Approach to Diagnosis

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Approach to Diagnosis Management of
Opportunistic Infections in HIV-infected
Patients

• O.C. Abraham, M.D., M.P.H.,
• Professor,
• Department of Medicine Unit 1 Infectious
  Diseases,
• Christian Medical College,
• Vellore

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Learning Objectives

• At the end of the session, the participant should
  be able to
• List the common OI in PLHA
• Recognize clinical manifestations, order
  appropriate diagnostic tests, initiate treatment
  refer (when appropriate) patients presenting
  with these OI
• Follow an algorithmic approach to diagnosis of
  common OI

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Typical Course of Untreated HIV Infection
Fauci AS. NEJM 1993 328327-335
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Opportunism

• The adaptation of policy or judgement to
  circumstances or opportunity, esp. regardless of
  principle
• The seizing of opportunities when they occur

The Concise Oxford Dictionary
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Approach to Diagnosis of OI

• Degree of immunodeficiency
• Exposure to potential pathogens in the
  environment
• Prophylactic therapy
• Clinical syndrome

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CD4 T-Cells Risk of OI
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The Burden of HIV-related Disease

• At any stage Virulent pathogens
• S. pneumoniae,
• non-typhoidal Salmonellae,
• M. tuberculosis
• Advanced immunosuppression Opportunistic
  pathogens
• P. jiroveci,
• C. neoformans,
• T. gondii,
• M. avium-intracellulare

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Aetiology of prolonged fever in
antiretroviral-naive HIV infected adults
Rupali P. Natl Med J India. 200316(4)193-9.
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Pulmonary Manifestations
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Case Presentation

• 38 yr. male
• HIV infection diagnosed May 02
• On empiric ATT x 5 months
• PC progressive breathlessness, dry cough, fever
  x 20 days
• O/E Temp 101 0F RR 28/min PR 108/min
  systemic exam - NAD

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Pulmonary Complications

• Pneumocystis pneumonia (PCP)
• Bacterial pneumonia
• Pulmonary tuberculosis

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Pneumocystis Pneumonia

• Interstitial pneumonia caused by the fungus P.
  jiroveci (formerly P. carinii)
• Symptoms nonproductive cough, progressive
  dyspnea, fever /- subacute onset (1-3 wk) CD4
  lt200 cells/?L
• Chest x-ray interstitial infiltrates, ground
  glass appearance
• Normal x-ray in 10
• Pleural effusions thoracic lymphadenopathy
  rare
• Diagnosis demonstration of pneumocystis (cysts /
  trphozoites) in induced sputum, BAL, lung tissue
• ? LDH sensitive not specific

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Source CDC Parasite Image Library
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PCP Treatment

• Preferred TMP-SMX (TMP 15 mg/kg/d) x 21 days
• Alternatives TMP dapsone, pentamidine,
  clindamycin primaquine
• Adjunctive steroids ? risks of respiratory
  failure death for pt. with severe disease
  (paO2 lt70 mm Hg or A-a gradient gt35 mm Hg) (NEJM
  19903231451-7)
• Maintenance TMP-SMX 1 DS tab od x life-long
• Maybe discontinued when CD4 counts gt200 cells/?L
  for 3-6 months

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PCP Treatment Failure

• Lack of clinical improvement or worsening of
  respiratory function after at least 4-8 days of
  treatment
• If patient not on corticosteroid therapy, early
  deterioration (day 3-5) may be due to
  inflammatory response to lysis of P jiroveci
  organisms
• Due to
• Drug toxicities switch to alternate regimen
• Lack of drug efficacy in 10 of patients
• No data to guide treatment decisions
• For TMP-SMX failure in moderate-to-severe PCP,
  consider primaquine clindamycin, IV
  pentamidine, or trimetrexate /- dapsone (and
  leucovorin)
• For mild disease, consider atovaquone

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Survival of HIV infected patients with PCP, by
years of diagnosis
Dworkin MS. J Infect Dis. 2001183(9)1409-12
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Bacterial Pneumonia

