Case 4-2005 — A 35-Year-Old Man with Nasal Congestion, Swelling, and Pain
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《新英格兰医药杂志》
Presentation of Case
A 35-year-old man presented to the emergency department of this hospital because of nasal congestion, swelling, and pain in his right nostril.
He had been in his usual state of health until six months previously, when he noticed an ulcer inside his right nostril. Two months before the evaluation, the ulcer began to enlarge, and pain and swelling developed, associated with crusting and mild pruritus. The patient did not have fever, sweats, cough, weight loss, or exposure to tuberculosis. He had had malaria in the past. He did not smoke or drink alcohol. He was a native of Brazil; he was divorced, worked in a restaurant, and lived with roommates.
In the emergency department, the blood pressure was 132/77 mm Hg, the pulse 59 beats per minute, the respiratory rate 20 breaths per minute, and the temperature 35.5°C. The oxygen saturation was 98 percent while the patient was breathing ambient air. An examination of the eyes, mouth, larynx, and neck revealed no abnormalities. There was swelling and erythema of the right nasal vestibule, with tenderness and crusting. A diagnosis of nasal vestibulitis was made, and therapy with oral cephalexin and topical bacitracin ointment twice daily was begun.
Ten days later, the lesion was unchanged, and a consultation with an infectious-disease specialist was obtained. Further questioning revealed that the patient had emigrated from a tropical area of Brazil seven months earlier. He did not use alcohol or intravenous drugs and had no history of sex with men, sexually transmitted diseases, or blood transfusions. He reported that two years earlier, while living in Brazil, he had had similar symptoms; a diagnosis of a "mycosis" had been made, and the lesion resolved after two weeks of antibiotic therapy. He had not had skin lesions or rash.
On examination, his vital signs remained normal and he was in no distress. The right side of the distal third of the nose was swollen and faintly erythematous. The right nostril was partially collapsed (Figure 1). At the lateral rim of the right nostril, there were several blisters (1 to 2 mm in diameter). The tissue under the rim was firm and thickened. The right nasal septal mucosa was inflamed and had a cobblestone appearance. Specimens were obtained for cultures and viral testing. The throat was clear and there was no cervical lymphadenopathy. An examination of the heart, lungs, abdomen, and extremities revealed no abnormalities. The results of measurements of serum electrolytes, urea nitrogen, levels of aspartate aminotransferase, and a complete blood count were normal.
Figure 1. Clinical Photograph of the Nose.
The patient's right nostril is partially collapsed, and the tissue under the rim is thickened. The right nasal septal mucosa is inflamed and has a cobblestone appearance.
The day after the physical examination, a report faxed from the hospital where the patient had been treated two years previously showed that the nasal infection had been caused by Streptococcus pyogenes. An immunofluorescence study for detection of the herpes simplex virus antigen was negative on the nasal smear taken during the examination the day before. Preliminary results of cultures suggested the presence of Proteus mirabilis. The cephalexin and bacitracin were discontinued and oral levofloxacin (500 mg daily) was begun, with frequent application of saline nasal spray.
In a follow-up examination one week later, the nasal skin was less erythematous and the blisters had resolved. There was a slight decrease in the inflammation of the septal mucosa. There was an ulcer just inside the superolateral rim of the right nostril. A bacterial culture from the swab taken during the visit a week earlier grew P. mirabilis, which was sensitive to levofloxacin. Cultures for fungi and viruses were negative. The levels of total protein, albumin, globulin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total and direct bilirubin were normal. A diagnostic procedure was performed.
Differential Diagnosis
Dr. Peter F. Weller: This patient had the signs and symptoms of nasal ulceration and inflammation. Potential causes of nasal ulceration and inflammation involve a broad range of both infectious and noninfectious causes (Table 1). A number of elements of the patient's history and physical examination can focus and direct our consideration of the differential diagnosis. First, this episode of nasal involvement has developed over more than six months and is therefore considered subacute. Second, the patient reported that he had had an episode of nasal disease two years previously. Third, this condition does not appear to be part of a systemic disease; the patient is afebrile, and the findings are limited to the nose. Fourth, the nasal disease seems to involve both the nasal septum and lateral aspects of the nose, with apparent collapse of the right nostril. Fifth, although bacteria (proteus) were cultured on this visit, as streptococci had been two years previously, these two different organisms were probably colonizing or superinfecting an underlying nasal process. Finally, we know that the patient has recently emigrated from a tropical region of Brazil and had his initial episode of nasal disease while he was in Brazil.
Table 1. Differential Diagnosis of Nasal Ulcers.
