM 2018

The INDIRA Project:

Less invasive

More performant

Abundant bacterial dominated by a single potential

pathogen detected by RNA sequencing in NPA samples.

Viruses detected by RNA sequencing and/or pan-viral group PCR in

children with pneumonia and asymptomatic control subjects.

NGS <<<PCR : The use of next generation sequencing in the

diagnosis and typing of respiratory infections.

89 nasopharyngeal swabs were tested

A viral pathogen was detected : in 43% of samples by NGS, in 54% by RT-PCR

Thorburn F et al. J Clin Virol. 2015

Acute respiratory infectionsCummings MJ, CID, 2018

Acute respiratory infections with no etiologies – 2010-2015 Ouganda

Infection clusters

Respiratory virus detections / nasopharyngeal swabs

NGS + Capture - oligonucleotide probe capture (VirCapSeq-VERT)

RHV 34,5%CMV 26,9%RSV 17,9%PIV 11,7%

Measles 12,4% We also detected a likely nosocomial SARI cluster associated with a novel picobirnavirus most closely related to swine and

dromedary viruses.

Based on

Host

signature

Three pathways (11 genes) as optimal markers for discriminating bacterial

infection leading to a classifier for bacterial LRTI with 90% (79% CV)

sensitivity and 83% (76% CV) specificity.

94 adults with

LRTI symptoms:

53 “non-

bacterial” / 41

“bacterial”

A streamlined protocol offering 1/ an integrated genomic portrait of

pathogen (metagenomic next-

generation sequencing (mNGS),

2/ airway microbiome,

3/ host transcriptome

Negative pred. value of 100%

Charles Langelier et al. PNAS

2018;115:52:E12353-E12362

Microbial relative abundance

RNAxDNA in Representative cases

Threshold to identify high-scoring taxa

Performance for detecting

pathogens versus commensal

microbiota in both the derivation

and validation cohorts (1000

rounds of training/testing on

randomized sets)

Microbes predicted to

represent putative pathogens

optimized probability

threshold for

pathogen assignment

Algorithmic approach for distinguishing LRTI

pathogens from respiratory commensals

Langelier et al. PNAS 2018;115:52

Clustering of gene expression profiles

based on the microarray result

Principle component analysis

(PCA) of the microarray data

Transcriptome = complete set of

RNA transcripts produced by the

genome (microarray analysis).

Comparison of transcriptomes

allows the identification of genes

that are differentially expressed in

distinct cell populations, or in

response to different treatments.

Azoulay et al. GRRR-OH. AJRCCM 2018

Clinical score for PjPVariables Category N points

Age <50 0

50-70 -1.5

>70 -2.5

Lymphoproliferation +2

No prophylaxis +1

Time from symptoms 3-5 days +3

>5 days +3

Shock -1.5

Interstitial pattern +2.5

Pleural involvement -2

Azoulay et al. GRRR-OH. AJRCCM 2018

The Pneumocystis Score

PjP Score + NGS + transcriptomic biomarkers

Pneumocystis Score

PCR

Pneumocystis

P pneumocystosis

X

XXX

Pjp score

BD glucan

NGS + Transcriptomic

Azoulay et al. Submitted 2019

ARF in Immunocompromised Patients

❺ Stay tuned …

29yo man with refractory ALL (post allo)

Received CAR-T cell therapy

16h following infusion:

Hypotension

SpO2 88 on room air

38°2

ICU admission

Temperature 38°8

Hypotension

DIC

Neutropenia

High Flow Oxygen therapy

50L/Min, 100% FiO2

PaO2 = 88

PaCO2 = 37

pH = 7,48

Chimeric Antigen Receptor (CAR) T-cellTherapy

Adverse effects: CAR T cells are no exception to

the armamentarium of anti-cancer therapies

Grade 3-4 CRS:

15-45%

Grade 3-4 neurotoxicity: 11-28%

Infection ~ 25% HLH

B-cell aplasia and hypogammaglobulinemia ~ 14-43%

Coagulopathy

Tumor lysis syndrome

Cytopenias ~ 20%

Cardiac toxicity (reversible) ~ 25%

GVHD (if prior alloBMT)

Intensive Care Med. 2017 Sep 27.

Save the date: January 6-10, 2020Paris, St-Louis Hospital

Acute Respiratory Failure in Immunocompromised Patients · Immunocompromised Patients ÉlieAzoulay,...

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