Manish Butte

BMC Pediatr. 2021 Sep 18;21(1):411. doi: 10.1186/s12887-021-02879-7.

ABSTRACT

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is an exaggerated inflammatory reaction secondary to a host’s inadequate immune response causing a self-perpetuating loop of altered regulation. Signs and symptoms of HLH are compatible with other common diseases and are nonspecific. Underdiagnosis makes it difficult to estimate the real incidence of HLH, especially in developing countries.

METHODS: Retrospective, descriptive study of pediatric patients admitted to a high-complexity institution in Cali, Colombia between 2012 and 2019 with HLH diagnosis. Medical history review to complete an electronic database and a secondary, descriptive analysis was carried out. The study was approved by the Institutional Ethics Committee.

RESULTS: Twenty-one patients were included. 52.4 % of the population was male with a median age of 9.3 years [IQR (3.0-13.7 years)]. More than half of patients (66.6 %) had viral disease at diagnosis, the most frequent being Epstein-Barr Virus (EBV) (52.3 %) and dengue (14.3 %). Three patients had confirmed gene mutations (G6PC3, XIAP, and UNC13D). 95 % of the patients were treated with the HLH 2004 protocol, half of them received incomplete protocol with intravenous immunoglobulin (IVIG) and/or systemic steroids, while the other half received the complete protocol including etoposide and cyclosporine. More than three-fourths (76.2 %) required admission to an ICU with a median stay of 14 days [IQR (11-37 days)] and a median hospital stay of 30 days [IQR (18-93 days)]. 14.3 % (n = 3) of patients died.

CONCLUSIONS: HLH is a complex disease that requires multidisciplinary management with secondary HLH due to EBV infection being a common cause. There is increasing awareness of HLH diagnosis in developing countries such as Colombia which can offer earlier treatment options and better outcomes.

PMID:34537050 | DOI:10.1186/s12887-021-02879-7

J Allergy Clin Immunol. 2021 Sep 15:S0091-6749(21)01394-4. doi: 10.1016/j.jaci.2021.08.023. Online ahead of print.

NO ABSTRACT

PMID:34536417 | DOI:10.1016/j.jaci.2021.08.023

Crit Care Med. 2021 Sep 16. doi: 10.1097/CCM.0000000000005270. Online ahead of print.

ABSTRACT

OBJECTIVES: The host response plays a central role in the pathophysiology of sepsis and severe injuries. So far, no study has comprehensively described the overtime changes of the injury-induced immune profile in a large cohort of critically ill patients with different etiologies.

DESIGN: Prospective observational cohort study.

SETTING: Adult ICU in a University Hospital in Lyon, France.

PATIENTS: Three hundred fifty-three septic, trauma, and surgical patients and 175 healthy volunteers were included in the REAnimation Low Immune Status Marker study.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: Extensive immune profiling was performed by assessing cellular phenotypes and functions, protein, and messenger RNA levels at days 1-2, 3-4, and 5-7 after inclusion using a panel of 30 standardized immune markers. Using this immunomonitoring panel, no specificity in the immune profile was observed among septic, trauma, and surgical patients. This common injury-induced immune response was characterized by an initial adaptive (i.e., physiologic) response engaging all constituents of the immune system (pro- and anti-inflammatory cytokine releases, and innate and adaptive immune responses) but not associated with increased risk of secondary infections. In contrary, the persistence in a subgroup of patients of profound immune alterations at the end of the first week after admission was associated with increased risk of secondary infections independently of exposure to invasive devices. The combined monitoring of markers of pro-/anti-inflammatory, innate, and adaptive immune responses allowed a better enrichment of patients with risk of secondary infections in the selected population.

CONCLUSIONS: Using REAnimation Low Immune Status Marker immunomonitoring panel, we detected delayed injury-acquired immunodeficiency in a subgroup of severely injured patients independently of primary disease. Critically ill patients’ immune status could be captured through the combined monitoring of a common panel of complementary markers of pro-/anti-inflammatory, innate, and adaptive immune responses. Such immune monitoring needs to be incorporated in larger study cohorts with more extensive immune surveillance to develop specific hypothesis allowing for identification of biological systems affecting altered immune function related to late infection in the setting of acute systemic injury.

