Lyme disease: Coinfections (part 8)

A lot of patients who are being treated for chronic Lyme are also being treated simultaneously for ongoing coinfections. There is a fairly long list of coinfections, most of which are known to be tickborne diseases. I focused on the ones that are thought to be the most common.

Ehrlichiosis, also known as human monocytic ehrlichiosis, is caused primarily by E. chaffeensis and E. ewingii. This organism infects monocytes and lives its life cycle inside them. This organism is transmitted primarily by the Lone Star tick, found mostly in the south east, south central and mid-west US. Well known in other animals, human infection was first described in 1986. Since then, more than 2300 cases have been reported to the CDC. Of cases reported from 2000-2007, 49% required hospitalization. 1.9% of cases were fatal.

Patients with ehrlichiosis often demonstrate low white counts, red counts and platelet counts fairly quickly. Liver function tests may be elevated. Up to 20% have significant neurocognitive effects, including meningitis type symptoms to 10%. Rash is less common in this condition than other tickborne diseases, affecting less than 30% of infected adults. Fever, severe headache, chills, malaise, muscle pain, nausea, vomiting, diarrhea and red eyes are common symptoms.

Ehrlichiosis is diagnosed by blood tests and in particular with a blood smear. However, like Lyme disease, testing can be negative in early infection. The most effective method for diagnosis is comparison of serum samples taken 2-3 weeks apart: a fourfold increase in IgM or IgG specific for this organism in the later sample compared to the earlier is considered diagnostic. A few of the papers I read on this topic commented that smear analysis alone only identifies microcolonies of Ehrlichia in the monocytes 20% of the time. I wasn’t able to find a primary reference for this statistic, and I would suspect it’s not that low, but I can’t find any evidence either way. I also saw the following phrase repeated in a few places: “Demonstrating the organism in tissue by immunohistochemistry or molecular studies in immunocompetent patients may be difficult, as few organisms are present.” I can’t find a primary reference for that either.

If ehrlichiosis is suspected, antibiotic treatment is recommended regardless of test results. Early treatment is key in avoiding severe complications, such as splenic rupture and death. It is treated with doxycycline orally or intravenously for 10-14 days. In children and adults, treatment with sulfonamide antibiotics are associated with increased morbidity.

Because the causative organisms live inside circulating white blood cells, it is possible it could be transmitted by blood transfusion or solid organ transplant. Multiple cases have been investigated, although no instances of ehrlichiosis spread by these methods have been confirmed.

There is also an infectious agent known as the Ehrlichia muria like Organism (EML). It is so called due to the similarity of disease as well as cross reactivity with Ehrlichia chaffeensis antibodies. This agent has been found to cause infections in Wisconsin and Minnesota. It is not yet clear what tick transmits this infection.

 

Anaplasmosis (formerly human granulocytic ehrlichiosis, now human granulocytic anaplasmosis) is caused by Anaplasmosis phagocytophilum. Very similar to the organism that causes ehrlichiosis, A. phagocytophilum was previously known as Ehrlichia phagocytophilum until it was reclassified. This organism infects neutrophils and lives its life cycle within them. This condition can be very difficult to distinguish from ehrlichiosis, especially during the acute phase. PCR testing can be used to distinguish based upon DNA sequences.

Anaplasmosis causes fever, severe headache, muscle pain, and chills. Presentation can be minor. Skin rash affects less than 10%. Low platelets and red counts, as well as elevated live function tests, are evident fairly early in infection. Like ehrlichiosis, it is treated with doxycycline and treatment should be started if suspected in spite of negative tests. Symptoms respond quickly to doxycycline, an dother antibiotics should be avoided as they are associated with poorer outcomes. Very ill patients may require longer treatment, but it is considered successful once the fever is resolved. Resistance of this organism to doxycycline has not been reported. I was not able to find evidence of relapse following post-treatment recovery.

Anaplasmosis can be transmitted to humans by at least three types of ticks and shares a vector for Lyme disease. One study found that about 10% of patients with serological evidence of anaplasmosis were also serologically positive for Lyme disease or babesiosis. It can theoretically be transmitted through blood transfusion or solid organ transplant.

 

Babesiosis in humans is primary caused by B. microti. There have been “isolated” cases of infection by other species in unlikely places, including B. divergens in the US and B. venatorum in Europe, among others. Babesiosis has long been known to affect other mammals, including cows and dogs. Unlike the other co-infecting organisms mentioned thusfar, Babesia spp. are not bacteria, but protozoan parasites. Babesia infection is not thought to be rare, and it is thought that up to half of children and a quarter of previously healthy adults have no symptoms when infected.

Symptomatic patients develop a syndrome similar to malaria patients. Symptoms usually start 1-4 weeks after tick bite, or 1-9 weeks after blood transfusion if contaminated. Symptoms are mostly generic: fever, chills, malaise, fatigue, chills, night sweats. However, it also causes low platelet count and hemolytic anemia. Like other infections, it is likely to be worst in those who with compromised immunity, including those who have no spleen.

