ID Clinical Case Conference

1
ID Clinical Case Conference

• Hidetaka Yanagi, MD
• 8/27/2007

2
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

3
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

4
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

5
Case 1

• 39 WM w/ h/o ESRD d/t IgAN s/p living unrelated
  renal xplant 7 months ago.
• CMV D/R-, EBV, -hepatitis, -HIV
• No lymphocyte-depleting Rx given.
• Put on Valcyte/Bactrim for prophylaxis
• Bactrim d/ced 3 months ago, Valcyte d/ced 3
  weeks ago. (given for 6 months)
• No complication or rejection so far.
• Presented w/ fever, myalgia, cough and
  progressive SOB of 1 week duration.

6
Case 1 39 M s/p renal xplant 7 mo ago

• PMH
• IgAN
• ESRD
• HTN
• Allergy NKDA
• FH
• Mom w/ pulmonary fibrosis
• SH
• No tobacco/drug
• Occ ETOH
• No sick contact, no exposure to animals, no
  recent travel
• ROS for diarrhea(resolving)

7
Case 1 39 M s/p renal xplant 7 mo ago

• Meds
• ASA
• Albuterol
• Metoprolol
• Protonix
• PSL
• Cellcept
• Isa247 (study drug--immunosuppressant)
• Valganciclovir d/ced 7/20 (6 weeks ago)
• Bactrim d/ced 5/18 (3 months ago)

8
Case 1 39 M s/p renal xplant 7 mo ago

• VS/PE
• Tm 103.2, P 98, R 18, BP 169/89
• SpO2 94 on RA
• Gen NAD
• HEENT PERRLA
• Chest crackles, wheezes
• Heart RRR, no MRG
• Abdomen soft, NT, BS
• Ext. no e/c/c
• Skin no rash

9
Case 1 39 M s/p renal xplant 7 mo ago

• Lab
• CBC
• W5.3 (Seg59, L31, M10, Eo0, B0)
• Hgb 11.6, Plt151
• CMP
• Cr 1.6, BUN 16, GFR 51
• Nml LFT
• UA no pyuria

10
Case 1 39 M s/p renal xplant 7 mo ago
8/28/07

• CXR 1/07

Normal
BL reticulonodular opacification
11
Case 1 39 M s/p renal xplant 7 mo ago
12
Case 1 39 M s/p renal xplant 7 mo ago
13
Case 1 39 M s/p renal xplant 7 mo ago
14
Case 1 39 M s/p renal xplant 7 mo ago
15
Case 1 39 M s/p renal xplant 7 mo ago
16
Case 1 39 M s/p renal xplant 7 mo ago
17
Case 1 39 M s/p renal xplant 7 mo ago
18
Case 1 39 M s/p renal xplant 7 mo ago
19
Case 1 39 M s/p renal xplant 7 mo ago

• Micro
• Blood negx2
• Urine neg
• C-diff neg
• OP neg
• Stool positive for Yersinia
• BAL
• Routine cx neg
• AFB/Fungal smear neg, cx pending
• Viral cx positive for CMV
• CMV PCR 8/22 neg
• 8/28 56,010?Cellcept, isa247
  d/ced

20
Case 1 39 M s/p renal xplant 7 mo ago

• Presented w/ fever, SOB, myalgia, diarrhea
• CMV D/R-, EBV, -hepatitis, -HIV
• Bactrim d/ced 3 months ago
• Valcyte d/ced 6 weeks ago
• Chest image diffuse nodular opacity
• BAL viral cx positive for CMV/ Cytology neg
• Stool cx positive for Yersinia
• CMV PCR positive
• Any thoughts?

21
Case 1 39 M s/p renal xplant 7 mo ago
Usual sequence of Infections after organ
transplantation NEJM 1998241743
22
Case 1 39 M s/p renal xplant 7 mo ago

• DDx
• CAP
• CMV pneumonitis
• Nocardia
• Cryptococcosis
• Histoplasmosis/Blastomycosis
• (?Yersinia colitis)

23
Case 1 39 M s/p renal xplant 7 mo ago

• Rec
• Moxifloxacin for CAP (and Yersinia)
• GCVCMV IVIG for CMV pneumonitis
• Fluconazole for possible endemic fungi
• Send crypto/histo/blasto antigen

24
Is Diffuse nodular opacity typical for CMV?(not
GGO?)
25
Diffuse nodular shadow is typical for CMV?(GGO
is typical?)

• Horger et al reported a retrospective review of
  HRCT in 30 consecutive pts with CMV pneumonitis
  after BMT
• Dx was made mostly by BAL Cx
• 17/30 (57) GGOmost common
• Of these 17, 13(76) progressed to diffuse air
  space opacity
• 6/30 (20) Consolidation
• 7/30 (23) Centrilobullar (Nodular) opacity
• Focal 50 vs. Diffuse 50
• Of 15 focal, multiple in 13/15(87) vs. solitary
  2/15

AJR 2006187W636
26
Diffuse nodular shadow is typical for CMV? (not
GGO?)

