Cryptococcal Immune Reconstitution Inflammatory Syndrome: From Blood and Cerebrospinal Fluid Biomarkers to Treatment Approaches

Brienze, Vânia Maria Sabadoto; André, Júlio César; Liso, Elisabéte; Louis, Irina Vlasova-St.

doi:10.3390/life11020095

Cited by 15 publications

(16 citation statements)

References 142 publications

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“…Transcriptome analysis of hosts' diseased tissues has been an integral part of the discovery of immune response biomarkers. University of Minnesota Division of Infectious Diseases (USA) leads intensive transcriptomic studies for discoveries of novel biomarkers of immune reconstitution inflammatory syndrome (IRIS) in the HIV-infected population [105,106]. IRIS presents as an exaggerated immune reaction (in a form of cytokine release syndrome) that occurs in immunocompromised patients who have commenced antiretroviral treatments (ART) [106].…”

Section: Assessment Of Host Response By Rna-seqmentioning

confidence: 99%

“…University of Minnesota Division of Infectious Diseases (USA) leads intensive transcriptomic studies for discoveries of novel biomarkers of immune reconstitution inflammatory syndrome (IRIS) in the HIV-infected population [105,106]. IRIS presents as an exaggerated immune reaction (in a form of cytokine release syndrome) that occurs in immunocompromised patients who have commenced antiretroviral treatments (ART) [106]. Several predictive and diagnostic biomarkers have already been identified in peripheral blood, utilizing Galaxy, JMP Genomics, or Partek Flow software (Figure 1).…”

Section: Assessment Of Host Response By Rna-seqmentioning

confidence: 99%

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Diagnostic Applications for RNA-Seq Technology and Transcriptome Analyses in Human Diseases Caused by RNA Viruses

Louis¹,

Gorzalski²,

Pandori³

2021

Applications of RNA-Seq in Biology and Medicine

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Human diseases caused by single-stranded, positive-sense RNA viruses, are among the deadliest of the 21st Century. In particular, there are two notable standouts: human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Detection of these disease-causing viral transcripts, by next-generation RNA sequencing (RNA-Seq), represents the most immediate opportunity for advances in diagnostic, therapeutic, and preventive applicability in infectious diseases (e.g., AIDS and COVID-19). Moreover, RNA-Seq technologies add significant value to public health studies by first, providing real-time surveillance of known viral strains, and second, by the augmentation of epidemiological databases, construction of annotations and classifications of novel sequence variants. This chapter intends to recapitulate the current knowledge of HIV and SARS-CoV-2 transcriptome architecture, pathogenicity, and some features of the host immune response. Additionally, it provides an overview of recent advances in diagnostic sequencing methodologies and discusses the future challenges and prospects on the utilization of RNA-Seq technologies.

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Section: Assessment Of Host Response By Rna-seqmentioning

confidence: 99%

Section: Assessment Of Host Response By Rna-seqmentioning

confidence: 99%

Diagnostic Applications for RNA-Seq Technology and Transcriptome Analyses in Human Diseases Caused by RNA Viruses

Louis¹,

Gorzalski²,

Pandori³

2021

Applications of RNA-Seq in Biology and Medicine

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“… 3 It has been reported that approximately 25% of HCM patients develop CM-IRIS in the first 4 months of ART, with an average mortality of 20 ± 10%. 4 Thus, an effective treatment for IRIS would be helpful to decrease the likelihood of cognitive impairment.…”

Section: Introductionmentioning

confidence: 99%

Outcome of Lenalidomide Treatment for Cognitive Impairment Caused by Immune Reconstitution Inflammatory Syndrome in Patients with HIV-Related Cryptococcal Meningitis

Tao¹,

Peng²,

Liu³

et al. 2022

JIR

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Purpose Cognitive impairment associated with human immunodeficiency virus (HIV)-related cryptococcal meningitis (HCM) in the context of immune reconstitution inflammatory syndrome is difficult to address. This study was a follow-up of lenalidomide treatment outcomes in patients with HCM and cognitive impairment after complete cryptococcal clearance. Patients and Methods Seven HCM patients with neuroinflammation and cognitive impairment after complete cryptococcal clearance were enrolled in this prospective study. Neurocognitive assessment, clinical examination and cerebrospinal fluid (CSF) assays were performed before and after lenalidomide treatment. Results After lenalidomide treatment, the Montreal Cognitive Assessment [week (W) 0 (median [interquartile range]: 23.0 (13.0–24.0) vs W24: 26.0 (24.0–28.00), P=0.018] and International HIV Dementia Scale scores [W0: 9.0 (2.5–10.5) vs W24: 11.0 (10.00–12.0), P=0.028] improved significantly, mainly in the domain of memory function. There was no significant difference in the Center for Epidemiological Research Depression scores for anxiety and depression before and after treatment. Further stratified analyses revealed that the patients with cognitive improvement group had higher levels of CSF white blood cells [94.0 (44.0–180.0) vs 0 (0–1.5), P=0.032], CSF protein [4.9 (3.0–6.6) vs 0.6 (0.5–0.7), P=0.034], CSF albumin [318.5 (190.9–346.5) vs 33.5 (30.4–46.2), P=0.034], and CSF IgG [160.5 (73.8–256. 0) vs 4.7 (4.3–7.4), P=0.034] but a lower CSF glucose level [2.4 (2.0–2.7) vs 2.8 (2.8–3.9), P=0.032] than the patients with cognitive non-improvement group before treatment. CSF inflammatory cytokines of the growth-related oncogene, interleukin [IL]-10, granulocyte-colony stimulating factor, IL-6, IL-8, complement factor H, tumor necrosis factor-α, and α-2 macroglobulin were obviously decreased in patients with cognitive improvement group after lenalidomide treatment. Conclusion Lenalidomide potentially reduces cognitive impairment caused by immune reconstitution inflammatory syndrome in patients with HCM after cryptococcal clearance by inhibiting intracranial inflammation.

