Clinical Application of Metagenomic Next-Generation Sequencing for Suspected Infections in Patients With Primary Immunodeficiency Disease.

Wenjing Tang,Zhiyong Zhang,Xiaodong Zhao,Chong Luo,Yunfei An,Yu Zhang,Lina Zhou,Xuemei Tang

doi:10.3389/fimmu.2021.696403

Abstract

BackgroundInfections are the major cause of morbidity and mortality in patients with primary immunodeficiency disease (PID). Timely and accurate microbiological diagnosis is particularly important in these patients. Metagenomic next-generation sequencing (mNGS) has been used for pathogen detection recently. However, few reports describe the use of mNGS for pathogen identification in patients with PID.ObjectiveTo evaluate the utility of mNGS for detecting pathogens in patients with PID, and to compare it with conventional microbiological tests (CMT).MethodsThis single center retrospective study investigated the diagnostic performance of mNGS for pathogens detection in PID patients and compared it with CMT. Sixteen PID patients with suspected infection were enrolled, and medical records were analyzed to extract detailed clinical characteristics such as gene variation, immune status, microbial distribution, time-consuming of mNGS and CMT, treatment, and outcomes.ResultsmNGS identified pathogenic microbe in 93.75% samples, compared to 31.25% for culture and 68.75% for conventional methods, and detected an extra 18 pathogenic microorganisms including rare opportunistic pathogens and Mycobacterium tuberculosis. Pathogen identification by mNGS required 48 hours, compared with bacterial culture for 3-7 days and even longer for fungus and Mycobacterium tuberculosis culture.ConclusionsmNGS has marked advantages over conventional methods for pathogenic diagnosis, particularly opportunistic pathogens and mixed infections, in patients with PID. This method might enable clinicians to make more timely and targeted therapeutic decisions, thereby improving the prognosis of these patients.

Highlights

Primary immunodeficiency disease (PID) or inborn errors of immunity are caused by monogenic mutations, resulting in lossor gain-of-function of the encoded protein
Specific primary diseases were as follows: X-linkedhyper IgM syndrome (XHIM) caused by a CD40LG mutation (n=4, P1 to P4); Wiskott-Aldrich syndrome (WAS) caused by a WASP mutation (n=2, P5 and P6); CTLA4 deficiency(P7); PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome (PAMI) caused by a PSTPIP1 mutation (P8); X-linked lymphoproliferative disease (XLP) caused by a SH2D1A mutation (P9); NEMO deficiency caused by a IKBKG mutation (P10); chronic granulomatous disease (CGD) caused by a CYBB mutation (n=2, P11 and P12); Artemis deficiency caused by a DCLRE1C mutation (P13); Mendelian susceptibility to mycobacterial disease (MSMD) caused by a STAT1 AD loss-offunction mutation (P14); X-linked agammaglobulinemia (XLA) caused by a BTK mutation (P15); and activated phosphoinositide 3-kinase-d syndrome (APDS) caused by a PIK3CD AD GOF mutation (P16)
The basic information, including age, gender, infection data, immunological characteristics, and gene variation are shown in Supplementary Table 1

Summary

Introduction

Primary immunodeficiency disease (PID) or inborn errors of immunity are caused by monogenic mutations, resulting in lossor gain-of-function of the encoded protein. They manifest as increased susceptibility to infectious diseases, as well as a growing diversity of autoimmune, autoinflammatory, allergic, lymphoproliferative, and/or malignant phenotypes. A report from France shows that 85% of non-transplant PID patients were admitted to hospital related to acute infections [3]. And effective anti-infection therapy is of great importance for reducing infection mortality and improving transplant success rates in PID patients. Infections are the major cause of morbidity and mortality in patients with primary immunodeficiency disease (PID). Few reports describe the use of mNGS for pathogen identification in patients with PID

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Conclusion