BADAblog

By Pamela Weintraub

January 2nd 2009

If one were to describe all the terrifying and macabre presentations of neuroborreliosis, they would fill a book. But even added together they are rare compared to the most common neurological problem-the confusional state known as encephalopathy, or, as Lyme patients call it, “brain fog.” Patients routinely reported the experience: a disorienting lapse of memory, an inability to concentrate, difficulty in falling asleep, and profound fatigue.

Lyme encephalopathy was hardly controversial. John Halperin’s colleagues at Stony Brook objectively measured deficits in spatial orientation, short-term memory, concentration, and mathematical and construction ability. Halperin himself used magnetic resonance imaging to scan patients’brains. In one study he found white-matter lesions, much like those seen in multiple sclerosis, in the brains of seven out of seventeen encephalopathic Lyme disease patients. The lesions represented brain damage. Following treatment he rescanned six patients, and found the lesions resolved in three. Even when the lesions resolved, symptoms sometimes did not.

As scary as brain lesions might sound, the academic description of these impairments as “mild” created dissonance between scientists like Halperin and patients on the ground. Sure, Lyme patients were not usually as impaired as those with bullets in their brains, but the brain fog, the deficits in language and organization, the psychiatric leftovers of anxiety, depression, and OCD, could still disrupt lives. Adults lost houses, marriages, and jobs and were compromised as parents. Children lost their childhoods when cognitive or emotional disabilities forced them to be home-schooled, sometimes for years. The impact was major, but mainstream experts continued to characterize such symptoms as “minor,” “nonspecific,” and “vague.”

The professionals able, finally, to traverse the space between the dismissive labels and the excruciating patient experience were the psychiatrists. If neurologists and rheumatologists deemed psychiatric symptoms “subjective,” the psychiatrists said, it was because, when it came to psychiatry, these physicians were unschooled.

One of the first to enter the fray was Brian Fallon, whose interest had been sparked in the late 1980s while helping a close relative overcome a serious case of Lyme disease. He had just finished his psychiatry residency and secured a gig as a fellow of the National Institute of Mental Health.

He was stationed at the New York State Psychiatric Institute, adjacent to the Columbia University Medical Center complex in New York City. The young doctor, whose kempt, longish hair, neat beard, and energetic demeanor made him look like he’d marched off the album cover of Abbey Road, specialized in anxiety disorders, with a focus on hypochondria. But news of his interest in Lyme disease had traveled through the grapevine to Polly Murray. Some of her friends in Old Lyme had developed psychiatric disorders after having Lyme disease. Could Fallon follow up?

Fallon and his psychiatrist wife, Jennifer Nields, drove out to Old Lyme and spent the day in Polly Murray’s living room surrounded by her watercolors, talking to her afflicted friends. One of the first things they decided as a result of that meeting was to impose formal discipline on the loosely knit reports of psychiatric symptoms made by neurologists and rheumatologists. Fallon was well aware of the single-case studies and series of anecdotes continually published in medical journals. The German researcher Kohler had even reported a staging of the psychiatric symptoms that paralleled progression in the neurological realm. In the first stage, mild depression could parallel a fibromyalgia-like illness. In the second stage, mood and personality disorders often emerged alongside meningitis or neuropathy. Finally, in stage three, with the onset of encephalomyelitis, the clinical picture might include psychosis or dementia.

Fallon felt that when it came to Lyme, none of these reports, even Kohler’s, was solid enough to vest psychiatry with the same objective underpinnings found in rheumatology or neurology. Part of the problem was a misperception about what psychiatrists did and what psychiatry was. Psychiatrists often started their work in the murky, subjective outback of a patient’s psyche. But the scientists among them, like Fallon, were charged with the mission of anchoring thought, feeling, and experience in the firmament of objective data. Neurologists and rheumatologists often dismissed the psychiatric symptoms of Lyme disease as subjective, but they did so without applying the rigorous methodology that psychiatric research entailed.

And that’s where Fallon hoped his contribution would matter most. His labor paid off. Conducting structured clinical interviews with people from southeastern Connecticut who had histories of Lyme disease he learned that depression or panic could worsen after the start of antibiotic treatment, suggesting a kind of psychiatric Herxheimer reaction that resulted as infection died off. Speaking to the patients, he found that neuropsychiatric Lyme disease and regular psychiatric disease appeared much the same. This was of particular concern since so many patients failed to notice a rash or register positive on standard tests, making it likely that the true cause of their psychiatric condition-Lyme disease-would be missed.

The patients were in psychiatric trouble, to say the least. Surveying 193 patients testing positive for Lyme, Fallon found that 84 percent had mood problems; of those reporting depression, 90 percent had never had an episode prior to Lyme disease, which suggested the two were linked. As for children with Lyme, Fallon showed they resembled accident victims with head injuries. Like adults, they had trouble with short-term memory, word-finding, and concentration. Their performance IQ and spatial reasoning were particularly impaired. The children could still remember and learn-but they processed the information slowly and needed more time for tasks.

Though selected for the study because of their cognitive disabilities, the children also suffered anxiety, mood, and behavioral disorders at higher rates than healthy children. Especially notable was the increased risk for depression and suicidal thoughts. The findings were important because children with Lyme disease could be “misdiagnosed as having a primary psychiatric problem,” while the root issue-infection with the spirochete B. burgdorferi-might never be addressed.

It was a dilemma that transcended Lyme disease. Time and again, Fallon, an expert in hypochondria, had seen frustrated doctors dismiss medically ill patients as psychiatric due to their own inability to diagnose the disease. In Lyme the mistake was especially damaging, he said, “since a delay in treatment could turn a curable, acute infection into a chronic, treatment-refractory disease.”

The solution, Fallon the scientist knew, was to gather objective evidence of physical damage to the brain. Working with radiologists at Columbia, he found one useful tool was the SPECT (single photon emission computed tomography) scan, which generated a moving picture of the brain. A radioactive “tracer” solution was delivered intravenously, and was thereafter tracked to measure blood flow through the brain. Even when MRI scans appeared normal in Lyme disease patients, SPECT could show something amiss. In symptomatic Lyme patients, decreased blood flow, known as hypoperfusion, could often be documented in the center of thought and higher functioning, the cerebral cortex. After treatment, many of the patients showed improvement on SPECT.

More on Neurological Lyme disease to come

Excerpted from Cure Unknown: Inside the Lyme Epidemic, St. Martin’s Press, 2008

http://blogs.psychologytoday.com/blog/emerging-diseases/200901/when-physicians-miss-the-diagnosis-patients-can-be-stigmatized-with-ps

By Pamela Weintraub

December 30th 2008

The first time I met a group of severely disabled Lyme disease patients I spent hours listening to their stories, some of them heartbreaking, and mourned, with them, their lives of frustration and pain. A month later, when I met the same patients again, several could not recall me. At first I was insulted. Had I been that forgettable, my empathy that banal?

Then I realized something I had never fully grasped despite my research, despite my own Lyme disease. Unless you have personally encountered the shadowland of the most afflicted patients-a world eclipsed by strange lapses of memory, broken speech, and the struggle to
follow the simplest train of thought-you cannot begin to fathom the dense, disabling fog that may accompany the disease.

To this day, popular perception holds that Lyme disease is an affliction of knees, characterized by swollen joints and an inability to serve in tennis or descend a flight of stairs. Musculoskeletal symptoms can be a hallmark of Lyme disease, but the early rheumatologists had recognized just one part of the elephant-it would take more time, and a broad array of specialists, for the widening picture to emerge.

