Dermatologic Therapy, Vol. 27, 2014, 131–134 Printed in the United States · All rights reserved
© 2013 Department of Dermatovenereology, 2nd Faculty of Medicine, Charles University in Prague and Hospital Bulovka. © 2013 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY ISSN 1396-0296
THERAPEUTIC HOTLINE Visceral leishmaniasis with cutaneous symptoms in a patient treated with infliximab followed by fatal consequences Katerina Juzlova*, Jana Votrubova*, Denisa Kacerovska†, Milan Lukas‡, Martin Bortlik‡, Hana Rohacova§, Eva Nohynkova¶, Nadezda Vojackova*, Jorga Fialova* & Jana Hercogova* *Department of Dermatovenereology, 2nd Faculty of Medicine, †Department of Pathology, Faculty of Medicine in Pilsen, ‡IBD Clinical and Research Centre, ISCARE a.s., 1st Faculty of Medicine, and §Department of Infectious Diseases, Bulovka Hospital, 2nd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic and ¶Department of Infectious and Tropical Diseases, 1st Faculty of Medicine, Charles University in Prague and Hospital Bulovka, Prague, Czech Republic
ABSTRACT: Leishmaniasis is an infectious disease caused by parasitic flagellates of the genus Leishmania. The authors present a case of 44-year-old man with Crohn’s disease treated successfully with infliximab. This case report shows rare visceral leishmaniasis with cutaneous symptoms in an immunocompromised patient. Skin manifestations may occur before or after the visceral infection and they are often diverse. KEYWORDS: immunosuppression, skin manifestation, visceral leishmaniasis
Introduction Leishmaniasis represents a broad clinical spectrum of a vector-transmitted disease caused by parasitic flagellates of the genus Leishmania. The estimated incidence of cutaneous leishmaniasis is Address correspondence and reprint requests to: Katerina Juzlova, MD, Department of Dermatovenereology, 2nd Faculty of Medicine, Charles University in Prague and Hospital Bulovka, Budinova 2, Prague 18081, Czech Republic, or email: [email protected].
0.2 to 0.4 million cases and 0.7 to 1.2 million cases of the visceral form occur per year. Visceral leishmaniasis (VL) may go unrecognized and it is frequently put in one group with opportunistic infections in immunosuppressed patients. Patients with autoimmune diseases, transplant patients or patients receiving immunosuppressive therapy (e.g., corticosteroids, methotrexate, cyclosporin or biologics with anti-tumor necrosis factor [TNF] effect) have a greater risk of developing VL (1).
131
Juzlova et al.
VL therapy consists of parenteral administration of organic compounds with pentavalent antimonials (meglumine antimoniate and sodium stibogluconate) or Amphotericin B. Further, it is possible to use paromomycin, pentamidine or oral administration of miltefosine. In the course of therapy with antimony, side effects may occur such as myalgia, headache, rash, increased activity of liver, increased pancreatic enzymes in serum, and electrocardiography abnormalities. These effects are usually reversible (2). In the course of therapy, rare, but fatal side effects such as arrhythmia can occur (typically in patients on high doses of antimonials or pancreatitis in patients with human immunodeficiency virus (HIV)). Given the emerging resistance to antimonial compounds, it is recommended to use colloidal dispersions and liposomal preparations of Amphotericin B in the treatment of leishmaniasis. These preparations are safer and more efficient, although their routine use is limited due to the high cost of drugs. Treatment with Amphotericin B usually lasts 6 to 7 days, and treatment with pentavalent antimonial preparations lasts 21 to 28 days (3). The advantage of miltefosine is the oral administration as well as its effectiveness in antimony-resistant leishmaniasis (4–8).
