Study: Clinical Course Of H5N1 In 22 Patients

 

 

# 4615

 

 

On of the great mysteries surrounding human H5N1 infections has been the abysmal survival rate, particularly in Indonesia and parts of South East Asia.   

 

Worldwide (among confirmed cases), 294 of 498 victims have died.  That’s roughly a 59% fatality rate.  The rate varies, however, with 82% of H5N1 cases dying in Indonesia while less than 32% have succumbed in Egypt.

 

Sobering numbers, particularly when compared to the 2.5%-5% fatality rate experienced during the 1918 pandemic.  Fortunately, the number of cases remains low, and the virus has yet to adapt well enough to human hosts to become a pandemic.

Although human cases have been detected and treated for more than a decade, we rarely get detailed information regarding their course of illness, treatment, or outcome.  

 

In August of 2008 we did get a review of 26 cases out of China, which shed some light on the pathogenesis of the virus (see Clinical Case Review Of 26 Chinese H5N1 Patients)

 

Today a glimpse, via an abstract for a study (subscription req.) in The Journal CHEST, that outlines the clinical course of 22 patients at one hospital in Indonesia. 

 

A hat tip to Dutchy at FluTrackers for this link.

 

 

Clinical course of H5N1 avian influenza in patients at the Persahabatan Hospital, Jakarta, Indonesia, 2005-2008.

Priyanti Z Soepandi, Erlina Burhan, Hadiarto Mangunnegoro, Arifin Nawas, Tjandra Yoga Aditama, Lia Partakusuma, Fathiyah Isbaniah, Suhud Malik, Rachel Benamore, J Kevin Baird, Walter RJ Taylor, and the H5N1 clinical team

Abstract

Background: Limited understanding of the presentation and course of influenza A/H5N1 infection in humans hinders evidence-based management.

Methods: Review of case records of patients with real time, PCR confirmed H5N1 influenza admitted to the Persahabatan Hospital (RSP), Jakarta, Indonesia.

Results: 22 previously well patients, age 3 to 47 years (median 24.5), were identified. All attended a clinic or hospital after a median of 2 days of illness (range 0-7). Times to first dose of oseltamivir (3 died before receiving oseltamivir) were 2 to 12 days (median 7), administered mostly (n=15) at RSP. 19 patients required mechanical ventilation. Deaths numbered 18 (case fatality=82%) occurring within hours to 6 days of RSP admission, corresponding to 6 to 16 days of illness.

Admission hyperglycemia (≥ 140 mg/dL), unrelated to steroids or known underlying diabetes mellitus, and raised d-dimers (0.81 – 5.2 mg/L, ULN < 0.5 mg/L) were present in 14/21 (67%) and 20/21 (95%) patients, respectively.

Fibrinogen concentrations were mostly low/normal 129.9-517.9 mg/dL (median 241.1, normal 200-400 mg/dL) whilst CRP (9/11) and ferritin (6/8) were raised. Risk factors for death (univariate analysis) included: (i) raised d-dimers, (ii) hyperglycemia, (iii) raised urea, (iv) more extensive chest X ray shadowing, and (v) lower admission oxygen saturation.

Conclusions: Early diagnosis and effective treatment of human H5N1 infection remains challenging. Most patients were referred late with advanced disease. Oseltamivir had limited clinical impact. Raised d-dimers, consistent with fibrinolysis, and hyperglycemia warrant more research to determine their underlying mechanisms and optimal treatment.

 

 

A little interpretation for non-medical readers may be helpful here, particularly regarding the elevated d-dimers readings. 

 

D-dimer is a protein fragment left behind in the blood after a fibrin clot has been degraded.  The test is normally used to diagnose thrombosis, but is also diagnostic for DIC (disseminated intravascular coagulation).

 

DIC (which can present as widespread internal bleeding, hemorrhagic shock, and renal failure) is a condition sometimes seen in severe cases of sepsis  and ARDS (Acute Respiratory Distress Syndrome).

 

Unlike Egypt, which has reported favorably on the efficacy of oseltamivir (Tamiflu) in the treatment of H5N1, this report states that oseltamivir had limited clinical impact.

 

Whether this has something to do with the clade of virus being encountered in Indonesia, or the delay in starting treatment, or some other unknown variable, isn’t clear.

 

The d-dimer readings, and hyperglycemia upon admission - which both appear linked to bad outcomes - add new and tantalizing clues to the  pathogenesis of this virus in humans. 

 

In February of 2009 we got a look at a study that compared the pathogenesis (disease progression) of non-human primates (macaques) infected with the H5N1 virus, seasonal flu, and with two altered viruses carrying genetic material from the 1918 Spanish Flu.

 

The study, entitled Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus by Carole Baskin et. al.  appeared PNAS (The Proceedings of the National Academy of Science).

