A Middle-Aged Man With a Severe Summertime Febrile Illness

A 48-year-old man with no significant past medical history presented for evaluation and treatment of fever and chills with associated headache and myalgia of 3 days’ duration. He also reported abdominal pain and nausea without vomiting. He had a decrease in oral intake over this timeframe. He denied any neck stiffness, phonophobia, or photophobia. He resided in the Philadelphia area and denied any recent travel. He had no known sick contacts. The patient worked as a landscaper and spent most of the time outdoors, as this was the summer season. He had not noticed any rashes recently. He reported a history of alcohol abuse, although he had quit drinking more than 1 year ago. He had no recent sexual partners.

Physical Examination

The patient was a well-appearing man. His temperature was 39.4°C, and all other vital signs were normal. His oropharynx was clear. The patient’s chest was clear to auscultation, and his heart sounds were normal without any appreciable murmurs. His abdomen was soft, nontender, and not distended. He had no cervical, supraclavicular, axillary, or inguinal lymphadenopathy. No rashes were appreciated on detailed dermatologic evaluation. He had no meningeal signs.

Diagnostic Testing

Results of a complete blood cell count (CBC) on presentation were significant for thrombocytopenia, with a platelet count of 20 × 10³/µL. His hemoglobin was 11.3 g/dL, and his white blood cell count was 6000/µL with a normal differential. Results of a comprehensive metabolic panel were significant for mild hyponatremia, with a sodium level of 130 mEq/L. He had mild transaminitis, with an aspartate transaminase level of 59 U/L and an alanine transaminase level of 59 U/L. His total bilirubin level was 2.0 mg/dL, with an indirect bilirubin of 1.3 mg/dL. Alkaline phosphatase was normal. The lactate dehydrogenase was 387 U/L. The haptoglobin level was undetectable. His C-reactive protein was elevated to a level of 14.7 mg/dL.

Chest radiographs showed no infiltrate or effusion. Results of a computed tomography (CT) scan of the head without contrast were unremarkable. CT scan of the abdomen and pelvis showed hepatomegaly with the liver measuring 19.7 cm and splenomegaly with the spleen measuring 14 cm.

Which one of the following is the least likely cause of this man's illness?

1. Poliomyelitis
2. Borrelia burgdorferi
3. Babesia microti
4. Anaplasma phagocytophilum
5. Borrelia miyamotoi

Answer: A, poliomyelitis is least likely for this patient.

When evaluating a patient for a summertime febrile illness, it is important to consider tickborne infections such as Lyme disease, babesiosis, anaplasmosis, and Borrelia miyamotoi disease (BMD) (Answers B, C, D and E). All of these possibilities should be included in the differential diagnosis here.

A recent review article focusing on tickborne diseases, and on B miyamotoi specifically, gave a crude estimate of incidence by testing for each of these infections in 11,515 patient samples obtained from people living in the US Northeast.¹ This study showed that B microti was the most common (3.1%), followed by B burgdorferi and other Borrelia species (1.7%), A phagocytophilum (1.4%), and B miyamotoi (0.8%). In fact, in the absence of the typical erythema migrans rash, which is the hallmark finding of Lyme disease, Lyme is actually less likely than some of the other, lesser-known tickborne diseases, 5.3% vs 1.7%.

The most well-known tickborne disease is Lyme disease,  which is caused by B burgdorferi (Answer B). The characteristic erythema migrans rash is present in approximately 80% of cases, which makes the diagnosis somewhat easier. In the earliest stage of the disease, and even in the absence of erythema migrans, patients may present with nonspecific findings such as low-grade fever, fatigue, malaise, arthralgia, myalgia, headache, and neck pain.² This results in marked overlap with essentially all the other tickborne illnesses.

Babesiosis is a tickborne infectious disease caused by an intraerythrocytic parasite in the Babesia genus. B microti (Answer C) is the most common cause of babesiosis in humans. Like Anaplasma and Borrelia species, Babesia are transmitted by the deer tick, Ixodes scapularis. Due to the life cycle of the tick and its primary reservoir host, the white-footed mouse, transmission to humans typically occurs from early summer through late fall. Patients become symptomatic between 1 and 4 weeks after exposure. They may complain of nonspecific symptoms such as malaise, fatigue, high-grade fever, and chills. They also may experience headache, photophobia, or gastrointestinal tract symptoms. On laboratory evaluation, thrombocytopenia and a mild to moderate hemolytic anemia may be seen. The course of illness often depends on the patient’s other comorbidities and immune status. Patients with advanced age, active malignancy, HIV infection, hemoglobinopathy, or chronic end-organ dysfunction typically have a more severe course.

Clinicians need to have a high index of suspicion to make the diagnosis of babesiosis, since there is no prototypical rash or symptomatic finding in this illness. The diagnosis should be considered for patients living in or traveling to an endemic region within 2 months and for patients who received a blood transfusion within the past 6 months.

