Cryptococcus neoformans Infection in Organ Transplant Recipients by 7X4L6G

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									  Cryptococcus neoformans
Infection in Organ Transplant
          Recipients


              Ri 張振昌
              2003/05/19
Background

   Incidence: 2.8% of organ transplant recipients
   Death rate: 42%
   Immunosuppressant affect cryptococcosis
    manifestation
   Invasive candidiasis decline: fluconazole use
    and technologic advances in surgery
The importance in transplant p’t

   HIV related C. neoformans
     infection declined
   In the group of immunocompromised p’t,
      transplant p’t more important in C.
      neoformance infection
Results (1)

   Totally, 178 cases of C. neoformans infection
   renal 145 cases
     liver    20 cases
     heart 10 cases
     lung      3 cases
Result (2)

   The mean incidence: 2.8 %
   In these patients
    79%, azathioprine as the primary immunosuppressive
     7%, tacrolimus
     9%, cyclosporine
     6% cyclosporine and azathioprine
Result (3)


   Incidence of cryptococcosis in different groups
     4.5 %, tacrolimus
     2.4 %, cyclosporine
     3.4 % azathioprine
Time to Onset (1)

   Occurred 1.6 years after transplantation
   15% within 3 months
    11% in 3 to 6 months
    16% in 6 to 12 months
    59% >12 months
Time to onset (2)


   In view of diffenrent organ transplantation
     35 months for kidney
     25 months for heart
     8.8 months for liver
     3 months for lung
Time to onset (3)


   Infection tends to occur later in using
    azathioprine than tacrolimus or cyclosporine
   In view of different immunosuppresant
     11.4 m in cyclosporine
      9.2 m in tacrolimus
      27 m in azathioprine
    Time to onset (4)

   not correlate with early or late cryptococcal
    infection:
      age
      cytomegalovirus infection
      prior rejection episodes
Clinical Manifestations

   Site of infection
    55% infection at the CNS only
    13% skin, soft tissue, osteoarticular infection
      6% pulmonary infection
     24% more than one site of infection
CNS Infection

   63 p’t with CNS cryptococcosis
    62% had headache
    48% had confusion or lethargy
   86% of 21 p’t with CNS: positive serum
          cryptococcal antigen
   100% of 37 p’t: positive CSF cryptococcal antigen
   93% of 82 p’t: CSF cultures yielded C. neoformans
   77% of 47 p’t: positive India ink
Pulmonary Infection

   Most radiographic signs
     unilateral
     nodular
     cavitary infiltrates
   100% of 12 patients: positive serum
                          cryptococcal antigen
Skin, Soft Tissue, Osteoarticular
Infection

   27% of patients with cutaneous
        cryptococcosis had cellulitis
   90% of 21 patients with skin or
    osteoarticula infections:
         positive serum cryptococcal antigen.
Death Rate


   The overall death rate: 42%
   No difference between using tacrolimus and
    primary immunosuppressive regimens
Predictors of death


   Only renal failure on admission
    was predictive of death
Factors influencing prognosis

   Poor outcome in CNS cryptococcal infection
     abnormal mental status
     absence of headache
   No correlation with bad outcome
     presence of fever, CSF pleocytosis
     positive blood cultures,
     CSF cryptococcal antigen titer
Discussion

    2.8% cryptococcus infection rate in organ
    transplant recipients
   42% overall death rate
   Immunosuppressant will influence the
    predominant clinical manifestation
Discussion (2)

   Tacrolimus and cyclosporin
      more skin, soft tissue, osteoarticular
      less CNS involvement
    compared with azathioprine
Tacrolimus effect (1)

   Tacrolimus, a natural macrolide antifungal agent
    found from Streptocyces tsukubaensis
   Use as immunosuppressive agent outweighs its
    antifungal effect
   Toxic to C. neoformans by inhibition of calcineurin
   Suppress C. neoformans at 37°C,not 24°C, suggesting
    calcineurin funtion at higher body temperatures
Tacrolimus (2)

   Mechanism of action:
    1.bind to cytoplasmic peptidyl-prolyl
      isomerases (FK-binding protein)
    2.the same as cyclosporine, inhibit cytoplasmic
      phosphatase, calcineurin, necessary for T
      cell-specific transcription factor, thus inhibit
      IL-2 synthesis
Cyclosporine effect


   Cyclosporine also possess antifungal activity
    by inhibition of calcineurin
   Cyclosporine poorly penetrate the CNS, while
    tacrolimus crosses the blood-brain barrier
How infected (1)

 newly acquired or a reactivation of latent
  infection ??
 Reactivation:
 1. Autopsy show granuloma with C. neoformans
 2. Molecular typing of Africans in Europe
 3. Serologic evidence in most children in NY city
How infected (2)

   Isolates from 29 patients diagnosed with
    cryptococcosis in France, nine of whom were
    from Africa but had lived in France for a
    median of over 9 years. There was a significant
    clustering of isolates from patients originating
    in Africa compared to those from Europe,
    suggesting that the patients had acquired their
    isolates long before the development of clinical
    disease.
Geograghic factor

   Northeastern United States with more
    cryptococcus infection than other US areas
   Epidemiologic studies of C. neoformans have
    been hampered by lack of sensitive and
    specific immunologic tests to evaluate the
    prevalence of latent infection
In pediatric patient

   The relative rarity of cryptococcal infections in
    pediatric organ transplant recipients has been
    noted
    –   pediatric transplant recipients may not yet have
        acquired the infection. C. neoformans
    –   thymic regeneration in bone marrow transplant
        recipients may render T cells more efficacious
        against cryptococci
Immunology

   Evidence from animal studies and the
    epidemiology of human infection clearly
    demonstrate that specific T-cell-mediated
    immunity is critical in a protective immune
    response.
   Only limited evidence for a role for specific
    antibody in natural immunity,
Immunology

   Macrophages are central to the immune
    response to C. neoforman, through antigen
    presentation and co-stimulation of T cells
   C. neoformans is capable of survival and
    multiplication within macrophages
Cutaneous infection

   Cutaneous cryptococcosis represents
    disseminated infection and should be treated
    with systemic antifungal agents.
    Cutaneous cryptococcal infection most
    frequently mimicked (and was clinically
    indistinguishable from) bacterial cellulitis.
Laboratory diagnosis
   Elevated CSF pressure without evidence of obstructive
    hydrocephalus:
     1.basilar meningitis
     2.impaired reabsorption of CSF across arachnoid villi
      important complication of cryptococcal meningitis
   high baseline opening pressure:correlated inversely
    and independently with survival
    intracranial pressure >140 mm of H2O : high death
    rate
Predictor of prognosis

   42% the transplant recipients with C.
    neoformans infection died
   Preexistent renal failure was an independently
    significant predictor of death in transplant
    recipients with cryptococcosis
Prevention of cryptococcosis


   Fluconazole is very effective in preventing
    cryptococcal meningitis in patients with AIDS.
     dose lower than 200 mg/day may be
    effective
Reference

1.From Veterans Affairs Medical Center and University of Pittsburgh,
   Thomas E. Starzl Transplantation Institute, Pittsburgh, Pennsylvania,
   USA
2. Journal of Infection (2000) 41, 12–17     Department of Infectious
   Diseases, Division of Cellular and Molecular Sciences, St. George’s
   Hospital Medical School,Cranmer Terrace, London SW17 ORE, U.K.

3.Basic and Clinical Pharmacology, 8th edition
4. Journal of Infection (2000) 41, 18–22, Division of Infectious
   Diseases, Washington University School of Medicine, St. Louis,
Thank for your
attention

								
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