Opportunistic Infections_2 Thilinie Bandaranayake MBBS 8/11/2020 Topics of discussion today • IRIS • Symptoms • Pneumocystis Pnuemonia • Diagnosis • Toxoplasma Encephalitis • Treatment • Disseminated MAC • Timing of ART • Cryptococcosis **Secondary prophylaxis • CMV disease • PML • Others: Immune reconstitution inflammatory syndrome (IRIS) • IRIS: An undesirable disease- or pathogen-specific inflammatory response that may be triggered by ART-associated immune system recovery. • It usually presents within the first 4 to 8 weeks after ART initiation • It can be associated with an increased risk of death, with a reported overall mortality rate of 4.5% • Paradoxical IRIS-Refers to the worsening of a previously diagnosed disease after ART initiation. • Unmasking- appearance of a previously undiagnosed disease following ART initiation. • IRIS Is most commonly observed in : a. disseminated Mycobacterium avium complex disease b. cryptococcal meningitis c. tuberculosis d. progressive multifocal leukoencephalopathy e. cytomegalovirus retinitis When to Start ART in the presence of an OI? Is there any concerns for Immune Reconstitution Inflammatory Syndrome? IRIS AIDS 2005;19(4):399-406. Case-1 • Mr G. is a 55 year old bisexual man who presents with a 2 week history of non productive cough and dyspnea. • On exam he is febrile to 101°F. O2 Sat 90% on RA • He has oral thrush. Lungs CTA, RRR, no S3 or murmur • Laboratory data: – WBC: 7,200 – 80% PMN and 10% lymphocytes – LDH 675 – CMP WNL – HIV test pending – CXR: What is the most likely diagnosis? a)Mycoplasma Pneumonia b)Pneumocystis Jiroveci Pneumonia c)Miliary Tuberculosis d)Mycobacterium Avium Intracellulare Pneumonia What is the most likely diagnosis? a)Mycoplasma Pneumonia b)Pneumocystis Jiroveci Pneumonia c)Miliary Tuberculosis d)Mycobacterium Avium Intracellulare Pneumonia Which one is the most likely finding on BAL ? a b d c BAL Findings Pneumocystis Tuberculosis Methenamine Silver Stain AFB Stain Gene Xpert Histoplasmosis Methenamine Silver Stain Aspergillus Histoplasma Ag Methenamine Silver Stain Pneumocystis pneumonia (PCP) Images: UW curriculum Clinical Manifestations: • subacute nonproductive cough, progressive dyspnea (particularly dyspnea on exertion), and fever • If untreated: worsening dyspnea and hypoxemic respiratory failure • Pulmonary physical exam: usually normal, rales+/- Signs and •symptomsDiagnosis: important to evaluate and confirm diagnosis since other infections • can mimic PCP Pneumonia • Nondefinitive tests: • CXR: often shows diffuse b/l perihilar infiltrates (ground glass or butterfly shaped) • 15-20% normal CXR • High resolution CT: more sensitive, pneumatoceles, cystic lesions • Exercise pulse oximetry: oxygen desaturation with exercise • Nonspecific labs: LDH over 500mg/dl • 1-3 beta-D-glucan 80pg/ml or greater (component of P.jirovecci cell wall). PJP Diagnosis: Definitive tests • Definitive diagnosis requires demonstrating organism on: • Induced sputum (sensitivity 50% to 90%)- spontaneous sputum is not helpful due to low sensitivity. • Bronchoscopy with bronchoalveolar lavage (sensitivity about 95%) • Transbronchial biopsy (sensitivity 95-100%)-rarely used due to high yield with BAL • Open-lung biopsy (sensitivity 95-100%) • Polymerase chain reaction (PCR) is an alternative diagnostic. • PCR is highly sensitive and specific for detecting Pneumocystis • PCR cannot reliably distinguish colonization from active disease Direct immunofluorescent stain to detect P.jirovecci in samples: many labs use this as the procedure of choice. Other tests are methanamine silver, Giemsa silver and toludineblue -O Lung biopsy using silver stain to demonstrate P jiroveci organisms in tissue (crescent or round intracystic sporozoites) Treatment of Pneumocystis pneumonia • If diagnosis is suspected- start empiric treatment without a delay • Mild to moderate Pneumocystis PNA: PaO2 of 70mmHg or greater and a calculated P(A-a O2) grater than 35• mmHg. • Moderate to severe Pneumocystis PNA: PaO2 less than 70mmHg or alveolar arterial O2 gradient greater than pidemiologyor equal to 35 mmHg. • Preferred Rx: Bactrim in three divided doses daily for 21 days • Alternative Rx: PJP Adjunctive treatment Corticosteroids- improve survival • For moderate-to-severe disease (room air PO2 <70 mmHg or A-a gradient >35 mmHg • Give as early as possible (within 72 hours) • Prednisone 40 mg BID days 1-5, 40 mg QD days 6-10, 20 mg QD days 11-21 PJP: Special Considerations • Timing of starting ARV: within 2 weeks of diagnosis of Pneumocystis PNA Secondary prophylaxis : • All with PJP PNA should start immediately after completing treatment • Bactrim 1SS or 1DS daily • Alternatives: similar to 1ry ppx • Until CD4 count >200 cell/dl for 3 months • Can consider for CD4 count 100-200 