PMID:34534131 | DOI:10.1097/CCM.0000000000005270

PeerJ. 2021 Aug 27;9:e12091. doi: 10.7717/peerj.12091. eCollection 2021.

ABSTRACT

Stromal cell-derived factor-1 (SDF-1) and Exendin-4 (EX-4) play beneficial roles in promoting periodontal ligament stem cells (PDLSCs) osteogenic differentiation, while the detailed mechanism has not been clarified. In this study, we aimed to evaluate the biological mechanism of SDF-1 and EX-4 alone or synergistic application in regulating PDLSCs differentiation by RNA-sequencing (RNA-seq). A total of 110, 116 and 109 differentially expressed genes (DEGs) were generated in osteogenic medium induced PDLSCs treated by SDF-1, EX-4, and SDF-1+EX-4, respectively. The DEGs in SDF-1 group were enriched in signal transduction related signaling pathways; the DEGs in EX-4 group were enriched in metabolism and biosynthesis-related pathways; and the DEGs generated in SDF-1+EX-4 group were mainly enriched in RNA polymerase II transcription, cell differentiation, chromatin organization, protein phosphorylation pathways. Based on Venn analysis, a total of 37 specific DEGs were identified in SDF-1+EX-4 group, which were mainly enriched in negative regulation of autophagy and cellular component disassembly signaling pathways. Short time-series expression miner (STEM) analysis grouped all expressed genes of PDLSCs into 49 clusters according to the dynamic expression patterns and 25 genes, including NRSN2, CHD9, TUBA1A, distributed in 10 gene clusters in SDF-1+EX-4 treated PDLSCs were significantly up-regulated compared with the SDF-1 and EX-4 alone groups. The gene set enrichment analysis indicated that SDF-1 could amplify the role of EX-4 in regulating varied signaling pathways, such as type II diabetes mellitus and insulin signaling pathways; while EX-4 could aggravate the effect of SDF-1 on PDLSCs biological roles via regulating primary immunodeficiency, tight junction signaling pathways. In summary, our study confirmed that SDF-1 and EX-4 combined application could enhance PDLSCs biological activity and promote PDLSCs osteogenic differentiation by regulating the metabolism, biosynthesis and immune-related signaling pathways.

PMID:34532163 | PMC:PMC8404574 | DOI:10.7717/peerj.12091

BMJ Case Rep. 2021 Sep 14;14(9):e244768. doi: 10.1136/bcr-2021-244768.

ABSTRACT

SARS-CoV-2 infection in children with primary immunodeficiency disease (PID) and its complications have not yet been well described, the course of COVID-19 can range from mild illness to death. We aim to report the case of a child with a PID who develop a severe and persistent pulmonary COVID-19 infection. We present chronologically his clinical course, tests, interventions and radiological findings showing his irregular evolution and poor response to infection. This case highlights the need to accurately monitor the immune response in these cases to try to stop the progression of the damage.

PMID:34521740 | DOI:10.1136/bcr-2021-244768

Autophagy. 2021 Sep 14:1-16. doi: 10.1080/15548627.2021.1968607. Online ahead of print.

