Expanding the pharyngitis paradigm – the rest of the story

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Category : Medical Rants

Readers know how excited I am to finally have my pharyngitis paper published in the Annals of Internal Medicine.  I have decided to write the story behind the article for educational purposes.  This story unfolds over many years.

According to PubMed, I have 87 published articles.  The current article has me more excited than anything else I have ever published.

This article would never have existed with this blog. While I had published several sore throat articles prior to the blog, I had decided to leave pharyngitis when I moved to Alabama in 1993.  I still followed the pharyngitis literature, but had no plans for further studies.

I started the blog in May of 2002, and in August I wrote this entry based on a BBC News story – Some sore throats are VERY serious

Very interesting story appears on the BBC site – Warning over killer throat disease. I have done sore throat research early in my career. This article describes a condition so unusual that I know little about it.

I started reading the Lemierre syndrome literature.  The literature was sparse, and while I paid attention, I did not know how to use the information.  Then, in 2006, I received this email:

My 19-year-old-daughter contracted Lemierre's Syndrome in September 2005 during her first week of her freshman year at college. She had both peritonsillar and brain abscesses and had to have a craniotomy (brain surgery) to remove a rapidly-enlarging brain abscess.

During a two-week hospital stay, her prognosis, treatment and recuperation were orchestrated by a team of doctors (including infectious disease, neurosurgeon, ear, nose & throat specialist and internal medicine) at St. Luke's Hospital in Duluth, MN. It was the UMD Student Health Services that were able to confirm her serious condition when tests revealed very high white blood cell counts, a swollen left temporal region and affirmed that she was having word-finding difficulty.

The week prior to the start of school she was seen by two pediatricians (at a practice where she had been seen since birth in St. Paul) who believed her condition was viral and that she would get better with time and rest. After the first doctor's appointment, Meredith had described the doctor's attitude as flippant when she told Meredith to just go home and take some ibuprofen and that she would soon feel just great.

Instead, Meredith had a bacterial infection; it was fusobacterium, which needed antibiotic treatment. Her diagnosis was confirmed when the bacteria could be grown from a sample of her blood. While Lemierre's is a rare disease (some say it is a 1 in a million) it apparently is increasing in incidence because of the hesitancy to prescribe antibiotics. The disease most often occurs in young, healthy adults (mean age 19 and more often males than females). In simple terms, Lemierre's is an illness that results in inflammation of the internal jugular vein, which in turn leads to septicemia (blood poisoning) and areas of infection at places elsewhere in the body. The powerful array of antibiotics helped arrest the spread of Meredith's disease into her lungs. A hospital x-ray confirmed that she had pneumonia in the hospital but it improved with the drug treatment.

During her hospital stay she spent five days in intensive care. Her brain (left temporal lobe) was so swollen for the first week that her forehead had an enlarged appearance, reminiscent of Herman Munster from the TV show. Just prior to the craniotomy, after it was determined that the first procedure, a brain aspiration, had not arrested the brain abscess from rapidly enlarging, one of her nurse's described her normally vibrant and dramatic personality as someone who had affectless emotion. The disease increased the fluids in her body, morphing her body shape and giving her a swollen appearance. She has limited recall of events in the hospital.

As an aftermath, Meredith has a finely etched 12-inch scar that stretches from her left forehead into her scalp and then down her cheek and alongside her left ear. She has several patches of numbness around her nose, cheek and tongue, indicative of the damage to the third branch of the fifth cranial nerve.

Meredith has made a near-full recovery. She resumed a reduced college academic course load last fall (against the advice of one doctor for staying in school but with the blessing from another if it could help her resume a normal life and maintain a positive state of mind). Nearly three months of recuperation, self-administered daily IVs and a brush with a rare disease are not what you expect for your freshman year in college.

Throughout this ordeal she has shown herself to be courageous, determined and resilient. Today (June 27, 2006) she had her tonsils out.

The mother, Kristie Estes, started regular email correspondence.  She shared her experiences in an online support group.  She sent me newspaper articles about victims of this infection.

I began to read more regularly about Fusobacterium and Lemierre syndrome. In 2007 I first invoked Fusobacterium as an issue in adult pharyngitis in the article – Pharyngitis Management: Defining the Controversy..

Now I was obsessed. I began to see Lemierre syndrome as a monster that attacked innocent teenagers and young adults.  Fortunately, this monster was easily defeated with simple antibiotics.  Unfortunately, too often physicians who did not know this syndrome allowed the monster to succeed.

In my reading, I began to understand that Lemierre syndrome occurred more commonly than the books and previous articles suggested.  I know it was a horrible disease, but in 2008 it became even more personal.  Kristie Estes introduced me to the family of Justin Rodgers.  I first wrote about Justin in this rant –
And Lemierre’s can kill.

I spent time talking to Justin's family.  I learned about his illness and struggle.  Making certain that physicians knew about this disease became a passion.

