Opportunistic Infections 2 - Yale University

Opportunistic Infections_28/11/2020
Topics of discussion today
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?
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
a)Mycoplasma Pneumonia b)Pneumocystis Jiroveci Pneumonia c)Miliary Tuberculosis d)Mycobacterium Avium Intracellulare Pneumonia
Which one is the most likely finding on BAL ?
c
ba
d
Tuberculosis AFB Stain Gene Xpert
Pneumocystis Methenamine Silver Stain
Aspergillus Methenamine Silver Stain
• Pulmonary physical exam: usually normal, rales+/-
• Diagnosis: 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
•
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 or 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 • 101 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
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?
• 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 CD• 4 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:
a) Acute bacterial meningitis b) Neurosyphilis c) Cryptococcal meningitis d) CNS Toxoplasmosis
Acute bacterial meningitisa) Neurosyphilisb) Cryptococcal meningitisc) CNS Toxoplasmosisd)
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
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
contangiosum
disease
consolidation, ARDS, mimic PCP
Cryptococcal meningitis: Diagnosis • Detection of cryptococcal antigen (CrAg) in CSF: CSF and serum CrAg are positive in more 95% with the
disease with tires over 1:2048 • Serum CrAg alone is not sufficient—need LP (CT prior to LP to rule out mass lesions) • Blood culture (positive in 55% of those with cryptococcal meningitis) • CSF cultures + in 95% with meningitis by day 7 • Patients with positive serum Crypto Ag should have CSF evaluation to exclude CNS disease • CSF findings
• Mildly elevated protein, normal or low glucose, pleocytosis (mostly lymphocytes), many yeast (Gram or India ink stain)
• Elevated opening pressure (>20 cm H2O in up to 75%) • CSF Culture positive in 95% of cases
Cerebrospinal fluid with C neoformans, India ink stain. Budding yeast indicated by arrow.
Cryptococcal meningitis: Treatment Induction- At least 2 weeks: Liposomal Amphotericin 3-4 mg/kg IV daily + Flucytosine 25 mg/kg po QID Amphotericin B deoxycholate 0.7-1mg/kg IV daily + Flucytosine 25 mg/kg po QID Flucytosine when added to amphotericine or fluconazole rapid CSF sterilization. Serial LP continue induction therapy until culture negative Monitor flucytosine levels, adjust dose in renal impairment Consolidation- At least 8 weeks: Fluconazole 400 mg daily- preferred Maintenance- 1 year: Fluconazole 200 mg daily Discontinuation: • After 1 year of treatment, if asymptomatic and CD4 count >100 cell/dl for 3 months
Serial monitoring of CrAg to determine response to therapy is not recommended.
Complications • Recurrence/refractory infection • Death • Cranial nerve palsy • Hydrocephalus
Fatal Cryptococcal Meningitis in an AIDS Patient Complicated with Immune Reconstitution Syndrome Refractory to Prolonged Amphotericin B Treatment. Int J STD AIDS 2018: doi: 10.1177/0956462418773219
A MRI showing worsening of Left temporal lesion extending into the occipital lobe while on therapy for CM(time 5 months); B MRI while on weekly AmB revealing massive ventricle(time 15 months); C Gross pathology of brain at autopsy; D GMS stain of brain biopsy
A B
C D
Cryptococcus Meningitis : Special Considerations
• Often associated with increase ICP (opening pressure over 20 H2O cm)
• Management of increased intracranial pressure- has a major impact on survival and outcome
• Study: Outcomes correlated with serial lumbar punctures during first two weeks, marked survival
benefit
• Medical therapy to reduce ICP (mannitol, acetazolamide, steroids)- not effective, not
recommended.
Pregnant women: Liposomal Ampho B preferred, no teratogenicity Flucytosine (teratogenic in animal studies) Fluconazole are teratogenic
Cryptococcus Meningitis and IRIS • Paradoxical worsening occurs in upto 30% if ART is started at the same time or soon after starting Rx for
Cryptococcosis
• Cryptococca meningitis associated IRIS is life threatening
• Increased risk of IRIS in lack of prior ARV, high baseline HIV viremia, low wbc in CSF, high CSF fungal burden
• Differential: Cryptococcal meningitis Rx failure (positive cultures) • New CNS disorder • IRIS (typically CSF fungal culture negative)
• IRIS management: continue antifungals and ARV • careful lowering of ICP when indicated • NSAIDS (if mild), oral steroids (in severe cases)
Cryptococcus Meningitis and ART initiation
Delay by 2-10 weeks until induction and /or consolidation therapy is complete
Case-4 • 48 yr old F originally from Portugal, presented to the ED s/p a fall. She c/o gradually
worsening HA for more than 1year, blurry vision and diplopia for 3 weeks, and a 50lb weight loss over the last few months.
