The swine flu discussion thread....for scientific discussion only.

tallaght01

I've decided to start a new swine flu thread, for those people who want to look at it from a scientific or clinical practice angle.
It's for discussion of the clinical and scientific issues relating to this virus only. You don't have to be a scientist or a medic, but you ave to be willing to engage in scientific or clinical discussion.

There's already another thread which has become a bit of a general chat thread ("I personally think it's blown out of all proportion", "I think the vaccine makers are trying to kill us" etc. Stuff with no solid evidence.), with not much in the way of actual scientific or medical discussion.

This thread is purely for discussion of clinical issues, public health strategy, or the basic sciences underlying this pandemic.

I'll get the ball rolling:

http://www.mja.com.au/public/issues/191_03_030809/kau10748_fm.html

This is a nice (and free) article in the medical journal of Australia, describing briefly, the first 6 patients in oz who ended up in ICU because of swine flu.

Note 2 of them were previously well. I think this is a point being missed. Not many previously well people are DYING of swine flu, but some are ending up ventilated in ICU.

Note also the pregnant woman. There have been a few case reports of pregnant women, and onset of preterm labour secondary to swine flu infection.

Note also patient 5, with COPD, who had no pyrexia, and a normal CRP.

With a ventilation rate of about 0.5% this could be big bananas if we get very high attack rates.

Also, look how long people were ventilated for in this series....about 2 weeks on average. That has pretty significant implications for ICU resources in the winter in Ireland.

DrIndy

So - are these people vulnerable because they have a random, rare innate immune weakness in fighting off the particular antigens of swine flu - or has the virus begun to mutate?

Is this just good old fashioned bad luck - where someone, somewhere previously healthy just gets into trouble?

Has a common variable or exposure been identified?

I'm buggered anyway - for two days I volunteered with one of the nurses to run an impromptu "piggy clinic" in my ED which involved seeing everyone with swine flu in 2 isolation rooms simply to get everyone in and out of the department ASAP. Most were the worried well (I told the ones with any sense of humour to come back if they noticed any curly tails or an uncontrollable desire to roll in mud) - and the rest who were sicker had in fact other types of pneumonia - this kept a lot of ambulance cases out of the main department and crossinfection down.

tallaght01

No new mutations have been thrown up so far. I suspect they're similar to the people who succumb to the normal flu every year. I remember admitting a kiddy to our ward last year straight after her young healthy mum had died of H3N1.

The flu clinics have been a bizarre setup. A friend of mine was working on one as an A+E SHO. She was convinced that the environment isn't conducive to properly examining people. Her example was that she was working in a tent, where they had to fully gown up between patients, and there was less equipment. Are they triaging properly? Does this involve them coming into the normal triage area and spreading their pox around? Remember, infection is thought to occur when you're within one metre of someone who's shedding for 15 minutes or more (though, from what i remember, that's derived from seasonal flu studies, rather than swine flu).

No common type of exposure has been identified, to my knowledge. For example, we're not seeing lots of hospitalised patients who have been exposed to people who might be expected to have a high viral load (what i mean is the families of ICU patients aren't ending up in ICU, or even becoming particularly unwell). I do, however, have to declare anecdote there :P

SomeDose

We've officially moved to Treatment phase, so diagnoses are being made in the community on a clinical basis rather than the need to swab and get virology involved. Patients are then issued with a token for their Tamiflu treatment and advised to get a "flu friend" (I kid you not) to pick them up from designated collection points. Although we still get occasional patients presenting at the hospital themselves trying to collect the drug from pharmacy...so we have to politely tell them to quickly vacate the premises ASAP!

There's still a few grey areas in our policy though. Inpatients with suspected swine flu are started on Tamiflu and swabbed, those coming back negative for swine flu (but Influenza A/B positive) are withdrawn from anti-viral treatment...but debate about whether or not it should be continued, considering that's what it's actually licensed for. How are these kind of cases being handled in Oz?

The other practical problem is regarding the really sick ITU cases who are mechanically ventilated. Tamiflu is theoretically contra-indicated in those who develop acute renal failure, so inhaled Relenza is then the drug of choice. Thing is, Relenza can't be put through a ventilator so Tamiflu has to be ground up and put down feeding tubes. I'm not aware of any bioavailability data or studies to see how effective this method may be, but it'd be interesting to see if it affects outcomes in any way.

EDIT: Also meant to say, we have mandatory notification to the national teratology service for any pregant women started on Tamiflu/Relenza...I presume this is the case in other jurisdictions?

tallaght01

SomeDose wrote: »

We've officially moved to Treatment phase, so diagnoses are being made in the community on a clinical basis rather than the need to swab and get virology involved. Patients are then issued with a token for their Tamiflu treatment and advised to get a "flu friend" (I kid you not) to pick them up from designated collection points. Although we still get occasional patients presenting at the hospital themselves trying to collect the drug from pharmacy...so we have to politely tell them to quickly vacate the premises ASAP!

