Download MORBIDITY and MORTALITY CONFERENCE

Anna M. Dapul, M.D.
Kathleen B. Miranda, M.D.
August 12, 2010



To present a case of pneumonia in a
Chronic Lymphocytic Leukemia
patient;
To discuss the infectious
complications in CLL patients
To discuss the syndrome of
Transfusion-related Acute Lung Injury
 E.B.
 71/male
 Difficulty
of breathing

1 week PTA 


2 days PTA 


1 day PTA 




Few hours PTA 

Cough self-medicated
w/unrecalled antibiotics
Colds, watery nasal
discharge
Productive cough
Fever T=39C
OPD HSP consult, given
Paracetamol,
Levofloxacin 750mg OD
DOB  ER
Admitted



General: (-) weakness, (-) weight changes,
(-) night sweats, (-) fever, (-) syncope
Skin: (-) pruritus, (-) rashes, (-) easy
bruising, (-) telangestasia, (-)
spiderangiomatas
HEENT: (-) headache, (-) dizziness, (-) BOV,
(-) eye redness, (-) epistaxis, (-) deafness,
(-) ear discharge, (-) bleeding gums, (-) oral
sores, (-) hoarseness, (-) neck pain, (-)
limitation of motion



Respiratory: (-) hemoptysis, (-) PND
Cardiovascular: (-) chest pain, (-)
palpitations, (-) orthopnea, (-) paroxysmal
nocturnal dyspnea
Gastrointestinal: (-) dysphagia, (+) early
satiety, (-) jaundice, (-) nausea, (-)
vomiting, (-) hematemesis, (-) constipation,
(-) diarrhea





Genitourinary: (-) polyuria, (-) hematuria, () nocturia, (-) oliguria, (-) dysuria
Extremities: (-) joint pains, (-) swelling
Neurologic: (-) seizures, (-) tremors, (-)
involuntary movements
Hematologic: (-) dizziness, (-) bleeding, (-)
easy bruising
Endocrinologic: (-) occasional excessive
sweating, (-) polyphagia, (-) polyuria, (-)
polydipsia
Chronic Lymphocytic Leukemia(B-Cell)2007
◦ On intermittent oral chemotherapy with
Chlorambucil, Prednisone, Folic Acid, and
Multivitamins
 Hypertension x 5years
◦ On Amlodipine 10mg tab OD
◦ Metoprolol 100mg OD
◦ Usual BP: 120/90; highest BP140/90
 No known allergies; no previous surgeries

Hypertension- mother
SOCIAL HISTORY


20 pack year smoker
Occasional alcoholic beverage drinker




Conscious, coherent
BP= 130/80 HR=107 RR=18 T=36.8C O2
SAT = 94% (room air)
Pale palpebral conjunctivae, anicteric sclera,
no tonsillopharyngeal congestion, no cervical
lymphadenopathy, no oral thrush
Equal chest expansion, no retractions,
bibasal crackles, no wheezes



Adynamic precordium, normal rate, regular
rhythm, distinct S1 and S2, no appreciated
murmurs
Flabby abdomen, soft abdomen, normoactive
bowel sounds, no tenderness, no
splenomegaly
No gross deformities of the extremities,
pulses full and equal, no cyanosis, no edema





71/male
Dyspnea
Fever
Productive cough
Known case of
Chronic Lymphocytic
Leukemia ~3years



Tachypnea
Pale palpebral
conjunctivae
Bibasal rales

Community Acquired Pneumonia in an
Immunocompromised Host
 Chronic Lymphocytic Leukemia
 Hypertensive Atherosclerotic
Cardiovascular Disease

