Some patients with HIV/AIDS experience worsening clinical symptoms and even death after starting HAART, despite improvements in plasma HIV load and CD4+ T lymphocyte counts. This phenomenon is currently referred to as Immune reconstitution inflammatory syndrome (IRIS) in AIDS. iris has a high incidence, unclear pathogenesis, diverse presentation and non-specific treatment.
1. Definition
There is no universally accepted gold standard for the diagnosis of IRIS, but at least the following three conditions must be met: (1) significant improvement in plasma HIV load and CD4+ T lymphocyte count after HAART in HIV/AIDS patients; (2) clinical signs and symptoms consistent with the inflammatory process; (3) exclusion of the natural course of previous infection or adverse drug reactions.
2. Pathogenesis
The pathogenesis of IRIS is not well understood. Antigenic stimuli in the organism (including clinically occult structurally intact pathogens, dead or dying pathogens and their residual antigens) are necessary factors for the development of IRIS. The incidence of pathogen-associated IRIS is related to its ability to be cleared in vivo. Streptococcus pneumoniae can be cleared rapidly and the incidence of IRIS is low; in contrast, MycobacCterium tuberculosis (MTB) and Cryptococcus are not easily cleared and the incidence of IRIS is high. It is generally accepted that IRIS is due to the recovery of immune function after HAART, and the body produces an excessive immune inflammatory response against the antigenic components of latent or treated pathogens in the body, which leads to clinical deterioration.TB-associated IRIS patients have a large number of CD4+ T lymphocytes that produce specific IFNγ, so it is considered to be associated with specific helper T The pathology of IRIS-associated leukoencephalopathy and Candida meningitis-associated IRIS also showed vasculitic manifestations with a large infiltration of CD8+ T lymphocytes. Mori and Levin suggest that impairment of normal immune regulatory mechanisms, such as a decrease in the number and function of regulatory T cells (Tregs), which are responsible for downregulating the inflammatory response, is also involved in excessive immune activation, as confirmed in a prospective cohort study of TB-associated IRIS.
3. Risk factors
Risk factors for the development of IRIS include.
① the body being in overt/subclinical opportunistic infection or the presence of residual inactive pathogens or their antigenic components in the body.
(ii) Low baseline CD4+ T lymphocyte count in the body, such as CD4+ T lymphocytes <50×106/L and CD4/CD8 <0.15.
(iii) Rapid decrease in viral load in patients after HAART adoption.
(iv) The time of HAART initiation is too short from the time of diagnosis or treatment of opportunistic infections.
Other risk factors such as gender, age, and specific genes have also been reported. For example, male patients, young patients, and especially infants are at high risk of occurrence; cytomegaoviyns (CMV)-associated IRIS correlates with human leukocyte antigen-B44; genetic polymorphisms of specifically regulated cytokines such as interleukin-6, interleukin-12, and tumor necrosis factor-α and excessive Th1 response to Mycobacterium antigens response to mycobacterial antigens are associated. Therefore, patients with diffuse infections, low CD4+ T lymphocyte counts, and premature initiation of HAART are at high risk of developing IRIS.
4. Clinical manifestations
(1) Infection-related IRIS.
(1) Exposure IRIS, i.e., no manifestation of associated infection before performing HAART and only after treatment, mainly in response to active pathogens.
(2) Paradoxical IRIS, i.e. the infection existed or was treated before performing HAART, but worsened after treatment, mainly in response to the persistent antigenic component of inactive pathogens. Common pathogens include mycobacteria (Mycobacterium avium, MTB, Mycobacterium leprae, etc.), fungi (Cryptococcus neoformans), viruses (herpes simplex virus, herpes zoster virus, CMV, papillary polyomavirus, HBV, HCV, etc.) and Pneumocystis carinii. The biggest difference between infection-associated IRIS and new opportunistic infections is that the former is caused by an imbalance in immune reconstitution after performing HAART, while the latter is caused by a defect in immune function.
