Immune Reconstitution Inflammatory Syndrome Research Articles

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

BackgroundActinomycosis 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 presentationA 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.ConclusionEsophageal 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.

Immune Reconstitution Inflammatory Syndrome in Aids Patient After Successful Induction of Virological Suppression with Cabotegravir/Rilpivirine.

This case highlights the efficacy of monthly CAB/RPV LA in rapidly reducing the HIV viral load level in a poorly controlled patient who lacked significant resistance to the two drugs.This is the first case of IRIS reported in the literature while using CAB/RPV LA. IRIS in the setting of occult MAI is well recognised. It would have occurred with good adherence to any regimen which rapidly suppressed the viral load and is unlikely to be due to CAB/RPV. CAB/RPV has no activity against HBV, which may have contributed to its reactivation.The patient had serologic evidence of resolution of prior HBV. However, some patients have covalently closed circular DNA (cccDNA) that may remain long term in hepatocyte nuclei.

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.

Characteristics of adverse event reports among people living with human immunodeficiency virus (HIV) in Japan: Data mining of the Japanese Adverse Drug Event Report database.

The development of new anti-HIV drugs and advances in antiretroviral therapy (ART) regimens have enabled longer and more effective treatments in people living with HIV (PLWH). However, the aging of PLWHs is another issue that needs to be addressed. In addition to ART, many PLWHs frequently receive medications for various comorbidities. However, real-world data on the occurrence of adverse events in PLWHs and their causative drugs are rare. Therefore, this study aimed to clarify the characteristics of adverse event reports among PLWHs in Japan. PLWH cases with adverse events were comprehensively searched and analyzed using the Japanese Adverse Drug Event Report database (JADER). Despite changes in guideline-recommended ART regimens, anti-HIV drugs were the main cause of adverse events in PLWHs throughout the study period. However, considerable variations have been observed in the reporting rate of anti-HIV drug classes registered as causative drugs in JADER, especially for anchor drugs. In other words, the reporting rate of integrase strand transfer inhibitors has increased in recent years, while that of protease inhibitors and non-nucleoside reverse transcriptase inhibitors has decreased. Immune reconstitution inflammatory syndrome was the most reported adverse event and was frequently noticed by healthcare providers managing patients with HIV infections. The trends in adverse event reports for female and older patients differed from those for the overall population. This study may provide insights that can help in the establishment of optimal management strategies for PLWHs.

T cell infiltration into the brain triggers pulmonary dysfunction in murine Cryptococcus-associated IRIS

Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) is a condition frequently occurring in immunocompromised patients receiving antiretroviral therapy. C-IRIS patients exhibit many critical symptoms, including pulmonary distress, potentially complicating the progression and recovery from this condition. Here, utilizing our previously established mouse model of unmasking C-IRIS (CnH99 preinfection and adoptive transfer of CD4+ T cells), we demonstrated that pulmonary dysfunction associated with the C-IRIS condition in mice could be attributed to the infiltration of CD4+ T cells into the brain via the CCL8-CCR5 axis, which triggers the nucleus tractus solitarius (NTS) neuronal damage and neuronal disconnection via upregulated ephrin B3 and semaphorin 6B in CD4+ T cells. Our findings provide unique insight into the mechanism behind pulmonary dysfunction in C-IRIS and nominate potential therapeutic targets for treatment.

Tuberculoma development in tuberculosis immune reconstitution inflammatory syndrome in an infant

Tuberculoma development in tuberculosis immune reconstitution inflammatory syndrome in an infant

Unmasking the truth Progressive multifocal leukoencephalopathy immune reconstitution inflammatory syndrome PML IRIS in a 36 year old male with HIV

Progressive Multifocal Leukoencephalopathy – Immune Reconstitution Inflammatory Syndrome (PMLIRIS) is the subacute onset of neurological deficits that appeared or was exacerbated after initiation antiretroviral therapy (ART) for treatment of PML. It is due to severe neuroinflammation with re-establishment of immuncompetence. Approximately 25% of patients with HIV and PML develop IRIS. Clinical trials on the treatment of PML-IRIS is lacking with only limited evidence supporting the use of investigative therapies such as corticosteroids and Maraviroc. We report a case of a 36-year old Filipino male, known hypertensive and diagnosed with HIV, who presented with memory problems. He was eventually treated as a case of PML-IRIS on the 3rd week after initiation of ART. He was treated with a course of intravenous Dexamethasone, oral Mefloquine and intravenous immunoglobulin, and ART was continued. Clinical outcome in our patient shows an overall improvement of symptoms and no deterioration of neurologic deficits.

