Virus, Lymphoma, and Worms, Oh My! Complications and Treatment

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Virus, Lymphoma, and Worms, Oh My! Complications and Treatment Powered By Docstoc
					Virus, Lymphoma, and Worms,
           Oh My!
Complications and Treatment of
            HTLV1




                 Boone Goodgame, MD
                         Case
• HPI: 69 year-old Japanese American woman presented
  with weakness, vomiting, and abdominal pain.
  Had one month of progressive abdominal discomfort and
  distension and had lost 8 lbs.
  No fevers, chills, NS, dysphagia, cough, dysuria, SOB,
  or neuro symptoms.

• PMH: no medical problems, no h/o blood transfusion.

• MEDICATIONS: None

• FHX: mother: gastric cancer, father: throat cancer.

• SOCIAL HX: Moved from Okinawa to Illinois at age 26.
  Last visit to Japan was 5 years ago. No alcohol or
  tobacco use.
         PHYSICAL EXAM:
• GENERAL: No acute distress.
• VITAL SIGNS: 88/43, P 92, RR 16.
• HEENT: dry mucous membranes
• NECK: Supple. No adenopathy or thyromegaly.
• LYMPH: No supraclavicular, infraclavicular,
  axillary, or inguinal adenopathy.
• CHEST: lungs clear, no wheezing or rales.
• CARDIOVASCULAR: RRR, no S3 or S4.
• ABDOMEN: Mildly diffusely tender, distended,
  tympanic. No masses or hepatosplenomegaly.
                    LABS:
• WBC: 48,000, NEUT: 48%, LYMPH: 51%
• HGB: 12, MCV: 94


• Na: 130, K: 3.2, Cr: 0.5, Albumin: 2.5
          ABDOMINAL CT:
The duodenum and proximal small bowel are
diffusely dilated and filled with dense contrast
material. There is diffuse thickening of the wall of
the entire colon with mild pericolonic fat
stranding.

Findings consistent with proximal partial small
bowel obstruction, possibly secondary to a
pancolitis.
FLOW CYTOMETRY OF PERIPHERAL
 BLOOD:
  Flow cytometry shows 52% T-cells.
  Cells express CD2, CD4, and CD5.
  No expression of CD25 seen

  The morphologic and immunophenotypic
  features are most consistent with adult T-cell
  leukemia/lymphoma. Lack of expression of
  CD25 is atypical.
SEROLOGY:
   HTLV 1 Antibody positive
                     EGD:
Multiple non-bleeding erosions in the gastric
  antrum and duodenum. Diffuse inflammation of
  the duodenum and proximal jejunum.
             PATHOLOGY:
SMALL INTESTINE, DUODENUM, BIOPSY:
 Acute and chronic duodenitis with abundant
 strongyloides stercoralis organisms
STOMACH, BIOPSY:
 Acute and chronic gastritis with abundant
 strongyloides stercoralis organisms
STOOL O&P: abundant strongyloides stercoralis.
Questions relevant to this case:
• How does HTLV1 infection lead to
  immunosuppression and is there a
  predisposition for parasitic infections?
• How does HTLV1 lead to Adult T-Cell
  leukemia/lymphoma (ATLL) and does infection
  play a role in transformation?
• How is HTLV1 associated ATLL treated?
                  Overview
• HTLV1 epidemiology and associated diseases.
• HTLV1 related immunosuppression and
  associated infections.
• Mechanisms of development of adult T-cell
  leukemia/lymphoma.
• Treatment of HTLV1 associated
  leukemia/lymphoma.
Global Prevalence of HTLV1




