Netherlands: Fatal Oseltamivir-Resistant Influenza Virus Infection

[Dutchy]

Fatal Oseltamivir-Resistant Influenza Virus Infection


To the Editor: The incidence of influenza A (H1N1) viruses that carry the neuraminidase H274Y mutation has increased by 30% this year in the Netherlands.1 Influenza A (H1N1) viruses that carry this mutation are resistant to oseltamivir but remain sensitive to zanamivir.2 However, these mutant viruses are considered to have attenuated pathogenicity.3,4

A 67-year-old man who had received a diagnosis of chronic lymphocytic leukemia 3 years earlier was admitted to the hospital because of dyspnea, dry cough, and fever.

One week before admission, he had received a course of cyclophosphamide, vincristine, and prednisolone chemotherapy.

At admission, his white-cell count was 137,000 per cubic millimeter, with 99% lymphocytes and no neutrophils. Because of acute respiratory failure, empirical antibacterial therapy was initiated, and mechanical ventilation was required by the second hospital day (Figure 1).

Computed tomography (CT) revealed patchy infiltrates in both lungs, and influenza A (H1N1) virus was detected in respiratory secretions. During the entire hospital course, no other respiratory pathogens were detected in bronchoalveolar-lavage specimens. The only other pathogens identified in blood cultures were Candida albicans and Enterococcus faecium, for which fluconazole and vancomycin were given.



Figure 1. Leukocyte Counts, Viral Loads, and Treatment during the Hospital Course in a Patient Infected with Influenza A (H1N1) Virus with the H274Y Mutation.

Panel A shows the patient's granulocyte and monocyte counts. The gradual increase in the granulocyte count was consistent with bone marrow recovery.

Panel B shows the viral load in the respiratory specimens. The dashed red line indicates the lower limit of detection. Various therapeutic and empirical antiviral therapies, shown in Panel C, and antibacterial and antifungal therapies, shown in Panel D, were given to the patient at different intervals (shaded bars).

The red portions of the bars in Panel C indicate detection of resistance mutations for either oseltamivir (neuraminidase H274Y) or amantidine (M2-channel L26F), and the blue boxes indicate detection of the wild-type genotype. The L26F resistance mutation in the M2 protein was detected only on day 20, whereas the H274Y mutation was present before and after oseltamivir was administered.

Oseltamivir was administered for the influenza virus infection, beginning on the sixth hospital day, but it was discontinued on day 13 because sequence analysis revealed the H274Y mutation, and no decrease in the viral load was observed. In retrospect, the H274Y mutation was present in the specimen obtained before oseltamivir therapy was initiated. The patient's hospital record and his family indicated that he had had no contact with patients who had received oseltamivir.

On day 15, amantadine was added to the patient's treatment regimen. Four days later, the neutrophil count increased, indicating bone marrow recovery. Mechanical ventilation was discontinued on day 20, and zanamivir by inhalation was initiated.

However, respiratory failure occurred on day 22, mechanical ventilation was reinstituted, and therapy with zanamivir was discontinued. On day 26, the influenza virus was no longer detectable.

Because sequence analyses showed an amantadine-resistance mutation in the viral M2 protein (L26F) and zanamivir therapy had been limited to three doses, clearance of the virus was probably due to recovery of the immune system. A second CT scan, obtained on day 28, revealed progression of the pulmonary infiltrates. Because of the poor prognosis, mechanical ventilation was discontinued on day 34. The patient died 3 days later.

It has been suggested that the H274Y mutation, which confers resistance to oseltamivir, leaves the influenza A (H1N1) virus severely compromised.3,4 However, the case we describe suggests that this oseltamivir-resistant virus can be pathogenic, at least in an immunocompromised patient.