There's still a few grey areas in our policy though. Inpatients with suspected swine flu are started on Tamiflu and swabbed, those coming back negative for swine flu (but Influenza A/B positive) are withdrawn from anti-viral treatment...but debate about whether or not it should be continued, considering that's what it's actually licensed for. How are these kind of cases being handled in Oz?

The other practical problem is regarding the really sick ITU cases who are mechanically ventilated. Tamiflu is theoretically contra-indicated in those who develop acute renal failure, so inhaled Relenza is then the drug of choice. Thing is, Relenza can't be put through a ventilator so Tamiflu has to be ground up and put down feeding tubes. I'm not aware of any bioavailability data or studies to see how effective this method may be, but it'd be interesting to see if it affects outcomes in any way.

EDIT: Also meant to say, we have mandatory notification to the national teratology service for any pregant women started on Tamiflu/Relenza...I presume this is the case in other jurisdictions?

We used the flu friend system here in oz. it's the only way to go for infection control purposes.

here's a paper on bioavailability of NG oseltamivir. it's free access, and was conducted during the avian flu scare, but should still hold water.

http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Search&db=pmc&term=1932-6203%5BTA%5D%20AND%202008%5BPDAT%5D%20AND%20e3410%5BPG%5D

Why aren't they using tamiflu syrup, btw?

Have you seen this paper?

The Influence of Oseltamivir Treatment on the Risk of Stroke after Influenza Infection. Cardiology 2009;113:98-107.

http://content.karger.com/ProdukteDB/produkte.asp?doi=10.1159/000172796

It's s study claiming that oseltemivir reduces risk of stroke post-influenza. I guess, as it reduces the severity of the primary illness, it may not be a huge surprise. But my (very basic) badstats radar is beeping. Confidence intervals for stroke rates cross over each other all over the place, and some non statistically significant numbers used to calculate hazard ratios. They've also got very small numbers of actual stroke in the first place. But I'll ask one of our epidemiologists about it today. it's also funded by the company who make tamiflu!

SomeDose

tallaght01 wrote: »

Why aren't they using tamiflu syrup, btw?

Lack of availability, plain and simple. It's rarer than hen's teeth around these parts, a situation which is unlikely to change in the short- to medium-term, and any syrup is strictly limited to only paeds cases <1yo.

Have you seen this paper?

The Influence of Oseltamivir Treatment on the Risk of Stroke after Influenza Infection. Cardiology 2009;113:98-107.

http://content.karger.com/ProdukteDB/produkte.asp?doi=10.1159/000172796

It's s study claiming that oseltemivir reduces risk of stroke post-influenza. I guess, as it reduces the severity of the primary illness, it may not be a huge surprise. But my (very basic) badstats radar is beeping. Confidence intervals for stroke rates cross over each other all over the place, and some non statistically significant numbers used to calculate hazard ratios. They've also got very small numbers of actual stroke in the first place. But I'll ask one of our epidemiologists about it today. it's also funded by the company who make tamiflu!

Seems a bit ropey alright. The average age of both cohorts is very low in terms of stroke risk, as you say the absolute stroke risk is small to start with, so I'm not sure how relevant it is in the grand scheme of things. And seeing as my badstat radar is as basic as they come, I can't really assess how robust their multivariate analysis was in terms of adjusting for all the confounders in the comparison group.

Overall: Meh!

tallaght01

What's happening for the rest of you guys with tamiflu, in terms of 2 issues:

1) Are health staff getting free tamiflu if they're exposed or get sick? Over here they're not, unless they have a pre-existing illness. They're supposed to pay for it, which is a bit much if it's caught in the line of work!

2) Is there a national stockpile of tamiflu in Ireland? We have a situation over here where a GP can give tamiflu to anyone on a private script. But we also have a national stockpile that's supplied for free if the patient meets certain criteria.

What's the access situation like in Ireland and the UK?

DrIndy

In oz the new update is to SWAB health care workers, but NOT treat.

In new zealand - its treat all health care workers and don't bother swabbing.

tallaght01

DrIndy wrote: »

In oz the new update is to SWAB health care workers, but NOT treat.

In new zealand - its treat all health care workers and don't bother swabbing.

No, we're treating health care workers in oz, but they're not getting it free. The hospitals were supposed to buy tamiflu for their staff. But they may not have Well, that's the guidelines anyway. I think some of the hospitals are freestyling it a bit :P

Staff who have a pre-existing risk factor get it free from the national stockpile though.

Ricky91t

Hello people,I'm not anything to do with biology but i do like it(5 years at school)

But would I be right in thinking when we get nearer to winter the common flu will being to spread and if swine flu and common flu mix will the tamiflu jab have any affect?

And if that can/might happen if there another vaccine being developed?