Immunocompromised host
◦ Alteration in phagocytic, cellular, or humoral
immunity
◦ Increased risk for an infectious complication or an
opportunistic process (ie lymphoproliferative
disorder or cancer)
◦ Alteration or breach of skin or mucosal defense
barriers that permits microorganisms to cause
either a local or systemic infection (ie indwelling
catheters, burns)
Pizzo, P. Fever in Immunocompromised Patients.NEJM.1999;341: 893
Host Defect
Disorders or Therapy
Likely Pathogens
Associated With Defect
Defective PMNs
Neutropenia
Defective chemotaxis
Acute leukemia,
aplastic anemia,
cancer chemotherapy
Gram-negative
bacteria,
Diabetes mellitus
S. aureus, gramnegative
Staphylococcus
aureus,
Aspergillus sp,
Candida sp
aerobes
Defective intracellular
killing
Chronic
granulomatous
disease
S. aureus
Defective alternative
pathway
Sickle cell disease
Streptococcus
pneumoniae,
Haemophilus
influenzae
C5 deficiency
Congenital disorder
S. pneumoniae, S.
aureus,
gram-negative
bacteria
Cell-mediated
immunodeficiency
(T-cell deficiency or
dysfunction)
Hodgkin lymphoma,
cancer
chemotherapy,
corticosteroid
therapy
Mycobacteria, viruses
(herpes simplex virus,
cytomegalovirus),
Strongyloides sp,
opportunistic
fungi (Aspergillus,
Mucor,
Cryptococcus spp),
Nocardia sp,
Toxoplasma sp
AIDS
Pneumocystis jiroveci,
Toxoplasma sp,
cytomegalovirus,
herpes simplex
virus, opportunistic
fungi (Aspergillus,
Mucor,
Cryptococcus spp),
mycobacteria
Humoral
Immunodeficiency
(B-cell deficiency or
dysfunction)
Multiple myeloma,
Agammaglobulinemia
S. pneumoniae, H.
influenzae,
Neisseria meningitidis
Selective deficiency:
IgA, IgG,IgM
S. pneumoniae, H.
influenzae
Hypogammaglobuline
mia
P. jiroveci,
cytomegalovirus,
S. pneumoniae, H.
influenzae

Disease affecting neoplastic B cells

Mostly asymptomatic


Common symptoms: lymph node
enlargement, constitutional symptoms, bone
marrow failure
Mainly affects elderly (median age=72 yrs)

Clinical diagnosis: absolute lymphocytosis
with lower threshold of >5000 matureappearing lymphocytes/uL
STAGING OF TYPICAL B
CELL LYMPHOID LEUKEMIA
Stage
Clinical Features
Median
Survival,
Years
0: Low risk
Lymphocytosis only in blood and marrow
>10
I: Intermediate
risk
Lymphocytosis + lymphadenopathy +
splenomegaly ± hepatomegaly
7
III: High risk
Lymphocytosis + anemia
1.5
IV
Lymphocytosis + thrombocytopenia
RAI System
II
STAGING OF TYPICAL B
CELL LYMPHOID LEUKEMIA
Stage
Clinical Features
Median
Survival,
Years
A
Fewer than three areas of clinical
lymphadenopathy; no anemia or
Thrombocytopenia
>10
B
Three or more involved node areas; no
anemia or thrombocytopenia
7
C
Hemoglobin </= 10 g/dL and/or platelets
<100,000/μL
2
Binet System
Inherent Immune Defects in patients with Chronic
Lymphocytic Leukemia
Hypogammaglobulinemia
Inhibition in B-cell proliferation
Cell-mediated immune defects
Functional abnormalities of T-lymphocytes, nonclonal CD5–
B lymphocytes
Abnormalities in T-cell subsets, with a decreased CD4/CD8
ratio
Excessive T-suppressor and deficient T-helper cell function
Downregulated T-cell function
Defects in NK-cell, lymphocyte-activated killer cell activity
Reduced T-cell colony-forming capacity
Defective antibody-dependent cytotoxicity
Defective delayed hypersensitivity responses
Defects in complement activity
Reduction in complement component levels
Defects in complement activation and binding
Neutrophil defects
Defects in neutrophil function (phagocytic,
bactericidal activity, chemotaxis)
Reduced absolute neutrophil count
Monocyte defects (deficiencies in β-glucuronidase,
lysozyme,myeloperoxidase)
Potential mucosal immune defects



Chills, bibasal rales
ECG: sinus
tachycardia
Hypotensive episode
Hgb
7.9
Hct
23.4
WBC
100.16
Segmenters
3
Lymphocytes
92
Prolymphocytes
2
Monocytes
3
Platelets
175k
ANC
3004.8




Admitted under ID
service
Oxygen at 4 LPM
Referred to:
nephrology,
cardiology,
hematology services
dopamine drip5mcg
(200mg/100ml)
 CXR
(3/30)
cardiomegaly
with
pulmonary
congestion


Infectious Disease
◦ Blood gs/cs,
sputum gs/cs,
urine gs/cs,
urinalysis
◦ PiperacillinTazobactam 2.25g
IV q8 hours
Cardiology
◦ 2D ECHO, specM,
Trop I/T, D dimer


