Clinical Case Conference

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Clinical Case Conference

• Vera Luther, MD
• November 7, 2005

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DisclosuresSection of Infectious Diseases

• Kevin High, M.D.
• Grant/Research Support Cubist Pharmaceuticals,
  Astellas Pharma US, Inc.
• Consultant Merck Co., Inc.
• Speakers Bureau Pfizer Pharmaceuticals
• James Peacock, M.D.
• Ownership in Common Stock Pfizer
  Pharmaceuticals
• Sam Pegram, M.D.
• Grant/Research Support Roche, Bristol-Myers
  Squibb, Gilead, Schering-Plough, Tibotec
  Pharmaceuticals
• Consultant Abbott Laboratories,
  GlaxoSmithKline, Boehringer Ingelheim, Gilead,
  Roche
• Speakers Bureau Abbott Laboratories,
  GlaxoSmithKline, Boehringer Ingelheim, Merck,
  Pfizer Pharmaceuticals

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Disclosure (continued)Section of Infectious
Diseases

• Aimee Wilkin, M.D.
• Grant/Research Support Abbott Laboratories,
  GlaxoSmithKline, Tibotec Pharmaceuticals,
  Bristol-Myers Squibb Company, Gilead
• Christopher Ohl, M.D.
• Grant/Research Support Cubist Pharmaceuticals,
  Gene-Ohm Sciences, Merck Pharmaceuticals
• Speakers Bureau/Consultant Ortho-McNeil
  Pharmaceuticals, Cubist Pharmaceuticals,
  Sanofi-Aventis Pharmaceuticals, Pfizer
  Pharmaceuticals, Bayer Pharmaceuticals

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Disclosure (continued)Section of Infectious
Diseases

• Tobi Karchmer, M.D.
• Grant/Research Support Gene-Ohm Sciences
• Speakers Bureau Pfizer Pharmaceuticals, Cubist
  Pharmaceuticals, Cepheid,
• Gene-Ohm Sciences
• Consultant C.R. Bard
• Robin Trotman, D.O.
• Speakers Bureau Pfizer Pharmaceuticals

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Case 1

• 30 y/o male WFU PhD student seen in ID clinic
  after returning from southeastern Peru where he
  was studying the biology of the rain forest.
• While in Peru, he noticed a papule on his left
  forearm. The lesion subsequently became
  ulcerated over the next few weeks. Approx one
  week prior to being seen in clinic, he
  experienced redness and pain over the lesion with
  extension of the redness up his arm. He was
  treated by a family member with Augmentin.

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Case 1

• ROS no f/c or other systemic symptoms
• PMH Bot fly myiasis
• Physical Examination
• afeb vss
• 3cm ulcerative lesion with yellow fibrinous base,
  minimal surrounding erythema, nontender cord
  extending from lesion to antecubital fossa and
  large epitrochlear lymph node approximately 2 x 3
  cm.

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Skin Biopsy
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Diagnosis?
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Cutaneous Leishmaniasis
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WHO classification

• Category 1 Emerging and uncontrolled
• 1.5 million new cases of CL each year
• 90 of New World cases in Brazil and Peru
• 90 of Old World cases in Afghanistan, Algeria,
  Iran, Iraq, Saudi Arabia, Syria

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Mucocutaneous (Mucosal) Leishmaniasis

• Complication of New World CL (1-10)
• Hematogenous or lymphatic dissemination of
  amastigotes from skin to naso-oropharyngeal
  mucosa
• Can ensue while lesions are present or decades
  after healing
• Life-threatening obstruction of oropharynx can
  occur
• Adequate systemic treatment seems to decrease risk

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Sandfly (Lutzomyia spp.)

• 2-3 mm long
• Can penetrate mosquito nets
• Noiseless
• Rest in dark, moist places
• Most active in evening and night-time

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Leishmania life cycle

• ? inoculated promastigotes are phagocytosed by
  macrophages
• ? lose their flagella to become amastigotes
• ? amastigotes multiply by binary fission in
  quiescent macrophages
• ? infected macrophages burst and release
  amastigotes to infect other macrophages

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• IL-12 induces naïve T cells to differentiate into
  Th1 cells
• Induces T cells and NK cells to produce
  interferon gamma
• Mediates resistance and leishmanicidal activity

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Diagnosis

• Microscopic examination of
• skin biopsy
• needle aspirate
• skin scrapings
• Culture lesions (NNN)
• promastigotes
• Species analysis
• Enzyme electrophoresis
• Monoclonal antibody binding

• PCR can be used as adjunct
• Serology not usually helpful
• Skin testing not usually helpful

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Microscopic Examination

• Look for amastigotes
• 2-4 micrometers in size
• Shape roud to oval
• Nucleus and kinetoplast

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Microscopic Examination

• Kinetoplast
• rod-shaped
• specialized mitochondrial structure
• contains extranuclear DNA

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Case 1
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Case 1

• One week after initial clinic visit
• The pt noticed a papule on the right side of his
  nose
• Lesion failed to improve
• Developed papular lesions on his left lower leg
  and right upper back
• Lesions were nontender, but mildly pruritic
• Skin biopsies sent to CDC
• L braziliensis

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Management?
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Why should we treat?

