Case Conference

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Case Conference

• Vipul Ganatra, MD

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DisclosuresSection of Infectious Diseases

• Robert Sherertz, M.D.
• Consultant Becton Dickson
• Kevin High, M.D.
• Grant/Research Support Cubist Pharmaceuticals,
  Astellas Pharma US, Inc.
• Consultant Merck Co., Inc.
• Speakers Bureau Wyeth 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
• Tobi Karchmer, M.D.
• Grant/Research Support Gene-Ohm Sciences
• Speakers Bureau Pfizer Pharmaceuticals, Cubist
  Pharmaceuticals, Cepheid,
• Gene-Ohm Sciences
• Consultant C.R. Bard
• 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
• Robin Trotman, D.O.
• Speakers Bureau Pfizer Pharmaceuticals

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Case 1

• 17 year old male presented to the OSH with chest
  pressure.
• He was diagnosed to have muscular pain and was
  sent home on pain medications.
• The next day he had another episode of chest pain
  and presented again to the OSH.
• He had an EKG done which showed ST segment
  elevation, PR interval depression and also had an
  elevated troponin.

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Case 1

• He was subsequently transferred to NCBH for
  further management.
• 2-3 weeks back he was diagnosed to have
  URI/sinusitis/UTI by his PCP.
• He had low a grade fever, SOB, nausea and
  vomiting.
• He was treated with amoxicillin.

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Case 1

• When he was transferred here, his troponin was
  16.47 ng/ml.
• EKG from the outside hospital showed normal sinus
  rhythm at 87 beats per minute, diffuse ST segment
  elevation with questionable PR interval
  depression.
• EKG done here showed normal sinus rhythm at 74
  beats per minute, diffuse ST segment elevation
  with PR interval depression.
• TTE showed an EF of 35 and a small mobile
  echodensity was seen on the distal
  interventricular septum, representing a small
  thrombus.

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Case 1

• Repeat TTE on the next day did not show any
  thrombus.
• His troponin peaked to 22.72ng/ml and was later
  on a downward trend.

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Case 1

• SH
• Occasional marijuana
• ¾ pack/day of cigarette smoking
• FH
• Positive for CAD

• PMH
• Cat-scratch fever 4 years ago.
• Stills murmur in childhood.
• MEDS
• Vanc
• Cipro
• Lopressor
• Zantac
• Indocin

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Case 1

• P/E
• Gen A/O
• Vitals Afebrile, VSS
• Chest CTA
• Cardiac RRR. No murmurs/rubs/gallops
• Abd soft, bowel sounds present.
• Ext No edema, cyanosis, clubbing.

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Case 1

• Differential Diagnosis ???
• Do we need to order more tests ???
• If so, what tests ???

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Case 1

• LABS
• WBC 10.4, Hb 13.7, Plt 345
• CMP WNL
• CMV IgG NEG
• RA factor NEG
• ANA NEG
• TSH 0.170
• LDH 454
• Urine Drug Screen NEG

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Case 1

• Throat swab Strep screen Positive
• Throat swab Strep culture Negative
• Blood culture x 2 No growth

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Case 1

• ASO titer 91
• Parvovirus B19 IgM 0.2
• EBV VCA IgG 4.82, EBNA - gt5, VCA IgM 0.06.
• Coxsackie B1 and B5 virus Ab 116
• CMV IgG lt 4
• Homocysteine 9 umol/l
• ANA Negative
• Anti-DNASE B 340

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Case 1

• CT Cardiac Angiography showed
• Reduced ejection fraction calculated at 48.
• Abnormal enhancement of the left ventricular
  myocardium. Such an abnormal pattern of
  enhancement has been similarly described in the
  MR literature with gadolinium in patients with
  myocarditis or infiltrative myocardiopathy.
• Small pericardial effusion.
• 4. Right-sided coronary dominance.

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Case 1

• MR Cardiac with and without infusion
• Significant improvement in the contractility of
  the left ventricular myocardium relative to a CT
  scan of the heart.
• The ejection fraction on was calculated to be
  65. This is significantly improved relative to
  approximately 50 on the CT scan and 35
  estimated on an echocardiogram.