Hematology
◦ Prepare 2u pRBC
◦ Start Chlorambucil
2mg tab TID
Nephrology
◦ ABGs, Na, K, crea,
Mg, Ca
◦ For central line
insertion
◦ Furosemide 40mg
2tabs BID
◦ Limit OFI 11.5L/day
Na
129
K
3.4
Bun
23.83
Creatinine
2.57
Trop I
ABG
O2 AT 2LPM
pO2
80
pH
7.5
0
pCO2
33.9
Trop T
0
HCO3
26.2
D dimer
1264.31
02 SAT
96.8
Calcium
7.9
B.E.
+ 3.6
Magnesium
1.82
TCO2
27.3


S> no complaints,
comfortable at o2 of 2
LPM; post 1 unit PRBC
O> BP90-110/60-70
on dopamine drip,
HR=95-110, crackles
mid-base L>R,
T=38.2C
I&O=1275 vs 1400
Hgb
9.2
Hct
25.5
WBC
35.47
Promyelocyte
1
Segmenters
4
Lymphocytes
94
Basophils
1
Platelets
130k
ANC
1418.8

CXR (4/1)
clearing of
pulmonary
congestion,
hazy infiltrates
with some
cystic lucencies
in LLL probably
due to
pneumonia with
underlying
bronchiectasis



2D Echo: IVSH, NWMC,
EF=63%, mild MR,
reversed mitral E/A
ratio and prolonged
IVRT indicative of
decreased LV
relaxation
Blood, urine, sputum
CS: no growth x 24hrs
UA: normal

Piperacillin
Tazobactam – day1

Infections

Hematologic abnormalities:
◦ anemia (autoimmune hemolytic anemia)
◦ pure red cell aplasia
◦ thrombocytopenia

Richter Syndrome or Richter transformation
◦ refers to the transformation of CLL into an
aggressive large B-cell lymphoma

Leading cause of mortality in 25-50%

Pathogenesis of infection is multifactorial

Major risk factor: inherent immune defects
and therapy-related immunosuppression


Front-line treatment usually involves purine
analogue such as Fludarabine in combination
with Cyclophosphamide combined with
monoclonal antibodies such as Rituximab
Chlorambucil is considered standard
treatment for elderly patients due to easier
administration and less immunosuppression

Zenz, T et. al. Treatment of CLL in Older Patient. Medscape CME Oncology.2010
The Impact of Chronic Lymphocytic Leukemia
Therapy on the Spectrum of Infection
Type of treatment
Spectrum of infection
Single-agent alkylator therapy
(+/- corticosteroids)
Common bacterial pathogens
(streptococcal/staphylococcal
spp., enteric Gram-negative
organisms)
Purine analogs
Candida, Aspergillus,
Herpesviruses, Pneumocystis
Monoclonal Antibodies
Rituximab
No definitive change in spectrum
of infection
Alemtuzumab
Herpesvirus, including
cytomegalovirus, Candida,
Aspergillus, Pneumocystis


S> awake, conversant,
no febrile episodes, D2
piperacillintazobactam
O> BP90-110/60-70
HR=90-100, crackles
L>R, Total I&O= 4030
vs 3500 on furosemide
80mg bid

Blood CS: no growth x
48 hours
Urine & Sputum CS: no
growth x 48hrs
Hgb
11.1
Hct
30.5
WBC
47.62
Segmenters
13
Lymphocytes
86
Prolymphocytes
1
Platelets
139k
ANC
6190.6
 CXR
(4/2)
complete
clearing of
pulmonary
congestion,
rest of the
chest findings
are
unchanged




Piperacillin-Tazobactam shifted to
Levofloxacin 500mg PO x 1 dose then 250mg
PO q48 hours
Started Metronidazole 500mg PO q8 hours
Furosemide decreased to 80mg PO q24 hours
Patient referred back to prior hematologist

De-escalation of initial empiric broadspectrum antibiotic to oral agent based on
available laboratory data is recommended
once the patient is
◦ clinically improving
◦ hemodynamically stable
◦ functioning gastrointestinal tract

Community-Acquired Pneumonia Clinical Practice Guidelines 2010 Update


One study that specifically focused on
levofloxacin found proactive conversion to
the oral formulation reduced length of stay by
3.5 days and saved medication/supply costs
Another recent study documented that early
conversion from IV to PO therapy in CAP
decreased length of stay by almost 2 days,
while having no negative effects on mortality
or clinical cure

Kuper, K. Intravenous to Oral Therapy Conversion. Competence Assessment Tools for
Health-System Pharmacies 4th Ed. 2008:347.




