Clinical and laboratory predictors and prevalence of immune reconstitution inflammatory syndrome in patients with Whipple's disease.

OBJECTIVES: Whipple's disease (WD) is a rare and potentially fatal infectious disease caused by Tropheryma whipplei. It is characterized by a long prodromal phase that mimics a rheumatological disease, often leading to immunosuppressant treatment. Immune reconstitution inflammatory syndrome (IRIS) is currently the most important complication of WD, requiring prompt recognition and treatment as it can be fatal. However, epidemiological data on IRIS are scarce. We aimed to identify the clinical and laboratory predictors of IRIS at WD diagnosis and to evaluate whether the prevalence of IRIS has changed over time. METHODS: Forty-five patients with WD (mean age 52 ± 11 years; 10 females) were followed up between January 2000 and December 2021. Clinical and laboratory data at WD diagnosis were retrospectively collected and compared among patients who developed IRIS and those who did not. RESULTS: Erythrocyte sedimentation rate (ESR; 33.4 ± 11.8 mm/h vs 67.1 ± 26.3 mm/h, P < 0.01), platelet (PLT; 234 × 109 /L vs 363 × 109 /L, P < 0.01), and body mass index (22.0 ± 2.0 kg/m2 vs 19.8 ± 3.0 kg/m2 , P = 0.04) differed significantly between patients who subsequently developed IRIS and those who did not. ROC analysis identified ESR ≤46 mm/h (AUROC 0.88, 95% CI 0.72-1.00) and PLT ≤ 327 × 109 /L (AUROC 0.85, 95% CI 0.70-1.00) as optimal cut-off values to discriminate WD patients at a high risk of developing IRIS. Prevalence of IRIS remained stable (22.2%) over time. CONCLUSIONS: Low ESR and PLT count at diagnosis help identify WD patients at high risk of developing IRIS. Instead, a greater inflammatory response suggests a lower risk of IRIS. Prevalence of IRIS did not change over two decades.

Unmasked immune reconstitution inflammatory syndrome towards B-cell non-Hodgkin lymphoma during treatment of esophageal actinomycosis in a patient with advanced HIV: a case report.

BACKGROUND: Actinomycosis is an unusual chronic bacterial infection, even rarer in people living with HIV. It is not considered an AIDS-defining disease. However, the role in co-presentation or overlap with other opportunistic conditions of advanced HIV is unknown. CASE PRESENTATION: A 49-year-old Peruvian male presented with a 4-month history of dysphagia, odynophagia, hyporexia and wasting. He underwent an upper digestive endoscopy, in which ulcers with a necrotic center were observed, therefore, the initial diagnostic assumption was esophageal cancer. Subsequent pathology report excluded neoplasms and confirmed the diagnosis of actinomycosis. Serology for human immunodeficiency virus was requested, yielding a positive result. Antimicrobial treatment with amoxicillin and antiretroviral therapy were indicated, with slow clinical improvement. After 4 months, epigastric discomfort presented, for which a new upper digestive endoscopy was performed, revealing a deep gastric ulcer, which was compatible with diffuse large B-cell non-Hodgkin lymphoma. CONCLUSION: Esophageal actinomycosis in people living with HIV is very rare. We suggest HIV-associated immunosuppression is not enough to allow for actinomycosis to develop, and masked underlying entities should be sought. The existence of such entities in people living with HIV should raise awareness of the possibility of unmasked immune reconstitution inflammatory syndrome once treatment has started.

Hyperinflammatory syndrome in a paediatric patient with a recent diagnosis of HIV/AIDS infection: hemophagocytic lymphohistiocytosis or immune reconstitution syndrome?