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Case 1

• ID service was consulted and the recommendations
  were
• - D/C Cipro and vancomycin
• - Treat strep throat with Penicillin VK or
  amoxicillin.
• - Await results of all the send out tests.

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Acute Rheumatic Fever (ARF)

• ARF is an inflammatory disease of the heart,
  joints, CNS and subcutaneous tissues.
• It develops after a nasopharyngeal infection by
  one of the group A beta-hemolytic streptococci.
• The overall incidence and severity of acute
  rheumatic fever have decreased in the recent
  years in the Western countries.
• It is said that Rheumatic fever licks the joints
  and bites the heart, a statement that holds true
  even today.

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Acute Rheumatic Fever

• Rheumatic fever occurs most commonly in children
  5 to 15 years of age.
• First attacks of rheumatic fever rarely occurs in
  children younger than 3 years of age or in adults
  older that 40 years of age.
• ARF occurs only after nasopharyngeal infection
  secondary to the rheumatogenic strains group A
  streptococci.

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Acute Rheumatic Fever

• M proteins from highly rheumatogenic group A
  streptococcal types share antigenic determinants
  with myosin, with the sarcolemma of cardiac
  muscle and with antigens of articular cartilage
  and synovium.
• The immune response to streptococci may thus
  mistake the host antigens as foreign and result
  in tissue damage.

Baird R et al. J Immunol 1991. 146 3132-3137.
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Acute Rheumatic Fever

• JONES CRITERIA
• Major Manifestations
• Carditis
• Polyarthritis
• Chorea
• Erythema marginatum
• Subcutaneous nodules

JAMA 1992. 2682069-2073
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Acute Rheumatic Fever

• JONES CRITERIA
• Minor Manifestations
• Clinical findings
• Arthralgia
• Fever
• Laboratory findings
• Elevated acute-phase reactants
• Elevated ESR
• Elevated C-reactive protein
• Prolonged PR interval

JAMA 1992. 2682069-2073
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Acute Rheumatic Fever

• Lab Findings
• The ASO titer is the most popular antibody test
  used.
• ASO titers of 500 Todd units or greater are good
  evidence of a recent streptococcal infection.
• ASO titers lt 250 Todd units could be considered
  normal and titers of 250-320 should be considered
  borderline elevated.

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Acute Rheumatic Fever

• In as many as 20 percent of ARF, ASO titers can
  be normal.
• A recent streptococcal infection is more likely
  to be demonstrated if more than one antibody
  titer is measured
• Anti-deoxyribonuclease B is the most favored
  because of better reproducibility.

Stollerman GH et al. Am J Med 1956
Feb20(2)163-9.
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Acute Rheumatic Fever

• Therapy for ARF is symptomatic
• Control the inflammation
• Decrease the fever, and
• Keep the cardiac failure in check
• Characteristically, the joint inflammation and
  fever subside in 24-48 hours with salicyclate
  treatment if the serum level is 10-20mg/dl, which
  is usually achieved by a dose of 60-100mg/kg/24
  hr.

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Acute Rheumatic Fever

• All patients should receive intramuscular
  benzathine penicillin, even if the throat culture
  does not reveal group A beta-hemolytic
  streptococci.
• Patients then can be placed on the secondary
  preventive treatment regimen, which may be
• either oral penicillin V, 250 mg bid, or
• benzathine penicillin, 1.2 MU IM every 4 weeks.
• The parenteral route has been shown to be more
  effective.

