Case 39-2005 — A 63-Year-Old Woman with a Positive Serologic Test for Syphilis and Persistent Eosinophilia
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《新英格兰医药杂志》
Presentation of Case
Dr. Jennifer Phillips (Internal Medicine): A 63-year-old woman was seen by infectious-disease specialists at this hospital because of a positive serologic test for syphilis and persistent peripheral-blood eosinophilia.
The patient was a native of Cameroon who had immigrated to the United States 11 months before these consultations. Ten days after she arrived in the United States, she was seen in the emergency department of this hospital because of headache and chest and abdominal pain. The blood pressure was 177/94 mm Hg; a systolic murmur, grade 3 of 6, was heard at the right upper sternal border. An electrocardiogram revealed a normal sinus rhythm with a ventricular rate of 82, normal intervals, left ventricular hypertrophy, and nonspecific ST-segment and T-wave abnormalities. A chest radiograph disclosed an enlarged cardiac silhouette and a tortuous and calcified aorta. The results of routine laboratory tests were normal except for a peripheral-blood eosinophil count of 1586 per cubic millimeter. Lisinopril (10 mg daily) and levothyroxine (100 μg daily) were prescribed.
One month later, the patient saw a primary care physician at this hospital. She had a history of hypertension, but she had not brought her medications from Africa. A thyroidectomy had been performed within the past year for a goiter. She had been treated for malaria in the past. She had eight children and had been a widow for 15 years. She did not use tobacco, alcohol, or illicit drugs. She had received a blood transfusion at the time of her thyroidectomy. She had been sexually active only with her husband. She had worked on banana and cocoa plantations. She lived with her daughter; she spoke no English, and her daughter served as her translator.
The blood pressure was 178/98 mm Hg, the pulse 92 beats per minute, and the temperature 36.9°C. She weighed 58.5 kg and appeared well. The results of examination of the head, eyes, ears, nose, mouth, and throat revealed no abnormalities, except for a healed thyroidectomy scar. The lungs were clear. The heart rate and rhythm and S1 and S2 were normal; there was a systolic murmur, grade 3 of 6, at the right upper sternal border radiating to the neck and a grade 1 of 4 diastolic murmur at the apex. The remainder of the examination was normal. Laboratory tests showed a peripheral-blood eosinophil count of 3955 per cubic millimeter. The results of microbiologic and serologic tests are shown in Table 1. Lisinopril (20 mg daily) and hydrochlorothiazide (25 mg daily) were prescribed, and albendazole (400 mg daily) was given for three days.
Table 1. Serologic and Microbiologic Laboratory Data.
A transthoracic echocardiogram obtained four months later disclosed a tricuspid aortic valve with thickening of the leaflets but no stenosis; there was moderate aortic insufficiency. The ascending aorta was dilated to 43 mm (normal, less than 36) and the aortic arch was dilated to 34 mm (normal, less than 31). The patient was seen by a cardiologist five months after the echocardiogram. The blood pressure was 160/100 mm Hg. There was a mid-peak systolic ejection murmur best heard at the base and a diastolic murmur, grade 2 of 4, at the right sternal border radiating to the apex. Lisinopril was increased to 40 mg daily; triamterene and hydrochlorothiazide (37.5 mg and 25 mg daily, respectively) and atenolol (50 mg daily) were added. A repeated rapid plasma reagin test was positive at a dilution of 1:2, with a reactive Treponema pallidum particle agglutination assay.
Two weeks after the visit to the cardiologist, the patient saw an infectious-disease specialist. Further questioning disclosed that her husband had had five wives and that the patient had been treated for filariasis. She intermittently had diffuse pruritus and disseminated dermatitis. She had had progressive bilateral hearing loss and tinnitus for several years, and according to her daughter, for the past five years had had some difficulty remembering recent events but had no other mental-status changes. She had no visual problems, numbness, tingling, weakness, joint pains, genital or oral ulcers, or swelling of the genitals or arms or legs. On physical examination, there was a leopard-skin appearance of the skin of the upper back, upper buttocks, and upper thighs, with scattered hypopigmented lesions, 3 to 4 mm in diameter, that were not anesthetic. There was a suggestion of decreased joint-position sensation on the right toes, and the patient's responses to vibration testing in her feet were inconsistent. The eosinophil count was 1958 per cubic millimeter; other results are shown in Table 1.
Magnetic resonance imaging (MRI) of the brain after the administration of gadolinium disclosed multiple, scattered, T2-weighted hyperintense foci in the periventricular and subcortical white matter bilaterally, which were thought to represent small-vessel ischemic disease. Computed tomographic (CT) scanning of the chest, abdomen, and pelvis after the intravenous administration of contrast material showed that the ascending aorta was 4.3 cm in diameter at the level of the pulmonary artery bifurcation, and the descending aorta was 3.1 cm in diameter. The remainder of the examination was normal.
An otolaryngologist performed an audiogram that showed a bilateral symmetric sensorineural hearing loss. An ophthalmologist found cataracts and macular drusen. A neurologist found normal position sense, intact reflexes throughout, and a mild decrease in vibratory sensation only at the toes that was consistent with a mild peripheral neuropathy, with no indication of neurosyphilis. A lumbar puncture showed clear, colorless cerebrospinal fluid with no white or red cells; the protein was 24 mg per deciliter and the glucose was 73 mg per deciliter; a specimen yielded no growth on culture; and a Venereal Disease Research Laboratory (VDRL) test was negative. The results of additional laboratory tests are shown in Table 1.
The patient was referred to the tropical and geographic medicine center for a diagnostic procedure.