Some of those early patients, selected for studies because of their remitting-relapsing arthritis, recalled the appearance of an expanding red rash before the arthritis had begun. Taking the cue, the Yale scientists looked for patients with the rash-early Lyme-and began studying them prospectively, at the true onset of disease. They found that only some patients went on to develop arthritis. In others, the rash gave way to headaches and stiff necks (meningitis); facial drooping, choking, or visual loss like I suffered (attack of the cranial nerves); or terrible shooting pains throughout the torso and limbs. When these devastating signs appeared together, often the diagnosis was Lyme.

At Stony Brook, meanwhile, the neurologist John Halperin studied a far less devastating but more common “peripheral neuropathy,” a kind of numbness or “pins and needles” feeling in the extremities. Could the intermittent numbness and tingling in one patient’s fingers derive from the same dysfunction as the stabbing pain in another patient’s torso and legs? By 1990, using the tool of electromyography (EMG) to study nerve cells, Halperin found that these symptoms, though diverse, were all due to the same thing: damaged nerve cells and, more specifically, abnormalities in the axon, the long, slender part of the cell that propagates nerve impulses along. The neurons were being “picked off” one at a time, in scattered clumps, as if snipers were at work. If the disease took out a big chunk in one place, you might get shooting pain. If it took out tiny, scattered groups of nerves you could get numbness in the toes or a weakness when you walked. Halperin’s study, published in the journal Brain, concluded that the underlying pattern of nerve cell abnormality was the same no matter what the complaint. “All of them really had the same disease,” he said. “It was just variations on a theme.”

Other times Lyme caused psychiatric disease. One of the first to have this insight was Andrew Pachner, a Yale neurologist who moonlighted at psychiatric hospitals. On one such gig he was asked to evaluate a twelve-year-old boy who, prior to admission, had pedaled his stationary
bicycle barely stopping to sleep or eat. Before the start of this behavior, the boy had been an excellent, hardworking student with a talent for soccer. But his soccer days were disrupted when he developed painful, swollen knees and was diagnosed with Lyme arthritis. The
child was treated with doxycycline and seemed to get well. When his obsessive pedaling began some years later, his prior Lyme disease was already a distant memory, and no one saw the relationship between the two.

Except for Pachner: Given what he knew about syphilis, he wondered whether Lyme disease and the obsessive cycling might be linked. In a leap of insight, he moved the boy to Yale and infused him with penicillin for fourteen days. It was like a miracle. Literally within days the child started to improve, interacting with staff and eating food. Two weeks later he returned home and went back to school. When Pachner saw him a few months after that he had even returned to soccer. He seemed cured. In 1989, writing for the Archives of Neurology, Andrew Pachner, by then at the Georgetown University School of Medicine, described six cases of central nervous system Lyme disease, of which his “bicycle boy” was just one. Another patient, a twenty-one-year-old man, had violent outbursts and wild laughing, attributed to a herpes virus thought to infect his brain. But he tested positive for Lyme disease and, treated with antibiotics, was finally cured. A six-year-old girl, so afflicted with vertigo that she staggered, tested positive for Lyme and was treated; she, too, got well.

The German neurologist Rudolph Ackermann found that the sickest of these neuroborreliosis patients suffered an inflammation of the brain and spinal cord called encephalomyelitis, also seen in syphilis. When the condition involved the spine it resembled multiple sclerosis and when it involved the brain, particularly the cerebral cortex, it could produce psychoses or seizures. The condition was progressive and degenerative without treatment, but even after antibiotic therapy, most of the patients retained the symptoms, though to a lesser degree.

From the devastating syndrome described by Ackermann to the odd presentations reported by Pachner, neuroborreliosis appeared almost protean, and, like syphilis, could be mistaken for a host of other ills. Syphilis had long been known as “the great imitator” among doctors.
Now Pachner declared that Lyme disease was “the new great imitator.”

His statement seemed to unleash a torrent of bizarre reports flowing into the medical journals. A group from Stanford described a twentyfive-
year-old woman with hallucinations, hypersexuality, nightmares, and a rash. Scientists from Germany found Lyme could cause Tourette’s syndrome, catatonia, and even schizophrenia. Several teams have reported Lyme disease masquerading as-or even triggering-Parkinson’s disease. And in what would be a breakthrough of enormous scope-if borne out in other studies-neuropathologist Judit Miklossy of the University of Lausanne in Switzerland reported that she had isolated spirochetes from the blood, cerebrospinal fluid, and brain tissue of fourteen Alzheimer’s patients upon autopsy. More than two dozen published papers associate neuroborreliosis with stroke, and others document that Lyme disease may cause seizures.

Perhaps most tantalizing is the work done on ALS. In 1987, for instance, a Wisconsin team found that four of fifty-four patients diagnosed with ALS also tested positive for Lyme disease-and since ALS is fatal, decided that treatment with antibiotics wouldn’t hurt. Following the treatment, one of the four patients was stabilized, the progression of her symptoms halted for good. Intrigued by the report, Halperin did a formal follow-up, testing nineteen ALS patients from the hyperendemic area of Suffolk County, New York. Of these, nine had Lyme antibodies and the Stony Brook doctors, like their Wisconsin colleagues, treated them with antibiotics. Three patients, those with abnormalities primarily in the lower part of the body, improved. But three of the sickest patients declined dramatically following treatment, which seemed to hasten their death. Though the Stony Brook scientists couldn’t say for sure what was going on, they affirmed the statistical significance between ALS and Lyme disease, and theorized that in those who deteriorated, the cause might be the flood of dying spirochetes themselves.

Excerpted from Cure Unknown: Inside the Lyme Epidemic, St. Martin’s Press, 2008

http://blogs.psychologytoday.com/blog/emerging-diseases/200812/shadowland-the-mind-neurological-lyme-disease-part-one

While others are a nuisance, these nasties can carry Lyme disease

By BRIAN MEDEL Yarmouth Bureau
Sat. Jan 3 - 10:34 AM

Tick specialists will soon be poring over their Nova Scotia maps as they plan where to search in 2009 for the blacklegged tick, which caries Lyme disease.

The Admiral Cove area of Bedford as well as Lunenburg have populations of blacklegged ticks, but the Gunning Cove area of Shelburne County was also found to be crawling with them in 2008.

About 50 blacklegged ticks were picked up in one hour in Gunning Cove last summer, said Jeff Ogden, an entomologist with the Natural Resources Department.

“When we tested the ticks, . . . about 20 per cent of the ticks were positive for the bacteria that causes Lyme disease,” he said in a recent interview.

Surveillance has continued and ticks continue to come from the area, he said.

The bad ticks are blacklegged ticks. But it’s the American dog tick that’s most prevalent in the province.

“That doesn’t carry any diseases. It’s just a nuisance,” said Mr. Ogden.

The American dog tick is twice as large as a blacklegged tick. The dog tick is brownish with some white on its back.

The adult female blacklegged tick has a bright red abdomen. The adult males are very small — about two to three millimetres across.

“We do have 12 to 13 other species of ticks that we get in the province,” said Mr. Ogden.

Ticks are carried by migratory birds and 10 per cent of ticks carried in such a manner also carry germs that cause Lyme disease.

“I’m guessing (blacklegged ticks) have always been here,” said Mr. Ogden.

The areas where they are established also have large deer populations.

