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HIV associated opportunistic infection
Susanne Burger, MD
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Impact of HAART on the Incidence of Opportunistic Infections
PCP MAC CMV Retinitis Toxoplasmosis PCP most common clinical manifestation
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Typical Relationship of Clinical Manifestations to CD4 Count in HIV Infected Patients
Lymphoma Tuberculosis Kaposi Sarcoma Herpes Zoster 50
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Criteria for Starting, Discontinuing, and Restarting Opportunistic Infection Prophylaxis for Adults with HIV OI Criteria for Initiating Primary Prophylaxis Criteria for Discontinuing Primary Prophylaxis Criteria for Restarting Primary Prophylaxis Criteria for Initiating Secondary Prophylaxis Criteria for Discontinuing Secondary Prophylaxis Criteria for Restarting Secondary Prophylaxis PCP CD4 < 200 or oral candidasis CD4 > 200 for 3 mos CD4 < 200 Prior PCP CD4 > 200 for 3 mos Toxoplasmosis + serum IgG CD4 < 100 CD4 < 100 – 200 Prior toxoplasmic encephalitis CD4 > 200 sustained and completed initial therapy and is asymptomatic MAC CD4 < 50 CD4 > 100 for 3 mos CD < 50 – 100 Documented disseminated disease CD4 > 100 sustained and completed 12 mos of MAC tx and asymptomatic Cryptococcosis none n/a Documented disease CD4 > 100 – 200 sustained and completed initial therapy and asymptomatic CD4 < Histoplasmosis No criteria recommended for stopping CMV Documented end-organ disease CD4 > 100 – 150 sustained and no evidence of active disease and regular exams CD4 < PCP prophylaxis for CD4 < 200 and for pts with oropharyngeal thrush regardless of CD4. Bactrim agent of choice, 1 single strength or one double strength daily or tiw, gradual dose escalation helpful with h/o intolerance. After splenectomy, cirrhosis, pregnancy go after %
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Pt with HIV and CD4 = 68 presents with fever, cough and dyspnea.
Rational approach, should include the same considerations as in any immunulogically normal patietn, as well as considerations for the processes that occur with special frequency or severity in patients with HIV infection.
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Approach to Respiratory Disease in HIV Infection: Diagnostic Clues
Parameter Example Rapidity of onset > 3 days: PCP, Tb < 3 days: bacteria Temperature Afebrile: neoplasm Character of sputum Purulent: bacteria Scant: PCP, Tb, virus Laboratory Tests WBC, LDH ↓O2 post exercise X-ray atypical Pattern: Beware! Most patients admitted to the hospital will have either bacterial pneumonia and PCP, less often for fungi, viruses or mycobacteria. Geographic considerations
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HIV + patient with CD4 = 58 presents with cough and fever.
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HR chest CT with patchy ground glass opacities.
CT useful in this scenario. Most patients with respiratory symptoms suggestive of PCP show radiograph is normal do not have PCP. Subjective these patients to bronchoscopy or empiric PCP treatment is ill advised.
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Isolation? One of the first decisions that clinicians face.
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Pneumocystis Jiroveci (Formerly P. carinii)
Taxonomy Fungus vs. Protozoan Epidemology Environmental source unknown Life Cycle Unknown Transmission Respiratory Well documented in rodents Presumptive in man
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Diagnosis of Pneumocystis Pneumonia
A 30 year-old male with HIV infection and fever, cough, and diffuse infiltrates has a bronchoscopy performed. Which of the following is the most sensitive and specific test to perform to establish whether or not pneumocystis is the causative pathogen? PCR of the bronchalveolar lavage (BAL) Culture of the BAL Immunoflourescent stain of the BAL ELISA of the BAL Serum PCR Other stains: Methamine silver stain, stains only cysts Immunoflourescence Giemsa
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Which of the following therapies would you recommend:
A patient with HIV infection presents with PCP (room air pO2=82mHg). He has a history of a severe exfoliative rash to TMP-SMX. Which of the following therapies would you recommend: TMP-SMX + Prednisone TMP + Dapsone Parenteral Pentamidine Clindamycin plus pyremethamine Atovaquone Bactrim always drug of choice unless patient has life threatening intolerance. More or as effective than any of the alternative drugs. Pentamidine similar clincal efficacy but more toxic. No need to give concurrent leukovorin with bactrim unless cytopenias develop that appear to be drug related. Pt may be managed as OP with mild disease. Atovaquone few life-threatening toxicities and a high degree of efficacy, but absorption is unpredicatable and steady state levels are not reached for several days.
