HIV and immune reconstitution inflammatory syndrome

BACKGROUND

Immune reconstitution occurs when a patient's impaired immune system function is restored. For instance, HIV patients have suppressed immune systems that are unable to adequately fight against infections and diseases, making them extremely vulnerable to opportunistic infections (infections that occur in individuals with weakened immune systems). When an infectious organism enters the body of an immunocompromised HIV patient, the inflammatory process is inhibited. Therefore, HIV patients receive antiretroviral therapy (ART), which helps stop the retrovirus from multiplying and subsequently repairs the body's immune system.

Some HIV patients with very weak immune systems, especially those receiving ART, experience immune reconstitution inflammatory syndrome (IRIS). Once the immunocompromised patient receives treatment that restores immune system function, the body is capable of recognizing infectious organisms. If an infectious organism is present, it will trigger an overproduction of inflammatory mediators. This condition is called IRIS.

While immune reconstitution syndrome signals a healthier immune system, it can be a serious and potentially fatal condition. Common infections associated with IRIS include cryptococcal meningitis, cytomegalovirus infections, mycobacterium avium complex (MAC) infections, tuberculosis (TB) and Pneumocystis jiroveci pneumonia (formerly known as Pneumocystis carinii pneumonia).

Researchers estimate that about 20% of patients receiving ART develop IRIS.

Most cases of IRIS resolve in a few weeks with continued HIV treatment. In addition, antibiotics, antifungals or antivirals may be administered to treat OIs, and corticosteroids may be used to suppress the inflammatory process.

CAUSES

Some HIV patients with very weak immune systems, especially those receiving antiretroviral therapy (ART), experience immune reconstitution inflammatory syndrome (IRIS). Once the immunocompromised patient receives treatment that restores immune system function, the body is capable of recognizing infectious organisms. If an infectious organism is present, it will trigger an inflammatory immune response known as IRIS.

Many of the reported IRIS cases in medical literature occurred a few months after ART was initiated. The specific mechanisms involved in the pathogenesis of IRIS are not well understood. However, many experts suggest that IRIS is the result of an enhanced immune response to disease-specific antigens, which subsequently causes an overproduction of inflammatory mediators.

IRIS may occur in response to many pathogens. The most common infections associated with IRIS include cryptococcal meningitis, cytomegalovirus infections, mycobacterium avium complex (MAC) infections, tuberculosis (TB) and Pneumocystis jiroveci pneumonia (formerly known as Pneumocystis carinii pneumonia).

RISK FACTORS

The risk factors associated with the development of IRIS are poorly understood. It appears that the risk is higher if ART is initiated soon after treatment for opportunistic infection (OI) is started. It also appears that patients who experience a sharp rise in CD4 cell counts in the early weeks or months after initiation of ART have an increased risk of developing IRIS.

However, the optimal timing of ART initiation in relation to OI treatment remains unclear because there are several factors to consider. For instance, the type of pathogen that induced the OI, the severity of the OI, the type of medication used to treat the OI and potential risk for drug toxicity or interactions should be taken into consideration.

SYMPTOMS

General: Symptoms vary depending on the specific OI associated with IRIS. In general, inflammatory signs that the immune system is functioning usually include fever, swelling and redness at the site of injury or infection, thick drainage and discharge at the site of infection and warmth and pain at the infection site. Below are some of the most common OIs that occur in IRIS patients.

Cryptococcal meningitis: Cryptococcal meningitis is an infection of the meninges (membranes that surround the brain and spinal cord) caused by the fungus Cryptococcus neoformans. Symptoms usually include fever, headache, enlarged lymph nodes, blurred vision, sensitivity to light, stiff neck, seizures, confusion, behavior or mood changes, coma, nausea and vomiting. Onset of the infection has been reported between one week and 11 months after initiating ART.

Cytomegalovirus (CMV): Cytomegalovirus (CMV) is a common viral infection that is related to herpes. The infection is usually a late complication, occurring about three years after HIV patients begin ART. Cytomegalovirus may affect one eye at first, but usually progresses to both eyes. Common symptoms include floaters (seeing spots or spider webs), light flashes, blind spots, blurred vision, obstructed areas of vision, photophobia (abnormal sensitivity to light) and sudden decrease of vision. Symptoms worsen as the patient's ability to fight off the infection decreases. In about 30% of cases there is evidence of retinal damage.