• Diffuse GGO

27
Diffuse nodular shadow is typical for CMV? (not
GGO?)

• Centrilobular (small nodular) opacities

28
Diffuse nodular shadow is typical for CMV? (not
GGO?)

• GGOConsolidation

Looks like halo sign?
29
Diffuse nodular shadow is typical for CMV? (not
GGO?)

• Prognosis was worst with GGO.
• CT findings Adjusted OR(95CI)
• GGO 27 (2.8-830)
• Consolidation 0.19(0.024-1.1)
• Nodular opacity 0.21(0.024-1.2)
• (adjusted for Rx timing, Seropositivity, and
  GVHD)

AJR 2006187W636
30
Can CMV Pneumonitis be Dxed by BAL Cx?
31
CMV Pneumonitis can be Dxed by BAL Cx?

• CMV infection (not disease) can be Dxed by one
  of the following findings
• Seroconversion with IgM
• Four fold increase in preexisting IgG
• CMV antigen in infected cells (pp65)
• CMV DNAemia by PCR
• Cx

J clin V 200225S1
32
CMV Pneumonitis can be Dxed by BAL Cx?

• CMV disease requires clinical Sx/Sx and organ
  involovement
• Hepatitis
• Pneumonitis
• Pancreatitis
• Colitis
• Meningoencephalitis
• Myocarditis
• chorioretinitis
• With the exception of retinitis, Dx of CMV
  disease has required histopath or cytology,
  classically.

J clin V 200225S1
33
CMV Pneumonitis can be Dxed by BAL Cx?

• Definition of CMV PNA includes
• Virus isolation or
• Histopathologic or immunohistochemical evidence
  of the presence of CMV in the lung
• In the setting of a clinically compatible
  syndrome (CMV DNAemia, diffuse PNA, s/p d/c of
  Valcyte, DR-, no other pathogens)

Clin Chest Med 200526691
34
Incidence of CMV pneumonitis

• Transplant populations Incidence ()
• HSCT
• Allogeneic 2002 1030
• Autologous 2001 19
• SOT
• Lung 2004 1555
• Heart-lung 1991 71
• Heart 2003 0.86.6
• Renal 2004 lt1
• Liver 1996 09.2

Clin Chest Med 200526691
35
Risk Factors in Renal transplant recepients

• D/R- status
• Antilymphocyte induction (OKT3, ATG)
• (Tacrolimus and Mycophenolate mofetil)
• High risk pts usually receive prophylactic
  GCV/Valcyte instead of preemptive Rx.

Clin Chest Med 200526691
36
Prophylaxis

• Pre-prevention era, CMV disease incidence was
  20-60
• IV GCV reduced the risk by 2/3
• 113 renal transplant recipients (R)
• Randomly assigned to receive either
• ganciclovir, 2.5 mg/kg
• or no Rx during OKT3
• CMV disease GCV 14 vs. Control 33

Clin Chest Med 200526691, Ann Intern Med
199512318
37
Prophylaxis

• RCT oral GCV vs. oral ACV
• 101 recipients of kidney transplants at high risk
  for CMV d/t OKT3
• 22 D-R- received no prophylaxis.
• 27 DR-
• 29 DR
• 23 D-R
• Pts were randomized to receive 3 months of either
  
• oral acyclovir (800 mg q.i.d.)
• oral ganciclovir (1000 mg t.i.d.). (poor
  bioavailability)
• Doses were adjusted according to the level of
  renal function.
• The DR- patients were also given CMV immune
  globulin biweekly for 16 weeks

Transplantation 1998 27661682
38
Prophylaxis

• RCT oral GCV vs. oral ACV
• acv gcv p
• 27 DR- 54 0 0.0008
• 29 DR 43 6.6 0.01
• 23 D-R 8.3 0 NS
• Oral acv is effective only for seronegative donor
  
• Oral gcv is a superior agent for seropositive
  donor
• No patient developed CMV infection while taking
  oral ganciclovir, however three delayed
  infections occurred 2-7 months after finishing
  therapy.
• These 3 pts were treated for acute rejection

