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A 70-year-old man presents to an emergency department (ED) after experiencing nausea and nightly fevers for several weeks, as well as swelling in both ankles. According to a recent report about the case in , his medical history includes prostate cancer, for which he had a prostatectomy.

On admission in mid-August, the patient tells clinicians he has had no changes in his state of health until about a month earlier, when he noticed a small raised red lesion on his left ankle. He assumed he had been bitten by an insect in the course of working as an electrician in the Philadelphia area. He notes that he applied hydrocortisone cream to the ankle when it became swollen with reddened patches, but this didn't help.

As he relates, 2 days later a similar patchy red rash developed on his neck and chest. He consulted his family physician, who prescribed an antihistamine as well as a 7-day course of trimethoprim-sulfamethoxazole (Bactrim). He notes that his chest rash cleared after taking the antibiotics for 5 days, but his ankle remained swollen and painful. A week later, an x-ray of the ankle showed mild degenerative changes.

He continued to have pain in his ankle as well as his left hip over the next 2 weeks, at which point he was diagnosed with sciatica and prescribed gabapentin (Gralise).

On further questioning, the emergency physicians learn that the patient had taken two trips during May and July to visit family in Boston, and had spent time in a heavily wooded area, although he says he does not think he had any insect bites. He explains that the nightly fevers started 2 weeks previously along with nausea, bloating, and bilateral lower extremity edema, thus bringing him to the ED. In addition, he says, he has gained eight pounds in the past week.

In the ED, the patient has a fever of 39°C and is otherwise hemodynamically stable. Physical exam finds nothing unusual, and except for the left leg pain with passive range of motion, there is no evidence of swelling or rashes.

Investigations

As described in the case report, laboratory studies reveal anemia, thrombocytopenia, acute kidney injury, and elevated levels of aminotransaminase, and blood cultures are negative for bacterial growth.

The patient is admitted to the medical service. Based on his presenting symptoms, lab findings, and his time spent in a wooded area of the northeastern U.S., clinicians suspect a possible tick-borne illness.

He is started on doxycycline (Monodox), and the infectious diseases team orders an enzyme-linked immunosorbent assay (ELISA) for Lyme disease, Babesia, Anaplasma, Ehrlichia, and Rickettsia immunoglobulin (Ig)M and IgG antibodies by indirect fluorescent antibody (IFA).

Additional tests identify a normal creatine kinase level, but elevated sedimentation rate and C-reactive protein, at 57 mm/hour and 6.1 mg/dL, respectively.

Clinicians also order a CT scan of the patient's abdomen and pelvis to investigate his musculoskeletal and gastrointestinal symptoms; there is no musculoskeletal pathology, but there is evidence of anasarca.

The patient is discharged from the hospital with planned clinic follow-up with the infectious diseases team.

Two days later, lab results prove positive for Borrelia burgdorferi, Anaplasma phagocytophilum, and Babesia microti serologies. Total Lyme antibodies are positive at 3.55 LIV (Lyme index value), and the patient's Bo. burgdorferi IgM and IgG are reported positive with more than five bands present on western blot.

In addition, A. phagocytophilum IgM titer is 1:64 with an IgG titer of 1:320, and B. microti IgM titer is more than 1:320 with an IgG titer over 1:256.

Although PCR testing for Babesia was not performed and a peripheral blood smear was negative for atypical cells or inclusion bodies, the patient's symptoms do not improve. Clinicians start him on atovaquone (Mepron) and azithromycin (Zithromax) to treat the babesiosis, and within 2 days of beginning these medications, his leg pain and swelling are significantly relieved.

The patient returns to the Philadelphia area and follows up with his primary care provider. One year after presenting to the ED, he reports symptoms of neuropathy affecting his left ankle, at the site of the presumed insect bite.

Discussion

The three authors of this of a patient with Lyme disease with two co-infections note that the hallmark erythema migrans rash was not seen, and that the delayed diagnosis was perhaps associated with the man's presentation of only vague generalized symptoms.