Mycobacterium avium complex (MAC): Mycobacterium avium complex (MAC), or mycobacterium avium intracellulare (MAI), is a bacterial infection that is caused by either Mycobacterium avium or Mycobacterium intracellulare. MAC can be mild and localized or it can be severe, requiring systemic anti-inflammatory therapy, in addition to anti-MAC (antibiotic) therapy. Enlarged lymph nodes and fever are the characteristic symptoms of MAC. Other symptoms may include high fever, drenching sweats, diarrhea, weight loss, abdominal pain, fatigue, weakness, anemia (low levels of red blood cells), neutropenia (low levels of white blood cells), thrombocytopenia (low levels of platelets), blood infections, viral hepatitis (liver infection), skin lesions, pneumonia and elevated liver function tests. The liver or spleen may be enlarged.

Tuberculosis (TB): Tuberculosis (TB) is a bacterial infection of the lungs, which is caused by the microorganism Mycobacterium tuberculosis. In an HIV patient who is receiving therapy for active TB, the onset of TB IRS typically occurs one to six weeks after the initiation of ART. The signs and symptoms of tuberculosis (TB) may include high fevers, lymphadenopathy (enlarged lymph nodes), worsening of pulmonary symptoms and infiltrates and pleural effusions. Non-pulmonary symptoms may include expanding central nervous system lesions, skin or visceral abscesses, bone lesions or hypercalcemia (high levels of calcium in the blood).

Pneumocystis jiroveci pneumonia: Pneumocystis jiroveci pneumonia (formerly called Pneumocystis carinii pneumonia) is the most common opportunistic infection that occurs in HIV patients. Originally, researchers thought a one-cell organism (protozoan) called Pneumocystis carinii caused the disease, but recent research suggests that is a fungus called Pneumocystis jiroveci. The disease almost always affects the lungs, causing a type of pneumonia. The first signs of PCP are difficulty breathing, fever and a dry cough.

Symptoms may include shortness of breath (especially after physical activity), fever, nonproductive cough, chest discomfort, weight loss, chills, hemoptysis (spitting up blood), tachypnea (rapid breathing), tachycardia (fast heart rate), mild crackles (bubbling, or rattling sounds that occur when air moves through fluid-filled airways), cyanosis (bluish discoloration of the skin), nasal flaring and intercostals retractions (visible use of muscles between the ribs, which indicates labored breathing). If IRIS occurs in patients with Pneumocystis jiroveci pneumonia, severe acute respiratory failure may result.

DIAGNOSIS

A working group in the AIDS CLINICAL TRIALS GROUP first proposed diagnostic criteria for IRIS. In June 2006, researchers confirmed that the criteria proposed could be used to diagnose IRIS in patients starting HIV treatment. Based on the criteria, a diagnosis can be made if the patient experiences new or worsening symptoms of an infection or inflammation after starting antiretroviral therapy, symptoms cannot be explained by a new infection or the expected course of an infection that was diagnosed previously and the patient experiences a decrease in viral load of at least 1 log10.

TREATMENT

General: Most cases of IRIS resolve within a few weeks with continued HIV treatment. In addition, antibiotics, antifungals or antivirals may be administered to treat OIs, and corticosteroids may be used to suppress the inflammatory process.

Highly active antiretroviral therapy (HAART): When HIV reproduces, different strains of the virus emerge, and some are resistant to antiretroviral drugs. Therefore, it is common for healthcare providers to recommend a combination of antiretroviral drugs known as HAART. This strategy, developed by NIAID-support researchers, usually combines drugs from at least two different classes of antiretroviral drugs, and it has been shown to suppress the virus. While these drugs cannot cure HIV infection or AIDS, they can suppress the virus.

Currently, the U.S. Food and Drug Administration (FDA) has approved 28 antiretroviral drugs to treat HIV. These drugs fall into three major classes - reverse transcriptase (RT) inhibitors, fusion inhibitors and protease inhibitors. In July 2006, the FDA approved a multi-class combination called Atripla©.

Fusion inhibitors prevent the virus from fusing with the cellular membrane, thus blocking entry into the cell. Only one fusion inhibitor, Fuzeon©, is FDA-approved.

Protease inhibitors (PIs) interfere with the protease enzyme that HIV uses to produce infectious viral particles. They are a class of medication used to treat or prevent viral infections, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of protease, an enzyme used by the virus to cleave nascent proteins for final assembly of new virons. FDA-approved protease inhibitors include Agenerase©, Aptivus©, Crixivan©, Invirase©, Kaletra©, Lexiva©, Norvir©, Prezista©, Reyataz© and Viracept©.

