Paradoxical Immune Reconstitution Inflammatory Syndrome Research Articles

Lymph node tuberculosis‐associated paradoxical immune reconstitution inflammatory syndrome in a non‐HIV patient: Case report and review of literature

AbstractTuberculosis (TB) is a global health threat, especially in HIV patients who may experience immune reconstitution inflammatory syndrome (IRIS) upon Mycobacterium tuberculosis infection. Diagnosing and defining IRIS in non‐HIV patients remains challenging. A 63‐year‐old male with acute leukaemia underwent induction therapy with a regimen containing fludarabine. Febrile neutropenia led to further investigations, revealing non‐cavitary pulmonary TB, prompting anti‐tuberculosis therapy (ATT) alongside resumed leukaemia treatment with sorafenib. Persistent extra‐pulmonary TB, specifically lymph node involvement, were observed and IRIS was suspected, evidenced by enlarged lymphadenopathies, scrofula, and skin lesions that developed during the 13‐month course of ATT, with no recurrence after its cessation. This article explores a case of lymph node TB‐associated paradoxical IRIS in a non‐HIV leukaemia patient, revealing the intricate interplay between tuberculosis and haematological malignancies and emphasizing the lack of standardized diagnostic criteria and treatment consensus. Challenges in lymph node TB diagnosis and management highlight the need for tailored therapeutic approaches. The report explores the potential immunomodulatory effects of fludarabine and sorafenib, questioning their roles in TB‐IRIS. This case illuminates TB‐IRIS dynamics in non‐HIV patients, urging further research and collaborative efforts to enhance understanding and outcomes. As medical complexities persist, personalized therapeutic approaches and advancements in TB‐IRIS research are crucial.

Paradoxical and Unmasking HIV Immune Reconstitution Inflammation Syndrome in Antiretroviral-Naïve Pregnant Women: A Prospective Cohort Study.

Following antiretroviral therapy (ART) initiation, HIV-associated immune reconstitution inflammatory syndrome (IRIS), indicated by an array of opportunistic infections, may occur, presenting as either paradoxical, a worsening of a previously treated infection, or unmasking, a flare-up of an underlying, previously undiagnosed infection. The impact of ART as the backbone of HIV treatment and prevention has prolonged the survival of people living with HIV. In pregnancy, benefits have been shown by slowing HIV progression and preventing perinatal transmission; however, there have been risks of adverse reactions with ART, including immune responses to both the fetus and mother. This study sought to estimate the incidence of HIV-IRIS cumulatively and by type either paradoxical or unmasking IRIS, determine the baseline maternal and HIV clinical markers as predictors of, and analyze the log-rank test for survival time to IRIS outcome assessed by relying on an increase in CD4 count and/or a rapid decrease in viral load. An active records study was conducted between June 2019 and March 2020 among ART-naïvepregnant women attending the antenatal care units (ANCu) at the Kenyatta National and MbagathiHospitals, Nairobi, Kenya. Participants were aged between 20 and 49 years and had a confirmed HIV-positive test. To ascertain a true case of IRIS, the diagnosis was adjudicated for accuracy and consistency by an independent review committee. Plasma HIV viral load, CD4 counts, and routine laboratory evaluations (hemoglobin, white blood cell count (WBC)) were performed by each hospital's clinical laboratory. The IRIS incidence was assessed using the International Network for Studies Against HIV-Associated IRIS (INSHI) during the first three months after ART initiation. Multivariate Cox regression with IRIS as the outcome, using the SPSSSurvival package, examined the relationship between baseline maternal characteristics and HIV clinical markers before ART initiation and IRIS, and finally, decision-tree analysis for predicting IRIS was performed. From a pool of 532 ART-naïvepregnant women, 133 (25%) developed IRIS, and 97 (72.9%) were in the unmasking category. The accumulated risk of experiencing IRIS symptoms increased from week two (hazard ratio (HR)=0.0287) to week 12 (HR=3.6158). Participants with a maternal BMI (MBMI) of 25-29.9 kg/m2 at baseline were at a higher risk of unmasking IRIS (HR=2.478; P=0.010). The WHO-HIV clinical stages 1 and 2 skewed towards paradoxical IRIS (regression coefficients =-0.111 and -0.276 (P<0.05)), while stage 4 skewed towards unmasking IRIS (regression coefficient=0.047, HR=1.048, P=0.941). A CD4 count > 500 cells/mm^3 skewed towards unmasking IRIS (regression coefficient=0.192, HR=1.211, P=0.416), while RNA-HIV viral loads >50 copies/ml towards paradoxical IRIS (regression coefficient=-0.199, HR=0.820, P=0.360. On decision tree analysis, 85% (P=0.001) of ART-naïve pregnant women with a baseline CD4 count below 500 copies/mm^3 presented with unmasking IRIS. For ART-naïvepregnant women, unmasking IRIS is the most common type, and an MBMI of 25-29.9 kg/m2, advanced HIV infection, a CD4 count <500 cells/mm^3, and a higher parity at baseline may be clinically useful predictors. The higher proportion of ART-naïvepregnant women experiencing unmasking as compared to paradoxical IRIS supports the need for earlier assessment based on potential predictors.

