‘Tis the season
Pulmonary Ground Rounds
Cheryl Pirozzi
December 8, 2011
Case
• Cc: cough
• HPI: 27 yo man p/w 1 week h/o progressive cough
productive of green/yellow mucus and SOB
• Fevers, body aches
• Sore throat, nausea, vomiting, diarrhea
• Went to PCP 3 days PTA, treated for bronchitis with
azithromycin → no improvement
• No response to albuterol inhaler
• To ER with severe SOB → found to be hypoxic
requiring 6 lpm
PMH
• Asthma: well controlled with prn albuterol prior to
exercise, no hospitalizations/steroids
• Obesity
• Depression / bipolar disorder
• HTN
• GERD
• PNA at age 5 requiring hospitalization, “valley fever”
at age 10
SH
• ½ ppd x 4 years, quit 1 y ago
• Prior cocaine (intranasal) and marijuana, quit 1 yr
ago. No h/o IDU
• Occas EtOH
• Multiple male partners, not currently sexually active
• Works in customer service.
• From CA, lived in AZ then UT. No recent travel.
• pet cat, no other significant exposures
FH
• DM, obesity, HTN
Home Meds
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Albuterol PRN- uses infrequently before exercise
Prilosec
Citalopram
Lamotrigine
Trazodone
HCTZ
MVI
Percocet prn back pain
Physical Exam
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VS: t 38.0, p 102, 110/52, R 18, 92%/6L
Gen: alert, oriented, no respiratory distress, obese
HEENT: erythema posterior oral pharynx
CV: reg tachy, no m/g/r
Lungs: decreased air movement bilaterally. No
rhonchi/wheeze/crackles
• Abd: obese, nt/nd
• Ext: no edema
Labs
• WBC 12, PMN 76%, Hgb 17, Hct 46, plt 388, BUN 15,
Cr 1.0
• AST 126, ALT 149, Alk Phos 66, bili 1.5
• BNP 74
• VTE +
• Rapid HIV neg
• ABG (4L) 7.47/35/64
CXR 4/1/11
CTA 4/2/11
CTA 4/2/11
CTA 4/2/11
CTA 4/2/11
Hospital Course
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Started on Abx for CAP: ceftriaxone and azithro
Fevers resolved but continued cough and SOB
O2 requirement increased to 60% FM
ABG (60%) 7.45/38/51/25 lact 1.2
Blood cx neg, Strep and legionella Ag (-)
Viral hepatitis panel neg
Respiratory viral panel (nasopharyngeal swab):
Influenza neg, RSV PCR +
CXR 4/4/11
Hospital Course
• Pulmonary consulted due to increasing hypoxia and
pulmonary infiltrates
• Bronchoscopy performed 4/6/11:
• BAL: neutrophilic inflammation (PMN 55%, MP 39%,
Lymph 6%)
• RSV DFA Neg. Viral cx Neg
• All other micro negative.
Hospital Course
• Pt continued on CAP Abx, bronchodilators,
and started on ICS and slowly improved
• O2 requirement decreased to 4L and pt was
discharged
• Sxs and hypoxemia resolved in ~ 2 weeks
RSV Pneumonia
• What’s the skinny on RSV in healthy adults?
• How do I interpret the conflicting RSV test results?
• Is there any treatment indicated?
Respiratory syncytial virus (RSV)
• Common wintertime respiratory virus
– In northern hemisphere November – April, peak Jan-Feb
• Major cause of serious lower respiratory tract
infections in young children
– Primary RSV infection is nearly universal by age 2 and
repeat infections are common due to incomplete
immunity.