Mucosal Leishmaniasis
My primary concern would be that this patient has a serious sequela of infection with a New World leishmania species. There are about 21 leishmania species that may infect humans and produce several, varied clinical syndromes, including visceral, cutaneous, and mucosal leishmaniasis.1,2,3 New World cutaneous leishmaniasis is caused by the Leishmania viannia and L. mexicana species complexes.3 Infections with L. viannia subspecies, especially L. viannia braziliensis and L. viannia panamensis, may be complicated by the subsequent development of mucosal disease, a syndrome termed espundia in Latin America, or mucocutaneous leishmaniasis.1,4 All leishmania is spread by the bites of sand flies. With New World leishmaniasis, cutaneous lesions typically begin as papules and progress to ulcers — often with heaped-up borders — that spontaneously heal over a varied time span, from months to years.4 Nodular skin lesions and lymphadenopathy may also be manifestations of cutaneous New World leishmaniasis.5
Mucosal leishmaniasis involves the mucosal membranes of the nose and mouth.4 Typically, the nose is involved at the outset, and oropharyngeal and laryngeal involvement, if they develop, represent later symptoms of the disease.4 Mucosal disease does not, as a rule, heal spontaneously; it often evolves over the course of several years before the patient seeks medical attention.5,6 The precise mechanisms by which amastigote forms of the parasite disseminate from the skin and localize within macrophages in the naso-oropharyngeal membranes are unknown, as is the reason why mucosal disease subsequently develops in only a few patients with cutaneous disease, perhaps less than 5 percent.1
Mucosal lesions may be present with cutaneous lesions, but more commonly mucosal disease appears years or even decades after the skin lesions have healed.4,7 Mucosal disease usually presents with chronic nasal symptoms that may include increased secretions, epistaxis, pain, and other evidence of inflammation. A common site for these lesions is over the cartilaginous septum inside the anterior nares; with time, perforation of the nasal septum may occur.4 If the lateral nasal cartilage is involved, there may be collapse of the anterior nose.4 As the disease progresses, extensive tissue destruction in the nose and within the mucosal and submucosal tissues of the mouth can occur. Mucosal disease is more common in boys and men than in girls and women, and the average age of the patient at the onset of the disease is later in life than that of the patient with cutaneous disease.
Would mucosal leishmaniasis explain this man's clinical course, with two episodes over two years of symptomatic and now subacutely evolving nasal disease? We are not told precisely which tropical area of Brazil this patient came from; however, L. viannia brasiliensis, the principal cause of mucosal leishmaniasis, is prevalent in many regions of tropical Brazil.8 Therefore, prior infection with this parasite is possible. It is notable that the patient was asked about but did not report any history of skin diseases. Whereas many patients with mucosal disease have a history of cutaneous lesions, evidence of cutaneous lesions can be lacking (in 16 percent of cases, as reported by Marsden,4 and in 56 percent, as reported by Saenz et al.9). Nevertheless, the physical examination should include a diligent search for signs of earlier skin lesions, which appear as slightly depressed scars, often hypopigmented, with loss of subcutaneous tissue.4 Small lesions may look like variola or bacille Calmette–Guérin vaccination scars.
The chronic nature of evolving nasal mucosal leishmaniasis in the absence of systemic symptoms would account for both this patient's presentation in Brazil two years earlier and his current presentation with an illness of six months' duration. Whether his previous antibiotic therapy treated bacterial superinfections at an altered nasal mucosal barrier remains a matter of conjecture. The involvement of the patient's nasal septum and other nasal tissues and the partial collapse of his right nostril, the hyperemia and thickening beneath the nasal mucosa, and the ulceration are all consistent with features of mucosal leishmaniasis.4 Thus, mucosal leishmaniasis is the most likely diagnosis. Other possibilities may need to be ruled out, however.
Paracoccidioidomycosis
Paracoccidioidomycosis is a deep mycosis caused by Paracoccidioides brasiliensis, which is endemic in Brazil.10 Since the nasal disease developed while the patient was in Brazil, should we also consider this organism as a possible cause of his nasal disease? Oropharyngeal involvement in paracoccidioidomycosis is common, often secondary to pulmonary involvement. Nasal involvement is distinctly uncommon, however.10,11 Thus, paracoccidioidomycosis is not a probable diagnosis. Fungal cultures of samples obtained after one week — at the follow-up visit — were negative, but P. brasiliensis often appears on culture only after 20 days,10 so early negative findings would not necessarily rule it out. Tissue obtained from any nasal biopsy should be stained and cultured for this fungus.
Diagnostic Testing
The differential diagnosis of ulcerative and inflammatory nasal lesions (Table 1) includes a range of other causes. The history, clinical course, and findings on physical examination make these other causes less likely than those already discussed, but examination of a biopsy specimen of nasal tissue would provide the most direct means to ascertain whether any of these processes are involved. With mucosal leishmaniasis as a leading candidate for the diagnosis in this case, testing for infection with the human immunodeficiency virus (HIV) would be appropriate, despite the absence of risk factors. In patients infected with HIV, visceral leishmaniasis is well recognized as a primary opportunistic infection.1 Clinical experience with coinfection with mucosal leishmaniasis and HIV is more limited, but a report from Brazil suggests that this form of leishmaniasis may frequently be fatal in persons infected with HIV.12
The diagnostic test would be an aspiration or, more definitively, a biopsy of involved nasal tissue. Since mucosal leishmaniasis is a probable diagnosis in this case, it would be appropriate to obtain leishmania culture medium from the Centers for Disease Control and Prevention (CDC) so that samples from either aspiration or biopsies could be cultured to recover and identify any leishmania species. In mucosal leishmaniasis, amastigote forms of the parasite are characteristically sparse, so appropriate Giemsa staining of lesions might not detect organisms.4 Immunofluorescent-antibody or polymerase-chain-reaction (PCR) analyses of the tissues can enhance the detection of organisms in lesions of mucosal leishmaniasis.13,14 Culture for leishmania is not only diagnostic but also makes possible definitive identification of the causative species by isoenzyme or PCR analyses. At the same time, routine histopathological evaluation, specific staining for other possible pathogens (e.g., mycobacteria), and cultures of tissues obtained at biopsy for bacteria, fungi, and mycobacteria would help to evaluate the more disparate potential causes of nasal ulcerative and inflammatory processes (Table 1).