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome in initiating ART among HIV-Infected patients in China-risk factors and management

BackgroundChina is a country burdened with a high incidence of both tuberculosis (TB) and HIV, Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important early complication in TB and HIV co-infected patients, but data from China are limited. Additionally, as an integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) regimen becomes the first-line treatment, concerns have arisen regarding the potential increase in the incidence of paradoxical TB-IRIS. Nevertheless, the existing data are inconclusive and contradictory.MethodsWe conducted a retrospective study at Chongqing Public Health Clinical Center from January 2018 to December 2021. We collected demographic and clinical data of HIV/TB co-infected patients who initiated ART. We described the patient characteristics, identified predictors for TB-IRIS, and determined clinical outcomes. The Statistical Package for Social Science (SPSS 25) was used to analyse the data. Continuous variables were compared using Student’s t-test or rank sum test. Counting data were compared using the chi-square test or Fisher’s exact test. The variables with statistical significance in the univariate analysis were added to the binary logistic regression. A p-value less than 0.05 was considered statistically significant.ResultsA total of 384 patients co-infected with naive HIV and pulmonary TB (PTB) who were given ATT and ART combination were included. 72 patients (18.8%) developed paradoxical TB-IRIS with a median of 15 (12, 21) days after initiating ART. Baseline age ≤ 40years, CD4 + T-cell counts ≤ 50cells/µL, HIV viral load ≥ 500,000 copies/mL were found to be significantly associated with development of paradoxical TB-IRIS. Mortality rates were similar in the TB-IRIS (n = 5, 6.9%) group and non-TB-IRIS (n = 13, 4.2%) group. Interestingly, CD4+ T-cell counts recovery post-ART was significant higher in the TB-IRIS group when compared to the non-TB-IRIS group at the end of 24 weeks (P = 0.004), as well as at 48 weeks (P = 0.015). In addition, we consider that INSTI- based ART regimen do not increased the risk of Paradoxical TB-IRIS.ConclusionParadoxical TB-IRIS, while often leading to clinical deterioration and hospitalization, is generally manageable. It appears to have a positive impact on the recovery of CD4 + T-cell counts over time. Importantly, our data suggest that INSTI-based ART regimens do not elevate the risk of TB-IRIS. Thus, paradoxical TB-IRIS should not be considered an impediment to initiating ART in adults with advanced immunodeficiency, except in the case of tuberculous meningitis (TBM).

Relationship Between LTA4H Promotor Polymorphism and Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome and Its Prevention With Prednisone.

The development of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) and its prevention using prednisone may potentially be mediated by the LTA4H genotype. We assessed this hypothesis in a clinical trial evaluating prednisone to prevent TB-IRIS. We did not find an association between LTA4H genotype and TB-IRIS incidence or prednisone efficacy.

Clinical metagenomics-assisted diagnosis of relapsed HIV-associated cryptococcal meningitis.