Differential Diagnosis
Dr. Donna Felsenstein: May we review the imaging studies?
Dr. Suzanne L. Aquino: The radiograph of the chest (Figure 1A) shows an enlarged cardiac silhouette, and a tortuous and ectatic aorta with focal calcification. The CT angiogram (Figure 1B) showed that the ascending aorta was dilated to 43 mm in diameter. There are small focal calcifications throughout the thoracic aorta that are consistent with atherosclerotic changes. Coronal and sagittal reconstructions of the CT scan show the dilatation of the ascending aorta (Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org).
Figure 1. Images of the Chest.
A chest radiograph (Panel A) reveals mild cardiomegaly. The aorta appears tortuous and ectatic. A CT scan of the thorax (Panel B) after the intravenous administration of contrast material shows a dilated ascending aorta.
Dr. John G. Morgan: The transthoracic echocardiogram shows that the ascending aorta is 43 mm in diameter; the sinuses and the sinotubular junction are of normal size (Figure 2A). The aortic valve is tricuspid, and there is no stenosis. The leaflets are minimally thickened. There is moderate aortic regurgitation detected by color Doppler (Figure 2B, and Video Clip 1 of the Supplementary Appendix).
Figure 2. Transthoracic Echocardiogram.
The standard parasternal long-axis view (Panel A) shows that the ascending aorta is 43 mm in diameter; the sinuses and the sinotubular junction are of normal size. The aortic leaflets are minimally thickened. Examination by color Doppler (Panel B) shows moderate aortic regurgitation.
Dr. Felsenstein: This 63-year-old widow from Cameroon had dermatitis, pruritus, hearing loss, hypertension, systolic and diastolic murmurs, nonanesthetic hypopigmented areas on her upper back, upper buttocks, and upper thighs, eosinophilia, a dilated ascending aorta, and moderate aortic insufficiency. The patient was referred to me for recommendations regarding the evaluation of and treatment for syphilis because of a positive rapid plasma reagin test. A treponemal antibody test was positive, confirming the diagnosis of a treponemal infection.
Diagnosis of Syphilis
Since syphilis serology can be confusing, I will review the diagnostic testing. The nontreponemal assays — the rapid plasma reagin test, the VDRL test, and the automated reagin test — measure antibodies against a cardiolipin–lecithin–cholesterol antigen. Although these tests are inexpensive, rapid, and highly sensitive except in early primary infection, they are relatively nonspecific. Biologic false positive results occur in a variety of inflammatory and infectious conditions.1 Thus, a positive nontreponemal assay must always be confirmed by a treponemal assay. Treponemal assays test for antibody to T. pallidum; techniques include the fluorescent treponemal antibody-absorption test and hemagglutination tests (such as the T. pallidum particle agglutination assay and the microhemagglutination assay for T. pallidum). The nontreponemal tests become positive within weeks to months after infection, rise with dissemination of the infection during the secondary stage, and after the first year, slowly decrease over years to decades, becoming negative in approximately 25 percent of patients,2 despite persistent infection. The treponemal assays become positive earlier than the nontreponemal tests3 and remain positive despite treatment in more than 75 percent of patients treated for primary, secondary, or early latent syphilis.4
This patient initially had a negative rapid plasma reagin test. Because of imaging studies showing an abnormal aorta, a repeated rapid plasma reagin was performed, which was positive at the low titer of 1:2. The diagnosis of treponemal infection was confirmed with the use of the T. pallidum particle agglutination assay. A third rapid plasma reagin test performed two weeks later was positive undiluted. Even within the same laboratory, the titer of a nontreponemal test can vary slightly on repeated testing; in this patient, the persistently low-level positive result on repeated testing and the lack of a rise in titer suggest an old rather than a recent infection.
How did the patient become infected? The absence of physical manifestations of congenital syphilis and the late onset of hearing loss argue against congenital infection. She received a blood transfusion a year before presentation, but if she had recently acquired syphilis, her nontreponemal titer should be higher. It is probable that the infection had been sexually acquired more than 15 years earlier from her husband. Serologic tests cannot differentiate between the nonvenereal treponematoses T. pallidum subspecies pertenue (yaws) and T. pallidum subspecies endemicum (bejel),5,6 and the venereally transmitted infection caused by T. pallidum subspecies pallidum (syphilis). All these infections usually respond to treatment with the proper dosage of penicillin.7
Staging of Syphilis
Treatment is mandatory for all patients with positive serology for syphilis. Appropriate treatment should always be confirmed; it is determined by the patient's stage of infection. Primary syphilis is manifested by the chancre, classically a single, indurated, nonpainful genital lesion and less typically by multiple and sometimes painful ulcerations. The lesions go unnoticed in 15 to 30 percent of patients. Dissemination of infection results in the secondary stage of syphilis, which may produce malaise, low-grade fever, headache, lymphadenopathy, hepatosplenomegaly, alopecia, and the classic maculopapular rash involving the palms and soles. Atypical rashes sparing the palms and soles may occur as well, which may result in misdiagnosis. During latent infection, serologic tests remain positive, but there are no clinical manifestations.8 Some form of tertiary infection, such as cardiovascular syphilis or neurosyphilis,develops in 30 to 40 percent of untreated patients.9,10,11
This patient had no signs of congenital, primary, or secondary syphilis. The symptoms and signs that suggest possible tertiary infection are a dilated ascending aorta with insufficiency, possibly reflecting cardiovascular syphilis, and the recent onset of hearing loss and decreased vibration sense, possibly implying neurosyphilis.