• HIV-infected persons at ? risk
• Pneumonia x 25
• Bacteremia x 50 -100
• Risk greatest with CD4 count lt200 cells/mm3
• Treatment Penicillin
• Prophylaxis
• HAART
• TMP-SMX
• Pneumococcal vaccine

1. Feikin DR. Lancet ID 200418744-55 2. IBIS
Investigators. Lancet 19993531216
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Case Presentation

• 36-year male
• Symptom Cough with expectoration, malaise,
  weight loss x 6 weeks no response to ATT
  diagnosed to have HIV infection
• Signs oral thrush wasting LLL consolidation

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Case Presentation

• 35 yr. male
• HIV infection diagnosed 6 years ago no specific
  therapy
• PC fever, weight loss x 3 months
• O/E febrile emaciated oral thrush bilateral
  cervical lymphadenopathy hepato-splenomegaly

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TB and HIV Infection

• Clinical Manifestations
• Degree of immunosuppression influences clinical,
  radiographic, histopathologic presentation of TB

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CxR Findings in TB Patients with HIV Infection
Late HIV Sputum smear often negative
Early HIV Sputum smear positive
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Diagnosis of TB

• AFB smear mycobacterial cultures
• Sputum, pleural/pericardial fluid, lymph node
  FNAC, blood, bone marrow
• Histopathology
• Nucleic acid amplification
• High specificity, PPV
• Low sensitivity, NPV
• Cannot replace conventional tests

Pai M. Natl Med J India. 200417(5)233-6
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A Review of Efficacy Studies of 6-Month
Short-Course Therapy for Tuberculosis Among
Patients Infected with HIV
El-Sadr W et al. Clin Infect Dis   200032623-632

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Initiation of Antiretroviral Therapy for Patients
with TB To Start or to Delay?

• Reasons to start ART
• Decrease morbidity and mortality related to
  HIV/AIDS
• Reasons to delay ART
• Complex drug-drug interactions
• Overlapping side effects from ART and anti-TB
  therapy
• Immune reconstitution inflammatory syndrome
• (paradoxical reactions)
• Difficulties with adherence to multiple
  medications
• Pill burden

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Effect of Rifampin on Serum Concentrations
of Protease Inhibitors and Non-Nucleoside
Reverse Transcriptase Inhibitors
PI
NNRTI
Nevirapine Efavirenz
? 37-58 ? 13-26
? 80 ? 35 ? 90 ? 82 ? 81 ? 75 not done
Saquinavir Ritonavir Indinavir Nelfinavir Amprenav
ir Lopinavir/ritonavir Atazanavir
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HIV TB Treatment

• Same as for HIV-negative TB
• Consider Cat 1 regimen 12-month therapy
• Ensure treatment completion (DOT in ALL patients)
• RIF contra-indicated with PI/NVP containing HAART
  regimens
• Possible options for ART in patients with active
  TB
• Defer ART until TB treatment is completed if CD4
  gt 200 cells/?L
• Defer ART until the continuation phase' of
  treatment for TB if CD4 lt 200 cells/?L
• If CD4 lt 50 cells/?L begin HAART in 2 weeks
• Treat TB with RIF containing regimen and use
  EFV-based HAART regimen

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Neurological Manifestations
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HIV and the Nervous System

• HIV enters the brain immediately after infection,
  is present throughout the course of the disease
• Can potentially involve all levels of the nervous
  system
• Neurologic disease is the first manifestation of
  symptomatic HIV infection in 10-20 of persons
• 60 of patients with advanced HIV disease will
  have clinically evident neurologic dysfunction
  during the course of their illness
• Autopsy studies of patients with AIDS show
  pathologic abnormalities of the nervous system in
  75-90 of cases

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Neurologic Complications of HIV Infection

• HIV Related
• Acute aseptic meningitis
• Chronic meningitis
• HIV encephalopathy (AIDS dementia)
• Vacuolar myelopathy
• Peripheral neuropathy (sensory)
• Myopathy

• O I
• Cryptococcal meningitis
• Cerebral toxoplasmosis
• CMV retinitis encephalitis
• PML
• Primary CNS lymphoma
• TB
• Syphilis

