Transcript AUTOIMMUNE HEPATITIS

MEDICAL
GRANDROUNDS
SUWENDI, M.D.
Medicine Resident
January 11, 2007
Ledesma Hall
Makati Medical Center
OBJECTIVES



To present a case of infection in an
immunocompromised host
To be able to do a thorough evaluation of an
immunocompromised patient with persistent cough
To discuss the pathogenesis, clinical manifestations,
diagnosis and management of an
immunocompromised patient with Aspergillosis
GENERAL DATA
Z. C.
47 y/o, female
single
Filipino
business woman
CHIEF COMPLAINT
Pancytopenia
HISTORY OF PRESENT ILLNESS
6 months PTA
 pallor
 easy bruisability
 generalized
body weakness
HISTORY OF PRESENT ILLNESS
1 month PTA

consult with AMD
 blood transfusion done
 advised BMA
 UTZ abdomen:
slightly enlarged
Hb
spleen
Hct
ADMISSION
CBC
6.4
16.4
WBC
27550
Seg
26
Lymph
6
Mono
10
Platelet
10,000
REVIEW OF SYSTEMS
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
fever
cough/colds
weight loss
nausea/vomiting
difficulty of breathing
chest pain
urinary or bowel changes
hematochezia / melena
PAST MEDICAL HISTORY
(-) Hypertension
(-) Diabetes mellitus
(-) Bronchial asthma
(+) Hyperthyroidism (2003)
-no maintenance medications
(-) history of previous operations
(-) food / drug allergies
FAMILY MEDICAL HISTORY
(-) Hypertension
(-) Diabetes mellitus
(+) Chronic kidney disease & PTB –
father (deceased)
(-) Blood dyscrasias
PERSONAL / SOCIAL HISTORY

Non-alcoholic beverage drinker

Non-smoker

denies illicit drug use nor environmental
exposure to chemicals
PHYSICAL EXAMINATION

conscious, coherent, ambulatory

BP 110/70, CR 112 bpm, RR 22 cpm, Temp. 37.2 C

Good skin turgor, no jaundice, no petechial rashes

Pale palpebral conjunctivae, anicteric sclerae

Supple neck, no cervical lymphadenopathies
PHYSICAL EXAMINATION

Symmetrical chest expansion, no retractions, clear
breath sounds

Adynamic precordium, AB 5th LICS MCL,
tachycardic, regular rate and rhythm, no murmurs


Soft, flat abdomen,normoactive bowel
sounds, non tender, no hepatosplenomegaly
Extremities : no edema, no cyanosis,
pulses full and equal
NEUROLOGIC EXAMINATION





Intact memory
Pupils 2-3 mm equally reactive to light
Full extra ocular muscles
(-) Facial asymmetry
(-) tongue deviation
(-) Babinski
(-) Brudzinski
5
5
100% 100%
(-) nystagmus
5
5
100% 100%
SALIENT FEATURES




47 y.o., female
Pallor, easy bruisability & generalized
body weakness
Ultrasound finding: slightly enlarged
spleen
Pancytopenia on CBC
ADMITTING IMPRESSION
Pancytopenia
R/o blood dyscrasia
st
1
HOSPITAL DAY
CBC
Hb
6.7
Eos
1
Hct
21.9
Myelo
1
RBC
2.3
Metamyelo
3
WBC
50.482
Stabs
4
Seg/Neutro
19
Lymph
21
Mono
15
Blast
36
Pt count
20000
1st HOSPITAL DAY