By then I knew that Fusobacterium necrophorum likely caused pharyngitis in adults, but not pre-teens.  We had some sparse data on the epidemiology of Lemierre Syndrome. 

At the same time working with colleagues, we published a new decision analysis of adult pharyngitis.  This analysis only considered group A strep.

During the next 2 years I "knew" that Fusobacterium was important, but I was not sure how important. The publication of a prospective epidemiologic paper in 2008 allowed me to make a big leap –

Hagelskjær Kristensen L, Prag J. Lemierre’s syndrome and other disseminated Fusobacterium necrophorum infections in Denmark: a prospective epidemiological and clinical survey. Eur J Clin Microbiol Infect Dis 2008; 27, 779-789.

This Danish article suggested that in the 15-24 age group, the incidence of Lemierre syndrome was 14.4 patients/million (or 1 in 70,000).  These data stimulated my thinking.

It took a few months for me to try out ideas in my mind.  First, I considered doing a formal decision analysis with my colleagues who did the strep decision analysis.  I gave up on that idea because of the imprecision of the necessary estimates.

I finally decided to try to estimate the morbidity and mortality from both group A strep and Fusobacterium necrophorum. I worked on the paper for several months, and then submitted the paper to a journal that I will not name.  It took about a month until I was crushed.  They rejected the paper, and I thought they were full of ………

I entered the Kubler Ross stages of grief:

  • Shock stage: Initial paralysis at hearing the bad news.
  • Denial stage: Trying to avoid the inevitable.
  • Anger stage: Frustrated outpouring of bottled-up emotion.
  • Bargaining stage: Seeking in vain for a way out.
  • Depression stage: Final realization of the inevitable.
  • Testing stage: Seeking realistic solutions.
  • Acceptance stage: Finally finding the way forward.

I quickly got to the anger stage, and stayed there for a couple of months.  How dare they?  The reviewers obviously had no clue what I was writing about.  I tried bargaining to no available.

I was acting depressed about the paper.  I could not look at it.  I had the reviews on my desk, but only wanted to spit on them.

One day I began testing round 2.  I spent a couple of hours trying to figure out what journal might publish my grand opus (of course I do suffer from delusions of grandeur).  After some thinking and searching, I decided on the Annals of Internal Medicine.

I was ready to improve the paper.  I accepted the previous reviews and did my best to address the legitimate concerns.

Revising is hard work.  I needed to make the article better.  I excluded some ideas that I knew were right, but that I thought some reviewers could reject.  I thought of the famous line uttered by Jack Nicholson in  A Few Good Men, "… you can't handle the truth".

Of course I was on my "high horse".  I was too emotionally involved in the paper.

Over the next couple of months I worked on crafting the paper into a strong statement that was relatively bullet proof.  I accepted that the paper was attacking common wisdom.  When you attack common wisdom, you had to choose word carefully.

After submission, I waited with modest anxiety.  In late May I received a rejection, but with encouragement to resubmit.  Those who write academic papers learn how to read these letters.  This letter was very positive.  I was not yet ready to celebrate, but I was optimistic and energized.

It took me less than a week to polish the paper.  The reviewers points were relatively easy to address.

Two weeks later they wrote me back and asked for some minor revisions.  Now I am getting excited.  This paper may actually end up in the Annals of Internal Medicine!  Wow!

Two weeks after that, right before the 4th of July I had official acceptance!  What a great holiday present.

Now I am waiting.  Three and a half months later I finally am contacted with editorial revisions.  I review the revisions (mostly rewriting sentences), change a few, and accept the edited paper.

The next week I got the proofs.  The proofs actually look like the article.  I found a couple of minor errors that I corrected.  As I signed off on the proofs, I had to agree to an embargo of the article.  I was not allowed to discuss publication date.

I would have loved to write about the article here on MedRants, but the Annals wanted an exclusive release.  So I waited.

In retrospect 6 weeks is not a long time, but to this author it felt like months.  I was given the December 1st publication date.  The week prior to publication I found publication Nirvana.

The Annals contacted me for press information.  They were including my article in their press release for this issue.  Then Michael Berkwitz contacted me.  For those who do not listen to the Annals podcasts, Michael does a superb job on the Annals podcasts.  Most issues he picks one subject to explore in depth.  He chose my article.  I was walking on air.

The response to the article has been great thus far.  I hope that the article is inducing thinking about sore throats.  I hope that some teenagers and young adults will have quicker diagnoses because of this article.

I write this extra long rant to share my feelings and the process of publishing this type of article. 

Comments (3)

Great article in Annals; true scholarship and indeed quite tight. As a family doc for 20+ years I still get defensive when someone presumes that "all you do is see sore throats." As I've grown older I've come to understand this attitude is more reflective of the questioner than my chosen line of work.

Hi there,
As a survivor of Lemierre's I just wanted to thank you for trying to make more physicians aware of this forgotten disease so that they might save a life, as my doctor saved mine. 
Thank you. 

[…] This post documents the story as of 2009 when I wrote about Expanding the Pharyngitis Paradigm […]

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