After returning from a school trip to rural Costa Rica, Ms. G, age 15 years, developed diarrhea and anorexia. Prior to consulting with me, her primary-care clinician diagnosed her with Rocky Mountain spotted fever (RMSF) and started her on doxycycline as empirical treatment. A couple of weeks later, Ms. G’s symptoms progressed to ecchymosis in her legs, dyspnea, and pronounced fatigue in addition to persistent diarrhea and anorexia. Two days later, Ms. G developed cyclical fevers, severe arthralgias, and leg pain. After another three days, she was left with only a headache, fatigue, sweats, and chills. Ms. G remembered being bitten by mosquitoes during her trip.
1. Physical examination
Ms. G was awake, alert, and coherent throughout the exam. She had dyspnea with labored breathing and a slightly agitated and uncomfortable appearance. Her vital signs were as follows: respiratory rate 25 breaths per minute, heart rate 90 beats per minute, BP 110/64 mm Hg, temperature 36.6°C, and oxygen saturation 96% on room air. Auscultation of the lungs revealed clear sounds bilaterally. Cardiac auscultation showed a regular rhythm without murmur, gallop, or rub. A 12-lead ECG reading was normal. The patient’s legs revealed diffuse, uniform ecchymosis. Skin elsewhere was pale, warm, and dry.
2. Laboratory findings
Hemoglobin (Hb) was low at 8.2 g/dL (normal 10.0-15.5). Hematocrit (HCT) was also low at 28% (normal 32%-44%), and her RBC was low at 3.8 μg/dL (normal 4.0-5.5). A comprehensive metabolic panel was within normal limits. Amylase and lipase were normal, as were phosphokinase and troponin, thus revealing normal pancreatic and heart function. Chest x-ray demonstrated clear lung fields bilaterally. Proof-reading polymerase chain reaction and immunoglobulin (Ig)M/IgG enzyme-linked immunosorbent assay were negative for dengue fever. A malaria smear was negative. Serology sent to the CDC for a microscopic agglutination test (MAT) came back negative for leptospirosis. The blood culture for typhoid fever was negative.
With regard to the cause of Ms. G’s anemia, free erythrocyte porphyrin levels were normal, thus ruling out lead poisoning. An isopropanol instability test ruled out unstable Hb. Blood findings also were not consistent with sideroblastic anemia, which typically features increased ferritin levels, decreased total iron-binding capacity (TIBC), and high transferrin saturation. The patient’s iron measured 55 μg/dL (normal 70-180); TIBC saturation 350 μg/dL (normal 250-460); transferrin 300 mg/dL (normal 250-380); transferrin saturation 35% (normal 15%-50%) and ferritin 70 ng/mL (normal 7-142).
These values were not consistent with an anemia of chronic illness, in which one would typically have reduced TIBC, transferrin, transferrin saturation, and serum iron with elevated HCT and ferritin. These findings, however, were in line with iron-deficiency anemia (except for the ferritin levels, which were normal [low ferritin levels are the most accurate indicator of iron deficiency]). On the whole, these results were more suggestive of a possible acute insufficient intake of dietary iron.
Finally, peripheral smear showed microcytes, target cells, and poikilocytes, and an Hb electrophoresis test revealed elevation of HbA2 to 5.2% (normal 2.3%-3.7%). Based on the presence of mild microcytic anemia, target cells on a peripheral blood smear, normal RBC count, and elevated HbA2, Ms. G was diagnosed with thalassemia minor.
Individuals with the thalassemia trait typically do not require specific treatment. Iron supplements have no effect on the anemia. Ms. G, however, had moderately low Hb, HCT, and iron, which was attributed in part to inadequate diet, and was therefore given iron supplements (those with thalassemia minor have normal iron levels unless they are deficient for other reasons). Folic acid and a B vitamin (to facilitate production of RBCs) were also prescribed. The patient was re-evaluated one month later, and her iron levels and RBCs were at the low end of the normal range, oxygen saturation was 98%, and other vital signs were within normal limits, so no further action was required. Ms. G’s Hb and HCT increased slightly but remained below normal (expected values for thalassemia minor). She was instructed to discontinue both the folic acid and iron supplements and return in one month. Re-evaluation showed no change in the previous findings.