Implementing a Rapid Antiretroviral Therapy Program Using Starter Packs for Emergency Department Patients Diagnosed With HIV Infection.

Emergency departments (ED) have been identified as essential partners in the national plan to end the HIV epidemic. The initiation of rapid antiretroviral therapy (ART) may be an important strategy to minimize the treatment barriers faced by many ED patients diagnosed with HIV. We describe the implementation and outcomes of a protocol to provide rapid ART by using starter packs for eligible ED patients testing HIV antigen/antibody (Ag/Ab) reactive. Eligible patients were not pregnant, were unlikely to have a false-positive Ag/Ab test result, were discharged home, were ART naive, had acceptable liver and renal function, lacked symptoms of an opportunistic infection, and were judged to be a good candidate. During the 1-year study period, 10 606 HIV tests were performed, and 106 patients were HIV Ag/Ab reactive and assessed for ED rapid ART eligibility. Thirty-one patients (29.2%) were eligible for ED rapid ART; 26 (24.5%) were offered it; and 25 accepted and were provided starter packs for an overall ED rapid ART treatment rate of 23.6%. Two patients receiving ED rapid ART were confirmed to be HIV negative. Patients provided ED rapid ART were more likely to follow up by 30 days (82.6% vs 50.0%, P = .01) than patients not provided ED rapid ART. The 6-month incidence of immune reconstitution inflammatory syndrome was 4.3% among the 23 patients who were HIV positive and receiving ED rapid ART. The initiation of ED rapid ART for patients testing HIV Ag/Ab reactive is feasible, well accepted, and safe and may be an important facilitator of linkage to care.

Neurological worsening during treatment ofHIV-negative cryptococcal meningitis in apatient with Evans syndrome.

A 49-year-old woman with a rare autoimmune hematological disease, Evans syndrome, was admitted tothe 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, herclinical 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.

Thalidomide for Recurrence of Symptoms following HIV-Associated Cryptococcal Meningitis.

Cryptococcal meningitis (CM) is a serious and fatal fungal infection that affects individuals infected with human immunodeficiency virus (HIV). Despite treatment, recurrence of symptoms is common and could lead to poor outcomes. Corticosteroids are not always useful in treating symptom recurrence following HIV/CM; thus, alternative therapy is needed. Thalidomide has been reported to be effective in treating symptom recurrence in several patients with HIV/CM. This retrospective study aimed to investigate the efficacy and safety of thalidomide in the treatment of symptom recurrence following HIV/CM. Patients who were treated with thalidomide for symptom recurrence following HIV/CM were retrospectively included. Clinical outcomes and adverse events were recorded and analyzed. Sixteen patients admitted between July 2018 and September 2020 were included in the analysis. During a median follow-up period of 295 (166, 419) days, all patients achieved clinical improvement in a median of 7 (4, 20) days. Among them, nine (56%) achieved complete resolution of symptoms at a median of 187 (131, 253) days, including 40% (2/5) of immune reconstitution inflammatory syndrome (IRIS), 50% (3/6) of patients with elevated ICP only, and 80% (4/5) of patients with symptoms only. Seven (43%) patients experienced nine episodes of adverse events, but no severe adverse event attributable to thalidomide was observed. None of the patients withdrew from thalidomide due to adverse events. Thalidomide appears to be effective and safe in treating different types of symptom recurrence in HIV/CM. This study provides preliminary evidence supporting future randomized clinical trials to further investigate the efficacy and safety of thalidomide in treating symptom recurrence in this population.

Incidence and pattern of tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) in patients on anti-retroviral therapy: An observational study

BackgroundTuberculosis-immune reconstitution inflammatory syndrome is an atypical, immoderate immune response mounted by the refurbishing immune system against the mycobacterium tuberculosis, commonly seen in HIV-infected individuals. ART significantly enhances one's immunity. However, this enhancement in immunity also sets off a number of inflammatory processes termed as Immune Reconstitution Inflammatory Syndrome (IRIS). MethodsThis observational study was conducted with the aim of assessing the incidence and pattern of TB-IRIS in people living with HIV/AIDS on ART registered at the ART Centre of S.C.B. Medical College and Hospital, Cuttack. They were evaluated for their plasma viral load and CD4 count at baseline. Thereafter, the plasma viral load was assessed every week and the CD4 count was assessed fortnightly. Each study participant was followed-up for a period of three months to look for any onset of TB-IRIS. ResultsA total of 286 patients were included the study. The overall incidence of TB-IRIS was 7.7%. The occurrence of paradoxical TB-IRIS was nearly double than ART-associated TB-IRIS. There was a significant rise in the CD4 cell count in the patients of both paradoxical (p = 0.001) and ART-associated (p = 0.017) TB-IRIS. The plasma viral load at baseline also showed significant differences from the levels documented at the appearance of the TB-IRIS both in both the types i.e. paradoxical (p = 0.001) and ART-associated (p = 0.012) TB-IRIS. ConclusionPeople with HIV/TB coinfection experience high morbidity and death from all kinds of TB-IRIS, necessitating specific attention. As HIV-positive cases and implementation of ART continue to rise, it's vital to quickly rule out TB coinfection.