Syphilitic involvement of the cardiovascular system can result in aortic aneurysm (40 percent of cases), often with eggshell-like calcifications,12 aortic regurgitation (9 percent), and stenosis of the coronary ostia (26 percent), and rarely, gummatous involvement.11 Syphilitic aneurysms may be fusiform or saccular and generally involve the ascending aorta above the sinuses of Valsalva. The aortic dilatation and insufficiency seen in this patient may be due to syphilis, but these findings are nonspecific and may be a result of the hypertension.
Neurosyphilis can be asymptomatic, or it may present as acute meningitis, meningovascular disease (cerebrovascular accident), meningoencephalitis (general paresis), or with posterior spinal column involvement (tabes dorsalis). The patient's history of hearing loss and diminished vibratory sense mandates that neurosyphilis be ruled out. Neurologic examination did not show cranial-nerve involvement; in particular, her pupillary reflexes were normal. Position sense in her toes was determined to be normal on repeated testing. The neurology consultant thought that the minor vibratory abnormality was consistent with a peripheral neuropathy. An MRI of the brain disclosed small-vessel ischemic disease; this finding can be caused by atherosclerosis, but it can also be associated with syphilis. The results of the cerebrospinal fluid examination, including a cell count, protein level, and VDRL test, were normal. Although a positive cerebrospinal fluid VDRL test is diagnostic for neurosyphilis, a negative result does not rule out the diagnosis, particularly if there is an abnormal cell count or elevated protein level.13 Although the presentation varies, most patients with otic syphilis have gradual bilateral but asymmetric sensorineural hearing loss over the course of months to years, often with tinnitus or vestibular dysfunction.14,15 The hearing loss is usually fluctuating but progressive. This patient had symmetric, bilateral high-tone sensorineural hearing loss without vestibular involvement, believed by the otolaryngologist to be consistent with presbyacusis, or age-related hearing loss. The results of lumbar puncture may be normal in otic syphilis. Given the negative results of the examination of cerebrospinal fluid and the negative neurologic and otologic evaluations, it is unlikely that this patient had neurologic involvement caused by syphilis. When the clinical manifestations, however, are suggestive of neurosyphilis, treatment for that disorder with intravenous penicillin may be reasonable, despite a negative cerebrospinal fluid profile. The patient was asked to return for follow-up.
All patients with syphilis should be tested for the human immunodeficiency virus (HIV) and vice versa, as the coinfection rate is high. An HIV test in this case was negative.
Eosinophilia
This patient's other problem was persistent eosinophilia, and additional testing disclosed Dientamoeba fragilis, for which she received doxycycline (100 mg twice daily for 10 days), and strongyloides infection, as well as evidence of filarial infection. I referred her to the tropical and geographic medicine center for specific testing and additional treatment.
Dr. Edward T. Ryan: Although a peripheral eosinophil count greater than 400 cells per cubic millimeter may be associated with allergic or hematologic conditions (Table 2), infectious causes need to be considered, especially in persons who have traveled internationally.16,17 Viral, bacterial, and fungal causes of eosinophilia are rare, associated with low-to-moderate eosinophilia (400 to 800 cells per cubic millimeter), and often have distinctive clinical presentations. Most parasite-associated eosinophilia is due to migratory or invasive helminths (worms). This patient's chronic dermatologic manifestations, pruritus, residence in the Cameroon, high-level peripheral eosinophilia, and history of previous filariasis all suggested active filarial infection.
Table 2. Causes of Eosinophilia.
Filariasis
There are eight filarial infections for which humans are the definitive host (Table 3). Distinctions among the various types are made on the basis of a patient's possible geographic exposure, the clinical manifestations, and morphologic characterization and localization of microfilariae. Although this patient had lived in an area endemic for five species of filaria (Wuchereria bancrofti, Loa loa, Mansonella perstans, M. streptocerca, and Onchocerca volvulus), the pruritus and chronic dermatitis strongly suggested onchocerciasis. Humans become infected with O. volvulus through the bite of Simulium species black flies, which lay their eggs attached to rocks or vegetation in rapidly flowing rivers and streams. Onchocerciasis is thus most prevalent around rivers, leading to the name "river blindness." When a fly bites a human, infective larvae enter the skin and mature into adult male and female worms. Adult worms may live 10 to 15 years and usually reside in fibrotic nodules (onchocercomata) in subcutaneous or deeper tissues. Microfilariae migrate through subcutaneous, dermal, and ocular tissues, surviving for 6 to 24 months. When microfilariae in the skin are ingested by a black fly, they mature within the fly into larvae that can be inoculated into another human host.
Table 3. Human Filariasis.
The classic clinical manifestations of onchocerciasis are skin and eye changes.18,19 Inflammatory responses are typically associated with microfilariae rather than adult worms. Dermatologic manifestations include acute papular or chronic dermatitis, and depigmentation that manifests as spotty areas of hypopigmented skin (leopard skin), as in this patient (Figure 3). A reaction to corneal microfilariae leads to a sclerosing keratitis that causes blindness. Iridocyclitis with synechiae and secondary glaucoma, chorioretinitis, and optic neuritis all may occur and impair vision.
Figure 3. Clinical Photograph of Another Patient Showing Skin Changes of Onchocerciasis.
There are areas of hypopigmentation, forming a "leopard-skin" pattern. (Photograph credit: WHO/TDR/Murdoch, World Health Organization, Special Program for Research and Training in Tropical Diseases, available at www-nt.who.int/tropical_diseases/databases/imagelib.pl?imageid=9403365.)
The diagnosis of onchocerciasis is based on clinical recognition, ophthalmologic examination (in which patients should be asked to sit with their head between their knees for approximately 10 minutes to allow microfilariae to move into the anterior chamber to be visualized) and skin-snip analysis. Commercially available serologic assays are sensitive but have low specificity and cannot distinguish between an active infection and a previous infection or among the eight filarial species; in addition, positive assays may represent cross-reactivity to other nematodes.
