A stem cell transplant A stem cell transplant patient with cough and patient with cough and

SOB.SOB.

ID Case ConferenceID Case Conference

Wednesday September 26Wednesday September 26thth, , 20072007

David Fitzgerald, MDDavid Fitzgerald, MD

History of Present IllnessHistory of Present Illness

23 year old white male with h/o Hodgkin's disease s/p 23 year old white male with h/o Hodgkin's disease s/p allogenic matched sibling stem cell transplant 4/16/2007 allogenic matched sibling stem cell transplant 4/16/2007 complicated by cutaneous GVHD who is now admitted for complicated by cutaneous GVHD who is now admitted for acute SOB and hypoxia. acute SOB and hypoxia.

He was at his baseline state until a few days PTA when he He was at his baseline state until a few days PTA when he developed a non-productive cough and rhinitis. He became developed a non-productive cough and rhinitis. He became progressivly more SOB and was having increasing difficulty progressivly more SOB and was having increasing difficulty with ADLs due to DOE, with ADLs due to DOE,

Was referred by oncology for PFT evaluation on 9/3/07 – Was referred by oncology for PFT evaluation on 9/3/07 – this demonstrated markedly reduced FEV1, FVC and DLCO this demonstrated markedly reduced FEV1, FVC and DLCO with a pulse oximetry reading in the mid 80s on RA.with a pulse oximetry reading in the mid 80s on RA.

Patient was admitted to BM transplant unit for further Patient was admitted to BM transplant unit for further evaluation.evaluation.

HPIHPI

Cough is non-productive with no Cough is non-productive with no hemoptysis.hemoptysis.

Increasing fatigue over last 2 weeks.Increasing fatigue over last 2 weeks. He denies any fever, chills, NS, chest He denies any fever, chills, NS, chest

pain, leg swelling.pain, leg swelling. No unusual activity or exposureNo unusual activity or exposure Sick contacts – father with a “cold” Sick contacts – father with a “cold”

several weeks prior. No TB contacts.several weeks prior. No TB contacts.

PMHPMH

Hodgkin's disease - diagnosed in 2000 treated with Hodgkin's disease - diagnosed in 2000 treated with combined chemotherapy and XRT with prolonged combined chemotherapy and XRT with prolonged remission relapse in 2004. remission relapse in 2004. Relapsed and treated with salvage gemcitabine and Relapsed and treated with salvage gemcitabine and

vinorelbine and then autologous SCT.vinorelbine and then autologous SCT. Relapse again in 10/06 with mediastinal and neck disease Relapse again in 10/06 with mediastinal and neck disease

treated with etoposide and Ara-C + steroids. treated with etoposide and Ara-C + steroids. Allogenic matched sibling SCT in 4/07 – campath Allogenic matched sibling SCT in 4/07 – campath

conditioning and fludarabine, busulfanconditioning and fludarabine, busulfan History of glucose intolerance/diabetes mellitus History of glucose intolerance/diabetes mellitus

due to steroids due to steroids Skin GVHD Skin GVHD History of Klebsiella pneumoniae bacteremia/sepsis History of Klebsiella pneumoniae bacteremia/sepsis

Social HistorySocial History No tobacco, no No tobacco, no

EtOH, no drugs. EtOH, no drugs. Lives with father.Lives with father. No recent travel.No recent travel. No pets.No pets. Not sexually activeNot sexually active

Family HistoryFamily History Mother died of an Mother died of an

accident.accident. Father and sister Father and sister

are well.are well.