Erhard van der Vries, M.Sc.
Bart van den Berg, M.D., Ph.D.
Martin Schutten, Ph.D.
Erasmus University Medical Center
3015 CE Rotterdam, the Netherlands

http://content.nejm.org/cgi/content/full/359/10/1074

[ironorehopper]

''At admission, his white-cell count was 137,000 per cubic millimeter, with 99% lymphocytes and no neutrophils''

This patient was very ill and presence of H1N1-oseltamivir-resistant in his lung may have accelerate exitus but with no neutrophils how could he fight a infectious disease?

[HenryN]

Commentary

http://www.recombinomics.com/News/09...74Y_Fatal.html

[ironorehopper]

This piece of news is dated back 5/23/2008:

[SEASONAL INFLUENZA, THE NETHERLANDS, ANTIVIRALS] Influenza virus claimed young lives
(http://www.ad.nl/binnenland/2312068/...ge_levens.html)

By RONALD OF GEENEN - ROTTERDAM - [Automatic Translation by Google - ms.]

An influenza virus strain that is the most commonly used anti viral, claimed the lives of two young patients demanded.

One patient was in a Rotterdam hospital, the other in Utrecht.

They were immunocompromised and were treated with the anti viral Tamiflu.

But the flu virus appeared insensitive to the drug.

That requires the Medical Journal Medical Contact today.

The news is a significant damper for doctors and virusfighters. Until recently, Tamiflu was seen as a last resort. The plea is our country's millions of doses stored to cope with large, life-influenza preparedness.

,, Until recently we thought that there was no flu strains were resistant to Tamiflu. This is incorrect. It is important that hospitals consider them,''says Charles Boucher Rotterdam virologists in Medical Contact.

Boucher:,, Each year thousand people die to the flu, but that his elderly. It was hard to lose these young people with flu.''

According to virologists Ab Osterhaus is still not entirely clear why the anti viral to the young patients offered no relief. ,, The virus goes very quickly around them in people with a weak immune system. Sometimes we see that Tamiflu than no control over the disease.''

Osterhaus can not exclude that the young patients were hit by a flu virus that is immune to Tamiflu. He urges doctors in hospitals, therefore, to be extra vigilant. ,, Now it is clear that Tamiflu is not helped, I recommend them to other virusremmers to deploy, as Relenza.''

Early this year it became known that a flu virus that is insensitive to Tamiflu is circulating in our country. Information provided by the Dutch Influenza Center proved to be the fourth of the surveyed flu samples.
-
------

[HenryN]

