A 28-year-old man presents with weakness and an inability to speak "normally". He complains of fever, dry cough, and dyspnea. He has been treated for urethritis and genital warts in the past, and admits to bisexual behavior. He denies any IV drug use. A recent male partner developed pneumonia and lost over 10 lbs. He keeps a pet parrot. He reports a poor appetite, intermittent episodes of a non-productive cough and difficulty with breathing. Vital Signs: Pulse 85, BP 110/65. Temp 39C. Multiple violaceous patches, plaques, and nodules are noted on his back and legs. Auscultation of the lungs reveals scattered rales. He was disoriented to time and place. CBC: HCT 38, MCV 79, WBC 4,400 with predominance of neutrophils CD4+ T-lymphocyte count 95 per mm. Chest film shows bilateral interstitial and alveolar infiltrates. pO2 on room air= 54 mm Hg. What is causing his condition?
INFECTION: HIV gp120 binds CD4+ T-cells and destroys them. This results in deficient cell-mediated immunity, B-cell function, increased opportunistic and typical infections. CNS: You see Hodgkins and Non-Hodgkisn lymphoma (especially in the CNS). Toxoplasmosis and cryptococcus can infiltrate the CNS. Infected microglia are activated, release cytokines and have negative effects on the CNS. SYSTEMIC: CD4+ macrophages are infected by HIV, harbor it as a reservoir and allow it to disseminate systemically.
A 12 year old boy developed fever, malaise, myalgia, inability to eat, and irritability. Temp 102°F. Bilateral cervical adenopathy, ulcerative lesions on the hard and soft palate, gingiva, tongue, lip, and facial area. What would you expect to see on histologic analysis of these lesions?
HSV intranuclear inclusions. Note that the cells are not enlarged as they would be with CMV.
A 39-year-old navy nurse complained of fatigue, weight loss, night sweats and a productive cough. Generally in good health. Father died of heart attack, age 75; mother 80 y/o in good health. She served several tours on the USNS Comfort. She complained of heavy menses for many years.Thin, tired and pale appearing female; frequent coughing, HR 85, RR 20. A PPD test showed induration of 12 mm. A chest X-ray showed disseminated fibro-nodular densities. What would you likely see on biopsy of these densities?
Presence of apical cavitary lesions indicates that this is a secondary Tb infection. You would see giant cells, lymphocytes and caseating necrotizing granulomas.
A 62 year old female was discharged following an aortic valve replacement. She returns several days later with complaints of fever and malaise. On admission, a new systolic murmur is heard, and oral exam discloses whitish exudates in the mouth. The patient expires unexpectedly. C. albicans grows out of the blood cultures. What is causing her condition?
In healthy people, endocarditis will be very acute (for example s. aureus) because you need a very virulent organism to overcome host defenses. Candida is not one of these organisms and can more easily take root in a replaced valve like this patient has.
A 23 year old sexually active male complains of onset of a whitish and mucoid urethral discharge, dysuria, and urethral itching. Meatal erythema and tenderness and a demonstrable urethral discharge. Negative for Neisseria gonorrhea by gram stain and culture. What other conditions is she at risk for?
She likely has chlamydia. This puts her at risk for PID, reactive arthritis, keratitis (trachoma) and lymphogranuloma venereum.
Why do lymphomas have a propensity to arise in patients with HIV? What other carcinomas can arise due to this?
EBV latency and reactivation in immunocompromised patients because of CD8 dysfunction due to CD4 T-cell loss. Burkitt’s, Non-Hodgkins and certain subsets of Hodgkin lymphomas can be caused by EBV. Note that you also get hairy leukoplakia of the tongue due to squamous epithelial proliferation. Nasopharyngeal carcinoma can also be caused by EBV.
What is the pathogenesis of the condition shown below?
HIV infection -> CD4 depletion -> KSHV infection of spindle cells -> cytokine and growth factor release -> Endothelial proliferation and angiogenesis -> Kaposi sarcoma
Top cause of mortality in AIDS patients?