To date, the identification of crypotococcal relapse remains clinically challenging as it often has similar manifestation with paradoxical immune reconstitution inflammatory syndrome. This study reports on the use of metagenomics assisted next generation sequencing to aid in diagnosing recurrent cryptococcal meningitis in an person living with HIV experiencing recurring symptoms, despite negative culture results for Cryptococcus neoformans in the cerebrospinal fluid. Although fungal culture was negative, when reads from metagenomic and metatranscriptomic sequencing performed on the Day 308 cerebrospinal fluid sample were mapped onto the genome from the Day 4 isolate, 589 specific reads were identified. NCBI BLAST search also revealed Cryptococcus-specific 18S/25S/28S ribosomal RNA, indicating a relapse of the disease.

Clinical Profile of Patients with Immune Reconstitution Inflammatory Syndrome in Human Immunodeficiency Virus/Tuberculosis Coinfection and their Outcome: A Prospective Observational Study

Introduction: Antiretroviral therapy (ART) is a life-saving treatment for the human immunodeficiency virus (HIV). However, the starting of ART is often complicated by immune reconstitution inflammatory syndrome (IRIS) in tuberculosis (TB). This study was done to examine the clinical profile of patients with IRIS in HIV-TB coinfection and their outcomes. Materials and methods: A prospective observational study was conducted at the Government Hospital of Thoracic Medicine, Chennai, Tamil Nadu, India, from January to December 2013. Patients diagnosed to have HIV and TB coinfection, those on anti-tuberculosis therapy (ATT) and ART, patients with paradoxical IRIS, and ART-naïve patients were included in the study. A total of 230 patients were studied and followed up for 1 year. Clinical examination and chest X-rays, sputum smear for acid-fast bacillus (AFB), baseline CD4 count, ultrasonogram of the abdomen, routine blood investigations, and other necessary parameters required to determine IRIS TB in HIV/TB coinfected patients were taken. Results: Among the 230 HIV patients studied, 74.3% were males, and the mean age was 39.01 ± 9.60 years. The incidence of IRIS was 20.9%, and the mortality rate was 25% among them. Oral candidiasis was the most common opportunistic infection (37.8%). Among IRIS patients, 62.5% had stage III clinical disease. Conclusion: The time of starting ART is critical to reducing IRIS-associated morbidity. Improved knowledge of the pathophysiology of IRIS will enable better diagnostic modalities and targeted treatments to be developed.

Recurrence of Symptoms Following Cryptococcal Meningitis: Characterizing a Diagnostic Conundrum With Multiple Etiologies.

Cryptococcal meningitis is a common cause of AIDS-related mortality. Although symptom recurrence after initial treatment is common, the etiology is often difficult to decipher. We sought to summarize characteristics, etiologies, and outcomes among persons with second-episode symptomatic recurrence. We prospectively enrolled Ugandans with cryptococcal meningitis and obtained patient characteristics, antiretroviral therapy (ART) and cryptococcosis histories, clinical outcomes, and cerebrospinal fluid (CSF) analysis results. We independently adjudicated cases of second-episode meningitis to categorize patients as (1) microbiological relapse, (2) paradoxical immune reconstitution inflammatory syndrome (IRIS), (3) persistent elevated intracranial pressure (ICP) only, or (4) persistent symptoms only, along with controls of primary cryptococcal meningitis. We compared groups with chi-square or Kruskal-Wallis tests as appropriate. 724 participants were included (n = 607 primary episode, 81 relapse, 28 paradoxical IRIS, 2 persistently elevated ICP, 6 persistent symptoms). Participants with culture-positive relapse had lower CD4 (25 cells/μL; IQR: 9-76) and lower CSF white blood cell (WBC; 4 cells/μL; IQR: 4-85) counts than paradoxical IRIS (CD4: 78 cells/μL; IQR: 47-142; WBC: 45 cells/μL; IQR: 8-128). Among those with CSF WBC <5 cells/μL, 86% (43/50) had relapse. Among those with CD4 counts <50 cells/μL, 91% (39/43) had relapse. Eighteen-week mortality (from current symptom onset) was 47% among first episodes of cryptococcal meningitis, 31% in culture-positive relapses, and 14% in paradoxical IRIS. Poor immune reconstitution was noted more often in relapse than IRIS as evidenced by lower CSF WBC and blood CD4 counts. These easily obtained laboratory values should prompt initiation of antifungal treatment while awaiting culture results. NCT01802385.