Newman JE et al. N.Z.Med. J 1984. 97 678-680.
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Myocarditis

• The diagnosis of infectious myocarditis is
  considered when unexplained heart failure or
  arrhythmias occur in the setting of a systemic
  illness or after symptoms of an upper respiratory
  tract infection.
• One or more of at least four mechanisms appear to
  be involved
• Direct damage to cells by an infectious agent
• Cytotoxicity caused by a circulating toxin
• Cytotoxicity caused by infection-induced immune
  reactions
• Nonspecific damage to myocytes as a result of an
  adjacent inflammatory process

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Myocarditis

• Enteroviruses were associated with a greater
  degree of myocardial inflammation than
  adenoviruses in patients with acute myocarditis
  and DCM.
• The relatively high prevalence of human
  adenoviruses and group B coxsackieviruses, as
  causes of viral myocarditis may be explained, at
  least in part, by the discovery that adenoviruses
  and group B coxsackieviruses both bind to a
  common receptor, the coxsackievirus-adenovirus
  receptor (CAR), that is expressed on the surface
  of cardiac myocytes.

Noutsias M et al. Circulation2001. 104 265-280.
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Myocarditis

• The gold standard for the premortem diagnosis of
  myocarditis has traditionally been endomyocardial
  biopsy.
• Biopsy confirmation of the clinical diagnosis of
  myocarditis is highly variable, ranging from 10
  to 100 in different series.
• Results of endomyocardial biopsy have also been
  highly variable in patients with unexplained
  congestive heart failure, with evidence of active
  myocarditis being found in 2 to 80 of these
  patients

Peter NS et al. Am Heart J 1991. 121942-947
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Myocarditis

• To date, diagnosis of viral myocarditis has
  generally been based on the isolation of virus
  from another site (e.g., stool), the
  demonstration of a fourfold or greater rise in
  antibody titer from acute to convalescent sera,
  or the demonstration of a high titer of
  virus-specific immunoglobulin M antibody in
  serum.

Reyes MP et al. Prog Cardiovasc Dis 1985
May-Jun27(6)373-94
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Myocarditis

• Bed rest and avoiding exercise are important part
  of the therapy.
• In mice infected with either coxsackievirus B3 or
  encephalomyocarditis virus, treatment with
  captopril, an ACEI used in the treatment of heart
  failure from a variety of causes, reduced
  inflammation and enhanced survival.

Matsumori A et al. Circulation 1990
Mar81(3)1039-46
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Myocarditis

• A study was done to see the effect of a new
  calcium-channel blocker, amlodipine, in patients
  with severe chronic heart failure.
• 1153 patients with severe chronic heart failure
  and ejection fractions of less than 30 percent
  were randomized to double-blind treatment with
  either placebo (582 patients) or amlodipine (571
  patients) for 6 to 33 months, while their usual
  therapy was continued.

Packer M et al. NEJM 1996 Oct 10335(15)1107-14
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Myocarditis

• The randomization was stratified on the basis of
  whether patients had ischemic or nonischemic
  causes of heart failure.
• The primary end point of the study was death from
  any cause and hospitalization for major
  cardiovascular events.

Packer M et al. NEJM 1996 Oct 10335(15)1107-14
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Myocarditis

• A total of 38 percent of the patients in the
  placebo group died, as compared with 33 percent
  of those in the amlodipine group.
• Among patients with ischemic heart disease,
  there was no difference between the amlodipine
  and placebo groups in the occurrence of either
  end point.
• In contrast, among patients with nonischemic
  cardiomyopathy, amlodipine reduced the combined
  risk of fatal and nonfatal events by 31 percent
  (P 0.04) and decreased the risk of death by 46
  percent (Plt0.001).

Packer M et al. NEJM 1996 Oct 10335(15)1107-14
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Myocarditis

• The effect of prednisolone on viral myocarditis
  was studied in BALB/c mice with
  encephalomyocarditis virus myocarditis was
  studied.
• Prednisolone was injected intramuscularly, 10
  mg/kg once a day, on days 4 - 13(experiment 1)
  and on days 8 -17 (experiment 2).
• The control mice in each experiment received
  injections of distilled water.

Tomoika N et al. J Am Coll Cardiol 1986
Apr7(4)868-72.
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Myocarditis

• In experiment 1, myocardial virus titers were
  maximal but neutralizing antibodies were rarely
  present on day 4, and viral titers were still
  elevated and antibody titers were high on day 8.
• The survival rate of the prednisolone group was
  significantly lower (p lt 0.05) than that of the
  control group on days 21, 22 and 23.
• On day 10, the antibody titers of the
  prednisolone group were significantly lower (p
  less than 0.01) than those of the control group,
  and viral titers of the prednisolone group
  remained significantly elevated (p less than
  0.01), whereas viruses were rarely isolated in
  the control group.