In order to evaluate whether she had active onchocerciasis, we evaluated snips of the patient's skin for microfilariae. Snips of skin are taken with a corneoscleral punch-biopsy device, or by lifting a small piece of skin with a needle and gently shaving off approximately 1 mg of skin with a scalpel blade. Skin snips should be bloodless to minimize contamination with microfilariae from peripheral blood. Six are usually performed (one from each scapula, iliac crest, and lateral calf), and placed in normal saline or physiologic buffer and observed under low-power microscopy to detect living microfilariae emerging from skin. If a person has lived in an area of the world endemic for M. streptocerca, as did this patient, microfilariae should be fixed and stained to make a definitive diagnosis of onchocerciasis.
A Medical Student: This patient's persistent eosinophilia could be due to neoplasia, inflammatory and atopic disorders, or parasitic infection. The patient recently immigrated from Cameroon and tested positive for multiple parasites. However, the eosinophilia did not resolve after treatment of those infections. Further exploration of the patient's history disclosed a prior exposure to filariae, and examination revealed pruritus and nonanesthetic leopard-skin dermatitis, which were consistent with cutaneous onchocerciasis. A skin biopsy could confirm this diagnosis.
Our diagnosis is onchocerciasis.
Dr. Edward T. Ryan's Diagnosis
Onchocerciasis.
Pathological Discussion
Dr. John A. Branda: Skin snips were obtained, placed in saline, and concentrated by centrifugation, and saline wet mounts were prepared from the sediment. Examination by light microscopy revealed a very few microfilariae, measuring approximately 250 μm in length (Video Clip 2 of the Supplementary Appendix). The wet mounts were air-dried, fixed with methanol, and stained with Giemsa (Figure 4). The microfilariae had prominent cephalic and nerve-ring spaces. The nuclear column did not extend to the tip of the tail, and the tail tapered to a point but was not curled. These morphologic features are typical of O. volvulus.20,21
Figure 4. Microfilaria of O. volvulus (Giemsa Stain).
The microfilariae (top) have a substantial cephalic space and a well-demarcated nerve-ring space. The nuclear column did not extend to the tip of the tail, and the tail tapered to a point but was not curled. In the high-power photograph of the cephalic end of a microfilaria (inset left), the arrow points to the cephalic space. The arrowhead points to the nerve-ring space. In a high-power view of the caudal end of the microfilaria (inset right), the nuclear column does not extend to the tip of the tail (arrow). These morphologic features are typical of O. volvulus. M. streptocerca is distinguished from O. volvulus by its smaller size (180 to 240 μm; mean, 210 μm), a nuclear column that extends to the tip of the tail, a curled (crooked) tail, and a less prominent nerve-ring space.
Discussion of Management
Dr. Felsenstein: Benzathine penicillin is used to treat late latent syphilis because of its extremely low solubility, which results in more prolonged blood levels than those of other penicillin preparations. The treatment for latent syphilis is benzathine penicillin (2.4 million units intramuscularly weekly for three weeks), which this patient received. Treatment for neurosyphilis requires the use of intravenous aqueous penicillin (4 million units every four hours for 10 to 14 days), followed with benzathine penicillin for an additional 1 to 2 weeks.
Dr. Ryan: There is no nontoxic therapy that kills adult O. volvulus worms, although these worms contain endosymbiotic Wolbachia species bacteria, and the role of antibacterial therapy is currently being evaluated.22 Therapy is thus targeted to controlling microfilariae, preventing blindness and dermatitis, and interrupting disease transmission. The mainstay of therapy is ivermectin, a semisynthetic macrocyclic lactone that hyperpolarizes nematode cells. Skin microfilariae are killed in days, reaching a maximal reduction in approximately two weeks. Ocular microfilariae resolve more slowly. Ivermectin also kills microfilariae in utero in adult female worms, resulting in the suppression of microfilarial burden for 6 to 12 months. Therefore, it is usually administered as a single dose of 150 μg per kilogram every 6 months for up to 10 years in patients with onchocerciasis. Side effects are rare, although some patients report pruritus, urticaria, fever, and arthralgias, particularly after initial treatment. Concomitant loiasis should be ruled out if the patient has lived in an area of the world endemic for both infections, because in patients with high-level microfilaremia from loiasis, ivermectin may cause encephalopathy and death. There are ongoing efforts by the World Health Organization, The World Bank, pharmaceutical companies, not-for-profit organizations, and local ministries of health to control onchocerciasis using vector control and mass-treatment programs.23,24
For this patient, we recommended a dose of ivermectin every six months for 10 years. Ivermectin would also treat the probable strongyloidiasis, and we considered the antitoxocara antibody to probably be cross-reactive.
Anatomical Diagnosis
Onchocerca volvulus infection (onchocerciasis).
Dr. Ryan reports having received consulting fees from Raytheon Corporation, Acambis, and New England Biolabs-BioHelix, and holding patents in heterologous antigens in live-cell Vibrio cholerae strains, V. cholerae proteins expressed during infection, and the use of the RTX secretion system to achieve heterologous polypeptide secretion by V. cholerae. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Tropical and Geographic Medicine Center (E.T.R.), the Divisions of Infectious Diseases (D.F.) and Cardiology (J.G.M.), Department of Medicine, and the Departments of Radiology (S.L.A.) and Pathology (J.A.B.), Massachusetts General Hospital; and the Departments of Medicine (E.T.R., D.F., J.G.M.), Radiology (S.L.A.), and Pathology (J.A.B.), Harvard Medical School.