Role of Corticosteroids in the Treatment of Tuberculosis: An Evidence-based Update

Corticosteroids are often used as an adjunct in the treatment of various forms of tuberculosis (TB) and for the prevention of complications, such as constrictive pericarditis, hydrocephalus, focal neurological deficits, pleural adhesions, and intestinal strictures. Notwithstanding, they have been proven in clinical trials to improve the following outcomes only--death or disability in human immunodeficiency virus (HIV)-seronegative patients with tubercular meningitis and tubercular pericarditis. Despite a lack of specific evidence for efficacy in HIV co-infected patients with tubercular meningitis or pericarditis, corticosteroids are generally recommended in them as well. Corticosteroids significantly decrease the risk of pleural thickening in patients with tubercular pleural effusion; the clinical significance of this finding, however, is unclear. Recently, it has been demonstrated that use of corticosteroids improve the morbidity in HIV co-infected patients with paradoxical TB immune reconstitution inflammatory syndrome (IRIS). However, evidence favouring the use of corticosteroids in other clinical situations is sparse or lacking. Likewise, the biological mechanisms underlying their beneficial effect in TB meningitis and pericarditis remain poorly understood.

Risk of Immune Reconstitution Inflammatory Syndrome With Integrase Inhibitors Versus Other Classes of Antiretrovirals: A Systematic Review and Meta-analysis of Randomized Trials.

BackgroundIntegrase strand transfer inhibitors (InSTIs) decrease HIV plasma viral load faster than other antiretroviral classes. More rapid viral load decline has been associated with higher risk of immune reconstitution inflammatory syndrome (IRIS). There are conflicting reports on the association between InSTI and IRIS. We performed a systematic review and meta-analysis to compare the risk of IRIS among treatment-naïve HIV-positive patients starting InSTI versus non-InSTI regimens.MethodsWe searched PubMed, Scopus, Web of Science, Africa-Wide, and Cochrane databases from earliest available date to 26 November 2021, for randomised controlled trials (RCTs) having intervention arms with InSTI versus control arms without InSTI in patients initiating first-line antiretroviral therapy. The primary outcome was relative risk (RR) of IRIS, while the secondary outcome was RR of paradoxical tuberculosis-associated IRIS (TB-IRIS). Data were combined by random-effects meta-analysis according to the Mantel-Haenszel method. The protocol for this study is registered with PROSPERO, CRD42020213976.ResultsWe included 14 RCTs comprising 8696 participants from six continents for the primary outcome of IRIS, and a subset of 674 participants (from three RCTs) for the secondary outcome of paradoxical TB-IRIS. Risk of IRIS was similar between InSTI and non-InSTI regimens (RR, 0.93, 95% confidence interval [CI], 0.75 – 1.14). There was a trend towards a lower risk of paradoxical TB-IRIS with InSTI versus efavirenz regimens that was not statistically significant (RR, 0.64, 95% CI, 0.34 – 1.19).ConclusionsIn this meta-analysis among treatment-naïve patients commencing first-line antiretroviral therapy, InSTI regimens were not associated with higher risk of IRIS.

CD4 Tcells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection.

HIV/Mycobacterium tuberculosis (Mtb) co-infected individuals have an increased risk of tuberculosis prior to loss of peripheral CD4 Tcells, raising the possibility that HIV co-infection leads to CD4 Tcell depletion in lung tissue before it is evident in blood. Here, we use rhesus macaques to study the early effects of simian immunodeficiency virus (SIV) co-infection on pulmonary granulomas. Two weeks after SIV inoculation of Mtb-infected macaques, Mtb-specific CD4 Tcells are dramatically depleted from granulomas, before CD4 Tcell loss in blood, airways, and lymph nodes, or increases in bacterial loads or radiographic evidence of disease. Spatially, CD4 Tcells are preferentially depleted from the granuloma core and cuff relative to B cell-rich regions. Moreover, live imaging of granuloma explants show that intralesional CD4 Tcell motility is reduced after SIV co-infection. Thus, granuloma CD4 Tcells may be decimated before many co-infected individuals experience the first symptoms of acute HIV infection.