In fact, Mr. Ogden linked lots of deer and migratory birds to blacklegged tick colonies.

In coastal locations with migratory birds but fewer deer, there are likely fewer ticks, he said.

Close to15 per cent of the Bedford ticks tested last summer carried Lyme disease. Lunenburg was higher at 25 to 30 per cent and the Shelburne County sample was about 20 per cent.

Lyme disease is a bacterial infection, but very few people bitten by a diseased tick will come down with the condition, said Mr. Ogden.

He said he has been bitten by ticks carrying Lyme disease ticks but has not had the disease because a tick must feed on you for at least 24 hours before bacteria is transmitted into our system.

And with mild winters, any time can now be tick time.

The adult blacklegged tick spends its winter in the forest floor.

“If it’s above plus four (degrees), they’ll become active,” said Mr. Ogden. “They’ll find a piece of foliage and climb up. If it gets below plus four, they drop back down.”

He has had ticks sent to him in January.

And Mr. Ogden wants people to send their ticks to him through their local Natural Resources office.

“If it’s a blacklegged tick, it will be tested.”

Before they head out in 2009, Natural Resources field staff will look at the 2008 blacklegged tick survey results to see where they should go.

“We’ll look at the map to see where the clusters are.”

Any areas with multiple submissions will be investigated further in the spring of 2009 using a method known as drag sampling.

They drag with something that resembles a baby blanket.

“It’s a metre-square piece of flannel,” said Mr. Ogden.

“Go out and enjoy yourself, but when you come back . . . do a quick tick check.

“Pull them off and send them to me.”

Lyme disease also affects dogs with an arthritis-like condition, he said.

http://thechronicleherald.ca/NovaScotia/1098812.html

Study: Hotter weather may make the pests more likely to bite humans

By Emily Sohn

updated 1:56 p.m. ET Dec. 30, 2008

The brown dog tick (Rhipicephalus sanguineus) rarely bites people, far preferring the taste of dog. But global warming could be changing that, exposing people to dangerous diseases as a result.

In the spring of 2007, three men in France became seriously ill after sustaining bites from disease-infected dog ticks. The bites occurred after the hottest April since 1950, said Didier Raoult, a professor at the University of Marseille School of Medicine in France.

The incident reminded Raoult of two other recent cases. A 2004 outbreak of Rocky Mountain spotted fever in Arizona was also associated with dog ticks. And during the exceptionally hot summer of 2003, a man died after 20 brown dog ticks bit him at once.
Raoult suspected that, in each of these cases, hot weather made dog ticks turn on humans. He decided to investigate.

First, he and colleagues visited the site of the most recent outbreak: a house in southern France, where a 50-year-old woman had been living with her tick-infested dog.

The dog died shortly before the outbreak began. The woman said the ticks became particularly aggressive in April 2007.

‘Perfect storm scenario’

In less than an hour of searching, the researchers collected 218 brown dog ticks from around the house and garage. Of the 133 ticks they tested, nearly 30 percent were infected with varieties of Rickettsia, a genus of bacteria that causes Rocky Mountain spotted fever, Mediterranean spotted fever, and other life-threatening diseases. In the general dog tick population, fewer than 1 percent are usually infected.

Next, the doctors examined two of the patients — a 25-year-old man and a 30-year-old man. Their symptoms were similar: fevers, headaches, night sweats, rashes, and loss of vision. Both were diagnosed with severe spotted fevers, but the species of pathogens they carried were different: Tests showed that the older man was infected with Rickettsia conorii, the agent of Mediterranean spotted fever, while the younger carried R. massiliae, an emerging pathogen.

“You had a set of conditions at this particular household that created, for lack of a better term, a perfect-storm scenario,” said Christopher Paddock, a pathologist with the Centers for Disease Control and Prevention in Atlanta. “There were lots of ticks, lots of infected ticks, warm temperatures, and the dog dying, which is the normal host. All that adds up to ticks feeding on people and transmitting infection.”

To see how much the temperature, in particular, mattered, Raoult and two colleagues turned themselves into human guinea pigs. They incubated 500 brown dog ticks at 77 degrees Fahrenheit and 500 at 104 degrees Fahrenheit. Then, they placed the ticks on their own arms.

“They take a very long time to attach,” Raoult said, bravely. “It’s not like a mosquito. They don’t have time to bite you.”
After an hour, about half of the ticks incubated at 104 degrees tried to burrow in, Raoult said. None of those incubated at 77 degrees did. The results appeared in November in the journal PLOS Neglected Tropical Diseases. Raoult suspects thirst drives the ticks to seek human blood at higher temperatures.

As global climate warms, dog ticks might be more likely to bite people, and tick-transmitted diseases might become more common, the researchers concluded.

Those conclusions are reasonable, Paddock agreed. But he was wary of inferring too much from this particular study. Temperature is just one factor that affects tick behavior, for one thing. And a sudden surge from 77 degrees to 104 degrees is too extreme to mimic a realistic global warming scenario.

“We’re witnessing small incremental changes over time,” Paddock said. “We don’t know what sort of changes we’ll see on a global scale.”

© 2008 Discovery Channel

http://www.msnbc.msn.com/id/28435738/

1: J Med Virol. 2008 Dec 23;81(2):309-316.

P. D’Agaro 1, E. Martinelli 1, P. Burgnich 1, F. Nazzi 2, S. Del Fabbro 2, A. Iob 3, M. Ruscio 4, P. Pischiutti 3, C. Campello 1 *

1Department of Public Medicine Sciences, U.C.O. Hygiene and Preventive Medicine, University of Trieste, and Institute of Child Health IRCCS Burlo Garofolo, Trieste, Italy
2Department of Biology and Plant Protection, University of Udine, Udine, Italy
3Department of Prevention, A.S.S.3 Alto Friuli, Gemona del Friuli, Italy
4San Daniele Hospital, San Daniele del Friuli, Italy
 
email: C. Campello (campello@burlo.trieste.it)

*Correspondence to C. Campello, Department of Public Medicine Sciences, University of Trieste, Via Dell’Istria 65/1, 34147 Trieste, Italy.

Funded by:
 Institute of Child Health IRCCS Burlo Garofolo; Grant Number: R.C. 73/05
 Azienda Servizi Sanitari n. 3 Alto Friuli

Keywords
TBEV • prevalence • Ixodes ricinus • sequencing • Italy

Abstract

In Alpine area of extreme North Eastern Italy the first autochthonous case of TBE was reported in 1998 and was followed by 45 cases during the period 2001-2007, thus defining this area as definitely endemic. An ecological survey evaluated the tick density and the Tick-borne encephalitis virus (TBEV) infection prevalence in tick collected in selected sites. In addition, TBE strains were characterized by sequencing and phylogenetic analysis. Overall, 2,361 ticks (2,198 nymphs and 163 adults) of the Ixodes ricinus L. species collected during 2005 and 2006 were examined. Five samples were positive for TBEV, corresponding to an overall prevalence rate of 0.21%. When analyzed by place, TBEV was discovered in three sites where the highest tick density was found. The difference of prevalence between high and low density areas tested to be statistically significant (P = 0.028). Phylogenetic analysis showed that four sequences clustered with the Neudoerfl prototype, while the other clustered with the Isosaari 17 strain and with a number of Slovenian isolates. In addition, a sequence detected in archival samples from one human case segregated with another variant, namely the Swedish Torö strain. J. Med. Virol. 81:309-316, 2009. © 2008 Wiley-Liss, Inc.

http://www.ncbi.nlm.nih.gov/pubmed/19107965?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Sarah Avery - Staff Writer
Published: Sun, Dec. 14, 2008 12:30AM

A notion struck Betsy Sigmon on the way to the hospital to tend to her 13-year-old son Jason.

