Added Diagnostic Utility of Clinical Metagenomics for the Diagnosis of Pneumonia in Immunocompromised Adults

doi:10.1016/j.chest.2020.11.008

Chest

Volume 159, Issue 4, April 2021, Pages 1356-1371

https://doi.org/10.1016/j.chest.2020.11.008 Get rights and content

Background

In the evaluation of community-acquired pneumonia, 30% to 60% of cases remain undiagnosed, despite extensive conventional microbiologic testing (CMT). Clinical metagenomics (CM) is an unbiased pathogen detection method that can increase diagnostic yield.

Research Question

Does adding clinical metagenomics to conventional microbiologic testing improve the diagnostic yield for pneumonia in immunocompromised adults?

Study Design and Methods

We performed a noninterventional prospective study of immunocompromised adults with pneumonia who underwent bronchoscopy and BAL over 2 years. CMT was performed per standard of care. A commercial CM test was performed on residual BAL fluid. Final microbiologic diagnoses were based on CMT vs CMT + CM. Final clinical diagnoses for CMT and CMT + CM were made based on laboratory results in conjunction with clinical and radiologic findings. Hypothetical impact of CMT + CM on management and antimicrobial stewardship was also assessed.

Results

A total of 30 immunocompromised adult patients (31 episodes of pneumonia) were included. Final microbiologic diagnoses were made in 11 cases (35%) with the use of CMT and in 18 cases (58%) with the use of CMT + CM. Bacterial pneumonia was diagnosed in five cases (16%) by CMT and in 13 cases (42%) by CMT + CM; fungal pneumonia was diagnosed in six cases (19%) by CMT and in seven cases (23%) by CMT + CM, and viral pneumonia was diagnosed in two cases (6%) by CMT and in five cases (16%) by CMT + CM. The hypothetical impact of CMT + CM on management was deemed probable in one case, possible in eight cases, and unlikely in two cases, whereas the impact on antimicrobial stewardship was possible in 13 cases and unlikely in seven cases. Final clinical diagnoses were made in 20 of 31 cases (65%) based on CMT and in 23 of 31 cases (74%) based on CMT + CM.

Interpretation

CMT + CM increased diagnostic yield in immunocompromised adults with pneumonia from 35% to 58%, mostly by the detection of additional bacterial causes but was less useful for fungal pneumonia.

Section snippets

Study Design, Population, and Procedures

We performed a prospective observational cohort study of immunocompromised hosts with a clinical syndrome of pneumonia. This pilot study was designed as a noninterventional evaluation of the diagnostic value and hypothetical clinical impact of CMT + CM compared with CMT alone. Immunocompromised adult patients (≥18 years old) who underwent clinically indicated bronchoscopy and BAL for pneumonia were screened prospectively over a 2-year period (2017 to 2019) at Yale New Haven Hospital (New Haven,

Results

A total of 30 immunocompromised patients were enrolled (one patient had two separate admissions for pneumonia [episodes 13 and 19] for 31 observations in total; e-Table 2). Of 30 patients, 16 (53%) were men; 26 (87%) were White, and the median age was 66 years (range, 29 to 89 years). Figure 2 gives underlying immunosuppressive conditions and agents, chest imaging findings, and antimicrobial regimens before bronchoscopy. In all but three subjects, antimicrobials were administered before

Discussion

In this study, we evaluated the diagnostic utility of a commercial BAL metagenomics test in combination with CMT for pneumonia in immunocompromised adult patients who underwent bronchoscopy/BAL. Compared with CMT alone, the addition of BAL CM increased the diagnostic yield of potential pathogens for pneumonia (35% vs 58%). In particular, the addition of CM to CMT lead to improved detection of bacterial organisms including aggressive pathogens that potentially accounted for the patient’s

Acknowledgments

Author contributions: M. A. and C. D. C. conceptualized the study; M. A. wrote the manuscript; R. S., M. M., S. B., T. S S., H. X., C. D. C. reviewed and edited the manuscript; R. S., T. S., and H. X. performed clinical metagenomics testing.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. S. reports personal fees from IDbyDNA Inc during the conduct of the study; grants and personal fees from Roche Molecular Diagnostics, personal fees from Hologic, outside

References (28)