• Facial lesions
• Progression of lesions
• Location
• Number
• Size
• Evolution
• Persistence
• Lymphangitis
• Risk of mucosal leishmaniasis
• New World cutaneous leishmaniasis except L
  mexicana

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Treatment

• Pentavalent antimonials Heavy metal compounds of
  uncertain mechanism of action (Inhibit glycolysis
  and fatty acid oxidation in leishmania)
• Meglumine antimoniate (Glucantime)
• Sodium stibogluconate (Pentostam)

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Treatment (continued)

• Pentamadine
• Second-line agent for antimony-resistant cases of
  CL and VL
• Toxicity hypoglycemia, diabetes, nephrotoxicity,
  tachycardia
• Amphotericin B
• Has been used to treat intractable cases of MCL
  and CL

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• Navin et al. Placebo-controlled clinical trial
  of meglumine antimonate (glucantime) vs.
  localized controlled heat in the treatment of
  cutaneous leishmaniasis in Guatemala. Am J Trop
  Med Hyg. 1990 Jan42(1)43-50.
• Patients received 850mg/d x 15 d of Glucantime vs
  controlled heat vs placebo
• 13 weeks after beginning treatment
• 11 out of 14 (79) cured in Glucantime group
• 9 out of 14 (64) cured in controlled heat group
• 0 out of 11 cured in placebo group
• Adverse events
• 75 LFT abnormalities
• 41 T-wave depression

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• Navin et al. Placebo-controlled clinical trial
  of sodium stibogluconate (Pentostam) versus
  ketoconazole for treating cutaneous leishmaniasis
  in Guatemala. J Infect Dis. 1992
  Mar165(3)528-34.
• 120 pts with CL randomized to antimony (20mg/kg/d
  x 20d) vs ketoconazole (600mg po q d x 28d) vs
  placebo
• Cure rate 10 weeks post-therapy in pts with L
  braziliensis
• 24/25 (96) of pts in the stibogluconate group
• 7/23 (30) of pts in the ketoconazole group
• Adverse events
• 15 arthralgias
• 50 LFT abnormalities
• 20 T-wave inversion

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• Anderson et al. Comparison of meglumine
  antimoniate and pentamidine for peruvian
  cutaneous leishmaniasis. Am J Trop Med Hyg. 2005
  Feb72(2)133-7.
• 80 pts with CL due to L braziliensis

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• Soto et al. Short report efficacy of
  pentavalent antimony for treatment of colombian
  cutaneous leishmaniasis. Am J Trop Med Hyg. 2005
  Apr72(4)421-2.
• 226 consecutive Colombian soldiers with CL were
  treated with Glucantime
• 81 cured
• Patients who failed had significantly lower total
  antimony dose
• 354mg/kg vs 405 mg/kg
• 39 failures were re-treated
• 59 cured

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• Aronson et al. Safety and efficacy of
  intravenous sodium stibogluconate in the
  treatment of leishmaniasis recent U.S. military
  experience. Clin Infect Dis. 1998 Dec 27
  (6)1457-64.
• 83 pts with CL recd sodium stibogluconate
  20mg/kg/day for 20 days ?Clinical cure in 91
• 13 pts with VL recd sodium stibogluconate
  20mg/kg/day for 28 days ? Clinical cure in 93
• Adverse effects (28 required treatment
  interruption)
• Pancreatitis (97)
• Transaminitits (67)
• Headache (22)
• Hematologic suppression (44)
• Rash (9)
• No mucosal leishmaniasis at 1 year f/u

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• Soto et al. Miltefosine for new world cutaneous
  leishmaniasis.Clin Infect Dis. 2004 May
  138(9)1266-72.
• Miltefosine 2.5 mg/kg/d po x 28 days vs placebo
• Cure rates for CL in
• Colombia (L panamensis)
• 40/44 (91) vs 9/24 (38) with placebo
• Guatemala (L braziliensis and L mexicana) 20/38
  (53) vs 4/19 (21) with placebo

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• Brown et al. Successful liposomal amphotericin B
  treatment of Leishmania braziliensis cutaneous
  leishmaniasis.Br J Dermatol. 2005
  Jul153(1)203-5.
• 19 y/o male who acquired multiple L braziliensis
  lesions in Belize
• Treated with liposomal amphotericin B 3 mg/kg/d x
  7 days, then 3 mg/kg/d twice weekly x 21 days
• Total dose 40 mg/kg
• Lesions healed in 6 weeks
• Clinical cure at 12 months

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Pentostam

• Baseline EKG
• CBC
• LFTs
• amylase/lipase
• Monitor weekly

• Discontinue/hold therapy if
• QTc gt .5 sec
• Significant arrhythmias
• T wave inversions with concave ST segments
• LFTs gt5 x normal
• Moderate-severe clinical pancreatitis