and VL undetectable for 3-6 months • If Pneumocystis PNA occurred at CD4 count >200 in a patient on ART most experts recommend continuing prophylaxis for life regardless of CD4 count Case-2 • 26 year old female perinatally infected with HIV, poor adherence to ART, fever and abdominal pain for 10 days. •On exam: Cachectic. Febrile to 101̊ F •CBC showed pancytopenia •Slightly elevated LFT (mainly with elevated alk phos) What would you do next other than starting antibiotics? a) Send AFB blood culture b) Bone marrow biopsy c) Lymph node biopsy d) Start RIPE e) Start IV Amphotericin What would you next other than starting antibiotics? a) Send AFB blood culture b) Bone marrow biopsy c) Lymph node biopsy d) Start RIPE e) Start IV Amphotericin • BC for AFB returned positive at 7 days: Heavy growth What is your diagnosis? Mycobacterium Avium Complex-MAC Disseminated MAC: Epidemiology • Incidence: 20-40% in AIDS patients who are not on effective ART or MAC prophylaxis • >90% of disseminated MAC are due to M. avium • Mode of acquisition: inhalation or ingestion from environmental exposure • Usually occurs in people with CD4 count<50 cells/mL • Other risk factors: plasma HIV RNA >100,000 copies/mL, previous opportunistic infections, previous colonization with MAC • Recent studies: the overall incidence of MAC disease was 0.6 per 100 person-months if on ART and virally suppressed Clinical Manifestations: • MAC most commonly presents as disseminated disease • Nonspecific symptoms: Fever, night sweats, weight loss, abdominal pain ,and diarrhea Extrahepatic obstruction (not common) • On exam: hepatosplenomegaly, lymphadenopathy • Labs: anemia, increased alk phos(often with normal bilirubin and aminotransferase), high LDH • CT: multiple, large retroperitoneal and mesenteric LN, Hepatosplenomegaly, thick SI wall Disseminated MAC Disseminated MAC: Diagnosis • Isolation of organism from blood, bone marrow, lymph node, or other normally sterile tissue or fluid • AFB blood culture is the preferred diagnostic test • Obtaining 2sets of BC sensitivity is greater than 90% (usually BC + by day 14) • DNA Probe is essential for differentiating MAC and TB MAC Treatment Macrolide alone can cause marked decline in MAC organism burden but can develop resistance. Recommend: Initial treatment with at least 2 active drugs Azithromycin 600 mg daily or Clarithromycin 500 mg BID + Ethambutol 15mg/kg daily Duration- at least for 12 months Alternative: three or four drug regimen if CD4 <50, high mycobacterial load of over 2 log CFU/ml blood or if not on effective ARV. Now most would use a 2 drug regimen +ARV and reserve 3 drug regimen for documented macrolide resistant infections. ART initiation and IRIS: Start ART as soon as possible/at the same time as starting MAC treatment 1. to improve response to antimycobacterial Rx 2. to reduce risk of other serious OIs. • MAC IRIS is a well documented complication • Usually present with intraabdominal and peripheral lymphadenopathy or pulmonary/thoracic disease, fever, no bacteremia. • Occurs in patients with low CD4 count and subclinical or known MAC who begin ART and have rapid increase in CD4 count. • Risk of death is low. NSAID can be used for IRIS Prednisone 20-40 mg daily for 4-8 weeks if symptoms persist Continue ARV in patients with MAC IRIS Case-3 • Mr H. is a 35 year old man with PMHx of IDU, Hepatitis C, presents with 3 weeks history of headache, diplopia and fatigue • On exam: • He has low grade fever 100.3°F • Skin rash • Left CN-VI palsy • No nuchal rigidity • CSF analysis: • OP= 25 cm H2O, WBC=18, Prot=55, Gl=60 Physical exam revealed: What is the most likely diagnosis? a) Acute bacterial meningitis b) Neurosyphilis c) Cryptococcal meningitis d) CNS Toxoplasmosis What is the most likely diagnosis? a) Acute bacterial meningitis b) Neurosyphilis c) Cryptococcal meningitis d) CNS Toxoplasmosis Which one of the following findings is associated with poor prognosis? a)Altered mental status b)CSF Crypto Ag >1:1024 c) CSF WBC <20 d)OP >250 mm H2O e)All of the above f) None of the above Which one of the following findings is associated with poor prognosis? a)Altered mental status b)CSF Crypto Ag >1:1024 c) CSF WBC <20 d)OP >250 mm H2O e)All of the above f) None of the above Cryptococcal neoformans Disease Cryptococcal meningitis • Mostly caused by Cryptococcus neoformans (C. gatti also can cause disease). • Most cases seen in patients with CD4 count <50 cells/µL • CF: indolent presentation than acute bacterial meningitis • Non specific symptoms: fever, HA, malaise, without signs of meningeal irritation early in the course • AMS, neck stiffness and CN abnormalities with disease progression • 10% have cutaneous manifestations similar to Molluscum contangiosum • Can have Pulmonary cryptococcosis with or