Turtwig

Ricky91t wrote: »

Hello people,I'm not anything to do with biology but i do like it(5 years at school)

But would I be right in thinking when we get nearer to winter the common flu will being to spread and if swine flu and common flu mix will the tamiflu jab have any affect?

And if that can/might happen if there another vaccine being developed?

It seems you may be mixing up at few things here. Firstly though I'm not a biologist either, so I'm guessing Tallaght or one of the folks will be alot more helpful

Tamiflu isn't a vaccine; it's an 'anti flu' medicine used to combat the flu, it was intially used a preventative measure to control the spread of swine flu by giving it to all people who were in contact with an infected person. However as most(all?) countries have moved away from containment this is no longer the case.

Apparently the thing to watch at moment is which flu is dominating in the Southern Hemisphere, which supposedly around 90%* of cases of flu are Swine flu : if current trends continue then supposedly only the Swine Flu vaccine will be necessary.

Read this in Newscientist will update with link as soon as I can.I'm pretty sure though that this figure was published when the pandemic was just beginning - the testing for swine flu was still being carried out.

Ricky91t

Malty_T wrote: »

It seems you may be mixing up at few things here. Firstly though I'm not a biologist either, so I'm guessing Tallaght or one of the folks will be alot more helpful

Tamiflu isn't a vaccine; it's an 'anti flu' medicine used to combat the flu, it was intially used a preventative measure to control the spread of swine flu by giving it to all people who were in contact with an infected person. However as most(all?) countries have moved away from containment this is no longer the case.

Apparently the thing to watch at moment is which flu is dominating in the Southern Hemisphere, which supposedly around 90%* of cases of flu are Swine flu : if current trends continue then supposedly only the Swine Flu vaccine will be necessary.

Read this in Newscientist will update with link as soon as I can.I'm pretty sure though that this figure was published when the pandemic was just beginning - the testing for swine flu was still being carried out.

Yeah sorry that's what i meant,An anti flu treatment,

But surely by the time the vaccine is released the flu could of mutated?

jen_23

A swine flu mutation has been discovered in Brazil

new strain of the H1N1 virus has been discovered in Brazil. Scientists from the Adolfo Lutz Bacteriological Institute in Sau Paulo discovered the new strain of the H1N1 virus in a 26-year-old patient on Tuesday, June 16.

http://www.nowpublic.com/health/swine-flu-mutation-new-strain-h1n1-discovered-brazil

Ricky to answer your question it's a haemagglutinin protein that has been mutated in this newly discovered strain.

The vaccine being used agains H1N1 is of HA (haemagglutinin) type so it may have the capability to work against a variety of mutations. (the vaccine is also effective against the H5N1 (or bird flu) strain).
However, there have been no reports of the vaccine being effective against different HA types.

Although cross protection against influenza strains of the same hemagglutinin or HA type has been achieved through the use of vaccines with adjuvants (e.g., cross-protection against H5N1 A/Vietnam and A/Indonesia strains), protection against strains with different HA types, as shown in this study, has not been reported.

http://www.dddmag.com/News-Investigational-H1N1-VLP-Vaccine-041609.aspx

I suppose that as of yet there may not be an answer to your question. We may just have to wait and see what happens.

tallaght01

The virus hasn't mutated on any large scale yet. No point on stressing too much about it until then. It's not the kind of thing you can really prepare for. It's very unlikely to mutate into some super virus. It will more likely mutate it's haemagluttingin or neuramindase, like the normal flu does all the time.

It's unlikely that it will have mutated by the time the vaccine arrives. Certainly to the extent that it would make the vaccine useless.

tallaght01

jen_23 wrote: »

(the vaccine is also effective against the H5N1 (or bird flu) strain).

What's your source for this??????

tallaght01

Anteater flu!!!!

This was just published in Emerging infectious diseases, the journal of the CDC in Atlanta.

Nofs S, Abd-Eldaim M, Thomas KV, Toplon D, Rouse D, Kennedy M. Influenza virus A (H1N1) in giant anteaters (Myrmecophaga tridactyla). Emerg Infect Dis [serial on the Internet]. 2009 July [date cited]. Available from http://www.cdc.gov/EID/content/15/7/1081.htm

It describes a colony of anteaters catching the flu from their human caretakers. It's not swine flu, and it happened in 2007.

But it looks like another species leap, with no real change in virulence factors.

The_Conductor

Hi-

I was wondering about the contra-indications and warnings from the manufacturer about prescribing Tamiflu to male adolescents, in light of the US reports concerning psychosis and incidents of self-harm. This does not appear to have been reported on other than stateside- does the HSE intend to do anything- after yesterday's NHS guidance to GPs?

S.

tallaght01

what was yesterday's NHS guidance?

The_Conductor

tallaght01 wrote: »

what was yesterday's NHS guidance?