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A 50 year-old male with HIV and PCP is receiving pentamidine 4mg/kg IV over 1 hr qd. On the ninth day of therapy, while awaiting transportation home, he has a syncopal episode.
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What is this rhythm? Drugs that might predispose him to this rhythm
Paxil, atazanavir, quinolones?, macrolides?
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Toxicity Regarding Antipneumocystis Therapy
Drug Issues TMP-SMX Toxicities: ↓WBC, ↓Plat, ↑LFT ↑Creat, ↑Amylase, rash, fever Cross reactivity: dapsone (+/- 50%) Pentamidine Hypotension, ↑Crea, ↑Amylase, ↓WBC ↓Glucose: related to ↑Crea occurs days-wks post-rx Torsade de Pointes Atovaquone Absorption Clindamycin + Primaquin Rash, LFT, diarrhea Methemoglobinemia Hemolytic anemia (G-6-PD) Dapsone Rash, fever, ↑LFT, Hemolytic anemia (G-6-PD), peripheral neuropathy
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22 y/o patient with CD4 = 69 and bilateral interstitial infiltrates on CXR has been started on treatment with iv bactrim for presumptive PCP. On day #3 he still c/o dyspnea and reports that his symptoms have not improved since admission to the hospital. What do you do?
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Management of Patients with AIDS Related PCP Who are Failing TMP-SMP
Add corticosteroids (if not already done) Switch to alternative treatment Reassess diagnosis Is PCP correct? Are there any other pathogens? Is aggressive/longer term support appropriate? Patient wishes Realistic assessment of prognosis Patients with PCP may have slow resolution of their disease, and it may be several days to a week or more until their clinical status improves. A general rule of thump: the number of days a patient was symptomatic before treatment was began is approximately the number of days before resolution or near resolution of the symptoms. Nevertheless one expects a patient with PCP to manifest initial signs of improvement by day 7-10 of treatment. CXR lags behind the clinical response. Bronchoscopy procedure of choice, as it will provide maximal diagnostic yield. Review of microbiology results, repeat CXR, repeat or obtain cultures. Serum CRAG, eye exam for patients with CD4 < 50 Drug resistance. Lack of culture system has limited the ability to confirm drug resistance. However specific point mutations in the Pneumocystis dihydopteroate synthase gene – the enzyme target of SMX and dapsone – are associated with increased risk of tx failure and mortality.x
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A 34 y/o man who has been HIV pos for ~ 10 years is brought to the ER after a witnessed seizure. He had been receiving HAART until ~ 5 years ago when he dropped out of care. Family members report that he has had some memory loss and unusual behavior for the past 2 weeks. On PE is he is confused and disoriented.
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Diff
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Evaluation of CNS Mass Lesions in Patients with AIDS
Radiologic non specific extra CNS lesions Toxoplasmosis Lymphoma PML Tuberculosis Fungus Nocardia Bacterial Syphilis Kaposi Sarcoma Glioblastoma Laboratory Serology – Toxo IgG, crypt Ag Blood culture – AFB, fungus CSF – Crypt Ag, CMV PCR, EBV PCR Urine – Histo Ag Location of lesion Timing Risk factors Empiric Therapy
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Tachyzoit form in involved tissue
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How is toxoplasmosis most often transmitted in the United States?