The youngster, who was admitted after suffering weeks of excruciating headaches, had been bitten by a tick days before he grew sick. While blood tests showed no hint of a tick-borne infection, the idea nagged at her.

Staff Photo by Jason Arthurs - Jason Sigmon, left, had severe headaches after being bitten by a tick. Doctors initially found no evidence of a tick-borne infection.

So Sigmon called Dr. Ed Breitschwerdt, a veterinary researcher at N.C. State University. Sigmon, herself a vet, knew Breitschwerdt studied tick-borne diseases.

“Do you know of any kind of infectious agent that might be causing Jason’s symptoms?” Sigmon recalls asking Breitschwerdt.

In reaching out to Breitschwerdt, Sigmon turned to a man who may know a hidden cause behind many chronic human ailments that often aren’t recognized as infections transmitted by animals and insects.

With the right diagnosis using a process he patented, Breitschwerdt says, many could be easily cured with antibiotics.

Medical doctors have been slow to listen to a veterinarian about how to treat humans, but promising results are helping Breitschwerdt’s views gain acceptance. Antibiotic treatment has cured people of pain and weakness doctors originally attributed to migraines, chronic fatigue and even multiple sclerosis.

At the heart of Breitschwerdt’s research is a pathogen carried by insects — a bacteria known as Bartonella. Spread by biting pests such as fleas, lice, sandflies and possibly ticks, Bartonella are difficult to detect in human blood. As a result, Breitschwerdt thinks the bacteria are taking an unacknowledged toll on human health.

“I believe it’s a silent epidemic,” says Breitschwerdt, who is also an adjunct professor in infectious diseases at Duke University Medical School.

His belief is based on his own patients — the cats, dogs, rabbits, cows and other animals that harbor Bartonella in their blood. With so many insects spreading the bacteria to so many animals, he contends, the bugs are certain to readily infect humans.

Breitschwerdt suspected a Bartonella infection was behind Jason Sigmon’s headaches. He urged Betsy Sigmon to ask the hospital staff at WakeMed to draw an extra vial of the youngster’s blood for him to test. Using a technique he patented and special equipment in his lab at N.C. State, Breitschwerdt went on the hunt for Bartonella.

Understanding evolves

As bugs go, Bartonella species are fairly recent entries on the list of known infectious germs. Bartonella was first noted as the culprit behind a severe fever illness that explorers picked up in Peru from sandfly bites. Then in World War I, a strain was identified as the cause of trench fever, which sickened thousands of soldiers who caught it from body lice that spread in the cramped, filthy conditions of war.

Thereafter, doctors figured Bartonella was a pathogen isolated by geography or limited to decrepit conditions.

That began to change in the early 1990s, however, when scientists determined that a Bartonella infection caused skin lesions on AIDS patients and among homeless people in the United States.

About the same time, another species of the bacteria was identified as the source of cat scratch disease. The illness, which afflicts about 22,000 people a year in the United States, had previously been attributed to another pathogen.

Marked by swollen lymph nodes, fever and general malaise, the disease occurs after contact with a Bartonella-infected cat. And those are legion. About half of cats in flea-prone regions harbor the bacteria at some point in their lives, spreading it through their saliva and in fleas. In fact, it gets on cats’ claws because they scratch at the fleas, raking up the germ from the fleas’ feces.

savery@newsobserver.com or 919-829-4882

http://www.newsobserver.com/news/health_science/story/1333377.html

Open Microbiol J. 2008; 2: 10–12.

Christer Larsson and Sven Bergström*

Umeå University, Department of Molecular Biology, Laboratory for Molecular Infection Medicine Sweden (MIMS) SE-901 87 Umeå, Sweden
*Address correspondence to this author at the Umeå University, Department of Molecular Biology, SE-901 87 Umeå, Sweden; Tel: +46-90-785-6726; Fax: +46-90-772-630; E-mail: sven.bergstrom@molbiol.umu.se

Received November 14, 2007; Revised December 18, 2007; Accepted December 20, 2007.

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Relapsing fever caused by Borrelia bacteria is often obscured by malaria and incorrectly treated. Here a novel method for diagnosis is presented. The method is cheap, simple and requires minimal laboratory material. Despite its simplicity, the method shows surprisingly high sensitivity, detecting concentrations less than 10 bacteria/ml blood.

Keywords: Borrelia, relapsing fever, diagnostics, detection, fever

INTRODUCTION

Relapsing fever (RF) is a disease caused by several species of bacteria belonging to the genus Borrelia. The illness occurs worldwide in tropical and sub-tropical areas, but is most common in Africa [1, 2]. In some areas, the incidence is the highest for any bacterial disease on the continent [3]. All species pathogenic to man are transmitted by ticks of the genus Ornithodoros with the single exception of B. recurrentis, which is transmitted by lice [4, 5].

The main manifestation is, as the name indicates, a recurring fever with massive amounts of bacteria in the blood during fever peaks [1, 2, 6]. The relapsing pattern is due to the reciprocal action between host antibody response and bacterial antigenic variation of surface proteins [7, 8]. However, fever is a common symptom of many diseases and RF is often atypical or causes mild or sub-clinical disease. Therefore it is neglected and overlooked in many areas, often mistaken as malaria and hence incorrectly treated. In Togo, West Africa RF was previously unknown although it was recently found to be the causative agent in about 10% of the fever patients [9]. The mortality ranges from 2-40% and is highest in children. RF also cause pregnancy complications such as stillbirth [2].

During fever peaks, diagnosis is simple since there is massive bacteraemia easily detected with e.g. the Giemsa staining used in malaria diagnosis but between the peaks and in milder disease the bacteria are few and very hard to find in a stained blood smear by microscopy. Protocols used for malaria diagnostics in which water is used to lyse erythrocytes usually also lyse spirochetes and are therefore useless for RF diagnostics. Phase contrast or dark field microscopy directly on10-fold diluted blood is useful when spirochetemia is high. Due to the spirochetes’ thin and transparent morphology, ordinary light microscopy is very difficult and therefore of limited use.

The use of acridine orange–coated quantitative buffy coat tubes, centrifugation, and fluorescence microscopy is effec-tive [10, 11]. However, this technique requires expensive equipment seldom available in RF endemic areas.

PCR is an excellent method for RF diagnostics. Briefly, DNA is extracted from about 100 µl blood, analysed by PCR using Borrelia-specific primers and separation on an agarose gel, or if using real-time PCR, the results can be directly monitored on the computer screen in real time [12, 13]. The method is fairly quick and sensitive if the instrument and all reagents, including specific primers, are accessible. The major drawback with PCR is the cost of necessary equipment and reagents. It is also labour intensive and sensitive to contamination, which can result in false positive results. Smaller hospitals often have limited possibility of using PCR in their diagnostics.