formed which excluded abscess or fistula and demonstrated significant thickening of skin in the perianal area. In April 2012, the patient was sent to dermatology clinic to investigate the etiology of his complaints. Local findings (FIG. 1) featured massive striated perianal plaques measuring 12 × 20 cm extending to the base of the penis with a yellowish pungent secretion and small perianal fissures. Biopsy from the lesion was performed, concluding a hypertrophic lichen planus. Because of the noncorrelating clinical-pathologic picture, a second biopsy was performed with the findings of small intracytoplasmic structures, offering leishmaniasis within differential diagnosis, followed by the presence of numerous fungal spores and hyphae in a histochemical coloring (FIG. 2). The sample was therefore sent to the National Reference Laboratory for Diagnostics of Tropical Parasitic Infections where leishmaniasis has been confirmed microscopically. Based on specific polymerase chain reaction amplification and a two-way direct sequencing of internal transcribed spacer, 100% homology with known
Case report A 44-year-old male patient, with no serious illness in childhood, was treated for Crohn’s disease since 2000, with the main manifestation in the terminal ileum and the right half of the colon. The disease was both stricturing and perforating type with a history of perianal fistula. In 2000, the patient underwent emergency surgery for intestinal perforation with purulent peritonitis. A resection of terminal ileum in the range of 30 cm was performed. In 2008, a surgery for stenosis of ascending colon and terminal ileum was performed. After the surgery, treatment with mesalazine at a dose of 2 g per day was initiated because the patient did not tolerate azathioprine at a dose of 100 mg per day. In March 2010, treatment with infliximab intravenously at a dose of 5 mg/kg and methotrexate at a dose of 15 mg intramuscularly weekly was initiated due to relapse of the disease. In the years 2008–2011, the patient visited the Belek area of Turkey a total of three times and Croatia. The main difficulties of the patient were oozing and painful bodies in the perianal area lasting and gradually progressing for about 2 years. In December 2011, a sonographic examination of the bodies was per-
132
FIG. 1. Local findings before the treatment.
Visceral leishmaniasis in a patient treated with infliximab
FIG. 2. Histopathologic finding from the lesion.
sequences of Leishmania infantum was determined. Positive serological examination (indirect hemagglutination test Cellognost) was highly suggestive for VL. The patient was transferred to the Clinic of Infectious Diseases and treated with intramuscular antimony (Glucantime) at a daily dose of 1960 mg in total for 23 days and for a significant superficial mycosis with oral fluconazole at a dose of 100 mg twice a day. During his admission, a regression of the local findings occurred (FIG. 3). On the 24th day after his admission, the patient suddenly expired. The cause of death was a fatal arrhythmia as a side effect of the treatment with antimony.
Discussion Given the size and location of the lesion, we considered Buschke-Löwenstein tumor in the differential diagnosis. It is a rare form of verrucous carcinoma in the anogenital region. In patients, we find cauliflower-like pinkish-grey sessile papillomatous vegetations, i.e., giant condylomata with invasive growth, which can usually lead even to destruction of the surrounding tissue. They may rarely metastasize (9). This tumor is considered to be associated with a human papillomavirus infection (10). The verrucous carcinoma is a highly differentiated form of spinalioma, i.e., invasive tumor with a slow tendency to metastasize. It was also necessary to exclude condylomata lata. These manifestations belong to the second stage of syphilis. These are oozy pink flat papules in the perianal and perigenital areas, in which treponemas occur abundantly.
FIG. 3. Regression of the local findings during the treatment.
Skin manifestations are the most common extraintestinal manifestations of Crohn’s disease, occurring in up to 22–44% of patients. In our case, we considered adjacent perianal manifestations, i.e., guard protuberances (“skin tag”), which are usually classified into two groups. The first group includes painless, broadly elevated protuberances, solitary or multiple, subtle or hard, referred to as “elephant ears.” The second type is characterized as painful edematous lesions, often hard, cyanotic, and emerges from an anal fissure, ulcer or hemorrhoids (11). Immunosuppressed patients are at greater risk of developing VL (1). In HIV-positive patients, the symptoms of VL are similar to those in immunocompetent patients, but there are more frequent relapses of the disease after adequate therapy, where parasites may be found in various locations in combination with frequent skin lesions. Skin manifestations may occur before or after visceral infection and they are often diverse. In HIV-positive patients with VL, macules, papules, nodules or even ulcers on the skin may occur (12– 14). Some authors advocate the hypothesis of cutaneous manifestations in patients with VL and HIV. They assume that the cutaneous manifestations
133
Juzlova et al.