 

At the time, I wrote a 3-part essay dissecting this study for the layperson, which some might still find useful.

 

Dissecting the Influenza Pathogenesis Study Pt. 1

Dissecting the Influenza Pathogenesis Study Pt. 2

Dissecting the Influenza Pathogenesis Study Pt. 3

 

Despite all we’ve learned from human cases, and lab research, there are plenty of  unanswered questions surrounding the virulence of H5N1.   

Questions that we would dearly love to have the answers to now, before the virus becomes a graver threat.

NIH: Post Mortem Studies Of H1N1

 

 

# 4131

 

 

There is an wry old medical saying that states:

 

Internists know everything and do nothing,

Surgeons know nothing and do everything,

Pathologists know everything and do everything-

but a day too late.

 

 

I have a great deal of respect of pathologists, since some of the most fascinating aspects of my paramedic training took place in the county medical examiner’s office.  We not only practiced certain high risk procedures on cadavers, we assisted in autopsies as well.

 

It was a terrific way to learn about human anatomy, the impact of trauma, and the ravages of disease first hand.  

 

While admittedly a grim subject, autopsies provide invaluable information to scientists and doctors about the pathogenesis of a disease.  And when it is a new virus like novel H1N1, the more that pathologists can glean from their examinations, the better shot doctors will have a devising effective treatments.

 

Today the NIH has announced the results of a series of autopsies conducted on H1N1 victims in New York City over the summer, which are chronicled in the Archives of Pathology & Laboratory Medicine.

 

The early release article (freely available) is entitled:

 

Pulmonary Pathologic Findings of Fatal 2009 Pandemic Influenza A/H1N1 Viral Infections

James R. Gill, MD; Zong-Mei Sheng, MD, PhD; Susan F. Ely, MD, MPHTM; Donald G. Guinee Jr, MD; Mary B. Beasley, MD; James Suh, MD; Charuhas Deshpande, MD; Daniel J. Mollura, MD; David M. Morens, MD; Mike Bray, MD; William D. Travis, MD; Jeffery K. Taubenberger, MD, PhD

 

The NIH has put together a press release, which is on their site, which provides the highlights of the study.

 

 

FOR IMMEDIATE RELEASE
Monday, Dec. 7, 2009

Media Contact: Anne A. Oplinger
(301) 402-1663
niaidnews@niaid.nih.gov

New York Autopsies Show 2009 H1N1 Influenza Virus Damages Entire Airway

In fatal cases of 2009 H1N1 influenza, the virus can damage cells throughout the respiratory airway, much like the viruses that caused the 1918 and 1957 influenza pandemics, report researchers from the National Institutes of Health (NIH) and the New York City Office of Chief Medical Examiner. The scientists reviewed autopsy reports, hospital records and other clinical data from 34 people who died of 2009 H1N1 influenza infection between May 15 and July 9, 2009. All but two of the deaths occurred in New York City. A microscopic examination of tissues throughout the airways revealed that the virus caused damage primarily to the upper airway—the trachea and bronchial tubes—but tissue damage in the lower airway, including deep in the lungs, was present as well. Evidence of secondary bacterial infection was seen in more than half of the victims.

 

The team was led by James R. Gill, M.D., of the New York City Office of Chief Medical Examiner and New York University School of Medicine, and Jeffery K. Taubenberger, M.D., Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID) at NIH. The findings are reported in the Archives of Pathology & Laboratory Medicine, now available online and scheduled to appear in the February 2010 print issue.

 

“This study provides clinicians with a clear and detailed picture of the disease caused by 2009 H1N1 influenza virus that will help inform patient management,” says NIAID Director Anthony S. Fauci, M.D. “In fatal cases of 2009 H1N1 influenza, it appears the novel pandemic influenza virus produces pulmonary damage that looks very much like that seen in earlier influenza pandemics.”

 

The new report also underscores the impact 2009 H1N1 influenza is having on younger people. While most deaths from seasonal influenza occur in adults over 65 years old, deaths from 2009 H1N1 influenza occur predominately among younger people. The majority of deaths (62 percent) in the 34 cases studied were among those 25 to 49 years old; two infants were also among the fatal cases.

 

Ninety-one percent of those autopsied had underlying medical conditions, such as heart disease or respiratory disease, including asthma, before becoming ill with 2009 H1N1 influenza. Seventy-two percent of the adults and adolescents who died were obese. This finding agrees with earlier reports, based on hospital records, linking obesity with an increased risk of death from 2009 H1N1 influenza.

 

The researchers examined tissue samples from the 34 deceased individuals to assess how 2009 H1N1 influenza virus damaged various parts of the respiratory system. “We saw a spectrum of damage to tissue in both the upper and lower respiratory tracts,” says Dr. Taubenberger. In all cases, the uppermost regions of the respiratory tract—the trachea and bronchial tubes—were inflamed, with severe damage in some cases. In 18 cases, evidence of damage lower down in the finer branches of the bronchial tubes, or bronchioles, was noted. In 25 cases, the researchers found damage to the small globular air sacs, or alveoli, of the lungs.