• Also important pathogen in adults, esp elderly,
chronic lung disease, or immunocompromised
• Approx 10,000 deaths in persons > age 65 in the
United States each year from RSV (2nd to influenza)
Falsey A. Respiratory Syncytial Virus Infection in Adults. Semin Respir Crit Care Med. 2007;28(2):171-181
Pathogenesis
• RSV is a single-stranded, enveloped RNA virus
• Paramyxovirus family
• Begins as upper respiratory tract infection, then can
spread to lower respiratory tract and cause
bronchiolitis, bronchospasm, pneumonia, and acute
respiratory failure
Falsey A. Respiratory Syncytial Virus Infection in Adults. Semin Respir Crit Care Med. 2007;28(2):171-181
RSV in adults
Risk factors in adults
• Immunocompromised patients (eg, severe combined
immunodeficiency, leukemia, BMT or lung
transplant)
• Asthma
• Other cardiopulmonary disease
• Elderly, esp institutionalized or with chronic
pulmonary disease or functional disability
Falsey A. Respiratory Syncytial Virus Infection in Adults. Semin Respir Crit Care Med. 2007;28(2):171-181
RSV in adults
Elderly
• Many outbreaks in nursing homes
• 3 – 7% of healthy community dwelling elderly
annually
– NEJM 2005;28:1749–59
• Pneumonia up to 33% and mortality up to 5%
Falsey A. Respiratory Syncytial Virus Infection in Adults. Semin Respir Crit Care Med. 2007;28(2):171-181
RSV in adults
Immunocompromised
• 40%–50% of RSV URIs in BMT recipients progress to
PNA
• RSV PNA in HSCT pts: mortality 70–80% if untreated
• Risk factors for RSV after HSCT: male, allogeneic
transplant, CMV seropositivity,
mismatched/unrelated transplant, advanced age,
GVHD, pre-engraftment or < 1 mo posttransplant
Boeckh et al. CID 2007;44:245–9
Shah et al. Blood 2011;117(10):2755-2763
RSV in adults
Immunocompromised
• Lung transplant pts: RSV bronchiolitis, pneumonia
and respiratory failure, and associated with
bronchiolitis obliterans syndrome
– Mortality RSV infections 10-20%
Pelaez et al. J Heart Lung Transplant 2009;28:67–71
RSV in adults
• COPD and Asthma
– Cause of COPD exacerbations in 0.8 to 22%
– RSV associated with 7% of asthma hospitalizations
Falsey A. Respiratory Syncytial Virus Infection in Adults. Semin Respir Crit Care Med. 2007;28(2):171-181
RSV infects healthy young adults
• RSV was identified by RT-PCR in 10 - 22% of adults
>45yo visiting a general practitioner during the
winter for a respiratory illness.
– Lancet 2001;358:1410-1416
• In 256 military trainees with respiratory symptoms,
RSV infection was identified in 11%
– Clinical Infectious Diseases 2005;41:311–7
• 2 - 5% of CAP throughout the year and 5 - 15%
during the winter months.
Dowell SF, Anderson LJ, Gary HE Jr, et al. Respiratory syncytial virus is an important cause of community-acquired lower
respiratory infection among hospitalized adults. J Infect Dis 1996;174:456-462
Falsey A. Respiratory Syncytial Virus Infection in Adults. Semin Respir Crit Care Med. 2007;28(2):171-181
Clinical manifestations in adults
• Ranges from trivial cold to severe respiratory disease
• Generally mild to moderately severe URI
• Of 211 healthy working adults, 26% had lower
respiratory tract symptoms, 40% fever, 38% missed
work, illnesses lasting an average of 9.5 days
– Clin Infect Dis 2001;33:792-796
• Airway reactivity for up to 8 weeks.
• Many case reports of healthy young adults
developing respiratory failure requiring mechanical
ventilation due to RSV
– Mortality 40-60%
Arch Bronconeumol. 2011 Mar 17
Falsey A. Respiratory Syncytial Virus Infection in Adults. Semin Respir Crit Care Med. 2007;28(2):171-181
Clinical manifestations in adults
• Compared with influenza
– In hospitalized pts, similar length of stay, ICU, and mortality
NEJM 2005;28:1749–59.