Tomoika N et al. J Am Coll Cardiol 1986
Apr7(4)868-72.
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Myocarditis

• In experiment 2, the survival rate and antibody
  titers were not significantly different in the
  prednisolone and control groups.
• In both experiments, no viruses were isolated on
  day 14.
• This study suggests that corticosteroids given in
  the early stage aggravate the course of acute
  viral myocarditis, and that they may not have
  detrimental effects if given when neutralizing
  antibody titer levels are high, although they are
  not expected to have a beneficial effect.

Tomoika N et al. J Am Coll Cardiol 1986
Apr7(4)868-72.
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Myocarditis

• To elucidate the mechanism underlying the actions
  of immunoglobulin, the authors examined its
  effects on murine coxsackievirus B3 (CB3)
  myocarditis.
• An in vitro study showed dose-dependent
  suppression of CB3 by immunoglobulin.
• Immunoglobulin 1 g.kg-1.d-1 IP was administered
  to CB3-infected C3H/He mice daily for 2 weeks,
  beginning simultaneously with virus inoculation
  in experiment 1 and on day 14 after virus
  inoculation in experiment 2.

Takada H et al. Circulation 1995 Sep
1592(6)1604-11
39
Myocarditis

• In both experiments, survival was higher in
  treated than in control mice at the time of
  death.
• Notably, in experiment 1, immunoglobulin
  administration completely suppressed the
  development of myocarditis.
• Serum-neutralizing antibody titers in the treated
  mice were significantly higher than those in
  untreated mice in experiment 1 but not in
  experiment 2.

Takada H et al. Circulation 1995 Sep
1592(6)1604-11
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Myocarditis

• The circulating antibodies of the treated mice
  were primarily of exogenous origin in experiment
  1 and of exogenous and endogenous origins in
  experiment 2.
• The analysis of splenic lymphocyte subsets
  revealed a marked decrease of the B cell
  population in the treated mice.

Takada H et al. Circulation 1995 Sep
1592(6)1604-11
41
Myocarditis

• The authors concluded that immunoglobulin therapy
  completely suppressed acute CB3 myocarditis by
  transferring the neutralizing antibody into the
  host in the acute viremic stage and induced an
  anti-inflammatory effect in the subsequent
  aviremic stage.
• It also caused the reduction of the splenic
  B-cell population that may be closely associated
  with an anti-inflammatory effect.

Takada H et al. Circulation 1995 Sep
1592(6)1604-11
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Myocarditis

• In a phase II study, 22 consecutive patients with
  persistence of LV dysfunction (history of
  symptoms, 4427 months) and polymerase chain
  reactionproven enteroviral or adenoviral genomes
  were treated with 18x106 IU/week IFN-ß
  (Beneferon) subcutaneously for 24 weeks.
• Histological and immunohistological analysis of
  endomyocardial biopsies was used to characterize
  myocardial inflammation.

Kuhl U et al. Circulation 2003 Jun
10107(22)2793-8.
43
Myocarditis

• LV diameters and ejection fraction were assessed
  by echocardiography and angiography,
  respectively.
• During the treatment period, IFN-ß was well
  tolerated by all patients.
• No patient deteriorated.
• Clearance of viral genomes was observed in 22 of
  22 of patients after antiviral therapy

Kuhl U et al. Circulation 2003 Jun
10107(22)2793-8.
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Myocarditis

• Virus clearance was paralleled by a significant
  decrease of LV end diastolic and end systolic
  diameters, decreasing from 59.711.1 to 56.510.0
  mm (Plt0.001) and 43.213.6 to 39.412.1 mm
  (Plt0.001), respectively.
• LV ejection fraction increased from 44.615.5 to
  53.116.8 (Plt0.001).