Transplantation 1998 27661682
39
Prophylaxis

• RCT Valganciclovir vs. GCV
• 364 CMV D/R- patients (120 renal) received
• valganciclovir 900 mg qd
• or oral ganciclovir 1000 mg tid
• within 10 days of transplant and continued
  through 100 days
• CMV disease, plasma viremia, acute graft
  rejection, graft loss and safety were analyzed up
  to 6 and 12 months post-transplant

Am J Transplant 20044611.
40
Prophylaxis

• RCT Valganciclovir vs. GCV
• Valcyte
  GCV
• CMV disease 12.1 15.2 by
  6 months
• 17.2
  18.4 by 12 months
• CMV viremia during prophylaxis was significantly
  lower with valganciclovir (2.9 vs. 10.4
  p0.001)
• but was comparable by 12 months (48.5
  valganciclovir vs 48.8 ganciclovir).
• ?The duration of 100 days may be insufficient.
• Rates of acute allograft rejection were generally
  lower with valganciclovir.
• Except for a higher incidence of neutropenia with
  valganciclovir (8.2, vs 3.2 ganciclovir) the
  safety profile was similar for both drugs.

Am J Transplant 20044611.
41
Prophylaxis vs. Preemptive Rx.

• Prophylaxis
• Give prophylactic dose of anti-CMV agent to all
  pts at risk (usually through 100days)
• May be associated with
• increased resistance
• and late-onset CMV disease
• Preemptive
• Short course (about 3 wks) of anti-CMV Rx
  targeted toward a subset of pts with DNAemia
• Needs extreme vigilance to be effective

CID 200540704
42
Prophylaxis vs. Preemptive Rx.

• RCT by Khoury et al (Washington Univ.)
• Kidney transplant recipients at risk for CMV
  (D/R-, D/R, D-/R) were randomized to
• prophylaxis (valganciclovir 900 mg q.d. for 100
  days, n49)
• or preemptive therapy (900 mg b.i.d. for 21 days,
  n49) for CMV DNAemia, assessed weekly for 16
  weeks and at 5, 6, 9 and 12 months.
• More patients in the preemptive group, 29 (59)
  than in the prophylaxis group, 14 (29) developed
  CMV DNAemia, p0.004.
• Late onset of CMV DNAemia (gt100 days after
  transplant) occurred in 11 (24) randomized to
  prophylaxis, and none randomized to preemptive
  therapy.

Am J Transplant. 200662134
43
Prophylaxis vs. Preemptive Rx.

• Symptomatic infection occurred in five patients
• four (3 D/R- and 1 D/R) in the prophylactic
  group
• one (D/R-) in the preemptive group.
• Both strategies were effective in preventing
  symptomatic CMV.
• Overall costs were similar
• No clinical or virologic failure of
  valganciclovir was evident to suggest the
  development of resistance.
• Sequencing of the CMV UL97 gene failed to detect
  any mutations known to cause resistance.

Am J Transplant. 200662134
44
Prophylaxis vs. Preemptive Rx.

• Possible advantages of preemptive treatment
  especially in the D/R- group
• Using the preemptive approach, most episodes of
  DNAemia occurred within 100 days of
  transplantation when
• monitoring for CMV DNAemia was frequent
• and initiation of treatment was prompt.
• Occurrence of CMV DNAemia may have allowed
  establishment of an immune response that protects
  from late onset recurrence.

Am J Transplant. 200662134
45
Prophylaxis vs. Preemptive Rx.

• Possible approaches for the D/R- population
  include
• (1) preemptive, since the overall incidence of
  DNAemia was similar, but symptomatic CMV disease
  was less than with prophylaxis
• (2) extended prophylaxis to 612 months
• (3) prophylaxis to approximately 100 days
  followed by preemptive therapy.

Am J Transplant. 200662134
46
Prophylaxis vs. Preemptive Rx.

• A meta-analysis by Small et al (Tufts univ.)
  showed
• proph peemp
• RRR of CMV disease 64 70
• Another meta-analysis by Kalil et al (Nebraska
  MC)
• proph peemp
• RRR of CMV disease 77 80

Ann Int Med 2005143870, CID 200643869
47
Prophylaxis vs. Preemptive Rx.