Reverse transcriptase (RT) inhibitors disrupt the reverse transcription stage in the HIV lifecycle. During this stage, an HIV enzyme, known as reverse transcriptase, converts HIV RNA to HIV DNA. There are two main types of RT inhibitors - non-nucleoside RT inhibitors and nucleoside/nucleotide RT inhibitors. Non-nucleoside RT inhibitors bind to reverse transcriptase, preventing HIV from converting the HIV RNA into HIV DNA. Approved non-nucleoside RT inhibitors include Rescriptor©, Sustiva© and Viramune©.

Nucleoside/nucleotide RT inhibitors serve as faulty DNA building blocks, and once they are incorporated into the HIV DNA, the DNA chain cannot be completed. Therefore, the drugs prevent HIV from replicating inside a cell. Approved drugs include Combivir©, Emtriva©, Epivir©, Epzicom©, Hivid©, Retrovir©, Trizivir©, Truvada©, Videx EC©, Videx©, Viread©, Zerit© and Ziagen©.

Corticosteroids: Corticosteroids have been used to suppress inflammation caused by IRIS. However, it is unclear whether corticosteroids are necessary because in most cases, patients get better with continued HIV and OI treatment alone.

Antifungals: Antifungals are usually administered intravenously. Amphotericin B (Amphocin©) and fluconazole (Diflucan©) are the most common drugs used to treat cryptococcus meningitis. Once the infection has been treated, it is usually recommended that the person continue treatment for life in order to prevent the infection from recurring.

Anti-virals: Anti-viral medications (like Ganciclovir© or Foscarnet©) are often prescribed to treat cytomegalovirus (CMV). These drugs can be administered orally, intravenously, injected directly into the eye or through an intravitreal implant.

Antibiotics: A combination of antibiotics (at least two drugs) is used to treat mycobacterium avium complex (MAC). Usually azithromycin or clarithromycin is used with up to three other drugs. MAC treatment must continue for life in order to prevent the infection from recurring. Commonly prescribed antibiotics include amikacin (Amkin©), azithromycin (Zithromax©), ciprofloxacin (Cipro© or Ciloxan©), clarithromycin (Biaxin©), ethambutol (Myambutol©), rifabutin (Mycobutin©) and rifampin (Rifampicin©, Rifadin©, Rimactane©). However, rifabutin (Mycobutin©) should not be used to treat HIV patients who are taking the protease inhibitor saquinavir or the non-nucleoside reverse transcriptase inhibitor delavirdine because there is an increased risk of serious side effects like uveitis (inflammation of the inner eye).

Combination antibiotics: HIV patients who have tuberculosis usually receive several different medications. The most common drugs used to treat tuberculosis include isoniazid, rifampin (Rifadin© or Rimactane©), ethambutol (Myambutol©) and pyrazinamide. Cycloserine (Seromycin©), capreomycin (Capastat©), aminosalicylic acid and streptomycin sulfate have also been used to treat tuberculosis. Standard tuberculosis treatments last from six to nine months.

TMP/SMX: TMP/SMX (Bactrim© or Septra©) is the most effective treatment for Pneumocystis jiroveci pneumonia. The drug, which is taken orally, is a combination of two antibiotics - trimethoprim (TMP) and sulfamethoxazole (SMX). The SMX antibiotic is a sulfa drug, which may induce an allergic reaction in some patients. Cutting back from one pill a day to three pills a week has shown to reduce the risk of allergy. Allergic reactions to the drug usually induce a skin rash and sometimes a fever. Allergic reactions can be overcome with a desensitization procedure. Patients start with a very small amount of the drug and take increasing doses until they can tolerate the full dose.

Dapsone: Dapsone is a sulfone anti-infective drug that is similar to TMP/SMX. Dapsone is almost as effective against Pneumocystis jiroveci pneumonia as TMP/SMX, and it causes fewer allergic reactions. Dapsone is taken orally.

Pentamidine: Pentamidine (NebuPent©, Pentam©, Pentacarinat©) is a drug that is inhaled in an aerosol form to prevent Pneumocystis jiroveci pneumonia. Pentamidine can also be administered intravenously (IV) to treat active Pneumocystis jiroveci pneumonia. Patients receive pentamidine at a health clinic that has a nebulizer. The nebulizer is a machine that produces a very fine mist of the drug. The mist is inhaled directly into the lungs. The procedure takes about 30 to 45 minutes.

