Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis

Cochrane team [1] and Freemantle and Calvert [2] did not discuss in
detail the harmful effects of Tamiflu. However, early use and late use of
Tamiflu may both be related to serious outcomes including death in influenza
infection. In this rapid response I would like to describe the
effect of late use of oseltamivir on survival of hospitalized patients.

One of the most important mechanisms of reactions with serious
outcome including death related to early use and late use of Tamiflu is
depression of the central nervous system, leading to respiratory
depression, neuropsychiatric symptoms and sudden death [3].

Unchanged oseltamivir (OT) easily enters the brain [3-8], if the
function of blood-brain barrier (BBB) decreased related to the low
activity of p-glycoprotein (p-gp), a major efflux transporter of OT [6-8].
Hypofunction of BBB is observed in animals before weaning (including human
infants) [5, 7] and under hypercytokinemia [9]. In vitro, BBB p-gp
activity is downregulated after short-term exposure to inflammatory
mediators [9] Of course, hypercytokinemia is observed in early phase of
influenza (around peak of fever). Inflammatory activation occurs modestly
with term labour, but much more robustly in preterm delivery, particularly
in the presence of intrauterine infection [10].

Moreover, hypercytokinemia is observed among the late presenters,
which correlated with hypercytokinemia [11]. It is easy to assume that
late presenters those presenting after day 3 might have treated themselves
with OTC antipyretics. If OTC antipyretics were non-steroidal anti-
inflammatory drugs (NSAIDs), they may promote induction of proinflammatory
cytokines resulting ARDS, encephalopathy with hepatic failure and
collectively multi-organ failure (MOF), while no study discussed the
harmful effect of NSAIDs in influenza [12, 13]

On the other hand, neuraminidase contributes to the maintenance of
normal human immune and repair systems [14] which might be impaired by the
neuraminidase inhibitor and could cause renal damage, glucose intolerance
[2, 14] and MOF [3].

2009 Pandemic Influenza A (H1N1) Hospitalizations Investigation Team
of CDC [16] reported that of the 268 patients for whom data were available
regarding the use of antiviral drugs, 200 (75%) received such drugs. Of
these patients, 188 received oseltamivir. They reported that the use of
antiviral drugs was beneficial in hospitalized patients, especially when
such therapy was initiated early (within 48 hour of onset). This is based
on the data, Of the 205 patients who were not admitted to an ICU and
survived, 62 (30 %) received antiviral therapy within 48 hours after the
onset of symptoms and of the 67 patients who were admitted to an ICU or
died 13 (20 %) received it.

However, if you look at another aspects of these data, of the 19
patients who died, 17 (90%) received antiviral treatment after 48 hours or
at unknown time after the onset of symptoms and of the 205 patients who
were not admitted to an ICU and survived 82 (40 %) received antiviral
therapy during the same period. Odds ratio was 12.75 (95% CI: 2.88-115.6,
p<_0.0001. p="p"/> I could find two other reports [17, 18] by which relation of late
initiation of oseltamivir and outcomes could be analysed: the first report
from Mexico [17] to which I already commented [19] and another CDC report
on the pregnant women [18].

In the former study [17] all seven fatal cases received Tamiflu,
while among 11 survived 7 received. Four patients who survived did not
receive oseltamivir. All 18 presented hospitals after 4 days after the
onset of symptoms and treatment by Tamiflu initiated after admission [17].

In the latter study [18] CDC reported all the 6 pregnant women who
died received Tamiflu at least after 6 days after the onset of symptoms.
They did not report how many pregnant women received Tamiflu and how many
did not. Anyway, number of pregnant women who did not receive Tamiflu and
died was zero. From the trend of increase of infected patients and
increase of proportion of Tamiflu takers, number of pregnant women who
received and did not received Tamiflu was estimated around 74 and 37
respectively.