Dr. Nancy Lee Harris (Pathology): Dr. Kazda, you saw this patient first in the emergency room; would you tell us your initial impression?
Dr. George Kazda (Otolaryngology, Massachusetts Eye and Ear Infirmary): The patient presented primarily with unilateral disease and an underlying simple deformity with local swelling. The leading diagnosis was bacterial vestibulitis, probably secondary to environmental factors or trauma. The initial treatment was with cephalexin and topical antibiotics. However, at the 10-day follow-up visit, the patient's symptoms were worse, so we decided to confer with our infectious-disease consultant.
Dr. Harris: Dr. Durand, would you describe your initial thoughts and the diagnostic procedure?
Dr. Marlene L. Durand: I saw the patient with otolaryngologists. Additional careful physical examination did not disclose any healed skin lesions. The patient was HIV-negative. Biopsy of the nasal mucosa was performed in the emergency room. The tissue specimens obtained were sent to the pathology department with a specific request to look for leishmania and to rule out other diagnoses, such as fungal disease or cancer. We realized that even if the pathological examination were negative for leishmania, it would not rule out the diagnosis, and we planned to send a specimen on special medium to the CDC for culture if the pathological findings were nondiagnostic.
Clinical Diagnosis
Mucocutaneous leishmaniasis.
Dr. Peter F. Weller's Diagnosis
Mucocutaneous leishmaniasis.
Pathological Discussion
Dr. Ben Z. Pilch: Tissue samples from the nasal septum and right nasal vestibule were submitted to the pathology department. Tissue from both areas showed ulceration, chronic inflammation consisting of infiltration by lymphocytes and plasma cells, and focal necrosis (Figure 2A). Tissue from the right nasal vestibule, in addition, showed granulomatous inflammation, with palisading histiocytes adjacent to a necrotic area, as well as epithelioid granuloma formation (Figure 2B). A search for leishmania organisms did not reveal the characteristic intracellular amastigotes in histiocytes,1,15,16 and neither fungi nor acid-fast bacilli were identified on specially stained sections. A neoplastic process was not identified. Thus, the histologic findings were consistent with a chronic infectious process, but causative organisms were not identified. The scarcity of organisms on histologic sections in cases of mucosal leishmaniasis is not surprising, since amastigotes are much less common in this condition than in cutaneous leishmaniasis.1
Figure 2. Biopsy Specimen of the Nose.
In Panel A, necrotic tissue in the lower portion of the photomicrograph is bordered by palisading histiocytes; a chronic inflammatory infiltrate containing lymphocytes and plasma cells fills the remainder of the image (hematoxylin and eosin). In Panel B, a granuloma, located in the upper portion of the image, consists of a localized collection of epithelioid histiocytes (hematoxylin and eosin).
Dr. Durand: When the first biopsy was nondiagnostic, I contacted the CDC's Division of Parasitic Diseases laboratory to obtain special Novy–MacNeal–Nicolle culture medium, which was sent by overnight mail. Additional biopsies were performed and tissue was obtained from the involved right side and also from the left side of the nasal septum, since new areas of cobblestoning of the mucosa had developed there in the interim. We applied some of the biopsy material to slides for touch preparations, and put the rest in the Novy–MacNeal–Nicolle medium. These samples were returned to the CDC by overnight mail.
Dr. Pilch: The culture grew leishmania, and speciation by means of electrophoresis for isoenzymes in culture lysate revealed L. viannia braziliensis. The diagnosis of mucosal leishmaniasis as a result of infection by L. viannia braziliensis was thus established.
A photomicrograph of a tissue section from another patient with cutaneous leishmaniasis illustrates the intracellular amastigotes in histiocytes (Figure 3A). Amastigotes may also be seen free in tissue. The organism has a pale cell membrane that surrounds clear cytoplasm containing a discrete nucleus. Another characteristic feature of the amastigote, the intracytoplasmic kinetoplast, a rod-shaped mitochondrial structure composed of DNA,1 is shown to better advantage in a photomicrograph of a touch preparation from a patient with visceral leishmaniasis due to L. donovani (Figure 3B).
Figure 3. Amastigotes of Leishmania.
In Panel A, a photomicrograph from a different patient who had cutaneous leishmaniasis, multiple intracellular amastigotes of leishmania are present in the cytoplasm of histiocytes (hematoxylin and eosin). The amastigotes are surrounded by a thin cell membrane and contain a dark nucleus. In Panel B, a photomicrograph of a touch preparation from a patient with visceral leishmaniasis caused by L. donovani, multiple amastigotes in a histiocytic cell have a round nucleus and a smaller, rod-shaped kinetoplast; all species of leishmania have identical histomorphologic features (Wright's stain). Figure provided by F. Steurer, CDC.
Dr. Harris: Dr. Durand, would you tell us about the treatment you prescribed for the patient and about his current status?