S> awake, coherent,
fever
O> Tmax=38.3C
BP90-120/60-70 on
dopamine, HR=90120, Total I&O 2565 vs
3400
UA: normal
Repeat blood CS taken



Furosemide held
Paracetamol as needed
for fever
Cefepime 1gram q24
hrs
 CXR
(4/3)
taken in poor
inspiratory
effort,
increase in
left lower lung
infiltrates


S> denied chest pain,
dob
O> BP90-108/60-70
on dopamine,
HR=100-115,
Tmax=38.5C,
02sat=88% @ 4lpm
Total I&O= 2859 vs
2000
Hgb
11.3
Hct
32.3
WBC
77.72
Segmenters
12
Lymphocytes
86
Monocytes
2
Platelets
140k
ANC
9326.4


Blood CS: no growth x
24 hours
ABG taken
ABG
02 at 5 LPM
pO2
51.6

pH
7.51

pCO2
32.7

HCO3
25.6
O2 sat
90
B.E.
+3.1
TCO2
26.6

Shifted to MVM 0.50
Pulmonary referral
Imp: Pneumonia in the
immunocompromised,
T/C COPD, R/O
Pulmonary Embolism
Started Acetylcysteine,
Ipratropium,
Enoxaparin 40mg SQ
OD, Doxofylline


S>(0850H) dyspneic
O> BP90-100/60-80
on dopamine,
HR=105-150,
02sat=84-88%,
crackles L>R

MVM shifted to in-line
neb 70%
Na
135
K
4.3
Crea
1.7
 CXR
(4/5)
accentuation of
pulmonary
vasculature
consistent with
congestion,
increase
haziness in left
base


(1200H)Hydrocortisone
200mg Furosemide
120mg
In-line neb  BiPAP 
intubated

(1305H) sustained V.
tach  defibrillation
360J x3, amiodarone
drip
ABG
AC mode 100%
pO2
68.3
pH
7.42
ABG
O2 at 6LPM
pO2
50.0
pH
7.48
pCO2
37.1
pCO2
36.6
HCO3
23.8
HCO3
26.9
O2 sat
94.2
O2 sat
88.1
B.E.
-0.2
B.E.
+3.7
TCO2
25


S> (1600H) drowsystuporous
O> BP 88/60, HR=145,
narrow QRS
tachycardia at 145bpm




Meropenem started
500mg IV OD
Blood and tracheal
aspirate CS
Femoral line inserted,
initial cvp=8
Hydrocortisone 50mg
IV TID, furosemide
40mg IV TID


S> awake, febrile
O> BP 80-120/40-80
on Dopamine,
HR=130-140s on
Amiodarone drip,
Tmax=39.8C
02sat=93-95%
at AC mode 100%



(1705H): unresponsive,
GCS=3, pupils
anisocoric, BP 70/50,
HR=140s, CVP=5-6 
norepinephrine drip
Referred to neurology
service
Imp: T/C ICH, left with
herniation


(2200H): S> comatose
O> BP60 palpatory on
Dopamine and
Norepinephrine,
HR=110s, 02sat=85%
at AC mode100%



DNR form signed
(2238H): Expired
Blood CS: candida
albicans



Cardiopulmonary Arrest secondary to Septic
Shock secondary to Severe Pneumonia with
Candidemia in an immunocompromised host
Transfusion related acute lung injury
Chronic Lymphocytic Leukemia



Associated co-morbids
Age
Loss of functional
activity

Inherent immune
defects
Other complications ie
anemia
Immunosuppression
Hypercoagulability

Mortality: 40%




Mortality: 16-40%
ELDERLY Patients
CLL Patients

Most common cause of invasive fungal
infections in humans, producing infections
that range from non–life-threatening
mucocutaneous disorders to invasive disease
that can involve any organ
Clinical Practice Guidelines for the Management of Candidiasis:
2009 Update by the Infectious Diseases Society of America

Broad-spectrum antibacterial agents, use of
central venous catheters, receipt of parenteral
nutrition, receipt of renal replacement
therapy by patients in ICUs, neutropenia, use
of implantable prosthetic devices, and receipt
of immunosuppressive agents (including
glucocorticosteroids, chemotherapeutic
agents, and immunomodulators)
Clinical Practice Guidelines for the Management of Candidiasis:
2009 Update by the Infectious Diseases Society of America


Empirical therapy for suspected candidiasis in
nonneutropenic patients is similar to that for
proven candidiasis
Fluconazole (800-mg [12-mg/kg] loading
dose, then 400 mg [6 mg/kg] daily),
caspofungin (70-mg loading dose, then
50mg daily), anidulafungin (200-mg loading
dose, then 100 mg daily), or micafungin (100
mg daily) is recommended as initial therapy
(B-III)



