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/maleDifficulty of breathing

Admitted1 week PTA

2 days PTA

1 day PTA

Few hours PTA Cough self-medicated w/unrecalled antibiotics

Colds, watery nasal discharge

Productive coughFever T=39C

OPD HSP consult, given Paracetamol, Levofloxacin 750mg ODDOB ER

General: (-) weakness, (-) weight changes, (-) night sweats, (-) fever, (-) syncopeSkin: (-) pruritus, (-) rashes, (-) easy bruising, (-) telangestasia, (-) spiderangiomatasHEENT: (-) headache, (-) dizziness, (-) BOV, (-) eye redness, (-) epistaxis, (-) deafness, (-) ear discharge, (-) bleeding gums, (-) oral sores, (-) hoarseness, (-) neck pain, (-) limitation of motion

Respiratory: (-) hemoptysis, (-) PNDCardiovascular: (-) chest pain, (-) palpitations, (-) orthopnea, (-) paroxysmal nocturnal dyspneaGastrointestinal: (-) dysphagia, (+) early satiety, (-) jaundice, (-) nausea, (-) vomiting, (-) hematemesis, (-) constipation, (-) diarrhea

Genitourinary: (-) polyuria, (-) hematuria, (-) nocturia, (-) oliguria, (-) dysuriaExtremities: (-) joint pains, (-) swellingNeurologic: (-) seizures, (-) tremors, (-) involuntary movementsHematologic: (-) dizziness, (-) bleeding, (-) easy bruisingEndocrinologic: (-) occasional excessive sweating, (-) polyphagia, (-) polyuria, (-) polydipsia

Chronic Lymphocytic Leukemia(B-Cell)-2007On intermittent oral chemotherapy with Chlorambucil, Prednisone, Folic Acid, and MultivitaminsHypertension x 5yearsOn Amlodipine 10mg tab OD Metoprolol 100mg ODUsual BP: 120/90; highest BP140/90No known allergies; no previous surgeries

Hypertension- mother

SOCIAL HISTORY20 pack year smokerOccasional alcoholic beverage drinker

Conscious, coherentBP= 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 thrushEqual chest expansion, no retractions, bibasal crackles, no wheezes

Adynamic precordium, normal rate, regular rhythm, distinct S1 and S2, no appreciated murmursFlabby abdomen, soft abdomen, normoactive bowel sounds, no tenderness, no splenomegalyNo gross deformities of the extremities, pulses full and equal, no cyanosis, no edema

71/maleDyspneaFeverProductive coughKnown case of Chronic Lymphocytic Leukemia ~3years

TachypneaPale palpebral conjunctivaeBibasal rales

Community Acquired Pneumonia in an Immunocompromised HostChronic Lymphocytic LeukemiaHypertensive Atherosclerotic Cardiovascular Disease

Immunocompromised host

Alteration in phagocytic, cellular, or humoral immunityIncreased 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 DefectDisorders or TherapyAssociated With DefectLikely PathogensDefective PMNsNeutropeniaAcute leukemia, aplastic anemia,cancer chemotherapyGram-negative bacteria,Staphylococcus aureus,Aspergillus sp, Candida spDefective chemotaxisDiabetes mellitusS. aureus, gram-negativeaerobesDefective intracellularkillingChronic granulomatous diseaseS. aureus

Defective alternativepathwaySickle cell diseaseStreptococcus pneumoniae,Haemophilus influenzaeC5 deficiencyCongenital disorderS. pneumoniae, S. aureus,gram-negative bacteriaCell-mediated immunodeficiency(T-cell deficiency ordysfunction)Hodgkin lymphoma, cancerchemotherapy, corticosteroidtherapyMycobacteria, viruses(herpes simplex virus,cytomegalovirus),Strongyloides sp, opportunisticfungi (Aspergillus, Mucor,Cryptococcus spp),Nocardia sp, Toxoplasma sp

AIDSPneumocystis jiroveci,Toxoplasma sp,cytomegalovirus, herpes simplexvirus, opportunisticfungi (Aspergillus, Mucor,Cryptococcus spp), mycobacteriaHumoralImmunodeficiency(B-cell deficiency ordysfunction)Multiple myeloma,AgammaglobulinemiaS. pneumoniae, H. influenzae,Neisseria meningitidisSelective deficiency: IgA, IgG,IgMS. pneumoniae, H. influenzaeHypogammaglobulinemiaP. 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