Discussion of Management
Dr. Durand: The options for therapy for mucosal leishmaniasis are intravenous amphotericin B and intravenous sodium stibogluconate or meglumine antimoniate, pentavalent antimony drugs. Organic antimony agents have been used since 1912, and sodium stibogluconate has been used for more than 50 years, yet it is an orphan drug in the United States, available only from the CDC. We treated the patient as an outpatient with daily infusions of sodium stibogluconate, 20 mg per kilogram of body weight, and continued the treatment for 28 days. We monitored him closely for side effects. Toxicity is cumulative and increases after the first week of therapy. Nausea and vomiting are common. Elevated amylase and lipase levels develop in nearly all patients, although symptomatic pancreatitis is rare. Arthralgia occurs in about half of affected patients and typically responds to nonsteroidal antiinflammatory agents. Elevated transaminase levels are common, although jaundice is rare. Cardiac side effects are of the greatest concern, and we followed our patient with electrocardiograms at least once weekly. Deaths have occurred when sodium stibogluconate has been given in higher-than-usual doses or given to patients with underlying cardiac disease. The prolongation of the corrected QT interval to more than 500 msec or the development of T-wave inversions with concave ST segments is an ominous sign; the drug should be stopped if either of these occurs. T-wave inversions and decreased T-wave amplitude are seen in 30 to 40 percent of patients and do not require that the drug be stopped.
The patient's nasal pain resolved quickly, and his mucosal lesions gradually regressed. Seven months after completion of therapy, the mucosa remained healed, with no signs of recurrent disease. We will continue to follow him closely, since recurrences are known to occur within the first year in up to 30 percent of patients with mucocutaneous leishmaniasis. Because the toxicity of sodium stibogluconate is cumulative, if there is a relapse, I would use another drug, such as amphotericin B.
Dr. Harris: I would like to ask Dr. Ryan to make a few comments about the evaluation of patients such as this one and, in particular, about coordination with the CDC for unusual infectious diseases.
Dr. Edward T. Ryan (Infectious Diseases): The typical person with leishmaniasis in the United States usually sees multiple physicians over many months before a correct diagnosis is made. The fact that the diagnosis was entertained within a week of this patient's presenting for medical care is a tribute to his physicians.
It is important for clinicians to be aware that it is only New World leishmaniasis that carries a risk of mucosal disease. Rigorous attempts should be made to establish a species diagnosis in patients with New World cutaneous leishmaniasis, since the risk of clinically evident mucosal involvement is species-dependent. The Division of Parasitic Diseases at the CDC offers a wide range of assistance in the diagnosis and care of patients with leishmaniasis, including providing culture medium, instructing caregivers in appropriate sampling techniques, culturing samples, speciating leishmania organisms, and providing general guidelines regarding therapeutic options. Clinicians should avail themselves of these resources.
Dr. David Hooper (Infectious Diseases): In a patient who has cutaneous disease with a species that has the potential for late mucosal relapse, would you treat the patient, given the toxicity of the available drugs?
Dr. Weller: I would treat definitively with sodium stibogluconate to decrease the possibility of recurrence years or decades later. A new compound, hexadecylphosphocholine (miltefosine), which has proved to be effective in the treatment of visceral leishmaniasis,17 may have some efficacy in mucocutaneous leishmaniasis.18
Dr. Harris: Are there known risk factors, such as HLA type or other factors related to immunity, that may predispose a person to mucosal lesions?
Dr. Weller: There is evidence that the risk of mucocutaneous disease is related to some HLA types.19 Recent studies suggest that patients with mucosal disease have an exaggerated and poorly regulated immune response to leishmania antigens, which may cause tissue damage without clearing the organisms.20
Anatomical Diagnosis
Mucocutaneous leishmaniasis due to infection by Leishmania viannia braziliensis.
Source Information
From the Division of Infectious Diseases and the Division of Allergy and Inflammation, Beth Israel Deaconess Medical Center (P.F.W.); the Infectious Disease Unit, Massachusetts General Hospital, and the Infectious Disease Service, Massachusetts Eye and Ear Infirmary (M.L.D.); the Department of Pathology, Massachusetts General Hospital (B.Z.P.); and the Departments of Medicine (P.F.W., M.L.D.) and Pathology (B.Z.P.), Harvard Medical School — all in Boston.
References
Herwaldt BL. Leishmaniasis. Lancet 1999;354:1191-1199.
Cutaneous leishmaniasis in U. S. military personnel -- Southwest/Central Asia, 2002-2003. MMWR Morb Mortal Wkly Rep 2003;52:1009-1012.
Pearson RD, Jeronimo SMD, Sousa AQ. Leishmaniasis. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical infectious diseases: principles, pathogens & practice. Philadelphia: Churchill Livingstone, 1999:797-813.
Marsden PD. Mucosal leishmaniasis ("espundia" Escomel, 1911). Trans R Soc Trop Med Hyg 1986;80:859-876.
Berman JD. Human leishmaniasis: clinical, diagnostic, and chemotherapeutic developments in the last 10 years. Clin Infect Dis 1997;24:684-703.
Scope A, Trau H, Bakon M, Yarom N, Nasereddin A, Schwartz E. Imported mucosal leishmaniasis in a traveler. Clin Infect Dis 2003;37:e83-e87.
Walton BC, Chinel LV, Eguia y Eguia O. Onset of espundia after many years of occult infection with Leishmania braziliensis. Am J Trop Med Hyg 1973;22:696-698.
Pearson RD, Sousa AQ. Clinical spectrum of leishmaniasis. Clin Infect Dis 1996;22:1-13.
Saenz RE, de Rodriguez CG, Johnson CM, Berman JD. Efficacy and toxicity of pentostam against Panamanian mucosal leishmaniasis. Am J Trop Med Hyg 1991;44:394-398.
Almeida OP, Jacks J Jr, Scully C. Paracoccidioidomycosis of the mouth: an emerging deep mycosis. Crit Rev Oral Biol Med 2003;14:377-383.
de Castro CC, Benard G, Ygaki Y, Shikanai-Yasuda M, Cerri GG. MRI of head and neck paracoccidioidomycosis. Br J Radiol 1999;72:717-722.