Dutch patient dies from Tamiflu-resistant H1N1 virus

Lisa Schnirring and Robert Roos Staff Writers

Sep 5, 2008 (CIDRAP News) – Amid concern about rising resistance to oseltamivir (Tamiflu) in influenza A/H1N1 viruses, a Dutch team this week reported the death of a leukemia patient who was infected with an H1N1 virus that was resistant to the antiviral drug.
In a letter in this week's New England Journal of Medicine (NEJM), the Dutch authors said the case suggests that oseltamivir-resistant H1N1 viruses can cause disease, despite evidence from animal studies that the resistance mutation makes the viruses much less dangerous. The letter said the man's virus was also resistant to amantadine, an older antiviral drug.
On Aug 20, the World Health Organization (WHO) reported that 31% of influenza A/H1N1 isolates from 16 countries that conducted recent tests carried the H274Y mutation, which confers resistance to oseltamivir. Resistance levels ranged from 100% (10 of 10 isolates) in Australia to 13% (4 of 32 isolates) in Chile.
Emergence of the oseltamivir-resistant H1N1 virus was first noted in Norway in January, and since then researchers have found the virus in 35 countries, including the United States and Canada.
The spread of the oseltamivir-resistant H1N1 virus has puzzled experts because it has not been clearly linked to treatment with the drug.
In the case report, authors from Erasmus University Medical Center in Rotterdam wrote that a 67-year-old man who was on chemotherapy in a 3-year battle with chronic lymphocytic leukemia was hospitalized with shortness of breath, a dry cough, and fever. On his second hospital day, he experienced acute respiratory failure, and his physicians placed him on a ventilator and started empirical antibiotic treatment.
Computed tomography (CT) revealed that the patient had patchy lung infiltrates, and tests on samples from his respiratory tract showed he had influenza A/H1N1.
On the sixth hospital day the man received oseltamivir, but by day 13 physicians discontinued the drug because sequence analysis of the virus revealed the H274Y mutation and there was no decrease in the viral load.
The authors reported that the mutation was found in samples obtained before the patient began oseltamivir therapy. The man's family and the hospital record revealed that he had had no contact with patients who were taking oseltamivir.
On the 15th hospital day the man's doctors prescribed amantadine, and after a few days his neutrophil count increased, a sign of bone marrow recovery, the group reported.
On day 20 doctors took the patient off the ventilator and instituted zanamivir treatment. However, 2 days later the man had respiratory failure again, and his medical team put him back on the ventilator and discontinued zanamivir therapy. (Like osteltamivir, zanamivir is a neuramnidase inhibitor, but no increase in zanamivir resistance has been reported recently.)
By day 26 physicians detected no influenza virus, but did note that sequence analysis showed an amantadine-resistance mutation in the viral M2 protein (L26F). They wrote that recovery of the immune system was probably responsible for clearing the virus, because the patient had received only three doses of zanamivir.
A repeat CT scan taken on day 28 showed that pulmonary infiltrates had progressed. Because of the man's poor prognosis, the ventilator was removed on day 34, and he died 3 days later.
The authors cited animal studies indicating that oseltamivir resistance leaves H1N1 viruses "severely compromised." Despite these reports, they wrote, "the case we describe suggests that this oseltamivir-resistant virus can be pathogenic, at least in an immunocompromised patient."
In an editorial published by Eurosurveillance in January, authorities said resistant viruses with the H274Y mutation had been seen in previous flu seasons but were rare and did not spread easily. But the more recent H1N1 isolates with the mutation were "fitter" and were spreading in the community, they wrote.
Van der Vries E, Van den Berg B, Schutten M. Fatal oseltamivir-resistant influenza virus infection. N Engl J Med 2008 Sep 4;359(10):1074-76 [Full text]
See also:
Aug 25 CIDRAP News story "H1N1 viruses growing more resistant to Tamiflu"

http://www.cidrap.umn.edu//cidrap/co...esistance.html

[AlaskaDenise]

Originally Posted by niman

Commentary

http://www.recombinomics.com/News/09...74Y_Fatal.html

Commentary

Fatal H1N1 Tamiflu Resistance
Recombinomics Commentary 17:58
September 5, 2008

Oseltamivir was administered for the influenza virus infection, beginning on the sixth hospital day, but it was discontinued on day 13 because sequence analysis revealed the H274Y mutation, and no decrease in the viral load was observed. In retrospect, the H274Y mutation was present in the specimen obtained before oseltamivir therapy was initiated. The patient's hospital record and his family indicated that he had had no contact with patients who had received oseltamivir. On day 15, amantadine was added to the patient's treatment regimen. Four days later, the neutrophil count increased, indicating bone marrow recovery. Mechanical ventilation was discontinued on day 20, and zanamivir by inhalation was initiated. However, respiratory failure occurred on day 22, mechanical ventilation was reinstituted, and therapy with zanamivir was discontinued. On day 26, the influenza virus was no longer detectable. Because sequence analyses showed an amantadine-resistance mutation in the viral M2 protein (L26F) and zanamivir therapy had been limited to three doses, clearance of the virus was probably due to recovery of the immune system. A second CT scan, obtained on day 28, revealed progression of the pulmonary infiltrates. Because of the poor prognosis, mechanical ventilation was discontinued on day 34. The patient died 3 days later.

The above comments are from a correspondence to the New England Journal of Medicine on a patient who was sequentially treated with three antivirals, oseltamivir (Tamiflu), amantadine, and zanamivir (Relenza). The death of the patient was directly linked to his underlying cancer, but the monitoring of viral load and sequencing of sequential isolates provided additional insight into antiviral resistance.