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Dr. Jennifer Phillips (Internal Medicine): A 63-year-old woman was seen by infectious-disease specialists at this hospital because of a positive serologic test for syphilis and persistent peripheral-blood eosinophilia.
The patient was a native of Cameroon who had immigrated to the United States 11 months before these consultations. Ten days after she arrived in the United States, she was seen in the emergency department of this hospital because of headache and chest and abdominal pain. The blood pressure was 177/94 mm Hg; a systolic murmur, grade 3 of 6, was heard at the right upper sternal border. An electrocardiogram revealed a normal sinus rhythm with a ventricular rate of 82, normal intervals, left ventricular hypertrophy, and nonspecific ST-segment and T-wave abnormalities. A chest radiograph disclosed an enlarged cardiac silhouette and a tortuous and calcified aorta. The results of routine laboratory tests were normal except for a peripheral-blood eosinophil count of 1586 per cubic millimeter. Lisinopril (10 mg daily) and levothyroxine (100 μg daily) were prescribed.
One month later, the patient saw a primary care physician at this hospital. She had a history of hypertension, but she had not brought her medications from Africa. A thyroidectomy had been performed within the past year for a goiter. She had been treated for malaria in the past. She had eight children and had been a widow for 15 years. She did not use tobacco, alcohol, or illicit drugs. She had received a blood transfusion at the time of her thyroidectomy. She had been sexually active only with her husband. She had worked on banana and cocoa plantations. She lived with her daughter; she spoke no English, and her daughter served as her translator.
The blood pressure was 178/98 mm Hg, the pulse 92 beats per minute, and the temperature 36.9°C. She weighed 58.5 kg and appeared well. The results of examination of the head, eyes, ears, nose, mouth, and throat revealed no abnormalities, except for a healed thyroidectomy scar. The lungs were clear. The heart rate and rhythm and S1 and S2 were normal; there was a systolic murmur, grade 3 of 6, at the right upper sternal border radiating to the neck and a grade 1 of 4 diastolic murmur at the apex. The remainder of the examination was normal. Laboratory tests showed a peripheral-blood eosinophil count of 3955 per cubic millimeter. The results of microbiologic and serologic tests are shown in Table 1. Lisinopril (20 mg daily) and hydrochlorothiazide (25 mg daily) were prescribed, and albendazole (400 mg daily) was given for three days.
Table 1. Serologic and Microbiologic Laboratory Data.
A transthoracic echocardiogram obtained four months later disclosed a tricuspid aortic valve with thickening of the leaflets but no stenosis; there was moderate aortic insufficiency. The ascending aorta was dilated to 43 mm (normal, less than 36) and the aortic arch was dilated to 34 mm (normal, less than 31). The patient was seen by a cardiologist five months after the echocardiogram. The blood pressure was 160/100 mm Hg. There was a mid-peak systolic ejection murmur best heard at the base and a diastolic murmur, grade 2 of 4, at the right sternal border radiating to the apex. Lisinopril was increased to 40 mg daily; triamterene and hydrochlorothiazide (37.5 mg and 25 mg daily, respectively) and atenolol (50 mg daily) were added. A repeated rapid plasma reagin test was positive at a dilution of 1:2, with a reactive Treponema pallidum particle agglutination assay.
Two weeks after the visit to the cardiologist, the patient saw an infectious-disease specialist. Further questioning disclosed that her husband had had five wives and that the patient had been treated for filariasis. She intermittently had diffuse pruritus and disseminated dermatitis. She had had progressive bilateral hearing loss and tinnitus for several years, and according to her daughter, for the past five years had had some difficulty remembering recent events but had no other mental-status changes. She had no visual problems, numbness, tingling, weakness, joint pains, genital or oral ulcers, or swelling of the genitals or arms or legs. On physical examination, there was a leopard-skin appearance of the skin of the upper back, upper buttocks, and upper thighs, with scattered hypopigmented lesions, 3 to 4 mm in diameter, that were not anesthetic. There was a suggestion of decreased joint-position sensation on the right toes, and the patient's responses to vibration testing in her feet were inconsistent. The eosinophil count was 1958 per cubic millimeter; other results are shown in Table 1.
Magnetic resonance imaging (MRI) of the brain after the administration of gadolinium disclosed multiple, scattered, T2-weighted hyperintense foci in the periventricular and subcortical white matter bilaterally, which were thought to represent small-vessel ischemic disease. Computed tomographic (CT) scanning of the chest, abdomen, and pelvis after the intravenous administration of contrast material showed that the ascending aorta was 4.3 cm in diameter at the level of the pulmonary artery bifurcation, and the descending aorta was 3.1 cm in diameter. The remainder of the examination was normal.
An otolaryngologist performed an audiogram that showed a bilateral symmetric sensorineural hearing loss. An ophthalmologist found cataracts and macular drusen. A neurologist found normal position sense, intact reflexes throughout, and a mild decrease in vibratory sensation only at the toes that was consistent with a mild peripheral neuropathy, with no indication of neurosyphilis. A lumbar puncture showed clear, colorless cerebrospinal fluid with no white or red cells; the protein was 24 mg per deciliter and the glucose was 73 mg per deciliter; a specimen yielded no growth on culture; and a Venereal Disease Research Laboratory (VDRL) test was negative. The results of additional laboratory tests are shown in Table 1.
The patient was referred to the tropical and geographic medicine center for a diagnostic procedure.
Differential Diagnosis
Dr. Donna Felsenstein: May we review the imaging studies?