 Brown: 1 - 5%. Tan: less than 1%,
           Global Epidemiology
• About 15–20 millions persons live with HTLV
  infection worldwide.
• Highes rates are in: southwestern Japan (up to 37%),
  the Caribbean: Jamaica and Trinidad (up to 6%), and
  several African countries: Benin, Cameroon and Guinea-
  Bissau (up to 5%)
• Lower prevalence rates are found in South America
  (Argentina, Brazil, Colombia and Peru).
• Transmission is parenteral: breastfeeding, sexual
  intercourse, needles, and blood transfusions, and
  requires live, infected cells, not virions.
   HTLV1 associated diseases
• Malignant: Adult T-cell leukemia/ lymphoma
  (ATLL)
• Myelopathy: HTLV1 associated myelopathy
  (HAM/TSP)
• Other inflammatory disease: uveitis,
  polymyositis, synovitis, thyroiditis, pneumonitis.
• Opportunistic infections
 Opportunistic Infections in HTLV1
• In the setting of acute ATLL: PCP, aspergillosis,
  CMV, zoster, MAI, and strongyloides
  hyperinfection.
• In chronic HTLV1 infection without ATLL:
  strongyloidiasis is the most commonly reported
  OI.
• Scabies, disseminated molluscum, extra-
  pulmonary histoplasmosis, and staph/strep
  dermatitis are also reported.
Strongyloides Life Cycle




Image courtesy of L’Asinerie, Bocage France
Strongyloides Life Cycle
Strongyloides Life Cycle
  Strongyloides clinical features
• Endemic in most tropical and subtropical areas,
  as well as in the southern United States.
• Infection is usually asymptomatic, can have non-
  specific GI symptoms: diarrhea, abdominal
  cramping.
• Chronic infestation occurs through auto-
  infection, when larvae invade the colonic
  mucosa, allowing them to mature to adults in the
  small intestine.
              “Hyperinfection”
• With immunosuppression, disseminated
  strongyloidiasis (or hyperinfection) can occur
  when the burden of auto-infection is accelerated.
• Hyperinfection begins with inflammatory
  diarrhea, duodenitis, and gastritis, and often
  paralytic ileus.
• Death can come from pan-colitis, respiratory
  failure, bacteremia, and meningitis.
  Risk factors for hyperinfection
• any immunosuppressing condition
• Corticosteroids
• hematologic malignancies
• HTLV1
• HIV
• diabetes, chronic renal failure, alcoholism.
Immune suppression due to HTLV1
• HTLV1 is a retrovirus that infects T-cells.
• The viral protein, Tax regulates viral gene expression.
• Tax also increases T cell growth and proliferation by
  stimulating the expression of IL-2, IL-15, GM-CSF, and
  IL-2 receptor.
• HTLV1 infected T cells activate un-infected T-cells,
  potentiating the Th1 response, characterized by high
  production of IFN-g.
• Th1 cytokines down-regulate Th2 cells.
• The inhibited Th2 response (IL-4, IL-5, & IgE) prevents
  parasite killing.
 HTLV1 and strongyloides
       stercoralis




Parasite Immunology, 2004, 26, 487–497
  HTLV1 and adult T-cell leukemia
• Occurs mostly in adults, at least 20-30 years
  after HTLV1 infection.
• Almost exclusively associated with virus
  acquisition through breast feeding.
• 6% of male & 2% of female HTLV1 carriers
  develop ATL.
• Tends to present in the fifth decade of life
• Risk factors for ATL: high anti-HTLV1 titer, low
  anti-Tax reactivity, vertical infection, and
  strongyloides infestation.
        Four sub-types of ATLL
• Smoldering: 1-5% peripheral blood lymphocytes, or
  limited skin lesions.
• Chronic: lymphocytosis, skin lesions,
  hepatosplenomegaly, liver or lymph node involvement.
• Lymphomatous: non-Hodgkins lymphoma, often with
  blood, skin, & bone involvement.
• Leukemic (Acute): lymphocytosis, hypercalcemia, lytic
  bone lesions, lymphadenopathy, visceral involvement,
  opportunistic infections.
• Acute comprises 55-75% and rapidly progresses with
  pulmonary complications, opportunistic infections, and
  sepsis.
Mechanism of malignant
    transformation