Mota Sasaki M, Matsumo Carvalho M, Schmitz Ferreira ML, Machado MP. Cutaneous leishmaniasis coinfection in AIDS patients: case report and literature review. Braz J Infect Dis 1997;1:142-144.
Pirmez C, da Silva Trajano V, Paes-Oliveira Neto M, et al. Use of PCR in diagnosis of human American tegumentary leishmaniasis in Rio de Janeiro, Brazil. J Clin Microbiol 1999;37:1819-1823.
Zajtchuk JT, Casler JD, Netto EM, et al. Mucosal leishmaniasis in Brazil. Laryngoscope 1989;99:925-939.
Protozoal infections. In: Weedon D. Skin pathology. 2nd ed. London: Churchill Livingstone, 2002:721-5.
Connor DH, Neafie RC. Cutaneous leishmaniasis. In: Binford CH, Connor DH, eds. Pathology of tropical and extraordinary diseases. Vol. 1. Washington, D.C.: Armed Forces Institute of Pathology, 1976:258-64.
Jha TK, Sundar S, Thakur CP, et al. Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis. N Engl J Med 1999;341:1795-1800.
Soto J, Toledo J, Gutierrez P, et al. Treatment of American cutaneous leishmaniasis with miltefosine, an oral agent. Clin Infect Dis 2001;33:e57-e61.
Petzl-Erler ML, Belich MP, Queiroz-Telles F. Association of mucosal leishmaniasis with HLA. Hum Immunol 1991;32:254-260.
Bacellar O, Lessa H, Schriefer A, et al. Up-regulation of Th1-type responses in mucosal leishmaniasis patients. Infect Immun 2002;70:6734-6740.(Peter F. Weller, M.D., Ma)
A 35-year-old man presented to the emergency department of this hospital because of nasal congestion, swelling, and pain in his right nostril.
He had been in his usual state of health until six months previously, when he noticed an ulcer inside his right nostril. Two months before the evaluation, the ulcer began to enlarge, and pain and swelling developed, associated with crusting and mild pruritus. The patient did not have fever, sweats, cough, weight loss, or exposure to tuberculosis. He had had malaria in the past. He did not smoke or drink alcohol. He was a native of Brazil; he was divorced, worked in a restaurant, and lived with roommates.
In the emergency department, the blood pressure was 132/77 mm Hg, the pulse 59 beats per minute, the respiratory rate 20 breaths per minute, and the temperature 35.5°C. The oxygen saturation was 98 percent while the patient was breathing ambient air. An examination of the eyes, mouth, larynx, and neck revealed no abnormalities. There was swelling and erythema of the right nasal vestibule, with tenderness and crusting. A diagnosis of nasal vestibulitis was made, and therapy with oral cephalexin and topical bacitracin ointment twice daily was begun.
Ten days later, the lesion was unchanged, and a consultation with an infectious-disease specialist was obtained. Further questioning revealed that the patient had emigrated from a tropical area of Brazil seven months earlier. He did not use alcohol or intravenous drugs and had no history of sex with men, sexually transmitted diseases, or blood transfusions. He reported that two years earlier, while living in Brazil, he had had similar symptoms; a diagnosis of a "mycosis" had been made, and the lesion resolved after two weeks of antibiotic therapy. He had not had skin lesions or rash.
On examination, his vital signs remained normal and he was in no distress. The right side of the distal third of the nose was swollen and faintly erythematous. The right nostril was partially collapsed (Figure 1). At the lateral rim of the right nostril, there were several blisters (1 to 2 mm in diameter). The tissue under the rim was firm and thickened. The right nasal septal mucosa was inflamed and had a cobblestone appearance. Specimens were obtained for cultures and viral testing. The throat was clear and there was no cervical lymphadenopathy. An examination of the heart, lungs, abdomen, and extremities revealed no abnormalities. The results of measurements of serum electrolytes, urea nitrogen, levels of aspartate aminotransferase, and a complete blood count were normal.
Figure 1. Clinical Photograph of the Nose.
The patient's right nostril is partially collapsed, and the tissue under the rim is thickened. The right nasal septal mucosa is inflamed and has a cobblestone appearance.
The day after the physical examination, a report faxed from the hospital where the patient had been treated two years previously showed that the nasal infection had been caused by Streptococcus pyogenes. An immunofluorescence study for detection of the herpes simplex virus antigen was negative on the nasal smear taken during the examination the day before. Preliminary results of cultures suggested the presence of Proteus mirabilis. The cephalexin and bacitracin were discontinued and oral levofloxacin (500 mg daily) was begun, with frequent application of saline nasal spray.
In a follow-up examination one week later, the nasal skin was less erythematous and the blisters had resolved. There was a slight decrease in the inflammation of the septal mucosa. There was an ulcer just inside the superolateral rim of the right nostril. A bacterial culture from the swab taken during the visit a week earlier grew P. mirabilis, which was sensitive to levofloxacin. Cultures for fungi and viruses were negative. The levels of total protein, albumin, globulin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total and direct bilirubin were normal. A diagnostic procedure was performed.
