Wednesday, January 19, 2011

2 Polymicrobial Infections

I know that in my comment on my last topical post, “Syphilis and Vaccines”,  I wrote about how I thought it was scary that infecting patients with Malaria in order to raise a fever to kill Syphilis because 10% of patients subjected to the procedure died. This was considered an acceptable risk at the time, since there was no cure for Syphilis and once it moved to the third stage, madness and death weren’t far behind.

In this day and age, Syphilis and Lyme Disease are both treated using antibiotics, and the thought of a Lyme patient adding one more infection to their bodies willingly makes me shudder. For the current LLMD maxum commonly is, “Treat the coinfections first, then work on the Lyme Disease”. The thought being that the immune system is too busy responding to the coinfection or coinfections to really begin fighting off the Lyme Disease, which is a more entrenched organism.

And I’ve wondered, is there any data to back this statement up? Surely someone must have done research, but it is not something an LLMD has sat down and explained to me in great detail.

In my entry, “Syphilis and Vaccines”, I discussed a number of attributes of Syphilis infections and Treponema pallidum. One thing I mentioned was that those who suffered from both Syphilis and HIV were more likely to have severe disease.

It is already fairly well documented that coinfections or polymicrobial infections do have an unusual effect on the immune system and often increase the severity of patient disease. Often, but not always.

Take a look at this graph as a short tutorial on the effect of concurrent infection with bacterial and fungal infections. The graph makes a point of how having both infections can contribute to patient outcome, emphasis mine:

"Given the complexity of the interactions that can occur in a polymicrobial infection, including those between the pathogens and between the pathogens and the host, it is useful to define the principles of survival-curve interpretation that can be applied to any model of a polymicrobial infection (see the figure).

If the host killing by a polymicrobial infection is equivalent to the sum of killing by infection with each pathogen alone (represented by the red and blue lines in the graph), then the killing can be termed 'additive' (represented by the solid black line in the graph).

This suggests that the virulence of the two pathogens together is greater than that of either alone, but it may not be due to pathogen–pathogen interactions or changes in host–pathogen interactions; the two pathogens could be killing through independent mechanisms acting over a similar time course.

If the host killing by a polymicrobial infection is greater than the sum of killing by infection with each pathogen alone, then the killing can be termed 'synergistic' (represented by the area below the black line in the graph). This implies that the virulence of the two pathogens is not only greater than that of either alone but also greater than that which would be expected if they were killing by independent mechanisms over a similar time course.

This pattern suggests a synergistic pathogen–pathogen interaction or a change in host–pathogen interactions that is characterized by increased host susceptibility to one or both of the pathogens. 

Interpretation becomes challenging when the host killing by a polymicrobial infection is less than additive killing (represented by the area above the black line in the graph).

This pattern could have several explanations:
  • that there is an antagonistic interaction between the pathogens, whereby the virulence of one organism is reduced by the other; 
  • that the host response to the combined infection is greater or more efficient than the response to infection with either pathogen alone; 
  • that the two pathogens mediate killing or virulence through the same pathway, which becomes saturated; or
  • that one pathogen kills more rapidly than the other, preventing the slower pathogen from having any impact on host killing. 
These simplistic concepts should serve well for the future interpretation of survival curves for polymicrobial infections. Moreover, they highlight the importance of assessing and reporting the virulence end point for the pathogens alone and in combination." [1]

Although bacteria and fungal coinfection or polymicrobial infection is outlined here, the same basic principles may be applied to bacterial-bacterial or bacterial-protozoan infection as well.

Are polymicrobial infections - simultaneous infection with more than one pathogen - always going to have a more serious effect on people? 

Not always, as some bacteria have a beneficial effect or neutral effect in a given organism. Consider how your body has many different bacteria that play a positive role, such as bacteria in your intestines that help break down food, produce vitamins, and support immunity. C. difficile, feared amongst those taking antibiotics, is often already living in us without causing any problem at all - it is only once it dominates the balance that it is problematic.