 

“This pattern of pathology in the airway tissues is similar to that reported in autopsy findings of victims of both the 1918 and 1957 influenza pandemics,” notes Dr. Taubenberger.

 

The researchers also examined 33 of the 34 cases for evidence of pulmonary bacterial infections. Of these cases, 18 (55 percent) were positive for such infections. Not all of those individuals who had bacterial pneumonia along with 2009 H1N1 virus infection had been hospitalized, however, indicating that some had acquired their bacterial infections outside of a health-care setting.  This raises the possibility, say the authors, that community-acquired bacterial pneumonia is playing a role in the current pandemic. “Even in an era of widespread and early antibiotic use,” write the authors, “bacterial pneumonia remains an important factor for severe or fatal influenza.”

 

Computerized tomography (CT) lung images were available in four cases of pulmonary bacterial infection. In all four cases, the CT scans showed an abnormality known as ground-glass opacity, which are patches of rounded haze not seen in normal lung images. It is not known, say the researchers, whether the abnormalities detected by CT in the four cases also occur in people who have milder H1N1 infections. They call for additional investigation into the utility of CT scans as a tool to help clinicians identify and better treat severe H1N1 infections.

 

(Continue . . . .)

Nature: One killer virus, three key questions

 

 

# 3994

 

Nature.com has been on the forefront of covering both avian and (now) H1N1 pandemic flu for years.  Declan Butler was writing about H5N1 more than 5 years ago, and truth be told, it was his blog that got me really interested in the subject.

 

You’ll find probably a dozen of his articles referenced in this blog, many of those coming since the emergence of the H1N1 virus last spring. 

 

Today Butler, along with Nature feature writer Brendan Maher, take a hard look at 3 crucial questions regarding the H1N1 `swine’ flu virus.

 

How the virus kills?

How it spreads?

Chances that the pandemic virus will reassort?

 

There's way too much here to excerpt, and so I’ll just tell you to go read it. 

 

Published online 11 November 2009 | Nature 462, 154-157 (2009) | doi:10.1038/462154a

Swine flu: One killer virus, three key questions : Nature News

As the world mobilizes against the H1N1 flu pandemic, researchers are working to answer pressing questions about the virus. Brendan Maher visited pathologists at the US Centers for Disease Control and Prevention who are looking at how the virus kills, and a New York laboratory that is testing how it spreads. Declan Butler spent time at a French biosafety level-4 facility where researchers are working out the chances that the pandemic virus will reassort with the H5N1 avian flu virus.

(Continue . . . )

Study: H1N1 A Threat To All Age Groups

 

 

# 3945

 

 

While it is true that 90% of the H1N1 infections have been among those under 65, when those over that age get this virus, it can provoke a very serious illness. 

That’s one of the messages from a study, published today in JAMA, entitled Factors Associated With Death or Hospitalization Due to Pandemic 2009 Influenza A(H1N1) Infection in California

 

Reuters summarizes the study below, and you’ll find excerpts from the abstract below that.

 

Swine flu not just a threat to young: study

Tue Nov 3, 2009 5:22pm EST

By Julie Steenhuysen

CHICAGO (Reuters) - Swine flu can cause severe disease in people of all ages and appears to pose a special threat to those who are obese, according to an analysis of H1N1 cases in California released on Tuesday.

 

Public health researchers analyzed the state's first 1,088 hospitalized and fatal cases of H1N1 infection between April 23 and August 1.

 

Like other studies, they found the average patient who was hospitalized with H1N1 flu was younger than what is commonly seen with seasonal flu, but they also found severe disease at both ends of the age spectrum.

 

"What our study shows was that once you were hospitalized, if you were elderly you have a higher risk of dying," Dr. Janice Louie of the California Department of Public Health in Richmond, whose study appears in the Journal of the American Medical Association.

 

Dr. Thomas Frieden, director of the U.S. Centers for Disease Control and Prevention, said the study matches the CDC's own observations -- that H1N1 affects all age groups, including people over 65.

 

(Continue. . . )

 

 

Factors Associated With Death or Hospitalization Due to Pandemic 2009 Influenza A(H1N1) Infection in California

Janice K. Louie, MD, MPH; Meileen Acosta, MPH; Kathleen Winter, MPH; Cynthia Jean, MPH; Shilpa Gavali, MPH; Robert Schechter, MD, MPH; Duc Vugia, MD; Kathleen Harriman, PhD; Bela Matyas, MD; Carol A. Glaser, MD, DVM; Michael C. Samuel, DrPH; Jon Rosenberg, MD; John Talarico, DO, MPH; Douglas Hatch, MD; for the California Pandemic (H1N1) Working Group

JAMA. 2009;302(17):1896-1902.