Differential Diagnosis
Dr. Peter F. Weller: This patient had the signs and symptoms of nasal ulceration and inflammation. Potential causes of nasal ulceration and inflammation involve a broad range of both infectious and noninfectious causes (Table 1). A number of elements of the patient's history and physical examination can focus and direct our consideration of the differential diagnosis. First, this episode of nasal involvement has developed over more than six months and is therefore considered subacute. Second, the patient reported that he had had an episode of nasal disease two years previously. Third, this condition does not appear to be part of a systemic disease; the patient is afebrile, and the findings are limited to the nose. Fourth, the nasal disease seems to involve both the nasal septum and lateral aspects of the nose, with apparent collapse of the right nostril. Fifth, although bacteria (proteus) were cultured on this visit, as streptococci had been two years previously, these two different organisms were probably colonizing or superinfecting an underlying nasal process. Finally, we know that the patient has recently emigrated from a tropical region of Brazil and had his initial episode of nasal disease while he was in Brazil.
Table 1. Differential Diagnosis of Nasal Ulcers.
Mucosal Leishmaniasis
My primary concern would be that this patient has a serious sequela of infection with a New World leishmania species. There are about 21 leishmania species that may infect humans and produce several, varied clinical syndromes, including visceral, cutaneous, and mucosal leishmaniasis.1,2,3 New World cutaneous leishmaniasis is caused by the Leishmania viannia and L. mexicana species complexes.3 Infections with L. viannia subspecies, especially L. viannia braziliensis and L. viannia panamensis, may be complicated by the subsequent development of mucosal disease, a syndrome termed espundia in Latin America, or mucocutaneous leishmaniasis.1,4 All leishmania is spread by the bites of sand flies. With New World leishmaniasis, cutaneous lesions typically begin as papules and progress to ulcers — often with heaped-up borders — that spontaneously heal over a varied time span, from months to years.4 Nodular skin lesions and lymphadenopathy may also be manifestations of cutaneous New World leishmaniasis.5
Mucosal leishmaniasis involves the mucosal membranes of the nose and mouth.4 Typically, the nose is involved at the outset, and oropharyngeal and laryngeal involvement, if they develop, represent later symptoms of the disease.4 Mucosal disease does not, as a rule, heal spontaneously; it often evolves over the course of several years before the patient seeks medical attention.5,6 The precise mechanisms by which amastigote forms of the parasite disseminate from the skin and localize within macrophages in the naso-oropharyngeal membranes are unknown, as is the reason why mucosal disease subsequently develops in only a few patients with cutaneous disease, perhaps less than 5 percent.1
Mucosal lesions may be present with cutaneous lesions, but more commonly mucosal disease appears years or even decades after the skin lesions have healed.4,7 Mucosal disease usually presents with chronic nasal symptoms that may include increased secretions, epistaxis, pain, and other evidence of inflammation. A common site for these lesions is over the cartilaginous septum inside the anterior nares; with time, perforation of the nasal septum may occur.4 If the lateral nasal cartilage is involved, there may be collapse of the anterior nose.4 As the disease progresses, extensive tissue destruction in the nose and within the mucosal and submucosal tissues of the mouth can occur. Mucosal disease is more common in boys and men than in girls and women, and the average age of the patient at the onset of the disease is later in life than that of the patient with cutaneous disease.
Would mucosal leishmaniasis explain this man's clinical course, with two episodes over two years of symptomatic and now subacutely evolving nasal disease? We are not told precisely which tropical area of Brazil this patient came from; however, L. viannia brasiliensis, the principal cause of mucosal leishmaniasis, is prevalent in many regions of tropical Brazil.8 Therefore, prior infection with this parasite is possible. It is notable that the patient was asked about but did not report any history of skin diseases. Whereas many patients with mucosal disease have a history of cutaneous lesions, evidence of cutaneous lesions can be lacking (in 16 percent of cases, as reported by Marsden,4 and in 56 percent, as reported by Saenz et al.9). Nevertheless, the physical examination should include a diligent search for signs of earlier skin lesions, which appear as slightly depressed scars, often hypopigmented, with loss of subcutaneous tissue.4 Small lesions may look like variola or bacille Calmette–Guérin vaccination scars.
The chronic nature of evolving nasal mucosal leishmaniasis in the absence of systemic symptoms would account for both this patient's presentation in Brazil two years earlier and his current presentation with an illness of six months' duration. Whether his previous antibiotic therapy treated bacterial superinfections at an altered nasal mucosal barrier remains a matter of conjecture. The involvement of the patient's nasal septum and other nasal tissues and the partial collapse of his right nostril, the hyperemia and thickening beneath the nasal mucosa, and the ulceration are all consistent with features of mucosal leishmaniasis.4 Thus, mucosal leishmaniasis is the most likely diagnosis. Other possibilities may need to be ruled out, however.
Paracoccidioidomycosis
Paracoccidioidomycosis is a deep mycosis caused by Paracoccidioides brasiliensis, which is endemic in Brazil.10 Since the nasal disease developed while the patient was in Brazil, should we also consider this organism as a possible cause of his nasal disease? Oropharyngeal involvement in paracoccidioidomycosis is common, often secondary to pulmonary involvement. Nasal involvement is distinctly uncommon, however.10,11 Thus, paracoccidioidomycosis is not a probable diagnosis. Fungal cultures of samples obtained after one week — at the follow-up visit — were negative, but P. brasiliensis often appears on culture only after 20 days,10 so early negative findings would not necessarily rule it out. Tissue obtained from any nasal biopsy should be stained and cultured for this fungus.