ELISA is a valuable scientific tool to screen sera for antibodies against pathogens. Most useful is recombinant GlpQ, a protein found in all RF Borrelia but not in other related bacteria such as B. burgdorferi or Treponema. An ELISA detecting antibodies recognizing GlpQ identifies patients who have encountered RF and mounted an immune response against the pathogen [9, 14, 15]. RF is an acute disease and in most fatal cases, the first attack is most critical. This lasts for a few days and thereafter it takes another couple of days until the fever drops as a result of the host antibody response. It is not until this time point that there are sufficient antibodies for detection by ELISA. Although superior in identifying persistent low-grade disease, ELISA is expensive and labour intensive. It is more valuable for less acute diseases and for epidemiological studies of RF.

It is obvious that improved RF diagnostics is urgently needed. Therefore, we have developed this centrifugation-based enrichment method to provide a novel inexpensive and simple, but rapid and powerful RF diagnostic method to be used in rural health centres and perhaps also at larger hospitals.

MATERIALS AND METHODS

Setup of Diagnostics Protocol

Blood from healthy volunteers was drawn into heparinised VacuTainer tubes. B. duttonii was grown in BSK II culture medium [16] with 1,4% gelatin and 10% rabbit serum (Sigma) at 37°C, washed in phosphate buffered saline three times, counted in a Petroff-Hauser chamber using phase contrast microscopy. Bacteria were then spiked into 10 ml blood at known concentrations. The first centrifugation in which blood cells are separated from the plasma containing bacteria was optimized at a speed and duration to obtain a supernatant free from erythrocytes and leukocytes without lowering the concentration of bacteria. The second centrifugation in which bacteria are pelleted was optimized at a speed and duration at which no spirochetes remained in the plasma.

Giemsa Staining and Microscopy

The plasma supernatant was aspirated and the almost invisible bacterial pellet was resuspended in the few remaining microliters of plasma. The suspension was smeared onto a glass slide as a “thick smear” the size of a coin and air-dried for a few minutes. The smear was then fixed by heating a few times over a flame followed by a 30 second dip in methanol. Staining was performed by a standard Giemsa staining protocol. Stained bacteria were visualized by light microscopy at 1000X magnification. Bacteria were either stained with Giemsa or directly visualized by phase contrast microscopy at 400X.

RESULTS AND DISCUSSION

Although RF is one of the most common bacterial diseases in Africa it is often mistaken, and treated, as malaria, especially since they often occur as co-infections [17-19]. If effective treatment is given, this is often started only after a failed malaria treatment. After finding a 10% incidence of RF in fever patients seeking healthcare in Togo, West Africa, although the disease was unknown in the country, we realized that the need for improved RF diagnostics is urgent [9].

Methods such as the quantitative buffy coat technique using acridine orange and fluorescent microscopy, PCR with RF specific primers and ELISA for e.g. detection of antibodies to RF GlpQ protein are useful in diagnostics [10-15]. However, such techniques are often inaccessible, too lengthy or too expensive to be used where resources are limited.

Therefore we have developed this centrifugation-based method to concentrate spirochetes from blood that can be used with minimal laboratory equipment (Fig. 1). Methods involving ready-made PCR kits, density gradient centrifugation and Western blot detection of Borrelia proteins were initially considered. When we changed perspective and instead focused on the equipment and protocols already available at small hospital laboratories in RF endemic areas, we came to the conclusion that this approach is superior in its simplicity, rapidity, low cost and high sensitivity. The choice of Giemsa staining as a detection method makes it possible to process malaria and RF samples simultaneously since this is the stain most widely used in malaria diagnostics. A light microscope and Giemsa stain are the very basic equipment available at rural health clinic laboratories in malaria endemic areas.

Fig. (1).

Centrifugation-based enrichment method for spirochetes in blood.
Venous blood is drawn into anticoagulant. Blood is thereafter centrifuged at 500 x g for 5 minutes, pelleting blood cells with most spirochetes remaining in the plasma. After transfer to a new test tube, the plasma is centrifuged at 5000 x g for 10 minutes to pellet bacteria. The supernatant is decanted, leaving spirochetes in the pellet. The suspended pellet is smeared onto a glass slide and stained with Giemsa for microscopic examination at 1000X magnification.

The availability and quality of centrifuges differ tremendously. The first, slow centrifugation can be performed in any centrifuge. This was optimized to obtain a supernatant free from erythrocytes with minimal loss of bacteria. Since about 1/3 of the blood volume consists of erythrocytes a lot of bacteria is lost at this stage anyway. A 5-minute centrifugation at 500 x g was found to be optimal. Naturally, a slower/shorter centrifugation will give erythrocyte contamination in the second pellet which will conceal the thin, blue bacteria although small amount of erythrocytes is acceptable (Fig. 2). At a faster/longer centrifugation the concentration of spirochetes in the supernatant gradually decreases.

Fig. (2).

Borrelia spirochetes concentrated from 10 ml blood and Giemsa stained.
Low numbers of bacteria were concentrated as described in the material and methods section, Giemsa stained and visualized by light microscopy at 1000X magnification. Cells stained red and blue are contaminating erythrocytes and leukocytes, respectively. Some of the bacteria are marked by arrows.

The plasma supernatant was carefully transferred into a new centrifuge tube avoiding erythrocyte contamination from the pellet. The second centrifugation was designed to pellet all bacteria in the remaining plasma. A quite fast centrifugation is necessary to completely pellet all the bacteria. We found 5000 x g for 10 minutes to be sufficient but the time and speed can be extended without negative side effects. If the centrifuge is slower than 5000 x g, the time can be extended to maximize recovery although slower centrifugation often leaves some bacteria remaining in the supernatant which may lower the detection limit. Nevertheless, the sensitivity will be dramatically higher compared to direct microscopy of blood or plasma.

To evaluate the sensitivity of the method, 100 bacteria were spiked into 10 ml blood. The samples were processed as described and about 10 spirochetes were recovered on the glass slides by microscopy. This is a concentration of 10 bacteria/ml and according to our result the laboratory technician has a fair chance of diagnosing spirochetemia at a bacterial concentration of 1 bacteria/ml. This sensitivity may even be superior to many PCR-based protocols where the maximal volume blood to be used for DNA purification is about 100 µl.

If using a regular single-step PCR followed by separation with agarose gel electrophoresis and ethidium bromide staining, it takes approximately 500-1000 cells to get a detectable band (personal communication, J. Bunikis). The sensitivity can be increased by using nested PCR in which a second PCR is performed with two other primers, using the first reaction as template [9]. Nested PCR can detect as few as 1-10 bacteria but is very sensitive to contamination, resulting in false positive results. The sensitivity of real-time PCR, in which either incorporation of a fluorescent dye or DNA probe is measured, is similar to that of nested PCR [20]. By combining the methods into nested real time PCR, where an ordinary PCR reaction is followed by a real-time PCR with a probe and a new set of primers, the sensitivity is as low as 0.1-1 cell (personal communication, J. Bunikis). The small sample volume, typically about 100µl, used for DNA preparation may be more limiting than the sensitivity of the PCR methods when spirochetemia is low. By combining the centrifugation protocol with PCR, the sensitivity of RF detection can be further increased.

Due to its low-tech approach, mainly using equipment already available for malaria diagnostics and well-known procedures, we believe this novel technique will be very valuable for RF diagnostics, especially at rural health centres and hospitals. Due to the superior sensitivity it may also be considered to be the first-hand choice at larger hospitals, when suitable, in combination with PCR.

