An 85-year-old man presented to his family physician with complaints of generalized weakness, fatigue, loss of appetite, excessive sleeping, and mild laryngitis. He reported that his temperature taken orally at home that morning was 102.6 °F. These symptoms arose during the previous week, before which he had been healthy, exercising vigorously every day. His past medical history included type 2 diabetes, hypercholesterolemia, and Paget disease of bone, and medications included metformin and pravastatin. One year earlier he had a tick bite followed by appearance of a bullseye rash and took a course of doxycycline. He was not symptomatic after that and was not known to have any additional tick bites. He lived in Long Island, New York, and did not have a history of travel or sick contacts.
On physical exam the patient was alert but somewhat confused, with shaking chills. Cardiac and respiratory exam findings were normal. Laboratory testing included examination of a peripheral blood smear, which revealed intraerythrocytic ring forms, consistent with Babesia species, in 2.7% of the cells. The patient also had a lipid panel drawn (presumably because it was a visit to his family physician who ordered this as a routine) and was found to have an undetectable concentration of HDL cholesterol (HDL-C).2 Other laboratory data are summarized in Table 1.
The patient was diagnosed with babesiosis and admitted to the hospital, where he was treated with atovaquone, azithromycin, and doxycycline. Follow-up molecular testing confirmed infection with Babesia microti. Parasitemia declined to <0.1%, symptoms improved greatly, and he was discharged after 3 days. Ten weeks after initial presentation, anemia and thrombocytopenia had resolved. HDL-C had returned to a value within the reference interval (52 mg/dL or 1.34 mmol/L), and ferritin, which had been high, also was within the reference interval (293 ng/mL).
QUESTIONS TO CONSIDER
What laboratory findings are characteristic of babesiosis?
What conditions can cause markedly decreased HDL-C?
What caused this patient to have a very marked, but transient, decrease in HDL-C?
Babesiosis is an intraerythrocytic protozoan infection that can be acquired by the bite of an Ixodes tick or by blood transfusion. First reported to cause human disease in 1957, it has become endemic in some parts of the US, including Long Island, New York. Infection typically causes a flu-like illness, but the clinical manifestations can range from asymptomatic to life threatening (1). The tick vector also transmits the pathogenic bacterium Borrelia burgdorferi, the causative agent of Lyme disease, and it is not uncommon to see infection with both of these. Less common infections transmitted by Ixodes ticks are human granulocytic anaplasmosis, caused by Anaplasma phagocytophilum, and Powassan virus. More than 100 species of Babesia have been identified, causing both veterinary and human disease, but the prevalent one in the northeast US is Babesia microti. These organisms are members of the phylum Apicomplexa, which also includes the Plasmodium species that cause malaria.
Laboratory findings commonly associated with babesiosis include anemia, thrombocytopenia, mildly increased bilirubin, increased transaminases, and atypical lymphocytosis with a normal total WBC count. Such findings, however, are too nonspecific to suggest the diagnosis. Diagnosis depends on a high index of suspicion followed by careful examination of a stained peripheral smear, which will usually reveal the organisms within erythrocytes, although occasionally the level of parasitemia is so low that it can be missed. Plasmodium species, especially Plasmodium falciparum, can have a similar appearance, but helpful distinguishing characteristics for Babesia are absence of hemozoin deposits in the ring form, absence of banana-shaped gametocytes, multiply infected red cells with the rare presence of tetrads (“Maltese crosses”), and appearance of extraerythrocytic organisms in severe cases. Confirmation of Babesia microti is possible through nucleic acid amplification testing, and serologic testing is also available at reference laboratories.
This patient also happened to have testing performed for lipids and ferritin. The unusual results—very low HDL-C and very high ferritin—appear to have a strong, but not widely known, association with babesiosis.
HDL-C, popularly known as “good cholesterol,” is commonly measured as part of a lipid panel for purposes of assessing coronary heart disease risk. It is a negative risk factor presumably because of its role as the acceptor of free cholesterol efflux from peripheral cells. Production of the HDL particle requires synthesis of its major protein component, apolipoprotein (apo) A-I, as well as lipid metabolism pathways that require the ATP-binding cassette transporter A1 (ABCA1), lipoprotein lipase, and lecithin-cholesterol acyltransferase (LCAT) (2). In the context of coronary risk, concentrations above 60 mg/dL (1.55 mmol/L) are considered optimal, whereas concentrations below 40 mg/dL (1.03 mmol/L) are considered “low” (conferring increased risk). Concentrations below 20 mg/dL (0.52 mmol/L) have been regarded as “very low.” By these criteria, low HDL-C occurs in a substantial fraction of the population, and is associated with diverse environmental and genetic factors. Very low HDL-C occurs in at most a few percent of the population and has a much narrower range of causes (2). It may possibly occur in patients with very high triglycerides (>500 mg/dL or >5.65 mmol/L), but more typically such patients have HDL-C in the low range, and the current patient had only a modest increase in triglycerides. It can be a measurement artifact. In modern, automated laboratories, HDL-C is usually measured by a direct homogeneous assay (in the present case, a popular commercial method in which cholesterol reacts with cholesterol oxidase to form a colored product, with addition of polyethylene glycol–modified enzymes and dextran sulfate to confer specificity to the HDL fraction) (3). It is known that paraproteinemia can interfere with this measurement, causing falsely undetectable HDL-C concentrations. That did not apply to the current case, and there were no other unusual conditions to raise suspicion of a method artifact. However, other types of HDL-C assays were not performed and some hitherto undescribed type of interference cannot be ruled out.
