‘Tis the season Pulmonary Ground Rounds Cheryl Pirozzi December 8, 2011.

‘Tis the season

Pulmonary Ground RoundsCheryl 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

• Albuterol PRN- uses infrequently before exercise• Prilosec• Citalopram• Lamotrigine• Trazodone• HCTZ• MVI• Percocet prn back pain

Physical Exam

• 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

• 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


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


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%


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;44:245–9Shah 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


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


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

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

• Culture• Very sensitive and specific in infants, but not in adults

due to much lower viral titers and thermolability (20-67% sensitivity, 100% specificity)

• Serologically: by RSV-specific IgM acutely or by rise in IgG between acute- and convalescent-phase sera.

– IgM sensitivity 58 – 81%, not available commercially– IgG change only useful retrospectively

Falsey, Walsh. Clin Microbiol Rev. 2000 July; 13(3): 371–384.

Testing

• Antigen detection by immunofluorescence assay (DFA) or enzyme immunoassay (EIA)

• Requires significant viral load• Sensitivity depends on specimen: nasal wash (15%),

endotracheal secretions (71%), BAL (89%)

• RNA detection by reverse transcription-PCR (RT-PCR)

• In adult nasal swabs: 73% sensitive and 99% specific



Testing

• Recommendation:– 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



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


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


• 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 well-

ventilated 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


• 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) – 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

Shah et al. Blood. 2011;117(10):2755-2763

→ Recommend combo rx for HSCT pts with RF for progression to LRTI

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

• Insufficient data to judge efficacy or make general recommendations.

• Some recommend considering inh ribavirin in severely ill elderly patients with documented RSV


Luo et al. Arch Bronconeumol. 2011 Mar 17

Treatment in nonimmunocompromised adultsSteroids?• Lee et al. Chest 2011 Nov;140(5):1155-

61• 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


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

• 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 virus-specific monoclonal antibody palivizumab in recipients of hematopoietic stem cell transplants. J Infect Dis. 2001;184(3): 350-354.

References

• 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

‘Tis the season Pulmonary Ground Rounds Cheryl Pirozzi December 8, 2011.

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