MEDICAL GRANDROUNDS

1
MEDICAL GRANDROUNDS

• July 3, 2008
• Abigail Cruz-Zaraspe M.D.

2
OBJECTIVES

• To present a case of bacteremia in aplastic
  anemia
• To discuss salmonella nontyphi bacteremia and
  myositis manifestations, diagnosis and treatment
• To discuss briefly the treatment of aplastic
  anemia

3
(No Transcript)
4
(No Transcript)
5
IDENTIFYING DATA

• A.R.
• 42/M
• Married
• Real-estate broker

6
CHIEF COMPLAINT

• Right thigh pain

7
HISTORY OF PRESENT ILLNESS

• 5 weeks PTA Easy fatigability, SOB, ()
  melena, () abdominal pain,
• ()palpitations
• 4 weeks PTA sought consult, CBC
  Pancytopenia
• admitted for the first time for
  transfusion

8
HISTORY OF PRESENT ILLNESS

• First admission blood transfusions
• BMA-hypocellular BM
• Dx Aplastic anemia
• treatment options were discussed
• (discharged-platelet ct 44k)

9
HISTORY OF PRESENT ILLNESS

• 3 weeks PTA intermittent fever
  (390C),body malaise, nose bleeding
• Consult WBC 1860,
• PLT 10k
• Tx Co-amoxyclav 625mg TID x7d,
  tranexamic acid 500mg TID GCSF
  300mcg

10
HISTORY OF PRESENT ILLNESS

• 3 weeks PTA generalized petechial rashes
  gum bleeding and was admitted
• 2nd admission CBC- pancytopenia Tx blood
  PC transfusions

11
CBC on SECOND ADMISSION
  22-Mar 24-Feb 25-Mar
hgb 8.5 8 10
hct 25.5 24.4 30.5
wbc 1850 2960 2190
stabs      
segmenter 54 72 48
lymphocyte 40 23 45
platelet ct 5000 2000 14000
anc 999 2131 1051
12
HISTORY OF PRESENT ILLNESS

• 2nd admission Initially given Cefepime
  1gm Q12

13
HISTORY OF PRESENT ILLNESS

• 2nd admission right thigh hip pain
  5/10 (dull, aching constant)
• direct tenderness
• no swelling
• no limitation in ROM
• no paresthesia

14
Hip Thigh pain
Avascular necrosis
Compartment syndrome
infection
neuropathy
fracture
15
NEUROPATHY

• Severe intractable pain
• Unusual burning, tingling or shock-like quality
• Triggered by light touch
• Sensory deficit on area of pain

16
Hip Thigh pain
Avascular necrosis
Compartment syndrome
infection
neuropathy
fracture
17
COMPARTMENT SYNDROME

• Pain
• Parasthesia
• Pulselessness
• Pallor
• pressure

18
Hip Thigh pain
Avascular necrosis
Compartment syndrome
infection
neuropathy
fracture
19
HISTORY OF PRESENT ILLNESS

• 2nd admission Pelvis and Right hip xray no
  pathologic finding

20
Hip Thigh pain
Avascular necrosis
Compartment syndrome
infection
neuropathy
fracture
21
HISTORY OF PRESENT ILLNESS

• 2nd admission Blood CS Salmonella
  enteritidis Grp C
• Sensitive Ceftriaxone Chloramphenicol
  Ciprofloxacin
• shifted to Ciprofloxacin 500mg/tab, 1
  tab BID

22
HISTORY OF PRESENT ILLNESS

• 2nd admission Dx Aplastic anemia
• Salmonella nontyphi bacteremia
• Advised treatment w/ Anti-thymocyte
  globulin / cyclosporine

23
HISTORY OF PRESENT ILLNESS

• 2nd admission THM Ciprofloxacin
  500mg/tab, 1 tab BID to complete 7 days
• Prednisone 30mg BID,
• Tranexamic acid Omeprazole

24
HISTORY OF PRESENT ILLNESS

• Since discharge episodes of fever
  progression R hip thigh pain on
  movement palpation
• unable to stand
• admitted 3rd time

25
REVIEW OF SYSTEMS

• (-) headache
• (-) loss of consciousness
• (-) cough or colds
• (-) weight loss
• (-) chest pain
• (-) dyspnea
• (-) palpitations
• (-) abdominal pain

• (-) nausea or vomiting
• (-) LBM/ constipation
• () melena
• (-) hematochezia
• (-) dysuria
• (-) hematuria