Diagnostic Testing
The differential diagnosis of ulcerative and inflammatory nasal lesions (Table 1) includes a range of other causes. The history, clinical course, and findings on physical examination make these other causes less likely than those already discussed, but examination of a biopsy specimen of nasal tissue would provide the most direct means to ascertain whether any of these processes are involved. With mucosal leishmaniasis as a leading candidate for the diagnosis in this case, testing for infection with the human immunodeficiency virus (HIV) would be appropriate, despite the absence of risk factors. In patients infected with HIV, visceral leishmaniasis is well recognized as a primary opportunistic infection.1 Clinical experience with coinfection with mucosal leishmaniasis and HIV is more limited, but a report from Brazil suggests that this form of leishmaniasis may frequently be fatal in persons infected with HIV.12
The diagnostic test would be an aspiration or, more definitively, a biopsy of involved nasal tissue. Since mucosal leishmaniasis is a probable diagnosis in this case, it would be appropriate to obtain leishmania culture medium from the Centers for Disease Control and Prevention (CDC) so that samples from either aspiration or biopsies could be cultured to recover and identify any leishmania species. In mucosal leishmaniasis, amastigote forms of the parasite are characteristically sparse, so appropriate Giemsa staining of lesions might not detect organisms.4 Immunofluorescent-antibody or polymerase-chain-reaction (PCR) analyses of the tissues can enhance the detection of organisms in lesions of mucosal leishmaniasis.13,14 Culture for leishmania is not only diagnostic but also makes possible definitive identification of the causative species by isoenzyme or PCR analyses. At the same time, routine histopathological evaluation, specific staining for other possible pathogens (e.g., mycobacteria), and cultures of tissues obtained at biopsy for bacteria, fungi, and mycobacteria would help to evaluate the more disparate potential causes of nasal ulcerative and inflammatory processes (Table 1).
Dr. Nancy Lee Harris (Pathology): Dr. Kazda, you saw this patient first in the emergency room; would you tell us your initial impression?
Dr. George Kazda (Otolaryngology, Massachusetts Eye and Ear Infirmary): The patient presented primarily with unilateral disease and an underlying simple deformity with local swelling. The leading diagnosis was bacterial vestibulitis, probably secondary to environmental factors or trauma. The initial treatment was with cephalexin and topical antibiotics. However, at the 10-day follow-up visit, the patient's symptoms were worse, so we decided to confer with our infectious-disease consultant.
Dr. Harris: Dr. Durand, would you describe your initial thoughts and the diagnostic procedure?
Dr. Marlene L. Durand: I saw the patient with otolaryngologists. Additional careful physical examination did not disclose any healed skin lesions. The patient was HIV-negative. Biopsy of the nasal mucosa was performed in the emergency room. The tissue specimens obtained were sent to the pathology department with a specific request to look for leishmania and to rule out other diagnoses, such as fungal disease or cancer. We realized that even if the pathological examination were negative for leishmania, it would not rule out the diagnosis, and we planned to send a specimen on special medium to the CDC for culture if the pathological findings were nondiagnostic.
Clinical Diagnosis
Mucocutaneous leishmaniasis.
Dr. Peter F. Weller's Diagnosis
Mucocutaneous leishmaniasis.
Pathological Discussion
Dr. Ben Z. Pilch: Tissue samples from the nasal septum and right nasal vestibule were submitted to the pathology department. Tissue from both areas showed ulceration, chronic inflammation consisting of infiltration by lymphocytes and plasma cells, and focal necrosis (Figure 2A). Tissue from the right nasal vestibule, in addition, showed granulomatous inflammation, with palisading histiocytes adjacent to a necrotic area, as well as epithelioid granuloma formation (Figure 2B). A search for leishmania organisms did not reveal the characteristic intracellular amastigotes in histiocytes,1,15,16 and neither fungi nor acid-fast bacilli were identified on specially stained sections. A neoplastic process was not identified. Thus, the histologic findings were consistent with a chronic infectious process, but causative organisms were not identified. The scarcity of organisms on histologic sections in cases of mucosal leishmaniasis is not surprising, since amastigotes are much less common in this condition than in cutaneous leishmaniasis.1
Figure 2. Biopsy Specimen of the Nose.
In Panel A, necrotic tissue in the lower portion of the photomicrograph is bordered by palisading histiocytes; a chronic inflammatory infiltrate containing lymphocytes and plasma cells fills the remainder of the image (hematoxylin and eosin). In Panel B, a granuloma, located in the upper portion of the image, consists of a localized collection of epithelioid histiocytes (hematoxylin and eosin).
Dr. Durand: When the first biopsy was nondiagnostic, I contacted the CDC's Division of Parasitic Diseases laboratory to obtain special Novy–MacNeal–Nicolle culture medium, which was sent by overnight mail. Additional biopsies were performed and tissue was obtained from the involved right side and also from the left side of the nasal septum, since new areas of cobblestoning of the mucosa had developed there in the interim. We applied some of the biopsy material to slides for touch preparations, and put the rest in the Novy–MacNeal–Nicolle medium. These samples were returned to the CDC by overnight mail.
Dr. Pilch: The culture grew leishmania, and speciation by means of electrophoresis for isoenzymes in culture lysate revealed L. viannia braziliensis. The diagnosis of mucosal leishmaniasis as a result of infection by L. viannia braziliensis was thus established.