Kuhl U et al. Circulation 2003 Jun
10107(22)2793-8.
45
Myocarditis

• The authors concluded a 6 months, IFN-ß treatment
  was safe in patients with myocardial enteroviral
  or adenoviral persistence and LV dysfunction and
  resulted in elimination of viral genomes (22 of
  22 patients) and improved LV function (15 of 22
  patients).

Kuhl U et al. Circulation 2003 Jun
10107(22)2793-8.
46
Myocarditis

• Ganciclovir has been used successfully in the
  treatment of severe cytomegalovirus infection,
  including myocarditis.
• No antiviral drugs with efficacy against the
  enteroviruses are commercially available at this
  time.

McCormack JG et al. CID 1998 26 1007-1008
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Case 2

• 57 year old female c/o flu-like symptoms for
  almost a week.
• 2 weeks prior to this episode she had returned
  from Cancun, Mexico after spending a week there.
• One week after her initial symptoms she had night
  sweats, fever(1010 F) and chills at home.

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Case 2

• She was seen in the urgent care clinic in High
  Point, NC where she had a CXR done and a CT scan
  of the abdomen done as she c/o abdominal pain.
• CT abdomen showed a right lobe liver abscess.
• The patient was admitted to High Point Medical
  Center and the abscess drained.

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Case 2

• She was started on cefotetan and metronidazole
• She improved clinically after the drain was put
  for 2-3 days.
• Later her symptoms i.e fever, RUQ pain, nausea
  recurred.
• She was transferred here, for further management
  as her symptoms worsened.

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Case 2

• PMH
• Diverticulitis in the past
• Hyperlipidemia
• PSH
• TAH
• Tonsillectomy
• Appendectomy

• Allergies
• Sulfa
• Macrobid
• MEDS
• Cipro
• Flagyl
• Lovenox
• Ibuprofen
• Phenergan

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Case 2

• P/E
• Gen A/O
• Vitals Tmax 102.40F VSS
• HEENT PERRLA
• Chest CTA
• Cardiac RRR
• Abd soft, RUQ drain present. RUQ tender. Bowel
  sounds present.
• Ext no edema

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Case 2

• LABS
• WBC 15.7, Hb 10.9 Plt 755
• CMP WNL except AP 175
• CT scan of the Abdomen
• The principle finding is that of a 7.8 cm
  cephalocaudal x 6.4 cm AP dimension peripheral
  enhancing, ill-marginated mass within the right
  lobe of the liver in which a pigtail catheter is
  present.
• This mass contains multiple enhancing septa
  indicative of loculation.

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Case 2

• What is the etiology??
• What should be the initial choice of the
  antibiotics??

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Case 2

• The culture of the aspirate from the liver
  abscess at the OSH grew Prevotella oralis
  beta-lactamase positive.
• The patient had a change in her drainage
  catheter.
• Unfortunately no cultures were done at that time.
• Serology for E.histolytica was negative.
• She was sent home on po metronidazole with a f/u
  in ID clinic in a month with a repeat CT scan of
  the abdomen.

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Case 2

• Pigmented and non-pigmented Prevotella species
  are, the most commonly encountered anaerobic
  bacteria in human infections, after the B.
  fragilis group.
• Prevotella species are important pathogens in
  oral, dental and bite infections.
• They are also isolated from infections of the
  head, neck, lower respiratory tract and
  gynecological infections.

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Case 2

• Resistance is increasingly common among anaerobic
  gram-negative rods.
• Approximately one-third of Prevotella species are
  beta-lactamase producers and beta-lactamase
  production among oral pigmented Prevotella
  species is also frequently present in young
  children.

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Case 2

• 76 of the strains isolated from the children and
  69 of the strains isolated from their mothers
  are beta-lactamase producers.
• Most strains are still susceptible to clindamycin
  and metronidazole, while resistant strains to
  tetracycline have been reported.

Kononen E et al. CID 1995 20 S364-366.
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Case 2

• Most of the Prevotella species are susceptible to
  beta-lactam/beta-lactamase inhibitors,
  clindamycin, metronidazole and chloramphenicol.

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Thank You