AIDS Block 3

Candida albicanes

Fungus that normally infects the mouth and throat - an early oral OI that can spread into the lungs if untreated.

Cryptococcosus neoformans

-Overview: Brain fungus that is commonly associated with bird poop. Spores are rehydrated in the lung and infect macrophages. Infected macrophages then travel through the blood-brain barrier and bring the fungus with them. Normally very easily cleared by CD4 cells.

-Symptoms: Nausea, malaise, headache, fever, confusion, untreated infections result in meningitis and can be fatal.

-Diagnosis: Via CAT scan or MRI to visualize signs of brain atrophy, or immunoblot cerebral spinal fluid for ______ antibodies.

-Treatment: Antifungals maintained for many months, and it is normally treated before starting ARVs to minimize risk of IRIS.

Encephalopathy

-Overview: Causes HIV-associated dementia and peripheral neuropathies (tingling + burning in extremeties)

-Cause: Directly caused by HIV crossing the blood brain barrier within an infected immune cells.

-The faster ARVs are administered, the less chance of HIV in the brain; however, this can happen at any time during HIV infection, even in people with healthy CD4 levels.

-CNS HIV forms can evolve separately and develop separate drug resistance profiles than HIV in other areas of the body, making treatment difficult.

Progressive Multifocal Leukoencephalopathy (JC Virus)

-Overview: Demyelination of multiple areas of the brain caused by _______. Upon reactivation, it can also cause kidney problems, as the virus is shed in the urine and can infect kidney cells.

-Cause: _______ commonly infects people in adolescence via GI tract and saliva, and remains as a latent infection controlled by CD8 cells. It only becomes an issue for immunocompromised people when they can no longer control the infection.

-Symptoms: Rapid changes in behavior, motor skills, and personality.

-Diagnosis: Difficult to diagnose due to similarities with other brain pathogens. Can check for _________ in cerebral spinal fluid or perform a brain biopsy.

-Treatment: Initiate ARV treatment if patient is not already on it. Generally bad prognosis, as no direct way to treat the virus besides CD8 control, and ARVs can potentially cause IRIS in the brain.

Toxoplasmosis

-Overview: An apicomplexan that infects the brain. Can potentially be deadly depending on the strain, and is especially dangerous for newborns.

-Lifecycle: Oocyte is ingested via the mouth (from uncooked meat, exposure to cat feces, or eating produce/shellfish that have been contaminated with cat feces) → 4 sporoziotes are released and associated with the epithelial surface of intestines → Become trophozoites, which divide into “meront” structures → 8 merozoites are released and go on to infect other cells. _______ specific merozoites leave the gut and initiate latent infections (Bradyzoite - slow growing) in muscles and brain by forming parasite filled cysts.

The sexual phase can ONLY BE COMPLETED IN CATS: Merozoites divide into gametes → two gametes fuse to form ooctye (contains 4 sporozoites). Oocyte then released in cat feces.

-Symptoms: Headache, confusion, lethargy, personality changes, seizures, fever.

-Diagnosis: Measuring for _______ antibodies or via brain biopsy to check for oocytes and bradyzoites.

-Treatment: Patient is first treated with antiparasitic Daphrim, then put on ARVs to maintain CD4 levels and avoid IRIS in brain. If patient has toxo antibodies but no obivous infection, they are treated prophylactically with bactrim to prevent proliferation

Pneumocystis pneumonia

-Overview: Common environmental fungus that can result in severe pneumonia for immunocompromised people. People can be reinfected, and there is a high relapse rate for immunocompromised people.

-Symptoms: Dry cough with difficulty breathing, other general symptoms like fever, malaise, weight loss, and night sweats.

-Diagnosis: Difficult to diagnose, can do a sputum analysis or broncholaveolar lavage to test for fungal spores, but very unreliable.

-Treatment: Responds to bactrim, and after treatment bactrim is prophylactically administered to prevent infection. There are antibiotic resistant strains that do not respond to bactrim, and these are very hard to treat.

Bacterial pneumonias

-Overview: Severe class of pneumonias caused by a range of pathogens: Streptococcus pneumonia (very common and recurrent in AIDS patients), Legionella pneumophilia (Legionnaire’s disease), Haemophilus influenzae (meningitis B), mycobacterium avium complex (MAC)

-Symptoms: High fever, cough, trouble breathing

-Diagnosis: Cultures of sputum or chest x-ray (only shows if pneumonia is present, not what is causing it)

-Treatment: Treated with antibiotics specific to the pathogen. Streptococcus pneumonia has a specific vaccine (Capavixe)

Tuberculosis

-Overview: Disease associated with crowded, unhealthy living conditions. Has evolved into a modern threat due to antibiotic resistance.

