When the Cure Becomes the Problem: A Case Report of Immune Reconstitution Inflammatory Syndrome Associated With Varicella Encephalitis.

Immune reconstitution inflammatory syndrome (IRIS) describes a constellation of inflammatory symptoms that develop following the initiation of antiretroviral therapy (ART) in patients with advanced human immunodeficiency virus (HIV). Here, we present a case of a 39-year-old male-to-female transgender patient with advanced HIV who was started on ART during a hospitalization for acute encephalopathy due to a combination of methicillin-resistant Staphylococcus aureus (MRSA) meningitis and varicella encephalitis. After adequate treatment of these infections and five weeks after initiation of ART, she developed inflammatory symptoms of malaise, fever, and tachycardia, as well as laboratory findings of leukocytosis consistent with an inflammatory process. Infectious workup did not reveal any evidence of a new infection, and no other undiagnosed inflammatory processes were discovered to explain these symptoms. A diagnosis of IRIS was suspected, possibly induced by a prior varicella infection. Diagnosis of IRIS can be difficult due to heterogeneous symptoms, differing etiologies, variable patient presentations, and the lack of universal diagnostic criteria. As instances of IRIS are not uncommon in patients with a low CD4 count who start on ART, there should be a high index of suspicion when patients present with inflammatory symptoms after initiation of ART. With increased recognition of the disease and improved standardization of diagnostic criteria, more could be understood about the underlying disease process which may allow for better targeted therapies and individualized treatments for patients who develop the immune reconstitution inflammatory syndrome.

mTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury.

The acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation (MV) maintains gas exchange in patients with ARDS but exposes lung cells to physical forces that exacerbate injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during MV impairs lung function. We found that mTORC1 is activated in lung epithelial cells following volutrauma and atelectrauma in mice and humanized in vitro models of the lung microenvironment. mTORC1 is also activated in lung tissue of mechanically ventilated patients with ARDS. Deletion of Tsc2, a negative regulator of mTORC1, in epithelial cells impairs lung compliance during MV. Conversely, treatment with rapamycin at the time MV is initiated improves lung compliance without altering lung inflammation or barrier permeability. mTORC1 inhibition mitigates physiologic lung injury by preventing surfactant dysfunction during MV. Our data demonstrate that, in contrast to canonical mTORC1 activation under favorable growth conditions, activation of mTORC1 during MV exacerbates lung injury and inhibition of this pathway may be a novel therapeutic target to mitigate ventilator-induced lung injury during ARDS.

Sirtuin 2 enhances allergic asthmatic inflammation.

Allergic eosinophilic asthma is a chronic condition causing airway remodeling resulting in lung dysfunction. We observed that expression of sirtuin 2 (Sirt2), a histone deacetylase, regulates the recruitment of eosinophils after sensitization and challenge with a triple antigen: dust mite, ragweed, and Aspergillus fumigatus (DRA). Our data demonstrate that IL-4 regulates the expression of Sirt2 isoform 3/5. Pharmacological inhibition of Sirt2 by AGK2 resulted in diminished cellular recruitment, decreased CCL17/TARC, and reduced goblet cell hyperplasia. YM1 and Fizz1 expression was reduced in AGK2-treated, IL-4-stimulated lung macrophages in vitro as well as in lung macrophages from AGK2-DRA-challenged mice. Conversely, overexpression of Sirt2 resulted in increased cellular recruitment, CCL17 production, and goblet cell hyperplasia following DRA challenge. Sirt2 isoform 3/5 was upregulated in primary human alveolar macrophages following IL-4 and AGK2 treatment, which resulted in reduced CCL17 and markers of alternative activation. These gain-of-function and loss-of-function studies indicate that Sirt2 could be developed as a treatment for eosinophilic asthma.