INTRODUCTION: Haemophagocytic lymphohistiocytosis is a rare and life-threatening condition caused by uncontrolled immune activation leading to excessive inflammation and tissue destruction. It could either be due to a primary genetic defect or be triggered by secondary causes such as infections, autoimmune diseases, rheumatological diseases or post-transplant immunosuppression. We here report the case of a 4-year-old child with a recent AIDS diagnosis who developed a severe systemic inflammation. CASE REPORT: We here report the case of a 4-year-old child with a recent AIDS diagnosis who was admitted to the ER with acute respiratory failure due to Pneumocystis jiroveci infection and Aspergillosis; the following microbiological assessment also showed a CMV, HSV, EBV and HHV-7 coinfection. On the 51st day after she'd started antiretroviral therapy, 39th after she'd followed a course of Bactrim and Caspofungin for PJI and Ambisome for pulmonary Aspergillosis, she started presenting fever, unresponsive to broad-spectrum antibiotic therapy. She also presented worsening of her clinical conditions, with evidence at the laboratory assessments of progressive raise in inflammatory indexes, coagulopathy, trilinear cytopenia and hyperferritinemia. To perform the differential diagnosis between IRIS and HLH, HLA-DR on T cells was studied, turning out negative for IRIS. Therefore, in the suspicion of HLH, a bone marrow aspirate and biopsy were performed with evidence of trilinear cytopenia, prevalence of T-cells and macrophages with signs of phagocytosis. She was started on high-dose steroids and Anakinra for a total of 29 days, resulting in prompt apyrexia and progressive improvement of her clinical conditions and laboratory results. CONCLUSION: To the best of our knowledge there is poor literature available about the differential diagnosis of HLH and IRIS, therefore medical management in the concurrence of these two conditions needs to be further investigated, especially in a setting where immunological testing is not quickly available. The clinical differences between these pathologies are blurred and the bone marrow biopsy within marker for IRIS helped us to distinguish these two entities.

Neurological worsening during treatment of HIV-negative cryptococcal meningitis in a patient with Evans syndrome.

A 49-year-old woman with a rare autoimmune hematological disease, Evans syndrome, was admitted to the authors' hospital with immune reconstitution inflammatory syndrome-like reconstitution syndrome after effective antifungal therapy for cryptococcal meningitis. She initially improved after receiving corticosteroid treatment; after prednisone was tapered, her clinical presentation and brain imaging deteriorated but finally improved with the addition of thalidomide. Immune reconstitution inflammatory syndrome-like reconstitution syndrome is a rare complication in cryptococcal meningitis patients receiving immunosuppressive therapy. Thalidomide can be given in addition to corticosteroid therapy to effectively control the paradoxical inflammatory response and improve clinical outcomes.

Hypercalcemia during initiation of antiretroviral therapy in human immunodeficiency virus and Leishmania coinfection: A case report.

RATIONALE: Hypercalcemia is a common complication of many granulomatous diseases but is not typically associated with leishmaniasis. Here we report an unusual case of hypercalcemia during the initiation of antiviral therapy in a patient with acquired immunodeficiency syndrome coinfected with visceral leishmaniasis. PATIENT CONCERNS: Our patient presented with malaise and altered mental status following antiretroviral therapy initiation. He was found to have de novo hypercalcemia complicated by acute kidney injury. DIAGNOSIS, INTERVENTIONS, AND OUTCOMES: An extensive workup for other etiologies of hypercalcemia was negative. The patient was ultimately thought to have hypercalcemia secondary to visceral leishmaniasis in the setting of immune reconstitution inflammatory syndrome. He was treated with intravenous volume expansion, bisphosphonates, and oral corticosteroid therapy with complete resolution. LESSONS: This case highlights an unusual presentation of immune reconstitution inflammatory syndrome, in which proinflammatory cytokine signaling during the restoration of cellular immunity may have led to increased ectopic calcitriol production by granuloma macrophages, thereby altering bone-mineral metabolism and driving hypercalcemia.

Reversal of uniocular blindness with corticosteroids in a solid organ transplant recipient with cryptococcal meningitis and immune reconstitution syndrome (IRIS): A case report.

Cryptococcal meningitis is a life-threatening infection commonly seen in patients with advanced HIV infection and solid organ transplant recipients. We report a case of cryptococcal meningitis with immune reconstitution syndrome (IRIS) who presented to us with a headache and complete loss of vision in the left eye. He was managed with antifungals and a short course of steroids, and he regained vision completely. In the hospital, he developed complications including tacrolimus toxicity, fluconazole-induced QT prolongation, and flucytosine-induced thrombocytopenia. Our case demonstrates the importance of a multidisciplinary approach in the management of complex cases like cryptococcal meningitis in solid organ transplant recipients.

Subcutaneous Microabscesses and Myositis as Part of Immune Reconstitution Inflammatory Syndrome due to Chronic Disseminated Candidiasis in a Child With Acute Lymphoblastic Leukemia.

BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) occurs when there is immune recovery after a prolonged period of leucopenia as a response to an underlying latent or chronic infection due to a proinflammatory cascade. It can occur in a child on chemotherapy for acute lymphoblastic leukemia (ALL) with underlying chronic disseminated candidiasis (CDC). OBSERVATION: We present a 7-year-old girl with pre-B ALL on chemotherapy who had prolonged febrile neutropenia and CDC with microabscesses in the liver, spleen, and kidney and a prolonged intensive care unit stay. Upon neutrophil recovery, she continued to have high-grade fever (blood and urine cultures negative). She also presented severe myositis of bilateral thigh muscles and developed unusual granulomas in the subcutaneous region of the lower back and right thigh. Although IRIS was suspected, she could not be initiated on steroids due to right upper lobe collapse consolidation due to multidrug-resistant Acinetobacter baumanni, which was treated with sensitive antibiotics. Treatment with steroids resolved her fever and normalized inflammatory markers. She is currently well on maintenance chemotherapy. CONCLUSIONS: IRIS can complicate the treatment of ALL in children. Diagnosing it while having a concurrent bacterial infection is challenging. Rarely CDC can present with subcutaneous granulomas. Treatment with steroids at the right time is very crucial.

Acute Immune Reconstitution Inflammatory Syndrome-HBV Flare in an HIV/HBV Coinfected Patient After Antiretroviral Therapy Initiation: Case Report and Literature Review.

BACKGROUND Immune reconstitution inflammatory syndrome (IRIS) is a well-recognized complication after antiretroviral therapy (ART) initiation among patients with HIV. Acute HBV flares after starting antiretroviral therapy have been reported in 20% to 25% of coinfected patients, among whom only 1% to 5% develop clinical hepatitis. Liver biopsy and serological evaluation help in diagnosis. CASE REPORT A 24-year-old man with history of HIV diagnosed in 2018 developed severe IRIS-related HBV flare after initiation of ART. He was taking ART since 2018 until his immigration to the United States in 2021. He came to establish care and was started on bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF). Three weeks later, he presented to the Emergency Department with polyarthralgia and loose stools; transaminases showed an increasing trend on follow-up. He was admitted for closer monitoring. Workup was remarkable for reactive HBsAg, HBeAg, and HBcIgM antibodies, with HBV viral load of 295 304 copies/mL. Abdominal imaging was unremarkable. ART was switched to rilpivirine/emtricitabine/tenofovir alafenamide (RPV/FTC/TAF), considering the hypothetical risk of hepatotoxicity from BIC/F/TAF. Despite therapy, transaminases were up-trending. He underwent computerized tomography-guided liver biopsy, showing moderate to severe acute hepatitis, compatible with IRIS. He received steroids, and ART was continued. Transaminases resolved, HBV load reduced significantly, HIV load became undetectable at 9 weeks, and he developed HBeAb (seroconversion) at 4 months after initiating ART. CONCLUSIONS Our case highlights the importance of early recognition and management of IRIS-HBV flares after initiation of ART among coinfected patients. Liver biopsy is indicated for definitive diagnosis. ART directed against both viruses should be continued.

The use of TNF-α antagonists in tuberculosis to control severe paradoxical reaction or immune reconstitution inflammatory syndrome: a case series and literature review.

Paradoxical reaction (PR) and immune reconstitution inflammatory syndrome (IRIS) are common complications of tuberculosis treatment. Corticosteroids are first-line treatment for severe PR or IRIS, particularly neurological. We report four cases of severe PR or IRIS during tuberculosis treatment who required TNF-α antagonists, and identified 20 additional cases through literature review. They were 14 women and 10 men, with a median age of 36 years (interquartile range, 28-52). Twelve were immunocompromised before tuberculosis: untreated HIV infection (n=6), or immunosuppressive treatment (TNF-α antagonists, n=5; tacrolimus, n=1). Tuberculosis was mostly neuromeningeal (n=15), pulmonary (n=10), lymph node (n=6), and miliary (n=6), multi-susceptible in 23 cases. PR or IRIS started after a median time of 6 weeks (IQR, 4-9) following anti-tuberculosis treatment start, and consisted primarily of tuberculomas (n=11), cerebral vasculitis (n=8), and lymphadenitis (n=6). First-line treatment of PR or IRIS was high-dose corticosteroids in 23 cases. TNF-α antagonists were used as salvage treatment in all cases, with infliximab (n=17), thalidomide (n=6), and adalimumab (n=3). All patients improved, but 6 had neurological sequelae, and 4 had TNF-α antagonist-related severe adverse events. TNF-α antagonists are safe and effective as salvage or corticosteroid-sparing therapeutic for severe PR or IRIS during tuberculosis treatment.

Paralytic Ileus during Treatment of Pulmonary and Renal Tuberculosis in a Non-Human Immunodeficiency Virus Patient: An Unusual Presentation of Tuberculosis-immune Reconstitution Inflammatory Syndrome.

