New Insights Into Transmission, Diagnosis, and Drug Treatment of Pneumocystis carinii Pneumonia

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New Insights Into Transmission, Diagnosis, and
Drug Treatment of Pneumocystis carinii Pneumonia

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• JAMA, November 21
• 2001-Vol 286, No.19

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Case Report

• A 49 year-old Hispanic man was referred to
  National Institutes of Health (NIH) for therapy
  of a HIV-related lymphoma.
• History diagnosed with HIV infection in 1995
• PCP was diagnosed in 2001-1 and was treated
  initially with pentamidine
• In April 2001, fever, S.O.B, and cough for 2
  weeks, He was treated with antiretroviral regimen
  and itraconazole, atovaquone, aerosolized
  pentamidine, and clarithromycin also augmentin
  and levofloxacin.

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Case Report (continue)

• 2 weeks later, S.O.B and fever had not improved.
• WBC 4500, T4 cell 4/ul, viral load 250000
  copies/ul
• Biopsy of the ant mediastinal mass a large
  B-cell lymphoma
• He developed respiratory failure and required
  intubation and mechanical ventilator.
• Treat with EPOCH for 4 days
• Pentamidine for 7 days but no improvement
• IV trimethoprim-sulfamethoxazole for 9 days and
  additional 14 days iv pentamidine

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Case Report (continue)

• direct flourescent Ab (DFA) and major surface
  glycoprotein (MSG) gene
• At 3 weeks DFA MSG 11920/20uL
• 5 weeks DFA - MSG
  20/20uL
• P carinii dihydropteroate synthase (DHPS) gene,
  the target of sulfamethoxazole therapy, revealed
  a single Thr Ala mutation at position 55,
  suggesting possible sulfa resistance.

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Discussion Pneumocystis carinii

• In 1912, pneumocystis was recognised as a new
  genus and named in honor of Carinii.
• Pneumocystis carinii was identified in 1952.
• In immunodeficient and immunosupressed patients
• the cases exploded in 1980s, following the onset
  of the AIDS

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The Incidence of PCP

• In the late 1960s and the early 1970s, lt100 cases
  per year
• increased since 1982 and peaked in 1990 at about
  20000 cases per year
• after 1990, a decline due to widespread use of
  PCP prophylaxis
• after 1995, a further decline due to the use of
  highly active antiretroviral therapy (HAART)

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Clinical Presentation

• Fever, S.O.B. ,substernal tightness and
  nonproductive cough
• CXR bil. interstitial infiltrates, which
  progress to an alveolar pattern
• HRCT scan ground glass attenuation
• histopathology intraaveolar acellular
  eosinophilic exudate filling the alveoli

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Biology of P carinii

• Protozoan Fungus
• Single strain multiple strains
• dihydropteroate synthase (DHPS)-sulfamethoxazole,
  dihydrofolate reductase (DHFR)-trimethoprim
• CD4 lymphocyte, macrophage, TNF-?
• MSG gene avoiding host immune defenses

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Epidemiology in Humans

• Mode of transmission
• 2 years of age
• molecular typing of isolates by rRNA (coinfection
  with multiple isolates, 2030)
• reinfection with a new type rather than
  reactivation of latency

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Diagnosis of PCP

• Stains of the specimen of open lung biopsy
• transbronchial biopsy and BAL specimen
• sputum induction with nebulized saline
• stains using monoclonal antibodies
• molecular amplification methods (mitochondrial
  rRNA or major surface glycoprotein)
• the diagnostic algorithm
• nonHIV immuocompromised patients

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The Prevention of PCP

• Reducing exposures--unknown transmission route
• enhance the immunocompetence
• chemoprophylaxis risks--table 1
• HIV patient CD4 cell count, esp lt200/uL
• other patients difficult to define
• efficacy, toxicity, convenience, and costs?
• Unaware, low adherence, no appropriate regimens

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Sulfa Drug-Resistant P carinii

• Sulfa and sulfone resistance--point mutation in
  the DHPS gene (since 1993 and decline after 1997)
  
• detect resistance of PCP looking for mutations
  in the P carinii DHPS gene
• 3-dimensional structure (Thr55, Arg56, Pro57) ,
  two commonly seen mutations Thr55Ala, Pro57Ser
• no DHFR mutation
• no association was seen between mutations and
  either response to therapy or survival.

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Atovaquone Resistance

• Binding to cytochrome b, where spontaneous
  mutation rates are 10-fold higher than nucleus
• resistance develops de novo in each patient
• Q box

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Thank You for Your Attention