Results During the study period there were 1088 cases of hospitalization or death due to pandemic 2009 influenza A(H1N1) infection reported in California. The median age was 27 years (range, <1-92 years) and 68% (741/1088) had risk factors for seasonal influenza complications.

 

Sixty-six percent (547/833) of those with chest radiographs performed had infiltrates and 31% (340/1088) required intensive care. Rapid antigen tests were falsely negative in 34% (208/618) of cases evaluated.

 

Secondary bacterial infection was identified in 4% (46/1088). Twenty-one percent (183/884) received no antiviral treatment. Overall fatality was 11% (118/1088) and was highest (18%-20%) in persons aged 50 years or older. The most common causes of death were viral pneumonia and acute respiratory distress syndrome.

Conclusions In the first 16 weeks of the current pandemic, the median age of hospitalized infected cases was younger than is common with seasonal influenza. Infants had the highest hospitalization rates and persons aged 50 years or older had the highest mortality rates once hospitalized. Most cases had established risk factors for complications of seasonal influenza.

Not Your Father’s Influenza (Revisited)

 

# 3846

 

 

Back in May, just a couple of weeks after the news of the novel H1N1 virus emergence was making the papers, I wrote a piece called H1N1: Apparently Not Your Father’s Influenza.  

 

In it I discussed some of the more unusual aspects of this illness’s presentation.  Even then, it was apparent that there was something different about this virus.

 

Since then, we’ve learned a lot more about the virus.  And so far, the good news is that for most people, it produces a short, miserable, but survivable bout of the flu. 

 

But for a very small subset of victims, it can produce a life threatening pneumonia.  And by and large, it favors younger adults and children.

 

Today, a long and detailed report from Rob Stein of the Washington Post, that looks at how these severe cases of H1N1 infection differ from regular seasonal flu.

 

While a lot of the territory that this article covers has been mentioned before in these pages, this is an excellent summary, and bring us nicely up to date. 

 

Well worth reading in its entirety.

 

A Hat tip to Commonground on FluTrackers for posting this link.

 

Swine Flu Characteristics Becoming More Evident

Links to Pneumonia, Rapid Effects on Young Noted

By Rob Stein

Washington Post Staff Writer
Saturday, October 17, 2009

As swine flu continues to spread around the globe, a clearer and in some ways more unnerving picture of the most serious cases has started to emerge, indicating that the virus could pose a greater threat to some young, otherwise vibrant people.

 

The virus can cause life-threatening viral pneumonia much more commonly than the typical flu, prompting the World Health Organization on Friday to warn hospitals to prepare for a possible wave of very sick patients and to urge doctors to treat suspected cases quickly with antiviral drugs.

 

Experts stress that most people who get the H1N1 virus either never get sick or recover easily. But some young adults, possibly especially women, are falling seriously ill at an unexpectedly rapid pace and are showing up in intensive care units and dying in unusually high numbers, they say.

 

Although why a minority of patients become so sick remains a mystery, new research indicates that H1N1 is different from typical seasonal flu viruses in crucial ways -- most notably in its ability to penetrate deep into the lungs and cause viral pneumonia.

(Continue . . .)

Jason Gale On Swine Flu Lung Damage

 

# 3783

 

 

Jason Gale, who writes regularly on pandemic flu issues for Bloomberg news, brings us news of a study from doctors in Australia and New Zealand who have been treating severely impacted Swine flu cases over their winter flu season.

 

Although the novel H1N1 virus normally remains in the upper airway and results in common flu-like-symptoms, on rare occasions it can infect deep into the lungs, and the result can be severe respiratory distress or even failure.

 

Doctors there have dubbed this phenomenon as FLAARDS (Flu A-Associated Acute Respiratory Disease Syndrome).

 

Follow the link to read the entire Bloomberg report.

 

 

Inflamed, Flooded Lungs Trigger Death by Swine Flu, Study Says

By Jason Gale

Sept. 29 (Bloomberg) -- Swine flu is most dangerous when it causes the lungs to become inflamed, flood with fluid and fail to function, doctors in Australia and New Zealand found.

 

 

While a majority of people infected with the virus have a mild illness, a small number develop life-threatening disease, intensive-care specialists Steven Webb and Ian Seppelt said. The doctors described the most common of three main complications from the pandemic strain as flu A-associated acute respiratory disease syndrome, or “flaards.”

 

“Flaards -- sometimes with associated multiple organ failure -- is the most common syndrome and has the highest attributable mortality,” Webb and Seppelt wrote in an editorial in the September issue of the medical journal Critical Care and Resuscitation.

