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MEDICAL GRANDROUNDS. July 3, 2008 Abigail Cruz-Zaraspe M.D. 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. IDENTIFYING DATA.

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MEDICAL GRANDROUNDS

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Medical grandrounds

MEDICAL GRANDROUNDS

July 3, 2008

Abigail Cruz-Zaraspe M.D.


Objectives

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


Identifying data

IDENTIFYING DATA

  • A.R.

  • 42/M

  • Married

  • Real-estate broker


Chief complaint

CHIEF COMPLAINT

  • Right thigh pain


History of present illness

HISTORY OF PRESENT ILLNESS

  • 5 weeks PTAEasy fatigability, SOB, (+) melena, (+) abdominal pain,

    (+)palpitations

  • 4 weeks PTAsought consult, CBC Pancytopenia

    admitted for the first time for transfusion


History of present illness1

HISTORY OF PRESENT ILLNESS

  • First admissionblood transfusions

    BMA-hypocellular BM

    Dx: Aplastic anemia

    treatment options were discussed

    (discharged-platelet ct 44k)


History of present illness2

HISTORY OF PRESENT ILLNESS

  • 3 weeks PTAintermittent fever (390C),body malaise, nose bleeding

    Consult:WBC 1860,

    PLT 10k

    Tx: Co-amoxyclav 625mg TID x7d, tranexamic acid 500mg TIDGCSF 300mcg


History of present illness3

HISTORY OF PRESENT ILLNESS

  • 3 weeks PTAgeneralized petechial rashes & gum bleeding and was admitted

  • 2nd admissionCBC- pancytopenia Tx: blood & PC transfusions


Cbc on second admission

CBC on SECOND ADMISSION


History of present illness4

HISTORY OF PRESENT ILLNESS

  • 2nd admissionInitially given Cefepime 1gm Q12


History of present illness5

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


Medical grandrounds

Hip & Thigh pain

Compartment syndrome

Avascular necrosis

neuropathy

infection

fracture


Neuropathy

NEUROPATHY

  • Severe intractable pain

  • Unusual burning, tingling or shock-like quality

  • Triggered by light touch

  • Sensory deficit on area of pain


Medical grandrounds

Hip & Thigh pain

Compartment syndrome

Avascular necrosis

neuropathy

infection

fracture


Compartment syndrome

COMPARTMENT SYNDROME

  • Pain

  • Parasthesia

  • Pulselessness

  • Pallor

  • pressure


Medical grandrounds

Hip & Thigh pain

Compartment syndrome

Avascular necrosis

neuropathy

infection

fracture


History of present illness6

HISTORY OF PRESENT ILLNESS

  • 2nd admissionPelvis and Right hip xray: no pathologic finding


Medical grandrounds

Hip & Thigh pain

Compartment syndrome

Avascular necrosis

neuropathy

infection

fracture


History of present illness7

HISTORY OF PRESENT ILLNESS

  • 2nd admissionBlood CS: Salmonella enteritidis Grp C

    Sensitive: CeftriaxoneChloramphenicolCiprofloxacin

    shifted to Ciprofloxacin 500mg/tab, 1 tab BID


History of present illness8

HISTORY OF PRESENT ILLNESS

  • 2nd admissionDx: Aplastic anemia

    Salmonella nontyphi bacteremia

    Advised treatment w/ Anti-thymocyte globulin / cyclosporine


History of present illness9

HISTORY OF PRESENT ILLNESS

  • 2nd admissionTHM:Ciprofloxacin 500mg/tab, 1 tab BID to complete 7 days

    Prednisone 30mg BID,

    Tranexamic acid & Omeprazole


History of present illness10

HISTORY OF PRESENT ILLNESS

  • Since dischargeepisodes of fever & progression R hip & thigh pain on movement & palpation

    unable to stand

    admitted 3rd time


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

REVIEW OF SYSTEMS


Past medical history

PAST MEDICAL HISTORY

  • Non-hypertensive

  • Non-diabetic

  • No known allergies


Family history

FAMILY HISTORY

  • No hypertension

  • No diabetes

  • No asthma

  • No blood dyscrasias

  • No cancer


Personal and social history

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


Physical examination

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


Physical examination1

PHYSICAL EXAMINATION

  • Chest/Lungs: Symmetrical chest expansion, no retractions, clear breath sounds

    Adynamic precordium, tachycardic with regular rhythm, no murmurs


Physical examination2

PHYSICAL EXAMINATION

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

    no splenomegaly


Physical examination3

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


Salient features

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


Medical grandrounds

Hip & Thigh pain

Compartment syndrome

Avascular necrosis

neuropathy

infection

fracture


Avascular necrosis

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


Avascular necrosis1

AVASCULAR NECROSIS

  • Most studies have found that the risk is low (< 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.


Medical grandrounds

Hip & Thigh pain

Compartment syndrome

Avascular necrosis

neuropathy

infection

fracture


Medical grandrounds

  • 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).


Impression

IMPRESSION

  • Aplastic anemia

  • Salmonella non-typhi bacteremia with secondary myositis

  • r/o Avascular necrosis, osteomyelitis


Course in the wards

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


Labs april 12 2008

LABS APRIL 12, 2008

CXR- normal


Medical grandrounds

Piperacillin-tazobactam

Febrile


Course in the wards1

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.


