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

Admitted

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

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 HISTORYSOCIAL 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 TherapyAssociated With Defect

Likely Pathogens

Defective PMNs

Neutropenia Acute leukemia, aplastic anemia,cancer chemotherapy

Gram-negative bacteria,Staphylococcus aureus,Aspergillus sp, Candida sp

Defective chemotaxis Diabetes mellitus S. aureus, gram-negativeaerobes

Defective intracellularkilling

Chronic granulomatous disease

S. aureus

Defective alternativepathway

Sickle cell disease Streptococcus pneumoniae,Haemophilus influenzae

C5 deficiency Congenital disorder S. pneumoniae, S. aureus,gram-negative bacteria

Cell-mediated immunodeficiency

(T-cell deficiency ordysfunction)

Hodgkin lymphoma, cancerchemotherapy, corticosteroidtherapy

Mycobacteria, viruses(herpes simplex virus,cytomegalovirus),Strongyloides sp, opportunisticfungi (Aspergillus, Mucor,Cryptococcus spp),Nocardia sp, Toxoplasma sp

AIDS Pneumocystis jiroveci,Toxoplasma sp,cytomegalovirus, herpes simplexvirus, opportunisticfungi (Aspergillus, Mucor,Cryptococcus spp), mycobacteria

HumoralImmunodeficiency

(B-cell deficiency ordysfunction)

Multiple myeloma,Agammaglobulinemia

S. pneumoniae, H. influenzae,Neisseria meningitidis

Selective deficiency: IgA, IgG,IgM

S. pneumoniae, H. influenzae

Hypogammaglobulinemia

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 mature-appearing lymphocytes/uL

STAGING OF TYPICAL B CELL LYMPHOID LEUKEMIA

Stage Clinical Features Median

Survival,Years

RAI System

0: Low risk Lymphocytosis only in blood and marrow >10

I: Intermediaterisk

Lymphocytosis + lymphadenopathy +splenomegaly ± hepatomegaly

7

II

III: High risk Lymphocytosis + anemia 1.5

IV Lymphocytosis + thrombocytopenia

Stage Clinical Features MedianSurvival,Years

Binet System

A Fewer than three areas of clinicallymphadenopathy; no anemia orThrombocytopenia

>10

B Three or more involved node areas; noanemia or thrombocytopenia

7

C Hemoglobin </= 10 g/dL and/or platelets<100,000/μL

2

STAGING OF TYPICAL B CELL LYMPHOID LEUKEMIA

Inherent Immune Defects in patients with Chronic Lymphocytic Leukemia

HypogammaglobulinemiaInhibition in B-cell proliferationCell-mediated immune defects

Functional abnormalities of T-lymphocytes, nonclonal CD5– B lymphocytes

Abnormalities in T-cell subsets, with a decreased CD4/CD8 ratioExcessive T-suppressor and deficient T-helper cell functionDownregulated T-cell functionDefects in NK-cell, lymphocyte-activated killer cell activityReduced T-cell colony-forming capacityDefective antibody-dependent cytotoxicityDefective delayed hypersensitivity responses

Defects in complement activityReduction in complement component levelsDefects in complement activation and binding

Neutrophil defectsDefects 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

Admitted under ID service

Oxygen at 4 LPM Referred to:

nephrology, cardiology, hematology services

dopamine drip-5mcg (200mg/100ml)

Hgb 7.9

Hct 23.4

WBC 100.16

Segmenters 3

Lymphocytes 92

Prolymphocytes 2

Monocytes 3

Platelets 175k

ANC 3004.8

CXR (3/30) cardiomegaly with pulmonary congestion

Infectious Disease◦Blood gs/cs,

sputum gs/cs, urine gs/cs, urinalysis

◦Piperacillin-Tazobactam 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

1-1.5L/day

Na 129

K 3.4

Bun 23.83

Creatinine 2.57

Trop I 0

Trop T 0

D dimer 1264.31

Calcium 7.9

Magnesium 1.82

ABG O2 AT 2LPM

pO2 80

pH 7.5

pCO2 33.9

HCO3 26.2

02 SAT 96.8

B.E. + 3.6

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 piperacillin-tazobactam

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 broad-spectrum 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=90-120, 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

Blood CS: no growth x 24 hours

ABG taken

Hgb 11.3

Hct 32.3

WBC 77.72

Segmenters 12

Lymphocytes 86

Monocytes 2

Platelets 140k

ANC 9326.4

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

pCO2 37.1

HCO3 23.8

O2 sat 94.2

B.E. -0.2

TCO2 25

ABG O2 at 6LPM

pO2 50.0

pH 7.48

pCO2 36.6

HCO3 26.9

O2 sat 88.1

B.E. +3.7

S> (1600H) drowsy-stuporous

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

ELDERLY Patients CLL Patients

Associated co-morbids Age Loss of functional

activity

Mortality: 16-40%

Inherent immune defects

Other complications ie anemia

Immunosuppression Hypercoagulability

Mortality: 40%

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 uncommon

Common

COURSE Usually resolves in 48-96 hours

Resolves slowly

RESOLUTION Complete May progress to fibroproliferative ARDS

MORTALITY 5-10 35-45

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

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 Normal Symptoms None Lymphocytes 4x109/L Neutrophils ≤1.5x109/L Platelets > 100x109/L Hemoglobin >11g/dL

(untransfused) Bone marrow < 30%; no nodules lymphocytes