-Lifecycle: Bacteria enter the body → phagocytosed by macrophages → bacterium alters endosome to prevent degradation → bacteria persist in modified endosomes → antigen presentation is inhibited, macrophages are not destroyed and infection persists. Latent infection will form when bacteria and bacterial infected cells are isolated into a granuloma (small cysts surrounded by immune cells).

-Symptoms: Latent infection persists with no symptoms when granulomas are in the lung, once activated it causes wieghtloss, paleness, fever, bloody sputum (consumption).

-Diagnosis: Latent infection is diagnosed via PDD + test (skin reaction to test for antibodies - does not differentiate between latent infection and vaccination), or T-spot test (assays for specific T-cells). Active infections are diagnosed by culture (can take 2-6 weeks so diagnosis is difficult), or via PCR (does not identify drug resistance profile).

-Treatment: Latent infections are treated with a cocktail of drugs taken for several months, and non-compliance can generate drug resistance. Active infections are treated with drug combos, but these can interfere with ARV treatment.

It is easier to turn a latent infection into an active infection when co-infected with HIV. It also speeds up HIV progression, and co-infection has a nearly 100% mortality rate when _______ is drug is resistant.

Cryptosporidiosis (Chronic)

-Overview: GI apicomplexan that is spread by fecal contamination of water. Normally cleared by immunocompotent host and is very common in US. It is the most common cause of chronic diarrhea in immunocompromised people.

-Symptoms: Profuse, watery diarrhea (lost 1-17 liters/day) and low grade fever.

-Diagnosis: Examination of stool samples for oocytes.

-Treatment: Nitazoxanide (newly created drug in 2016, previously impossible to cure), put HIV+ people on ARVs, and ensure a safe water supply

Cyclospora spp + Cystoisospora belli

-Overview: Common causes of traveler’s diarrhea in the tropics (apicomplexans)

-Diagnosis: Examination of stool sample for oocytes

-Treatment: Bactrim (TMP-SMX) antibioitc cocktail.

Microsporida

-Overview: Caused by many related species of fungi, but it is not commonly seen since the advent of HAART and is only considered if no other cause of diarrhea is found.

-Diagnosis: Stool smears

-Treatment: Antifungals

Salmonella septicemia (Recurrent)

Reccurent _________ infections that occur when _________ leaves the gut and infect macrophages, creating a modified endosome, then continuing to proliferate/exist in the body. Any subtype can do this in immunocompromised people, but it is very rare in immunocompotent people.

Bacterial Diarrheas

-Overview: Caused by a variety of illnesses:

Campylobacter spp. → common food-borne pathogen in chicken

Salmonella spp. → common food-borne pathogen with many subgroups with differing severities. (Can cause latent infection)

Shigella spp. → Caused by fecal contamination and enters cells by inducing actin assembly.

-Symptoms:

-Diagnosis: Bacteria are cultured from stool or blood of infected individual.

-Treatment: Antibiotics (ciprofloxacin) and prevention → proper food handling practices, no raw eggs or meat.

Mycobacterium Avium Complex (MAC)

General infection of the gut with mycobacteria that is treated with Zithromax.

Wasting Syndrome due to HIV

-Overview: The loss of more than 10% of baseline body weight due to chronic diarrhea associated with HIV only and not due to another infection.

-Symptoms: Severe, chronic diarrhea that can be fatal if body weight falls below 66% of ideal body weight.

-Treatment: Preserve lean body mass with a high protein diet, exercise, and appetite stimulants like steroids (megestrol).

Official AIDS Definition

Person must be HIV positive with either a CD4 count < 200 cells/ul or have any variety of AIDS defining pathologies:

-Karposi’s Sarcoma

-Pneumocystis pneumonia (PCP), or other pulmonary OIs

-TB, recurrent bacterial pneumonia

-Encephalopathy (Due to HIV or other pathogens)

-Any other non-AIDS defining illness that is recurrent

Long-term HIV Infection

-Heightened inflammation in immune tissues → scaring that can compromise the immune system.

-Continuous breakdown of dendritic cell networks in germinal centers, causing a release of HIV particles.

-Increased risk of cardiovascular disease + cancer

-Neurocognitive dysfunctions

SIV vs HIV

SIV causes less chronic inflammation than HIV, which suggests that chronic inflammation and activation is very damaging in humans → over-activation leads to bystander apoptosis, which causes sustained and sometimes serious damage to surrounding tissues.