While cases of tick-borne illnesses are increasing, this case is noteworthy, the authors state, in that the patient had Lyme disease plus two co-infections from one tick bite. The respective causes of Lyme, anaplasmosis, and babesiosis -- Bo. Burgdorferi, A. phagocytophilum, and B. microti -- are all transmitted by the Ixodes spp ticks, which are found mainly in the northeastern, upper Midwest, and Pacific coast of the U.S.

The case authors, all from Providence Health and Services Oregon and Southwest Washington in Portland, Oregon, cite a 2002 study of in which 39% of patients were co-infected with more than one organism, most commonly Lyme disease with babesiosis (81% of co-infections). However, only 5% of patients were concurrently infected with Lyme, anaplasmosis, and babesiosis, as in the situation with this patient. The authors reviewed key aspects of the three infections overall, noting that while the most common initial presentation of Lyme disease is a solitary erythema migrans rash, the next most common reported symptoms are fever and headache. Patient-reported rates of are as follows:

• Fatigue (reported in 76% of patients)

• Headache (70%)

• Rash (<70%)

• Fever, sweats, and chills (all at a rate of approximately 60%)

• Muscle pain (54%)

• Joint pain, neck pain, and sleep issues (all reported by about 40-50% of patients)

The authors note that while infection with Lyme disease rarely causes lab abnormalities, early recognition and treatment is crucial to prevent its progression to disseminated disease, with potential cardiac, neurologic, and rheumatologic long-term effects, including heart block, aseptic meningitis, facial palsy, and oligo-inflammatory arthritis.

Appropriate screening tests, the team explains, include Wright-stained peripheral blood smear, dark-field microscopy for spirochetes, and ELISA IFA, and diagnosis can be confirmed with western immunoblot and PCR assay. Lyme disease is typically treated with a 10- to 14-day course of doxycycline or 14-21 days of amoxicillin (Moxatag).

The authors note that anaplasmosis (previously known as human granulocytic ehrlichiosis) typically presents with fever, malaise, myalgia, and headache 1-2 weeks after a tick bite, and rarely causes rash. In contrast to Lyme disease, anaplasmosis may be associated with a variety of laboratory abnormalities, including leukopenia, thrombocytopenia, and elevated transaminases.

Recommended diagnostic tests, the team writes, include Wright-stained peripheral blood smear (which may show characteristic intracytoplasmic aggregates in neutrophils) followed by PCR assay and ELISA IFA, and recommended treatment is a 10-day course of doxycycline.

is a tick-borne protozoal infection associated with prolonged parasitemia in humans, who are susceptible to two types of babesiosis infections, the case authors explain:

• Babesia divergens is less common, and affects immunocompromised individuals, primarily those in cattle-ranching areas during the summer months

• B. microti, transmitted to humans by Ixodes ticks, is the more common source of babesiosis infection

The authors note that B. microtia co-infection with Lyme disease occurs in about two-thirds of cases, although young, healthy patients with babesiosis are often asymptomatic. When symptomatic, babesiosis is associated with a self-limited influenza-like febrile illness accompanied by loss of appetite, malaise, and lethargy, with potential complications such as hemolytic anemia, jaundice, and acute respiratory failure.

Babesosis can be diagnosed with a Giemsa-stained thin smear followed by testing for IgM antibodies and PCR-based assays, and blood smear may show intraerythrocytic ring forms as well as clumped extraerythrocytic forms, the authors write.

Abnormalities identified in lab tests may include anemia and thrombocytopenia, and patients with unexplained thrombocytopenia and/or anemia, as in this case, should be tested for co-infection, the authors emphasize.

The infection should be treated according to its severity: "Mild to moderate disease is treated with azithromycin and atovaquone, as in our patient's case, whereas life-threatening infections are treated with quinine [Qualaquin] and clindamycin," the case authors explain.

Conclusion

They conclude by noting that patients with Lyme disease co-infection -- and particularly older patients and patients with splenectomies -- tend to have more severe and prolonged symptoms, including high fever, sweats, and rigors, and that patients with a fever that persists for more than 24 hours despite adequate treatment for Lyme disease should be assessed for co-infection with other tick-borne illnesses, since untreated disease can result in long-term and sometimes life-threatening sequelae.

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