MedsMeds

Voriconazole 200 mg po BIDVoriconazole 200 mg po BID Septra DS once dailySeptra DS once daily Cellcept 1000 mg bidCellcept 1000 mg bid Prednisone 50 mg qdPrednisone 50 mg qd Prograf 1 mg BIDPrograf 1 mg BID Synthroid 100 mcg qdSynthroid 100 mcg qd

PhysicalPhysical

Tm 36.5 P 117 BP Tm 36.5 P 117 BP 108/81 R 18 Sat 108/81 R 18 Sat 100% ON 40 FiO2100% ON 40 FiO2

Chronically ill Chronically ill appearing with mild appearing with mild respiratory distressrespiratory distress

HEENT – Perrla, eomi, HEENT – Perrla, eomi, anicteric,anicteric,

OP without exudate or OP without exudate or lesionslesions

Neck suppleNeck supple No LANNo LAN

CV – tachy, but reg CV – tachy, but reg with no murmurwith no murmur

Lungs bibasilar Lungs bibasilar crackles R>Lcrackles R>L

Abd – soft, NT, ND, no Abd – soft, NT, ND, no HSMHSM

Skin – diffuse scaly Skin – diffuse scaly eruption on forearms eruption on forearms c/w GVHDc/w GVHD

Neuro – A+O x 3, Neuro – A+O x 3, grossly non-focalgrossly non-focal

DataData

WBC 5.1 ANC 4.9 Hgb WBC 5.1 ANC 4.9 Hgb 9.7 Plt 339.7 Plt 33

Basic panel WNLBasic panel WNL Bun/Cr 30/1.3Bun/Cr 30/1.3 T bili 0.6 T bili 0.6 AST 74 AST 74 ALT 108 ALT 108 Alk phos 342Alk phos 342 GGT 1716GGT 1716 LDH 3117LDH 3117 Alb 2.9Alb 2.9

BCx pendingBCx pending Ucx pendingUcx pending

ImagingImaging

ImagingImaging

CT readCT read

Numerous nodular groundglass Numerous nodular groundglass opacities scattered throughout all opacities scattered throughout all segments of the lungs. There are segments of the lungs. There are scattered foci of confluent ground scattered foci of confluent ground glass consolidation. There are no glass consolidation. There are no pleural effusions. pleural effusions.

Further testingFurther testing

Urine histo ag negativeUrine histo ag negative Serum crypto negativeSerum crypto negative Aspergillus Ag negativeAspergillus Ag negative Serum PCRSerum PCR

CMV <500 copies (repeat negative)CMV <500 copies (repeat negative) EBV negEBV neg Adeno negAdeno neg HHV6 negHHV6 neg Parvo negParvo neg

BronchBronch

Quant cx - < 10,000 organismQuant cx - < 10,000 organism PCP DFA negPCP DFA neg Bacterial Culture negBacterial Culture neg AFB cx negativeAFB cx negative Fungal cx negativeFungal cx negative

PCR on BALPCR on BAL HSV ½ negHSV ½ neg CMV negCMV neg

DiagnosisDiagnosis

BAL viral culture positive forBAL viral culture positive for Parainfluenza virus type 3Parainfluenza virus type 3

Transbronchial biopsy results suggestive of DAD Transbronchial biopsy results suggestive of DAD with type II pneumocyte, hyperplasia, fibrin, with type II pneumocyte, hyperplasia, fibrin, hemorrhage, sparse acute inflammation and focal hemorrhage, sparse acute inflammation and focal edema.edema.- Bronchial wall shows essentially no inflammation, - Bronchial wall shows essentially no inflammation, making graft versus host disease unlikely.making graft versus host disease unlikely.- No fungal or AFB organisms seen by fungus or - No fungal or AFB organisms seen by fungus or AFB stains.AFB stains.

DiagnosisDiagnosis

Parainfluenza virus type 2 Parainfluenza virus type 2 pneumoniapneumonia

Parainfluenza virusParainfluenza virus

RNA virusRNA virus Family of ParamyxoviridaeFamily of Paramyxoviridae 5 types – 1, 2, 3, 4a, 4b5 types – 1, 2, 3, 4a, 4b

Initially described 1950s as cause of Initially described 1950s as cause of croup layrngotracheobronchitis in croup layrngotracheobronchitis in childrenchildren

Parainfluenza virusParainfluenza virus

Virus has a tropism for the respiratory Virus has a tropism for the respiratory tract, replicating only in cells of the tract, replicating only in cells of the respiratory epithelial layerrespiratory epithelial layer

Causes acute respiratory tract infectionsCauses acute respiratory tract infections Repeated infections occur thoughout lifeRepeated infections occur thoughout life