HIV Diagnosis

Complete medical history → Physical Exam → Laboratory Assessment (to test for latent infections and sequence HIV to find resistance profile) → Procedures (prophylaxis with Bactrim) → Counseling (ensure people are taking ARVs and understand infection risk)

Immune Reconstitution Inflammation Syndrome (IRIS)

When ARVs are introduced to people with latent infections, the spike in CD4 cells can cause a large inflammatory response at the site of infection as the immune system reboots to fight infection.

IRIS can be deadly if inflammation is in the brain, lungs, or liver.

Ex. latent Toxo, TB, Hepatitis, or HHV

Early Oral OIs

Thrush (fungal), Hairy Leukoplakia (caused by Epstein-Barr virus, HHV-4), Canker sores (Herpes Simplex 1 or 2)

Early Skin OIs

Shingles (re-eruption of latent HHV-3 that causes chickenpox), cat-scratch disease

Early Genital OIs

Yeast infections (overgrowth of “bad bacteria”), Genital Warts or more severe cervical changes (Eruption of HPV)

AIDS vs Other Immune Syndromes

-Loss of CD4 cells leaves people susceptible to chronic viral infections (HHV, HPV, and JC), Intracellular Protozoa (Apicomplexan), Intracellular Bacteria (mycobacteria and salmonella), and Fungal Infections (Candida, Pneumocystis, Cryptococcus)

-In other syndromes like Severe Combined Immunodeficiency Syndrome (SCID) or Primary Immunodeficiency Disease (PID), a person is susceptible to all infections, as they have no B or T cells.

Importance of Bactrim

________ is a common antibiotic used to treat all manner of HIV OIs. It target Dihydrofolate Reductase (DHFR), which inhibits folic acid production, something that bacterial and some parasitic cells need to survive.

Active Opportunistic Infections

Pathogen is proliferating when proliferation is normally suppressed by competent CD4 cells and is causing an illness.

Normally occurs with environmental pathogens like fungi and protozoa.

Want to treat infection → start on ARVs to increase CD4 count → prevent new infection via vaccination or antibiotic prophylaxis.

Latent Infection

Pathogen is not actively proliferating when CD4 cells can maintain suppression.

Occurs in immunocompotent people, ex. TB, toxo, JC virus, HHVs.

Diagnose any latent infections when diagnosed with HIV → treat latent infections as quickly as possible so that they do not turn into active infection → prevent new infections via prophylaxis with Bactrim (TMP-SMX).

Chronic Infection

Virus is continually produced and may or may not be causing symptoms. NOT aids defining (except chronic salmonella)

Ex. Hep B and C

Treat infection (try to cure, but not always possible for these pathogens) → try to prevent new infection (HepB vaccine)

Koch’s Postulates

1. Organism must be regularly associated with the disease and its lesions.

2. Organism must be isolated from host and grown in culture.

3. Organism will cause the disease when introduced into a healthy, susceptible host.

4. Same organism must be re-isolated from new host.

Viral pneumonias

-Very severe class of pneumonias that often result in ARDS (Acute Respiratory Distress Snydrome), where the air sacs fill with fluid and inhibit O2 exchange, causing patient to “drown”. Cannot be treated, can only wait for the patient to clear the virus and then allow lung tissue to regenerate.

General Diarrhea OI

-Usually caused by parasite or bacteria, and multiple infections are not uncommon. Can lead to fatal dehydration and nutrient deficits.

-KS lesions + lymphoma can cause GI symptoms, needs to be ruled out if no other pathogens are found.

-Diagnosis: Via direct examination of the stool (protozoan oocytes), or stool culture (bacteria). PCR can also be conducted to sample for pathogen genes, but it is not always available in rural communities. MULTIPLE STOOL SAMPLES ARE NEEDED.

-Symptoms: Can be used to indicate pathogens:

• Bloating, abdominal cramps, nausea → parasite (Cryptosporidum, microsporida, cystoisospora belli, or giardia lamblia)

• Bloody stool → Bacteria (CMV, Shigella, Salmonella, Campylobacter, Clostridium difficile)

• Painful cramps → Bacteria (Herpes, Shigella, Salmonella, Campylobacter)

Plasmodium Falciparum (Malaria)

Similar to toxo, but with a much more complex lifestyle. Relies on mosquitos to be vector for sexual phase. A major comorbitity with HIV. Active ______ infection causes a 7-fold increase in viral load, causing HIV to rapidly progress for 6-8 weeks. HIV+ also makes people more susceptible to _______ and vice versa. It is important to target anti-malaria measures (like bed nets) at HIV+ populations.

Hepatitis A

-Overview: Virus spread through fecal contamination of food/water and oro-anal sex. It infects the liver and ends up in the bile/feces. Liver damage is caused by localized immune response where CD8 cells kill infected hepatocytes. Normally cleared by immune system, even in immunocompromised people, but it may cause liver failure or compound damage in someone who drinks or takes hepatotoxic meds.