 

(Continue . . . )

More On The Pathology Of Novel H1N1

 

 

# 3740

 

Increasingly, the evidence is piling up that this novel H1N1 `swine’ flu isn’t quite the docile virus that some people would like to believe. While the `no worse than seasonal flu’ mantra has been uttered repeatedly by public officials around the world, it isn’t always the case.

 

For the overwhelming majority of cases, it is true that novel H1N1 has produced mild-to-moderate illness.  No worse than seasonal flu.

 

But for a very small percentage of cases it can have a devastating impact, rapidly causing severe lung damage leading to multi-organ failure.

 

Exactly why some patients fare so poorly, while the majority do well, isn’t understood yet.

 

Over the past several weeks, I’ve featured other stories on this phenomenon by well known science reporters like Jason Gale of Bloomberg News, and Helen Branswell of the Canadian Press.   Including:

 

Jason Gale On The Swine Flu Mystery

Study: H1N1 Receptor Binding

Pathology Of Fatal H1N1 Lung Infections

 

Maggie Fox, Health and Science Editor for Reuters, brings us the latest details of this still emerging story, including comments by Dr. Sherif Zaki of the U.S. CDC who yesterday stated that "This is almost exactly what we see with avian flu. This looks like avian flu on steroids."

 

An ominous description, but one that luckily only applies to a small number of victims.

 

Included in this story are reports that the virus has been found in urine and fecal samples of infected patients, which conceivably could be a factor in the way the virus is spread.

 

Follow the links to read this report in its entirety, there is a lot here to consider.

 

 

Swine flu deaths show this flu is different – experts

 

Tue Sep 15, 2009 10:40pm BST

By Maggie Fox, Health and Science Editor

WASHINGTON (Reuters) - Autopsies on people who have died from the new pandemic H1N1 flu show this virus is different from seasonal influenza, even if it has not yet caused more deaths, experts told a meeting on Tuesday.

 

Americans who died from swine flu had infections deep in their lungs, Dr. Sherif Zaki of the U.S. Centres for Disease Control and Prevention told a meeting of flu experts, including damage to the alveoli -- the structures in the lung that deliver oxygen to the blood.

 

This in turn caused what is known as acute respiratory distress syndrome -- an often fatal development that leaves patients gasping for breath.

 

(Continue . . .)

Study: Half Of ICU H1N1 Patients Without Underlying Conditions

 

 

# 3729

 

 

A hat tip to Crof over at Crofsblog for finding this report in the Barcelona Reporter about a study, published on Friday in the journal Critical Care, that examines the risk factors of 32 ICU patients admitted for pandemic influenza.

 

First the news story, then the abstract to the paper.

 

Study involving 21 Spanish hospitals states 50% of swine flu, ICU patients had no health problems

About half of people admitted to ICU in hospitals for severe complications of influenza A had no risk factor or disease, according to a study conducted in 21 Spanish hospitals.

Study involving 21 Spanish hospitals states 50% of swine flu, ICU patients had no previous health problems

 

The study, presented on the website of the medical journal ‘Critical Care’ is the largest ever conducted in Europe on influenza cases requiring intensive care. Their findings contradict one of the messages on influenza A released by the Ministry of Health and the Department of Health, which have repeatedly reported that patients with influenza A cases had previous health problems.

 

The findings contain important messages for both the general population and for health authorities and medical intensivists. For the general population, an appeal to healthy people without risk factors to avoid falling prey to overconfidence in regard to influenza A. Although the vast majority of those affected will overcome the flu without complications, a small percentage will have pneumonia and should be hospitalized.

(Continue . . . )

 

Over the summer many countries have repeated the mantra that those who are experiencing severe illness nearly all have underlying medical conditions.   Apparently they feel this is a reassuring message.

 

Over and over, of course, we’ve seen reports to the contrary.  

 

While underlying conditions might put you at greater risk, previously healthy individuals are seeing bad outcomes with this virus as well. Once again, this study raises questions about obesity being an underlying factor – a theory that has fallen in and out of favor several times over the past few months.

 

The good news is, those who are seriously impacted by this virus remain a very small percentage of the total infected.

 

This (slightly reparagraphed) abstract is from the journal Critical Care.   A provisional PDF file of the study is available to download, as well.

 

 

Intensive care adult patients with severe respiratory failure caused by Influenza A (H1N1)v in Spain

Jordi Rello , Alejandro Rodriguez , Pedro Ibanez , Lorenzo Socias , Javier Cebrian , Asuncion Marques, Jose Guerrero, Sergio Ruiz-Santana , Enrique Marquez , Frutos del Nogal-Saez , Francisco Alvarez-Lerma , Sergio Martinez , Miquel Ferrer , Manuel Avellanas , Rosa Granada , Enrique Maravi-Poma , Patricia Albert , Rafael Sierra , Loreto Vidaur , Patricia Ortiz , Isidro Prieto del Portillo , Beatriz Galvan , Cristobal Leon-Gil  and The H1N1 SEMICYUC working group

Critical Care 2009, 13:R148doi:10.1186/cc8044

Published:
11 September 2009

Abstract (provisional)

Introduction

Patients with influenza A (H1N1)v infection have developed rapidly progressive lower respiratory tract disease resulting in respiratory failure. We describe the clinical and epidemiologic characteristics of the first 32 persons reported to be admitted to the intensive care unit (ICU) due to influenza A (H1N1)v infection in Spain.

