Treatment of Influenza with Convalescent Plasma - Professor Ivan Hung

Treatment of H1N1 Infection with Convalescent Plasma Therapy

Prof Ivan Hung, MD FRCP (Lon, Edin) Professor

Department of Medicine University of Hong Kong

Concurrent comparative study of hospitalized influenza cases at QMH(June to October 2009) To KK et al. Postgrad Med J. 2010;86:515-21

Age groups of 69 pandemic H1N1 vs 117 seasonal H1N1 patients

To KK et al. Postgrad Med J. 2010;86:515-21

To KK et al. Clin Infect Dis. 2010 Mar15;50(6):850-9.



Viral load after symptom onset

2

3

4

5

6

7

8

0-1 2-3 4-5 6-7 8-9 10-11

Days after symptom onset

Mea

n vir

al lo

ad (l

og10

cop

ies

per m

l)

ARDS-deathSurvived-without-ARDSMild-disease

A


Persistent elevation of pro-inflammatory cytokine IL-6


Risk factors for severe influenza in host •  Age

–  <2 years –  >65 years old

•  Chronic underlying illness –  chronic pulmonary disease –  chronic cardiac disease –  metabolic disorders (esp. diabetes mellitus) –  chronic renal disease, chronic hepatic disease, certain neurological

conditions –  Immunosuppression –  Children on chronic aspirin therapy

•  Pregnancy (third/second trimester/<2 wk postpartum), IgG2 deficiency

•  Obesity? (delayed or impaired interferon, proinflammatory cytokine/chemokine, NK cytotoxicity, dendritic/CD8 T cell function in diet-induced obese mice)

•  Chronic smoker

0

1

2

3

4

5

6

7

8

9

10

11

0 1 2 3 4 5 6 7 8 9

Daysaftersymptomonset

viralload(log 10copies/m

l)

case

control

Days after symptom onset

Number of patients with viral load checked on the particular day 0 1 2 3 4 5 6 7 8 9 Case (n = 110) 11 49 34 44 38 35 31 25 17 10 Control (n = 23) 6 12 4 9 5 11 11 7 4 3

Kruskal Wallis test: significant decreasing trend of mean viral load at D0–9 in case compared with control (p < 0.001).

Viral load at D5 lower in cases (4.30 log10 vs 5.71 log10 copies/mL, p = 0.025).

Initial VL correlates with symptom score p=0.05; Time of Rx initiation: 2.1 day post-symptom onset; Fever resolves 1.4 day earlier with oseltamivir

Li IW. Chest. 2010 Apr;137(4):759-68

Resistance of A/HK/423432/09 to oseltamivir due to quasispecies of 274 Y in NPA and virus isolate (adamantane resistant)

Chen HL, et al. Emerg Infect Dis. 2009 Dec;15(12):1970-2.Courtesy of Dr WL Lim, PHLC, DH, HKSAR.

Sample type

274H (%)

274Y (%)

IC50 (Oseltamivir)

IC50 (Zanamivir)

NPA 45 / 95 (47.37)

50 / 95 (52.63)

ND ND

MDCK culture

2 / 96 (2.08)

94 / 96 (97.92)

197.5 nM 0.8 nM

Will H274Y oseltamivir resistance in pandemic H1N1 2009 spread as that of previous seasonal H1N1 brisbane like???

Available Treatment Options

•  Supportive •  Extra-corporeal membrane oxygenation

•  Oseltamivir (problem with late presenters/ resistance) •  Intravenous/Nebulized zanamivir/ peramivir •  Ribavirin •  Statins •  Anti-oxidants: N-acetylcysteine/ambroxol

•  Convalescent plasma(IVIG) with neutralizing antibody

Dunning J et al. Lancet ID 2014;14:1259-70

Convalescent Plasma Treatment

Zhou et al. NEJM 2007

Luke TC, et al. Annals of Internal Medicine 2006

Practical limitations of convalescent plasma collection: a case scenario in pandemic preparation for influenza A

(H1N1) infection

Wong HK et al. Transfusion 2010;50:1967-1971.

Results

•  31 Oct 2009: a total of 9101 contacted

•  1309 screening •  619 whole blood donation •  786/ 1309 (60%) screening •  301 donated plasma by

apheresis •  379/619 (61.2%) donated blood



Results Conclusions

•  Highlighted practical limitations in CP collection

•  Programs, plasmapharesis

•  Learning experience for blood transfusion service


•  Total of 276L of convalescent plasma

•  Sufficient neutralizing antibody titers

Effect of Clinical & Virological Parameters on the Level of Neutralizing

Antibody Against H1N1 2009

Hung IF et al. Clin Infect Dis 2010;51:274-9

Results

•  90% of convalescent donors had seroprotective titer ≥ 1:40

•  GMT between day 21 & 42: 1:101.1


Results

•  Higher level of NAT •  Pneumonia: OR 3.39; 95% CI 1.49-7.61;

P=0.04 •  Sputum: OR 1.75; 95% CI 1.01-3.01;

P=0.046 •  Poor NAT (< 1:40) •  Afebrile upon presentation (P=0.04)


Results

•  Positive correlation between NPA VL upon presentation & NAT

•  Spearman correlation p,0.238; P=0.026


Convalescent Plasma Treatment Reduced Mortality in Patients with Severe H1N1 2009 Virus Infection

Hung IF et al. Clin Infect Dis 2010,52:447-56

Results

•  93 patients recruited

•  21.5% (20 patients) received plasma treatment

•  Treatment and control well matched




Effect of Convalescent Plasma on Cytokine and VL

Results

•  Mortality CP vs. control: 20% vs. 54.8%; P =0.01 •  Multivariate analysis: CP reduced mortality: OR

0.2 95% CI 0.6-0.69; P =0.011 •  ARF associated with mortality: OR 3.79 95% CI

1.15-12.4; P=0.028 •  44 subgroup: Lower VL and cytokine (IL6, 10 and

TNF-A 3-7 days: P <0.05)


H-IVIG Treatment A Multicentre Double-Blind Randomized Controlled Trial for Patients with Severe H1N1

2009 Virus Infection

Hung IF et al. Chest 2013

Methods

•  Randomized to H-IVIG/ simple IVIG (manufactured before 2009)

•  NAT <20 •  Compare clinical outcome and adverse

effects








Conclusions

Convalescent plasma and H-IVIG treatment 1. reduced VL 2. cytokine response 3. Mortality Important role in future pandemics and other viral diseases Need to shorten preparation time and cost

Health & Medicine

Treatment of Influenza with Convalescent Plasma - Professor Ivan Hung