• Vella et al (Maine MC) recommend
• When lymphocyte-depleting therapy (ATG, OKT3,
  Campath) is used, prophylaxis be extended to
• 6 mo for D/R
• 6-12 mo for D/R-
• (3 mo for D-/R)

Up To Date
48
Treatment of symptomatic CMV diseasein SOT
recipients

• Cessation of OKT3 and a reduction in azathioprine
  or MMF dose are indicated
• Drug of choice has been IV GCV
• A single center study of 21 kidney transplant
  patients with CMV disease found that antigenemia
  decreased with Valganciclovir therapy.
• CMV Hyperimmune globulin may also be added
• Especially for lung transplant recipients
• Prior to initiating this regimen, potential
  causes other than CMV disease need to be excluded
  (e.g. PJP, IPA)

Mayo Clin Proc 199267879, Transplant Proc
199527(5 S1)46, Transplantation. 2004 Jul
2778(2)283, Am J Transplant 200441219
49
Other meds

• Foscarnet
• Used for GCV-resistant CMV
• Nephrotoxic
• Cidofovir
• Used for GCV-resistant CMV
• Preferred by nephrologists since less nephrotoxic
  than foscarnet and has been used to treat BKV
  nephropathy
• Leflunomide
• A pyrimidine synthesis inhibitor and
  immunosuppressive agent
• currently utilized for the treatment of
  rheumatoid arthritis
• prevents CMV and HSVI replication by interfering
  with virion assembly
• may eventually assume a role in the management of
  CMV in transplant recipients

Transplantation 2004771460, Am J Transplant.
2006669
50
Other meds

• Maribavir
• a DNA synthesis inhibitor through inhibition of
  CMV UL97 kinase
• Only active against CMV and EBV
• Active against GCV-resistant CMV
• By interfering UL97 kinase, it antagonizes
  GCV/Valcyte, which depend on UL97 to become
  active.
• Advantages over GCV in vitro potency, safety
  profile, and lack or cross-resistance.

Curr Opin Investig Drugs. 20045898, Expert Rev.
Anti Infect. Ther. 20075295
51
Back to our pt

• Started on IV GCV5mg/kg q12 and CMVIVIG
• Cellcept, isa247 d/ced
• Improved
• Switched to Valcyte 900 bid
• 3 weeks later, was seen in ID clinic, doing well,
  switched to Valcyte 900 qd.

52
Case 2

• 44 yo Male w/ h/o paraplegia
• Presented to OSH with fever, chills, hypotension,
  and BL legs rash of 1 day duration.
• Transferred to NCBH for further management of
  sepsis syndrome.

53
Case 2 44 Male with sepsis with rash on the legs.

• PMH
• Paraplegia 2 to fall
• h/o pancreatitis
• DM
• Allergy
• Demerol
• SH
• ETOH, neg Tobacco/Drug
• Had been to Outerbanks, had well-cooked oysters
• FH
• Father w/ COPD

54
Case 2 44 Male with sepsis with rash on the legs.

• Meds
• Vancomycin
• Zosyn
• Gentamicin
• Hydrocortisone
• Protonix
• TPN

55
Case 2 44 Male with sepsis with rash on the legs.

• Physical exams.
• Tm99.2, BP 108/74 (levophed 5), HR 72, R24, SpO2
  99 (FiO2 50, peep5), in/out10756/2800
• HEENT pin point pupils
• Chest crackles, reduced BS
• Heart RRR, no MRG
• Abd. Distended, reduced BS
• Ext. rash, bullous lesions, ulcer, bleeding.

56
Case 2 44 Male with sepsis with rash on the legs.
57
(No Transcript)
58
Case 2 44 Male with sepsis with rash on the legs.

• Labs
• W78.0 (Seg78, Band 17, L2, M1, Myelo2)
• Hgb 9.7, Plt 28, D-dimer 6.4
• BUN 15, Cr 0.5, AST 24, ALT 16, Bil 1.5, ALP 226
• UA no pyuria

59
Case 2 44 Male with sepsis with rash on the legs.

• CXR
• BL edema
• CT chest/abd/pelvis
• Large rim-enhancing air and fluid collection in
  the low ventral abdomen
• Bilateral dependent pulmonary opacities
• Sequela of chronic pancreatitis
• Significant intra and extrahepatic biliary ductal
  dilatation of unknown cause
• No evidence of cirrhosis

60
Case 2 44 Male with sepsis with rash on the legs.
Abscess
Drain tube placed
61
Case 2 44 Male with sepsis with rash on the legs.
IHBD dilatation
62
Case 2 44 Male with sepsis with rash on the legs.

• Microbiology
• BC negx3
• BC _at_ OSH pending
• Urine neg
• Sputum neg
• Wound cx (foot) MRSA
• Abscess cx neg

63
Case 2 44 Male with sepsis with rash on the legs.

• Any thoughts or rec?