But there are many cases where polymicrobial infections are not a good thing - or even neutral thing - at all.

A search of PubMed and Oxford Journals on polymicrobial infections turns up a lot of data on MRSA polymicrobial infections (mostly soft tissue infections; some ventilator-based), infections involving the diabetic foot, immune-suppressed cancer patients, sepsis, and peritonitis.

Only a small fraction of all polymicrobial infection research is focused on the pathogens which concern tick-bitten patients; most of it is about serious acute infectious states that regularly dog hospital staff and surgeons.

That which has been published so far on polymicrobial tick-based infection has produced conflicting results. But there are some broad points to be made before drilling down, and there are things to consider even in just scratching the surface of this phenomenon. (My point in writing here today is to scratch the surface and introduce these ideas, anyway.)

So how common is a polymicrobial infection from a tick bite, anyway?

More studies are needed, but this should shed some light on a highly endemic region.

First of all, there is polymicrobialism with Borrelia alone.

Ticks can carry more than one genotype or strain of Borrelia simultaneously, with each strain having its own clinical significance and symptom presentation.

Dr. Ben Luft and a group of other researchers analyzed ticks collected from across four US states and in Southwestern Germany. In their analysis of American Ixodes ticks, of the 169 B. burgdorferi-positive adult I. scapularis ticks characterized, 62% (n=104) had a single genotype, 34% (n=57) contained two genotypes and 5% (n=8) had three or more genotypes of Borrelia.[2]

So just looking at Borrelia alone, we have may have nearly 40% of ticks with polymicrobialism. Then one can also consider adding other pathogens to the list...

Published in 2010,  Assessment of polymicrobial infections in ticks in New York state, contained this gem:
“A single tick bite can lead to a polymicrobial infection. We determined the prevalence of polymicrobial infection with Borrelia burgdorferi, Anaplasma phagocytophilum, Babesia microti, Borrelia miyamotoi, and Powassan virus in 286 adult ticks from the two counties in New York State where Lyme disease is endemic, utilizing a MassTag multiplex polymerase chain reaction assay. Seventy-one percent of the ticks harbored at least one organism; 30% had a polymicrobial infection. Infections with three microbes were detected in 5% of the ticks. One tick was infected with four organisms. Our results show that coinfection is a frequent occurrence in ticks in the two counties surveyed.” [3]
If 71% of 286 ticks were infected at all, I’d be making sure I’m dressed to the nines in permethrin soaked camos in those counties. That is pretty nasty endemic for Lyme Disease, right there. But it doesn’t stop there - 30% of those ticks were infected with more than one organism simultaneously. This at least gives us an idea how common polymicrobial infections are in ticks in part of New York.

If one of those ticks in that 30% has bit you - or your lottery draw is so awful you received four different pathogens at once - not including more than one kind of Borrelia - what are you going to do? 

Scream at first, probably.

What studies are available that show the impact of more than one tickborne infection on people?

Most of what we have are murine (mouse or related rodent) studies. This is a fairly common procedure, as mice are thought to replicate a lot of the same processes that occur in humans. So far, the data is mixed - but this may be due to study method and design as much as it is by polymicrobialism.

In the 2005 study, Babesia microti and Borrelia burgdorferi Follow Independent Courses of Infection in Mice, mice were simultaneously infected with Borrelia burgdorferi and Babesia microti and monitored for 21 days, then killed. Poor mice. Their organs were then examined and samples were taken. In this study, researchers compared the effect of coinfection on disease severity, by measuring the percentage of infected red blood cells (RBCs) and degree of splenomegaly (Babesiosis) and by spirochete dissemination, carditis, and arthritis (Lyme Disease), in mouse models simulating risk factors for human disease.

The result of this study was that “Babesiosis followed its normal course of infection in coinfected mice, without evidence for increased severity, as reflected by percentage of parasitemia, spleen weights, and hematologic and clinical chemistry parameters. Likewise, Lyme Disease followed its established course and severity in coinfected mice, as reflected by the degrees of spirochete dissemination and arthritis.” [4]

In other words, unlike the black line on the chart we saw earlier on, coinfection with both Babesiosis and Lyme Disease was not synergistic, and severity of each disease was the same as it would be if the patient would have been infected with each pathogen individually and independently. 