Paralytic ileus as tuberculosis-immune reconstitution inflammatory syndrome (TB-IRIS) is extremely rare. We herein report a 44-year-old man with pulmonary and renal tuberculosis who developed paralytic ileus 14 days after starting antituberculosis therapy (ATT) despite an initial favorable response to ATT. Paralytic ileus was successfully managed with conservative care. He initially required hemodialysis because of obstructive uropathy due to renal tuberculosis, but he was able to withdraw from dialysis after placement of ureteral stents. TB-IRIS can affect organs other than the original sites of tuberculosis, and the combined use of steroids may be effective for its prevention and treatment.

Treatment management of M. simiae infection complicated by severe immune reconstitution syndrome in two patients living with HIV.

Nontuberculosis mycobacterium are increasingly being identified as sources of disseminated infections in immunocompromised patients. These infections can be challenging to identify and treat due complexities of diagnosis and inherent resistance to many medications. We present two cases of patients with human immunodeficiency virus who had Mycobacterium simiae infections, complicated by immune reconstruction inflammatory syndrome (IRIS). We also present a review of the English literature surrounding the disease, including reported resistance patterns to antimicrobial therapy, which can be highly variable.

Changes in Brain Volumes Are Relevant during Natalizumab-Associated Progressive Multifocal Leukoencephalopathy: Lessons from a Case Report.

This is a case report concerning a Natalizumab-associated Progressive Multifocal Leukoencephalopathy (PML) with cerebellar localization and wakefulness disturbances. Awakening and clinical improvement dramatically occurred as soon as the immune reconstitution inflammatory syndrome (IRIS) took place, being it mild in nature and colocalizing with the PML lesion. In these ideal experimental conditions, we applied brain magnetic resonance imaging post-analysis in order to know changes in brain volumes underlying the pathological process over the infection period. White matter volume increased with a decrease in grey matter during IRIS. Conversely, we found a constant increase in cerebrospinal fluid volume throughout the duration of PML, suggesting a widespread abiotrophic effect, far from the lesion. Furthermore, brain parenchymal fraction significantly decreased as expected while the total brain volume remained stable at all times. Neurodegeneration is the main contributor to the steady disability in Natalizumab-associated PML. This process is thought to be widespread and inflammatory in nature as well as sustained by IRIS and humoral factors derived from the PML lesion.

Inflammasome genetic variants are associated with tuberculosis, HIV-1 infection, and TB/HIV-immune reconstitution inflammatory syndrome outcomes.

Background: Tuberculosis (TB) and AIDS are the leading causes of infectious diseases death worldwide. Here, we investigated the relationship between from single nucleotide polymorphisms (SNPs) of the NLRP3, CARD8, AIM2, CASP-1, IFI16, and IL-1ß inflammasome genes, as well as the profiles of secreted proinflammatory cytokines (e.g., IL-1ß, IL-18, IL-33, and IL-6) with the TB clinical profiles, TB-HIV coinfection, and IRIS onset. Methods: The individuals were divided into four groups: TB-HIV group (n=88; 11 of them with IRIS), HIV-1 group (n=20), TB group (n=24) and healthy volunteers (HC) group (n=10), and were followed up at INI/FIOCRUZ and HGNI (Rio de Janeiro/Brazil) from 2006 to 2016. Real-time PCR was used to determine the genotypes of the Single Nucleotide Polymorphism (SNPs), and ELISA was used to measure the plasma cytokine levels. Unconditional logistic regression models were used to perform risk estimations. Results: A higher risk for extrapulmonary TB was associated with the TT genotype (aOR=6.76; P=0.026) in the NLRP3 rs4612666 Single Nucleotide Polymorphism (SNP) and the C-C-T-G-C haplotype (aOR=4.99; P= 0.017) in the NLRP3 variants. This same Single Nucleotide Polymorphism (SNP) was associated with lower risk against extrapulmonary TB when the carrier allele C (aOR=0.15; P=0.021) was present. Among those with HIV-1 infections, a higher risk for TB onset was associated with the GA genotype (aOR=5.5; P=0.044) in the IL1-ß rs1143634 Single Nucleotide Polymorphism (SNP). In contrast, lower risk against TB onset was associated with the A-G haplotype (aOR=0.17; P= 0.026) in the CARD8 variants. Higher IL-6 and IL-33 levels were observed in individuals with TB. A higher risk for IRIS onset was associated with CD8 counts ≤ 500 cells/mm3 (aOR=12.32; P=0.010), the presence of extrapulmonary TB (aOR=6.6; P=0.038), and the CT genotype (aOR=61.06; P=0.026) or carrier allele T (aOR=61.06; P=0.026) in the AIM2 rs2276405 Single Nucleotide Polymorphism (SNP), whereas lower risk against IRIS onset was associated with the AT genotype (aOR=0.02; P=0.033) or carrier allele T (aOR=0.02; P=0.029) in the CARD8 rs2043211 Single Nucleotide Polymorphism (SNP) and the T-G haplotype (aOR=0.07; P= 0.033) in the CARD8 variants. No other significant associations were observed. Conclusions: Our results depict the involvement of genetic polymorphisms of crucial innate immunity genes and proinflammatory cytokines in the clinical outcomes related to TB-HIV coinfection.