A nomogram for predicting paradoxical immune reconstitution inflammatory syndrome associated with cryptococcal meningitis among HIV-infected individuals in China

BackgroundCryptococcal meningitis (CM) associated immune reconstitution inflammatory syndrome (CM-IRIS) is the second most common complication in HIV-infected individuals with cryptococcal meningitis, with a reported mortality rate ranging from 8 to 30%. Given the devastating consequences of CM-IRIS related intracranial neuroinflammation and its challenging in diagnosis, we conducted a study to explore the risk factors and the occurrence of paradoxical CM-IRIS in HIV-infected patients, which is of great value for prevention and clinical management.MethodsWe conducted a retrospective cohort study to identify the indicators associated with paradoxical CM-IRIS among 86 HIV-infected patients with CM using univariate and multivariate cox analysis. A nomogram was constructed using selected variables to evaluate the occurrence of paradoxical CM-IRIS at 6 months and 12 months after ART initiation. The discrimination and calibration of the nomogram were assessed by concordance index (C-index) and calibration plots. Decision curves analysis (DCA) were used to evaluate clinical effectiveness of the nomogram. Subsequently, to help clinicians recognize patients at high risk faster, patients were divided into high-risk and low-risk groups according to the best cutoff point identified by X-tile.ResultsOf 86 AIDS patients with CM, 22.1% experienced paradoxical CM-IRIS at a median of 32 days after antiretroviral therapy (ART) initiation. The occurrence of paradoxical CM-IRIS was associated with age, ART initiation within 4 weeks of antifungal treatment, a four-fold increase in CD4 T cell counts, C-reactive protein levels, and hemoglobin levels independently. These five variables were further used to construct a predictive nomogram. The C-index (0.876) showed the favorable discriminative ability of the nomogram. The calibration plot revealed a high consistency between the predicted and actual observations. DCA showed that the nomogram was clinically useful. Risk stratification based on the total score of the nomogram showed well-differentiated in the high-risk and low-risk groups. Clinicians should pay attention to patients with total points high than 273.ConclusionsWe identified the predictive factors of paradoxical CM-IRIS and constructed a nomogram to evaluate the occurrence of paradoxical CM-IRIS in 6 months and 12 months. The nomogram represents satisfactory performance and might be applied clinically to the screening and management of high-risk patients.

Frequency of CXCR3+ CD8+ T-Lymphocyte Subsets in Peripheral Blood Is Associated With the Risk of Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome Development in Advanced HIV Disease.

BackgroundTuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a clinical aggravation of TB symptoms observed among a fraction of HIV coinfected patients shortly after the start of antiretroviral therapy (ART). Of note, TB-IRIS is characterized by exacerbated inflammation and tissue damage that occurs in response to the elevated production of CD4+ T cell-derived IFN-γ. Nevertheless, the possible participation of CD8+ T cells in TB-IRIS development remains unclear.MethodsWe performed a comprehensive assessment of the composition of CD8+ T cell memory subsets and their association with circulating inflammation-related molecules in TB-HIV coinfected patients initiating ART.ResultsWe found that TB-IRIS individuals display higher frequencies of Antigen-experienced CD8+ T cells during the onset of IRIS and that the levels of these cells positively correlate with baseline mycobacterial smear grade. TB-IRIS individuals exhibited higher frequencies of effector memory and lower percentages of naïve CD8+ T cells than their Non-IRIS counterparts. In both TB-IRIS and Non-IRIS patients, ART commencement was associated with fewer significant correlations among memory CD8+ T cells and cells from other immune compartments. Networks analysis revealed distinct patterns of correlation between each memory subset with inflammatory cytokines suggesting different dynamics of CD8+ T cell memory subsets reconstitution. TB-IRIS patients displayed lower levels of memory cells positive for CXCR3 (a chemokine receptor that plays a role in trafficking activated CD8+ T cells to the tissues) than Non-IRIS individuals before and after ART. Furthermore, we found that CXCR3+ naïve CD8+ T cells were inversely associated with the risk of TB-IRIS development. On the other hand, we noticed that the frequencies of CXCR3+ effector CD8+ T cells were positively associated with the probability of TB-IRIS development.ConclusionOur data suggest that TB-IRIS individuals display a distinct profile of memory CD8+ T cell subsets reconstitution after ART initiation. Moreover, our data point to a differential association between the frequencies of CXCR3+ CD8+ T cells and the risk of TB-IRIS development. Collectively, our findings lend insights into the potential role of memory CD8+ T cells in TB-IRIS pathophysiology.