But this is just one study from 2005 with a specific design that may or may not prove what polymicrobial infection with these agents means for the patient.

In fact, this specific study was criticized later by reviewers for two design flaws: 1) the Babesia microti strain used was adapted to lab mice and may have been made less virulent than strains of Babesia which had been used in previous experiments demonstrating how coinfections increase disease severity, and 2) it lacked more concrete markers to determine disease severity such as cytokine levels and symptoms of arthritis in their mice.

The shortcomings I see in this study are that it doesn't map changes in cyotkine levels over time nor does it capture the effects of long-term infection on subjects. If the infected mice are put down for autopsy after only 21 days of infection, does this truly give an idea of how disease has affected them?

I am already not pleased that animal research and testing is still a required part of science as it is, and the thought of placing animals in a position where they suffer more isn't pleasing to me any more than it is for the next person. But I do think there is a correlation between the severity of a disease and its duration that cannot go unobserved, and somehow there must be a means to test it.

Certain studies need to be made where one is not just looking at peak infection levels of Babesia in the blood or acute infection, but the effect of long-term coinfection on the immune system with subclinical through moderate levels of infection. This is more likely to be the case in humans who are underdiagnosed or misdiagnosed, who may not get a rash from the specific Borrelia bacteria infecting them and may not show evidence of Babesia infections either through blood smears or early and acute symptom presentation.

In an earlier study, Concurrent Lyme Disease and Babesiosis: evidence for increased severity and duration of illness, fatigue was notably increased in coinfected patients, and there was an increased array of symptoms of longer duration in the subjects. However, even with greater detection of Borrelia burgdorferi DNA in the blood, arthritic, cardiac, and neurologic symptoms were actually similar to control (uninfected) groups [5]. And in yet another study there was no association between B. microti and B. burgdorferi coinfection and increased Lyme Disease severity.[6]

Looking at another earlier study, Increased Arthritis Severity in Mice Coinfected with Borrelia burgdorferi and Babesia microti, the authors stated, "As observed in previous studies, BALB/c mice infected with B. burgdorferi alone developed mild arthritis at 15 and 30 days, reaching maximum (albeit low) arthritis severity scores 15 days after inoculation. In contrast, the severity of arthritis was significantly increased for the coinfected BALB/c group at day 30."[7] So in this study, arthritis severity was significantly worse in coinfected mice than those infected with Borrelia burgdorferi alone.

Interestingly, the authors made this statement, too: "Recent studies of B. burgdorferi and Anaplasma coinfection suggest an immunologic interaction that ultimately enhances pathogenicity of B. burgdorferi [8]. These effects may have a significant impact on the persistence of B. burgdorferi and the immunologic selective pressure it is subjected to. We did not observe an increase in B. microti parasitemia as a function of coinfection, but B. burgdorferi infection might conversely affect immune responses to B. microti."

In other words, it is Borrelia burgdorferi which affected the immune system's response to Babesia microti, and not the coinfection affecting the Borrelia burgdorferi as it had been predicted.

In the 2002 study, Disease-Specific Diagnosis of Coinfecting Tickborne Zoonoses: Babesiosis, Human Granulocytic Ehrlichiosis, and Lyme Disease, the authors state that,"Because these diverse Ixodes-transmitted infections frequently are cotransmitted, the spectrum of acute disease may be highly variable. Previous descriptions of the clinical manifestations of these diseases were recorded before the likelihood of coinfection was widely recognized and before many current diagnostic tests became available. Only 2 such systematic analyses of the clinical course of acute infection with 2 of these agents in North America are now available. [5, 9]