in the immunocompromised patient occur due to hematogenous dissemination of the visceral form (15). VL is an opportunistic infection in immunocompromised patients, especially in patients treated with anti-TNF drugs. The diagnosis of VL in the Czech Republic is very rare. In years 1999–2009, there were 15 imported infections; although due to the increasing number of patients treated with anti-TNF drugs, it is necessary to think about this diagnosis in iatrogenically immunosuppressed patients.
5.
6.
7.
8.
9.
Acknowledgement The project was supported by Internal Grant Agency- Ministry of Health of the Czech Republic (Grant NT 14300-3). Conflicts of interest: none declared.
References 1. Bogdan C. Leishmaniasis in rheumatology, haematology and oncology: epidemiological, immunological and clinical aspects and caveats. Ann Rheum Dis 2012: 71 (Suppl. 2): i60–i66. 2. Rosenthal E, Marty P. Recent understanding in the treatment of visceral leishmaniasis. J Postgrad Med 2003: 49: 61–68. 3. Gradoni L, Gramiccia M, Scalone A. Visceral leishmaniasis treatment, Italy. Emerg Infect Dis 2003: 9 (12): 1617–1620. 4. Sundar S, Jha TK, Sindermann H, Junge K, Bachmann P, Berman J. Oral miltefosine treatment in children with mild
134
10.
11.
12.
13.
14.
15.
to moderate Indian visceral leishmaniasis. Pediatr Infect Dis J 2003: 22: 434–438. Paris C, Loiseau PM, Bories C, Bréard J. Miltefosine induces apoptosis-like death in Leishmania donovani promastigotes. Antimicrob Agents Chemother 2004: 48: 852–859. Sindermann H, Croft SL, Engel KR, et al. Miltefosine (Impavido): the first oral treatment against leishmaniasis. Med Microbiol Immunol (Berl) 2004: 193: 173–180. More B, Bhatt H, Kukreja V, Ainapure SS. Miltefosine: great expectations against visceral leishmaniasis. J Postgrad Med 2003: 49: 101–103. Prasad R, Kumar R, Jaiswal BP, Singh UK. Miltefosine: an oral drug for visceral leishmaniasis. Indian J Pediatr 2004: 71: 143–144. Ovesen A. Perianal Buschke-Löwenstein tumour. Ugeskr Laeger 2012: 174 (23): 1616–1617. Skerlev M, Ljubojevic S. The specifities of the HPV-genital infections in males. Med Glas Ljek komore Zenicko-doboj kantona 2010: 7 (2): 89–95. Bonheur JL, Braunstein J, Korelitz BI, Panagopoulos G. Anal skin tags in inflammatory bowel disease: new observations and a clinical review. Inflamm Bowel Dis 2008: 14: 1–6. Danden E, Peñas PF, Rios L, et al. Leishmania presenting as dermatomyositis-like eruption in AIDS. J Am Acad Dermatol 1996: 35: 316–319. Perrin C, Taillan B, Hofman P, Mondain V, Lefichoux Y, Michiels JF. Atypical cutaneous histopathological features of visceral leishmaniasis in acquired immunodeficiency syndrome. Am J Dermatopathol 1995: 17: 145–150. Colebunders R, Depraetera K, Verstraeten T, et al. Unusual cutaneous lesions in two patients with visceral leishmaniasis and HIV infection. J Am Acad Dermatol 1999: 41: 847–850. Santos-Oliveira JR, Da-Cruz AM, Pires LH, et al. Atypical lesions as a sign of cutaneous dissemination of visceral leishmaniasis in a human immunodeficiency virus-positive patient simultaneously infected by two viscerotropic Leishmania species. Am J Trop Med Hyg 2011: 85 (1): 55–59.