Dr. Suzanne L. Aquino: The radiograph of the chest (Figure 1A) shows an enlarged cardiac silhouette, and a tortuous and ectatic aorta with focal calcification. The CT angiogram (Figure 1B) showed that the ascending aorta was dilated to 43 mm in diameter. There are small focal calcifications throughout the thoracic aorta that are consistent with atherosclerotic changes. Coronal and sagittal reconstructions of the CT scan show the dilatation of the ascending aorta (Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org).
Figure 1. Images of the Chest.
A chest radiograph (Panel A) reveals mild cardiomegaly. The aorta appears tortuous and ectatic. A CT scan of the thorax (Panel B) after the intravenous administration of contrast material shows a dilated ascending aorta.
Dr. John G. Morgan: The transthoracic echocardiogram shows that the ascending aorta is 43 mm in diameter; the sinuses and the sinotubular junction are of normal size (Figure 2A). The aortic valve is tricuspid, and there is no stenosis. The leaflets are minimally thickened. There is moderate aortic regurgitation detected by color Doppler (Figure 2B, and Video Clip 1 of the Supplementary Appendix).
Figure 2. Transthoracic Echocardiogram.
The standard parasternal long-axis view (Panel A) shows that the ascending aorta is 43 mm in diameter; the sinuses and the sinotubular junction are of normal size. The aortic leaflets are minimally thickened. Examination by color Doppler (Panel B) shows moderate aortic regurgitation.
Dr. Felsenstein: This 63-year-old widow from Cameroon had dermatitis, pruritus, hearing loss, hypertension, systolic and diastolic murmurs, nonanesthetic hypopigmented areas on her upper back, upper buttocks, and upper thighs, eosinophilia, a dilated ascending aorta, and moderate aortic insufficiency. The patient was referred to me for recommendations regarding the evaluation of and treatment for syphilis because of a positive rapid plasma reagin test. A treponemal antibody test was positive, confirming the diagnosis of a treponemal infection.
Diagnosis of Syphilis
Since syphilis serology can be confusing, I will review the diagnostic testing. The nontreponemal assays — the rapid plasma reagin test, the VDRL test, and the automated reagin test — measure antibodies against a cardiolipin–lecithin–cholesterol antigen. Although these tests are inexpensive, rapid, and highly sensitive except in early primary infection, they are relatively nonspecific. Biologic false positive results occur in a variety of inflammatory and infectious conditions.1 Thus, a positive nontreponemal assay must always be confirmed by a treponemal assay. Treponemal assays test for antibody to T. pallidum; techniques include the fluorescent treponemal antibody-absorption test and hemagglutination tests (such as the T. pallidum particle agglutination assay and the microhemagglutination assay for T. pallidum). The nontreponemal tests become positive within weeks to months after infection, rise with dissemination of the infection during the secondary stage, and after the first year, slowly decrease over years to decades, becoming negative in approximately 25 percent of patients,2 despite persistent infection. The treponemal assays become positive earlier than the nontreponemal tests3 and remain positive despite treatment in more than 75 percent of patients treated for primary, secondary, or early latent syphilis.4
This patient initially had a negative rapid plasma reagin test. Because of imaging studies showing an abnormal aorta, a repeated rapid plasma reagin was performed, which was positive at the low titer of 1:2. The diagnosis of treponemal infection was confirmed with the use of the T. pallidum particle agglutination assay. A third rapid plasma reagin test performed two weeks later was positive undiluted. Even within the same laboratory, the titer of a nontreponemal test can vary slightly on repeated testing; in this patient, the persistently low-level positive result on repeated testing and the lack of a rise in titer suggest an old rather than a recent infection.
How did the patient become infected? The absence of physical manifestations of congenital syphilis and the late onset of hearing loss argue against congenital infection. She received a blood transfusion a year before presentation, but if she had recently acquired syphilis, her nontreponemal titer should be higher. It is probable that the infection had been sexually acquired more than 15 years earlier from her husband. Serologic tests cannot differentiate between the nonvenereal treponematoses T. pallidum subspecies pertenue (yaws) and T. pallidum subspecies endemicum (bejel),5,6 and the venereally transmitted infection caused by T. pallidum subspecies pallidum (syphilis). All these infections usually respond to treatment with the proper dosage of penicillin.7
Staging of Syphilis
Treatment is mandatory for all patients with positive serology for syphilis. Appropriate treatment should always be confirmed; it is determined by the patient's stage of infection. Primary syphilis is manifested by the chancre, classically a single, indurated, nonpainful genital lesion and less typically by multiple and sometimes painful ulcerations. The lesions go unnoticed in 15 to 30 percent of patients. Dissemination of infection results in the secondary stage of syphilis, which may produce malaise, low-grade fever, headache, lymphadenopathy, hepatosplenomegaly, alopecia, and the classic maculopapular rash involving the palms and soles. Atypical rashes sparing the palms and soles may occur as well, which may result in misdiagnosis. During latent infection, serologic tests remain positive, but there are no clinical manifestations.8 Some form of tertiary infection, such as cardiovascular syphilis or neurosyphilis,develops in 30 to 40 percent of untreated patients.9,10,11
This patient had no signs of congenital, primary, or secondary syphilis. The symptoms and signs that suggest possible tertiary infection are a dilated ascending aorta with insufficiency, possibly reflecting cardiovascular syphilis, and the recent onset of hearing loss and decreased vibration sense, possibly implying neurosyphilis.