<SNIP>

Results

Illness onset of the 32 patients occurred between June 23 and July 31, 2009. The median age was 36 years (IQR = 31 - 52).

 

Ten (31.2%) were obese, 2 (6.3%) pregnant and 16 (50%) had pre-existing medical complications.

 

Twenty-nine (90.6%) had primary viral pneumonitis, 2 (6.3%) exacerbation of structural respiratory disease and 1 (3.1%) secondary bacterial pneumonia.

 

Twenty-four patients (75.0%) developed multiorgan dysfunction, 7 (21.9%) received renal replacement techniques and 24 (75.0%) required mechanical ventilation. Six patients died within 28 days, with two additional late deaths. Oseltamivir administration delay ranged from 2 to 8 days after illness onset, 31.2% received high-dose (300mg/day), and treatment duration ranged from 5 to 10 days (mean 8.0 + 3.3).

 

Conclusions

Over a 5-week period, influenza A (H1N1)v infection led to ICU admission in 32 adult patients, with frequently observed severe hypoxemia and a relatively high case-fatality rate. Clinicians should be aware of pulmonary complications of influenza A (H1N1)v infection, particularly in pregnant and young obese but previously healthy persons.

Jason Gale On The Swine Flu Mystery

 

 

# 3727

 

 

Jason Gale of Bloomberg News today takes a fascinating look at the mystery over how some small percentage of young and previously healthy H1N1 flu victims can experience severe, life threatening symptoms while the majority get by with mild or moderate illness.

 

Is it genetics?  Or is it simply taking a deep breath at the wrong time?

 

This article is well worth reading in its entirety.

 

 

Swine Flu Mystery in Healthy Young Spurs Search for a Cause

By Jason Gale

Sept. 14 (Bloomberg) -- After being infected with swine flu, Brent Robb, a 34-year-old New Zealander with no pre- existing medical conditions, spent 11 days in a coma induced by doctors in a last-ditch effort to save his life.

 

A printer who liked to bike 12 miles a week for exercise, Robb lost two months of work while sick, and a sixth of his body weight. He survives as an example of a mystery hovering over the fast-moving pandemic that has spread to 177 countries in four months, yet causes little more than a fever and a cough in all but a select few.

 

Seasonal flu kills predominantly the frail elderly. Researchers are trying to determine why the H1N1 swine flu virus, much like the Spanish Flu of 1918, is lethal to a portion of young people in good health. The reason may involve a person’s genetics, or simply taking a deep breath just as a nearby infected person sneezes.

 

“That’s a question we have to find the answer to,” said Nikki Shindo, a Geneva-based doctor who has led the World Health Organization’s investigation of swine flu patients since the virus was discovered in Mexico in April.

(Continue . . . )

Study: H1N1 Receptor Binding

 

 

# 3714

 

 

An interesting study in the current issue of Nature Biotechnology which helps explain why, in a small percentage of novel H1N1 infections, patients experience severe deep lung infections.  

 

It all has to do with how this virus binds to receptor cells.

 

The receptor binding domain (RBD) of an influenza virus is that area of its genetic sequence that allows it to attach to, and infect, host cells.   

 

Much like a key into a padlock, the RBD must `fit' the host cell in order for it to bind.

 

(Very Simplified Illustration of RBDs)

 

A little science.   I’ll try to be gentle.

 

Animal cell membranes are comprised of a lipid bilayer with lots of strands (or chains) of sugars (carbohydrates), proteins, and fat molecules poking through them.

  

These carbohydrate molecules, some being glycolipids (carbohydrate and fat) and others glyoproteins (carbohydrate and Protein), form a dense sugary coating to all animal cell membranes.

 

Since there are a lot of different sugars, there are a lot of combinations to be found.  The most accessible of these sugars for a virus are the ones at the tips of these chains, where a special sugar called sialic acid is often found. 

 

Now, not all sialic acid molecules are the same. 

 

Essentially, they are identified by what molecules they are attached to, and how they are attached. It gets pretty complicated, but suffice to say there are two special sialic acid configurations that are of particular interest to us when dealing with Influenza; the α-2,3 and the α-2,6 combinations.

 

The α-2,6 receptor cells are commonly found in the upper airway of humans, while the α-2,3 receptor cells are most often found deep in the lungs.