Tranfused 2 unit of PRBC & 4 units of
platelet concentrate
nd
2
HOSPITAL DAY
Bone Marrow Aspiration Biopsy :
• myeloblastosis with minimal maturation
with predominantly dysplastic and
megaloblastic erythroid
2nd HOSPITAL DAY
Bone Marrow Aspiration Biopsy :
• The rest of the hematopoetic cells shows
unremarkable morphology:
lymp (5,18%) , mono(0.52%) , plasma cells
(0.52%), macrophages (1.55%) and
megakaryocytes (0.0%)
• Histopathological Diagnosis :
ACUTE MYELOGENOUS LEUKEMIA
4TH HOSPITAL DAY
•
•
•
•
(+) non-productive cough
(+) low grade fever
decreased breath sounds, RLF
Chest x-ray:
Pleural effusion (R)
R/O concomitant pneumonia
Cardiomegaly
• Levofloxacin 500 mg OD
• 2 u pRBC & 2 u platelet concentrate
CBC
Hb
6.6
Hct
21.60
WBC
12,809
Eos
2
Myelo
4
Metamyelo
1
Stabs
1
Seg
24
Lymph
15
Mono
4
Blast
48
Platelet
62000
FEVER PATTERN
37.7
37.6
37.5
37.4
37.3
37.2
37.1
37
36.9
Levofloxacin
36.8
HD
10
th
HD
9t
h
HD
8t
h
HD
7t
h
HD
6t
h
HD
5t
h
HD
4t
h
HD
3r
d
HD
2n
d
1s
t
HD
36.7
th
6
HOSPITAL DAY
Acute Myelogenous Leukemia
Chemotherapy started:
 Idarubicin 15 mg IV
every 24 hrs x 3 d (12mg/m2 x 1.5)

Cytarabine 150mg IV
every 12 hrs x 7 d (100mg/m2 x 1.5)
CBC
Hb
6.8
Hct
23.3
WBC
19598
Stabs
1
Seg
21
Lymph
15
Mono
2
Blast
61
Platelet
30000
Serial CBC monitoring
CBC
9th HD
12nd HD
Hb
6.6
6.6
Hct
21.7
21.3
WBC
1100
940
Eos
1
3
Seg
74
55
Lymph
21
40
Mono
4
2
25000
10000
814
517
Platelet
ANC
th
14



(+) episodes of diarrhea
On Day # 10 of Levofloxacin
Clostridium difficile toxin test : negative


HOSPITAL DAY
Loperamide
Started on Diflucan 200 mg po OD
Acyclovir 400 mg po TID
Serial CBC monitoring
CBC
16th HD
19th HD
Hb
7.2
8.7
Hct
22.4
26.6
WBC
620
320
Seg
8
5
27
44
Lymph
Mono
Platelet
ANC
1
30000
45000
50
16
TH
18
HOSPITAL DAY
• (+ low-grade fever (Tmax 37.8 C)
• (+) oral ulcers with mucositis
• D/C Levofloxacin
• Started on Piperacillin-tazobactam
4.5 gm IV q8h
CBC 19th HD
Hb
8.7
Hct
26.6
WBC
320
Seg
5
Lymph
Mono
Platelet
ANC
44
1
45,000
16
th
23
HOSPITAL DAY
Post Chemotherapy Bone Marrow Biopsy
Histopathological Diagnosis :
 Findings consistent with Post Chemotherapy
 No evidence of malignancy
31st HOSPITAL DAY
•
•
•
(+)febrile episodes, T max – 38.5 C
(+)occasional productive cough
CBC 31st HD
harsh breath sounds
Hb
8.5
Hct
26.5
 Blood cs done
WBC
390
•
D/C Pip tazo
Seg
Lymph
47
•
Started on
Mono
3
Cefepime 2 g IV q 12h
Platelet
50000
FEVER PATTERN
Temperature
39
38.5
38
37.5
37
36.5
Levofloxacin
Pip-Tazo
Cefepime
5t
hH
D
8t
hH
D
11
th
HD
14
th
HD
17
th
HD
20
th
HD
23
rd
H
26 D
th
HD
29
th
HD
32
nd
H
D
35
th
HD
38
th
HD
36
RD
33
HOSPITAL DAY
• afebrile, (+) persistent cough
• harsh breath sounds
- CXR :RUL pneumonia
• Blood CS – 1 out of 2 cultures
• (+) for oxacillin resistant,
coagulase negative staphylococci
• Sensitive to Vancomycin and Linezolid
• Cefepime continued Day # 2
• Vancomycin 1gm IV q 12h
CBC 33rd HD
Hb
10.9
Hct
33.4
WBC
920
Seg
31
Lymph
64
Mono
5
Platelet
ANC
30000
285
35TH HOSPITAL DAY
•
•
•
•
•
afebrile
(+)persistence of cough
(+)chest pain, right sided, pleuritic
Chest CT scan was also requested
D/C Vanco,Cefepime,
Diflucan & acyclovir
• Moxifloxacin 400 mg tab, 1 tab OD
CBC 35th HD
Hb
10.6
Hct
32.6
WBC
5040
Seg
73
Lymph
13
Mono
11
Platelet
ANC
56000
3679
th
HD
29
th
HD
30
th
HD
31
st
HD
32
nd
HD
33
rd
HD
34
th
HD
35
th
HD
36
th
HD
37
th
HD
38
th
HD
28
FEVER PATTERN
39
38.5
38
37.5
37
Cefepime
Moxifloxacin
36.5
Vancomycin
36
CHEST CT SCAN RESULT
• 2.8 x 2.4 cm. lobulated soft tissue mass density,
superior segment of the right lower lobe with
ground glass haziness, nodular infiltrates, and air
space consolidation with air bronchogram.
• Infectious vs. pulmonary new growth
 Aspergilloma (fungus-ball), superior segment of the
right lower lobe
TH
38
HOSPITAL DAY
CT - GUIDED LUNG BIOPSY
Smears show ciliated respiratory epithelial cells
mixed with abundant inflammatory cells
composed of lymphocytes, polymorphonuclears
and macrophages.The cellblock shows numerous
fungal spores & hyphae mixed with
inflammatory cells.
 Diagnosis: Cytomorphologic features consistent
with a FUNGAL INFECTION
th
38