In this data-rich survey, of the 192 patients from New England (CT, MA, RI) surveyed:
  • Most patients with Lyme Disease, either alone or in combination with Babesiosis or HGE, presented both with an erythema migrans rash and flulike symptoms.
  • A higher percentage of patients with concurrent Lyme Disease and Babesiosis or HGE experienced flulike symptoms than did those with Lyme disease alone.
  • An erythema migrans rash by itself is more suggestive of Lyme Disease alone than it is of Lyme Disease with a concurrent disease, whereas flulike symptoms without an erythema migrans rash are more suggestive of Lyme Disease with a concurrent disease than of Lyme Disease alone.
  • The combination of fever, chills, and headache was noted in approximately one-half of the patients with Lyme Disease coinfection (32 [44%]), compared with approximately one-tenth (12 [13%]) of those with Lyme Disease alone.
  • Patients with Lyme Disease alone reported fewer and more-transient symptoms than did those infected with the agents of Babesiosis or HGE or those with Lyme Disease and concurrent Babesiosis or HGE.
In summary, the combination of fever, chills, and headache in patients with Lyme Disease suggests that these patients are concurrently infected with the agents of Babesiosis, HGE, or both. Concurrent infection tends to increase the diversity and duration of symptoms attributed to Lyme disease.

Early Symptom Profile of 192 Surveyed Patients

In terms of dissemination of the disease in patients:
"Spirochetal dissemination into skin, as assessed by the development of disseminated erythema migrans rash, was observed in 13 (15%) of the patients with Lyme disease alone and in 13 (18%) of the patients with Lyme Disease and concurrent babesial or ehrlichial infection. Joints became swollen in 8 (9%) of the patients with Lyme disease alone and 6 (8%) of the patients with Lyme Disease and concurrent infection. Only 1 patient (1%) with Lyme disease alone received a physician's diagnosis of arthritis, compared with none of the patients who had Lyme Disease and concurrent infection. A physician's diagnosis of acute neurologic abnormalities (e.g., Bells palsy or meningitis) was made for 2 (2%) of the subjects with Lyme Disease alone and 2 (3%) of those with Lyme disease and concurrent infection. None of our patients had acute cardiac complications diagnosed. In sum, concurrent Babesiosis or HGE does not appear to increase the probability of acute dissemination of the Lyme Disease spirochete into blood, skin, joint, nerve, or heart tissue."
In other words, those patients surveyed did not demonstrate earlier acute dissemination rates due to coinfection compared to patients infected with a single organism.

Arguably, one of the supporting arguments for longer term treatment of Borrelia infection would be to show that coinfection with other tick-borne pathogens could increase the severity and persistence of Borrelia burgdorferi infection due to limited immune response. But we have a ways to go yet, and more research is needed to understand the individual mechanisms and processes of tickborne infections independently - let alone as a group.

So knowing all this now, what is the patient's best choice? Treat the coinfection first, then treat the Lyme Disease, as has been said by LLMDs all along?

Logic seems to dictate that one treats first and foremost the disease that is giving one the greatest number of symptoms and is of the greatest severity. Treating an acute infection requires immediate attention, as the symptoms of acute Babesiosis can be serious and lead to complications - and in a small percentage of cases, it is fatal when acute. Treating a subclinical case or mild case requires a different approach, and while literature supports letting a subclinical case of Babesiosis resolve on its own, if the immune system is already beating down a polymicrobial infection, it might not resolve so easily.

The bottom line seems to be thus far that if you have more severe flulike illness after a tick bite, look for coinfections - especially Babesia. But know that odds are good that you have Lyme Disease, too. Treat them both.

Disclaimer: I am not a doctor, nor do I play one on television. The preceding is not to be used for medical advice and is only informational.