StageClinical FeaturesMedianSurvival,Years

RAI System0: Low risk Lymphocytosis only in blood and marrow >10

I: IntermediateriskLymphocytosis + lymphadenopathy +splenomegaly hepatomegaly7IIIII: High risk Lymphocytosis + anemia 1.5IVLymphocytosis + thrombocytopenia

STAGING OF TYPICAL B CELL LYMPHOID LEUKEMIA

StageClinical FeaturesMedianSurvival,YearsBinet SystemAFewer than three areas of clinicallymphadenopathy; no anemia orThrombocytopenia>10BThree or more involved node areas; noanemia or thrombocytopenia7CHemoglobin

Inherent Immune Defects in patients with Chronic Lymphocytic Leukemia

HypogammaglobulinemiaInhibition in B-cell proliferationCell-mediated immune defectsFunctional abnormalities of T-lymphocytes, nonclonal CD5 B lymphocytesAbnormalities 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 bindingNeutrophil defectsDefects in neutrophil function (phagocytic, bactericidal activity, chemotaxis)Reduced absolute neutrophil countMonocyte defects (deficiencies in -glucuronidase, lysozyme,myeloperoxidase)Potential mucosal immune defects

Chills, bibasal ralesECG: sinus tachycardiaHypotensive episode

Admitted under ID serviceOxygen at 4 LPMReferred to: nephrology, cardiology, hematology servicesdopamine drip-5mcg (200mg/100ml)

Hgb7.9Hct23.4WBC100.16Segmenters3Lymphocytes92Prolymphocytes2Monocytes3Platelets175kANC3004.8

CXR (3/30) cardiomegaly with pulmonary congestion

Infectious DiseaseBlood gs/cs, sputum gs/cs, urine gs/cs, urinalysisPiperacillin-Tazobactam 2.25g IV q8 hoursCardiology2D ECHO, specM, Trop I/T, D dimer

HematologyPrepare 2u pRBCStart Chlorambucil 2mg tab TIDNephrologyABGs, Na, K, crea, Mg, CaFor central line insertionFurosemide 40mg 2tabs BIDLimit OFI 1-1.5L/day

Na129K3.4Bun23.83Creatinine2.57Trop I0Trop T0D dimer1264.31Calcium7.9Magnesium1.82

ABGO2 AT 2LPMpO280pH7.5pCO233.9HCO326.202 SAT96.8B.E.+ 3.6TCO227.3

S> no complaints, comfortable at o2 of 2 LPM; post 1 unit PRBCO> BP90-110/60-70 on dopamine drip, HR=95-110, crackles mid-base L>R, T=38.2C I&O=1275 vs 1400

Hgb9.2Hct25.5WBC35.47Promyelocyte1Segmenters4Lymphocytes94Basophils1Platelets130kANC1418.8

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 relaxationBlood, urine, sputum CS: no growth x 24hrsUA: normal

Piperacillin Tazobactam day1

Infections

Hematologic abnormalities: anemia (autoimmune hemolytic anemia)pure red cell aplasiathrombocytopenia

Richter Syndrome or Richter transformationrefers 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 RituximabChlorambucil 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 infectionSingle-agent alkylator therapy (+/- corticosteroids)Common bacterial pathogens (streptococcal/staphylococcal spp., enteric Gram-negative organisms)Purine analogsCandida, Aspergillus, Herpesviruses, PneumocystisMonoclonal AntibodiesRituximabNo definitive change in spectrum of infectionAlemtuzumabHerpesvirus, including cytomegalovirus, Candida, Aspergillus, Pneumocystis

S> awake, conversant, no febrile episodes, D2 piperacillin-tazobactamO> 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 hoursUrine & Sputum CS: no growth x 48hrs

Hgb11.1Hct30.5WBC47.62Segmenters13Lymphocytes86Prolymphocytes1Platelets139kANC6190.6

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 hoursStarted Metronidazole 500mg PO q8 hoursFurosemide decreased to 80mg PO q24 hoursPatient 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 improvinghemodynamically 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 costsAnother 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 cureKuper, K. Intravenous to Oral Therapy Conversion. Competence Assessment Tools for Health-System Pharmacies 4th Ed. 2008:347.