Unmasking the Truth: Progressive Multifocal Leukoencephalopathy–Immune Reconstitution Inflammatory Syndrome (PML-IRIS) in a 36-year Old Male with HIV, A Case Report

Progressive Multifocal Leukoencephalopathy Immune Reconstitution Inflammatory Syndrome (PMLIRIS) is the subacute onset of neurological deficits that appeared or was exacerbated after initiation antiretroviral therapy (ART) for treatment of PML. It is due to severe neuroinflammation with reestablishment of immunocompetence. Approximately 25% of patients with HIV and PML develop IRIS. Clinical trials on the treatment of PML-IRIS is lacking with only limited evidence supporting the use of investigative therapies such as corticosteroids and Maraviroc. We report a case of a 36-year old Filipino male, known hypertensive and diagnosed with HIV, who presented with memory problems. He was eventually treated as a case of PML-IRIS on the 3rd week after initiation of ART. He was treated with a course of intravenous Dexamethasone, oral Mefloquine and intravenous immunoglobulin, and ART was continued. Clinical outcome in our patient shows an overall improvement of symptoms and no deterioration of neurologic deficits.

A case of syphilis associated with immune reconstitution inflammatory syndrome and review of the literature

BackgroundImmune reconstitution inflammatory syndrome (IRIS) associated with syphilis has rarely been described in HIV-infected patients. Diagnosis can be challenging because it is not always possible to discern it from a recent infection or a worsening of an undiagnosed one.Case presentationAn HIV-positive 42-year-old man with a poor compliance history of antiretroviral therapy presented at our unit and complained of ocular symptoms. Ocular syphilis diagnosis was posed after initial misdiagnosing with cytomegalovirus infection, and antiretroviral therapy compliance improved after switching to a bictegravir-based regimen. Despite intravenous (IV) penicillin, we observed an initial worsening with the appearance of new skin lesions, and IRIS syphilis was suspected. In the literature, 14 cases of IRIS syphilis are described, all regarding male patients. Seven were HIV naïve to therapy, and 7 HIV-experienced with poor therapy compliance. Basal syphilis serology was negative in ten, with subsequent seroconversion after the development of IRIS. IRIS-syphilis development was observed after a median time of 28 days from ART initiation; 10 cases were considered "unmasking-IRIS" and 4 "paradoxical-IRIS". Skin and ocular involvement were the most often reported. In most cases, it was not necessary to use a systemic steroid. A good outcome was reported in 12.ConclusionsSyphilis should be considered in differential diagnosis with other diseases associated with IRIS. A negative syphilis serology before beginning antiretroviral therapy could convey the impression that syphilis has been ruled out. Whereas a high index of suspicion should be maintained when symptoms suggestive of syphilis, such as ocular and skin manifestations, are noticed after therapy has begun.