26
PAST MEDICAL HISTORY

• Non-hypertensive
• Non-diabetic
• No known allergies

27
FAMILY HISTORY

• No hypertension
• No diabetes
• No asthma
• No blood dyscrasias
• No cancer

28
PERSONAL AND SOCIAL HISTORY

• Previous smoker, stopped in late 90s
• Occasional beer drinker
• Lived near an electroplating factory
• Previously worked as a cashier in a gasoline
  station
• Real estate broker

29
PHYSICAL EXAMINATION

• General conscious, coherent, bed-bound
• Vital signs BP 130/80, HR 103 bpm, reg, RR
  22/min, T 390C
• HEENT Pale conjunctivae, icteric sclerae, no
  tonsillopharyngeal congestion, no
  cervical lymphadenopathy

30
PHYSICAL EXAMINATION

• Chest/Lungs Symmetrical chest expansion,
  no retractions, clear breath sounds
• Adynamic precordium, tachycardic with
  regular rhythm, no murmurs

31
PHYSICAL EXAMINATION

• Abdomen Flabby, normoactive bowel sounds,
  soft, non-tender, no hepatomegaly
• no splenomegaly

32
PHYSICAL EXAMINATION

• Extremities () erythema and hyperemia,
  right thigh extending to mid-leg area
• No discharge, no open wounds
• no sensory deficit
• Left leg was grossly normal
• pulses full and equal

33
SALIENT FEATURES

• 42/M
• Known case of aplastic anemia
• Known case of non-typhi salmonella bacteremia
• Treated with ciprofloxacin 500mg BID x 1 week
• Still febrile
• Right thigh and hip pain
• Erythema and swelling of right lower extremity

34
Hip Thigh pain
Avascular necrosis
Compartment syndrome
infection
neuropathy
fracture
35
AVASCULAR NECROSIS

• results from infarction of bone trabeculae and
  marrow cells
• equal frequency in the femoral and humeral heads
• The femoral heads more commonly undergo
  progressive joint destruction as a result of
  chronic weight bearing. The changes are best
  detected by MRI

36
AVASCULAR NECROSIS

• Most studies have found that the risk is low (lt 3
  percent) in patients treated with doses of
  prednisone less than 15 to 20 mg/day
• In one series, the prednisone dose in the highest
  month of therapy exceeded 40 mg/day in 93
  percent, and 20 mg/day in 100 percent of patients
  with osteonecrosis.

37
Hip Thigh pain
Avascular necrosis
Compartment syndrome
infection
neuropathy
fracture
38

• 150 patients with aplastic anemia treated at
  Clinical Hematology Branch of the National Heart,
  Lung and Blood Institute (NHLBI) between 1978 and
  1990
• Infection was documented in 47 of cases
• respiratory tract (32 percent)
• soft tissues (24 percent)
• blood (22 percent)
• gastrointestinal tract (17 percent)
• urinary tract (6 percent).

39
IMPRESSION

• Aplastic anemia
• Salmonella non-typhi bacteremia with secondary
  myositis
• r/o Avascular necrosis, osteomyelitis

40
COURSE IN THE WARDS

• On admission
• CBC, PT, PTT, UA, CXR, crea, BUN, K, Na were
  requested. He was placed on a neutropenic diet.
• He was started on Piperacillin-tazobactam
  4.5mg/IV x 1dose then 2.25mg q8 hours

41
LABS APRIL 12, 2008
  12-Apr
hgb 8.5
hct 24.9
rbc 2.9
wbc 2880
metamyelocytes 1
stabs  
segmenter 67
lymphocyte 25
mono 7
platelet ct 6000
anc 1929
  12-Apr
na 134
k 4.2
bun 21
crea 1.2
CXR- normal
42
Piperacillin-tazobactam
Febrile
43
COURSE IN THE WARDS

• 2nd hospital day
• severe leg pain, unrelieved by Tramadol.
• referred to Orthopedic service
• Impression t/c pathologic fracture vs. avascular
  necrosis, R hip aplastic anemia.
• Tx Ketorolac and Morphine.

44
COURSE IN THE WARDS

• 2nd hospital day
• Pelvic MRI was requested
• Myositis with fasciitis involving the right
  gluteal and right thigh muscle and the right
  obturator internus muscle.
• Avascular necrosis of the right femoral head
  considered

45
COURSE IN THE WARDS

• 2nd hospital day
• still with fever and leg pain
• Blood CS
• Salmonella Enteritidis Group C
• sensitive to Ceftriaxone and Ciprofloxacin
• resistant to Co-trimoxazole and Ampicillin.