S> awake, coherent, feverO> Tmax=38.3C BP90-120/60-70 on dopamine, HR=90-120, Total I&O 2565 vs 3400UA: normalRepeat blood CS taken

Furosemide heldParacetamol as needed for feverCefepime 1gram q24 hrs

CXR (4/3) taken in poor inspiratory effort, increase in left lower lung infiltrates

S> denied chest pain, dobO> 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 hoursABG taken

Hgb11.3Hct32.3WBC77.72Segmenters12Lymphocytes86Monocytes2Platelets140kANC9326.4

Shifted to MVM 0.50Pulmonary referralImp: Pneumonia in the immunocompromised, T/C COPD, R/O Pulmonary EmbolismStarted Acetylcysteine, Ipratropium, Enoxaparin 40mg SQ OD, Doxofylline

ABG02 at 5 LPMpO251.6pH7.51pCO232.7HCO325.6O2 sat90B.E.+3.1TCO226.6

S>(0850H) dyspneicO> BP90-100/60-80 on dopamine, HR=105-150, 02sat=84-88%, crackles L>R

MVM shifted to in-line neb 70%

Na135K4.3Crea1.7

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

ABGAC mode 100%pO268.3pH7.42pCO237.1HCO323.8O2 sat94.2B.E.-0.2TCO225

ABGO2 at 6LPMpO250.0pH7.48pCO236.6HCO326.9O2 sat88.1B.E.+3.7

S> (1600H) drowsy-stuporousO> BP 88/60, HR=145, narrow QRS tachycardia at 145bpm

Meropenem started 500mg IV ODBlood and tracheal aspirate CS Femoral line inserted, initial cvp=8Hydrocortisone 50mg IV TID, furosemide 40mg IV TID

S> awake, febrileO> 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 dripReferred to neurology serviceImp: T/C ICH, left with herniation

(2200H): S> comatoseO> BP60 palpatory on Dopamine and Norepinephrine, HR=110s, 02sat=85% at AC mode100%DNR form signed(2238H): ExpiredBlood CS: candida albicans

Cardiopulmonary Arrest secondary to Septic Shock secondary to Severe Pneumonia with Candidemia in an immunocompromised host Transfusion related acute lung injuryChronic Lymphocytic Leukemia

ELDERLY PatientsCLL PatientsAssociated co-morbidsAgeLoss of functional activity

Mortality: 16-40%Inherent immune defectsOther complications ie anemiaImmunosuppressionHypercoagulability

Mortality: 40%

Most common cause of invasive fungal infections in humans, producing infections that range from nonlife-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 candidiasisFluconazole (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 CLLIn a non randomized study, the majority of patients had significantly lower rates of serious bacterial infectionsIVIg 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 personsLederman, 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

CLASSICDELAYEDTIME of ONSETWithin 2-6hrs6-72 hoursRATE OF DEVTRapidOver several hoursSETTINGOutside ICUICU patientCOFACTORSNoneSepsis, trauma, burnsPATHOPHYSIOAntineutrophil antibodiesBioactive mediatorsINCIDENCERelatively uncommonCommonCOURSEUsually resolves in 48-96 hoursResolves slowlyRESOLUTIONCompleteMay progress to fibroproliferative ARDSMORTALITY5-1035-45

Although the exact mechanism of TRALI is not known, there is increasing evidence that this reaction can be triggered by 2 distinct mechanismsThe 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 componentThe 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, MDTarcela Gler, MDGregorio Ocampo, MDReynato Kasilag, MDJose Mari Anson, MDCarla Chuatico, MDJesus Relos, MD

Faye Salindong, MDMench Echiverri, MDChristian Estanislao, MDPaul Quetua, MD2245 family

Diagnosis often difficult to obtain and is frequently missedMortality in untreated PE is approximately 30%, but with adequate (anticoagulant) treatment, this can be reduced to 28%.Common causes of illness and death after surgery, injury, childbirth and in a variety of medical conditionsNevertheless numerous cases go unrecognized and hence untreated, with serious outcomes

Prevalence of PE at autopsy (approximately 1215% in hospitalized patients) has not changed over three decadesAs 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/L) and bone marrow (< 30% lymphocytes, no nodules) and recovery of hemoglobin, neutrophil and platelet counts

Physical examination NormalSymptoms NoneLymphocytes 4x109/LNeutrophils 1.5x109/LPlatelets > 100x109/LHemoglobin >11g/dL (untransfused)Bone marrow< 30%; no nodules lymphocytes