Whipple’s disease presenting as weight gain and constipation in a Chinese woman

BackgroundWhipple’s disease is a chronic infection due to Tropheryma whipplei, commonly reported in the Caucasian but not in the Chinese population.Case presentationA 52-year-old female with good past health, was diagnosed with Whipple’s disease, presenting with constipation, unintentional weight gain, and fleeting polyarthralgia. Investigations prior to admission showed raised CA125 and computed tomography of the abdomen showed multiple retroperitoneal mesenteric lymphadenopathies. Extensive investigations performed on secondary causes of weight gain were unrevealing. Subsequent PET-CT scan revealed generalized lymphadenopathy involving the left deep cervical, supraclavicular, and retroperitoneal mesenteric area. Excisional biopsy of the left supraclavicular lymph node was performed, with histology showing infiltrations of Periodic acid-Schiff positive foamy macrophages. T. whipplei DNA was detected in her serum, saliva, stool, and lymph node by PCR targeting the 16S ribosomal RNA gene. She was started on intravenous ceftriaxone, and then stepped down to oral antibiotics for a total of 44 months. The recurrence of fever after 12 days of ceftriaxone raised the suspicion of Immune Reconstitution Inflammatory Syndrome (IRIS). Serial imaging showed a gradual reduction in the size of retroperitoneal lymphadenopathies. Literature review on Whipple’s disease in the Chinese population identified 13 reports of detectable T. whipplei DNA in clinical specimens. The majority of the cases were pneumonia, followed by culture-negative endocarditis, encephalitis, and skin and soft tissue infection. However, most patients with pneumonia were diagnosed based on next generation sequencing alone, with the resolution of pulmonary infiltrates without adequate duration of antibiotics, suggesting the possibility of colonization instead of infection. The recommendation of long-term doxycycline suppression after treatment may be supported by the slow response of retroperitoneal lymphadenopathies to antibiotics in our patient.ConclusionsUnintentional weight gain and constipation could be atypical presentations of Whipple’s disease. It is a rare disease in the Chinese population despite the advancement of molecular techniques in the diagnosis of infections. A prolonged course of antibiotics may be required due to slow clinical response as documented by serial imaging in our case. The possibility of IRIS should be considered in patients with breakthrough fever during treatment of Whipple’s disease.

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 manifestations, treatment and outcomes of patients infected with Mycobacterium haemophilum with a focus on immune reconstitution inflammatory syndrome: a retrospective multi-site study

Background Mycobacterium haemophilum is a nontuberculous mycobacterium with fastidious in vitro growth requirements and an increasingly reported cause of extrapulmonary disease. Timely diagnosis and management of M. haemophilum infections and the immune reconstitution inflammatory syndromes (IRIS) observed in a subset of patients during treatment remain challenging. Methods We conducted a retrospective chart review between January 1, 2010, and January 1, 2022 and identified 26 patients diagnosed with M. haemophilum infection at our institution. We describe their clinical presentation, diagnostic results, management, and outcomes. Results The majority of patients in our cohort had upper and/or lower extremity skin involvement, were immunosuppressed, and had generally favourable treatment outcomes. All tested M. haemophilum isolates were susceptible in vitro to clarithromycin and trimethoprim-sulfamethoxazole. Moreover, high rates of susceptibility were noted for ciprofloxacin (95%), linezolid (90%), and rifampin (85%). IRIS was identified in 31% of cases and should be considered in patients who develop worsening skin lesions or systemic symptoms following the initiation of effective antimicrobial therapy. Visualisation of acid-fast bacilli on initial tissue stains, a positive mycobacterial blood culture, and rapid de-escalation of tumour necrosis factor-α inhibitors and/or corticosteroids were more frequently encountered among patients in our cohort who developed IRIS. Conclusion M. haemophilum infection should be considered among patients receiving immunomodulatory therapy who develop discoloured or nodular skin lesions involving the extremities, worsening focal arthritis, tenosynovitis, or isolated adenopathy. A heightened awareness of this pathogen’s clinical and laboratory characteristics can lead to a timely diagnosis and favourable outcome.

Cutaneous Tuberculosis in Heart Transplant

Tuberculosis is a disease with a significant global burden in terms of morbidity and mortality. It usually presents as a pulmonary disease but can occasionally have extrapulmonary presentations. Immunosuppressed people are at an increased risk of tuberculosis and more frequently have atypical manifestations of the disease. Cutaneous involvement is estimated to occur in only 2% of extrapulmonary presentations. We report a case of a heart transplant recipient with disseminated tuberculosis who initially presented with cutaneous manifestations in the form of multiple abscesses that were mistaken for a community-acquired bacterial infection. The diagnosis was made after positive nucleic acid amplification testing and cultures for Mycobacterium tuberculosis from the drainage of the abscesses. After initiating antituberculous treatment, the patient had 2 instances of immune reconstitution inflammatory syndrome. A combination of diminished immunosuppression due to discontinuation of mycophenolate mofetil in the setting of acute infection, rifampin drug interactions with cyclosporine, and the beginning of treatment of tuberculosis all contributed to this paradoxical worsening. The patient responded favorably to increased glucocorticoid therapy and showed no signs of treatment failure after 6 months of antituberculous therapy.

Review: The application of corticosteroids in cryptococcal meningitis.