ACKNOWLEDGMENTS

This work was supported by grants from the Swedish Research Council (VR-M) 07922, the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas), Swedish Foundation for Strategic Re-search, MicMan, and the JC Kempe foundation. Betty Guo is greatly acknowledged for proof reading the manuscript

REFERENCES

1.Felsenfeld, O. Human and Animal Borreliosis. St Louis MO: Green; 1971. Borrelia: Strains, Vectors.
2.Southern, P; Sanford, J. Relapsing: fever A clinical and microbiological review. Medicine. 1969;48:129–149.
3.Vial, L; Diatta, G ; Tall, A, et al. Incidence of tick-borne relapsing fever in west Africa: longitudinal study. Lancet. 2006;368:37–43. [PubMed]
4.Raoult, D; Roux, V. The body louse as a vector of reemerging human diseases. Clin Infect Dis. 1999;29:888–911. [PubMed]
5.Sonenshine, DE. Biology of Ticks. Oxford University Press; 1997.
6.Cook, G; Zumla, A. Manson’s Tropical Diseases. Saunders; 2002.
7.Dai, Q; Restrepo, BI; Porcella, SF; Raffel, SJ; Schwan, TG; Barbour, AG. Antigenic variation by Borrelia hermsii occurs through recombination between extragenic repetitive elements on linear plasmids. Mol Microbiol. 2006;60:1329–1343. [PubMed]
8.Barbour, AG. Am Soc Microbiol. Washington DC: 1989. Antigenic Variation in Relapsing Fever Borrelia Species: Genetic Aspects; pp. 783–790.
9.Nordstrand, A; Bunikis, I; Larsson, C, et al. Tickborne relapsing fever diagnosis obscured by malaria, Togo. Emerg Infect Dis. 2007;13:117–123. [PubMed]
10.van Dam, AP; Van Gool, T; Wetsteyn, JC; Dankert, J. Tick-borne relapsing fever imported from West Africa: diagnosis by quantitative buffy coat analysis and in vitro culture of Borrelia crocidurae. J Clin Microbiol. 1999;37:2027–2030. [PubMed]
11.Cobey, FC; Goldbarg, SH; Levine, RA; Patton, CL. Short report: Detection of Borrelia (relapsing fever) in rural Ethiopia by means of the quantitative buffy coat technique. Am J Trop Med Hyg. 2001;65:164–165. [PubMed]
12.Halperin, T; Orr, N; Cohen, R, et al. Detection of relapsing fever in human blood samples from Israel using PCR targeting the glycerophosphodiester phosphodiesterase (GlpQ) gene. Acta Trop. 2006;98:189–195. [PubMed]
13.Ras, N; Lascola, B; Postic, D, et al. Phylogenesis of relapsing fever Borrelia spp. Int J Syst Bacteriol. 1996;46:859–865. [PubMed]
14.Porcella, SF; Raffe, SJl; Schrumpf, ME; Schriefer, ME; Dennis, DT; Schwan, TG. Serodiagnosis of Louse-Borne relapsing fever with glycerophosphodiester phosphodiesterase (GlpQ) from Borrelia recurrentis. J Clin Microbiol. 2000;38:3561–3571. [PubMed]
15.Schwan, TG; Schrumpf, ME; Hinnebusch, BJ; Anderson DE, Jr; Konkel, ME. GlpQ an antigen for serological discrimination between relapsing fever and Lyme borreliosis. J Clin Microbiol. 1996;34:2483–2492. [PubMed]
16.Barbour, AG. Isolation and cultivation of Lyme disease spirochetes. Yale J Biol Med. 1984;57:521–525. [PubMed]
17.Miron, D; Olshinsky, A; Assy, N; Zuker, M; Efrat, M; Hussein, O. Plasmodium and Borrelia co-infection. J Travel Med. 2004;11:115–116. [PubMed]
18.Gallien, S; Sarfati, C; Haas, L; Lagrange-Xelot, M; Molina, JM. Borreliosis: a rare and alternative diagnosis in travellers’ febrile illness. Travel Med Infect Dis. 2007;5:247–250. [PubMed]
19.Berger, SA; David, L. Pseudo-borreliosis in patients with malaria. Am J Trop Med Hyg. 2005;73:207–209. [PubMed]
20.Tsao, JI; Wootton, JT; Bunikis, J; Luna, MG; Fish, D; Barbour, AG. An ecological approach to preventing human infection: Vaccinating wild mouse reservoirs intervenes in the Lyme disease cycle. Proc Natl Acad Sci USA. 2004;101:18159–18164. [PubMed]

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2593045
 

Last Update: 12/19 4:21 pm 

Imagine waking up and not being able to smile, to eat or blink. It’s a terrifying thought, especially for a child.

10-year-old Ryan Ferrell can brighten a room with his smile. But lately, that smile has been tough to crack. Ryan has Bell’s palsy, a term used to describe paralysis on one side of the face.

“He’s been upset that his face doesn’t move. Sometimes when he drinks water it doesn’t stay in his mouth,” Barbara Ferrell, Ryan’s mother, says.

Most of the 40,000 new cases a year are adults. But children can also be afflicted.
“I think many parents worry this is a stroke or some life-threatening occasion,” Dr. Michael Goldstein, American Academy of Neurology, says.

That’s because symptoms include a facial droop, twitching, pain behind the ear or the eye, dry mouth, and difficulty tasting food. Ryan started complaining of a headache and pain in his right eye.

“And I noticed that his mouth on one side was not matching the other side,” his mom says.

While the exact cause of Bell’s palsy is not known in all cases, Dr. Goldstein says typically the cause is an inflammation of the nerve that goes from the brain to the face, caused by a virus.

That virus is similar to the one that causes cold sores or the common cold. It can also be caused by illnesses such as Lyme disease. That’s what’s believed to be the culprit in Ryan’s case.

Dr. Babak Azizzadeh is the founder of the Bell’s palsy and Facial Paralysis Foundation. He says the condition affects patients, especially kids, emotionally as well as physically.

“Imagine how much kids make fun of other kids who have big ears or big noses or are a little overweight,” Azizzadeh says. “Multiply that by 10 or 100 when a kid can’t smile.”

Kelly Ellison was diagnosed with Bell’s palsy when she was 17-years-old

“Kids were so mean to me. I would go into school and they would just say the most hateful things,” she says.

Today at 21, she still has trouble forming a smile. But Kelly is in the minority. Dr. Goldstein says about 85 percent of children recover from Bell’s palsy completely. Sometimes, doctors will prescribe anti-viral medication.

“We usually see some kind of improvement within two to four weeks. The cycle of improvement often will take three to six months,” he says.

Because Ryan has Lyme disease, his course of treatment is much different. He will be on IV drugs for at least four weeks.

In some cases of Bell’s palsy, surgery is required, but only as a last resort. Dr. Goldstein says it’s important to take your child to the doctor the instant you start to notice any symptoms.

http://www.keyetv.com/content/news/coverstory/story/Thousands-of-children-affected-by-Bells-palsy/YSfe8A89HUqdsF2sVPA4Zg.cspx

JAMA. 2008;300(23):2718-2720.