Promise and Challenges of Checkpoint Inhibitor Therapy for Progressive Multifocal Leukoencephalopathy in HIV.

PURPOSE OF REVIEW: Progressive multifocal leukoencephalopathy (PML) is a severe opportunistic infection that remains an important cause of morbidity and mortality in people living with HIV (PLWH). Immune checkpoint molecules are negative regulators of the immune response that have been targeted as a strategy to bolster anti-viral immunity in PML, with varied outcomes reported. While initiation and optimization of antiretroviral therapy remains the standard of care in HIV-related PML, the specific opportunities and risks for checkpoint blockade in these cases should be explored. RECENT FINDINGS: As of April 15, 2022, only 5 of the 53 total published cases of PML treated with checkpoint blockade had underlying HIV infection; four of these had a favorable outcome. The risk of promoting immune reconstitution inflammatory syndrome is a major concern and underscores the importance of patient selection and monitoring. Checkpoint blockade warrants further exploration as a potentially promising option for treatment escalation in HIV-related PML.

Host transcriptomic signatures of tuberculosis can predict immune reconstitution inflammatory syndrome in HIV patients.

Immune reconstitution inflammatory syndrome (IRIS) can be a complication of antiretroviral therapy (ART) in patients with advanced HIV, but its pathogenesis is uncertain. In tuberculosis (TB) endemic countries, IRIS is often associated with mycobacterial infections or Bacille-Calmette-Guerin (BCG) vaccination in children. With no predictive or confirmatory tests at present, IRIS remains a diagnosis of exclusion. We tested whether RISK6 and Sweeney3, validated immune-based blood transcriptomic signatures for TB, could predict or diagnose IRIS in HIV+ children and adults. Transcripts were measured by RT-qPCR in BCG-vaccinated children and by microarray in HIV+ adults with TB including TB meningitis (TBM). Signature scores before ART initiation and up to IRIS diagnosis were compared between participants who did or did not develop IRIS. In children, RISK6 and Sweeney3 discriminated IRIS cases from non-IRIS controls before ART, and at diagnosis. In adults with TB, RISK6 discriminated IRIS cases from controls after half-week on ART and at TB-IRIS onset. In adults with TBM, only Sweeney3 discriminated IRIS cases from controls before ART, while both signatures distinguished cases from controls at TB-IRIS onset. Parsimonious whole blood transcriptomic signatures for TB showed potential to predict and diagnose IRIS in HIV+ children and adults.

Rapidly enlarging pulmonary mass due to immune reconstitution inflammatory syndrome (IRIS) in an immunocompetent host with pulmonary Cryptococcus neoformans.

An immunocompetent man presented with Cryptococcus neoformans disease manifesting as a large pulmonary mass (cryptococcoma). Despite an initial induction course of 4 weeks of liposomal amphotericin B (LAmB), followed by 8 weeks of fluconazole, the cryptococcoma enlarged in size. Ten days into a second course of induction therapy with LAmB and flucytosine, the cryptococcoma markedly increased in size with encroachment on critical vascular structures. Due to concern for immune reconstitution inflammatory syndrome (IRIS), prednisone was added with significant decrease in the size of the mass. To our knowledge, this is the first reported case of pulmonary cryptococcal-IRIS in an immunocompetent host.

Immune reconstitution inflammatory syndrome induced by gluteal silicones in a transgender woman living with HIV.

We report a case of an immune reconstitution inflammatory syndrome induced by gluteal silicones in a transgender woman living with HIV following the start of antiretroviral therapy. This case resembles the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) syndrome that has been described as a complication of insertions of materials such as injected or implanted silicones. The potential of developing an inflammatory response in patient with injected or implanted silicones/foreign substances should be considered in patients who have recently started antiretroviral therapy.