RSV: Imaging
• CXR: diffuse bilat interstitial
• CT: Bronchitis-bronchiolitis pattern: bronchial wall
thickening and tree-in-bud opacities
• Multifocal ground glass opacities or consolidation
Miller W T , Shah R M AJR 2005;184:613-622
How do I interpret the conflicting RSV test
results?
Testing
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Culture
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Very sensitive and specific in infants, but not in adults
due to much lower viral titers and thermolability (2067% sensitivity, 100% specificity)
Serologically: by RSV-specific IgM acutely or by rise
in IgG between acute- and convalescent-phase sera.
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IgM sensitivity 58 – 81%, not available commercially
IgG change only useful retrospectively
Falsey, Walsh. Clin Microbiol Rev. 2000 July; 13(3): 371–384.
Testing
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Antigen detection by immunofluorescence assay
(DFA) or enzyme immunoassay (EIA)
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Requires significant viral load
Sensitivity depends on specimen: nasal wash (15%),
endotracheal secretions (71%), BAL (89%)
RNA detection by reverse transcription-PCR (RTPCR)
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In adult nasal swabs: 73% sensitive and 99% specific
Falsey A. Respiratory Syncytial Virus Infection in Adults. Semin Respir Crit Care Med. 2007;28(2):171-181
Falsey, Walsh. Clin Microbiol Rev. 2000 July; 13(3): 371–384.
Testing
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Recommendation:
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Send nasopharyngeal swab for culture, + PCR if pt is
severely ill / immunocompromised
Consider DFA if BAL or endotracheal specimen
Given sensitivity and specificity of RT-PCR and DFA,
our patient’s nasopharyngeal PCR was likely true
positive and BAL DFA false negative
Falsey A. Respiratory Syncytial Virus Infection in Adults. Semin Respir Crit Care Med. 2007;28(2):171-181
Falsey, Walsh. Clin Microbiol Rev. 2000 July; 13(3): 371–384.
Is there any treatment indicated?
Treatment
• Generally supportive: fluids, oxygen, and antipyretics
• Bacterial infection may complicate 10 to 30% of RSV
and require antibiotics
• Bronchodilators
– Unproven benefit
• No data to support steroids
Falsey A. Respiratory Syncytial Virus Infection in Adults. Semin Respir Crit Care Med. 2007;28(2):171-181
Other treatment modalities
• Ribavirin (aerosolized, IV, PO)
• IVIG or RSV-IVIG
• Immunomodulators: Palivizumab (PVZ)
– RSV-specific monoclonal Ab
Shah et al. Blood. 2011;117(10):2755-2763
Other treatment modalities
• Ribavirin (aerosolized, IV, PO)
– guanosine analog active against RNA and DNA viruses
– Inh ribavirin is cumbersome:, precipitates in ETT and
ventilator, administer x 18 hours/day or 2h q8h
– mutagenic, tumorigenic and gonadotoxic → need wellventilated rooms/scavenging tent
– Also high rates of nephrotoxicity and hemolytic anemia
– 10d course = $50,000
– Officially approved only for infants
Shah et al. Blood. 2011;117(10):2755-2763
http://160.109.101.132/respcare/ribaviri.htm
In immunocompromised patients
• Aerosolized ribavirin in HSCT pts
– Only one RCT: 14 pts with RSV URI: trend towards
decreased viral load but no diff in progression to PNA
– Boeckh et al. CID 2007;44:245–9
P = 0.07
Other treatment modalities
• IVIG or RSV-IVIG:
– No RCT
– Pilot study of IVIG + aRibavirin in 14 BMT pts with RSV URI
– Well tolerated, 29% progression to PNA and 14% mortality
• Ghosh. Bone Marrow Transplantation (2000) 25, 751–755
– RSV-IVIG no longer available
Shah et al. Blood. 2011;117(10):2755-2763
In immunocompromised patients
• Immunomodulators: Palivizumab (PVZ)
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RSV-specific monoclonal Ab
↓ hospitalization in high risk children < 2 yo
Approved for prevention in high risk children
No RCT in adults
Phase 1 study in 15 HSCT pts with RSV URI or PNA: safe
and well tolerated, 83% survival of RSV PNA
• Boeckh et al. J Infect Dis. 2001;184(3): 350-354.