46
COURSE IN THE WARDS

• 5th HD
• referred to Infectious Disease service.
• Impression Salmonella nontyphi bacteremia with
  secondary myositis.
• Tx shift Piperacillin-tazobactam to
  Ciprofloxacin 500mg/tab 2x a day ceftriaxone
  2g/IV OD

47
CP CT
PT
Febrile
48
COURSE IN THE WARDS

• 11th HD
• patient was still febrile (Tmax400C)
• endovascular Salmonella was considered
• Ceftriaxone was discontinued
• Piperacilin-Tazobactam was resumed increased to
  4.5 IV Q8
• dexamethasone 4mg/tab 12 hrs

49
CPCT
CP
PT
CT
dexa
Febrile
50
COURSE IN THE WARDS

• 13th HD
• Afebrile
• pain decreased
• Dexamethasone was tapered to 4mg/tab bid.

51
COURSE IN THE WARDS

• 18th HD
• Cyclosporine (Neoral)100mg/cap BID
• ATG 1000mg in PNSS x 4 hrs, once daily until D11
  ( 5/9/08)

52
PT
CP
dexa
Febrile
ATG Cyclo
53
COURSE IN THE WARDS

• 21st HD
• patient was afebrile, Piperacillin-tazobactam was
  discontinued

54
PT
CP
PT
Febrile
ATG Cyclo
ATG
55
COURSE IN THE WARDS

• 38th HD
• fever recurred
• Increased severity of R thigh pain
• Blood CS negative after 5 days
• CBC still showed pancytopenia.

56
CP
Febrile
Cyclo
57
COURSE IN THE WARDS

• 41st HD
• persistence of fever
• CXR,urinalysis,CBC were requested
• CXR urinalysis were normal
• CBC still showed pancytopenia.
• Piperacillin-tazobactam 4.5g/IV q8 was resumed

58
CP
PT
Febrile
Cyclo
59
COURSE IN THE WARDS

• 46th HD
• BMA beginning bone marrow recovery. Some
  section shows good cellularity with myeloid
  and erythroid precursors, although
  megakaryocytes are still decreased but present

60
CP
Febrile
61
(No Transcript)
62
(No Transcript)
63
COURSE IN THE WARDS

• 47th HD
• again had febrile episodes
• Blood culture negative
• MRI of R leg myositis, fasciitis avascular
  necrosis of the R thigh

64
CP
Febrile
Cyclo
65
COURSE IN THE WARDS

• 53rd HD
• sent home
• afebrile
• medications
• Tranexamic acid, Cyclosporine 100mg BID,
  ciprofloxacin 500mg BID

66
FINAL DIAGNOSIS

• Aplastic anemia
• Salmonella enteritides myositis
• Avascular necrosis, femoral head

67
DISCUSSION
68
SALMONELLA MICROBIOLOGY

• Gram-negative
• non-spore forming
• Facultatively anaerobic bacilli
• Produce acid on glucose fermentation
• Motile
• Do not ferment lactose (99)
• Differential metabolism of sugars is used to
  distinguish serotypes
• S. typhi does not produce gas on sugar
  fermentation

69
NON-TYPHOIDAL SALMONELLA EPIDEMIOLOGY

• 1996-1999 estimated 1.4M cases of NTS in US
• 2004 14.7/100,000 persons
• Typhimurium 20
• Enteritidis 15
• Newport 10

70
NON-TYPHOIDAL SALMONELLA EPIDEMIOLOGY - HOST
FACTORS

• Impaired cell-mediated immunity
• AIDS
• Corticosteroid use
• Malignancy
• Impaired phagocytic function
• Hemoglobinopathies
• Chronic granulomatous disease
• Schistosomiasis
• Histoplasmosis
• Malaria

71
NON-TYPHOIDAL SALMONELLA EPIDEMIOLOGY - HOST
FACTORS

• Extremes of ages
• Neonates
• Elderly
• Decreased gastric acidity
• achlorhydria
• Antacids or suppression of gastric acidity
• Altered intestinal function
• IBD
• Prior antibiotic therapy