Rare meat (lamb/pork)
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Clinical Manifestation of Toxoplasmosis when Acquired Post-Partum
Acute infection Asymptomatic (80 – 95%) Lymphadenopathic (5-10%) Chronic Latent Infection Normal Immunity (Most) Retinochorioditis (Few) Abnormal Immunity (HIV, Hodgkin’s, etc) Cerebral Disseminated Specific Organ Dysfunction (Rare)
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Toxoplasmosis - Diagnosis
Definite diagnosis: Biopsy with demonstration of tachyzoites Presumptive diagnosis acceptable when CD4 < 200 Compatible neurologic disease No prophylaxis Serology: positive toxo IgG
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Therapy for Cerebral Toxoplasmosis
Preferred Regimen Sulfadiazine + pyremethamine Alternative Regimen Clindamycin + pyremethamine Less studied regimens TMP-SMX Atovaquone + sulfadiazine Azithromycin + pyremethamine Dapsone + pyremethamine If pt has not improved in 2 weeks rethink diagnosis
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A 35 year-old male with HIV (CD4 = 30, VL 100k copies) not on HAART, is brought to the emergency room with several weeks of declining cognitive function, ataxia, and aphasia. CT scan shows multiple hypodense, non enhancing cerebral white matter lesions. The gray matter is spared. CSF analysis shows: WBC 25 (100% lymphs), protein 110 mg/dl; glucose 90 mg/dl; VDRL neg, Crypt Ag neg, PCR for JC virus positive What therapy is effective for this condition: a. high dose acyclovir b. Cidofovir c. Vidarabine d. Foscarnet e. None of the above PCR pos in 90%, very specific Only brain, PCR for JC of sources other than CSF NOT diagnostic if pos
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PML Polyomavirus (JC) Transmission likely respiratory Prevalence 70% seropositive Disease: slowly progressive, no fever or HA, monoparetic or hemiparetic weakness, sensory loss, gait disturbance Involves white matter Diagnosis is primarily based on clinical findings and a compatible MRI, confirmed by the presence of JCV and r/o other opportunistis infection. Lesions are primary of white matter and appear as single or multiple large of small bright areas on T2 weighted images.
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Figure 62-3 MRI images of patient with stage 2 ADC
Figure 62-3 MRI images of patient with stage 2 ADC. The T2-weighted images show brain atrophy and striking increase in signal (white) in the white matter that is most prominent centrally, less so peripherally and spares the U fibers posteriorly. The hyperintensity likely represents breakdown of the blood–brain barrier and increased water content. Syndrome of cognitive and motor dysfunction, caused by HIV itself. Late complication. Neuroimaging is usually performed to evidence of alternative conditions. Most patients have some degree of atrophy. ADC can be associated with focal white matter changes. However ADC typically involves deeper white matter and localized image abnormalities are typically not correlated with focal neurologic deficits.
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Figure 1. An MRI Scan of the Brain Obtained with Fluid-Attenuated Inversion Recovery, Showing Areas of Hyperintensity Primarily in the Periventricular White Matter.
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(Panel C, hematoxylin and eosin),
there are basophilic, circular, glassy, “owl’s eye” intranuclear inclusions of CMV within markedly enlarged hepatocytes. Rare manifestation, usually CMV also found elsewhere
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Infectious Non-focal Brain Disease
Clinical Features Lesion Type Temporal Progression Level of Alertness Fever PML Weeks Preserved Absent AIDS dementia complex Weeks/months CMV encephalitis Days/weeks Reduced Common
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HIV associated CMV Disease
Pre-HAART, 30% of patients developed: Retinitis Colitis Others: Pneumonitis Ventriculoencephalitis Myelitis Radiculomyelopathy Adrenalitis
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Diagnosis of CMV Disease
Serology (IgG, IgM) Viremia common in asymptomatic persons with low CD4 Histology required for diagnosis of colitis and pneumonitis ‘owl’s eye ‘ intranuclear inclusion bodies pathognomonic Rare cells in the absence of clinical disease insignificant Retinitis clinical diagnoses Fluffy exudate CNS – CMV PCR
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CMV Detection in Specific Anatomic Sites
Significance BAL None Blood (cells, plasma) maybe CSF Qualitative: probably
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Mycobacterium Avium Intracellulare Complex
Epidemiology: Ubiquitous in dirt, animals etc Avium: 95% isolates Transmission Respiratory and GI, environmental source undetermined Person-to-person NOT likely Clinical manifestations Fever, wasting, ↑nodes, ↑liver, ↑spleen Rare as cause of lung disease Labs: ↑alk pho, ↓Hb (severe), ↓albumin Never cause of lung disease in HIV, generally associated with disseminated multiorgan infection. Peripheral lymphadenopathy uncommon
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Mycobacterium Avium Intracellulare: Diagnosis and Treatment
Compatible clinical syndrome + Isolation of M. avium Source of Isolates Blood (if patient symptomatic) Pos culture 80 – 90 %: Bactec (7-14 days), solid (21 days) Sputum/Stool/Urine Low predictive value Treatment: Clarithro (or Azithro) + Ethambutol (+/- Rifabutin) x 1 year
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Show and Tell What is the cause of the following skin lesions in a patient with HIV infection, fever and CD4 cG-6-PD, peripheral neuropathy ount of 15 cells/μl?