MMWR. 2008;57:1145-1148

1 table omitted

Anaplasma phagocytophilum, a gram-negative, obligate intracellular bacterium of neutrophils, causes human anaplasmosis, a tickborne rickettsial disease formerly known as human granulocytic ehrlichiosis.1 In November 2007, the Minnesota Department of Health was contacted about A. phagocytophilum infection in a hospitalized Minnesota resident who had recently undergone multiple blood transfusions. Subsequent investigation indicated the infection likely was acquired through a transfusion of red blood cells. This report describes the patient’s clinical history and the epidemiologic and laboratory investigations. Although a previous case of transfusion-transmitted anaplasmosis was reported,2 this is the first published report in which transfusion transmission of A. phagocytophilum was confirmed by testing of the recipient and a donor. Although polymerase chain reaction (PCR) assays provided reliable evidence of transmission in this case, no cost-effective method for screening blood donors for A. phagocytophilum exists. Screening donors for a recent history of tick bite is not likely to be sensitive or specific because such exposures are common and often not recalled by persons with anaplasmosis.3 Physicians should consider the possibility of anaplasmosis in patients who develop posttransfusion acute thrombocytopenia, especially if accompanied by fever, and should report suspected transfusion-associated cases to health authorities.

Case Report  

The patient, a male aged 68 years with a medical history of chronic renal insufficiency, psoriatic arthritis, ankylosing spondylitis, and corticosteroid therapy, underwent elective knee arthroplasty and synovectomy on October 12, 2007. Three weeks before his hospitalization, the patient had traveled to an area where blacklegged ticks (Ixodes spp.) were endemic, but he did not spend time outdoors and had no known tick bites. Several hours after the procedure, the patient developed bleeding at the surgical site and associated coagulopathy, indicated by elevated international normalized ratio (INR) and partial thromboplastin time (PTT) and by decreased fibrinogen and platelet counts. The extensive hemorrhage required two surgical evacuations of hematoma from the knee, popliteal artery embolization, and transfusion of multiple blood components. During October 12-21, the patient received 34 units of nonleukoreduced red blood cells (RBC), 4 units of leukocyte-reduced apheresis platelets, 14 units of fresh frozen plasma (FFP), and 7 units of cryoprecipitate. The components came from 59 individual blood donors; all donations were collected by Memorial Blood Centers (St. Paul, Minnesota). On October 19, the patient developed sepsis and multisystem failure. He was treated empirically with antibiotics (cefazolin, piperacillin/tazobactam, vancomycin, and levofloxacin). Blood cultures were negative on October 18, 20, and 31, and urine cultures were negative on October 19 and 25.

On October 31, the patient was found to have worsening thrombocytopenia. His platelet count declined from 178,000/mm3 on October 31 to 54,000/mm3 on November 5. On November 1, he developed hypotension and fever attributed to urinary tract infection. He was treated with levofloxacin and sulfamethoxazole/trimethoprim and was afebrile by November 3. On November 3, 22 days after admission, a peripheral blood smear from the patient demonstrated inclusions compatible with A. phagocytophilum morulae in neutrophils. Retrospective review of an October 15 blood smear from the patient showed no evidence of intracellular morulae. Whole blood specimens from November 3-5 were positive for A. phagocytophilum DNA by PCR assays conducted at the Mayo Medical Laboratory, Minnesota Department of Health, and CDC. Serum from November 3-5 was tested at CDC and found to be weakly positive by indirect immunofluorescence assay (IFA) (titer 1:64) for immunoglobulin G (IgG) antibodies to A. phagocytophilum. Doxycycline treatment was begun on November 5. The patient’s platelet count steadily improved and returned to a normal level of 163,000/mm3 on November 10. Pretransfusion blood samples and serum from the patient’s convalescence period were not available for further testing. The patient improved clinically and was transferred to a rehabilitation unit on November 13. After rehabilitation, the patient was discharged on December 3, 2007.

Epidemiologic and Laboratory Investigation 

In early November, Memorial Blood Centers began an investigation to identify whether any of the 59 blood donors associated with the 34 RBC, 4 platelet, 14 FFP, and 7 cryoprecipitate units had evidence of A. phagocytophilum infection. Paired whole blood specimens from the original donations had been retained from all 34 RBC donors and eight of 14 FFP donors and were available for PCR testing. During November 2007–March 2008, Memorial Blood Centers also collected postdonation blood samples for serologic testing and information on recent illness history and potential tick exposure from 53 of the 59 donors. In addition, plasma components from two FFP donors and two cryoprecipitate donors who donated again during December 2007–January 2008 were retained for serologic testing. The whole blood specimens retained from initial donation were tested by PCR, followed by sequencing of the PCR amplicons at CDC. Serum and plasma specimens were tested by IFA for IgG antibodies to A. phagocytophilum.

PCR and IFA tests on samples from a female RBC donor aged 64 years were positive for A. phagocytophilum infection. A. phagocytophilum DNA was found in an RBC product donated by this woman on September 28 and transfused to the patient on October 13. IgG IFA titers to A. phagocytophilum were 1:512 and 1:256, respectively, in subsequent sera collected November 17 and December 18. The donor did not recall being bitten by a tick, but had spent time in wooded areas of northeast Minnesota where anaplasmosis is endemic within the month before her donation. She reported no history of fever during the month before or after her donation. No other patients received blood components from her donation.

No whole blood samples from other tested donors were PCR positive for A. phagocytophilum. Sera from two RBC donors were weakly positive by IFA (titer 1:64), but their respective whole blood samples from the original transfused units were PCR negative. These two donors did not live on wooded property and reported they had no tick exposure or illness during the 2 months before donation. Available postdonation serum samples from other donors were negative for A. phagocytophilum by IFA (titer <1:32).

Reported by: 

M Kemperman, MPH, D Neitzel, MS, Minnesota Dept of Health; K Jensen, J Gorlin, MD, E Perry, MD, Memorial Blood Centers, Saint Paul; T Myers, MD, T Miley, MD, Park Nicollet Methodist Hospital, Saint Louis Park, Minnesota. J McQuiston, DVM, ME Eremeeva, MD, PhD, ScD, W Nicholson, PhD, J Singleton, National Center for Zoonotic, Vector-Borne, and Enteric Diseases; J Adjemian, PhD, EIS Officer, CDC.
CDC Editorial Note: 

A. phagocytophilum, the causative agent of anaplasmosis, typically is transmitted to humans by infected Ixodes spp. ticks. In wooded areas of the United States, A. phagocytophilum is transmitted by the blacklegged tick (Ixodes scapularis) in the Northeast and upper Midwest and by the western blacklegged tick (Ixodes pacificus) on the West Coast. In infected persons who are symptomatic, illness onset occurs 5-21 days after a bite from an infected tick. Initial presentation typically includes sudden onset of fever, headache, malaise, and myalgia, often accompanied by thrombocytopenia, leukopenia, and elevated liver transaminases. Severe infections can include prolonged fever, shock, confusion, seizures, pneumonitis, renal failure, hemorrhages, opportunistic infections, and death.1 Anaplasmosis and other tickborne diseases, including human ehrlichiosis, Rocky Mountain spotted fever, and babesiosis, caused by Ehrlichia chaffeensis or Ehrlichia ewingii, Rickettsia rickettsii, and Babesia spp., respectively, represent a potential risk for transmission via blood transfusion in the United States.2-6

The case described in this report provides strong presumptive evidence that A. phagocytophilum infection in this patient was acquired through blood transfusion. Pretransfusion blood samples and convalescent serum from the transfusion recipient were not available for PCR or serologic testing to demonstrate conclusively that the patient was free of A. phagocytophilum infection before his hospitalization on October 12. However, the patient reported limited outdoor exposure that might include potential tick contact during the 3 weeks before hospitalization, and a blood smear collected 3 days after hospital admission showed no evidence of intracellular morulae. The timing of events and the expected incubation period for anaplasmosis (5-21 days) suggest that the patient’s exposure most likely occurred during hospitalization. A. phagocytophilum DNA was found in a retained sample from the implicated RBC product that was transfused to the recipient, providing strong evidence that this was the likely route of disease transmission to the blood transfusion recipient.