© 2013 Department of Dermatovenereology, 2nd Faculty of Medicine, Charles University in Prague and Hospital Bulovka. © 2013 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY ISSN 1396-0296
THERAPEUTIC HOTLINE Visceral leishmaniasis with cutaneous symptoms in a patient treated with infliximab followed by fatal consequences Katerina Juzlova*, Jana Votrubova*, Denisa Kacerovska†, Milan Lukas‡, Martin Bortlik‡, Hana Rohacova§, Eva Nohynkova¶, Nadezda Vojackova*, Jorga Fialova* & Jana Hercogova* *Department of Dermatovenereology, 2nd Faculty of Medicine, †Department of Pathology, Faculty of Medicine in Pilsen, ‡IBD Clinical and Research Centre, ISCARE a.s., 1st Faculty of Medicine, and §Department of Infectious Diseases, Bulovka Hospital, 2nd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic and ¶Department of Infectious and Tropical Diseases, 1st Faculty of Medicine, Charles University in Prague and Hospital Bulovka, Prague, Czech Republic
ABSTRACT: Leishmaniasis is an infectious disease caused by parasitic flagellates of the genus Leishmania. The authors present a case of 44-year-old man with Crohn’s disease treated successfully with infliximab. This case report shows rare visceral leishmaniasis with cutaneous symptoms in an immunocompromised patient. Skin manifestations may occur before or after the visceral infection and they are often diverse. KEYWORDS: immunosuppression, skin manifestation, visceral leishmaniasis
Introduction Leishmaniasis represents a broad clinical spectrum of a vector-transmitted disease caused by parasitic flagellates of the genus Leishmania. The estimated incidence of cutaneous leishmaniasis is Address correspondence and reprint requests to: Katerina Juzlova, MD, Department of Dermatovenereology, 2nd Faculty of Medicine, Charles University in Prague and Hospital Bulovka, Budinova 2, Prague 18081, Czech Republic, or email: [email protected].
0.2 to 0.4 million cases and 0.7 to 1.2 million cases of the visceral form occur per year. Visceral leishmaniasis (VL) may go unrecognized and it is frequently put in one group with opportunistic infections in immunosuppressed patients. Patients with autoimmune diseases, transplant patients or patients receiving immunosuppressive therapy (e.g., corticosteroids, methotrexate, cyclosporin or biologics with anti-tumor necrosis factor [TNF] effect) have a greater risk of developing VL (1).
131
Juzlova et al.
VL therapy consists of parenteral administration of organic compounds with pentavalent antimonials (meglumine antimoniate and sodium stibogluconate) or Amphotericin B. Further, it is possible to use paromomycin, pentamidine or oral administration of miltefosine. In the course of therapy with antimony, side effects may occur such as myalgia, headache, rash, increased activity of liver, increased pancreatic enzymes in serum, and electrocardiography abnormalities. These effects are usually reversible (2). In the course of therapy, rare, but fatal side effects such as arrhythmia can occur (typically in patients on high doses of antimonials or pancreatitis in patients with human immunodeficiency virus (HIV)). Given the emerging resistance to antimonial compounds, it is recommended to use colloidal dispersions and liposomal preparations of Amphotericin B in the treatment of leishmaniasis. These preparations are safer and more efficient, although their routine use is limited due to the high cost of drugs. Treatment with Amphotericin B usually lasts 6 to 7 days, and treatment with pentavalent antimonial preparations lasts 21 to 28 days (3). The advantage of miltefosine is the oral administration as well as its effectiveness in antimony-resistant leishmaniasis (4–8).