References:
[1] Anton Y. Peleg, Deborah A. Hogan, Eleftherios Mylonakis. Medically important bacterial–fungal interactions. Nature Reviews Microbiology 8, 340-349.
[2] Chris D. Crowder, Heather E. Matthews, Steven Schutzer, Megan A. Rounds, Benjamin J. Luft, Oliver Nolte, Scott R. Campbell, Curtis A. Phillipson, Feng Li, Ranga Sampath, David J. Ecker, and Mark W. Eshoo Genotypic Variation and Mixtures of Lyme Borrelia in Ixodes Ticks from North America and Europe. PLoS One. 2010;  5(5): e10650.
[3] Tokarz R, Jain K, Bennett A, Briese T, Lipkin WI. Assessment of polymicrobial infections in ticks in New York state. Vector Borne Zoonotic Dis. 2010 Apr 10 (3):217-21.
Infect Immun. 2005 Sep;73 (9):6055-63.
[4] James L. Coleman, Dreania LeVine, Charles Thill, Christopher Kuhlow, and Jorge L. Benach Babesia microti and Borrelia burgdorferi Follow Independent Courses of Infection in Mice. J Infect Dis. 2005 192(9): 1634-1641.
[5] Krause PJ, Telford SR 3rd, Spielman A, et al. Concurrent Lyme disease and babesiosis: evidence for increased severity and duration of illness. JAMA 275:1657-60.
[6]  Wang TJ, Liang MH, Sangha O, et al. Coexposure to Borrelia burgdorferi and Babesia microti does not worsen the long‐term outcome of Lyme disease. Clin Infect Dis 31:1149-54.
[7]  Increased Arthritis Severity in Mice Coinfected with Borrelia burgdorferi and Babesia microti.
[8] Thomas V, Anguita J, Barthold SW, Fikrig E. Coinfection with Borrelia burgdorferi and the agent of human granulocytic ehrlichiosis alters murine immune responses, pathogen burden and severity of Lyme arthritis. Infect Immun 2001; 69:3359-71.
[9] Belongia EA, Reed KD, Mitchell PD, et al. Clinical and epidemiological features of early Lyme disease and human granulocytic ehrlichiosis in Wisconsin. Clin Infect Dis 1999; 29:1472-7.

Additional Resources:
Interesting article on using mice for research, “The Rodent Revolution”: http://f1000scientist.com/article/display/16597/

2 comments:

  1. If I remember correctly, at the IOM hearing the experts on Babesia and Ehrlichia both said those diseases make for a more severe case of Lyme.

    Also if neither disease affects the other, and one does X amount of damage and the other does Y damage. That is worse than X or Y damage alone. Synergism would be X+Y+C damage.

    When I first became ill I had the rash and symptoms like Malaria for a few days. I could barely even walk. And they never treated any co-infections. I don't doubt that if you have symptoms like this, it is probably harder to treat and more likely you have a co-infection.

    John S

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  2. John S, can you point to which talks they were? I might have missed those. I do have a another more recent study here on my desk that discusses this.

    The problem is that if you do a survey of the research to date, the results are mixed. But I think there are underlying factors for the results being what they are, based on differences of the virulence of different genotypes and coinfections involved. They can't all be weighed the same, and the outcome will not be the same with different pathogens/pathogen combinations.

    The tutorial on synergy in the first half of my post describes the issue you mention. Synergism does not seem to be recorded in all cases of coinfection, but it definitely is an issue with some tickborne polymicrobialism.

    If I knew then what I know now, I would have nailed the Babesia harder - had I known I had it when I first got bit. I was incredibly sick - bone achingly, muscle burningly sick and I tried to find one position to literally not move from because any movement resulted in excruciating pain.

    I am in agreement with you that if symptoms hit hard and heavy early on, it's going to be harder to treat yourself overall. It would be good to have more published studies on tickborne polymicrobialism to make the point to the IDSA and mainstream medical professionals so that more people are diagnosed and treated thoroughly for coinfections.

    Maybe progress can be made here for treatment and diagnosis more easily than for Lyme, since coinfections do not seem to carry the controversial weight that Lyme does.

    Not only that, but I think at this point when the Lyme patient community uses the term "Lyme Disease", they don't really mean "Lyme Disease" - which is what the IDSA means. They mean "Lyme plus all these other tickborne infections". So someone needs to either change the nomenclature or someone needs to make this point clear when they use the term, "Lyme Disease.

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