Some blood transfusion recipients (i.e., those who are immune compromised) likely are at increased risk for developing severe complications associated with tickborne diseases. Both A. phagocytophilum and E. chaffeensis can survive in refrigerated RBCs, and possible transfusion-transmission cases have been reported for anaplasmosis (Minnesota Department of Health, unpublished data, 1998).2-3,5-6 However, because of the rarity of transfusion-associated cases, concerns regarding the specificity of available tests, (none of which are approved by the Food and Drug Administration), and the economic costs associated with implementation, the U.S. blood supply is not routinely screened for tickborne disease using laboratory methods.7

As a method to reduce the risk for certain pathogens in blood products, blood banks often defer donations if the potential donor is ill at the time of donation. However, persons infected with tickborne disease might experience mild illness or have asymptomatic infection, as was the case with the implicated donor in this report.1, 3 Screening donors for a recent history of tick bite is unlikely to identify high-risk donors, because this type of exposure frequently is not recalled by persons with anaplasmosis.3 In this case, the implicated donor did not recall a tick bite, although she did report contact with wooded habitat in an anaplasmosis-endemic area. Nearly 75% of the other blood donors in this investigation reported similar outdoor contact, making the screening of blood donors for tick-related exposures poorly predictive for possible infection. Because Ehrlichia and Anaplasma are associated with white blood cells, leukoreduction techniques would be expected to reduce the risk for Ehrlichia and Anaplasma transfusion-transmission through RBC components.5, 8 In the absence of effective screening tools to identify donors or products infected with the organisms, physicians should weigh the benefits of using leukoreduced blood components, to potentially reduce the risk for Ehrlichia and Anaplasma transmissions.

Although transfusion-associated transmission of A. phagocytophilum appears to be rare, reported incidences of anaplasmosis and other tickborne diseases are increasing in the United States.1 A record 322 cases of anaplasmosis were reported in Minnesota in 2007 (6.2 cases per 100,000 population).9 As the incidence of tickborne diseases increases, physician vigilance for possible transmission of these agents via transfusions also should increase. In addition to other more common etiologies, physicians should suspect possible rickettsial infection if transfusion recipients develop acute thrombocytopenia posttransfusion, especially if accompanied by fever. Such signs should lead to rapid assessment for rickettsial agents and empiric treatment with doxycycline.1 Although insensitive, blood smear can provide timely support for a presumptive diagnosis of anaplasmosis, followed by IFA or PCR to confirm the diagnosis.1 Similarly, babesiosis should be suspected in patients who develop hemolytic anemia and fever posttransfusion.3-4

Anaplasmosis and ehrliciosis are nationally notifiable diseases. Suspected cases of tickborne rickettsial diseases should be reported promptly to the state or local health department, and suspected transfusion-associated transmission should be reported to the supplying blood center and appropriate public health authorities.
Acknowledgments 

The findings in this report are based, in part, on contributions by G Liu, PhD, and K Smith, DVM, PhD, Minnesota Dept of Health; M Kuehnert, MD, National Center for Preparedness, Detection, and Control of Infectious Diseases, and S Holzbauer, DVM, Coordinating Office for Terrorism Preparedness and Emergency Response, CDC.

REFERENCES 

1. CDC. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichiosis, and anaplasmosis—United States. MMWR. 2006;55(No.RR-4). 
2. Eastlund T, Persing D, Mathiesen D; et al. Human granulocytic ehrlichiosis after red cell transfusion. Transfusion. 1999;39:117S. 
3. McQuiston JH, Childs JE, Chamberland ME, Tabor E. Transmission of tickborne agents of disease by blood transfusion: a review of known and potential risks in the United States. Transfusion. 2000;40(3):274-284. FULL TEXT | ISI | PUBMED 
4. Herwaldt BL, Neitzel DF, Gorlin JB; et al. Transmission of Babesia microti in Minnesota through four blood donations from the same donor over a 6-month period. Transfusion. 2002;42(9):1154-1158. PUBMED 
5. McKechnie DB, Slater KS, Childs JE, Massung RF, Paddock CD. Survial of Ehrlichia chaffeensis in refrigerated, ADSOL-treated RBCs. Transfusion. 2000;40(9):1041-1047. FULL TEXT | PUBMED 
6. Kalantarpour F, Chowdhury I, Wormser GP, Aguero-Rosenfeld ME. Survival of the human granulocytic ehrlichiosis agent under refrigeration conditions. J Clin Microbiol. 2000;38(6):2398-2399. FREE FULL TEXT 
7. AuBuchon JP. Meeting transfusion safety expectations. Ann Intern Med. 2005;143(7):537-538. FREE FULL TEXT 
8. Mettille FC, Salata KF, Belanger KJ, Casleton BG, Kelly DJ. Reducing the risk of transfusion-transmitted rickettsial disease by WBC filtration, using Orientia tsutsugamushi in a model system. Transfusion. 2000;40(3):290-296. FULL TEXT | PUBMED 
9. CDC. Final 2007 reports of nationally notifiable infectious diseases. MMWR. 2008;57:901, 903-13.

http://jama.ama-assn.org/cgi/content/full/300/23/2718

Tuesday, 16 December 2008 
BERKELEY, CA (UroToday.com) -

Nonbladder Syndromes Often Precede Onset of BPS

In this important article, Dr. John Warren and colleagues from Baltimore, Rochester, New York, and Ann Arbor prove their hypothesis that certain syndromes precede BPS and thus might provide clues to its pathogenesis. They studied 313 cases of BPS (bladder pain syndrome) and matched them to 313 controls by sex, age, region, and index date-interview interval. Only 1 syndrome was diagnosed in significantly fewer cases than in controls: diabetes treated with oral medications. This interesting finding has been alluded to in the past, and merits further investigation.

No significant differences were found between cases and controls in 12 diseases diagnosed by physicians: hypothyroidism, mitral valve prolapse, shingles, cancer, inflammatory bowel disease, insulin-treated diabetes, hyperthyroidism, Lyme disease, multiple chemical hypersensitivity, or systemic lupus erythematosis. Antecedent syndromes significantly more prevalent in the cases by physician diagnosis were: fibromyalgia, irritable bowel syndrome, migraine, panic disorder, endometriosis, asthma, and depression. Allergy was more common by self-report. Vulvadynia and sicca syndrome symptoms were more common in the BPS population as well.

Warren notes that vulvodynia, no matter how it was defined, had an antecedent prevalence of 2-8%, far less that its 12-61% reported association with BPS. He suggests that the data implies that vulvodynia is an infrequent antecedent predictor of BPS, but is a common referred pain from the condition. Fibromyalgia-chronic widespread pain, chronic fatigue syndrome, sicca syndrome, and irritable bowel syndrome were associated with each other by pairwise and factor analyses using numerous assumptions. The conclusion of the article is hard to escape. In some patients, BPS is a local manifestation of a systemic syndrome.

Warren JW, Howard FM, Cross RK, Good JL, Weissman MM, Wesselmann U, Langenberg P, Greenberg P, Clauw DJ

http://www.urotoday.com/49/browse_categories/icpbsbps/editorial__antecedent_nonbladder_syndromes_in_casecontrol_study_of_interstitial_cystitispainful_bladder_syndrome.html