Meta-analysis of these data from three reports by random effect model
yields odds ratio 10.90 (95%CI; 3.22-36.89, p<_0.0001 xmlns:_="urn:x-prefix:_" xmlns:ci="urn:x-prefix:ci" i2="0" _:_="_:_" _95="_95" ci:_="ci:_" _0-72.9="_0-72.9" figure="figure" which="which" indicates="indicates" that="that" late="late" initiated="initiated" oseltamivir="oseltamivir" might="might" be="be" related="related" to="to" death="death" of="of" the="the" hospitalized="hospitalized" patients.="patients." p="p"/> Patients who were admitted to an ICU and those who died were more
likely than patients who were not admitted to an ICU to have shortness of
breath, a neurologic disorder, radiographically confirmed pneumonia,
abnormality of laboratory data such as high creatine kinase, high
creatinine and high serum transaminase, ARDS, or sepsis [11, 16, 20].

Discussion on the harmful effect of Tamiflu to the mother themselves
and to the new born when used in pregnancy [21, 22] will be discussed in
the other rapid responses.

In conclusion, reanalysed data obtained from the observational
studies so far are consistent with the previous evidence on the
pharmacological and toxicological properties of Tamiflu. Both suggest the
harmful effects of Tamiflu in the exacerbation during late phase of
influenza probably after treatment by NSAIDs antipyretics. Tamiflu as
unchanged oseltamivir which enter the brain in hypercytokinemia in the
very early phase and in the relatively late exacerbation phase of
influenza infection may depress central nervous system, leading to
respiratory depression, neuropsychiatric symptoms and sudden death.

References

1. Tom Jefferson, Mark Jones, Peter Doshi, and Chris Del Mar
Neuraminidase inhibitors for preventing and treating influenza in healthy
adults: systematic review and meta-analysis. BMJ 2009;339:b5106, doi:
10.1136/bmj.b5106

2. Freemantle N and Calvert M. What can we learn from observational
studies of oseltamivir to treat influenza in healthy adults? BMJ 2009 339:
b5248.

3. Hama R. Fatal neuropsychiatric adverse reactions to oseltamivir?F
case series and overview of causal relationships. Internat J Risk Safety
Med 2008;20:5-36. : available at :
http://npojip.org/english/no11.html

4. Chugai Pharm Co 2004. New drug approval package (NAP) of
oseltmivir (in Japanese); Oseltamivir capsule for prevention (2004) (in
Japanese): available at:
http://211.132.8.246/shinyaku/g0407/g040703/index.html

5. Chugai Pharm Co. 2002. New drug approval package (NAP) of
oseltmivir (in Japanese); Tamiflu dry syrup (in Japanese): available at:
http://211.132.8.246/shinyaku/g0201/11/5303990_21400AMY00010.html

6. Morimoto K, Nakakariya M, Shirasaka Y, Kakinuma C, Fujita T, Tamai
I, Ogihara T. 2007. Oseltamivir (Tamiflu) efflux transport at the blood-
brain barrier via P-glycoprotein.
Drug Metab Dispos. (2008) 36(1):6-9. Epub 2007 Oct 16.

7. Ose A, Kusuhara H, Yamatsugu K, Kanai M, Shibasaki M, Fujita T,
Yamamoto A, Sugiyama Y. 2007. P-glycoprotein restricts the penetration of
oseltamivir across the blood-brain barrier. Drug Metab Dispos. (2008)
36(2):427-34. Epub 2007 Nov 26

8. Chugai Co. Ltd., Documents list for the fifth working panel for
drug safety in 2007, held on 25th December, 2007:
http://www.mhlw.go.jp/shingi/2007/12/s1225-7.html document-2-2;
on non-clinical studies ordered by the scientific working panel (part 1):
http://www.mhlw.go.jp/shingi/2007/12/dl/s1225-7b.pdf.