Syphilitic involvement of the cardiovascular system can result in aortic aneurysm (40 percent of cases), often with eggshell-like calcifications,12 aortic regurgitation (9 percent), and stenosis of the coronary ostia (26 percent), and rarely, gummatous involvement.11 Syphilitic aneurysms may be fusiform or saccular and generally involve the ascending aorta above the sinuses of Valsalva. The aortic dilatation and insufficiency seen in this patient may be due to syphilis, but these findings are nonspecific and may be a result of the hypertension.
Neurosyphilis can be asymptomatic, or it may present as acute meningitis, meningovascular disease (cerebrovascular accident), meningoencephalitis (general paresis), or with posterior spinal column involvement (tabes dorsalis). The patient's history of hearing loss and diminished vibratory sense mandates that neurosyphilis be ruled out. Neurologic examination did not show cranial-nerve involvement; in particular, her pupillary reflexes were normal. Position sense in her toes was determined to be normal on repeated testing. The neurology consultant thought that the minor vibratory abnormality was consistent with a peripheral neuropathy. An MRI of the brain disclosed small-vessel ischemic disease; this finding can be caused by atherosclerosis, but it can also be associated with syphilis. The results of the cerebrospinal fluid examination, including a cell count, protein level, and VDRL test, were normal. Although a positive cerebrospinal fluid VDRL test is diagnostic for neurosyphilis, a negative result does not rule out the diagnosis, particularly if there is an abnormal cell count or elevated protein level.13 Although the presentation varies, most patients with otic syphilis have gradual bilateral but asymmetric sensorineural hearing loss over the course of months to years, often with tinnitus or vestibular dysfunction.14,15 The hearing loss is usually fluctuating but progressive. This patient had symmetric, bilateral high-tone sensorineural hearing loss without vestibular involvement, believed by the otolaryngologist to be consistent with presbyacusis, or age-related hearing loss. The results of lumbar puncture may be normal in otic syphilis. Given the negative results of the examination of cerebrospinal fluid and the negative neurologic and otologic evaluations, it is unlikely that this patient had neurologic involvement caused by syphilis. When the clinical manifestations, however, are suggestive of neurosyphilis, treatment for that disorder with intravenous penicillin may be reasonable, despite a negative cerebrospinal fluid profile. The patient was asked to return for follow-up.
All patients with syphilis should be tested for the human immunodeficiency virus (HIV) and vice versa, as the coinfection rate is high. An HIV test in this case was negative.
Eosinophilia
This patient's other problem was persistent eosinophilia, and additional testing disclosed Dientamoeba fragilis, for which she received doxycycline (100 mg twice daily for 10 days), and strongyloides infection, as well as evidence of filarial infection. I referred her to the tropical and geographic medicine center for specific testing and additional treatment.
Dr. Edward T. Ryan: Although a peripheral eosinophil count greater than 400 cells per cubic millimeter may be associated with allergic or hematologic conditions (Table 2), infectious causes need to be considered, especially in persons who have traveled internationally.16,17 Viral, bacterial, and fungal causes of eosinophilia are rare, associated with low-to-moderate eosinophilia (400 to 800 cells per cubic millimeter), and often have distinctive clinical presentations. Most parasite-associated eosinophilia is due to migratory or invasive helminths (worms). This patient's chronic dermatologic manifestations, pruritus, residence in the Cameroon, high-level peripheral eosinophilia, and history of previous filariasis all suggested active filarial infection.
Table 2. Causes of Eosinophilia.
Filariasis
There are eight filarial infections for which humans are the definitive host (Table 3). Distinctions among the various types are made on the basis of a patient's possible geographic exposure, the clinical manifestations, and morphologic characterization and localization of microfilariae. Although this patient had lived in an area endemic for five species of filaria (Wuchereria bancrofti, Loa loa, Mansonella perstans, M. streptocerca, and Onchocerca volvulus), the pruritus and chronic dermatitis strongly suggested onchocerciasis. Humans become infected with O. volvulus through the bite of Simulium species black flies, which lay their eggs attached to rocks or vegetation in rapidly flowing rivers and streams. Onchocerciasis is thus most prevalent around rivers, leading to the name "river blindness." When a fly bites a human, infective larvae enter the skin and mature into adult male and female worms. Adult worms may live 10 to 15 years and usually reside in fibrotic nodules (onchocercomata) in subcutaneous or deeper tissues. Microfilariae migrate through subcutaneous, dermal, and ocular tissues, surviving for 6 to 24 months. When microfilariae in the skin are ingested by a black fly, they mature within the fly into larvae that can be inoculated into another human host.
Table 3. Human Filariasis.
The classic clinical manifestations of onchocerciasis are skin and eye changes.18,19 Inflammatory responses are typically associated with microfilariae rather than adult worms. Dermatologic manifestations include acute papular or chronic dermatitis, and depigmentation that manifests as spotty areas of hypopigmented skin (leopard skin), as in this patient (Figure 3). A reaction to corneal microfilariae leads to a sclerosing keratitis that causes blindness. Iridocyclitis with synechiae and secondary glaucoma, chorioretinitis, and optic neuritis all may occur and impair vision.
Figure 3. Clinical Photograph of Another Patient Showing Skin Changes of Onchocerciasis.
There are areas of hypopigmentation, forming a "leopard-skin" pattern. (Photograph credit: WHO/TDR/Murdoch, World Health Organization, Special Program for Research and Training in Tropical Diseases, available at www-nt.who.int/tropical_diseases/databases/imagelib.pl?imageid=9403365.)
The diagnosis of onchocerciasis is based on clinical recognition, ophthalmologic examination (in which patients should be asked to sit with their head between their knees for approximately 10 minutes to allow microfilariae to move into the anterior chamber to be visualized) and skin-snip analysis. Commercially available serologic assays are sensitive but have low specificity and cannot distinguish between an active infection and a previous infection or among the eight filarial species; in addition, positive assays may represent cross-reactivity to other nematodes.