What is causing pneumonia in this AIDS patient?
Note the pink bubbly amorphous material in the alveoli indicative of PJP
What is causing pneumonia in this AIDS patient?
Note the intranuclear and intracytoplasmic inclusions indicative of CMV.
Histology of Tb in a patient with HIV?
They will have way more acid-fast bacilli (red snappers seen in MAC shown below) and fewer granulomas due to deficient Th1 response.
How can HSV cause blindness?
Direct infection of corneal epithelial cells that causes direct keratitis or immune reaction against the HSV that causes stromal opacification
Which of these is primary Tb and which is secondary Tb?
Right = granulomatous peripheral involvement with pleuritis indicates primary Tb. Left = cavitary, destructive, necrotic lesions seen in secondary Tb.
What are the clinical implications of a cavitary Tb infection?
Cavitation = open place of transmission of Tb with cough and systemic hematogenous spread.
What causes this?
Secondary Tb from the lung spreads hematogenously then seeds the lung and causes miliary Tb.
Is this a primary or secondary Tb lesion?
Note the white spot in the middle periphery of the lung. This is a ghon complex of primary Tb.
What other stain would you want to do on a patient who has a cavitary pulmonary lesion after acid-fast stain?
Silver stain for fungi
What causes the induration in a +PPD test? When might you see false PPDs? How do you account for this?
T-cell memory response. BCG vaccine will give a false positive. Immunosuppression will give a false negative test and should be confirmed with candida injection. If candida is negative, you know they are immunosuppressed.
Sequelae of Tb infection?
Osteomyelitis (Pott’s disease of vertebrae) and cranial nerve palsy (3rd w/ptosis)
Immune response critical for control of candida infection?
Th17 activation of neutrophils. Note that in general immunosuppression there may be neutropenia and have problems controlling candida infection.
What predisposes someone to Reiter’s syndrome (conjunctivitis + reactive arthritis)?
Enterics (shigella, salmonella, campylobacter, yersinia), STIs (chlamydia, gonorrhea) + HLA-B27
What cells are typical targets of the HIV virus?
CD4+ cells. This includes T-cells and cells of the monocytic-macrophage lineage.
Why are HIV patients at increased risk for epithelial malignancies?
Impaired immune surveillance mechanisms
Most common way HIV is transmitted?
How does HIV enter host cells?
HIV gp120 binds CD4 receptor -> gp120 binds CCR5 or CXCR4 coreceptor -> gp41 unfolds and penetrates plasma membrane -> Viral membrane fuses with host cell membrane
HIV target tissues
CNS and lymph nodes
Common causes of death in HIV patients
Reactivation of latent HSV or disseminated infection (bacterial and fungal). Note that respiratory tract infections are the chief causes of morbidity and mortality in patients with AIDS.
Suspected pathogen if a patient with AIDS presents with bilateral pulmonary congestion on radiographs
Most common malignancy secondary to HIV
Lymphomas (peripheral and CNS)
When should patients receive prophylactic TMP-SMX for Pneumocystis jirovecii carinii?
CD4 T-cell count < 200 or hx of oral candidiasis
What type of virus is HIV?
+ssRNA, this is why it needs a reverse transcriptase
After HIV infects a CD4 cell and viral explosion occurs in the lymph node, how does the virus get disseminated systemically?
Macrophages and monocytes
A 30 year old homosexual male presents with fever, generalized lymphadenopathy, headache, myalgia and pharyngitis. If he has HIV, what is causing his symptoms? What residual symptoms will he have when he recovers?
He has primary HIV infection. This is a result of initial CD4+ decline followed by immune response and CD8+ action against virally infected cells. Lymphadenopathy will persist throughout the asymptomatic and AIDS stages.
When are patients defined as having AIDS?
CD4+ < 200 or AIDS-defining illness.