The babesiosis diagnosis can be made by microscopic examination of a thin-film peripheral blood smear, looking for trophozoites or merozoites on Giemsa or Wright staining. Due to a differing burden of infection between patients, peripheral smears may need to be repeated every 12 to 24 hours in order to make the diagnosis. Polymerase chain reaction (PCR) assay for Babesia DNA in the blood is highly sensitive and specific. Immunofluorescence can detect immunoglobulin M and G antibodies in a patient, although the antibody levels often lag behind the acute phase of the illness.

Historically, patients with babesiosis had been treated with clindamycin and quinine. However, this regimen is poorly tolerated. Now, patients with mild to moderate disease should be treated with a combination of oral atovaquone and azithromycin. For patients with severe disease, intravenous clindamycin and oral quinine probably remain the best choice. The recommended treatment duration for most cases of babesiosis is 7 to 10 days, but longer courses may be indicated in patients who are immunocompromised or in patients who have refractory or relapsing infection.³

The lesser-known tickborne diseases include human granulocytic anaplasmosis, caused by A phagocytophilum (Answer D), and the more recently described BMD, caused by B miyamotoi (Answer E). The latter has a slightly different epidemiology than Lyme disease. Its incidence is later in the summer, with the majority of confirmed cases found between July and September. This is contrasted with the majority of Lyme cases being encountered between June and mid-July.⁴ This is due to differences in transmission: Lyme is more likely to be transmitted by nymphal deer ticks, while BMD is transmitted by larval deer ticks. The subtle difference in infection timing is likely attributable to the different life cycles of the different tick reservoirs. BMD also seems to distinguish itself by being clinically more severe than Lyme disease. Although symptoms are similar in form—fever, chills, headache, myalgia, malaise, and fatigue in more than 80% of cases—the symptom severity is worse. One study showed a hospital admission rate of 24% in patients diagnosed with BMD.¹ Fortunately, a typical doxycycline regimen seems effective in treating this illness. Now that BMD is on the radar, so to speak, it will be interesting to see where exactly it fits in terms of incidence and clinical burden of disease.

For all tickborne diseases, the optimal and most accurate diagnostic method is PCR assay of blood samples for pathogen DNA. Serologic studies require a typical seroconversion period and therefore are less helpful, particularly in the acute setting.

Poliomyelitis, caused by the poliovirus, was once the most feared summertime febrile illness, and its initial phases can cause many of the symptoms of tickborne diseases discussed above. The current universal vaccination program in the United States has rendered polio infection very rare, such that it is far less likely than the other answers, making Answer A the correct response here.

Case Report Follow-Up

The tentative admitting diagnosis in our patient was meningitis. Blood cultures were obtained, and broad-spectrum antibiotics were initiated. Lumbar puncture was deferred due to patient’s profound thrombocytopenia. Enzyme-linked immunosorbent assay results were negative for HIV, and results of serology tests for hepatitis A, B, and C were negative.

The infectious disease service was consulted and suggested sending a specimen to evaluate for a tickborne pathogen. The hematology service was consulted and looked at the peripheral smear in conjunction with the hematology-pathology service. The blood smear was significant for a markedly decreased platelet count, with occasional giant platelets observed. The red blood cell and white blood cell morphologies were normal. Within the red blood cells, however, there were intracellular ring-form parasites and occasional merozoites arranged in tetrads, in a “Maltese cross” formation.

PCR results were sent to the Pennsylvania Department of Health, which confirmed the diagnosis of babesiosis.

The patient received a 10-day course of azithromycin, doxycycline, and atovaquone. He was seen 1 week after discharge from the hospital, at which time his symptoms had abated. He had a repeat CBC, which showed normalization of his platelet count. A repeat peripheral smear was negative for Plasmodium, Babesia, or other blood parasites. The patient has since been lost to follow-up.

Adam Goldrich, MD, is a fellow in the Temple University Hospital and Fox Chase Cancer Center Hematology-Oncology Fellowship Program in Philadelphia, Pennsylvania.

A. Koneti Rao, MD, is the Sol Sherry Professor of Medicine and director of Benign Hematology, Hemostasis, and Thrombosis at Temple University Hospital and School of Medicine in Philadelphia, Pennsylvania.

Ronald Rubin, MD, is a professor of medicine at the Temple University School of Medicine and is chief of clinical hematology in the Department of Medicine at Temple University Hospital in Philadelphia, Pennsylvania.

References:

1. Molloy PJ, Telford SR III, Chowdri HR, et al. Borrelia miyamotoi disease in the Northeastern United States: a case series. Ann Intern Med. 2015;163(2):91-98.
2. Wormser GP. Early Lyme disease. N Engl J Med. 2006;354(26):2794-2801.
3. Vannier E, Krause PJ. Human babesiosis. N Engl J Med. 2012;366(25):2397-2407.
4. Bacon RM, Kugeler KJ, Mead PS. Surveillance for Lyme disease—United States, 1992-2006. MMWR Surveill Summ. 2008;57(10):1-9.