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Neurological Complications

• Global cerebral syndromes
• Chronic meningitis / meningo-encephalitis
  cryptococcosis, TB, syphilis
• Focal cerebral lesions
• Toxoplasma encephalitis, primary CNS lymphoma,
  Progressive Multifocal Leukoencephalopathy (PML)
• Cognitive decline
• Myelopathy
• Peripheral neuropathy

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Case Presentation

• 38 yr. male
• HIV infection diagnosed 98
• Disseminated tuberculosis in Dec 01 received
  ATT x 1 year, TMP-SMX
• PC Holocranial headache x 3 weeks confusion x 3
  days
• O/E oral thrush afebrile no focal neurological
  deficits no neck stiffness

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Cryptococcus neoformans

• Encapsulated basidiomycete yeast-like fungus
• Environmental saprophyte
• Found in soil contaminated with desiccated pigeon
  or chicken droppings
• Four serotypes divided into 2 groups
• C. neoformans var. neoformans
• C. neoformans var. gatti

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Pathology

• Meningo-encephalitis
• Massive fungal infestation with poor host immune
  response
• CSF contains large numbers of cryptococci
• Minimal to absent host cellular response

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Incidence

• 510 of AIDS patients in the USA, Europe and
  Australia (pre-HAART era)
• 19 of AIDS-defining illnesses in Thailand
• 10.3 cases/100 p.y. follow-up in Uganda
• Most frequent life-threatening fungal infection
  in AIDS

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Cryptococcal Meningitis

• Subacute meningo-encephalitis
• Average duration of symptoms 30 days
• Headache (90), fever (60-80)
• Neck stiffness (40-45), seizures (5-10)
• CD4 lt100/?L
• Disseminated disease common lung, skin, fungemia
• Predictors of poor outcomes
• Coma
• High opening pressure (gt250 mm)
• WBC lt20 cells/mm3
• India ink preparation
• Cryptococci isolated from extra-neural sites

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Lab Diagnosis
Diagnosis confirmed by CSF examination India
ink (74-88) Crypto Ag serum/CSF (99) CSF
culture
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Cryptococcal Meningitis Induction Therapy
Confirmed Cryptococcal MeningitisSerial LPs if
Opening Pressure gt 250 mm H2O
1
3
2
Ampho B0.7-1.0 mg/kg/d/-5-Flucytosine100
mg/kg/d
Ampho B0.7-1.0 mg/kg/d
Fluconazole400-800 mg/d

• Initial LP Reduce opening pressure by 50
• Daily LPs Maintain opening lt 200 mm H2O
• Cessation of LPs once opening pressure normal
  for several consecutive days

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Cryptococcal Meningitis Consolidation Therapy
Cryptococcal MeningitisInduction therapy
completed clinical improvement
Fluconazole400 mg/day
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Cryptococcal Meningitis Therapy

• Acute
• Induction Ampho B (0.7 mg/kg/d) 5-FC 25 mg/kg
  QID x 14 days
• Consolidation Fluconazole 400 mg/d for 8-10
  weeks
• Maintenance Fluconazole 200 mg/d x lifelong
• Maybe D/C with immune restoration with HAART
• Repeated lumbar puncture for elevated ICP (OP
  gt250 mm)
• Steroid treatment associated with treatment
  failure death hence, not recommended

1. N Engl J Med. 1997337(1)15-21. 2. Clin
Infect Dis. 199928(2)291-6. 3. Clin Infect Dis.
200030(4)710-8.
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Cryptococcal Meningitis Monitoring

• If clinical improvement after treatment
  initiation, no need to repeat LP to check
  clearance of cryptococcus
• If new symptoms or signs after 2 weeks of
  treatment, repeat LP
• Serum CrAg titers do not correlate with clinical
  response not useful in management
• CSF CrAg may be useful but requires repeated LP
  not routinely recommended for monitoring response
• Tretament failure
• Clinical deterioration despite appropriate
  therapy (including management of elevated ICP)
• Lack of clinical improvement after 2 weeks of
  appropriate therapy
• Relapse after initial clinical response