The oseltamivir treatment did not decrease viral load, but when H274Y was identified in an isolate, treatment shifted from oseltamivir to amantadine, which cause a brief decline in viral load, but the emergence of L26F in the M2 target. This led to a shift to zanamivir, and an associated re-emergence of a wild type M2, indicting the L26F variant was not evolutionarily fit. Zanamivir treatment was only for three days, and the viral load subsequently declined, but the H274Y was present in all isolates, including an isolate from a sample collected prior to treatment.

The above case demonstrates the evolutionarily fitness of H1N1 with H274Y, and the failure of oseltamivir treatment to reduce the viral load. Thus, in countries with high levels of H274Y in H1N1, initial treatment with zanamivir is preferred in the absence of sequence data demonstrating a wild type N1.

H274Y was reported widespread in northern Europe, but recent reports suggest resistance may now be at 100% in South Africa, Australia, Guatemala, and Honduras. The vaccine targets for 2007/2008 in the northern hemisphere, and 2008 in the summer hemisphere have Solomon Island/3 as the H1N1 target. The new vaccine for 2008/2009 has replaced Solomon Island/3 (clade 2A) with Brisbane/59 (clade 2B). The isolates described above are clade 2B, but the dominant sub-clade in South Africa has already acquire a cluster of polymorphisms, which may limit the utility of the new vaccine.

Thus, H274Y levels in H1N1 may increase in the upcoming season, which would lead to increased zanamivir usage. However, zanamivir resistance, Q136K or Q136R, has been reported on a clade 2B background in 2008 isolates in Thailand and the United States as well as 2007 isolates in South Africa and Australia, raising concerns of an increase in evolutionarily fit H1N1 with Q136K.


.

[ironorehopper]

One shouldn't leave behind the underlying conditions of this patient, that probably caused the death finally. The patient was admistered chemotherapy and his immune system was badly affected by this drugs with agranulocytopenia.

Blood staining was positive for Candidiasis.

I cared elderly people in nursing home and seasonal human influenza epidemics caused usually very high mortality and even people with severe immunosuppression (transplanted patients, disabled people) were badly affected.

This happened well before NA-inhibitors were sold.

This patient was very ill at the time of influenza infection and it is almost impossible to demostrate that he died because infected by H1N1 with H274Y.

That's only for say an otherwise expected death in an immunocompromised patient shouldn't be taken as example of potential increased virulence of H1N1 during past season or in the incoming one.

[kent nickell]

""Fatal H1N1 Tamiflu Resistance
Recombinomics Commentary 17:58
September 5, 2008

The above case demonstrates the evolutionarily fitness of H1N1 with H274Y, and the failure of oseltamivir treatment to reduce the viral load. Thus, in countries with high levels of H274Y in H1N1, initial treatment with zanamivir is preferred in the absence of sequence data demonstrating a wild type N1.

Thus, H274Y levels in H1N1 may increase in the upcoming season, which would lead to increased zanamivir usage. However, zanamivir resistance, Q136K or Q136R, has been reported on a clade 2B background in 2008 isolates in Thailand and the United States as well as 2007 isolates in South Africa and Australia, raising concerns of an increase in evolutionarily fit H1N1 with Q136K.""


If these resistance patterns developing on N1 also become widely applicable to H5N1 it would take most of our antivirals out of play. They may still be somewhat useful in decreasing viral load but I think these results should suggest caution on an over reliance on antivirals for protection or treatment. Planners would probably want to think more about social distancing, good N95 mask fitting, prepandemic vaccine use etc...