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly and a tongue ulcer. Labs show oval yeast cells within macrophages and a CD4 count < 100. What is the most likely cause of his symptoms?
He has HIV and this presentation is consistent with opportunistic Histoplasmosis, which typically only causes pulmonary symptoms in healthy individuals. Note that this commonly happens when CD4 count is < 100.
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly and oral fluffy white cottage-cheese lesions that can be scraped off. CD4 count is < 400. Silver stain with budding yeast (blastoconida) and pseudohyphae are shown below. How might his presentation differ if his CD4 count was < 100?
He has HIV and opportunistic oral Candidiasis, which commonly occurs when CD4 count is < 400. With a CD4 count < 100 he is at increased risk for esophageal candidiasis.
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly and hairy leukoplakia on his lateral tongue that cannot be scraped off. What is most likely causing his condition?
He has HIV with an opportunistic EBV infection.
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly and superficial vascular proliferation. Biopsy of the vascular proliferation reveals neutrophilic inflammation. What is the most likely cause of his vascular proliferation?
He has HIV with an opportunistic Bartonella henselae infection causing bacillary angiomatosis. Note that biopsy of this condition is essential in differentiating it from Kaposi sarcoma, which will have a LYMPHOCYTIC inflammation due to HHV-8 infection.
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly and chronic, watery diarrhea. Stool culture shows acid-fast cysts and CD4 count < 200. What is most likely causing his condition?
He has HIV with an opportunistic cryptosporidium infection.
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly and neurologic symptoms. Imaging reveals several ring-enhancing lesions throughout the basal ganglia and corticomedullary junction. Labs show a CD4 count < 100. What is most likely causing his condition?
HIV compounded by opportunistic toxoplasma abscesses. Note that his commonly occurs when CD4 count is < 100.
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly and encephalopathy. Labs show a CD4 count < 200. What virus is the most likely culprit if this were an opportunistic infection due to HIV?
JC virus causes progressive multifocal leukencephalopathy (a demyelination of neurons).
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly and meningitis. Lab shows yeast with narrow-based budding and large capsules after staining with india ink. CD4 count is < 50. What is the most likely cause of his condition?
HIV compounded by opportunistic cryptococcus neoformans. Note that this typically occurs when CD4 count is < 50.
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly, esophagitis and retinitis. Fundoscopic exam shows cotton-wool spots. CD4 count is < 50. What is the most likely cause of his condition?
HIV compounded by opportunistic CMV infection. Note that opportunistic CMV typically occurs when CD4 is < 50.
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly and an oropharyngeal mass that is obstructing his breathing. Labs show that the mass is associated with EBV. What is the most likely cause of his condition?
Diffuse Large B-cell Non-Hodgkin Lymphoma is associated with EBV and HIV because of chronic B-cell proliferation and formation of monoclonal proliferations.
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly and focal neurological deficits. Imaging shows a single lesion with subependymal spread and solid enhancement. Serology labs are negative for toxoplasmosis but positive for EBV. What is most likely causing his condition?
Primary CNS lymphoma from HIV loss of immune surveillance and increased B-cell proliferation. EBV is associated with lymphomas in HIV.
Common locations you see squamous cell carcinoma arise in patients with HIV?
Cervix and anus.
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly and interstitial pneumonia. What would biopsy show if this were due to opportunistic CMV infection?
Intranuclear inclusion bodies (owl’s eye)
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly, pleuritic pain, hemoptysis and infiltrates on CXR. What is the most likely cause of his condition?
HIV complicated by invasive and opportunistic apergillosis.
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly and ground-glass appearance on CXR. CD4 count is < 200. What is the most likely cause of his pneumonia? What if he had a parrot and lobar consolidation?
Pneumocystis jirovecii is a common opportunistic infection in patients with HIV and CD4 counts less than 200. If he had a parrot you would suspect psittacosis.