A Severe Case of Molluscum Contagiosum Immune Reconstitution Inflammatory Syndrome in a Patient with Human Immunodeficiency Virus.

Paradoxical immune reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV)-positive patients initiating antiretroviral treatment (ART) is caused by restored immunity to specific antigens, resulting in worsening of a pre-existing infection. Molluscum contagiosum (MC) is commonly noted in HIV-positive individuals but ART alone is usually sufficient to bring about resolution. We present a rare case of severe MC-IRIS that worsened despite immune reconstitution.LEARNING POINTSMolluscum contagiosum is a common opportunistic infection which can have severe manifestations in immunocompromised individuals.Antiretroviral treatment alone is usually sufficient to clear the infection, however refractory cases can persist despite immune reconstitution.Failure to improve or worsening immune reconstitution inflammatory syndrome should raise suspicion for additional immunological dysfunction.Surgery, cytodestructive therapies and chemotherapeutic agents can be considered in extensive, persistent disease.

A case of cryptococcal necrotizing fasciitis and immune reconstitution inflammatory syndrome in a renal transplantation recipient.

Introduction and importanceImmunocompromised patients are at high risk of unexpectedly serious infections caused by uncommon bacteria or fungi. We experienced a case of Cryptococcus neoformans-induced necrotizing fasciitis (NF) of the lower extremities. The progress so far has been reported by the urology department [1].Moreover, after the NF had been treated, the patient developed immune reconstitution inflammatory syndrome (IRIS). We report from surgeon's view point.Case presentationA 51-year-old male renal transplant patient complained of pain in both lower extremities (LE). After the initial debridement, periodic acid-Schiff after diastase digestion (D-PAS) staining confirmed the diagnosis. No symptoms were seen in the lungs or cerebrospinal system. The patient was reluctant to undergo surgical treatment but several debridement improved patient's condition. After the LE wound healed, prednisolone was discontinued, then painful nodules appeared on both LE. Based on the negative culture results and the fact that the patient had been treated with flucytosine and fluconazole, we suspected that the nodules had been caused by IRIS.Clinical discussionIt was difficult to diagnose Cryptococcus-induced NF and paradoxical IRIS. Cooperation from other specialists was essential.ConclusionWe think this patient needed earlier and more definitive debridement. Fortunately, we were able to save the patient's life and maintain his LE function. In immunocompromised patients, cryptococcus can be a pathogen. In addition, IRIS can occur during treatment. Management of IRIS is the capital point of sepsis management, careful anti-inflammatory drug control by specialists is required.

Risk factors for IRIS in HIV-associated Pneumocystis-pneumonia following ART initiation

HIV-infected patients with Pneumocystis-pneumonia (PCP) may develop paradoxical immune reconstitution inflammatory syndrome (IRIS), when combination antiretroviral therapy (cART) is started early during the course of PCP-treatment (PCPT). The aim of this study was to identify risk factors and predictors for PCP-IRIS and to improve individualized patient care. An ICD-10 code hospital database query identified all Frankfurt HIV Cohort patients being diagnosed with PCP from January 2010 - June 2016. Patient charts were evaluated retrospectively for demographic, clinical and therapeutic (cART/PCPT) characteristics and incidence of paradoxical IRIS according to French's case definitions. IRIS occurred in 12/97 patients that started cART while on PCPT (12.4%). They had a higher rate of re-hospitalization (41.7vs. 4.7%; odds ratio (OR) 14.46; p=0.009), intensive care treatment (66.7vs. 30.6%; OR=4.54; p=0.018), and longer median hospitalization (48 days vs. 23; p<0.001). A high HIV-RNA level (>6Log10/ml) before cART initiation was associated with IRIS development (41.6vs. 15.0%; OR 4.05; p=0.042). Serum immunoglobulin G-levels (IgG) [mg/dl] were lower (894.0vs. 1446.5; p=0.023). Higher hospitalization rate and morbidity parameters underscore the clinical importance of PCP-related paradoxical IRIS. A baseline viral load of >6Log10/ml and serum IgG may help to assess individual risks for PCP-IRIS.