Ms. G’s case was initially very perplexing. Her symptoms were first thought to be related to a tropical illness. Culture taken by her primary-care clinician had revealed low positives for RMSF, a disease that is not common in Costa Rica but is endemic to the region. RMSF is also one of the more serious rickettsial infections, and since it is diagnosed mainly by symptoms, empirical treatment with doxycycline or tetracycline is common protocol.
Other differential diagnoses included dengue fever, a response to chloroquine (taken for malaria prophylaxis), G6PD deficiency, and leptospirosis. After the initial laboratory results came in, the list expanded to include iron-deficiency anemia, anemia of chronic disease, lead poisoning, sideroblastic anemia, unstable Hb levels, and thalassemia minor.
Dengue fever is a vector-borne viral disease spread by daytime biting mosquitoes found more often in urban areas than rural. The clinical presentation includes a significant headache, myalgias, arthralgias, rash, fever, abdominal pain, vomiting, and diarrhea. Some of Ms. G’s symptoms were consistent with dengue fever, but the laboratory results did not confirm this diagnosis.
A reaction to chloroquine with an unknown underlying G6PD deficiency—a contraindication to taking this medicine—was another possibility. This reacation can result in a hemolytic crisis in which one’s RBCs have a decreased capacity to transport oxygen, leading to shortness of breath. However, such a delayed reaction is not likely since the course starts two weeks before departure. Visual disturbances are a more common side effect of this medication.
Leptospirosis, also known as Weil’s disease, is an infection caused by any bacteria of the Leptospira genus. The bacteria are found in fresh water and can enter the body through any mucous membrane, the eyes, or a break in the skin. Because of its low recovery rates and difficult laboratory diagnosis (attributable to low sensitivity of acute serology and long culture times), empirical treatment with doxycycline is often begun based on symptoms alone. Ms. G had compatible symptoms of a high fever and headache as well as a plausible exposure history, but she was already on a course of doxycycline for RMSF.
Typhoid fever is caused by the Salmonella typhi bacterium and is found in food and water throughout the world. Symptoms consistent with a mild presentation of typhoid fever include fever, malaise, and a dry cough. Severe disease is marked by abdominal discomfort and multiple complications. Ms. G’s blood culture came back negative for typhoid fever.
A colleague passed on an anecdotal story about a “tonic-water-swilling” traveler who developed a quinine-induced thrombocytopenia resulting in a platelet count of 5,000. Ms. G, however, reported no consumption of tonic water, and her platelet counts were within normal limits.
Iron-deficiency anemia was considered but excluded after a series of lab tests confirmed a temporary iron deficiency along with thalassemia minor. When Ms. G returned for follow-up after completing iron and folic acid supplementation and improving her diet, her levels were reflective only of thalassemia minor.
Thalassemia minor is an autosomal recessive disease in which one has a reduced rate of synthesis of one of the globin chains that make up hemoglobin. Normal hemoglobin is composed of two chains each of alpha and beta globin. In beta thalassemia minor, there is a mutation in one of the two beta-globin genes. Alpha thalassemia is characterized by a complete absence of one or more of the alpha genes. Both types of thalassemia result in an impaired synthesis of the alpha- or beta-globin proteins. This causes abnormal production of hemoglobin molecules and leads to anemia, the characteristic presenting symptom of the thalassemias.
In beta thalassemia minor (heterozygous carrier-type), one of the beta genes is defective, thus reducing beta-globin production by half. In beta thalassemia major (homozygous beta thalassemia), both genes fail, and no beta-globin protein is produced. The expression of patients with thalassemia minor is typically asymptomatic and identified only when routine blood-count evaluation reveals slight anemia. Patients with beta thalassemia major, on the other hand, typically have severe anemia, jaundice, cardiac disease, and abnormal changes in the liver, gallbladder, and spleen.
In Ms. G’s case, there was never an explanation for the spikes in her fever or ecchymosed legs. It was speculated that she contracted some sort of virus along with a splenomegaly most likely secondary to thalassemia minor, resulting in easy bruising. Based on the history and timeline, it is likely Ms. G developed an infection that caused her already compromised body to shut down. A sufficient diet is particularly important to someone with thalassemia minor, especially when he or she is still growing. Ms. G will always have low Hb, which will cause her to be lethargic—especially when she has her menses.