64
Case 2 44 Male with sepsis with rash on the legs.

• BC from OSH Vibrio Vulnificus

65
Vibrio Vulnificus infection

• Has it been associated with abscesses?

66
Vibrio Vulnificus infection

• Has it been associated with abscesses?
• ?very rare
• Midturi et al reported a case with Tubo-ovarian
  abscess caused by Vibrio vulnificus.
  (Diagn Microbiol Infect Dis. 2005 Feb51(2)131)
• Patel et al reported a case series on pts with
  subcutaneous neutrophilic abscess by V.
  vulnificus. (J Am Acad Dermatol. 2002 May46(5
  Suppl)S144)

67
Vibrio Vulnificus infection

• First identified in the late 1970s
• A gram-negative bacterium in the Vibrio family
• Can cause serious wound infections and
  septicemia.
• The leading cause of shellfish-associated deaths
  in the United States.
• Infection due to V. vulnificus is most common in
  individuals who have chronic, underlying illness
• with persons with liver disease or
  hemochromatosis at greatest risk.

N Engl J Med 1985312343
68
Vibrio Vulnificus infection

• Risk Factors include
• Alcoholic cirrhosis 31 to 43
• Cirrhosis and chronic hepatitis 24 to 31
• Alcohol abuse without documented liver disease
  12 to 27
• Hereditary hemochromatosis 12 percent
• Chronic diseases such as DM, RA, thalassemia
  major, chronic renal failure, "preleukemia", and
  lymphoma 7 to 8 percent

J Infect Dis 1984149(4)558, N Engl J Med
1979300(1)1
69
Vibrio Vulnificus infection

• Has been associated with the presence of a
  polysaccharide capsule
• Which can directly trigger some cytokine
  responses, contributing to the development of the
  sepsis syndrome
• Growth of V. vulnificus is dependent in part upon
  the availability of iron.
• When transferrin iron saturation exceeds 70
  percent, growth of the bacterium is nearly
  exponential.
• This may account for the clear increase in
  susceptibility of patients with hemochromatosis
• However, the majority of patients have normal
  iron saturation levels.

Up To Date
70
Vibrio Vulnificus infection

• V. vulnificus exists as a free-living bacterium
  inhabiting marine environments.
• Accounts for approximately 8 of the aerobic
  bacteria, which can be cultured from Bay water
• Filter-feeding shellfish, such as oysters,
  concentrate bacteria and may have counts of V.
  vulnificus two orders of magnitude greater than
  those in the surrounding water.
• V. vulnificus can be isolated from virtually all
  oysters harvested in the Gulf Coast when water
  temperatures exceed 20ºC

Up To Date
71
Vibrio Vulnificus infection

• Surveillance identified 14 V. vulnificus wound
  infections after Hurricane Katrina in August
  through September 2005.
• Most of the cases occurred among persons with
  medical conditions that predisposed them to
  Vibrio infections.
• Three of the 14 patients died (21 percent).

MMWR 2005 Sep 2354(37)928
72
Vibrio Vulnificus infection

• The diagnosis is confirmed by culture.
• V. vulnificus will grow without difficulty in
  standard blood culture media or on nonselective
  media routinely used for wound cultures.
• As with all Vibrio species, isolation of the
  organism from stool generally requires TCBS
  media.

Up To Date
73
Vibrio Vulnificus infection

• Group A streptococcus, NF

74
Vibrio Vulnificus infection

• Group G streptococcus bacteremia/TSS

75
Vibrio Vulnificus infection

• Treatment
• In vitro and in vivo studies in mice have
  demonstrated an apparent synergism between
  minocycline and cefotaxime
• Subsequent studies showed comparable survival in
  mice treated with newer quinolones as a single
  agent (cipro,levo,moxi)
• In vitro study showed susceptibility to
  ampicillin and imipenem.
• In a case series of 93 patients with V.
  vulnificus septicemia, combination treatment with
  a third generation cephalosporin and a
  tetracycline significantly reduced mortality
  rates
• odds ratio 0.04 95 CI, 0.01-0.19

AAC 1998461319, Arch Intern Med. 20061662117,
Appl Environ Microbiol. 2007 Sep 7 E-pub ahead
of print
76
Back to our pt

• Recommended
• Vancomycin for MRSA
• Cefotaximedoxycycline for V. vulnificus
• Metronidazole for anaerobe
• Improved (WBC 65.9?14.5, pressor d/ced)
• Pt started and continued to eat AMA, despite
  swallowing disturbance
• Transferred to palliative care d/t pts and
  familys decision for comfort care only
• Continued to decline gradually and died day 23.