Diagnostic Accuracy of the INSHI Consensus Case Definition for the Diagnosis of Paradoxical Tuberculosis-IRIS.

The diagnosis of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) relies on characteristic clinical features synthesized as the International Network for the Study of HIV-associated IRIS (INSHI) case definition. There is no confirmatory laboratory test. Site B HIV-TB clinic in Khayelitsha, Cape Town, South Africa. Using data of participants with HIV-associated tuberculosis starting antiretroviral treatment from a prospective trial evaluating prednisone for TB-IRIS prevention, we applied latent class analysis to model a gold standard for TB-IRIS. The model-predicted probability of TB-IRIS for each participant was used to assess the performance of the INSHI case definition and compare its diagnostic accuracy with several adapted case definitions. Data for this analysis were complete for 217 participants; 41% developed TB-IRIS. Our latent class model included the following parameters: respiratory symptoms; night sweats; INSHI major criteria 1, 2, and 4; maximum C-reactive protein >90 mg/L; maximum heart rate >120/min; maximum temperature >37.7°C; and preantiretroviral therapy CD4 count <50 cells/µL. The model estimated a TB-IRIS incidence of 43% and had optimal goodness of fit (χ2 = 337, P = 1.0). The INSHI case definition displayed a sensitivity of 0.77 and a specificity of 0.86. Replacing all the minor INSHI criteria with objectives measures (C-reactive protein elevation, fever, and/or tachycardia) resulted in a definition with better diagnostic accuracy, with a sensitivity of 0.89 and a specificity of 0.88. The INSHI case definition identifies TB-IRIS with reasonable accuracy. Amending the case definition by replacing INSHI minor criteria with objective variables improved sensitivity without loss of specificity.

RAPID ONSET MILIARY TB: A MANIFESTATION OF IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME

SESSION TITLE: Medical Student/Resident Chest Infections Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Tuberculosis (TB) is now an uncommon entity in the United States, with an estimated incidence of 2.7 per 100,000 persons. (1) Infection with human immunodeficiency virus (HIV) is a significant risk factor for TB infection. The initiation of antiretroviral therapy (ART) may be associated with immune reconstitution inflammatory syndrome (IRIS), with the subsequent unmasking of previously subclinical infections, including TB. We present an uncommon case that dramatically presented with miliary TB shortly following the initiation of ART. CASE PRESENTATION: A 68-year-old female immigrant with a history depression, parkinson's disease, and known acquired immunodeficiency syndrome (AIDS)/HIV infection not treated for 6 years, presented with weakness, night sweats, and progressive dry cough for two weeks. She had been started on ART (bictegravir/emtricitabine/tenofovir) one month prior, with a pre-treatment viral load of 84,000 copy/mL, and CD4 count of 69 /µL. Physical examination at presentation revealed normal vital signs and bilateral rhonchi. Laboratory testing was notable for leukopenia (3.99 x10^6 /µL). Chest radiograph showed multiple bilateral nodules. Chest computed tomography (CT) revealed innumerable bilateral nodules, with mediastinal and axillary lymphadenopathy. (Fig 1) Three consecutive sputum samples were positive for acid fast bacilli. The diagnosis of miliary tuberculosis was made, and she was started on rifampin, isoniazid, ethambutol, and pyrazinamide (RIPE therapy), along with pyridoxine. Given the potential for drug interaction between rifampin and bictegravir, the latter was switched to dolutegravir for the duration of six planned months of antibiotic treatment. DISCUSSION: Paradoxical tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) is an early complication of antiretroviral therapy in patients with TB, that results from the rapid restoration of immune function, with a consequent exaggerated immune response, causing an exacerbation of pre-existing infections, or the unmasking of subclinical infections. TB-IRIS is characterized by severe localized or systemic inflammatory reactions against Mycobacterium tuberculosis antigens. One retrospective study showed an incidence of 8% in HIV and TB co-infected patients who were started on ART. (2) Our case notably had a dramatic presentation, with severe miliary TB on chest imaging, with no known history of TB. Additionally, chest radiography obtained merely one month prior to her presentation had been normal, demonstrating the rapidity with which miliary TB may develop following the initiation of ART. CONCLUSIONS: Patients with risk factors, such as immigration, should be monitored closed following the initiation of ART, for the manifestation of previously subclinical infections, such as TB. Reference #1: Schwartz, MD, Price SF, Pratt RH, et al. Tuberculosis - United States, 2019. MMWR Morb Mortal Wkly Rep. 2020;69:286-289 Reference #2: Kumarasamy N, Chaguturu S, Mayer KH, et al. Incidence of immune reconstitution syndrome in HIV/tuberculosis-coinfected patients after initiation of generic antiretroviral therapy in India. J Acquir Immune Defic Syndr. 2004 Dec 15;37(5):1574-6. DISCLOSURES: No relevant relationships by Rohan Kataria, source=Web Response No relevant relationships by Pius Ochieng, source=Web Response No relevant relationships by NISHANT SHARMA, source=Web Response No relevant relationships by Pandi Todhe, source=Web Response