In short- its just further info about abondoning containment- and the evolution of treatment and other strategies. It includes:

• No more lab testing- diagnosis to be made solely on basis of presented symptoms
• Tracing of those in contact with confirmed or suspected cases to cease
• Decision on closure of schools and other local facilities devolved to local decision makers
• The decision on whether to prescribe Tamiflu or Relenza is entirely discretionary- manufacturer guidelines updated as attached
• No further prescriptions of either Tamiflu or Relenza to healthy population members other than long-term conditions, children under five and pregnant women- buffer creation to be abondoned.
• Antiviral voucher scheme to be implemented (doctors to give antiviral vouchers to patients, medicine to be distributed at local distribution points- which may be a local pharmacy or a designated public building
• General phone line to be given to patients with queries Telephone: 020 7084 84 84

All pretty standard.
The updated manufacturer guidance does mention adolescent males and incidents of self harming being associated in a small but statistically significant number of cases of those prescribed Tamiflu.

Further info about the MHRAs site for reporting side-effects of Tamiflu or Relenza: http://www.mhra.gov.uk/Safetyinformation/Swinefluinformation/index.htm

No details on what the other antivirals are.

The latest news concerns the likelyhood of 30% population showing symptoms by week 35- and gives details of the new pandemic phone line for GPs.

SAGE is updating the risk profile group- but at present it includes:

* Patients who have had drug treatment for asthma in the past three years
* Pregnant women
* People aged 65 years and older
* Children under five years old people with chronic lung disease
* People with chronic heart disease
* People with chronic kidney disease
* People with chronic liver disease
* People with chronic neurological disease
* People with immunosuppression (whether caused by disease or treatment)
* People diabetes mellitus

Its thought SAGE's risk profile may take into account the reports from Argentina of young healthy adults being particularly badly affected- this is ongoing.

tallaght01

The journal Nature have pre-released an abstract/letter of this paper online. It's suggesting that swine flu is more pathological to the lungs (in experimental mice) than normal influenza A. Their experiments showed more severe lesions in the mice lungs. they also talk about the virus replicating more effectively that seasonal flu. i presume they mean it replicates more effectively in the lungs, but the methodology isn't available yet:

http://www.nature.com/nature/journal/vnfv/ncurrent/abs/nature08260.html

Influenza A viruses cause recurrent outbreaks at local or global scale with potentially severe consequences for human health and the global economy. Recently, a new strain of influenza A virus was detected that causes disease in and transmits among humans, probably owing to little or no pre-existing immunity to the new strain. On 11 June 2009 the World Health Organization declared that the infections caused by the new strain had reached pandemic proportion. Characterized as an influenza A virus of the H1N1 subtype, the genomic segments of the new strain were most closely related to swine viruses1. Most human infections with swine-origin H1N1 influenza viruses (S-OIVs) seem to be mild; however, a substantial number of hospitalized individuals do not have underlying health issues, attesting to the pathogenic potential of S-OIVs. To achieve a better assessment of the risk posed by the new virus, we characterized one of the first US S-OIV isolates, A/California/04/09 (H1N1; hereafter referred to as CA04), as well as several other S-OIV isolates, in vitro and in vivo. In mice and ferrets, CA04 and other S-OIV isolates tested replicate more efficiently than a currently circulating human H1N1 virus. In addition, CA04 replicates efficiently in non-human primates, causes more severe pathological lesions in the lungs of infected mice, ferrets and non-human primates than a currently circulating human H1N1 virus, and transmits among ferrets. In specific-pathogen-free miniature pigs, CA04 replicates without clinical symptoms. The assessment of human sera from different age groups suggests that infection with human H1N1 viruses antigenically closely related to viruses circulating in 1918 confers neutralizing antibody activity to CA04. Finally, we show that CA04 is sensitive to approved and experimental antiviral drugs, suggesting that these compounds could function as a first line of defence against the recently declared S-OIV pandemic.

tallaght01

Nice report from the CDC about the patterns of swine flu patients in a specialised ICU in Michigan. It really highlights how this virus is hitting the very obese. Note also the use of high dose oseltamivir. Underlining is my own. Just done to highlight what I thought were some interesting points:

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5827a4.htm?s_cid=mm5827a4_e


-Care Patients With Severe Novel Influenza A (H1N1) Virus Infection --- Michigan, June 2009

On July10, 2009, this report was posted as an MMWR Dispatch on the MMWR website (http://www.cdc.gov/mmwr).