Genetic causes of very low HDL-C have been well described but are rare. Tangier disease is a homozygous defect in ABCA1 that typically results in very low HDL-C, peripheral neuropathy, and lipid-laden reticuloendothelial cells manifesting as characteristic enlarged orange tonsils and hepatosplenomegaly. LCAT deficiency can be complete, resulting in a syndrome including corneal opacification, anemia, and renal disease, or partial, resulting in “fish-eye disease,” in which corneal opacification is not accompanied by the anemia or renal component. Patients with genetic deficiency of apoA-I can present with cutaneous xanthomas and corneal opacities. Interestingly, coronary disease is variable in patients with genetic causes of very low HDL-C. All of these genetic diseases are ruled out in the current patient by the return of HDL-C to normal.
Known acquired causes for low and possibly very low HDL-C include some malignancies, severe sepsis, and other systemic illnesses that cause increased interleukin (IL)-10, and certain drugs, including anabolic steroids, fibrates, and thiazolidinediones (2, 4, 5). None of these applied to the patient under discussion, except perhaps for the possibility of increased IL-10 production as discussed in the next paragraph.
The present patient had a measured HDL-C concentration that was not only very low, but actually below the assay's limit of quantification of 4 mg/dL (0.1 mmol/L), thus perhaps placing it in a separate category of “extremely low” HDL-C. The likely cause is the patient's primary diagnosis of babesiosis. In 1990 Cunha and coworkers reported a series of 11 babesiosis patients in whom HDL-C was measured, and the results ranged from 0–13 mg/dL, with a median of 2 (6). We have observed other such cases, and hence it appears that it is common for patients with this infection to have HDL-C that is not only very low, but extremely low The pathophysiology of this finding has not been defined but may possibly relate to increased production of IL-10 in babesiosis (7). The biology of the parasite may also be relevant. Species of both Babesia and Plasmodium have been shown to lack the ability to synthesize essential lipids and to transfer these from host lipoproteins, particularly HDL (8). For Plasmodium (malaria) infection, an association with decreased HDL-C has been observed, but it has been inconsistent and generally not to extremely low concentrations (9). We are unaware of any other specific infection associated with extremely low HDL-C, although, as mentioned above, HDL-C can be depressed in severe sepsis. We are also unaware of HDL-C measurements in babesiosis patients using more definitive methods than the typical direct, homogeneous assays, and hence a novel type of measurement artifact cannot be ruled out.
The other markedly abnormal chemistry result in this patient was a ferritin that was about 4 times the upper limit of the reference interval. In contrast to very low HDL, very high ferritin has a broad range of causes, including multiple transfusions, infections, liver damage, renal failure, and cancers. Very high ferritin has often been defined as concentrations >1000 ng/mL, whereas some conditions, notably erythrophagocytic syndrome, can cause concentrations exceeding 5000 or even 50000 ng/mL. In a recent series of 8 babesiosis cases where ferritin was measured, concentrations were found to range from 1130 to 3694 ng/mL, and they generally decreased to within the reference interval within weeks after treatment (10).
In conclusion, the unusual clinical chemistry results observed in this patient appear to actually be quite typical for babesiosis infection. Although, as indicated above, babesiosis can be readily diagnosed when it is suspected, its variable presentation, nonspecific clinical findings, and unfamiliarity to many physicians may easily cause the diagnosis to be missed. A high ferritin, and especially a very low concentration of HDL-C, may provide a useful diagnostic clue.
POINTS TO REMEMBER
Very low HDL cholesterol (<20 mg/dL or <0.52 mmol/L) in an ambulatory patient may be due to one of a few rare genetic conditions, including apoA-I deficiency, Tangier disease, and LCAT deficiency.
Very low HDL-C may also be a result of a measurement artifact (for example, caused by a paraprotein), of drugs including anabolic steroids, fibrates, and thiazolidinediones, or of severe systemic disease.
Babesiosis appears to be a unique acquired, reversible cause of extremely low HDL-C (<4 mg/dL or <0.1 mmol/L).
Babesiosis can also cause very high concentrations of serum ferritin.
↵2 Nonstandard abbreviations:
- HDL cholesterol;
- white blood cell;
- ATP-binding cassette transporter A1;
- lecithin-cholesterol acyltransferase;
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
- Received for publication April 5, 2016.
- Accepted for publication June 10, 2016.
- © 2016 American Association for Clinical Chemistry