formed which excluded abscess or fistula and demonstrated significant thickening of skin in the perianal area. In April 2012, the patient was sent to dermatology clinic to investigate the etiology of his complaints. Local findings (FIG. 1) featured massive striated perianal plaques measuring 12 × 20 cm extending to the base of the penis with a yellowish pungent secretion and small perianal fissures. Biopsy from the lesion was performed, concluding a hypertrophic lichen planus. Because of the noncorrelating clinical-pathologic picture, a second biopsy was performed with the findings of small intracytoplasmic structures, offering leishmaniasis within differential diagnosis, followed by the presence of numerous fungal spores and hyphae in a histochemical coloring (FIG. 2). The sample was therefore sent to the National Reference Laboratory for Diagnostics of Tropical Parasitic Infections where leishmaniasis has been confirmed microscopically. Based on specific polymerase chain reaction amplification and a two-way direct sequencing of internal transcribed spacer, 100% homology with known
Case report A 44-year-old male patient, with no serious illness in childhood, was treated for Crohn’s disease since 2000, with the main manifestation in the terminal ileum and the right half of the colon. The disease was both stricturing and perforating type with a history of perianal fistula. In 2000, the patient underwent emergency surgery for intestinal perforation with purulent peritonitis. A resection of terminal ileum in the range of 30 cm was performed. In 2008, a surgery for stenosis of ascending colon and terminal ileum was performed. After the surgery, treatment with mesalazine at a dose of 2 g per day was initiated because the patient did not tolerate azathioprine at a dose of 100 mg per day. In March 2010, treatment with infliximab intravenously at a dose of 5 mg/kg and methotrexate at a dose of 15 mg intramuscularly weekly was initiated due to relapse of the disease. In the years 2008–2011, the patient visited the Belek area of Turkey a total of three times and Croatia. The main difficulties of the patient were oozing and painful bodies in the perianal area lasting and gradually progressing for about 2 years. In December 2011, a sonographic examination of the bodies was per-
132
FIG. 1. Local findings before the treatment.
Visceral leishmaniasis in a patient treated with infliximab
FIG. 2. Histopathologic finding from the lesion.
sequences of Leishmania infantum was determined. Positive serological examination (indirect hemagglutination test Cellognost) was highly suggestive for VL. The patient was transferred to the Clinic of Infectious Diseases and treated with intramuscular antimony (Glucantime) at a daily dose of 1960 mg in total for 23 days and for a significant superficial mycosis with oral fluconazole at a dose of 100 mg twice a day. During his admission, a regression of the local findings occurred (FIG. 3). On the 24th day after his admission, the patient suddenly expired. The cause of death was a fatal arrhythmia as a side effect of the treatment with antimony.
Discussion Given the size and location of the lesion, we considered Buschke-Löwenstein tumor in the differential diagnosis. It is a rare form of verrucous carcinoma in the anogenital region. In patients, we find cauliflower-like pinkish-grey sessile papillomatous vegetations, i.e., giant condylomata with invasive growth, which can usually lead even to destruction of the surrounding tissue. They may rarely metastasize (9). This tumor is considered to be associated with a human papillomavirus infection (10). The verrucous carcinoma is a highly differentiated form of spinalioma, i.e., invasive tumor with a slow tendency to metastasize. It was also necessary to exclude condylomata lata. These manifestations belong to the second stage of syphilis. These are oozy pink flat papules in the perianal and perigenital areas, in which treponemas occur abundantly.
FIG. 3. Regression of the local findings during the treatment.
Skin manifestations are the most common extraintestinal manifestations of Crohn’s disease, occurring in up to 22–44% of patients. In our case, we considered adjacent perianal manifestations, i.e., guard protuberances (“skin tag”), which are usually classified into two groups. The first group includes painless, broadly elevated protuberances, solitary or multiple, subtle or hard, referred to as “elephant ears.” The second type is characterized as painful edematous lesions, often hard, cyanotic, and emerges from an anal fissure, ulcer or hemorrhoids (11). Immunosuppressed patients are at greater risk of developing VL (1). In HIV-positive patients, the symptoms of VL are similar to those in immunocompetent patients, but there are more frequent relapses of the disease after adequate therapy, where parasites may be found in various locations in combination with frequent skin lesions. Skin manifestations may occur before or after visceral infection and they are often diverse. In HIV-positive patients with VL, macules, papules, nodules or even ulcers on the skin may occur (12– 14). Some authors advocate the hypothesis of cutaneous manifestations in patients with VL and HIV. They assume that the cutaneous manifestations
133
Juzlova et al.