In April 2009, CDC reported the first two cases in the United States of human infection with a novel influenza A (H1N1) virus (1). As of July 6, a total of 122 countries had reported 94,512 cases of novel influenza A (H1N1) virus infection, 429 of which were fatal; in the United States, a total of 33,902 cases were reported, 170 of which were fatal.* Cases of novel influenza A (H1N1) virus infection have included rapidly progressive lower respiratory tract disease resulting in respiratory failure, development of acute respiratory distress syndrome (ARDS), and prolonged intensive care unit (ICU) admission (2). Since April 26, communitywide transmission of novel influenza A (H1N1) virus has occurred in Michigan, with 655 probable and confirmed cases reported as of June 18 (Michigan Department of Community Health [MDCH], unpublished data, 2009). This report summarizes the clinical characteristics of a series of 10 patients with novel influenza A (H1N1) virus infection and ARDS at a tertiary-care ICU in Michigan. Of the 10 patients, nine were obese (body mass index [BMI] ≥30), including seven who were extremely obese (BMI ≥40); five had pulmonary emboli; and nine had multiorgan dysfunction syndrome (MODS). Three patients died. Clinicians should be aware of the potential for severe complications of novel influenza A (H1N1) virus infection, particularly in extremely obese patients.

The surgical intensive care unit (SICU) at the University of Michigan Health System (UMHS) specializes in the evaluation of adult patients with severe ARDS for advanced mechanical ventilation and possible extracorporeal membrane oxygenation (ECMO). During May 26--June 18, the unit received 13 patients for evaluation from outlying hospitals, 10 of whom were confirmed to have novel influenza A (H1N1) virus infection by testing of respiratory specimens with real-time reverse transcription--polymerase chain reaction (rRT-PCR) at MDCH and CDC. Direct immunofluorescent antibody staining at UMHS was negative for influenza A in all 10 patients. Viral culture at UMHS was positive for influenza A in two patients. All 10 patients were referred to the SICU because of severe hypoxemia, ARDS, and an inability to achieve adequate oxygenation with conventional ventilation modalities. Medical records of all 10 patients were reviewed for demographics, case characteristics, clinical findings, and clinical course.

Illness onset of the 10 patients occurred during May 22--June 13. The median age was 46 years (range: 21--53 years); nine patients were obese, including seven who were extremely obese (Table). In the three fatal cases, the time from illness onset to death ranged from 17 to 30 days. Four patients received steroids during their illness before transfer to the SICU; two with asthma received oral steroids as outpatients during the initial evaluation and treatment of their acute respiratory illness (one was on chronic oral steroids for underlying lung disease, and one without chronic pulmonary disease was prescribed oral steroids and oral antimicrobials). Five patients received intravenous corticosteroids during their SICU hospitalization: four for treatment of severe vasopressor-dependent refractory septic shock, and one for continuation of therapy for chronic pulmonary disease.

All 10 patients required initial advanced mechanical ventilation (high-frequency oscillatory or bilevel ventilation with high mean airway pressures [32--55 cm H20]). Two patients required veno-venous ECMO support. Six required continuous renal replacement therapy (CRRT) for acute renal failure. Upon transfer to the SICU, five had elevated white blood cell counts, and one had a decreased white blood cell count. The median white blood cell count (WBC) was 9,500 cells/mm3 (range: 3,700--19,700 cells/mm3; normal: 4,000--10,000 cells/mm3). All ten patients had elevated aspartate transaminase (AST) levels. The median AST level was 83.5 IU/L (range: 41--109 IU/L; normal: 8--30 IU/L). Six of the nine patients who were tested had elevated creatine phosphokinase (CPK) levels. The median CPK level was 999 IU/L (range: 51-- 6,572 IU/L; normal: 38--240 IU/L). Nine patients were admitted to the SICU with MODS, and nine manifested septic shock requiring vasopressor support. All 10 patients required tracheostomy.

Chest radiograph findings in all 10 patients were abnormal, with bilateral infiltrates consistent with severe multilobar pneumonia or ARDS. Computed tomography (CT) of the chest confirmed pulmonary emboli in four patients at admission to the SICU and in one additional patient who deteriorated 6 days after admission to the SICU. A hypercoagulable state was evident in two additional patients. One of these patients had frequent clotting of the CRRT circuit despite regional citrate anticoagulation. Another patient had bilateral iliofemoral deep venous thromboses, necessitating systemic heparin anticoagulation. None of the 10 patients had evidence of concomitant disseminated intravascular coagulation by laboratory studies.

As of July 8, none of the 10 patients had evidence of bacterial infection after admission to the SICU or in subsequent blood, bronchoalveolar lavage, or urine cultures. All patients received antibiotic therapy upon admission to the initial hospitals, and broad spectrum antibiotics were continued upon transfer to the SICU.

The timing of antiviral treatment initiation was difficult to determine because patients were transferred from other hospitals; however, the estimated median number of days from illness onset to initiation of antiviral treatment was 8 days (range: 5--12 days). During their care at the SICU, all 10 patients were administered oseltamivir and amantadine beyond the standard 5-day course, including higher-dose oseltamivir (up to 150 mg orally twice a day), with dose adjustment for decreased renal function.