Atovaquone (Mepron©): Atovaquone (Mepron©) is an antibiotic that is used in patients who have mild or moderate cases of Pneumocystis jiroveci pneumonia who cannot take TMP/SMX or pentamidine.

INTEGRATIVE THERAPIES

Good scientific evidence :

Bromelain : Several preliminary studies suggest that when taken by mouth, bromelain can reduce inflammation or pain caused by inflammation. Better quality studies are needed to confirm these results.

Avoid if allergic to bromelain, pineapple, honeybee, venom, latex, birth pollen, carrots, celery, fennel, cypress pollen, grass pollen, papain, rye flour, wheat flour or other members of the Bromeliaceae family. Use cautiously in patients who have a history of bleeding disorders, stomach ulcers, heart disease, liver disease or kidney disease. Use cautiously before dental or surgical procedures or while driving or operating machinery. Avoid if pregnant or breastfeeding due to limited scientific evidence of safety. Also, bromelain may cause abnormal uterine bleeding.

Comfrey : In vitro studies have found that comfrey may have anti-inflammatory effects. Clinical trials investigating topical application of comfrey-containing creams have found significant reductions in inflammation and pain associated with sprains and muscle injuries. Overall, these studies have been well designed although some improvements in reporting are needed.

Avoid if allergic or hypersensitive to comfrey, its constituents or members of the Boraginaceae family. Avoid oral comfrey due to hepatotoxic (liver toxicity) and carcinogenic (cancer-causing) pyrrolizidine alkaloids. Oral use has caused death. Avoid topical comfrey on broken skin due to hepatotoxic and carcinogenic pyrrolizidine alkaloids. Avoid topical comfrey in individuals with or at risk for hepatic disorders, cancer or immune disorders. Use topical creams containing comfrey cautiously if taking anti-inflammatory medications or cytochrome P450 3A4-inducing agents. Use extreme caution when using topical creams containing comfrey for extended periods. Avoid topical comfrey in pregnant or lactating patients due to potential for absorption of toxic compounds.

Probiotics : Limited evidence with day care children suggests supplementation with Lactobacillus GG may reduce number of sick days, frequency of respiratory tract infections, and frequency of related antibiotic treatments.

Fermented milk (with yogurt cultures and L. casei DN-114001) may reduce the duration of winter infections (gastrointestinal and respiratory), as well as average body temperature, in elderly people.

Probiotics are generally considered safe and well tolerated. Avoid if allergic or hypersensitive to probiotics. Use cautiously if lactose intolerant.

Unclear or conflicting scientific evidence :

Astragalus : One clinical trial suggests the potential for benefit of astragalus in patients with tuberculosis. Further well-designed clinical trials are required before recommendations can be made.

Beta-sitosterol : Beta-sitosterol and beta-sitosterol glucoside have been studied for the adjunct treatment of tuberculosis with anti-tuberculin regimens. Only one randomized controlled trial, which included a small number of patients, studied beta-sitosterol and beta-sitosterol for this indication. Larger populations of patients with tuberculosis should be evaluated in randomized controlled trials if conclusions are to be made.

Black tea : In one small study, inhaled tea catechin was reported as temporarily effective in the reduction of methicillin-resistant Staphylococcus aureus (MRSA) infection and shortening of hospitalization in elderly patients with MRSA infected sputum. Additional research is needed to further explore these results.

Blessed thistle : Laboratory studies report that blessed thistle (and chemicals in blessed thistle such as cnicin and polyacetylene) has activity against several types of bacteria and no effects on some types. Reliable human study is lacking. Further evidence is necessary in this area before a firm conclusion can be drawn.

Cat's claw : Several laboratory and animal studies suggest that cat's claw may reduce inflammation, and this has led to research of cat's claw for conditions such as rheumatoid arthritis. Large, high-quality human studies are needed comparing effects of cat's claw alone vs. placebo before a conclusion can be drawn.

Cranberry : Study results of cranberry as an antibacterial in other conditions show conflicting results. Further studies are needed before a conclusion can be drawn.

Dandelion : Research in laboratory animals suggests that dandelion root may possess anti-inflammatory properties. There are no well-conducted human studies currently available in this area.