9. Th¨¦ron D, Barraud de Lagerie S, Tardivel S, P¨¦lerin H, Demeuse
P, Mercier C, Mabondzo A, Farinotti R, Lacour B, Roux F, Gimenez F. 2003.
Influence of tumor necrosis factor-alpha on the expression and function of
P-glycoprotein in an immortalised rat brain capillary endothelial cell
line, GPNT. Biochem Pharmacol. 66: 579¨C587.

10. Keelan JA, Blumenstein M, Helliwell RJ, Sato TA, Marvin KW,
Mitchell MD. 2003. Cytokines, prostaglandins and parturition--a review.
Placenta. 24 Suppl A: S33-46.

11. Lee N, Cockram CS, Chan PK, Hui DS, Choi KW, Sung JJ. Antiviral
treatment for patients hospitalized with severe influenza infection may
affect clinical outcomes. Clin Infect Dis 2008;46:1323-1324

12. Hama R. Rapid response. Potential harm of oseltamivir and NSAIDs
should be discussed, before the threat of a 2009A/H1N1 influenza-caused
pandemic is feared.
www.bmj.com/cgi/eletters/338/may12_3/b1962#214206

13. Hama R. Rapid response. What can we learn from observational
studies of oseltamivir without examining NSAIDs use?

http://www.bmj.com/cgi/eletters/339/dec07_2/b5248#227268

14. Miyagi T, Wada T et al. Sialidase and malignancy: a minireview.
Glycoconj J 2004;20(3):189-98.

15. Hama R. Rapid response. Oseltamivir: psychotic and neurological
adverse reactions in the randomized controlled trials.
http://www.bmj.com/cgi/eletters/339/dec07_2/b5106#227187

16. 2009 Pandemic Influenza A (H1N1) Virus Hospitalizations
Investigation Team: Jain S, Kamimoto L, Bramley AM et al. Hospitalized
patients with 2009 H1N1 influenza in the United States, April-June 2009.
Engl J Med. 2009 Nov 12;361(20):1935-44. Epub 2009 Oct 8.

17. INER Working Group on Influenza: Perez-Padilla R, de la Rosa-
Zamboni D, Ponce de Leon S et al. Pneumonia and respiratory failure from
swine-origin influenza A (H1N1) in Mexico. N Engl J Med. 2009 Aug
13;361(7):680-9. Epub 2009 Jun 29.

18. Novel Influenza A (H1N1) Pregnancy Working Group. Jamieson DJ,
Honein MA, Rasmussen SA, H1N1 2009 influenza virus infection during
pregnancy in the USA.
Lancet. 2009 Aug 8;374(9688):451-8. Epub 2009 Jul 28.
19. Hama R. Rapid response: Re: Influenza treated with NSAIDs or
oseltamivir: case-control studies urgently needed.
http://www.bmj.com/cgi/eletters/339/jul08_3/b2731

20. Dom¨ªnguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically
ill patients with 2009 influenza A(H1N1) in Mexico. JAMA 2009;302:1880-
1887

21. Hama R. Oseltamivir (Tamiflu) is harmful for pregnant women (1).
The Informed Prescriber: 2009: 24 (6): 66-70.(in Japanese)

22. Hama R. Oseltamivir (Tamiflu) is harmful for pregnant women (2).
The Informed Prescriber: 2009: 24 (7): 77-82.(in Japanese)

Competing interests:
None declared

Sirs;

In the article by Jefferson et.al. (1), the route of administration
for zanamivir (Relenza®) is denoted as nebulised. Healthcare prescribers
should be aware that the approved use of zanamivir in the U.S. and in the
EU is via inhalation, not nebulisation (2,3). The FDA has recently issued
a warning against using the inhalation formulation in a solubilised form
for nebulised delivery (4) and has sent letters to healthcare prescribers
in the U.S. (5) proscribing the use of zanamivir via the nebulised route
due to a reported death following administration via this method.
Alternatives should be considered.

Yours sincerely,

Barry A. Eagel, M.D.