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Case 1 Monitoring
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Follow-up Visit
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Management?
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• Almeida et al. Successful treatment of
  refractory cutaneous leishmaniasis with GM-CSF
  and antimonials. Am J Trop Med Hyg. 2005
  Jul73(1)79-81.
• 5 patients who had recd three or more courses of
  pentavalent antimony 20mg/kg/d x 20 d
• Topical granulocyte macrophage colony-stimulating
  facor (GM-CSF) three times a week for 3 weeks
  with parenteral antimony 20mg/kg/d x 20 d
• All ulcers healed

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• Miranda-Verástegui et al. Randomized,
  double-blind clinical trial of topical imiquimod
  5 with parenteral meglumine antimoniate in the
  treatment of cutaneous leishmaniasis in Peru.
  Clin Infect Dis. 2005 May 1540(10)1395-403.
• All 40 subjects recd meglumine antimoniate
  20mg/kg/d x 20d
• Randomized to receive either imiquimod 5 cream
  or placebo
• Lesions resolved more rapidly in the imiquimod
  group
• Cure at 1 month in 50 of the imiquimod group vs
  15 of placebo (P .02)
• Cure at 2 months in 61 of the imiquimod group vs
  25 of placebo (P .03)
• Cure at 3 months in 72 of the imiquimod group vs
  35 of placebo (P .02)
• Residual scarring in the imiquimod group was less
  prominent than in the vehicle cream group

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• Nonata et al. Mucosal leishmaniasis unresponsive
  to glucantime therapy successfully treated with
  AmBisome. Trans R Soc Trop Med Hyg. 1997
  Jan-Feb91(1)77.
• Case report of liposomal amphotericin B for the
  treatment of refractory leishmaniasis

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Case 1

• Currently undergoing second course of Pentostam

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Case 2

• 61 y/o female admitted to hospital with fevers to
  103F, HA, myalgias, abdominal cramping, nausea,
  vomiting, and diarrhea.
• Pt also c/o erythematous lesions on left arm,
  neck, legs, back, buttocks. Lesions were
  nonpainful, nonpruritic.
• SH recently spent 2 weeks in South Africa where
  she was involved in missionary work and camped by
  a river. She reported several dogs on campsite.
  Travel companion has similar symptoms.

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• Physical Examination
• afeb vss
• Tender left axillary nodes
• Skin two erythematous lesions with a central
  escar over the left forearm, 2 lesions over the
  right buttock, 2 lesions on leg, 1 lesion on
  neck, 1 on back
• Labs wnl
• Pt had been treated for 3 days with mefloquine
• (d/cd when malaria smears negative)

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Thoughts?
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African tick-bite feverR. africae

• First described in 1992 as separate entity from
  Mediterranean spotted fever

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African tick-bite feverR. africae

• Transmitted by tick Amblyomma hebraeum
• Bites legs
• Often several tick bites

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• Jensenius et al. African tick bite fever in
  travelers to rural sub-Equatorial Africa. Clin
  Infect Dis. 2003 Jun 136(11)1411-7.
• Prospectively studied a cohort of 940 travelers
  to rural sub-Equatorial Africa to identify
  incidence and risk factors for ATBF
• Diagnosis based on PCR and detection of specific
  antibodies to Rickettsia africae in serum
  samples.
• Found 38 travelers (4.0 of the cohort) had ATBF
  diagnosed

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Clinical characteristics of 38 patients with
travel-associated ATBF
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• Jensenius et al. African tick bite fever in
  travelers to rural sub-Equatorial Africa. Clin
  Infect Dis. 2003 Jun 136(11)1411-7.
• Independent risk factors for ATBF
• Game hunting
• Travel to South Africa
• Travel during November-April

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• Raoult et al. Rickettsia africae, a tick-borne
  pathogen in travelers to sub-Saharan Africa. N
  Engl J Med. 2001 May 17344(20)1504-10.
• Evaluated 417 patients pts who had an
  influenza-like syndrome after returning from a
  trip to Africa or Guadeloupe
• blood smear negative for malaria
• Describe the epidemiologic, clinical, and
  diagnostic features of African tick-bite fever
• 119 found to have Rickettsia africae infection
  via PCR, cell culture, and/or and serology

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Clinical presentation
R. africae
R. conorii
ERUPTION
Rare
Frequent
100
70
ESCHAR
LYMPH NODES
-

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• Raoult et al. Rickettsia africae, a tick-borne
  pathogen in travelers to sub-Saharan Africa. N
  Engl J Med. 2001 May 17344(20)1504-10.
• Information about treatment for 88 pts
• 74 received doxycycline
• Mean 6.3 d (range 7-15d)
• 1 minocycline
• 6 erythromycin
• 3 ciprofloxacin
• 16 no antibiotic therapy
• All patients recovered without sequelae

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Prevention

• Educate patients during travel clinic visits
• Protective clothing if feasible

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Case 2 follow-up

• Reported resolution of symptoms at 2 week
  follow-up

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