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HHV8 associated 17% in MSM, rare in others in US Can occur at any CD4 count Diagnosis biopsy, not cytology Treatment: HAART Mucositis – radiation Chemo
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Bacillary Angiomatosis
B. Henselae > B. quintana Transmission Cat associated (fleas and probably scratches) – B. henselae Cat unassociated (low socio-economic) (lice) – B. quintana Clinical Manifestations: purple skin lesions, cutaneous or subcutaneous, mm-cm in size, 1 to > 100 in number Both cause fever, weight loss (distinguishes this from KS) Diagnosis: histology (vascular proliferation), culture (enriched agar8-40 days), PCR serology Therapy: Erythromycin (preferred) or doxycicline (CNS) 3-4 months
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Atypical cutaneous lesions caused by acyclovir R VZV
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Cells are scraped from the base of cutaneous lesions and
smeared on a glass slide for microscopy. Panel A shows a positive Tzanck smear (¬400). Wright’s stain demonstrates multinucleated giant cells. (Photograph courtesy of Henry Skelton, M.D.) Panel B shows a positive direct immunofluorescence assay (¬400). Cells are stained with fluorescein-conjugated monoclonal antibodies against varicella–zoster virus; green fluorescence indicates the presence of varicella–zoster virus antigens.
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Cryptococcal Meningitis in Patients with HIV Infection
Epidemiology: CD4 count < 50 cells/mm3 (75% cases) Diagnosis CSF: Ag positive % Serum: CRAG positive 95-99%, Blood Culture: positive 75% Poor prognosis Abnormal mental status Low CSF WBC Beware unusual presentations Skin (molluscum) Lung (variable x-ray) Screening with CRAG: Titer > 1:8 should be treated
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Therapy of Cryptococcal Meningitis
Amphotericine B 0.7 mg/kg qd +/- Flucytosine 25mg/kg qd Daily LP if CSF pressure elevated 2 weeks Fluconazole 400 mg po 8 weeks Fluconazole 200 mg po > 14 weeks
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Increased Intracranial Pressure (ICP) Association of Mortality with Baseline CSF Opening Pressure
<190 – 249 mm n = 102 250 – 349 mm n = 59 > 350 mm n = 60 # (%) of Deaths 21 (21%) 16 (27%) 23 (38%) Median mos. To death 10.5 7 6◊ ◊ Pts with the highest baseline Ops (>250) also had higher titers CRAG and more frequent H/A, meningismus, papilledema, hearing loss and pathologic reflexes Graybill et al. Clin Infect Dis. 2000;30:47
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Management of increased ICP
For pts with ICP > 250 mm H2O perform daily or qod LPs. Remove CSF volume up to 30 cc to reduce OP to 50% of the baseline OP. Placement of lumbar drain and option, but infections and drain malfunction are major concerns. Ventriculostomy catheter to drain and monitor ICP. High risk for infection. Ventriculoperitoneal (internalized) shunt in pts with or without evidence of hydrocephalus. Risks include potential infection, dissemination of cryptococcus, and shunt obstruction.
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Serial Crypt Antigen Titers
Serum Changes do NOT correlate with therapeutic response CSF Changes are helpful but repeated LPs not necessary if patient is responding well clinically Note: Some clinicians advocate LP with culture and Ag before stopping maintenance: controversial
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