72
NON-TYPHOIDAL SALMONELLA EPIDEMIOLOGY

• Small but significant number
• Associated with food products (meat, poultry,
  eggs or dairy products)
• Associated with shell eggs
• Associated with exotic pets, especially reptiles

73
NON-TYPHOIDAL SALMONELLA EPIDEMIOLOGY
74
NON-TYPHOIDAL SALMONELLA PATHOGENESIS

• Ingestion from contaminated food/water
• Infectious dose 103-106 CFU
• Gastric acidity is the initial barrier
• Bacteria mediated endocytosis

75
NON-TYPHOIDAL SALMONELLA PATHOGENESIS

• Innate immune system
• May be determining factor for severity
• Depressed PMN function increases incidence
• Cell-mediated immunity
• Role in clearing infection and protecting against
  subsequent Salmonella infection
• Humoral immune responses
• Protective immunity

76
NON-TYPHI SALMONELLA CLINICAL MANIFESTATIONS

• Gastroenteritis
• Bacteremia and vascular infection
• Localized infection
• Chronic carrier state
• Clinically useful, have no pathogenic nor
  prognostic significance

77
NON-TYPHI SALMONELLA BACTEREMIA AND VASCULAR
INFECTIONS

• 5 of patients with NTS
• Infants, elderly and immunocompromised
• Salmonella has high propensity for infection of
  vascular sites
• 10-25 in persons gt 50
• Aorta
• Venous septic thrombophlebitis

78
NON-TYPHI SALMONELLA LOCALIZED INFECTION

• Occurs in 5-10 of patients with NTS bacteremia

79
NON-TYPHI SALMONELLA LOCALIZED INFECTION
80
NON-TYPHI SALMONELLA LOCALIZED INFECTION
81
(No Transcript)
82
(No Transcript)
83
(No Transcript)
84
(No Transcript)
85
NON-TYPHI SALMONELLA SPECIAL POPULATIONS

• Immunosuppression
• Biliary and urinary tract abnormalities
• Hemoglobinopathies
• Malaria
• Schistosomiasis
• Histoplasmosis
• AIDS

86
(No Transcript)
87
(No Transcript)
88
NON-TYPHI SALMONELLOSIS TREATMENT

• Neonates, gt50 years of age and in patients with
  immunosuppresion or valvular/endovascular
  abnormalities
• Oral or IV antimicrobial for 48 to 72 hours or
  until patient is afebrile

89
SALMONELLA NON-TYPHI BACTEREMIA TREATMENT

• Empiric 3rd generation cephalosporin and a
  fluoroquinolone
• Low-grade 7-14 days of Tx
• High-grade 6 weeks IV therapy with ß-lactam
  (ampicillin or ceftriaxone) is recommended to
  treat documented or suspected endovascular
  infection
• IV Ciprofloxacin, followed by prolonged oral
  therapy

90
SALMONELLA NON-TYPHI LOCALIZED INFECTION TREATMENT

• Ceftriaxone 2g/d or Cefotaxime 2g q8h
• Ciprofloxacin 500mg/tab BID or 400mg/IV BID
• Ampicillin 2g/IV q6h

91
SALMONELLA ANTIMICROBIAL RESISTANCE

• Widespread use of over-the-counter antibiotics
• Plasmid-encoded resistance
• Empirical treatment of febrile syndromes and as
  growth promoters in animal production
• DT104
• resistant to ACSSuT ampicillin, chloramphenicol,
  streptomycin, sulfonamides and tetracyclines
• Acquired from plasmids in Pseudomonas species

92
SALMONELLA ANTIMICROBIAL RESISTANCE

• Increase in ceftriaxone and fluoroquinolone
  resistant nontyphoidal Salmonella

93
(No Transcript)
94
(No Transcript)
95
SALMONELLA PREVENTION AND CONTROL

• Hand washing
• Safe drinking water and effective sewage
  treatment
• Improved food safety practices
• Good personal hygiene
• Prudent antimicrobial use

96
TREATMENT OF APLASTIC ANEMIA

• Hematopoietic stem cell transplantation
• Immunosuppression
• Anti-thymocyte globulin induces hematologic
  recovery
• Addition of cyclosporine increases response rate
  up to 70 esp. in children
• Improvement in leukocyte count apparent within 2
  months

97
TREATMENT OF APLASTIC ANEMIA(IMMUNOSUPPRESSIVE
THERAPY)

• improvement in blood counts occurred in 60
  percent of patients after three months
• The actuarial risk of relapse was 35 percent at
  five years.
• Most of the relapsing patients responded to
  additional courses of immunosuppression, and
  relapse was not associated with a significant
  survival disadvantage..