As of July 8, one patient remained in the SICU requiring ECMO, one remained on advanced mechanical ventilation, five were transferred back to the referring facility in stable condition, and three had died. Autopsies were performed on two patients; results in both patients confirmed bilateral severe hemorrhagic viral pneumonitis with interstitial inflammation and diffuse alveolar damage and concurrent bilateral pulmonary emboli.

Reported by: LM Napolitano, MD, PK Park, MD, KC Sihler, MD, T Papadimos, MD, Div of Acute Care Surgery, Univ of Michigan Health System; C Chenoweth, MD, S Cinti, MD, C Zalewski, MPH, Div of Infectious Diseases and Infection Control, Univ of Michigan Health System; R Sharangpani, MD, Univ of Michigan School of Public Health; P Somsel, DrPH, E Wells, MD, Michigan Dept of Community Health. AM Fry, MD, AE Fiore, MD, MPH, JM Villanueva, PhD, S Lindstrom, PhD, TM Uyeki, MD, Influenza Div, National Center for Immunization and Respiratory Diseases, CDC.

Editorial Note:

This report describes the clinical findings of a limited series of patients with novel influenza A (H1N1) virus infection and refractory ARDS admitted to a tertiary-care ICU for advanced mechanical ventilation. This patient group represents the most severely ill subset of persons with novel influenza A (H1N1) virus infection and is notable for the predominance of males, the high prevalence of obesity (especially extreme obesity), and the frequency of clinically significant pulmonary emboli and MODS. All required advanced mechanical ventilator support, reflecting severe pulmonary damage. The pulmonary compromise described in this report suggests that severe pulmonary damage occurred as a result of primary viral pneumonia. Although data are not available, this damage also might be attributable to secondary host immune responses (e.g., through cytokine dysregulation triggered by high viral replication). However, bacterial coinfection in the lung not identified by blood culture or bronchoalveolar lavage cannot be excluded.

Only three of the patients in this series had underlying conditions associated with a higher risk for seasonal influenza complications. Conditions associated with an increased risk for complications from seasonal influenza include extremes of age, pregnancy, chronic underlying medical conditions (e.g., pulmonary, cardiovascular, hepatic, hematologic, neurologic, and neuromuscular conditions and metabolic disorders or immunosuppression), long-term aspirin therapy in persons aged ≤18 years, and being a resident of a nursing home or other chronic-care facility (3). However, fatal disease associated with novel influenza A (H1N1) virus infection has occurred among persons without these conditions who previously were healthy (2).

The high prevalence of obesity in this case series is striking. Whether obesity is an independent risk factor for severe complications of novel influenza A (H1N1) virus infection is unknown. Obesity has not been identified previously as a risk factor for severe complications of seasonal influenza. In a mouse model, diet-induced obese mice had significantly higher mortality when infected with seasonal influenza virus compared with their leaner counterparts (4). In addition, extremely obese patients have a higher prevalence of comorbid conditions that confer higher risk for influenza complications, including chronic heart, lung, liver, and metabolic diseases.

One study of patients admitted to critical-care units indicated that obesity was an independent risk factor for mortality (5). A meta-analysis concluded that prolonged duration of mechanical ventilation and longer SICU length of stay, but not mortality, are associated with obesity (6). Another study reported that extremely obese ICU patients had higher rates of mortality, nursing home admission, and ICU complications compared with moderately obese patients (BMI 30--39) (7). Further investigations of the role of extreme obesity and accompanying comorbidities in severely ill patients with novel influenza A (H1N1) virus infection are needed.

Pulmonary emboli are not known to be a common complication of ARDS or of sepsis syndrome, but both ARDS and sepsis represent hypercoagulable states (8). Pulmonary emboli were not noted in patients hospitalized with novel influenza A (H1N1) virus infection in Mexico (3). One clinical study did not identify any increased risk for pulmonary embolism with seasonal influenza virus infection (9). However, a report of two patients with rapidly progressive hypoxemia associated with influenza A (H3N2) virus infection noted that they received a diagnosis of acute pulmonary embolism (10). Clinicians providing care to patients with novel influenza A (H1N1) virus infection should be aware of the potential for patients with ARDS to develop a hypercoagulable state and for pulmonary emboli to cause severe complications, including fatal outcomes.

Two observational studies have demonstrated a reduction in mortality with oseltamivir treatment among hospitalized patients with seasonal influenza compared with untreated patients (11,12). Although early antiviral treatment (<48 hours from illness onset) is optimal to reduce illness among outpatients with seasonal influenza (13), a reduction in mortality of hospitalized persons with seasonal influenza or avian influenza A (H5N1) virus infection was reported even when oseltamivir treatment was initiated later (11,14). Early antiviral treatment of hospitalized patients with suspected influenza is recommended, including for patients admitted ≥48 hours after illness onset (13).