Babesia infect red blood cells. It is primarily diagnosed by peripheral blood smears stained with Giemsa stain. PCR is also used. Unlike the other organisms mentioned here, doxycycline is not effective. There are two therapies: atovaquone and azithromycin OR clindamycin and quinine. In severe cases, patients may require exchange transfusion, in which their red cells are removed and replaced with healthy ones. Babesia can be life threatening or even fatal. It can cause heart attack, renal failure, and disseminated intravascular coagulation, among other things. Additionally, Babesia can be transmitted via transfusion, solid organ transplantation or in utero (through infection, not through inheritance – the baby does not inherit a “gene” for Babesia, but instead contracts the infection for the mother.)

So how often are B. burgdorferi, B. microti and A. phagocytophilum found in the same tick?

A 2014 paper found that B. burgdorferi and B. microti were found together 5.96%; A. phagocytophilum and B. burgdorferi together were 2.35%; and A. phagocytophilum and B. microti together were 0.53%. Triple infection was found in 0.52% ticks sampled.

Another 2014 paper found that in one location, 6.4% adult ticks were coinfected, and 5.2% nymphs were; in another location 4% of adults and 1% of nymphs were. In the location with the highest level of infection, 2.5% of adult ticks were infected with B. microti; 37.5%, B. burgdorferi; 7.5% with EML; 0.4% coinfected with A. phagocytophilum; 5% A. phagocytophilum and B. burgdorferi; 1% with A. phagocytophilum and EML; 0.4% with B. microti and B. burgdorferi; 3% with B. burgdorferi and EML; and 0.4% triple infected with B. burgdorferi, A. phagocytophilum and B. microti. Incident was less common in nymphs, except for solitary B. microti infection (3.3%), and B. microti and B. burgdorferi coinfection (2%).

So, sometimes, but not often. Also, the fact that they are found together does not mean they are always transmitted together. That needs to be studied.

It is my finding that yes, coinfection with Borrelia and another organism can cause symptomatic disease. But I find this to be true in a much narrower scope than the internet at large may lead you to believe.

Firstly, I want to clarify that the Lone Star tick is not known to carry Borrelia spp. and is not known to cause Lyme disease. It causes a similar illness through an unknown organism, but really, most tick borne diseases cause similar symptoms, at least at first. So if you are bitten by a Lone Star tick, there is no evidence that you can contract Borrelia this way.

Some people have said that they have both Lyme and ehrlichiosis. Because ehrlichiosis in the true sense is transmitted by the Lone Star tick, this is unlikely. It is possible in theory to be bitten by both ticks and to contract both separately. Some people mean they have contracted the EML agent and Borrelia from one bite. This may be possible, but we have no idea if it is. Additionally, the number of cases verified as being caused by the EML agent is extremely low. So even if this were possible, it is not yet widespread enough to be causative in the number of people who suspect they have both.

I cannot find reliably sourced information on a recurring/relapsing presentation of ehrlichiosis or anaplasmosis. By most accounts, they can cause grave illness if not treated promptly. So I find this idea of “dormancy” unlikely. I understand that the idea of living intracellularly lends for some people more plausibility to this idea of dormancy. While infected cells may live longer, they don’t live that much longer. We’re talking weeks/months, not years here. Also, please look further in the ways cells tell immune cells that they are infected. It is incredibly detailed and too much for me to get into.

I also cannot find reliably sourced information on recurring/relapsing presentation of babesiosis. I agree that it might take longer to find, and it will not be treated effectively with doxycycline. However, my gut feeling tells me that if any of the coinfecting organisms mentioned in this post were likely to cause a long term problem, it is probably going to Babesia spp. That does not mean that I think it can cause a remitting/relapsing type of infection. I just think it can take longer to find and effectively treat it.

However, it is important to realize that a fair amount of people test positive for Babesia who have no symptoms of any kind. There are clear demarcations for what populations are most likely to have severe infections and it is people over 50, people who have HIV, people who are being treated with sulfonamides, and people who are immunocompromised, including those who are asplenic.

Diagnostics for Lyme have been well studied. Diagnostics for these organisms have been less well studied and are less well controlled. However, after early infection, I feel like smears are going to telling. Furthermore, all of these organisms can cause major blood count deficits, which is hard to miss. I think the likelihood of being symptomatic with one of these infections for years without ending up in the hospital or at least ending up on an effective antibiotic empirically (Babesia not withstanding) is pretty low.

Something else I haven’t gotten around to is the fact that you can get reinfected Lyme disease by another tick bite after having (and resolving) Lyme disease previously. I’m not sure if this is true for the other organisms due to the much lower rate of infection and the fact that it has not been well researched.

In literature, a unifying characteristic of the bacterial coinfections is that once the fever is gone, treatment is successful. Antibiotic treatment is recommended until a short time after the fever has broken. Given that I can’t find support for “persistent” infection of these coinfectors, I likewise cannot understand why long term antibiotics are helpful, beyond the inherent anti-inflammatory and immune modulating behaviors of antibiotics. (Which I’m not ignoring – I think if you have continuous health issues years after being bitten by a tick, and antibiotics help – that’s an important clue – but does not necessarily mean it helps because it treats an ongoing infection.)