CLL is one of the very few indications for
which IVIG has been approved by the FDA
IVIg is a fractionated blood product derived
from plasma and primarily contains IgG
It has been postulated that the risk of
infection should be reduced by parenteral
administration of normal Ig



It is one of the primary means of improving
immune function in patients with CLL
In a non randomized study, the majority of
patients had significantly lower rates of
serious bacterial infections
IVIg was also associated with significant
reductions in hospital admissions and febrile
episodes

Matutes, E. Management of Infectious Complications in Chronic Lymphocytic Leukemia.
Eur J of Clin and Med Onco. (2009)


There is no contraindication for use of either
pneumococcal or influenza vaccine on
immunocompromised patients
Vaccines that are not composed of live
viruses or bacteria are generally safe for
administration to immunocompromised
persons

Lederman, et al. Immunuzation of the Immunocompromised Host. Clin Focus on Primary
Immune Deficiencies.1998.(1):2

However, studies by Morrison stated that
immunization responses are suboptimal due
to impaired antibody production as well as
defects in antigen presentation

Morrison, V. Management of Infectious Complications in Patients with CLL. Am Soc
Hema.2007
TRALI is a clinical syndrome that is temporally
associated with transfusion of plasma
containing blood components, including
whole blood, PRBC, platelet, FFP,
cryoprecipitate and IVIG.
TRALI, whose incidence maybe 1 in 5000
transfusions has long been recognized as a
subtype of ARDS and there is a growing
appreciation that TRALI maybe
underrecognized and underreported
Zilberberg et al. Critical Care 2007,11:R63
CLASSIC
DELAYED
TIME of ONSET
Within 2-6hrs
6-72 hours
RATE OF DEVT
Rapid
Over several hours
SETTING
Outside ICU
ICU patient
COFACTORS
None
Sepsis, trauma,
burns
PATHOPHYSIO
Antineutrophil
antibodies
Bioactive mediators
INCIDENCE
Relatively
Common
uncommon
Usually resolves in Resolves slowly
48-96 hours
Complete
May progress to
fibroproliferative
ARDS
COURSE
RESOLUTION


Although the exact mechanism of TRALI is
not known, there is increasing evidence that
this reaction can be triggered by 2 distinct
mechanisms
The first suggests that TRALI is caused by
donor antibodies against human neutrophil
antigens or human leukocyte antigens in the
lungs of the recipient



The second implicates a 2 event model:
The first event is an inflammatory condition
of the patient causing sequestration and
priming of neutrophils in the pulmonary
component
The second event is the transfusion
containing either antibodies or bioactive
lipids that have accumulated during blood
storage stimulating the primed neutrophils to
release proteases

The result in both hypothesis is endothelial
damage, capillary leak, and extravasation of
neutrophils


It has a spectrum of clinical presentation,
however, pulmonary symptoms are always
present and can range in severity from mild
dyspnea to fulminant respiratory distress and
pulmonary failure
Pulmonary symptoms may be accompanied
by fever, chills, tachycardia, bilateral
pulmonary edema, hypoxemia, hypotension.

There is no specific treatment for TRALI. It is
based on the maintenance of the
hemodynamic balance of the patient and on
the necessity for the earliest possible
application of ventilatory support







Rosalio Torres, MD
Tarcela Gler, MD
Gregorio Ocampo,
MD
Reynato Kasilag,
MD
Jose Mari Anson,
MD
Carla Chuatico, MD
Jesus Relos, MD





Faye Salindong, MD
Mench Echiverri,
MD
Christian
Estanislao, MD
Paul Quetua, MD
2245 family




Diagnosis often difficult to obtain and is frequently
missed
Mortality in untreated PE is approximately 30%, but
with adequate (anticoagulant) treatment, this can
be reduced to 2–8%.
Common causes of illness and death after surgery,
injury, childbirth and in a variety of medical
conditions
Nevertheless numerous cases go unrecognized and
hence untreated, with serious outcomes


Prevalence of PE at autopsy (approximately
12–15% in hospitalized patients) has not
changed over three decades
As modern medicine improves the longevity
of patients with malignancy and cardiac and
respiratory disease, PE may become an even
more common clinical problem

Requires no evidence of disease on physical
examination or microscopic examination of
blood (ALC < 4000/μL) and bone marrow
(< 30% lymphocytes, no nodules) and
recovery of hemoglobin, neutrophil and
platelet counts







Physical examination
Symptoms
Lymphocytes
Neutrophils
Platelets
Hemoglobin
Bone marrow
lymphocytes
Normal
None
4x109/L
≤1.5x109/L
> 100x109/L
>11g/dL
(untransfused)
< 30%; no nodules