Pulmonary tuberculosis masquerading as coronavirus disease 2019 in an HIV-infected individual with advanced immune suppression

Pulmonary tuberculosis masquerading as coronavirus disease 2019 in an HIV-infected individual with advanced immune suppression

Prevalence and risk factors of paradoxical tuberculosis associated immune reconstitution inflammatory syndrome among HIV-infected patients in Beijing, China

BackgroundIn this study, we aimed to describe the prevalence, clinical presentation and risk factors of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) cases in China.MethodsWe performed a descriptive analysis of demographic and clinical data of HIV/TB coinfected patients receiving ART at Beijing Ditan Hospital between January 2014 and October 2018.ResultsOf 199 patients included, 45 (22.6%) developed paradoxical TB-IRIS, and 19 (9.5%) TB-IRIS cases presented miliary TB. The pre-ART CD4 count lower than 50 cells/mm3 was found to be significantly associated with development of TB-IRIS. Similarly, patients with higher than 4-fold increase in CD4 cell count after antiretroviral therapy (ART) had significantly higher odds of having TB-IRIS. When patients aged 25–44 years were utilized as the control group, youths (< 25 years old) were more likely to have miliary TB. No significant difference was observed in the intervals from initiation of ART to IRIS presentation between miliary and non-miliary group.ConclusionsIn conclusion, our data demonstrate that approximate one quarter of patients coinfected with TB and HIV develop paradoxical TB-IRIS after initial of ART therapy in China. Lower baseline CD4 count and rapid increase in CD4 count are the major risk factors associated with the occurrence of paradoxical TB-IRIS.

Characteristics of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome and its influence on tuberculosis treatment outcomes in persons living with HIV

ObjectiveThe influence of tuberculosis (TB)-immune reconstitution inflammatory syndrome (IRIS) on TB treatment outcomes and its risk factors were investigated among people with human immunodeficiency virus (HIV) and co-infected with TB. MethodsNewly diagnosed, culture-confirmed, pulmonary TB patients with HIV and enrolled in a clinical trial (NCT00933790) were retrospectively analysed for IRIS occurrence. Risk factors and TB outcomes (up to 18 months after initiation of anti-TB treatment [ATT]) were compared between people who experienced IRIS (IRIS group) and those who did not (non-IRIS group). ResultsTB-IRIS occurred in 82 of 292 (28%) participants. Significant baseline risk factors predisposing to TB-IRIS occurrence in univariate analysis were: lower CD4+ T-cell count, CD4/CD8 ratio, haemoglobin levels, presence of extra-pulmonary TB focus, and higher HIV viral load; the last two retained significance in the multivariate analysis. After 2 months of ATT commencement, sputum smear conversion was documented in 45 of 80 (56.2%) vs. 124 of 194 (63.9%) (p=0.23), culture conversion was in 75 of 80 (93.7%) vs. 178 of 194 (91.7%) (p=0.57) and the median decline in viral load (log10copies/mm3) was 2.7 in the IRIS vs. 1.1 in the non-IRIS groups (p<0.0001), respectively. An unfavourable response to TB therapy was detected in 17 of 82 (20.7%) and 28 of 210 (13.3%) in the IRIS and non-IRIS groups, respectively (p=0.14). ConclusionsTB-IRIS frequently occurred in people with advanced HIV infection and in those who presented with extra-pulmonary TB lesions, without influencing subsequent TB treatment outcomes.