HOSPITAL DAY
CHEST X RAY
No evidence of pneumothorax
Patient was discharged pending CT guided lung
aspirate culture results
THM: Moxifloxacin 400 mg OD x 3 more days
CT - GUIDED LUNG ASPIRATE :
Light growth of Aspergillus spp.
FOLLOW UP TREATMENT
Patient was started on
Voriconazole 200 mg BID
FOLLOW UP
CT SCAN
Blood Transfusion Summary
1st HD
4th HD
9th HD
12th HD
16th HD
19th HD
Hb
6.7
6.6
6.6
6.6
7.2
8.7
Ht
21.9
21.6
21.7
22.4
22.4
26.6
RBC
2.3
2.2
2.3
2.5
2.5
3.1
WBC
50482
19598
1100
940
620
320
Platelet
20000
30000
25000
10000
30000
45000
1 u PRBC
2u
platelet
pharesis
3 u PRBC
2u
platelet
pharesis
1 u PRBC
2 u PRBC
2 unit
platelet
pharesis
2 u PRBC
1 u PRBC
4 u platelet 2 u platelet
concentrate concentrate
Blood Transfusion Summary
22nd HD
26th HD
29th HD
31st HD
33rd HD
35th HD
Hb
8.7
10.7
9.6
8.5
10.9
10.6
Ht
27.5
34.3
30.5
26.5
33.4
32.6
RBC
3.1
3.8
3.5
3.0
3.9
3.8
WBC
590
670
510
390
920
5040
65000
70000
30000
50000
30000
56000
1 unit
platelet
pharesis
2 u PRBC
GCSF
1 unit
platelet
pharesis
Platelet
1 u pRBC
1 u platelet
pharesis
DISCUSSION
Immunocompromised Host

DEFINITION
These patients are defined by their susceptibility
to infection with organisms of low native
virulence for the immunologically normal hosts.
Immunocompromised Host
Spectrum of immunocompromised hosts has
expanded with prolonged survival of



solid organ and hematopoietic transplant recipients
congenital immune deficits and autoimmune disorders
epidemic of human immunodeficiency
syndrome/acquired immunodeficiency syndrome
(HIV/AIDS).
Immunocompromised Host

RISK FACTOR:
Immunosuppressive therapies create a
diverse set of immune deficits that create
the substrate for opportunistic infections.
Most Common Organisms in
Immunocompromised Host