Reinfection usually involves only the upper Reinfection usually involves only the upper respiratory tract in immunocompetent adultsrespiratory tract in immunocompetent adults

LRI more common with type 3 infectionLRI more common with type 3 infection Immunity wanes quicklyImmunity wanes quickly

Parainfluenza virusParainfluenza virus

TypesTypes 1 and 2 cause seasonal fall epidemics 1 and 2 cause seasonal fall epidemics

that often will alternate yearsthat often will alternate years 3 is endemic but has an April May spring 3 is endemic but has an April May spring

peakpeak Most common isolate in childrenMost common isolate in children More common to cause pneumoniaMore common to cause pneumonia

Types 4a and 4 b are rareTypes 4a and 4 b are rare

Clinical manifestationsClinical manifestations

Children – PIV causes 60% of croup Children – PIV causes 60% of croup cases cases barking cough , hoarseness and stridorbarking cough , hoarseness and stridor

Adults – causes 15% of URIsAdults – causes 15% of URIs Immunocompromised adults – Immunocompromised adults –

common cause of URIs and also LRIscommon cause of URIs and also LRIs

DiagnosisDiagnosis

Cell culture – grows in cell cultureCell culture – grows in cell culture PCR also availablePCR also available

Parainfluenza in Parainfluenza in immunocompromised hostsimmunocompromised hosts

Significant cause of morbidity and Significant cause of morbidity and mortality among HSCT recipients mortality among HSCT recipients

Limited data available on its Limited data available on its presentation and treatmentpresentation and treatment

Clinical Trial Data

Large study from Fred Hutchinson Cancer Large study from Fred Hutchinson Cancer center center Evaluated data on 3577 HSCT recipients 1990-Evaluated data on 3577 HSCT recipients 1990-

19991999 All pts with URI sxs received Nasopharyngeal swabAll pts with URI sxs received Nasopharyngeal swab Also cxs done on all bronch specimens, lung bxps Also cxs done on all bronch specimens, lung bxps

and autopsyand autopsy Ribavirin was used at discretion of treating Ribavirin was used at discretion of treating

physician but was a standardized dose and course physician but was a standardized dose and course

Nichols W, et al. Parainfluenza virus infections after Nichols W, et al. Parainfluenza virus infections after hematopoietic stem cell transplantation: rick factors, hematopoietic stem cell transplantation: rick factors, response to antiviral therapy and effect on transplant response to antiviral therapy and effect on transplant outcome. Blood 2001;98:573-78.outcome. Blood 2001;98:573-78.

Epidemiology in SCT ptsEpidemiology in SCT pts PIV was isolated from 7.1% of the PIV was isolated from 7.1% of the

3577 patients 3577 patients PIV3 was most common form (90%)PIV3 was most common form (90%) Occurred year round but in clusters Occurred year round but in clusters

Results

Clinical presentationClinical presentation 81% of PIV 3 infections were URI, 7% 81% of PIV 3 infections were URI, 7%

with pneumonia and 6% bothwith pneumonia and 6% both No real difference in clinical No real difference in clinical

characteristics of the patients who did characteristics of the patients who did and did not develop PIV 3and did not develop PIV 3

ResultsResults

Risk factors for progression to LRIRisk factors for progression to LRI Receipt of corticosteroids was the only Receipt of corticosteroids was the only

dependent risk factordependent risk factor

Corticosteroid use and Corticosteroid use and progression to LRIprogression to LRI

Association present for both Association present for both autologous and allogenic transplantsautologous and allogenic transplants

Dose dependentDose dependent

Copathogens

53% of pts with PIV3 LRI had copathogens53% of pts with PIV3 LRI had copathogens Aspergillus fumigatus was most common Aspergillus fumigatus was most common

copathogen - 24%copathogen - 24% Similar to association of Staph aureus with Similar to association of Staph aureus with

influenza influenza PIV3 infection may damage the epithelium PIV3 infection may damage the epithelium

and allow other organisms to penetrate or and allow other organisms to penetrate or may exert an immunosuppressive effectmay exert an immunosuppressive effect