Cryptococcal meningitis (CM) is a serious disease with high morbidity and mortality. Although the patients who received corticosteroids were at high risk of having CM, corticosteroids also have been used as an adjunct to antifungal drugs for treating people with CM in some situations (such as immune reconstitution inflammatory syndrome, cerebral cyptococcoma, et al.). Here, we summarize the current knowledge on the application of the corticosteroids in CM, aiming to help clinicians to reasonably use corticosteroids in patients with CM.

Immune reconstitution inflammatory syndrome following disseminated TB with cerebral venous thrombosis in HIV-negative women during their postpartum period: a case report.

We report an exceptional case of a 19-year-old HIV-negative lady who presented as IRIS following disseminated TB with cerebral venous thrombosis during her postpartum period. After 1 month of starting anti-TB therapy, we found a paradoxical worsening of her symptoms and further deterioration of radiological features showing extensive tubercular spondylodiscitis involving almost all the vertebral with extensive prevertebral and paravertebral soft tissue collections. Significant improvement was observed after 3 months of continuation of steroids along with an adequate dose of anti-TB therapy. The possible mechanism that could explain this dysregulated and exuberant immune response in HIV-negative postpartum women would be rapidly changing immunologic repertoire, as the recovery of the immune system causes an abrupt shift of host immunity from an anti-inflammatory and immunosuppressive status toward a pathogenic proinflammatory state. Its diagnosis mostly depends on having a high degree of suspicion and ruling out alternative etiology. Therefore, clinicians should be aware of the paradoxical worsening of TB-related symptoms and/or radiological features at the primary site of infection or new location following an initial improvement in adequate anti-TB therapy despite HIV status.

Cryptococcal Meningoencephalitis and Immune Reconstitution Inflammatory Syndrome in a patient on Tocilizumab Therapy: A Case Report (P1-10.005)

<h3>Objective:</h3> To describe a case of cryptococcal meningoencephalitis complicated by immune reconstitution inflammatory syndrome (IRIS), vasculitis, ischemic strokes, and hydrocephalus. <h3>Background:</h3> Cryptococcus neoformans is the most common cause of fungal meningitis worldwide and typically affects individuals with defects in cell-mediated immunity. A 71-year-old female with giant cell arteritis on daily prednisone and monthly Tocilizumab infusions presented with worsening headaches for 2 weeks and new-onset confusion for 3 days. Initial workup revealed hyponatremia (sodium 125 mmol/L) and community acquired pneumonia. She was treated with antibiotics, but her mental status rapidly declined necessitating endotracheal intubation. MRI Brain demonstrated multifocal areas of diffusion restriction in the bilateral cerebral and cerebellar hemispheres, basal ganglia, and brainstem with diffuse leptomeningeal enhancement. Cerebrospinal fluid (CSF) studies revealed an elevated opening pressure of 28 cm H₂O, positive CSF cryptococcal antigen, and CSF fungal cultures grew cryptococcus neoformans. She was started on empiric liposomal amphotericin B and flucytosine before the cryptococcal antigen and cultures resulted. Despite treatment, her neurological status continued to decline with repeat MRI showing new ischemic infarctions, subarachnoid hemorrhages, and leptomeningeal and parenchymal enhancement. Digital subtraction angiography revealed cerebral vasospasm and possible vasculitis. Repeat lumbar puncture demonstrated persistently elevated opening pressure, continued pleocytosis, and increased protein. She was continued on antifungal therapy and received IV methylprednisolone for IRIS. She additionally underwent ventriculoperitoneal (VP) shunt placement. Despite these interventions, her clinical status continued to deteriorate and she was palliatively extubated. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> N/A <h3>Conclusions:</h3> This patient presented with cryptococcal meningoencephalitis in the setting of immune suppression from prednisone and tocilizumab, a monoclonal antibody that targets the IL-6 receptor. Despite early and appropriate treatment, she continued to worsen with multiple complications including IRIS, a dysfunctional inflammatory response to infection precipitated by immune recovery. In patients treated appropriately for cryptococcal meningoencephalitis, a failure to respond should raise concern for complicating conditions. <b>Disclosure:</b> Dr. Navalkar has nothing to disclose. Dr. Sui has nothing to disclose. The institution of Dr. Bashir has received research support from NIH. The institution of Dr. Bashir has received research support from PICORI. The institution of Dr. Bashir has received research support from Sanofi. Dr. Bashir has received research support from GWSP. The institution of Dr. Bashir has received research support from Roche. The institution of Dr. Bashir has received research support from Novartis. The institution of Dr. Bashir has received research support from Hoffmann-La Roche.