M.L. Fernandez Guerrero et al.
Bacteremic pneumococcal infections in immunocompromised patients without AIDS: the impact of beta-lactam resistance on mortality
Int J Infect Dis
(2003)
H. Masur et al.
The management of pneumonias in immunocompromised patients
JAMA
(1985)
S.E. Evans et al.
Pneumonia in the neutropenic cancer patient
Curr Opin Pulm Med
(2015)
A.B. van Gageldonk-Lafeber et al.
A case-control study of acute respiratory tract infection in general practice patients in The Netherlands
Clin Infect Dis
(2005)
S. Ewig et al.
Factors associated with unknown aetiology in patients with community-acquired pneumonia
Eur Respir J
(2002)
M.M. van der Eerden et al.
Value of intensive diagnostic microbiological investigation in low- and high-risk patients with community-acquired pneumonia
Eur J Clin Microbiol Infect Dis
(2005)
N.J. Gadsby et al.
Comprehensive molecular testing for respiratory pathogens in community-acquired pneumonia
Clin Infect Dis
(2016)
M.M. Azar et al.
Gomori methenamine silver stain on bronchoalveolar lavage fluid is poorly sensitive for diagnosis of pneumocystis jiroveci pneumonia in HIV-negative immunocompromised patients and may lead to missed or delayed diagnoses
Arch Pathol Lab Med
(2020)
K.A. Marr et al.
Design issues in studies evaluating diagnostic tests for aspergillosis
Clin Infect Dis
(2005)
N. Singh et al.
Performance characteristics of galactomannan and beta-d-glucan in high-risk liver transplant recipients
Transplantation
(2015)

K.A. Marr et al.

Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance

J Infect Dis

(2004)

N. Johansson et al.

Etiology of community-acquired pneumonia: increased microbiological yield with new diagnostic methods

Clin Infect Dis

(2010)

C.H. Heath et al.

Delay in appropriate therapy of Legionella pneumonia associated with increased mortality

Eur J Clin Microbiol Infect Dis

(1996)

R. Schlaberg et al.

Validation of metagenomic next-generation sequencing tests for universal pathogen detection

Arch Pathol Lab Med

(2017)

Cited by (20)

A Diagnostic Approach to Fungal Pneumonia: An Infectious Diseases Perspective
2024, Chest
Although bacteria significantly exceed fungi as the most common cause of lower respiratory tract infection, the incidence of fungal pneumonia is increasing because of a growing at-risk population of immunocompromised individuals as well as anthropogenic global heating and environmental disruption. When a patient presents with a clinical syndrome of pneumonia, a constellation of factors must be considered to determine the probability of a fungal pneumonia, including host factors, epidemiologic exposures, suggestive radiographic patterns, and the presence of a non-resolving pneumonia. In addition, knowledge of clinically important fungal pathogens, their epidemiology, and associated clinical syndromes are key in guiding appropriate diagnostic testing and result interpretation, and ultimately rendering a correct diagnosis of a fungal pneumonia. This article aims to provide a framework for the evaluation and appropriate diagnostic testing of patients with suspected fungal pneumonia.
Evaluation of the Diagnostic Performance of Plasma Metagenomic Next-Generation Sequencing in Febrile Events in the First 30 Days after Chimeric Antigen Receptor T Cell Infusion
2023, Transplantation and Cellular Therapy
Chimeric antigen receptor-modified T cell (CAR-T) therapy is a promising novel immunotherapy for hematologic malignancies, and the diagnosis of infection after CAR-T infusion (CTI) presents challenges for clinicians. Plasma metagenomic next-generation sequencing (mNGS) has been shown to be a reliable diagnostic approach for infection, especially in immunocompromised patients. We aimed to investigate the diagnostic performance of plasma mNGS for infection in the first 30 days after CTI. A cohort of 153 patients who experienced a total of 170 febrile events during the first 30 days post-CTI were enrolled. Of these events, 51 were evaluated with both mNGS and CDM and 119 were assessed by conventional detection methods (CDM) only. We also explored the epidemiology of infections and differences in infection complications in cases with severe (>2) and moderate (≤2) cytokine release syndrome (CRS). Cases with febrile events were clinically divided into an infection group (IG) (95 of 170; 55.9%) and a noninfection group (NIG) (75 of 170; 44.1%). The sensitivity and specificity of mNGS for the diagnosis of infectious complications in the first 30 days after CTI were 69.2% and 89.2%, respectively, with the sensitivity superior to that of culture (P < .001). More infection cases assessed with both mNGS and CDM than those assessed with CDM only were laboratory-confirmed (63.9% versus 11.9%; P < .001). The serum C-reactive protein level was higher and the IFN-γ level was lower in the IG group, particularly in cases with CRS grade ≤2. Infection is a common complication in the first 30 days after CTI. The addition of mNGS to CDM improved the diagnostic yield, and mNGS showed relatively high sensitivity and specificity in post-CAR-T therapy febrile events.
A consensus conference to define the utility of advanced infectious disease diagnostics in solid organ transplant recipients
2022, American Journal of Transplantation
The last decade has seen an explosion of advanced assays for the diagnosis of infectious diseases, yet evidence-based recommendations to inform their optimal use in the care of transplant recipients are lacking. A consensus conference sponsored by the American Society of Transplantation (AST) was convened on December 7, 2021, to define the utility of novel infectious disease diagnostics in organ transplant recipients. The conference represented a collaborative effort by experts in transplant infectious diseases, diagnostic stewardship, and clinical microbiology from centers across North America to evaluate current uses, unmet needs, and future directions for assays in 5 categories including (1) multiplex molecular assays, (2) rapid antimicrobial resistance detection methods, (3) pathogen-specific T-cell reactivity assays, (4) next-generation sequencing assays, and (5) mass spectrometry-based assays. Participants reviewed and appraised available literature, determined assay advantages and limitations, developed best practice guidance largely based on expert opinion for clinical use, and identified areas of future investigation in the setting of transplantation. In addition, attendees emphasized the need for well-designed studies to generate high-quality evidence needed to guide care, identified regulatory and financial barriers, and discussed the role of regulatory agencies in facilitating research and implementation of these assays. Findings and consensus statements are presented.
Metagenomics for Diagnosis of Complex Infections: A Prospective Multicenter Study
2024, SSRN
Serial Quantitation of Plasma Microbial Cell-Free DNA Before and After Diagnosis of Pulmonary Invasive Mold Infections After Hematopoietic Cell Transplant
2024, Journal of Infectious Diseases
Severe Community-Acquired Pneumonia in Immunocompromised Patients
2024, Seminars in Respiratory and Critical Care Medicine