Mortality

Overall mortality in PIV3 LRI was 35% Overall mortality in PIV3 LRI was 35% at 30 days and 75% at 180 days at 30 days and 75% at 180 days after dx of pneumoniaafter dx of pneumonia

The majority died with persistent The majority died with persistent radiographic or clinical evidence of radiographic or clinical evidence of pneumoniapneumonia

MortalityMortality

Risk factors for mortalityRisk factors for mortality Presence of co-pathogens on BAL at Presence of co-pathogens on BAL at

time of PIV3 diagnosis was associated time of PIV3 diagnosis was associated with increased mortalitywith increased mortality

48% vs 19% at 30 days48% vs 19% at 30 days 96% vs 50 % at 180 days96% vs 50 % at 180 days

Need for mechanical ventilation also Need for mechanical ventilation also mortality risk mortality risk

Treatment

Aerosolized ribavirin +/- IVIG were Aerosolized ribavirin +/- IVIG were used in 33 of 55 patients with PIV3 used in 33 of 55 patients with PIV3 pneumoniapneumonia

Characteristics of the two groups Characteristics of the two groups were similar but treated group had were similar but treated group had more intubated patients and more more intubated patients and more pts requiring O2pts requiring O2

Treatment and Viral Shedding

No difference in duration of viral No difference in duration of viral sheddingshedding 35% of treated pts continued to shed at 35% of treated pts continued to shed at

3 weeks compared to 33% of untreated 3 weeks compared to 33% of untreated patientspatients

Only 35% of treated patients shed for < Only 35% of treated patients shed for < 10 days compared to 50% of untreated 10 days compared to 50% of untreated patientspatients

Treatment and Mortality

No difference in 30 day mortality No difference in 30 day mortality between the treated and untreated between the treated and untreated groups groups Even after stratification by presense of Even after stratification by presense of

copathogencopathogen

ConclusionsConclusions

PIV infections were relatively common PIV infections were relatively common after SCTafter SCT

Associated with increased mortalityAssociated with increased mortality Overall 24.1% of patients with PIV3 Overall 24.1% of patients with PIV3

infection developed pneumoniainfection developed pneumonia Development of LRI was driven by Development of LRI was driven by

administration of steroids for GVHD administration of steroids for GVHD Copathogens were commonly isolated Copathogens were commonly isolated

from Pts with PIV pneumoniafrom Pts with PIV pneumonia Copathogens were associated with increased Copathogens were associated with increased

mortalitymortality

No real benefit seen with ribavirin No real benefit seen with ribavirin and IVIG although not a randomized and IVIG although not a randomized trialtrial

Further courseFurther course

Initially covered with broad spectrum antibiotics including Initially covered with broad spectrum antibiotics including imipenim, vanco, voriconazole, bactrim, doxy.imipenim, vanco, voriconazole, bactrim, doxy.

Received increasing doses of steroids due to concern that may be Received increasing doses of steroids due to concern that may be GVHD GVHD

When cx + for PIV pt begun on oral ribavirin and IVIGWhen cx + for PIV pt begun on oral ribavirin and IVIG Had a worsened course and received several days of pulse dose Had a worsened course and received several days of pulse dose

steroids 850 mg bid with some improvementsteroids 850 mg bid with some improvement Steroids weaned to 125 mg BIDSteroids weaned to 125 mg BID

Rebronch 12 days later still with viral cx + for PIV3. No other Rebronch 12 days later still with viral cx + for PIV3. No other copathogens identifiedcopathogens identified

Remains on broad spectrum abx with relatively stable O2 Remains on broad spectrum abx with relatively stable O2 requirement at 4 Lrequirement at 4 L

Could not obtain aerosolized ribavirin since not used at UNC for 5 Could not obtain aerosolized ribavirin since not used at UNC for 5 yearsyears

Difficult to use as it is teratogenic and mutagenic and aerosol gets Difficult to use as it is teratogenic and mutagenic and aerosol gets everywhereeverywhere

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Parainfluenza Virus Type 2 Case Reports Reviews Differential Diagnosis Drug Therapy