Patient 1

Patient 1 was a healthy 57-year-old man who lived on a 70-acre farm in northwestern Missouri. In early June 2009, he noticed a small nymphal tick embedded on his abdomen. The tick was subsequently removed with tweezers. There was no rash or localized itching. The following day, fever developed, which was followed by severe fatigue, headache, anorexia, nausea, and nonbloody diarrhea. Four days later, he was admitted to the hospital with a temperature of 37.9°C, which increased to 39.1°C the next day. Laboratory tests revealed a low white-cell count of 1900 cells per cubic millimeter, a low platelet count of 115,000 cells per cubic millimeter, and a low sodium level of 132 mmol per liter. Serum levels of liver aminotransferases were slightly elevated, with an alanine aminotransferase level of 57 U per liter and an aspartate aminotransferase level of 44 U per liter. The serum level of C-reactive protein was elevated at 2.9 mg per deciliter. (Laboratory details are provided in Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org.)

Figure 1. Figure 1. Laboratory Values for Patients 1 and 2. Panel A shows the absolute values for the white-cell count and differential count for Patients 1 and 2 during hospitalization. The dashed lines indicate normal values. The asterisks indicate the day on which the novel virus was isolated from leukocytes obtained from the patients. Panel B shows levels of alanine aminotransferase (ALT, solid lines) and aspartate aminotransferase (AST, dashed lines) for the patients during hospitalization. The gray lines indicate normal values. Panel C shows hematocrit values (green) and platelet counts (gold) during the patients' hospitalization. The dashed lines indicate normal values.

The patient was hospitalized for 10 days. There was progression from moderate to severe thrombocytopenia, with a nadir of 37,000 cells per cubic millimeter on day 5 and 40,000 cells per cubic millimeter on days 6 and 7. Leukopenia continued throughout the hospitalization, with notable lymphopenia and mild neutropenia that progressed to moderate neutropenia on day 7 (Figure 1A). Band forms were detected on days 2 and 8. An erythrocyte sedimentation rate was within the normal range at 9 mm per hour, and the erythrocyte count and hemoglobin were unremarkable and stable. The hematocrit was slightly low during hospitalization (Figure 1C). The prothrombin time and partial-thromboplastin time were normal.

Serum hepatic aminotransferase levels increased and peaked, with an alanine aminotransferase level of 315 U per liter and an aspartate aminotransferase level of 431 U per liter on day 8 (Figure 1B). Serum alkaline phosphatase levels rose within normal limits and peaked at 101 U per liter on day 9. Levels of creatinine and blood urea nitrogen remained normal. Urinalysis showed trace protein and 1+ ketones and was otherwise normal. Serum albumin levels were low, and serum sodium and calcium levels were mildly low.

On the second day of hospitalization, blood was sent to the Rickettsial Zoonoses Branch of the Centers for Disease Control and Prevention (CDC) and was subsequently shown to be negative for E. chaffeensis, E. ewingii, and rickettsiae of the spotted fever group on PCR assay. Serologic analysis later confirmed negative results of IgM and IgG assays for the spotted fever group and typhus. A rapid test for influenza A and B antigens was negative (Meridian Bioscience). Two blood cultures were sterile.

The patient was empirically placed on doxycycline (100 mg) intravenously twice daily for 14 days for suspected ehrlichiosis. Nonbloody diarrhea persisted through the fourth day of hospitalization. Stool specimens were negative for leukocytes, Clostridium difficile toxins, and salmonella, shigella, and campylobacter species. The results of two-dimensional echocardiography and chest radiography were normal.

The patient has reported fatigue and recurrent headaches in the 2 years since his hospitalization, but these symptoms cannot be clearly attributed to the viral infection. In addition, he initially had short-term memory difficulty, which has slowly improved, and anorexia, which resolved 4 to 6 weeks after discharge.

Patient 2

Patient 2 was a 67-year-old man with a 5-year history of type 2 diabetes who was otherwise healthy. He lived on an approximately 100-acre farm in northwestern Missouri. While on his property in early 2009, he received an average of 20 tick bites daily for approximately 2 weeks. He removed the embedded ticks with his fingers and tweezers. The last tick bite was noticed 1 week before hospitalization. Approximately 4 days before hospitalization, subjective fever, fatigue, and anorexia developed. Additional symptoms included myalgia, dry cough, and nonbloody diarrhea. No rash was noted before or during hospitalization.

On hospital admission in June 2009, his temperature was 38.1°C and reached 39.1°C the following day. Laboratory studies that were conducted on admission showed a low white-cell count of 2100 cells per cubic millimeter, a low platelet count of 78,000 cells per cubic millimeter, and a slightly elevated aspartate aminotransferase level of 54 U per liter (Figure 1A, 1B, and 1C). The serum sodium level was slightly low at 130 mmol per liter, as was the calcium level at 7.8 mg per deciliter (1.95 mmol per liter). The results of urinalysis were normal.

The patient was hospitalized for 12 days. After day 2, thrombocytopenia progressed from moderate to severe, with a nadir of 34,000 cells per cubic millimeter on days 5 and 6. Platelet numbers increased starting on day 8 and reached a normal level by day 11 (Figure 1C). Testing for antiplatelet antibodies was negative. Leukopenia continued until day 10, with mild neutropenia progressing to moderate neutropenia on days 6 to 8 (Figure 1A). Band forms were present on days 2 to 7, and lymphocytes gradually increased to a normal range by day 8 (Figure 1A). Erythrocyte counts and hemoglobin were within normal limits, and the hematocrit was slightly low throughout hospitalization. The prothrombin time, partial thromboplastin time, and fibrinogen levels were normal, but the serum D-dimer level was elevated, at 4.08 mg per liter.

Blood was collected on day 2 of hospitalization and sent to the CDC. PCR results were found to be negative for E. chaffeensis and a range of ehrlichia and anaplasma species. Testing that was specific for borrelia antibody (Quest Diagnostics) was negative.

Alanine and aspartate aminotransferase levels were elevated and increased to 355 U per liter on day 8 and 302 U per liter on day 10, respectively (Figure 1B). The alkaline phosphatase level was temporally high on day 10 but then resumed normal levels. Levels of creatinine and blood urea nitrogen remained normal. Levels of serum albumin and sodium remained low throughout hospitalization. Low serum calcium levels increased to normal by day 10. Results on chest radiography and abdominal ultrasonography were normal.

A bone marrow aspiration and biopsy were performed on day 2 of hospitalization. Trilineage hematopoiesis was detected, with less than 1% blasts and no ringed sideroblasts. There was notable defective development of erythrocytes (dyserythropoiesis) and megakaryocytes (dysmegakaryocytopoiesis). Flow cytometry confirmed 3 to 4% plasma cells with monoclonal lambda restriction, indicating response to infection. Cultures for fungi and mycobacteria were sterile.

The patient was initially treated empirically with intravenous piperacillin–tazobactam and was switched to ceftriaxone on hospital day 2 and to oral doxycycline (100 mg) twice daily on day 3 for suspected ehrlichiosis. He completed a 14-day course of doxycycline.

After hospital discharge, the patient noted fatigue, short-term memory difficulty, and anorexia. All the symptoms abated after 4 to 6 weeks and have not recurred in 2 years. Six months after discharge, the CDC confirmed the patient was negative for E. chaffeensis and Anaplasma phagocytophilum on IgG assay.