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Primary Prophylaxis

• 4 trials
• N Engl J Med. 1995332(11)700-5
• Clin Infect Dis. 199623(6)1282-6
• Clin Infect Dis. 200234(2)277-84
• HIV Med. 20045(3)140-3
• Azoles (Flu Itra) reduce incidence of
  cryptococcosis in patients with advanced HIV
  infection
• Benefit in patients with CD4 cells lt 100/?L
• No survival advantage

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TUBERCULOUS MENINGITIS Ventricular dilatation is
present (asterisks), as well as inflammatory
exudate in the ambient cistern (black arrows) and
multiple foci of vasculitis-associated subacute,
ischemic necrosis (white arrows)
NEJM 2004 351 (17) 1719
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Tuberculous Meningitis

• Diagnostic challenges
• AFB stain poor sensitivity
• Culture slow, poor sensitivity
• PCR poor sensitivity poor reliability cost
• Decision to treat a patient for TBM is frequently
  empirical

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TBM Diagnostic Criteria

• Definite M tuberculosis isolated from CSF
• Probable Clinical meningitis with negative Gram
  India ink stains, sterile bacterial and
  fungal cultures, 1 of the following
• CAT scan brain consistent with TBM
  (hydrocephalus, exudates in basal cisterns,
  tuberculoma)
• Evidence of active TB elsewhere (culture, AFB
  smear, histology, CxR)

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Total score 4 TBM Total score gt 4
bacterial meningitis
Lancet. 2002360(9342)1287-92
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TBM Therapy

• Cat 1 RNTCP regimen
• Duration 9 12 months
• Paradoxical worsening
• Delayed resolution of intracranial tuberculoma
• Adjunctive steroid (dexamethasone) therapy

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Dexamethasone for the Treatment of Tuberculous
Meningitis in Adolescents and Adults

• Significant ? in risk of death
  (RR, 0.69 95 CI, 0.52 to 0.92
  P0.01)
• IV treatment x 4 weeks (0.4 mg/kg/day for week 1,
  0.3 mg/kg/day for week 2, 0.2 mg/kg/day for week
  3, 0.1 mg/kg/day for week 4) and then oral
  treatment x 4 weeks, starting at a total of 4
  mg/day and decreasing by 1 mg each week
• No effect on severe disability
• 18.2 among survivors in the DEXA group vs. 13.8
  in the placebo group, P0.27
• Treatment effect consistent across subgroups
• Disease-severity grade (stratified RR of death,
  0.68 95 CI, 0.52 to 0.91 P0.007)
• HIV status (stratified RR of death, 0.78 95 CI
  , 0.59 to 1.04 P0.08)

N Engl J Med. 2004351(17)1741-51
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Neurosyphilis

• Asymptomatic
• Syphilitic meningitis
• Meningo-vascular
• Parenchymal GPI, tabes dorsalis, gumma
• Occular uveitis, chorio-retinitis, optic
  neuritis
• Otologic S-N hearing loss

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Evaluation of CSF for Neurosyphilis

• Any HIV seropositive patient with neurologic,
  ophthalmic, or otologic signs or symptoms
• All patients who fail treatment
• HIV-infected patients with late latent syphilis
  of gt1 year duration or with syphilis of unknown
  duration

http//www.cdc.gov/STD/treatment/2-2002TG.htm
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Neurosyphilis Diagnosis

• Positive CSF VDRL with abnormal CSF pleocytosis
  (usually 10-200 cells/mm3) mildly elevated
  protein (46-200 mg/dL)
• CSF VDRL specific not sensitive (only 70)
• CSF treponemal tests sensitive not specific

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Neurosyphilis Treatment

• Aqueous crystalline penicillin G, 3-4 million
  units IV Q4H x 10 - 14 days
• For patients allergic to penicillin, consider
  penicillin desensitization
• Treatment failure 4-fold decrease in VDRL titer
  6-12 months after therapy
• Repeat CSF exam at 6 months intervals until CSF
  WBC is normal and CSF VDRL is non-reactive
• Re-treat if
• CSF WBC count has not decreased 6 months after
  completion of treatment, or
• CSF-VDRL remains reactive 2 years after treatment

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24-year old male with seizures
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Cerebral Toxoplasmosis