View all citing articles on Scopus

: FUNDING/SUPPORT: This work was supported by the institutional funds supporting the Center for Pulmonary Infection Research and Treatment at Yale which covered the recruitment collection and operational costs of the study and by IDbyDNA, which provided Explify CM testing and results.

View full text

Chest

Chest Infections: Original ResearchAdded Diagnostic Utility of Clinical Metagenomics for the Diagnosis of Pneumonia in Immunocompromised Adults

Background

Research Question

Study Design and Methods

Results

Interpretation

Section snippets

Study Design, Population, and Procedures

Results

Discussion

Acknowledgments

Int J Infect Dis

The management of pneumonias in immunocompromised patients

JAMA

Pneumonia in the neutropenic cancer patient

Curr Opin Pulm Med

A case-control study of acute respiratory tract infection in general practice patients in The Netherlands

Clin Infect Dis

Factors associated with unknown aetiology in patients with community-acquired pneumonia

Eur Respir J

Value of intensive diagnostic microbiological investigation in low- and high-risk patients with community-acquired pneumonia

Eur J Clin Microbiol Infect Dis

Comprehensive molecular testing for respiratory pathogens in community-acquired pneumonia

Clin Infect Dis

Gomori methenamine silver stain on bronchoalveolar lavage fluid is poorly sensitive for diagnosis of pneumocystis jiroveci pneumonia in HIV-negative immunocompromised patients and may lead to missed or delayed diagnoses

Arch Pathol Lab Med

Design issues in studies evaluating diagnostic tests for aspergillosis

Clin Infect Dis

Performance characteristics of galactomannan and beta-d-glucan in high-risk liver transplant recipients

Transplantation

Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance

J Infect Dis

Etiology of community-acquired pneumonia: increased microbiological yield with new diagnostic methods

Clin Infect Dis

Delay in appropriate therapy of Legionella pneumonia associated with increased mortality

Eur J Clin Microbiol Infect Dis

Validation of metagenomic next-generation sequencing tests for universal pathogen detection

Arch Pathol Lab Med

Chest Infections: Original Research
Added Diagnostic Utility of Clinical Metagenomics for the Diagnosis of Pneumonia in Immunocompromised Adults