             Oncogene (2005) 24, 6047–6057
         Mechanism of malignant
             transformation
• Tax increases the number of HTLV-I-infected cells by
  promoting proliferation and inhibiting apoptosis.
• Tax also evokes the host immune response, triggering
  cytotoxic T cells to kill infected cells.
• Accumulation of genetic changes in clonally proliferating
  cells leads to Tax independent proliferation and loss of
  Tax (66% of ATLL).
• p53 and p16 mutations as well as DNA methylation have
  been identified.
• Loss of FasL has been demonstrated in ATL cells,
  enabling them to avoid apoptosis.
Does strongyloides infection predispose to
       the development of ATLL?
 • Several studies have associated the presence of
   strongyloides with a higher frequency of ATLL but they
   have not been well controlled.
 • Other studies have found that co-infection with
   Strongyloides stercoralis was associated with a better
   prognosis in ATLL.
 • Strongyloides antigen induces IL-2 and therefore may
   induce polyclonal expansion of HTLV1 infected cells.
 • Patients with ATLL have the highest levels of type 1
   cytokines, which decreases defenses against
   strongyloides and is the most likely reason for the
   association.
                ATL Treatment
• Median survival is less than 1 year and has not
  significantly improved significantly in the past two
  decades.
• Multiple therapies have been studied:
     Conventional lymphoma chemotherapy
     Nucleoside analogues
     Topoisomerase inhibitors
     Interferon-a
     Zidovudine
     Arsenic
     Monoclonal antibodies (anti-CD25, anti-CD52)
Oncogene (2005) 24, 6047–6057
Oncogene (2005) 24, 6047–6057
Oncogene (2005) 24, 6047–6057
Oncogene (2005) 24, 6047–6057
      Conventional chemotherapy
              regimens
• CHOP is most commonly used therapy with
  median survival 6 – 8 months.
• Best reported outcome is with seven cycles of
  VCAP (vincristine, cyclophosphamide,
  doxorubicin, and prednisone), AMP
  (doxorubicin, ranimustine, and prednisone), and
  VECP (vindesine, etoposide, carboplatin, and
  prednisone).
• Grade 4 haematological toxicity in the majority of
  patients, but a median survival of 13 months.
  (2001). Br. J. Haematol., 113, 375–382.
  Addition of zidovudine (AZT) and
              interferon
• Reverse transcriptase inhibitors are effective in
  controlling replication of HTLV1.
• Addition of interferon-a improves the response
  rate in ATLL.
• Survival has been prolonged in some studies
  which followed conventional chemotherapy with
  zidovudine and interferon (11-18 months).
AMC 033: Phase II Trial of Induction Therapy
with EPOCH Chemotherapy and Maintenance
 Therapy with Combivir/Interferon for HTLV-1
 Associated T-cell non-Hodgkin’s Lymphoma

• Rationale:
  Induction with a regimen active in refractory
  lymphomas (up to 6 cycles).
• More intensive anti-retroviral therapy for one
  year.
        Monoclonal Antibodies
• Most ATLL cells express CD25 (IL-2 receptor)
• Anti-CD25 therapies have shown pre-clinical
  efficacy.
• Studies are enrolling of:
   – denileukin difitox (Ontak): fusion protein of
     diphtheria toxin and anti-CD25
   – dacluzimab (Zenapax): humanized anti-Tac
     (IL-2R alpha)
  Allogenic stem cell transplant
• Graft versus ATLL effect is active, relapses
  respond to withdrawal of immunosuppression.
• Most recent case series is of 40 patients with
  33% 3 year DFS.
  Leukemia. 2005 May;19(5):829-34.
                 SUMMARY
• Immigrants from HTLV1 endemic areas may be
  susceptible to opportunistic infections.
• Less than 10% of HTLV1 carriers develop ATL
  which worsens immunosuppression.
• Combinations of chemotherapy and anti-
  retrovirals are currently the most effective
  treatment.
• Better therapies are needed to prolong survival
  more than 1 year.
       Tax Oncoprotein Activites
• Transcriptional Activities
   Serum-response factor
   cAMP-response factor – Activation of viral promoter
   Nuclear factor κB – Activation of cytokines, anti-apoptosis genes,
  cell proliferation genes, and angiogenesis

   Post-Transcriptional Activities
    Proliferation – Inhibition of p16 cell cycle inhibitor, Activation of
   cyclin-dependent kinase 4 and Cyclin 2
    Apoptosis – Inactivation of p53
    Genetic Instability Defect in G2/M checkpoint due to binding mitotic
   arrest defect 1 protein, Cdc20 anaphase-promoting complex, and
   checkpoint kinases Chk1 and 2