(2) TB-associated IRIS.
The incidence of this disease ranges from 7% to 45% and accounts for almost 1/3 of all IRIS. risk factors for the development of IRIS include: the patient’s combination of extrapulmonary or disseminated TB; HAART initiation within 6 weeks of anti-TB therapy; and the patient’s low baseline CD4+ T lymphocyte count and high viral load at the time of HAART initiation. The disease presents with recurrence or worsening of TB-related symptoms, such as high fever, enlarged or even suppurating lymph nodes, worsening pulmonary symptoms, or worsening imaging lesions. Abdominal TB-associated IRIS presents with abdominal pain and obstructive jaundice. CNS TB-associated IRIS appears later, usually 5 to 10 months after HAART is performed. Once it appears, the symptoms are severe, so the clinic should be on high alert. There is a lack of diagnostic criteria for this disease. For patients with HIV-combined TB, if symptoms worsen after HAART, especially within the first 2 months, the disease should be highly alerted after first ruling out deterioration due to anti-TB treatment failure (due to the presence of drug-resistant MTB or inadequate treatment), adverse drug reactions or other opportunistic infections.
(3) Atypical mycobacteria-associated.
IRIS Mycobacterium avium infection-associated IRIS is mainly characterized by a limited inflammatory response, unlike the disseminated infection commonly seen in patients with advanced AIDS, and mainly presents with high fever and lymph node enlargement, with some patients showing pneumonia, chest radiographs showing inflammatory infiltrative shadow in the lungs, and possibly bone destruction and brain abscess. The disease mostly occurs within the first 3 months of HAART and is difficult to distinguish from other mycobacterial infections on imaging.
(4) Novel cryptococcal-associated.
IRIS has two main clinical manifestations: central nervous system damage (including meningitis and brain parenchymal disease) and lymphadenitis. Cryptococcal IRIS is more likely to occur after HAART in AIDS patients with cryptococcal meningitis, and the clinical symptoms are mainly headache, which can occur 2 weeks to 4 months after HAART. Patients have higher CSF pressure and detectable higher WBC counts with negative cryptococcal cultures compared to the start of treatment.
(5) CMV-associated IRIS.
This disease is most commonly associated with ocular involvement and presents as new or recurrent retinitis, usually occurring within the first 3 months of performing HAART. In addition to typical CMV retinitis, it can also cause new disease, including immune recovery vitritis (IRV), immune recovery uveitis (IRU), papillitis, and macular edema. While typical CMV retinitis is primarily a mild intracellular inflammation, the aforementioned neoplastic disease is primarily an inflammatory response to residual CMV antigen or protein components in the eye, manifesting as impaired vision or floating black shadows in front of the eyes.
(6) HBV/HCV-related.
IRIS The disease usually appears 2-8 weeks after performing HAART, with an incidence of 1-5%. It presents with fever, night sweats, poor appetite, nausea and malaise, jaundice and signs of hepatomegaly on examination, and biochemical tests showing elevated liver enzymes. Other causes of elevated liver enzymes must be excluded, including hepatotoxicity of drugs (e.g., protease inhibitors or nevirapine), drug-induced lactic acidosis, Kaposi’s sarcoma, or other hepatophilic viral infections. The diagnostic value of liver puncture pathology findings is high, which show significant necrosis of liver tissue with a large infiltration of CD8+ T lymphocytes, suggesting an active inflammatory response, and no microbiological evidence of other associated infectious diseases that can cause liver damage was found. In HIV co-infected HBV patients, high HBV DNA and ALT levels prior to HAART were risk factors for hepatitis recurrence. The prognosis of HBV/HCV-associated IRIS depends on the patient’s residual liver function reserve. Some patients have only transient elevated levels of liver enzymes and HBV DNA or HCV RNA; however, others may rapidly progress to cirrhosis even if HAART is discontinued.
(7) Progressive multifocal leukoencephalopathy (PML)-associated IRIS.