• On exam: Afebrile, VSS, pleasant, thin female • Neuro- EOM intact, decreased sensation L-face, LUE, LLE, strength LUE and LLE 4/5,
mild hyperreflexia of LUE, cerebellar function intact. • Otherwise exam was unremarkable
• Labs: WBC 12.1 (79% PMN, 10% lymph), Ht 37.0, Plt 232, CMP WNL • HIV Test positive
MRI brain
What would you next?
a) Start empiric treatment with Pyrimethamine and Sulfadiazine b) Perform lumbar puncture to check CSF JC virus PCR c) Perform a stereotactic biopsy to r/o CNS lymphoma d) Perform lumbar puncture to check Toxo IgM, Crypto Ag, and AFB e) None of the above
What would you next?
a) Start empiric treatment with Pyrimethamine and Sulfadiazine b) Perform lumbar puncture to check CSF JC virus PCR c) Perform a stereotactic biopsy to r/o CNS lymphoma d) Perform lumbar puncture to check Toxo IgM, Crypto Ag, and AFB e) None of the above
Toxoplasma gondii • focal encephalitis • rarely, retinitis, pneumonitis,
and disseminated disease. • Most Toxoplasma disease
in persons with HIV infection occurs from reactivation of latent organisms in patients who have a CD4 count less than 100 cells/mm
• All individuals diagnosed with HIV infection should be tested for IgG antibody to T. gondii at their initial medical visit.
Brain CT MRI
* *
* *
TE is the commonest Extracerebral – lung and ocular involvement occur in 1-2% with AIDS and Toxo
CNS Toxoplasmosis (TE): Diagnosis Usually a presumptive diagnosis based on a combination of clinical manifestations, positive serum •
Toxoplasma Ab and characteristic findings on CNS imaging.
HIV positive with CD• 4 count <100
Serum • Toxo IgG + in 95% of patients with TE
Symptoms: HA (• 55%), confusion (52%), focal neuro (69%)
Imaging• - CT shows enhancing lesions in 90% of patients.
MRI is more sensitive, CT: > • 2 ring-enhancing lesions with surrounding edema, often in basal ganglia.
CSF• - Not usually helpful. Mild mononuclear/lymphocytic pleocytosis, elevated protein. Tachyzoites with Giemsa stain• - poor sensitivity. T. gondii • PCR sensitivity 50% but specificity 96-100%
Brain biopsy and H&E stain• - Definitive diagnosis (fatal disease or failure to respond to therapy)
Toxoplasma gondii Encephalitis:
CT scan of the brain showing multiple ring enhancing lesions
TE Treatment Start intensive high dose initial anti- Toxoplasma therapy immediately in suspected patients.
Induction • at least 6 weeks (or longer)
Pyrimethamine 50-75 mg daily and Sulfadiazine 1000-1500 mg Q6h + Leucovorin 10-25 mg daily
Chronic Maintenance • until CD4 count >200
Pyrimethamine 15-50 mg daily and Sulfadiazine 500-1000 mg Q6h + Leucovorin 10- 25 mg daily
CNS Toxoplasmosis Alternative Treatment Alternative Treatment:
Pyrimethamine and Clindamycin 600 mg IV Q6H TMP 5mg/SMX 25 mg IV or PO BID Atovaquone 1,500 mg BID +Pyrimethamine+leucovorin Atovaquone 1,500 mg BID +Sulfadiazine Atovaquone 1,500 mg BID alone
Adjuvant corticosteroids: Only in case of cerebral edema or mass effect Primary CNS lymphoma may respond to steroids and may confound
diagnosis. Discontinuation:
Clinical response to treatment and CD4 count >200 for 6 months.
CNS Toxoplasmosis: Special Considerations
Response to initial Therapy: Over 70% show clinical and radiologic improvement within 14days of
appropriate Rx If by day 14 there is no response-> consider brain biopsy, alternative
diagnosis
Treatment in pregnant women: Same
ART initiation: No data to base recommendations Many initiate ART within 2-3 weeks
Case-5
• 42 year old female diagnosed with HIV 15 years ago, Hx of PCP, Hx of IVDU, last CD4 count 20 cells/ml and HIV VL of 353,000 copies. She is not on ART. She presents with 2 week history of blurred vision and 1 day history of left eye peripheral vision loss.
• On exam: Afebrile, wasted • Cervical LAD • Oral thrush • Lungs CTA • RRR with no murmur • Abd soft non tender • Neuro: left peripheral vision loss
What is your next step?
Perform a • funduscopic exam Get urgent ophthalmology consult• Get blood cultures and start broad spectrum antibiotics for endocarditis• Check serum CMV PCR• All of the above• None of the above•
What is your next step?