I addressed before the fact that controlled trials of long term antibiotics have not shown gains in the group receiving antibiotics above the placebo group. About 1/3 of the patients in the largest study improved on placebo. But as a scientist, this idea that every person who feels better with antibiotics is experiencing a placebo effect is… unsatisfying. I don’t know how to explain it. It just seems unlikely to me. Which means I think the antibiotics are doing something. But I’m not convinced that what they are doing is treating long term infections. Especially not of these coinfecting organisms.

Furthermore, antibiotics and antimalarials are not benign. I think some people are really playing with fire here. Especially those people who get IV antibiotics long term and who have indwelling lines for that purpose. Like everything else, this is a risk/reward situation, and I’m not judging anyone who is choosing the risk because these drugs make them feel better. I just feel like there is somewhere in this mess an explanation that may allow them to use more benign medications. And I want that.

Tomorrow I’m going to give you the view on IDSA/ILADS from where I’m sitting and then I’ll be calling it a day on Lyme disease and coinfections. Once tomorrow’s post goes up, feel free to ask questions and discuss. Please be civil. I am sensitive to the fact that a significant number of patients are being treated for chronic Lyme and I have tried to be thorough and fair in my assessment of the situation. If you feel that I have gotten something factually wrong, please provide a peer reviewed literature source. If I have read it, it has already factored into my interpretation. If I haven’t, I will read it, and make amendments if I feel appropriate. I make mistakes and have no problem with people fact checking me. Just please remember that I have really tried to get to the best of my ability to get to the bottom of this.

 

References:

Hersh, Michelle H., et al. Co-infection of blacklegged ticks with Babesia microti and Borrelia burgdorferi is higher than expected and acquired from small mammal hosts. PLOS One 2014.

Stromdahl et al. Comparison of phenology and pathogen prevalence, including infection with the Ehrlichia muris-like (EML) agent, of Ixodes scapularis removed from soldiers in the midwestern and the northeastern United States over a 15 year period (1997-2012). Parasites & Vectors 2014 7:553.

Pritt BS, Sloan LM, Johnson DK, Munderloh UG, Paskewitz SM, McElroy KM, McFadden JD, Binnicker MJ, Neitzel DF, Liu G, Nicholson WL, Nelson CM, Franson JJ, Martin SA, Cunningham SA, Steward CR, Bogumill K, Bjorgaad ME, Davis JP, McQuiston JH, Warshauer DM, Wilhelm MP, Patel R, Trivedi VA, Eremeeva ME: Emergence of a new pathogenic Ehrlichia species, Wisconsin and Minnesota, 2009. New Engl J Med 2011, 365:422-429.

Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler JS, Nadelman RB: The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006, 43:1089-1134.

Steiner FE, Pinger RR, Vann CN, Grindle N, Civitello D, Clay K, Fuqua C: Infection and co-infection rates of Anaplasma phagocytophilum variants, Babesia spp., Borrelia burgdorferi, and the rickettsial endosymbiont in Ixodes scapularis (Acari : Ixodidae) from sites in Indiana, Maine, Pennsylvania, and Wisconsin. J Med Entomol 2008, 45:289-297.

Nonaka E, Ebel GD, Wearing HJ: Persistence of pathogens with short infectious periods in seasonal tick populations: the relative importance of three transmission routes. PLoS ONE 2010, 5:e11745.

Dahlgren F, Mandel E, Krebs J, Massung R, McQuiston J (2011) Increasing incidence of Ehrlichia chaffeensis and Anaplasma phagocytophilum in the United States, 2000–2007. Am J Trop Med Hyg 85: 124–131 doi:10.4269/ajtmh.2011.10-0613.

Ostfeld RS (2010) Lyme disease: the ecology of a complex system. New York, NY, USA: Oxford University Press. 232 p.

Krause PJ, McKay K, Thompson CA, Sikand VK, Lentz R, et al. (2002) Disease-specific diagnosis of coinfecting tickborne zoonoses: Babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Clin Infect Dis 34: 1184–1191 doi:10.1086/339813.

Robert B. Nadelman, M.D., Klára Hanincová, Ph.D., Priyanka Mukherjee, B.S., Dionysios Liveris, Ph.D.,

John Nowakowski, M.D., Donna McKenna, A.N.P., Dustin Brisson, Ph.D., Denise Cooper, B.S., Susan Bittker, M.S., Gul Madison, M.D., Diane Holmgren, R.N., Ira Schwartz, Ph.D., and Gary P. Wormser, M.D. Differentiation of Reinfection from Relapse in Recurrent Lyme Disease. N Engl J Med 2012. 367; 20.

 

1 Response

  1. Ket July 25, 2015 / 6:28 pm

    I’d agree very strongly with your idea that antibiotics making people feel better is a clue – not a cure.

    Many people don’t know that antibiotics are anti inflammatory, so a long-term inflammation type illness may seem to respond to antibiotics.

    That was my experience, until I became intolerant to the antibiotics, which is not a good health situation at all!

    Great blog.

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