-Treatment: Can be vaccinated if traveling abroad, and practice safe food and water practices in endemic areas.

Hepatitis B

-Overview: DNA virus that many carry as an asymptomatic chronic infection. It is transmitted via blood products, shared needs, unprotected sex, and perinatally. Chronic infections occur when the virus is retained as covalently closed circular DNA in hepatocytes. Coinfection with HIV is more likely to progress to liver disease or cancer, and possibility of IRIS in the liver.

-Symptoms: Acute, flu-like infection, anorexia, low grade fever, and jaundice.

-Diagnosis: Blood antibody test

-Treatment: ARVs that inhibit the virus, vaccination, ______ specific polymerase inhibitors.

Hepatitis C

-Overview: Spread by blood products, very high risk of developing ________ infection from a needle stick. Large outbreaks in the 60s due to unsafe medical practices, and on the rise in the US due to IV drug use.

-Symptoms: Largely asymptomatic, but left untreated can cause severe liver damage - leading cause of liver disease, cirrhosis, and hepatocarcinoma (end stage liver disease is a common cause of death for HIV+ patients)

-Treatment: No vaccine, but recent treatment from 2014 (direct acting antiviral polytherapy) taken for 8-12 weeks clears the infection.

Oncogenic Viruses

-Hep B + C → Hepatocellular carcinoma

-Papillomavirus → Papillomas and carcinomas

-Herpes → Lymphomas, carcinomas, and sarcomas

Cancers Associated with HIV Infection

-AIDS Defining

• Non-hodgkins lymphoma

• KS

• Cervical Cancer

-Non-AIDS Defining

• Lung cancer

• Anal cancer

• Hodgkin’s Lymphoma

• Oral and Pharyngeal Cancer

• Hepatocellular Carcinoma

• Vulvar Cancer

• Penile Cancer

HPV - Human Papilloma Virus

-Overview: Infects basal cells of the epidermis, associated with benign warts, but some subtypes are known to cause cancer.

-Symptoms: Often asymptomatic

-Diagnosis: Diagnosed via PCR, direct observation, colonoscopies, and biopsies.

-Treatment: Monitoring low-grade growths, excision of more severe tumors, with chemo and radiation

Herpes Simplex (HHV-1 and 2)

-Overview: Causes canker sores and other ulcerations in the mouth and throat. Chronic in HIV infections.

Varicella-Zoster (HHV-3)

-Overview: Virus that causes chickenpox and shingles - can reerupt in HIV infection.

Epstein-Barr Virus (HHV-4)

-Overview: Can cause mononucleosis, hairy leukoplakia (early OI), B-cell lymphoma, Burkitt lymphoma, and other lymphomas. Spread through the exchange of saliva. Tricks B cells into becoming long-lived memory cells by mimicking host processes independent of T-cells. Malignancy occurs when growth is reactivated (multi-hit model where as cells continue replicating, they continually develop more mutations)

-Symptoms: Mono-debilitating symptoms, fatigue, fever, sore throat, swollen lymph nodes, skin rash, liver + spleen swelling. B-cell lymphoma - Unexplained fever, malaise, weight loss, swollen lymph nodes, CNS problems, unexplained upper GI problems and appetite loss.

-Diagnosis: B-cell lymphoma - biopsy and imaging (normally widespread and metastatic when diagnosed)

-Treatment: Classic chemotherapy (inhibits DNA synthesis and mitotic spindle formation), and new immunotherapy treatments.

Cytomegalovirus (HHV-5)

-Overview: Can cause mononucleosis, retinitis (can cause blindness), ulcerations of the esophagus, GI tract, and lung. Normally controlled by CD8 killing in immunocompotent host.

-Diagnosis: Blood smears

Kaposi’s Sarcoma Herpes (HHV-8)

-Overview: Causes Kaposi’s Sarcoma, Castleman’s disease, and body cavity-based lymphoma. Initially infects B-cells, then the virus spreads into the endothelial cells of blood vessels. Upon second reactivation of immune system, infected cells will express oncogenes. Many different tumors that initiate at different times. Only will be fatal if lesions move into vital organs, like the lungs.

Previously common in older, Mediterranean men, or in specific areas in Africa. Both populations have weakened immune systems.

-Symptoms: Purple, bruising like tumors that extend far into the skin due to ruptured blood vessels.

-Diagnosis: Visually

-Treatment: Maintain HIV+ patients on ARVs to decrease chronic immune activation, which will slow tumor growth. If tumors are minimal or slow progressing, treatment is local (laser ablations, topical chemo). If it is aggressive, large scale chemo, but prognosis is not usually good.