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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
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
To KK et al. Clin Infect Dis. 2010 Mar15;50(6):850-9.
Persistent elevation of pro-inflammatory cytokine IL-6
To KK et al. Clin Infect Dis. 2010 Mar15;50(6):850-9.
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
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
Wong HK et al. Transfusion 2010;50:1967-1971.
Results Conclusions
• Highlighted practical limitations in CP collection
• Programs, plasmapharesis
• Learning experience for blood transfusion service
Wong HK et al. Transfusion 2010;50:1967-1971.
• 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
Hung IF et al. Clin Infect Dis 2010;51:274-9
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)
Hung IF et al. Clin Infect Dis 2010;51:274-9
Results
• Positive correlation between NPA VL upon presentation & NAT
• Spearman correlation p,0.238; P=0.026
Hung IF et al. Clin Infect Dis 2010;51:274-9
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
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)
Hung IF et al. Clin Infect Dis 2010,52:447-56
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
Hung IF et al. Chest 2013