– $10, 000/dose
In HSCT patients
• Review of RSV rx in adult HSCT pts:
– Progression to LRTI and death lower with ribavirin (any form, +/immunomodulator) than with no rx
– aRibavirin + (IVIG/PVZ) had lower mortality and trend towards lowest
progression to LRTI
– However, many limitations
→ Recommend combo rx for
HSCT pts with RF for
progression to LRTI
Shah et al. Blood. 2011;117(10):2755-2763
In heart and lung transplant patients
No RCTs, just case series:
• 18 lung tx pts with RSV: IV ribavirin + PO prednisolone:
mortality 0%, FEV1 recovered within 3 mo
– J Heart Lung Transplant 2005;24:2114–9
• 5 lung transplant pts with RSV: PO ribavirin x 10 d +
solumedrol x 3 d: mortality 0%, FEV1 recovered
– $700 compared with $14,000 for 10d course
– J Heart Lung Transplant 2009;28:67–71
In heart and lung transplant patients
No RCTs, just case series:
• 25 lung and heart-lung tx pts with RSV or PIV: inhaled
ribavirin, methylprednisolone, and IVIG + palivizumab if RSV:
RSV mortality 0%, FEV1 recovered
– Transpl Infect Dis 2010: 12: 38–44
But… ? may have good recovery even without treatment
• Retrospective review of 10 cases of LRT RSV infections in adult
LTRs, 2 rxd with ribavirin and palivizumab, 8 no anti-RSV
treatment
– All pts fully recovered, though 6 later had worsening
bronchiolitis obliterans (independent of RSV rx)
– Uçkay et al. J Heart Lung Transplant 2010;29:299–305
Treatment in nonimmunocompromised adults
• Only anecdotal
case reports
Luo et al. Arch Bronconeumol. 2011 Mar 17
• Insufficient data to judge efficacy or make general
recommendations.
• Some recommend considering inh ribavirin in
severely ill elderly patients with documented RSV
Falsey A. Respiratory Syncytial Virus Infection in Adults. Semin Respir Crit Care Med. 2007;28(2):171-181
Treatment in nonimmunocompromised adults
Steroids?
• Lee et al. Chest 2011 Nov;140(5):115561
• Prospective observ study of 50 adults
hospitalized with RSV (any respir illness,
+ RT-PCR), 66% received systemic
steroids
• no significant differences in peak viral
load, duration of RSV shedding, nasal
cytokines, or lymphocyte subsets
• Blunted antibody responses to RSV in
the steroid-treated group
• No major deleterious effects
Infection control / prevention
• Shedding during natural RSV infection in young
adults averages 3 to 6 days, with a range of 1 to 12
days.
• Droplet precautions
• No licensed RSV vaccination at this time; however, in
progress
– MEDI-559: live, attenuated vaccine for intranasal
administration
– Clinical trials ongoing in children
Falsey A. Respiratory Syncytial Virus Infection in Adults. Semin Respir Crit Care Med. 2007;28(2):171-181
Empey et al. Clinical Infectious Diseases 2010;50(9):1258–1267, Pediatr Infect Dis J. 2011 Sep 15
New treatment options coming?
• Motavizumab: novel IgG1 monoclonal antibody
against RSV F glycoprotein, more potent than
Palivizumab with activity in both the upper and
lower airways.