PML is a lethal opportunistic infection in AIDS patients. the incidence of IRIS in PML patients after HAART is as high as 23%, and whether PML develops into IRIS has no impact on the prognosis itself.
(8) Non-infection related IRIS.
Granulomatous inflammation, also a manifestation of IRIS, is an immune-mediated inflammation similar to sarcoidosis, but the former is an inflammatory response to HAART, whereas the latter is a disease that commonly occurs in HIV-positive patients not on HAART. Autoimmune diseases can be new or worsening of existing diseases, such as toxic diffuse goiter, systemic lupus erythematosus, polymyositis, rheumatoid arthritis, Guillain-Barré syndrome, etc. Malignant diseases such as Kaposi’s sarcoma and lymphoma are also seen in IRIS. Kaposi’s sarcoma-associated IRIS usually occurs within the first 2 to 3 months of performing HAART. Cutaneous Kaposi’s sarcoma presents with further expansion of skin damage or pain; visceral Kaposi’s sarcoma, once present, is fatal and effective when treated with cytotoxic drugs.
5.Prevention and treatment
Active and effective prevention of IRIS is very important. Given that the patient’s level of immune status prior to HAART, the presence of opportunistic infections, and the interval between starting HAART and the diagnosis and treatment of opportunistic infections are all associated with the risk of IRIS, we recommend that the timing of starting HAART is: before the patient develops severe immunodeficiency and after existing opportunistic infections have been identified and stabilized by treatment. Therefore, a comprehensive screening for opportunistic infections should be performed first before starting HAART. When opportunistic infections are present, especially in patients in a highly immunosuppressed state, the possible risks of delaying HAART versus the benefits gained by reducing the occurrence of IRIS should be carefully evaluated to determine the optimal timing of HAART initiation.
Currently, there are no guidelines to follow for the treatment of IRIS, which are derived only from experience and expert consensus. The key to treatment is early diagnosis and identification of adverse drug reactions and new infections. For IRIS associated with opportunistic infections, aggressive treatment should be directed at the pathogen to reduce the antigenic load in the body and mitigate the immune response caused by the causative agent. NSAIDs and hormones have been widely used in patients with IRIS to control the inflammatory response, especially in patients with severe disease (including CNS disease, obstructive lymphadenopathy, and severe respiratory symptoms), however, their safety and efficacy need to be further evaluated. In severe TB-related IRIS, such as the presence of enlarged lymph nodes compressing the airway, refractory lymphadenitis, severe respiratory symptoms including wheezing or acute respiratory distress syndrome, the application of hormones is justified. Hormones may be applied in recurrent immune restorative uveitis, and local hormonal intravitreal injections may be performed in primary retinal vasculitis. In novel cryptococcal-associated IRIS, HAART should be delayed as much as possible, with antifungal therapy first and combined with intravenous administration of glucocorticoids to reduce the inflammatory response.
It is now generally accepted that interruption of HAART will increase the risk of other opportunistic infections. Therefore, HAART should be adhered to as much as possible unless IRIS causes severe disease or even has a risk of fatal or permanent sequelae.
6. Prognosis
The vast majority of patients with IRIS have a self-limiting course, but the prognosis varies widely from patient to patient. IRIS-related deaths are relatively rare. In general, those with cryptococcal and MTB invasion of the central nervous system have a poor prognosis.
7. Conclusion
Although the widespread use of HAART has significantly improved the course of HIV infection, the increasing incidence of IRIS, a group of diseases that emerge after antiretroviral therapy in some HIV-infected/AIDS patients, poses a challenge to clinicians year by year. The clinical manifestations of immune reconstitution inflammatory syndrome are diverse, and there is a lack of accepted diagnostic criteria and treatment guidelines. Therefore, early identification of risk factors for immune reconstitution inflammatory syndrome, active exploration of the pathogenesis of IRIS and diagnostic and prevention strategies, and early formulation of IRIS-related treatment guidelines are among the important issues in the future treatment of AIDS.