Immunocompromised host- immune system is impaired by disease or treatment due to disease which causes.*This table just shows the likely pathogens causing pneumonia in immunocompromised patients. Our patient whose on cancer chemotherapy, the most likely pathogens for his pneumonia would be*Characterized by the accumulation of small, mature-appearing B lymphocytes in the blood, bone marrow, lymph nodes, or other lymphoid tissue.Progressive immunodeficiency characterized by defects in humoral and cell-mediated immunity is a defining feature in the majority of patients with CLL. Defects in immune function manifests as an increased likelihood of developing infections, particularly bacterial infections of the respiratory tract, skin, or urinary tract.*This table lists the known inherent immune defects in CLL patients. Disease-related defects include hypogammaglobulinemia, as well as pertubations in cell-mediated immunity, complement activity, and neutrophil function. Hypogammaglobulinemia which occurs in virtually all patients will CLL, may be profound and correlates with disease duration and stage. *In literature, noted complications of CLL are increased likelihood of developing.Richter syndrome or Richter transformation refers to the transformation of CLL into an aggressive large B-cell lymphoma and is seen in ~3-10% of cases. Patients will often present with symptoms of weight loss, fevers, night sweats, muscle wasting, and increasing hepatosplenomegaly and lymphadenopathy. Lymph node biopsy is necessary for the diagnosis. Epstein-Barr virus (EBV) may play a role in transformation. Immunosuppression has also been implicated.

*In patients with CLL, infection is the.*For decades, chlorambucil, given alone or with corticosteroids, was the mainstay of therapy for CLL. In these pxs, the majority of infections are bacterial in origin, caused by common organisms such as s. aureus, s. pneumoniae, h. influenzae, e. coli, k. pneumoniae, and p. aeruginosa. Recurrent infections are also commonplace, as are infections originating at mucosal sites. The respiratory tract is, and remains, the most common site of infection in these patients. In contrast, fungal and viral infections occur much less frequently in chlorambucil-treated patients, generally occuring in the setting of therapy-related neutropenia in advanced stage disease patients.*no change in left lower lung infiltrates, heart is not enlarged

*How can response to initial therapy be assessed? 1. Temp, rr, hr, bp, sensorium, 02 sat, inspired 02 concentration should be monitored to assess response to therapy. 2. Response to therapy is expected w/in 24-72hrs of initiating tx. Failure to improve after 72 hours of treatment is an indication to repeat cxr (grade A). 3. follow-up cultures of blood and sputum are not indicated for patients who are responding to treatment.*Indications for streamlining of antibiotic therapy: 1. Resolution of fever for >24hr 2. Less cough & resolution of respiratory distress (Normal RR) 3. Improving WBC, no bacteremia 4. Etio agent is not a high-risk (virulent/resistant) pathogen eg Legionella, S. aureus, or gram neg enteric bacilli 5. no unstable co-morbid condition or life-threatening complication such as MI, CHF, complete heart block, new AF, SVT, etc 6. No sign of organ dysfunction such as HPoN, acute mental changes, bun to crea ratio of >10:1, hypoxemia, and metabolic acidosis 7. patient is clinically hydrated, taking oral fluids and is able to take oral medications*Sequential therapy refers to the act of replacing a parenteral version of a medication with its oral counterpart. An example is the conversion of famotidine 20 mg IV to famotidine 20 mg PO. There are many classes of medications that have oral dosage forms that are therapeutically equivalent to the parenteral form of the same medication.2. Switch therapy is used to describe a conversion from an IV medication to the PO equivalent that may be within the same class and have the level of potency, but is a different compound. An example is the conversion of IV pantoprazole to rapidly dissolving lansoprazoletablets or omeprazole capsules.3. Step-down therapy refers to converting from an injectable medication to an oral agent in another class or to a different medication within the same class where the frequency, dose, and the spectrum of activity (in the case of antibiotics) may not be exactly the same.Converting from ampicillin/sulbactam 3 g IV q 6 hr to amoxicillin/clavulanate 875 mg PO q12 hr is an example of step-down therapy.***Hypogammaglobulinemia is considered the most important factor in patient susceptibility to infection, and it is more common in patients with advanced disease and those with prolonged disease duration. The incidence of infection and the risk of re-infection can be correlated with serum levels of Ig. *Delayed TRALI is distinct from the classic TRALI although there is some overlap between the 2 syndromes, they differ considerably**