Conventional bacteria
— 37%

Fungi —14 %

Viruses — 15 %

Pneumocystis
carinii/jiroveci — 8 %

Nocardia asteroides
—7%

Mycobacterium
tuberculosis — 1 %

Mixed infections - 20%
CHEMOTHERAPEUTIC AGENTS: EFFECT
ON PULMONARY HOST DEFENSE
CHEMOTHERAPY

NEUTROPENIA major dose-limiting side effect
-defined as an absolute neutrophil count of less than 1,500/µl
- risk of infection begins to increase at an absolute neutrophil
count below 1,000/µl.
 Decrease in the number of neutrophils - results in chemotactic and
phagocytic defects.
 Ladina
Joos and Michael Tamm. Breakdown of Pulmonary Host Defense in the
Immunocompromised Host. The Proceedings of the American Thoracic Society 2:445-448
(2005)
CHEMOTHERAPEUTIC AGENTS: EFFECT
ON PULMONARY HOST DEFENSE
Pulmonary infiltrates emerge in
15 to 25% of patients with profound
neutropenia after chemotherapy.
Approach to Immunocompromised
patients with Pulmonary Infiltrates
Pulmonary Fungal Infections
 a major problem in neutropenic patients


usually angioinvasive pulmonary aspergillosis
develop in patients with hematologic malignancies after
high-dose chemotherapy
The risk of developing invasive pulmonary aspergillosis is
directly related to the duration of the neutropenic
phase.

Ladina Joos and Michael Tamm. Breakdown of Pulmonary Host Defense in the
Immunocompromised Host. The Proceedings of the American Thoracic Society 2:445448 (2005)
Pulmonary Fungal Infections


“After intensive chemotherapy for hematologic
malignancies, the estimated risk of developing
invasive pulmonary aspergillosis is
about 5%, and the reported mortality ranges
from 30 to 80%.”
“The diagnostic yield of bronchoalveolar lavage
(BAL) to detect invasive pulmonary aspergillosis
is extremely low.”

Denning DW. Therapeutic outcome in invasive aspergillosis. Clin Infect
Dis 1996;23:608–615.
CLASSIFICATION OF ASPERGILLUS
INFECTION
ALLERGIC ASPERGILLOSIS
IN AN IMMUNOCOMPROMISED HOST
-Allergic bronchopulmonary aspergillosis
-1º Cutaneous or mucous mem. aspergillosis
-Allergic aspergillus sinusitis
- Pulmonary aspergillosis
SAPROPHYTIC ASPERGILLOSIS
- Airway aspergillosis
-Pulmonary aspergilloma
- Nasal or paranasal sinusitis
-Sinus aspergilloma
- ACUTE INVASIVE ASPERGILLOSIS
SUPERFICIAL ASPERGILLOSIS
-Otomycosis
-Onchomycosis
-Cutaneous aspergillosis
INVASIVE ASPERGILLOSIS
in the immunocompromised host
- acute, rapidly progressive, with densely
consolidated pulmonary infiltrate
- spread through direct extension across tissue
planes & by hematogenous dissemination to the
lungs, brain and other organs
PATHOGENESIS
Aspergillus conidia reaches the alveoli
high inoculum of fungi
 macrophage dysfunction
 Decreased macrophages
(post chemotherapy)

conidia germinates
forms hyphae
PATHOGENESIS


With the development of Aspergillus hyphae
 influx of neutrophils
 recruited neutrophils attaches & damages the hyphae
During hyphal growth, the fungus produces various
metabolites that help it evade host defenses.(i.e.
complement inhibitors, proteases, and several
mycotoxins, including gliotoxin and aflatoxin)
PATHOLOGY
-
progression of the infection across tissue planes

vascular invasion

subsequent infarction

tissue necrosis
INVASIVE PULMONARY
ASPERGILLOSIS
Dense right lower lobe consolidation, consistent
with invasive pulmonary aspergillosis
ASPERGILLOMA
 Vast majority of fungus balls in the lungs are due
to aspergillus, with rare cases caused by
Pseudoallescheria boydii or Mucorales
Clinical manifestations:
• asymptomatic
• some may present with persistent productive
cough, hemoptysis, wheezing, weight loss and
finger clubbing.
ASPERGILLOMA
• Complications:
mild or massive hemoptysis, spread of infection to the
pleura and contiguous vertebral bodies, dissemination to
distant body sites (rare)
• Approx. 10% resolve spontaneously
• Tx :
-Intracavitary Amphotericin B by transthoracic inj
-Oral itraconazole
-Surgical resection
-Embolization
ASPERGILLOMA
Aspergilloma or fungus ball on Chest CT scan
TREATMENT
TYPE OF DISEASE
PREFERRED TX
ALTERNATIVES
Fungus ball of the lung
surgical resection
bead embolization
Allergic bronchopul.
Short courses of
Itraconazole
aspergillosis
glucocorticoids
prophylaxis
Invasive aspergillosis
Voriconazole,
Amphotericin B,
(liposomal or
Itraconazole or
conventional)
Caspofungin
TREATMENT
3 classes of antifungal agents are available
for the treatment of Aspergillosis :
1. Polyenes (eg : Amphotericin B)
2. Azoles (eg : Itraconazole, Voriconazole)
3. Echinocandins (eg : Caspofungin)
TREATMENT
AMPHOTERICIN B