 

One of the reasons that the H5N1 (bird flu) virus hasn’t managed to transmit efficiently from human-to-human is because it is adapted to the kind of receptor cells most commonly found in the digestive tract of birds; the α-2,3  -  not the α-2,6 receptor cells found in the human upper airway.

 

AI (Avian Influenza) viruses must make their way deep into the lungs to infect humans.   And while it rarely happens, when it does, the resultant infection is generally far more severe than an upper airway infection.

 

Most human-adapted influenzas attach to the easy-to-reach  α-2,6 receptor cells commonly found in nose, throat, and pharynx.

 

While 99% of novel H1N1 victims seem to experience relatively mild upper airway infections, an unlucky 1% see the infection go deeper into the lungs.    Helen Branswell of the Canadian Press wrote about this phenomenon about a week ago, which I covered in a blog called Pathology Of Fatal H1N1 Lung Infections.

 

 

Lung damage in fatal swine flu cases more bird flu than seasonal flu: expert

 

By Helen Branswell Medical Reporter (CP) 

TORONTO — The lungs of people who have died from swine flu look more like those of the victims of H5N1 avian influenza than those of people who succumb to regular flu, the chief of infectious diseases pathology at the U.S. Centers for Disease Control says.

 

 

Today, in a study that appears in Nature Biotechnology, we learn that researchers have determined that the novel H1N1 virus has the ability to infect both upper respiratory α-2,6 receptor cells, and to a lesser extent, the deep lung α-2,3 cells.

 

Which makes novel H1N1 a versatile virus, indeed.

 

 

Receptor-binding specificity of pandemic influenza A (H1N1) 2009 virus determined by carbohydrate microarray - pp797 - 799

Robert A Childs, Angelina S Palma, Steve Wharton, Tatyana Matrosovich, Yan Liu, Wengang Chai, Maria A Campanero-Rhodes, Yibing Zhang, Markus Eickmann, Makoto Kiso, Alan Hay, Mikhail Matrosovich & Ten Feizi

doi:10.1038/nbt0909-797

 

 

This paper isn’t open access, but the Medical Research Council (which partnered to fund this research) has an overview of the paper, and an interview with Professor Ten Feizi, a corresponding author of the paper.

 

Professor Feizi, in the accompanying article, expresses the concern that:

 

"If the flu virus mutates in the future, it may attach to the receptors deep inside the lungs more strongly, and this could mean that more people would experience serious symptoms. We think scientists should be on the lookout for these kinds of changes in the virus so we can try to find ways of minimising the impact of such changes," added Professor Feizi.

 

 

Pandemic flu can infect cells deep in the lungs, says new research

10 September 2009

Pandemic swine flu can infect cells deeper in the lungs than seasonal flu can, according to a new study published today in Nature Biotechnology. The researchers, funded by the Medical Research Council, Wellcome Trust and Engineering Physical Sciences Research Council, say this may explain why people infected with the pandemic strain of swine-origin H1N1 influenza are more likely to suffer more severe symptoms than those infected with the seasonal strain of H1N1. They also suggest that scientists should monitor the current pandemic H1N1 influenza virus for changes in the way it infects cells that could make infections more serious.

 

Influenza viruses infect cells by attaching to bead-like molecules on the outside of the cell, called receptors. Different viruses attach to different receptors, and if a virus cannot find its specific receptors, it cannot get into the cell. Once inside the cell, the virus uses the cell's machinery to make thousands more viruses, which then burst out of the cell and infect neighbouring ones, establishing an infection.

 

Seasonal influenza viruses attach to receptors found on cells in the nose, throat and upper airway, enabling them to infect a person's respiratory tract. The research shows that pandemic H1N1 swine flu can also attach to a receptor found on cells deep inside the lungs, which can result in a more severe lung infection.

 

(Continue . . . )

The Unlucky 1 Percent

 

 

# 3708

 

An interesting piece today in the New Scientist, which reaffirms something we’ve discussed  often in these pages often over the past few months.

 

We are basically seeing two novel H1N1 pandemics going on here: a mild one, and a severe one.

 

For the vast majority of people – probably 99 out of 100  - this novel H1N1 virus has (thus far) produced a mild-to-moderate illness that can be usually be weathered at home.

 

But for an unlucky 1% (or less), this pandemic virus has produced a rapidly developing-potentially life threatening illness, requiring aggressive medical intervention and sometimes extended ventilator support.

 

Exactly why the vast majority of people do okay with this virus, and a select few do not, isn’t known right now.   It may simply be random chance, like hitting a lottery.  But there are other possibilities as well.

 

Some of the most severely affected victims have had underlying conditions like asthma, diabetes, or pregnancy. But reports are that 30% or more of those hospitalized were regarded to have been good health prior to infection.

 

Doctors and scientists are also working to determine if there could be some genetic predisposition that makes one person more susceptible to severe lung damage from this virus than another. 