Course in the wards2

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


Course in the wards3

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.


Course in the wards4

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


Medical grandrounds

CP & CT

PT

Febrile


Course in the wards5

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


Medical grandrounds

CP+CT

CP

PT

CT

dexa

Febrile


Course in the wards6

COURSE IN THE WARDS

  • 13th HD

    • Afebrile

    • pain decreased

    • Dexamethasone was tapered to 4mg/tab bid.


Course in the wards7

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)


Medical grandrounds

PT

CP

dexa

ATG

Cyclo

Febrile


Course in the wards8

COURSE IN THE WARDS

  • 21st HD

    • patient was afebrile, Piperacillin-tazobactam was discontinued


Medical grandrounds

PT

CP

PT

Febrile

ATG

Cyclo

ATG


Course in the wards9

COURSE IN THE WARDS

  • 38th HD

    • fever recurred

    • Increased severity of R thigh pain

    • Blood CS: negative after 5 days

    • CBC still showed pancytopenia.


Medical grandrounds

CP

Febrile

Cyclo


Course in the wards10

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


Medical grandrounds

CP

PT

Febrile

Cyclo


Course in the wards11

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


Medical grandrounds

BMA

ATG

Cyclo

CP

Febrile


Medical grandrounds

BMA

ATG

Cyclo


Medical grandrounds

ATG

Cyclo


Course in the wards12

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


Medical grandrounds

CP

Febrile

Cyclo


Course in the wards13

COURSE IN THE WARDS

  • 53rd HD

    • sent home

    • afebrile

      • medications:

        • Tranexamic acid, Cyclosporine 100mg BID, ciprofloxacin 500mg BID


Final diagnosis

FINAL DIAGNOSIS

  • Aplastic anemia

  • Salmonella enteritides myositis

  • Avascular necrosis, femoral head


Discussion

DISCUSSION


Salmonella microbiology

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


Non typhoidal salmonella epidemiology

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%


Non typhoidal salmonella epidemiology host factors

NON-TYPHOIDAL SALMONELLA: EPIDEMIOLOGY - HOST FACTORS

Impaired cell-mediated immunity

  • AIDS

  • Corticosteroid use

  • Malignancy

    Impaired phagocytic function

  • Hemoglobinopathies

  • Chronic granulomatous disease

  • Schistosomiasis

  • Histoplasmosis

  • Malaria


Non typhoidal salmonella epidemiology host factors1

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


Non typhoidal salmonella epidemiology1

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


Non typhoidal salmonella epidemiology2

NON-TYPHOIDAL SALMONELLA: EPIDEMIOLOGY


Non typhoidal salmonella pathogenesis

NON-TYPHOIDAL SALMONELLA: PATHOGENESIS

  • Ingestion from contaminated food/water

    • Infectious dose: 103-106 CFU

  • Gastric acidity is the initial barrier

  • Bacteria mediated endocytosis


Non typhoidal salmonella pathogenesis1

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


Non typhi salmonella clinical manifestations

NON-TYPHI SALMONELLA CLINICAL MANIFESTATIONS

  • Gastroenteritis

  • Bacteremia and vascular infection

  • Localized infection

  • Chronic carrier state

  • Clinically useful, have no pathogenic nor prognostic significance


Non typhi salmonella bacteremia and vascular infections

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 > 50

    • Aorta

    • Venous septic thrombophlebitis


Non typhi salmonella localized infection

NON-TYPHI SALMONELLA : LOCALIZED INFECTION

  • Occurs in 5-10% of patients with NTS bacteremia


Non typhi salmonella localized infection1

NON-TYPHI SALMONELLA : LOCALIZED INFECTION


Non typhi salmonella localized infection2

NON-TYPHI SALMONELLA : LOCALIZED INFECTION


Non typhi salmonella special populations

NON-TYPHI SALMONELLA SPECIAL POPULATIONS

  • Immunosuppression

  • Biliary and urinary tract abnormalities

  • Hemoglobinopathies

  • Malaria

  • Schistosomiasis

  • Histoplasmosis

  • AIDS


Non typhi salmonellosis treatment

NON-TYPHI SALMONELLOSIS TREATMENT

  • Neonates, >50 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


Salmonella non typhi bacteremia treatment

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


Salmonella non typhi localized infection treatment

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


Salmonella antimicrobial resistance

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


Salmonella antimicrobial resistance1

SALMONELLA: ANTIMICROBIAL RESISTANCE

  • Increase in ceftriaxone and fluoroquinolone resistant nontyphoidal Salmonella


Salmonella prevention and control

SALMONELLA: PREVENTION AND CONTROL

  • Hand washing

  • Safe drinking water and effective sewage treatment

  • Improved food safety practices

  • Good personal hygiene

  • Prudent antimicrobial use


Treatment of aplastic anemia

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


Treatment of aplastic anemia immunosuppressive therapy

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; 85:3058.


Medical grandrounds

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


Thank you

THANK YOU!


Medical grandrounds

CBC


Medical grandrounds

CBC


Treatment of aplastic anemia immunosuppressive therapy1

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; 85:3058.


Treatment of aplastic anemia immunosuppressive therapy2

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; 85:3058.


Treatment of aplastic anemia immunosuppressive therapy3

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; 85:3058.


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