Treatment is limited by poor toleration &
nephrotoxicity
Dose : 1 – 1,5 mg / kg per day
Lipid formulation is currently available
which can be administered with larger
doses but showed fewer toxic effects
TREATMENT
CASPOFUNGIN


Is approved for the treatment of invasive
aspergillosis in pts who cannot tolerate or
who are refractory to standard therapy
Dose : IV :loading dose 70mg/day,
followed by 50 mg/day
TREATMENT
ITRACONAZOLE



Is considered a 2nd line agent for the tx of
aspergillosis and is rarely used in
immunocompromised pts with invasive
disease
Dose : 400 mg per day po
Require acid environment for absorption,
poor bioavailability and important drug
interaction
VORICONAZOLE
• A triazole that is structurally related to fluconazole. Its clinical use
was approved by FDA in May 2002. The trade name of
voriconazole is Vfend™.
• It was approved for primary treatment of acute invasive
aspergillosis and salvage therapy for rare but serious fungal
infections caused by the pathogens Scedosporium apiospermum
and Fusarium spp
VORICONAZOLE
- works principally by inhibition of cytochrome P450 14ademethylase (P45014DM).
- favorable in vitro activity against a variety of fungi. These
include, Candida spp., Aspergillus spp., Cryptococcus
neoformans, Blastomyces dermatitidis, Coccidioides immitis,
Histoplasma capsulatum, Fusarium spp., and Penicillium
marneffei.
- a fungistatic agent against Candida spp. and Cryptococcus
neoformans. It may be fungicidal against Aspergillus spp.
VORICONAZOLE
- active
Doses
following both oral and intravenous administrations
Oral: 200 mg twice daily
IV: 3 to 6 mg/kg every 12 h doses
SIDE EFFECTS: transient visual disturbances, skin rash and
elevated hepatic enzyme levels
TREATMENT
POSACONAZOLE


is a broad spectrum triazole that is
currently in development.
Its activity is similar to Voriconazole
against Aspergillus sp, but there is little
published to date on its efficacy
CLINICAL STUDIES
Voriconazole vs. Amphotericin B: Acute invasive
aspergillosis
National Institute of Allergy and Infectious Diseases Mycoses Study Group
June 2001
- 277 patients treated for 12 weeks with Voriconazole and
Amphotericin B
- majority of study patients had underlying hematologic
malignancies, including bone marrow transplantation; patients with
solid organ transplantation, solid tumors, and AIDS.
CONCLUSION: A satisfactory global response at 12 weeks was seen
in 53% of voriconazole treated patients compared to 32% of
amphotericin B treated patients. A benefit of voriconazole compared to
amphotericin B on patient survival at Day 84 was seen with a 71%
survival rate on voriconazole compared to 58% on amphotericin B.
CLINICAL STUDIES
Fluconazole and Voriconazole Multidisk Testing of Candida
Species for Disk Test Calibration and MIC Estimation
Göran Kronvall* and Inga Karlsson
Department of Microbiology and Tumor Biology, Sweden
January 2001
Fluconazole and voriconazole MICs were determined for 114 clinical
Candida isolates, including isolates of Candida albicans, Candida
glabrata, Candida krusei, Candida lusitaniae, Candida parapsilosis, and
Candida tropicalis. All strains were susceptible to voriconazole, and most
strains were also susceptible to fluconazole, with the exception of
C. glabrata and C. krusei, the latter being fully fluconazole resistant.
Single-strain regression analysis (SRA) was applied to 54 strains.
CONCLUSION: Voriconazole might be a first-choice azole in treating
Candida infections.
THANK YOU!