 

Most likely, it is dependent upon a host of reasons.

 

While less than 1% of pandemic flu patients are likely to suffer severe illness, when you have tens of millions of people infected, the number of critically ill people who will need medical resources escalates quickly.

 

The fear right now is, that could put hospitals and ICU’s under enormous pressures over the next few months.

 

While it should help put things into perspective to know that 99% of those who are infected will recover without incident, that is likely to be little solace to the 1%, and their friends and family, who do not.

 

 

Don't be fooled: swine flu still poses a deadly threat

• 17:01 08 September 2009 by Debora MacKenzie

Swine flu has still not grown more severe, as many feared it would but as the pandemic's second, autumn wave begins in the northern hemisphere, the virus is posing a different threat. While H1N1 mostly causes mild disease, some people – estimates suggest fewer than 1 per cent – become deathly ill, very fast.

 

At a meeting last week in Winnipeg, Canada, experts warned that these cases could overwhelm hospitals. "These were the sickest people I've ever seen," says Anand Kumar, an intensive care expert at the University of Manitoba in Winnipeg.

 

Kumar helped manage a wave of severe cases in the city in June, mostly in young Canadian aboriginals, who required the most advanced care. "This pandemic is like two diseases," he says. "Either you're off work a few days, or you go to hospital, often to the intensive care unit. There's no middle ground."

 

In the southern hemisphere, 15 to 33 per cent of hospitalised cases went to ICU in the past two months. "That's very high for flu," says Richard Wenzel of Virginia Commonwealth University in Richmond. "When this flu is bad, it's very bad."

(Continue . . . )

Pathology Of Fatal H1N1 Lung Infections

 

# 3695

 

Despite all of the assurances that the novel H1N1 virus is `similar in severity to seasonal flu’, there are obviously differences in the way the novel virus behaves.

 

We’ve heard a great deal about the `age-shift’ to younger victims – something we often see with pandemic viruses – but so far we’ve heard very little about the pathogenesis of the virus; how the disease progresses inside the body.

Today Helen Branswell of the Canadian Press brings us a fascinating interview with the CDC’s chief pathologist regarding post-mortem examinations of the lungs of H1N1 fatalities.

I’ll just get out of the way and let Ms. Branswell take it from here.

 

 

Lung damage in fatal swine flu cases more bird flu than seasonal flu: expert

By Helen Branswell Medical Reporter (CP) 

TORONTO — The lungs of people who have died from swine flu look more like those of the victims of H5N1 avian influenza than those of people who succumb to regular flu, the chief of infectious diseases pathology at the U.S. Centers for Disease Control says.

 

Study of about 70 fatal H1N1 cases so far also reveals there may be more incidences of co-infections with bacteria than was earlier thought, Dr. Sherif Zaki told The Canadian Press in an interview.

 

The damage to lung tissue is consistent with that inflicted by ARDS or acute respiratory distress symptom, Zaki says, referring to an often-fatal, difficult-to-treat syndrome that can have a number of causes. The U.S. National Heart, Lung and Blood Institute estimates about 30 per cent of people who develop ARDS die.

 

"In terms of the disease, yes, it (H1N1) is remarkably different than seasonal flu," Zaki says. "The pathology looks very similar to H5(N1)."

(Continue . . . )

 

 

Up until now we’ve heard little about bacterial co-infections in fatal H1N1 cases.  Dr. Zaki makes the point that pneumococcal vaccines might be of value in younger people, to prevent some of these infections.

 

Although I don’t offer medical advice in this blog, I have suggested on many occasions that people should consult with their primary care provider about the advisability of taking the Pneumococcal polysaccharide vaccine (PPV) – even if you aren’t sure you fall into a recommended category.

A couple of blogs on the subject include:

 

Referral: Effect Measure On Pneumococcal Vaccines

CDC Issues Pneumococcal Vaccine Recommendations

 

 

Given the comparisons being made between the lung damage wrought by the novel H1N1 virus and H5N1 Bird flu, it might be an appropriate time to take another look at the PNAS paper entitled Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus by Carole Baskin et. al., which analyses the pathogenesis of the H5N1 virus compared to seasonal flu, and 1918-like viruses.

 

With much trepidation I wrote a 3-part-layman’s guide to this paper last January.  It was an ambitious undertaking, but to my delight the study’s author Carole Baskin, read it and commented positively on it. 

 

Dissecting the Influenza Pathogenesis Study Pt. 1

Dissecting the Influenza Pathogenesis Study Pt. 2

Dissecting the Influenza Pathogenesis Study Pt. 3

 

I’m not sure that we can assume that the same damage observed at the cellular level with H5N1 is occurring with H1N1, but upon gross examination the two appear to be producing similar pathologies.

 

In any event, these three essays are a good review of the immune system, and our defense against viruses – novel and otherwise.