Clinical Monitoring Research Program,
SAIC-Frederick, Inc.,
NCI-Frederick,
Frederick, MD 21702

This project has been funded in whole or in part with federal funds
from the National Cancer Institute, National Institutes of Health, under
Contract No. HHSN261200800001E. The content of this publication does not
necessarily reflect the views or policies of the Department of Health and
Human Services, nor does mention of trade names, commercial products, or
organizations imply endorsement by the U.S. Government.

References

1. Jefferson T., Neuraminidase inhibitors for preventing and
treating influenza in healthy adults: systematic review and meta-analysis,
BMJ 2009;339:b5106

2. Relenza [package insert], Research Triangle Park, NC:
GlaxoSmithKline; 2009.
http://us.gsk.com/products/assets/us_relenza.pdf. Accessed December 9,
2009.

3. Summary of the Product Characteristics,
http://www.lakemedelsverket.se/SPC_PIL/Pdf/enhumspc/Relenza%20inhalation...
-dispensed%20ENG.pdf. Accessed December 9, 2009.

4.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHuma....
Accessed 09 Dec, 2009.

5. FDA Safety.
http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAle....
Accessed 09 Dec, 2009.

Competing interests:
None declared

Dear Editor:

Jefferson, et al. and Freemantle and Calvert describe a selection of
randomised placebo controlled and observational studies respectively
regarding the use of neuraminidase inhibitors in otherwise healthy adults
infected with seasonal influenza virus. [1,2] However, in Europe, North
America, China, and South East Asia the predominant influenza virus
circulating is the new 2009 pandemic influenza A (H1N1) virus. [3,4] The
age groups and other patient population groups most severely affected
include children, pregnant women, and people with underlying conditions
that are risk factors for severe disease. The elderly are relatively
spared. The United States (U.S.) Centers for Disease Control and
Prevention estimates that hospitalisation rates are highest among children
under 18 years old. [5] Pregnant women have been affected
disproportionately compared with others and in excess of their population
distribution. [6] However, depending on the age group, 15-40% of those
who are hospitalised are without known risk factors for severe disease.
[7,8,9] The scope and magnitude of the current pandemic is greater than
that of a typical influenza season among those younger than 65 years
because all children and most adults less than 65 years of age are
immunologically naïve to this new virus and thus experience high illness
rates. The impact is also substantially affected by limited amounts of
strain-specific vaccine available prior to the fall and winter outbreaks
in northern temperate climates during the 2009-10 season and where no
vaccine was available during the 2009 influenza season in the southern
hemisphere. This is in contrast to seasonal influenza where much of the
severe morbidity and mortality occurs among the elderly, fewer persons are
immunologically naïve, and where the vast majority of vaccine, where in
use, is administered prior to increases in influenza activity.

Given limited amounts of influenza vaccine available to date to
combat 2009 pandemic influenza A (H1N1), influenza antiviral medications
have assumed a prominent role in the reducing severe influenza-related
morbidity and mortality during the pandemic. The data that indicate a
benefit from neuraminidase inhibitor treatment in reducing complications,
including death, among hospitalized patients with 2009 pandemic influenza
A (H1N1) infection have been summarized recently. [10] These data were
collected during the current pandemic in the U.S. and Mexico, with neither
investigation supported by industry
funding. [11,12] Treatment with a neuraminidase inhibitor was associated
with a lower risk for intensive care unit admission and death. These
findings are supported by data from seasonal influenza investigations that
also showed a reduced risk of death among hospitalized patients with
laboratory confirmed influenza who received a neuraminidase inhibitor,
even when initiated more than 48 hours after symptom onset. [13,14,15]

The risks associated with the use of neuraminidase inhibitors during
the pandemic are being monitored. In the United Kingdom, for example,
information on approximately 1,000,000 treatment courses of neuraminidase
inhibitors has been collected. No change has been found from the adverse
effects recognized for these drugs, and no new safety concerns have been
identified. No evidence has been found of oseltamivir being directly
responsible for any fatality. [16]

Neuraminidase inhibitors provide a modest benefit in healthy people
with mild seasonal influenza based on randomised trials. In the context of
2009 pandemic influenza A (H1N1), the benefits of treatment with
neuraminidase inhibitors clearly outweigh the risk for adverse events
among those people who present with severe disease or who have risk
factors for developing severe disease (including pregnancy). In addition
to vaccination, antiviral treatment remains an effective and essential
element of a strategy to reduce severe illness and death among patients
with 2009 pandemic influenza A (H1N1).