In order to evaluate whether she had active onchocerciasis, we evaluated snips of the patient's skin for microfilariae. Snips of skin are taken with a corneoscleral punch-biopsy device, or by lifting a small piece of skin with a needle and gently shaving off approximately 1 mg of skin with a scalpel blade. Skin snips should be bloodless to minimize contamination with microfilariae from peripheral blood. Six are usually performed (one from each scapula, iliac crest, and lateral calf), and placed in normal saline or physiologic buffer and observed under low-power microscopy to detect living microfilariae emerging from skin. If a person has lived in an area of the world endemic for M. streptocerca, as did this patient, microfilariae should be fixed and stained to make a definitive diagnosis of onchocerciasis.
A Medical Student: This patient's persistent eosinophilia could be due to neoplasia, inflammatory and atopic disorders, or parasitic infection. The patient recently immigrated from Cameroon and tested positive for multiple parasites. However, the eosinophilia did not resolve after treatment of those infections. Further exploration of the patient's history disclosed a prior exposure to filariae, and examination revealed pruritus and nonanesthetic leopard-skin dermatitis, which were consistent with cutaneous onchocerciasis. A skin biopsy could confirm this diagnosis.
Our diagnosis is onchocerciasis.
Dr. Edward T. Ryan's Diagnosis
Onchocerciasis.
Pathological Discussion
Dr. John A. Branda: Skin snips were obtained, placed in saline, and concentrated by centrifugation, and saline wet mounts were prepared from the sediment. Examination by light microscopy revealed a very few microfilariae, measuring approximately 250 μm in length (Video Clip 2 of the Supplementary Appendix). The wet mounts were air-dried, fixed with methanol, and stained with Giemsa (Figure 4). The microfilariae had prominent cephalic and nerve-ring spaces. The nuclear column did not extend to the tip of the tail, and the tail tapered to a point but was not curled. These morphologic features are typical of O. volvulus.20,21
Figure 4. Microfilaria of O. volvulus (Giemsa Stain).
The microfilariae (top) have a substantial cephalic space and a well-demarcated nerve-ring space. The nuclear column did not extend to the tip of the tail, and the tail tapered to a point but was not curled. In the high-power photograph of the cephalic end of a microfilaria (inset left), the arrow points to the cephalic space. The arrowhead points to the nerve-ring space. In a high-power view of the caudal end of the microfilaria (inset right), the nuclear column does not extend to the tip of the tail (arrow). These morphologic features are typical of O. volvulus. M. streptocerca is distinguished from O. volvulus by its smaller size (180 to 240 μm; mean, 210 μm), a nuclear column that extends to the tip of the tail, a curled (crooked) tail, and a less prominent nerve-ring space.
Discussion of Management
Dr. Felsenstein: Benzathine penicillin is used to treat late latent syphilis because of its extremely low solubility, which results in more prolonged blood levels than those of other penicillin preparations. The treatment for latent syphilis is benzathine penicillin (2.4 million units intramuscularly weekly for three weeks), which this patient received. Treatment for neurosyphilis requires the use of intravenous aqueous penicillin (4 million units every four hours for 10 to 14 days), followed with benzathine penicillin for an additional 1 to 2 weeks.
Dr. Ryan: There is no nontoxic therapy that kills adult O. volvulus worms, although these worms contain endosymbiotic Wolbachia species bacteria, and the role of antibacterial therapy is currently being evaluated.22 Therapy is thus targeted to controlling microfilariae, preventing blindness and dermatitis, and interrupting disease transmission. The mainstay of therapy is ivermectin, a semisynthetic macrocyclic lactone that hyperpolarizes nematode cells. Skin microfilariae are killed in days, reaching a maximal reduction in approximately two weeks. Ocular microfilariae resolve more slowly. Ivermectin also kills microfilariae in utero in adult female worms, resulting in the suppression of microfilarial burden for 6 to 12 months. Therefore, it is usually administered as a single dose of 150 μg per kilogram every 6 months for up to 10 years in patients with onchocerciasis. Side effects are rare, although some patients report pruritus, urticaria, fever, and arthralgias, particularly after initial treatment. Concomitant loiasis should be ruled out if the patient has lived in an area of the world endemic for both infections, because in patients with high-level microfilaremia from loiasis, ivermectin may cause encephalopathy and death. There are ongoing efforts by the World Health Organization, The World Bank, pharmaceutical companies, not-for-profit organizations, and local ministries of health to control onchocerciasis using vector control and mass-treatment programs.23,24
For this patient, we recommended a dose of ivermectin every six months for 10 years. Ivermectin would also treat the probable strongyloidiasis, and we considered the antitoxocara antibody to probably be cross-reactive.
Anatomical Diagnosis
Onchocerca volvulus infection (onchocerciasis).
Dr. Ryan reports having received consulting fees from Raytheon Corporation, Acambis, and New England Biolabs-BioHelix, and holding patents in heterologous antigens in live-cell Vibrio cholerae strains, V. cholerae proteins expressed during infection, and the use of the RTX secretion system to achieve heterologous polypeptide secretion by V. cholerae. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Tropical and Geographic Medicine Center (E.T.R.), the Divisions of Infectious Diseases (D.F.) and Cardiology (J.G.M.), Department of Medicine, and the Departments of Radiology (S.L.A.) and Pathology (J.A.B.), Massachusetts General Hospital; and the Departments of Medicine (E.T.R., D.F., J.G.M.), Radiology (S.L.A.), and Pathology (J.A.B.), Harvard Medical School.
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