Euphorbia : One clinical trial on patients with acute dental pulpitis has been done with Euphorbia balsamifera and it was concluded that the effect of this herbal was comparable to that of pulpal nerve caustics.

Eyebright : Limited evidence from animal research suggests that several iridoid glycosides isolated from eyebright, particularly aucubin, possess anti-inflammatory properties comparable to those of indomethacin. The mechanism of action may be by the inhibition of thromboxane-synthase. The clinical relevance in humans is unclear, and there are no known human clinical observations or controlled trials in this area. Therefore, there is currently insufficient evidence to recommend for or against eyebright as an anti-inflammatory agent.

Garlic : Preliminary studies documented potential benefits of oral plus intravenous garlic in the management of cryptococcal meningitis. Further research is needed before recommending for or against the use of garlic in the treatment of this potentially serious condition, for which other treatments are available.

Ginseng": In patients treated with Hochu-ekki-to, which contains ginseng and several other herbs, urinary MRSA has been reported to decrease after a 10-week treatment period. Further studies of ginseng alone are necessary in order to draw a firm conclusion.

Goldenseal : The goldenseal component berberine has effects against bacteria and inflammation. Several poorly designed human studies report benefits of berberine used in the eye to treat trachoma (infectious eye disease). Better research is needed before a recommendation can be made.

Hydrotherapy : There is preliminary evidence that some hydrotherapy techniques may reduce bacteria on the surface of the skin. It is not known if there are benefits (or potentially harmful effects) of reducing skin bacteria. There may be benefits in people with skin wounds or ulcers who are at risk of infection. There is no evidence that infection of the skin itself (cellulitis) is improved.

L-carnitine : A preliminary study suggests anti-bacterial activity may be increased in patients who have tuberculosis given acetyl-L-carnitine. Well-designed clinical trials are required before recommendations can be made.

Lavender : Early laboratory studies suggest that lavender oils may have antibiotic activity. However, this has not been well tested in animal or human studies.

Probiotics : As a bacterial reservoir, the nose may harbor many varieties of potentially disease-causing bacteria. There is limited evidence that probiotic supplementation may reduce the presence of harmful bacteria in the upper respiratory tract. More studies are needed to establish this relationship and its implications for health.

Results are mixed regarding the ability of probiotics to reduce infective complications of medical treatment. Reduced incidence of infection has been seen in patients treated for brain injury, abdominal surgery and liver transplantation. Other studies have shown no such reduction in elective abdominal surgery and critical care patients.

Seaweed, kelp, bladderwrack : Laboratory studies suggest antifungal and antibacterial activity of bladderwrack. However, there are no reliable human studies to support use as an antibacterial or antifungal agent.

Selenium : Preliminary research reports that selenium can be beneficial in the prevention of several types of infection, including recurrence of erysipelas (bacterial skin infection associated with lymphedema) or Mycoplasma pneumonia. Further research is needed to confirm these results before a clear recommendation can be made.

Sorrel : There are no well-conducted published studies that demonstrate sorrel to possess activity against viruses or bacteria that are important human pathogens.

Tea tree oil : Laboratory studies report that tea tree oil has activity against MRSA. It has been proposed that using tea tree oil ointment in the nose, as well as a tea tree body wash may treat colonization by the bacteria. However, there is currently not enough information from studies in humans to make recommendations for or against this use of tea tree oil.

Turmeric : Laboratory and animal studies show anti-inflammatory activity of turmeric and its constituent curcumin. However, reliable human research is lacking.

Vitamin D : Preliminary human evidence suggests that vitamin D and its analogues, such as alfacalcidol, may act as immunomodulatory agents. More studies are needed to confirm these results.

Fair negative scientific evidence :

Probiotics : Bacterial translocation (passage of bacteria from the gut to other areas of the body where they can cause disease) is of special concern in surgery. Limited evidence suggests that supplementation with probiotics may not reduce this problem.

PREVENTION

Currently, there is no known method of prevention.

AUTHOR INFORMATION

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

• AIDS Education and Training Centers National Resource Center. www.aidsetc.org.
• AIDS INFONET. Immune restoration syndrome. www.aidsinfonet.org.
• HIV Medicine. www.hivmedicine.com.
• Natural Standard: The Authority on Integrative Medicine. www.naturalstandard.com. Copyright © 2008.
• Robertson J, Meier M, Wall J, et al. Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clin Infect Dis 42: 1639-1646, 2006. View abstract