References:

1. Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors
for preventing and treating influenza in healthy adults: systematic review
and meta-analysis BMJ 2009;339:b5106 Available from:
http://www.bmj.com/cgi/content/full/339/dec07_2/b5106

2. Freemantle N, Calvert M. What can we learn from observational
studies of oseltamivir to treat influenza in healthy adults? BMJ
2009;339:b5248 Available from:
http://www.bmj.com/cgi/content/full/339/dec07_2/b5248

3. World Health Organization [Internet]. Geneva. Pandemic (H1N1) 2009
- update 75. Available from:
http://www.who.int/csr/don/2009_11_20a/en/index.html

4. Weekly Influenza Surveillance Overview Accessed 9 December 2009
(Week 48) Available from:
http://www.ecdc.europa.eu/en/activities/surveillance/EISN/Pages/EISN_Bul...

5. U.S. Centers for Disease Control and Prevention [Internet].
Atlanta, GA, U.S. CDC Estimates of 2009 H1N1 Influenza Cases,
Hospitalizations and Deaths in the United States, April – October 17, 2009
Available from: http://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm

6. Jamieson DJ, Honein MA, Rasmussen SA, et al. H1N1 2009 influenza
virus infection during pregnancy in the USA. Lancet. 2009 Aug
8;374(9688):451-8.

7. Cullen G, Martin J, O’Donnell J et al Surveillance of the first
205 confirmed hospitalised cases of pandemic H1N1 influenza in Ireland, 28
April – 3 October 2009 Eurosurveillance 2009; 14, 44
http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19389

8. Domínguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically Ill
patients with 2009 influenza A(H1N1) in Mexico. JAMA. 2009 Nov
4;302(17):1880-7.

9. Louie JK, Acosta M, Winter K, et al. Factors associated with death
or hospitalization due to pandemic 2009 influenza A(H1N1) infection in
California. JAMA. 2009 Nov 4; 302(17):1896-902.

10. Uyeki T. Antiviral Treatment for Patients Hospitalized with 2009
Pandemic Influenza A (H1N1). N Eng J Med. (10.1056/NEJMopv0910738) 18
November 2009. Available from: http://h1n1.nejm.org/?p=1188

11. Jain S, Kamimoto L, Bramley AM, et al. Hospitalized patients with
2009 H1N1 influenza in the United States, April-June 2009. N Engl J Med
2009;361:1935-1944

12. Domínguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically ill
patients with 2009 influenza A(H1N1) in Mexico. JAMA 2009;302:1880-1887

13. McGeer A, Green KA, Plevneshi A, et al. Antiviral therapy and
outcomes of influenza requiring hospitalization in Ontario, Canada. Clin
Infect Dis 2007;45:1568-1575

14. Lee N, Cockram CS, Chan PK, Hui DS, Choi KW, Sung JJ. Antiviral
treatment for patients hospitalized with severe influenza infection may
affect clinical outcomes. Clin Infect Dis 2008;46:1323-1324

15. Hanshaoworakul W, Simmerman JM, Narueponjirakul U, et al. Severe
human influenza infections in Thailand: oseltamivir treatment and risk
factors for fatal outcome. PLoS One 2009;4(6):e6051

16. UK Suspected Adverse Drug Reaction (ADR) Analysis Influenza
antivirals - oseltamivir (Tamiflu) and zanamivir (Relenza) 26th November
2009 Available from:

http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=CON06290...

Competing interests:
None declared