ABSTRACT

Mutations in the macroautophagy/autophagy gene EPG5 are responsible for Vici syndrome, a human genetic disease characterized by combined immunodeficiency. Previously, we found that epg5^-/- mice exhibit hyperinflammation in the lungs mediated by IL1B/IL-1β and TNF/TNFα, resulting in resistance to influenza. Here, we find that disruption of Epg5 results in protection against multiple enteric viruses including norovirus and rotavirus. Gene expression analysis reveals IFNL/IFN-λ responsive genes as a key alteration. Further, mice lacking Epg5 exhibit substantial alterations of the intestinal microbiota. Surprisingly, germ-free mouse studies indicate Epg5-associated inflammation of both the intestine and lung is microbiota-independent. Genetic studies support IFNL signaling as the primary mediator of resistance to enteric viruses, but not of microbial dysbiosis, in epg5^-/- mice. This study unveils an important role, unexpectedly independent of the microbiota, for autophagy gene Epg5 in host organism protection by modulating intestinal IFNL responses.Abbreviations: CTNNB1: catenin (cadherin associated protein), beta 1; DAPI: 4′,6-diamidino-2-phenylindole; EPG5: ectopic P-granules autophagy protein 5 homolog (C. elegans); FT: fecal transplant; IFI44: interferon-induced protein 44; IFIT1: interferon-induced protein with tetratricopeptide repeats 1; IFNG/IFN-γ: interferon gamma; IFNL/IFN-λ: interferon lambda; IFNLR1: interferon lambda receptor 1; IL1B/IL-1β: interleukin 1 beta; ISG: interferon stimulated gene; GF: germ-free; LEfSe: linear discriminant analysis effect size; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MNoV: murine norovirus; MX2: MX dynamin-like GTPase 2; OAS1A: 2′-5′ oligoadenylate synthetase 1A; RV: rotavirus; SPF: specific-pathogen free; SQSTM1/p62: sequestosome 1; STAT1: signal transducer and activator of transcription 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK-binding kinase 1; TNF/TNFα: tumor necrosis factor.

PMID:34520306 | DOI:10.1080/15548627.2021.1968607

BMC Immunol. 2021 Sep 13;22(1):62. doi: 10.1186/s12865-021-00452-6.

ABSTRACT

BACKGROUND: Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a primary immunodeficiency (PID) characterised by a predisposition to infection by weakly-pathogenic mycobacteria. In countries with a high prevalence of tuberculosis (TB), individuals with MSMD are also prone to infections by Mycobacterium tuberculosis. Several MSMD-associated genes have been described, all resulting in a disruption of IL-12 and IFN-γ cytokine axis, which is essential for control of mycobacterial infections. An accurate molecular diagnosis, confirmed by phenotypic and functional immune investigations, is essential to ensure that the patient receives optimal treatment and prophylaxis for infections. The aim of this study was to implement a set of functional assays to assess the integrity of the IL-12-IFN-γ cytokine pathways in patients presenting with severe, persistent, unusual and/or recurrent TB, mycobacterial infections or other clinical MSMD-defining infections such as Salmonella.

METHODS: Blood was collected for subsequent PBMC isolation from 16 participants with MSMD-like clinical phenotypes. A set of flow cytometry (phenotype and signalling integrity) and ELISA-based (cytokine production) functional assays were implemented to assess the integrity of the IL-12-IFN-γ pathway.

RESULTS: The combination of the three assays for the assessment of the integrity of the IL-12-IFN-γ pathway was successful in identifying immune deficits in the IL-12-IFN-γ pathway in all of the participants included in this study.

CONCLUSIONS: The data presented here emphasise the importance of investigating PID and TB susceptibility in TB endemic regions such as South Africa as MSMD and other previously described PIDs relating to TB susceptibility may present differently in such regions. It is therefore important to have access to in vitro functional investigations to better understand the immune function of these individuals. Although functional assays alone are unlikely to always provide a clear diagnosis, they do give an overview of the integrity of the IL-12-IFN-γ pathway. It would be beneficial to apply these assays routinely to patients with suspected PID relating to mycobacterial susceptibility. A molecular diagnosis with confirmed functional impairment paves the way for targeted treatment and improved disease management options for these patients.

PMID:34517836 | DOI:10.1186/s12865-021-00452-6

J Clin Exp Hematop. 2021 Sep 10. doi: 10.3960/jslrt.21003. Online ahead of print.