The patients in this series received higher oseltamivir dosing and longer duration of treatment than standard therapy. Data to inform clinical guidance are needed on viral shedding, pharmacokinetics, and clinical effectiveness of standard versus higher-dose oseltamivir treatment and on optimal duration of therapy for patients, including obese persons, with severe or progressive novel influenza A (H1N1) virus infection. Limited data for seasonal influenza treatment suggest that doubling the oseltamivir dose is well-tolerated with a comparable adverse event profile as the standard adult dose (75 mg orally twice a day) (15). Higher oseltamivir dosing and longer duration of treatment has been suggested for H5N1 (avian influenza) patients with severe pulmonary disease (14). Until additional data are available, higher oseltamivir dosage (e.g., 150 mg orally twice a day for adults) or extending the duration of treatment can be considered for severely ill hospitalized patients with novel influenza A (H1N1) virus infection.

Further characterization of severe cases of novel influenza A (H1N1) virus infection in the United States and worldwide is needed to determine the frequency of the findings from this limited case-series. Clinicians caring for patients with suspected novel influenza A (H1N1) virus infection should monitor them closely for rapid clinical deterioration, especially with regard to increasing oxygenation requirements and potential for development of complications (e.g., respiratory failure, ARDS, multiorgan failure, septic shock, and pulmonary emboli). Empiric antiviral treatment is recommended for all hospitalized patients at admission with suspected novel influenza A (H1N1) virus infection, † including persons who have received a diagnosis of community-acquired pneumonia. Empiric antibiotic agents also should be used as appropriate for suspected bacterial infection. Depending on the antiviral susceptibilities of circulating influenza A virus strains, either zanamivir monotherapy or combination therapy with oseltamivir (for treatment of novel influenza A [H1N1] virus infection) and rimantadine (for treatment of oseltamivir-resistant seasonal influenza A [H1N1]) might be indicated in hospitalized patients until final virus identification is available. In communities in which novel influenza A (H1N1) virus is the predominant circulating influenza virus, oseltamivir or zanamivir should be administered as early as possible to hospitalized patients with suspected novel influenza A (H1N1) virus infection, even before diagnostic testing results are available. Clinicians should be aware that negative results of rapid influenza diagnostic tests, immunoflouresence, or viral culture do not exclude the possibility of novel influenza A (H1N1) virus infection. Although five patients in this case-series received corticosteroids, their role in the management of severely ill patients with novel influenza A (H1N1) virus infection is unclear, and routine corticosteroid use is not recommended.§

Many hospitalized patients with novel influenza A (H1N1) virus infection have had underlying comorbidities recognized to be high-risk conditions for complications of seasonal influenza. However, clinicians should be aware that severe illness and fatal outcomes also can occur in patients without known risk factors for complications of seasonal influenza, including persons with extreme obesity.

Acknowledgment

This report is based, in part, on contributions from C Miller, PhD, Michigan Department of Community Health.

References

CDC. Swine influenza A (H1N1) infection in two children---Southern California, March--April 2009. MMWR 2009;58:400--2.
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. Available at: http://content.nejm.org/cgi/reprint/NEJMoa0904252.pdf.
CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR 2008;57(No. RR-7).
Smith AG, Sheridan PA, Harp JB, Beck MA. Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus. J Nutr 2007;137:1236--43.
Bercault N, Boulain R, Kuteifan K, et al. Obesity-related excess mortality rate in an adult intensive care unit: a risk-adjusted matched cohort study. Crit Care Med 2004;32:998--1003.
Akinnusi ME, Pineda LA, El Solh AA. Effect of obesity on intensive care morbidity and mortality: a meta analysis. Crit Care Med 2008;36:151--8.
Yaegashi M, Jean R, Zuriqat M, Noack S, Homel P. Outcome of morbid obesity in the intensive care unit. J Intensive Care Med 2005;20:147--54.
Schultz MJ, Haitsma JJ, Zhang H, Slutsky AS. Pulmonary coagulopathy as a new target in therapeutic studies of acute lung injury or pneumonia---a review. Crit Care Med 2006;34:871--7.
van Wissen M, Keller TT, Ronkes B, et al. Influenza infection and risk of acute pulmonary embolism. Thromb J 2007;5:16.
Ohrui T, Takahashi H, Ebihara S, et al. Influenza A virus infection and pulmonary microthromboembolism. Tohoku J Exp Med 2000;192:81--6.
McGeer A, Green KA, Plevneshi A. Shigayeva A, et al Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada. Clin Infect Dis 2007;45:1568--75.
Hanshaoworakul W, Simmerman JM, Narueponjirakul U, et al. Severe human influenza infections in Thailand: oseltamivir treatment and risk factors for fatal outcome. PlosMed 2009;4:e6051.
Harper SA, Bradley JS, Englund JA, et al. Seasonal influenza in adults and children-diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2009;48:1003--32.
Abdel-Ghafar AN, Chotpitayasunohdh T, Gao Z, et al. Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med 2008;358:261--73.
Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA 2000;282:1016--24.

tallaght01

Is it true they're using Relenza in pregnant women in the UK??