in the immunocompromised patient occur due to hematogenous dissemination of the visceral form (15). VL is an opportunistic infection in immunocompromised patients, especially in patients treated with anti-TNF drugs. The diagnosis of VL in the Czech Republic is very rare. In years 1999–2009, there were 15 imported infections; although due to the increasing number of patients treated with anti-TNF drugs, it is necessary to think about this diagnosis in iatrogenically immunosuppressed patients.
5.
6.
7.
8.
9.
Acknowledgement The project was supported by Internal Grant Agency- Ministry of Health of the Czech Republic (Grant NT 14300-3). Conflicts of interest: none declared.
References 1. Bogdan C. Leishmaniasis in rheumatology, haematology and oncology: epidemiological, immunological and clinical aspects and caveats. Ann Rheum Dis 2012: 71 (Suppl. 2): i60–i66. 2. Rosenthal E, Marty P. Recent understanding in the treatment of visceral leishmaniasis. J Postgrad Med 2003: 49: 61–68. 3. Gradoni L, Gramiccia M, Scalone A. Visceral leishmaniasis treatment, Italy. Emerg Infect Dis 2003: 9 (12): 1617–1620. 4. Sundar S, Jha TK, Sindermann H, Junge K, Bachmann P, Berman J. Oral miltefosine treatment in children with mild
134
10.
11.
12.
13.
14.
15.
to moderate Indian visceral leishmaniasis. Pediatr Infect Dis J 2003: 22: 434–438. Paris C, Loiseau PM, Bories C, Bréard J. Miltefosine induces apoptosis-like death in Leishmania donovani promastigotes. Antimicrob Agents Chemother 2004: 48: 852–859. Sindermann H, Croft SL, Engel KR, et al. Miltefosine (Impavido): the first oral treatment against leishmaniasis. Med Microbiol Immunol (Berl) 2004: 193: 173–180. More B, Bhatt H, Kukreja V, Ainapure SS. Miltefosine: great expectations against visceral leishmaniasis. J Postgrad Med 2003: 49: 101–103. Prasad R, Kumar R, Jaiswal BP, Singh UK. Miltefosine: an oral drug for visceral leishmaniasis. Indian J Pediatr 2004: 71: 143–144. Ovesen A. Perianal Buschke-Löwenstein tumour. Ugeskr Laeger 2012: 174 (23): 1616–1617. Skerlev M, Ljubojevic S. The specifities of the HPV-genital infections in males. Med Glas Ljek komore Zenicko-doboj kantona 2010: 7 (2): 89–95. Bonheur JL, Braunstein J, Korelitz BI, Panagopoulos G. Anal skin tags in inflammatory bowel disease: new observations and a clinical review. Inflamm Bowel Dis 2008: 14: 1–6. Danden E, Peñas PF, Rios L, et al. Leishmania presenting as dermatomyositis-like eruption in AIDS. J Am Acad Dermatol 1996: 35: 316–319. Perrin C, Taillan B, Hofman P, Mondain V, Lefichoux Y, Michiels JF. Atypical cutaneous histopathological features of visceral leishmaniasis in acquired immunodeficiency syndrome. Am J Dermatopathol 1995: 17: 145–150. Colebunders R, Depraetera K, Verstraeten T, et al. Unusual cutaneous lesions in two patients with visceral leishmaniasis and HIV infection. J Am Acad Dermatol 1999: 41: 847–850. Santos-Oliveira JR, Da-Cruz AM, Pires LH, et al. Atypical lesions as a sign of cutaneous dissemination of visceral leishmaniasis in a human immunodeficiency virus-positive patient simultaneously infected by two viscerotropic Leishmania species. Am J Trop Med Hyg 2011: 85 (1): 55–59.