• T gondii - Obligate intracellular protozoan
• Commonest cause of CNS mass lesion in AIDS
• Incidence 5-20
• CD4 lt100/?L

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Toxoplasma Encephalitis

• Pathology Focal encephalitis
• Clinical presentation
• Focal neurological deficits (50-89), seizures
  (15-20), fever (56), generalized cerebral
  dysfunction (confusion, coma), neuro-psychiatric
  manifestations
• CT/MRI
• Multiple ring-enhancing lesions located in
  frontal, parietal lobes and/or basal ganglia
  lesions often at corticomedullary junction MRI
  more sensitive than CT
• Serum Toxoplasma IgG usually positive (97)

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Toxoplasma Encephalitis

• Diagnosis is presumptive based on clinical
  presentation, characteristic lesions, risk strata
  positive serology
• Presumptive diagnosis confirmed by tissue sample
  or response to TOXO therapy in appropriate time
  frame
• 86 patients show clinical improvement by day 7
  of treatment 95 show radiographic improvement
  by day 14
• Clinical or radiological deterioration during
  first week of therapy, or lack of clinical
  improvement within 2 weeks - consider alternative
  diagnosis indication for brain biopsy

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TE Time to a Neurologic Response in 35 Patients
Studied by Quantifiable Neurologic Assessment
Luft BJ et.al. N Engl J Med. 1993329995-1000
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Cerebral Toxoplasmosis
December 14, 2004
January 06, 2005
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Toxoplasma Encephalitis

• Treatment (for at least 6 weeks, 80-90
  response)
• Acute SD (4-6 gm/d) Pyrimethamine (200 mg x 1
  dose then 50-75mg/d) with folinic acid (10-20
  mg/d)
• Alternatives clindamycin / macrolides
  (azithromycin, clarithromycin) pyrimethamine
  and folinic acid TMP-SMX
• Maintenance Pyrimethamine 25-50 mg/day SD
  0.5-1.0 G Q6H (life long)
• Consider stopping in patients who have completed
  primary treatment, are asymptomatic, and have
  sustained (gt6 months) increase in CD4 cell count
  to gt200/µL with HAART
• Steroids for cerebral edema mass effect

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Progressive Multifocal Leukoencephalopathy

• Multifocal demyelination caused by JC-virus
• Relatively rapidly progressive neurologic
  syndrome over weeks or months
• Cognitive dysfunction, ataxia, aphasia, cranial
  nerve deficits, hemiparesis or quadriparesis, and
  eventually coma
• Typical CT abnormalities include single or
  multiple hypodense, non-enhancing cerebral white
  matter lesions

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Case Presentation

• Mr. S., a 28-year old male, was diagnosed to have
  AIDS six months ago
• Weight loss chronic diarrhea due to
  isosporiasis
• Symptomatic improvement after a course of TMP-SMX
  loperamide
• P. C. His wife had noticed that the patient had
  become increasingly forgetful over the last
  couple of months. She had also noticed slowness
  of gait, deterioration of handwriting and that S.
  had become very withdrawn apathetic.
• No fever, headache, seizures or limb weakness
• O/E thinly built male, who was conscious and
  alert
• Recent memory impaired poor attention span
  concentration
• Unable to perform fine repetitive movements
• No focal neurological deficits, papilledema or
  signs of meningeal irritation

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AIDS Dementia

• CD4 100-200 cells/?L
• Gradual onset slow progression of symptoms
• Cognition
• Motor function
• Behavior
• Neurologic exam alert, with non-focal or diffuse
  signs

• Diagnosis of exclusion
• CSF non-specific
• CT/MRI cerebral atrophy, ventricular dilatation
• Therapy HAART include drugs which cross BBB

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Algorithm for the management of brain lesions in
patients with HIV infection
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Algorithm for the management of brain lesions in
patients with HIV infection
Simpson, D. M. et. al. Ann Intern Med
1994121769-785
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Neuropathy

• Distal symmetric polyneuropathy (DSPN)
• Mononeuropathy multiplex
• Chronic inflammatory demyelinating polyneuropathy
  