• Perform a funduscopic exam • Get urgent ophthalmology consult • Get blood cultures and start broad spectrum Abx for endocarditis • Check serum CMV PCR • All of the above • None of the above
CMV
HIV retinopathy
HIV RETINOPATHY
CMV Disease: Epidemiology • Disseminated or localized disease • Occurs in patients with advanced immunosuppression (CD4 count <50 cells/µL) • Usually caused by reactivation of latent infection • CMV PCR has low positive predictive value and is not recommended to be done to r/o CMV end organ
disease
CMV Disease: Clinical Manifestations • Retinitis • GI • Neurologic
CMV Disease: Retinitis • Most common CMV end-organ disease in HIV • Before use of potent ART in the United States, 30% of AIDS patients developed CMV retinitis
• Usually unilateral, if untreated is likely to progress to involve both eyes; may cause blindness
• Symptoms: floaters, flashes or a visual field cut or faliing vision (four Fs), no pain or redness of the eye
• Diagnosis: clinical based on characteristic fundoscopic exam.
• Fundoscopic examination: perivascular fluffy yellow-white retinal infiltrates, with or without hemorrhage • Need an experience ophthalmologist to distinguish CMV retinitis from HIV retinopathy.
• CMV PCR detected in vitreous in 80% of cases and in blood in 70 % of cases- not practical.
CMV Disease: Retinitis
CMV Disease: Colitis • Second most common clinical manifestation of CMV
• Occurs in 5-10% of persons with CMV end-organ disease
• Odynophagia is the most prominent symptom with CMV esophagitis.
• CMV colitis: weight loss, anorexia, abdominal pain, , malaise, severe diarrhea (sometimes bloody, may have GI perforation)
• Diagnosis: mucosal ulcerations on endoscopy + biopsy with characteristic intranuclear and intracytoplasmic inclusions Credit: P. Volberding, MD,
UCSF Center for HIV Information Image Library
CMV Disease: Neurologic
• Ventriculitis/encephalitis: o Acute course o Cranial nerve palsies, nystagmus, other focal neurologic signs, rapid
progression to death o CT or MRI: periventricular enhancement
• Ascending polyradiculomyelopathy: o Resembles Guillian-Barré syndrome o Urinary retention, progressive bilateral leg weakness; progresses over
weeks to loss of bowel and bladder control, flaccid paraplegia o Spastic myelopathy, sacral paresthesia possible o CSF: neutrophilic pleocytosis, low glucose, elevated protein
CMV Neurological Disease • Neurologic disease: clinical syndrome + CMV in CSF or brain tissue; detection
enhanced by PCR
Brain biopsy with CMV inclusions
CMV- Treatment Sight- threatening Retinitis: Ganciclovir intraocular implants for 6 months is no longer manufactured Repeated intraocular injections of GCV or Foscarnet in combination with oral Valgancyclovir Valganciclovir 900 mg BID for 14-21 days then 900 mg daily for chronic maintenance
For small peripheral lesions PO Valganciclovir is sufficient
CNS disease: IV Ganciclovir for 14-21 days then Valganciclovir 900 mg daily
GI disease: Initially IV Ganciclovir then Valganciclovir for 21-42 days or until clinical symptoms resolve. Maintenance
usually not required.
CMV- Treatment
Discontinuation: Treatment for 3-6 months and clinical response, in addition to CD4 count
>100 for 3-6 months Pregnancy: Intravitreous injection of Ganciclovir in the first trimester if possible to limit
fetal exposure to systemic antivirals Systemic Valganciclovir after the first trimester ART initiation: Within 2 weeks Risk for immune reconstitution uveitis (IRU), and encephalitis/ventriculitis
Progressive Multifocal Leukoencephalopathy (PML) • Focal demyelinating disease of the CNS • Caused by reactivation of JC virus • Often from HIV associated immunosuppression.
• CF: subacute progressive focal neuropsychiatric signs and symptoms; cognitive disturbances, visual changes, paresis, ataxia etc
• DDx: HIV dementia, stroke
• Diagnosis: clinical picture+ MRI findings(focal white matter lesions)
• CSF JC virus DNA PCR+ in 70-90% (not essential to diagnose)
• Plasma JC virus PCR (high specificity but low sensitivity).
• No definitive Rx. Immune restoration with ART.
Case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org, rID: 22071 Case courtesy of Dr Roberto Schubert, Radiopaedia.org, rID: 14095
A B C
PML CMV with ventriculitis HIV
Focal white matter lesions non specific increased T2/FLAIR signal in the white matter. No enhancement unless ventriculitis is present, similar to HIV encephalitis
symmetric periventricular and deep white matter T2 hyperintensity , no enhancement, considerable atrophy+
Opportunistic Infections_2
Immune reconstitution inflammatory syndrome (IRIS)
When to Start ART in the presence of an OI?Is there any concerns for Immune Reconstitution Inflammatory Syndrome?
IRIS
Case-1
Slide Number 9
Slide Number 10
Pneumocystis pneumonia (PCP)
Signs and symptoms
What would you next other than starting antibiotics?
Mycobacterium Avium Complex-MAC
Disseminated MAC: Epidemiology
Cryptococcal neoformans Disease
CMV

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Opportunistic Infections 2 - Yale University