[Treyfish]

Date: Fri 05 Sep 2008
Source: CDRAP [edited]
<http://www.cidrap.umn.edu/cidrap/content/influenza/general/news/sep0508resistance.html>


Dutch patient dies from Tamiflu-resistant H1N1 virus
----------------------------------------------------
Amid concern about rising resistance to oseltamivir (Tamiflu) in
influenza A/H1N1 viruses, a Dutch team this week reported the death
of a leukemia patient who was infected with an H1N1 virus that was
resistant to the antiviral drug. In a letter in this week's New
England Journal of Medicine (NEJM) [week of 31 Aug 2008], the Dutch
authors said the case suggests that oseltamivir-resistant H1N1
viruses can cause disease, despite evidence from animal studies that
the resistance mutation makes the viruses much less dangerous. The
letter said the man's virus was also resistant to amantadine, an
older antiviral drug.

On 20 Aug 2008, the World Health Organization (WHO) reported that 31
percent of influenza A/H1N1 isolates from 16 countries that conducted
recent tests carried the H274Y mutation, which confers resistance to
oseltamivir. Resistance levels ranged from 100 percent (10 of 10
isolates) in Australia to 13 percent (4 of 32 isolates) in Chile.

Emergence of the oseltamivir-resistant H1N1 virus was first noted in
Norway in January, and since then researchers have found the virus in
35 countries, including the United States and Canada.

The spread of the oseltamivir-resistant H1N1 virus has puzzled
experts because it has not been clearly linked to treatment with the
drug. In the case report, authors from Erasmus University Medical
Center in Rotterdam wrote that a 67-year-old man who was on
chemotherapy in a 3-year battle with chronic lymphocytic leukemia was
hospitalized with shortness of breath, a dry cough, and fever. On his
2nd hospital day, he experienced acute respiratory failure, and his
physicians placed him on a ventilator and started empirical
antibiotic treatment.

Computed tomography (CT) revealed that the patient had patchy lung
infiltrates, and tests on samples from his respiratory tract showed
he had influenza A/H1N1. On the 6h hospital day the man received
oseltamivir, but by day 13 physicians discontinued the drug because
sequence analysis of the virus revealed the H274Y mutation and there
was no decrease in the viral load. The authors reported that the
mutation was found in samples obtained before the patient began
oseltamivir therapy. The man's family and the hospital record
revealed that he had had no contact with patients who were taking oseltamivir.

On the 15th hospital day the man's doctors prescribed amantadine, and
after a few days his neutrophil count increased, a sign of bone
marrow recovery, the group reported.

On day 20 doctors took the patient off the ventilator and instituted
zanamivir treatment. However, 2 days later the man had respiratory
failure again, and his medical team put him back on the ventilator
and discontinued zanamivir therapy. (Like osteltamivir, zanamivir is
a neuramnidase inhibitor, but no increase in zanamivir resistance has
been reported recently.)

By day 26 physicians detected no influenza virus, but did note that
sequence analysis showed an amantadine-resistance mutation in the
viral M2 protein (L26F). They wrote that recovery of the immune
system was probably responsible for clearing the virus, because the
patient had received only 3 doses of zanamivir.

A repeat CT scan taken on day 28 showed that pulmonary infiltrates
had progressed. Because of the man's poor prognosis, the ventilator
was removed on day 34, and he died 3 days later.

The authors cited animal studies indicating that oseltamivir
resistance leaves H1N1 viruses "severely compromised." Despite these
reports, they wrote, "the case we describe suggests that this
oseltamivir-resistant virus can be pathogenic, at least in an
immunocompromised patient."

In an editorial published by Eurosurveillance in January 2008,
authorities said resistant viruses with the H274Y mutation had been
seen in previous flu seasons but were rare and did not spread easily.
But the more recent H1N1 isolates with the mutation were "fitter" and
were spreading in the community, they wrote.

[Reference] Van der Vries E, Van den Berg B, Schutten M. Fatal
oseltamivir-resistant influenza virus infection. N Engl J Med 04 Sep
2008 359(10):1074-76

[Byline: Lisa Schnirring and Robert Roos]

--
Communicated by:
ProMED-mail Rapporteur Brent Barrett

[It is not clear if the increased pathogenesis of the virus that
fatally infected this patient was due to its improved fitness or to
the immunocompromised state of the patient himself. - Mod.TY]
http://tinyurl.com/5fb5m4