• Progressive lumbosacral polyradiculopathy (CMV)

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D S P N

• Most common type of neuropathy
• Symptoms tingling, numbness, burning pain in
  the feet, ascending over time.
• Exam bilateral depressed ankle reflexes loss of
  vibration sense decreased appreciation of
  temperature distally motor weakness mild
• Diagnosis of exclusion

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Vacuolar Myelopathy

• Pathology non-inflammatory vacuolation of
  myelin, particularly in the lateral and posterior
  columns of the spinal cord
• Upper thoracic cord affected most commonly
• Clinically pathologically identical to subacute
  combined degeneration (B12 deficiency)
• Subacute progression of motor (spastic
  paraparesis, brisk knee reflex absent ankle
  reflex)) and sensory deficits over several months

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GI Manifestations
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GI Complications Syndromic Approach

• Odynophagia
• Diarrhoea
• Jaundice, RUQ pain, hepatomegaly

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Case Presentation

• M, a 32-year old male was diagnosed to have HIV
  infection 5 years ago. He has completed treatment
  for TB lymphadenitis 3 months ago is on regular
  TMP-SMX prophylaxis. He now presents with
  progressive pain discomfort retrosternally
  while swallowing.

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Odynophagia

• OI or tumor
• Common Candida spp.
• Less common CMV, HSV, aphthous ulcers
• Rare TB, MAI, histoplasmosis, cryptosporidia,
  KS, lymphoma
• GERD
• Medications
• ddC, AZT, tetracycline, NSAIDs, ASA

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Oral Candidiasis

• Symptoms thrush, sore mouth
• Types
• Pseudomembranous
• Atrophic
• Hyperplastic
• Angular cheilitis
• Treatment Nystatin, Fluconazole

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Oesophageal Candidiasis

• 1/3 of AIDS pts develop esophageal symptoms
  (dysphagia, odynophagia)
• 50-70 due to Candida
• oral thrush in 50-70
• Usually treated empirically endoscopy biopsy,
  with HPE cultures, if no response in 7-10 days

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Chronic Diarrhoea

• Occurs in 60-90 of pt. with HIV infection
• Presenting symptom in 1/3
• OIs most common cause
• Many pts. have no likely microbial pathogen
• Enteric infections not always associated with
  diarrhoea

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Enteric pathogens in southern Indian HIV-infected
patients with without diarrhoea

• Enteric pathogens in stool 57.4 of diarrhoeal
  patients vs 40 those without diarrhoea (P gt
  0.05)
• Protozoal pathogens 71.8
• Most commonly isolated pathogens
• Chronic diarrhoea Isospora belli (25)
• Controls Giardia lamblia (16)
• In acute diarrhoea patients, there was no
  definite prominent pathogen

Mukhopadhya A. IJMR 199910985-9.
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Common Enteric Pathogens
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Diagnostic Approach

• The step up approach consists of
• Step I stool for ova parasites (with special
  stains - modified AFB, trichome stains) and
  stool culture
• Step II endoscopic biopsy (gastroscopic /
  colonoscopic) for LM and EM

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Three coccidian parasites that most commonly
infect humans, seen in acid-fast stained smears
(A, C, F), bright-field differential interference
contrast (B, D, G) and UV fluorescence (E, H, C.
parvum oocysts do not autofluoresce)
Source CDC Parasite Image Library
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Therapy

• Cryptosporidiosis Nitazoxanide
• Isosporiasis Co-trimoxazole
• Cyclosporiasis Co-trimoxazole
• Micosporidiosis Albendazole
• Giardiasis Tinidazole
• Bacteria Ciprofloxacin
• Strongyloidiasis Ivermectin, Thiabendazole

• Symptomatic therapy
• HAART

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Management Algorithm
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Jaundice

• Hepatitis
• drug induced
• ethanol use
• HBV, HCV
• MAI
• Acalculous cholecystitis and cholangitis
• CMV
• cryptosporidium
• microsporidium

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SUMMARY

• OI are the hallmark of HIV-induced
  immunosuppression
• Systematic approach utilizing knowledge of
  host-pathogen-environment interaction

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Thank You!