Anyone know the reason for this. Tamiflu has a good safety profile in pregnancy. Better than Relanza in the last paper I read. That was about 6 weeks ago. It's what we're using in Oz.

What's being used in Ireland? Anyone know the rationale for using relenza?

The_Conductor

tallaght01 wrote: »

Is it true they're using Relenza in pregnant women in the UK??

Anyone know the reason for this. Tamiflu has a good safety profile in pregnancy. Better than Relanza in the last paper I read. That was about 6 weeks ago. It's what we're using in Oz.

What's being used in Ireland? Anyone know the rationale for using relenza?

Don't know the rationale. Its Relenza in Ireland too- unless they have a history of respiratory problems (obviously).

tallaght01

This paper was the basis for the decision here:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19528139

It's free access, like a lot of the swine flu stuff.

It's showing reasonably safety in a small number of pregnant women who got tamiflu. There' was next to no data about relenza at the time (about 5 weeks ago). Hence why we use tamiflu.

I'm not aware of any other new data, though. Anyone know any different?

locum-motion

smccarrick wrote: »

Its Relenza in Ireland too-

Is it? News to me, and as you know I'm a pharmacist. I do know that a supply of Tamiflu has been sent from the "National Emergency Stockpile" to each pharmacy in the country. Have heard no mention of Relenza at all!
Or are you referring to what they're using in hospitals? (I have no info on hospitals)

tallaght01

Someone on a tr#head in the parenting forum says the nhs website in the uk is saying they use relenza. Seems to be true when you do a search for it.

The_Conductor

locum-motion wrote: »

Is it? News to me, and as you know I'm a pharmacist. I do know that a supply of Tamiflu has been sent from the "National Emergency Stockpile" to each pharmacy in the country. Have heard no mention of Relenza at all!
Or are you referring to what they're using in hospitals? (I have no info on hospitals)

Sorry- I have no idea whats in the pharmacies. I was going on info from the Mater.

SomeDose

Yes, Relenza is the preferred treatment for swine/pandemic flu in pregnant women in the UK. I think initially Tamiflu may have been recommended but it's since been changed by the DoH. I believe Tamiflu is still the preferred choice in US & Canada. The CMA paper that Tallaght linked to was included as part of the review process, but the rationale behind choosing Relenza was based on the fact it has much lower systemic absorption than Tamiflu and hence it less likely to cross the placenta in significant amounts. Safety data for either drug in pregnancy is still fairly scanty, so we still need to notify the National Teratology Service of any pregnant women treated with them, and follow up accordingly.

tallaght01

SomeDose wrote: »

Yes, Relenza is the preferred treatment for swine/pandemic flu in pregnant women in the UK. I think initially Tamiflu may have been recommended but it's since been changed by the DoH. I believe Tamiflu is still the preferred choice in US & Canada. The CMA paper that Tallaght linked to was included as part of the review process, but the rationale behind choosing Relenza was based on the fact it has much lower systemic absorption than Tamiflu and hence it less likely to cross the placenta in significant amounts. Safety data for either drug in pregnancy is still fairly scanty, so we still need to notify the National Teratology Service of any pregnant women treated with them, and follow up accordingly.

I figured that might be the case, actually. We're gonna have a serious amount of data on tamiflu and pregnancy in the next few months, though. The severity of this bug in pregnant woman has meant the GPs are giving tamiflu to an awful lot of asymptomatic women in their 2nd and 3rd trimester.

Having worked in the NHS, and knowing how it works.....is relenza cheaper? :P

locum-motion

locum-motion wrote: »

Is it? News to me, and as you know I'm a pharmacist. I do know that a supply of Tamiflu has been sent from the "National Emergency Stockpile" to each pharmacy in the country. Have heard no mention of Relenza at all!
Or are you referring to what they're using in hospitals? (I have no info on hospitals)

Sorry, I thought we were talking about general population, not pregnant women. Misunderstanding on my part.

SomeDose

tallaght01 wrote: »

I figured that might be the case, actually. We're gonna have a serious amount of data on tamiflu and pregnancy in the next few months, though. The severity of this bug in pregnant woman has meant the GPs are giving tamiflu to an awful lot of asymptomatic women in their 2nd and 3rd trimester.

Having worked in the NHS, and knowing how it works.....is relenza cheaper? :P

Funnily enough, there's little no difference in cost for the typical bd x 5 days flu regimen...but I salute your cynicism nevertheless!

On a side note, we're starting to see a few isolated cases of raised INRs in warfarinised patients treated with Tamiflu...which in theory wouldn't be expected as it's metabolised outwith the CYP system. Agree on your point regarding the coming months, it'll be a crucial period for pharmacovigilance in many different patient groups.