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly and lobar consolidation on CXR. CD4 count is > 200. What is the most likely cause of his condition?
S. pneumoniae is a common cause of pneumonia in patients with HIV and a CD4 count > 200.
A 30 year old homosexual male presents with low-grade fevers, cough, hepatosplenomegaly, hemoptysis and pneumonia. His CD4 count is < 50 and acid-fast stain is shown below. What is most likely causing his condition? What should you add to his treatment regimen if he is already taking TMP-SMX?
Mycobacterium avium-intracellulare infections are common when CD4 count is < 50. You should add azithromycin.
What antibodies are tested for in initial ELISA tests for HIV? How is HIV confirmed?
Anti-p24 (capsid), anti-p17 (matrix), anti-gp120 (docking) and anti-gp41 (transmembrane). To confirm HIV you need a Western Blot with positivity for at least 2 of these antigens.
When is the HIV/ELISA falsely negative and falsely positive?
Falsely negative in primary HIV infection and falsely positive in newborns because anti-gp120 crosses the placenta.
Components of HAART
2 reverse transcriptase inhibitors + 1 protease inhibitor
Drug given to pregnant women with HIV
What makes HSV unique among all other viruses?
It is derived from the envelope of the nuclear membrane.
Respiratory secretions or saliva
Sexually or perinatally
A 25 year old woman presents with swelling of the gums, red eyes and a vesicular lesion on her hand and lip. Lip biopsy is shown below. What complications is she at risk for?
Gingivostomatitis, keratoconjunctivitis, herpetic whitlow and herpes labialis are common presenting factors of HSV-1 infection. This virus resides dormant in the trigeminal ganglia and can cause recurrent infections, temporal lobe encephalitis and olfactory hallucinations.
A 25 year old woman presents with ulcerating genital lesions and a vesicular lesion on her hand. She previously gave birth to a child with neonatal encephalitis. What is causing her symptoms?
HSV-2 resides in the lumbosacral ganglia and causes these symptoms.
What are the herpesviruses? What do they cause? Where are they latent? What reactivates them?
HSV (vesicular lesions, 1 is latent in trigeminal ganglia, 2 is latent in lumbosacral ganglia), VZV (chicken pox and shingles, latent in dorsal roots or trigeminal ganglia), CMV (causes mono w/negative monospot, retinitis and pneumonia, latent in mononuclear cells), EBV (causes mono, lymphoma and nasopharyngeal CA, latent in B cells), HHV-6 (causes roseola, latent in lymphocytes/monocytes) and HHV-8 (causes Kaposi sarcoma, latent in B cells). These are all reactivated by stress and infection (especially AIDS).
A 25 year old woman presents with ulcerating genital lesions and a vesicular lesion on her hand. She previously gave birth to a child with neonatal encephalitis. How would you proceed to narrow your diagnosis?
Viral culture, Tzanck smear (looking for multinucleate giant cells or intranuclear Cowdry A inclusion bodies shown below).
Tx for HSV
What factors inherent to mycobacterium tuberculosis allow it to live inside of host macrophages?
Cord factor: inhibits macrophage maturation and induces release of TNF-alpha. Sulfatides on its cell wall prevent phagolysosome fusion.
How is Tb transmitted?
Why are people with AIDS at high risk for reactivation of latent Tb?
Typically Tb is controlled by Th1 immunity and granuloma formation. As HIV kills off CD4 cells, the number of cells that can progress to differentiated Th1 cells is decreased and M. Tb is able to escape the granulomas.
How does a primary Tb infection progress?
It is typically asymptomatic. The bacteria initially seed in the central lung fields and cause a focal caseating necrosis. From there is can progress to bacteremia (miliary Tb), become dormant in a granuloma or be resolved by fibrosis and calcification (forming the Ghon complex).
How does a secondary Tb infection progress?
When people become immunocompromised, Tb tends to cause cavitary lesions in the lung apices. Patients also present with fever, night sweats, weight loss and hemoptysis.