– pending FDA approval
• ALN-RSV01: Antisense anti-RSV small interfering
RNAs (siRNA) targeting RSV N protein
• Phase 2 safe and tolerable in lung transplant pts
• Immunomodulatory agents
– Multiple in preclinical studies
Empey et al. Clinical Infectious Diseases 2010;50(9):1258–1267
Conclusions
• RSV typically causes more severe disease in
immunocompromised or elderly adults, but can
infect healthy young adults
• PCR is the most sensitive and specific test for RSV,
but DFA can be used in BAL
• Treatment with ribavirin ± IVIG and/or palivizumab
is indicated in BMT or transplant pts, but there is
insufficient data to support treating healthy adults
Questions / comments?
References
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Falsey A. Respiratory Syncytial Virus Infection in Adults. Semin Respir Crit Care Med. 2007;28(2):171-181
Shah J, Chemaly R. Management of RSV infections in adult recipients of hematopoietic stem cell transplantation. Blood.
2011;117(10):2755-2763
O'Shea MK, Ryan MA, Hawksworth AW, Alsip BJ, Gray GC. Symptomatic respiratory syncytial virus infection in previously
healthy young adults living in a crowded military environment. Clin Infect Dis. 2005 Aug 1;41(3):311-7.
Ann R. Falsey and Edward E. Walsh. Respiratory Syncytial Virus Infection in Adults. Clin Microbiol Rev. 2000 July; 13(3): 371–
384.
Luo YH, Huang CY, Yang KY, Lee YC. Inhaled Ribavirin Therapy in Adult Respiratory Syncytial Virus-Induced Acute Respiratory
Distress Syndrome. Arch Bronconeumol. 2011 Mar 17. [Epub ahead of print]
Dowell SF, Anderson LJ, Gary Jr HE, Erdman DD, Plouffe JF, File Jr TM, et al. Respiratory syncytial virus is an important cause
of community-acquired lower respiratory infection among hospitalized adults. J Infect Dis. 1996;174: 456–62.
Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality associated with influenza and
respiratory syncytial virus in the Uni ted States. JAMA. 2003;289:179–86. 4.
Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus infection in elderly and high-risk adults. N
Engl JMed. 2005;28:1749–59.
Zambon MC, Stockton JD, Clewley JP, Fleming DM. Contribution of influenza and respiratory syncytial virus to community
cases of influenza-like illness: an observational study. Lancet 2001;358:1410-1416
Boeckh M, Englund J, Li Y, Miller C, Cross A, Fernandez H, Kuypers J, Kim H, Gnann J, Whitley R. Randomized Controlled
Multicenter Trial of Aerosolized Ribavirin for Respiratory Syncytial Virus Upper Respiratory Tract Infection in Hematopoietic
Cell Transplant Recipients. Clinical Infectious Diseases 2007;44:245–9
S Ghosh, RE Champlin, J Englund, SA Giralt, K Rolston, I Raad, K Jacobson, J Neumann, C Ippoliti, S Mallik and E Whimbey.
Respiratory syncytial virus upper respiratory tract illnesses in adult blood and marrow transplant recipients: combination
therapy with aerosolized ribavirin and intravenous immunoglobulin. Bone Marrow Transplantation (2000) 25, 751–755
Boeckh M, Berrey MM, Bowden RA, Crawford SW, Balsley J, Corey L. Phase 1 evaluation of the respiratory syncytial virusspecific monoclonal antibody palivizumab in recipients of hematopoi- etic stem cell transplants. J Infect Dis. 2001;184(3):
350-354.
References
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Empey K, Peebles S, Kolls J. Pharmacologic Advances in the Treatment and
Prevention of Respiratory Syncytial Virus. Clinical Infectious Diseases
2010;50(9):1258–1267
Uçkay I, Gasche-Soccal P, Kaiser L, Stern R, Mazza-Stalder J, Aubert J, van Delden C.
Low incidence of severe respiratory syncytial virus infections in lung transplant
recipients despite the absence of specific therapy. J Heart Lung Transplant
2010;29:299–305