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The reply:

      Dr. Porwancher questions whether study methodology was the reason that gastrointestinal or respiratory symptoms were rarely seen in our series of 42 patients who had systemic symptoms without erythema migrans (
      • Steere A.C.
      • Dhar A.
      • Hernandez J.
      • et al.
      Systemic symptoms without erythema migrans as the presenting picture of early Lyme disease.
      ). We do not think so. Early symptoms of Lyme disease were originally described in 314 patients with erythema migrans (
      • Steere A.C.
      • Bartenhagen N.H.
      • Craft J.E.
      • et al.
      The early clinical manifestations of Lyme disease.
      ). These patients often had malaise and fatigue, headache, fever and chills, myalgias, or arthralgias. A few patients had cough, chest pain, or diarrhea, but these were not the predominant symptoms. In our recent study (
      • Steere A.C.
      • Dhar A.
      • Hernandez J.
      • et al.
      Systemic symptoms without erythema migrans as the presenting picture of early Lyme disease.
      ), the same clinical picture was observed in patients without erythema migrans.
      The vaccine study was designed to identify all participants who developed Borrelia burgdorferi infection (
      • Steere A.C.
      • Sikand V.K.
      • Meurice F.
      • et al.
      Vaccination against Lyme disease with recombinant outer-surface protein A in adjuvant.
      ). Patients were encouraged to report to their study physician if they had any symptoms, alone or in combination, which might be due to Lyme disease, as previously described in the medical literature. During the study, more than 400 participants were evaluated for flu-like illness, but only 28 had immunoglobulin (Ig) G seroconversion to B. burgdorferi when these symptoms were present (
      • Steere A.C.
      • Dhar A.
      • Hernandez J.
      • et al.
      Systemic symptoms without erythema migrans as the presenting picture of early Lyme disease.
      ). In these patients, headache and arthralgias were common, but gastrointestinal and respiratory symptoms were not. We do not think that Lyme disease cases were missed, because serum samples were obtained from all of the nearly 11,000 study participants before and after the summer tick transmission season. Of the 30 additional patients who were identified with IgG seroconversion, 9 reported myalgias or arthralgias, sometimes with fever, during the period of seroconversion, but none reported gastrointestinal or respiratory symptoms.
      The unexpected finding was that about 16% of the Lyme disease cases presented with systemic symptoms during summer without erythema migrans (
      • Steere A.C.
      • Dhar A.
      • Hernandez J.
      • et al.
      Systemic symptoms without erythema migrans as the presenting picture of early Lyme disease.
      ). A challenge for physicians is early recognition and treatment of such cases before the more debilitating and harder to treat later manifestations of the infection develop.
      Drs. Stricker and Phillips are concerned about antibiotic treatment for chronic, post–Lyme disease syndrome (sometimes called chronic Lyme disease), the reliability of serologic tests, and the possible role of coinfection. None of these issues was addressed in our study. In our study, 7 patients, including 2 with coinfection, had arthralgias or fatigue that persisted for weeks or months after 3- or 4-week courses of oral doxycycline or amoxicillin. However, none of the 42 patients developed later manifestations of Lyme disease or chronic, post–Lyme disease syndrome. Moreover, long-term persistence of the spirochete has not been substantiated in any large series of patients treated with currently recommended antibiotic regimens (
      • Nocton J.J.
      • Dressler F.
      • Rutledge B.J.
      • et al.
      Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid in Lyme arthritis.
      ,
      • Nocton J.J.
      • Bloom B.J.
      • Rutledge B.J.
      • et al.
      Detection of Borrelia burgdorferi DNA by polymerase chain reaction in cerebrospinal fluid in patients with Lyme neuroborreliosis.
      ). In a double-blind placebo-controlled trial that sought to determine whether patients with post–Lyme disease syndrome would benefit from additional 3-month courses of therapy (
      • Klempner M.S.
      • Hu L.T.
      • Evans J.
      • et al.
      Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease.
      ), none had positive cultures or positive results by polymerase chain reaction before treatment, and no differences were noted in outcome between the antibiotic and placebo groups.
      After several weeks of infection, the sensitivity and specificity of the IgG response to B. burgdorferi is high, using the two-test approach of enzyme-linked immunosorbent assay (ELISA) and Western blot (
      • Dressler F.
      • Whalen J.A.
      • Reinhardt B.N.
      • Steere A.C.
      Western blotting in the serodiagnosis of Lyme disease.
      ). The new IgG VlsE peptide ELISA has been shown to be promising as an improved serologic test (
      • Liang F.T.
      • Steere A.C.
      • Marques A.R.
      • Johnson B.J.
      • Miller J.N.
      • Philipp M.T.
      Sensitive and specific serodiagnosis of Lyme disease by enzyme-linked immunosorbent assay with a peptide based on an immunodominant conserved region of Borrelia burgdorferi VlsE.
      ). Although these tests do not distinguish between active or past infection, they are reliable in showing exposure to B. burgdorferi in patients with systemic infection.
      Patients with early Lyme disease who are infected with other tick-borne agents, including Babesia microti or Anaplasma phagocytophila, may have more severe disease (
      • Krause P.J.
      • Telford S.R.
      • Spielman A.
      • et al.
      Concurrent Lyme disease and babesiosis: evidence for increased severity and duration of illness.
      ) or fatigue for months after treatment (
      • Krause P.J.
      • McKay K.
      • Thompson C.A.
      • et al.
      Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease.
      ). However, neither babesiosis nor human anaplasmosis has been shown to cause chronic infection. As with patients infected with B. burgdorferi alone, there is no evidence that longer courses of antibiotic therapy are beneficial in coinfected patients.

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