A photomicrograph of a tissue section from another patient with cutaneous leishmaniasis illustrates the intracellular amastigotes in histiocytes (Figure 3A). Amastigotes may also be seen free in tissue. The organism has a pale cell membrane that surrounds clear cytoplasm containing a discrete nucleus. Another characteristic feature of the amastigote, the intracytoplasmic kinetoplast, a rod-shaped mitochondrial structure composed of DNA,1 is shown to better advantage in a photomicrograph of a touch preparation from a patient with visceral leishmaniasis due to L. donovani (Figure 3B).
Figure 3. Amastigotes of Leishmania.
In Panel A, a photomicrograph from a different patient who had cutaneous leishmaniasis, multiple intracellular amastigotes of leishmania are present in the cytoplasm of histiocytes (hematoxylin and eosin). The amastigotes are surrounded by a thin cell membrane and contain a dark nucleus. In Panel B, a photomicrograph of a touch preparation from a patient with visceral leishmaniasis caused by L. donovani, multiple amastigotes in a histiocytic cell have a round nucleus and a smaller, rod-shaped kinetoplast; all species of leishmania have identical histomorphologic features (Wright's stain). Figure provided by F. Steurer, CDC.
Dr. Harris: Dr. Durand, would you tell us about the treatment you prescribed for the patient and about his current status?
Discussion of Management
Dr. Durand: The options for therapy for mucosal leishmaniasis are intravenous amphotericin B and intravenous sodium stibogluconate or meglumine antimoniate, pentavalent antimony drugs. Organic antimony agents have been used since 1912, and sodium stibogluconate has been used for more than 50 years, yet it is an orphan drug in the United States, available only from the CDC. We treated the patient as an outpatient with daily infusions of sodium stibogluconate, 20 mg per kilogram of body weight, and continued the treatment for 28 days. We monitored him closely for side effects. Toxicity is cumulative and increases after the first week of therapy. Nausea and vomiting are common. Elevated amylase and lipase levels develop in nearly all patients, although symptomatic pancreatitis is rare. Arthralgia occurs in about half of affected patients and typically responds to nonsteroidal antiinflammatory agents. Elevated transaminase levels are common, although jaundice is rare. Cardiac side effects are of the greatest concern, and we followed our patient with electrocardiograms at least once weekly. Deaths have occurred when sodium stibogluconate has been given in higher-than-usual doses or given to patients with underlying cardiac disease. The prolongation of the corrected QT interval to more than 500 msec or the development of T-wave inversions with concave ST segments is an ominous sign; the drug should be stopped if either of these occurs. T-wave inversions and decreased T-wave amplitude are seen in 30 to 40 percent of patients and do not require that the drug be stopped.
The patient's nasal pain resolved quickly, and his mucosal lesions gradually regressed. Seven months after completion of therapy, the mucosa remained healed, with no signs of recurrent disease. We will continue to follow him closely, since recurrences are known to occur within the first year in up to 30 percent of patients with mucocutaneous leishmaniasis. Because the toxicity of sodium stibogluconate is cumulative, if there is a relapse, I would use another drug, such as amphotericin B.
Dr. Harris: I would like to ask Dr. Ryan to make a few comments about the evaluation of patients such as this one and, in particular, about coordination with the CDC for unusual infectious diseases.
Dr. Edward T. Ryan (Infectious Diseases): The typical person with leishmaniasis in the United States usually sees multiple physicians over many months before a correct diagnosis is made. The fact that the diagnosis was entertained within a week of this patient's presenting for medical care is a tribute to his physicians.
It is important for clinicians to be aware that it is only New World leishmaniasis that carries a risk of mucosal disease. Rigorous attempts should be made to establish a species diagnosis in patients with New World cutaneous leishmaniasis, since the risk of clinically evident mucosal involvement is species-dependent. The Division of Parasitic Diseases at the CDC offers a wide range of assistance in the diagnosis and care of patients with leishmaniasis, including providing culture medium, instructing caregivers in appropriate sampling techniques, culturing samples, speciating leishmania organisms, and providing general guidelines regarding therapeutic options. Clinicians should avail themselves of these resources.
Dr. David Hooper (Infectious Diseases): In a patient who has cutaneous disease with a species that has the potential for late mucosal relapse, would you treat the patient, given the toxicity of the available drugs?
Dr. Weller: I would treat definitively with sodium stibogluconate to decrease the possibility of recurrence years or decades later. A new compound, hexadecylphosphocholine (miltefosine), which has proved to be effective in the treatment of visceral leishmaniasis,17 may have some efficacy in mucocutaneous leishmaniasis.18
Dr. Harris: Are there known risk factors, such as HLA type or other factors related to immunity, that may predispose a person to mucosal lesions?
Dr. Weller: There is evidence that the risk of mucocutaneous disease is related to some HLA types.19 Recent studies suggest that patients with mucosal disease have an exaggerated and poorly regulated immune response to leishmania antigens, which may cause tissue damage without clearing the organisms.20
Anatomical Diagnosis
Mucocutaneous leishmaniasis due to infection by Leishmania viannia braziliensis.
Source Information
From the Division of Infectious Diseases and the Division of Allergy and Inflammation, Beth Israel Deaconess Medical Center (P.F.W.); the Infectious Disease Unit, Massachusetts General Hospital, and the Infectious Disease Service, Massachusetts Eye and Ear Infirmary (M.L.D.); the Department of Pathology, Massachusetts General Hospital (B.Z.P.); and the Departments of Medicine (P.F.W., M.L.D.) and Pathology (B.Z.P.), Harvard Medical School — all in Boston.
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