ABSTRACT

The programmed cell death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in tumor cell escape from immune control and has been most extensively investigated for therapeutic purposes. However, PD-L1 immunohistochemistry is still not used widely for diagnosis. We review the diagnostic utility of PD-L1 (by clone SP142) immunohistochemistry in large-cell lymphomas, mainly consisting of classic Hodgkin lymphoma (CHL) and diffuse large B-cell lymphoma (DLBCL). Neoplastic PD-L1 (nPD-L1) expression on Hodgkin and Reed-Sternberg cells is well-established among prototypic CHL. Of note, EBV+ CHL often poses a challenge for differential diagnosis from peripheral T-cell lymphoma with EBV+ non-malignant large B-cells; their distinction is based on the lack of PD-L1 expression on large B-cells in the latter. The nPD-L1 expression further provides a good diagnostic consensus for CHL with primary extranodal disease conceivably characterized by a combined pathogenesis of immune escape of tumor cells and immunodeficiency. Compared with CHL, the nPD-L1 expression rate is much lower in DLBCL, highlighting some specific subgroups of intravascular large B-cell lymphoma, primary mediastinal large B-cell lymphoma, and EBV+ DLBCL. They consist of nPD-L1-positive and -negative subgroups, but their clinicopathological significance remains to be elucidated. Microenvironmental PD-L1 positivity on immune cells may be associated with a favorable prognosis in extranodal DLBCL. PD-L1 (by SP142) immunohistochemistry has helped us to understand the immune biology of lymphoid neoplasms possibly related by immune escape and/or immunodeficiency. However, knowledge of these issues remains limited and should be clarified for diagnostic consensus in the future.

PMID:34511582 | DOI:10.3960/jslrt.21003

J Clin Med. 2021 Aug 25;10(17):3809. doi: 10.3390/jcm10173809.

ABSTRACT

Selective IgA deficiency (sIgAD) is the most common primary immunodeficiency disease (PID), with an estimated occurrence from about 1:3000 to even 1:150, depending on population. sIgAD is diagnosed in adults and children after the 4th year of age, with immunoglobulin A level below 0.07 g/L and normal levels of IgM and IgG. Usually, the disease remains undiagnosed throughout the patient’s life, due to its frequent asymptomatic course. If symptomatic, sIgAD is connected to more frequent viral and bacterial infections of upper respiratory, urinary, and gastrointestinal tracts, as well as autoimmune and allergic diseases. Interestingly, it may also be associated with other PIDs, such as IgG subclasses deficiency or specific antibodies deficiency. Rarely sIgAD can evolve to common variable immunodeficiency disease (CVID). It should also be remembered that IgA deficiency may occur in the course of other conditions or result from their treatment. It is hypothesized that allergic diseases (e.g., eczema, rhinitis, asthma) are more common in patients diagnosed with this particular PID. Selective IgA deficiency, although usually mildly symptomatic, can be difficult for clinicians. The aim of the study is to summarize the connection between selective IgA deficiency and atopic diseases.

PMID:34501259 | DOI:10.3390/jcm10173809

Pediatr Pulmonol. 2021 Sep 9. doi: 10.1002/ppul.25657. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary involvement which can be infectious or noninfectious is one of the most frequent complications in patients with primary immunodeficiency (PID).

OBJECTIVE: The aim of this study is to assess the pulmonary system of the pediatric patients with PID and report the demographical, clinical, and radiological findings regarding the underlying PID.

METHODS: The present study included pediatric patients who were receiving immunoglobulin replacement therapy (IGRT) for PID (combined immunodeficiency [CVID] (23), common variable immunodeficiency (15), and agamaglobulinemia [10]) so far or newly diagnosed and started IGRT at Hacettepe University Immunology Department, between January 2015 and January 2018.

RESULTS: A total of 48 patients (60.4% male), aged 9.9 (6.1-14) years were included. Time of delay in the diagnosis of immundeficiency was 2.27 (interquartile range: 1.0-6.75) years. CVID patients exhibited higher respiratory system symptoms, as well as a history of recurrent lung infection and hospitalization. Hilar and mediastinal lymphadenopathies, peribronchial thickening, and bronchiectasis were the most common pulmonary complications and more than three lung lobes were affected in 69%. Among the newly diagnosed patients, bronchiectasis was present in 25% and more than three lobes were affected in 62.5%. Although pulmonary nodules and mediastinal lymphadenopathy were frequently computed tomography findings in our patients, only two patients (4.16%) were diagnosed with interstitial lung disease.

CONCLUSION: Although bronchiectasis is predominantly reported as a long-term complication in adult patients with PID, half of our pediatric patient cohort with PID had bronchiectasis, even the newly diagnosed patients. Long-term follow-up is needed to assess the extent to which these pulmonary complications that develop in the natural course of the disease can be prevented by IGRT.

PMID:34499824 | DOI:10.1002/ppul.25657