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“…Previous studies showed that this phenomenon occurs because of persistent intracranial in ammation mediated brain injury [9].Despite the ART, the residual low levels of viral replication from HIV latent reservoirs and the subsequent antiviral immune response may be the cause of sustained immune activation in the central nervous system (CNS) [10].Subsequently, the positive feedback loop of immunemediated tissue damage and repair processes can lead to persistent chronic CNS in ammation [9].On the one hand, chronic CNS in ammation caninduce neuronal insults, leading to cognitive dysfunction [11],and on another hand, continuous intracranial in ammation can lead to increased intracranial pressure and brain oedema, thereby increasing the risk of seizures and brain herniation [12].Therefore, safe and effective interventions are urgently needed for these patients to manage persistent intracranial in ammation to improve their clinical outcomes.Mechanismstudies suggest thatthepersistent intracranial in ammationare characterized by high levels of CSF T helper1 (Th1)associated proin ammatory cytokines suchasinterferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), granulocyte colony-stimulating factor (G-CSF) and interleukin(IL)-6 [13,14]. Thus, anti-in ammatory or immunomodulatory methods have become the primarytherapy options for persistent intracranial in ammation.Several case reports documented neurological improvement after the use of immunosuppressive drug corticosteroids, hydroxychloroquine thalidomide and adalimumab [15]. However, due to the lack of prospective clinical trial data and the small number of patients treated, it is not yet su cient to judge the e cacy and safety of the above immune modulators [16].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Lenalidomide in HIV-associated Cryptococcal Meningitis (HIV-CM) Patients with Persistent Intracranial Inflammation： An Open-label, Single-arm Prospective Cohort Study

Tao

Wan

Hui

et al. 2022

Preprint

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Background Several HIV-associated cryptococcal meningitis (HIV-CM) patients were found to have persistent intracranial inflammation despite negative Cerebrospinal fluid (CSF) fungal cultures after being optimally treated for CM, which could be devastating for the central nervous system. However, there is no definitive treatment strategy for this condition. Method We identified 14 HIV-CM patients with persistent intracranial inflammation and conducted a 24 weeks, prospective cohort study. All participants received oral lenalidomide 25 mg on days 1 to 21 of a 28-day cycle. The follow-up lasted for 24 weeks with visits performed at the baseline, week 4,8,12,24. The primary endpoint was the efficacy of lenalidomide therapy which was determined by the clinical manifestations, the changes in routine CSF parameters, and radiological findings within 24 weeks post-treatment. In addition, an exploratory analysis was made on the changes of CSF cytokine. Safety and efficacy analysis was performed in patients who received at least one dose of lenalidomide. Results Of the 14 participants, 11 patients completed the 24 weeks of follow-up. it was observed that rapid clinical remission followed lenalidomide therapy, clinical presentation such as fever, headache, and cognitive impairment was fully recovered at week 4 and remained stable during follow-up. And a significant reduction of CSF white blood cell (WBC) count occurred at week 4 [Median count 3.00×10 6 /L (IQR 0-45.00 P=0.009)] from baseline [35×10 6 /L (IQR 4.50 to 90.00)]. Median CSF protein concentration decreased from 1.39 g/L (IQR 0.74-3.23) at baseline to 0.91 g/L (IQR 0.63-1.41) at week 4 (P=0.004). CSF WBC count, CSF protein remained stable and approached the normal range through week 24. And after the 24‐week lenalidomide therapy, CSF IgG levels were also decreased, though not statistically significant. Brain MRI demonstrated that the multiple lesions were also absorbed post-therapy. In addition, it was observed that TNF-α G-CSF, IL-6, IL-17A decreased significantly during the 24-week follow-up. 2(14.3%) patients had a mild skin rash, which resolved spontaneously without drug interruption. No study drug-related serious adverse events were observed and no patient withdrew from therapy because of unacceptable toxicity. Conclusion Our study found that lenalidomide can significantly improve persistent intracranial inflammation of HIV-CM patients and have well tolerance and without notable side effects.

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Cryptococcal Immune Reconstitution Inflammatory Syndrome: From Blood and Cerebrospinal Fluid Biomarkers to Treatment Approaches

Cited by 15 publications

References 142 publications

Diagnostic Applications for RNA-Seq Technology and Transcriptome Analyses in Human Diseases Caused by RNA Viruses

Diagnostic Applications for RNA-Seq Technology and Transcriptome Analyses in Human Diseases Caused by RNA Viruses

Outcome of Lenalidomide Treatment for Cognitive Impairment Caused by Immune Reconstitution Inflammatory Syndrome in Patients with HIV-Related Cryptococcal Meningitis

Efficacy and Safety of Lenalidomide in HIV-associated Cryptococcal Meningitis (HIV-CM) Patients with Persistent Intracranial Inflammation： An Open-label, Single-arm Prospective Cohort Study

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