Rosenfeld, SJ, Kimball, et.al Intensive
immunosuppression with antithymocyte globulin and
cyclosporine as treatment forsevere acquired
aplastic anemia. Blood 1995 853058.
98
Treatment of aplastic anemia with antilymphocyte
globulin and methylprednisolone with or without
cyclosporine. The German Aplastic Anemia Study
Group

• antilymphocyte globulin, methylprednisolone, and
  cyclosporine appears to be more effective than a
  regimen of antilymphocyte globulin and
  methylprednisolone without cyclosporine
• may thus represent a treatment of choice for
  patients who are not eligible for bone marrow
  transplantation

Frickhofen N, Kaltwasser JP, Schrezenmeier H,
Raghavachar A, Vogt HG, Herrmann F, Freund M,
Meusers P, Salama A, Heimpel H
99
THANK YOU!
100
(No Transcript)
101
CBC
12-Apr 13-Apr 15-Apr 17-Apr 19-Apr 23-Apr 25-Apr 26-Apr 28-Apr 30Apr
hgb 8.5 8.6 9.4 6.4 8.2 9.6 6.8 8.5 9.8 9.3
hct 24.9 26.3 27.7 19.3 24.4 29 20.7 25.8 30 28.5
rbc 2.9 2.9 3.1 2.26 2.9 3.4 2.46 3.24 3.98 3.75
wbc 2880 1360 3700 2860 2570 2,000 2,690 3200 4290 1940
Seg 67 25 45 42 34 35 46 50 29 59
Lym 25 73 50 50 60 56 42 37 63 28
Mon 7 2 5 8 6 9 11 13 8 13
Plate 6k 16k 10k 15k 20k 9k 24k 10k 20k 10k
Anc 1929 340 1665 1200 873.8 774 1237 1600 1154 2212
102
CBC
  1-May 2-May 4-May 6-May 7-May 11-May 13-May 14-May 19-May 22-May
hgb 9.3 9 8.8 9.6 10.4 9.8 8.1 11.1 9.8 9.1
hct 29.1 27 26.3 28.6 31 27.2 25.3 33.5 29.5 27.4
rbc 3.8 3.54   4.06   3.94 3.64 4.55 4.02 3.67
wbc 2940 5840 4150 8420 4500 5520 4400 4400 4400 4900
Seg 57 80 61 65 45 45 42 44 45 56
Lymph 26 37 30 28 40 46 47 42 43 30
Mono 7           11 11 . 14
PC 14k 51k 39k 11k 22k 10k 28k 29k 7k 74k
Anc 1675 4192 2531 5473 2025 2484 1848 1936 1980 2744
103
TREATMENT OF APLASTIC ANEMIA(IMMUNOSUPPRESSIVE
THERAPY)

• Horse ATG at a dose 40 mg/kg per day in 500 mL of
  saline given over four to six hours for four
  consecutive days.

Rosenfeld, SJ, Kimball, et.al Intensive
immunosuppression with antithymocyte globulin and
cyclosporine as treatment forsevere acquired
aplastic anemia. Blood 1995 853058.
104
TREATMENT OF APLASTIC ANEMIA(IMMUNOSUPPRESSIVE
THERAPY)

• Prednisone or methylprednisolone in divided doses
  of 1 mg/kg per day. Steroids were given for two
  weeks, with the dose tapered so that the
  corticosteroids were discontinued by day 30.

Rosenfeld, SJ, Kimball, et.al Intensive
immunosuppression with antithymocyte globulin and
cyclosporine as treatment forsevere acquired
aplastic anemia. Blood 1995 853058.
105
TREATMENT OF APLASTIC ANEMIA(IMMUNOSUPPRESSIVE
THERAPY)

• Cyclosporine, 10-12 mkd, in two equally divided
  doses,
• aiming for trough levels of 100 to 200 ng/mL of
  serum or 500 to 800 ng/mL in whole blood.
• Cyclosporine is generally continued for about six
  months, although the dose may be tapered after
  one month to trough whole blood levels of 200 to
  500 ng/mL.

Rosenfeld, SJ, Kimball, et.al Intensive
immunosuppression with antithymocyte globulin and
cyclosporine as treatment forsevere acquired
aplastic anemia. Blood 1995 853058.