What other organ systems will you examine if your patient’s CXR comes back with a miliary pattern of Tb infection?
Skeletal (Pott disease = lumbar osteomyelitis, also check hips/knees). GI (cholestatic jaundice, small bowel ulcerations/strictures). CNS (meningitis). Adrenal (Addison’s disease). Cardiac (pericarditis: hemorrhagic and fibrotic). GU (hematuria, proteinuria, abnormal menstruation and genital tenderness)
Tests for Tb
PPD, IFN-gamma release assay and acid-fast stain.
Tx for Tb
“RIPE”: Rifampin, Isoniazid, Pyrazinamide and Ethambutol for 2 months, then INH + rifampin for 4-6 months. If +PPD, INH prophylaxis 9 months.
Where does Candida albicans come from?
Normal skin flora
How does candida look at 37C vs. 20C?
37 = pseudohyphae. 20 = budding yeast.
Presentation of candidiasis in immunocompetent hosts
Oral thrush, vulvovaginitis and diaper rash, especially post-antibiotic therapy.
Presentation of candidiasis in immunocompromised hosts
Esophagitis, skin infection, DIC, septicemia and chronic mucocutaneous candidiasis. Not that it can also be introduced systemically by IV lines, catheters or IV drug abuse (endocarditis).
A patient presents with fever, pleuritic chest pain and hemoptysis. He is neutropenic. Labs show monomorphic fungus w/septate hyphae at 45-degree angles with fruiting bodies at the ends of the hyphae. What people are at risk for this condition? How else can it present?
Aspergillus fumigatus shows up in immunocompromised patients and patients with chronic granulomatous disease (defect in NADPH oxidase). There is allergic bronchopulmonary aspergillosis which is seen in people with asthma and CF and presents with bronchiectasis and eosinophilia. There is invasive aspergillosis like this patient has. There is aspergilloma that forms a “fungus ball" in lung cavities, especially after Tb infection, bronchiectasis, healed abscesses and other cavitary lesions. Finally, there is hepatocellular CA caused by aflatoxin production. Note aspergillus in the lung and heart below.
A patient presents with headache, facial pain, black facial eschar and cranial nerve palsies. He has a history of diabetes. Labs show aseptate hyphae that branch at 90-degree angles. What is causing his condition?
Mucor. This commonly affects patients with DKA or leukemia because the fungi proliferate in blood vessel walls when there is an abundance of glucose and ketones. They proliferate and penetrate the cribriform plate to cause frontal lobe abscesses.
A patient presents with "soap bubble" lesions in the CNS and meningitis. Labs show a budding yeast with a thick polysaccharide capsule on India ink and mucicarmine stains. He has birds at home. What is causing his condition?
Cryptococcus neoformans is a fungus that is transmitted in bird droppings and spreads hematogenously to the CNS.
Chlamydia that causes follicular conjunctivitis, scarring and blindness in Africa, Middle East and India
A-C. Note that these serotypes are transmitted hand-to-eye and from contaminated clothing.
Chlamydia that causes neonatal conjunctivitis and infantile pneumonia; adult urethritis, cervicitis and PID?
Cervical motion tenderness
Liver capsular inflammation and adhensions
Chlamydia that causes painless inguinal pustules with painful lymphadenopathy and buboes that may rupture>
Genetic association in Reactive arthritis
HLA-B27 is common in patients that get seronegative spondyloarthropathies.
Molecules specific for gram + surface
Protein F (adherence) and Protein M (immune-evasion)
What are the different spectrums of Tb shown below?
A) Tubercle B) Caseating granuloma C) Acid fast organisms D) Sheets of foamy macrophages packed with mycobacteria in an immunocompromised patin
This patient has numbness in a stocking and glove distribution. Acid-fast stain is shown below. What is causing his condition?
Hansen’s disease from mycobacterium leprae (red snappers). Note the endo and epineural invasion.